HRP980201A2

HRP980201A2 - Captopril tablets

Info

Publication number: HRP980201A2
Authority: HR
Inventors: Palne Szentgroti
Original assignee: Egyt Gyogyszervegyeszeti Gyar
Priority date: 1998-04-09
Filing date: 1998-04-09
Publication date: 1999-10-31

Description

Područje izuma Field of invention

Izum je iz područja farmakologije i farmaceutske tehnologije. The invention is from the field of pharmacology and pharmaceutical technology.

Stanje tehnike State of the art

Ovaj izum odnosi se na tablete koje sadrže kaptopril kao aktivnu tvar i na proces njihova priređivanja. This invention relates to tablets containing captopril as an active substance and to the process of their preparation.

Poznato je da (S)-1-(3-merkapto-2-metil-1-okso-propil)-L-prolin (međunarodno nezaštićeno ime, INN) je kompetitivni ACE inhibitor, koji smanjuje arterijski i venski krvožilni tonus, ukupni periferni vaskularnu rezistenciju, srčano pre- i post-opterećenje te povećava minutni volumen. Priređivanje kaptoprila opisano je u mađarskom patentu br. 181,965. Sadržaj aktivne tvari u tabletama kaptoprila koje se rabe u terapijske svrhe iznosi 6,25-100 mg i dnevna doza iznosi 6,25-300 mg. Kaptopril je visokoosjetljiv prema oksidaciji i kaptoprilski disulfid nastaje na tiolnoj skupini u procesu oksidacije slobodnim radikalima. U čvrstim farmaceutskim smjesama brzina raspada povećava se tijekom stupnja sušenja u postupku proizvodnje te zbog prisutnosti vlage u smjesi. Pri priređivanju kaptoprilskih smjesa posebna pozornost usmjerena je prema odabiru sustava pogodnog pomoćnog agensa i postupku proizvodnje, koji bi izazvao raspad i oksidaciju aktivne tvari u najmanjoj mogućoj mjeri. It is known that (S)-1-(3-mercapto-2-methyl-1-oxo-propyl)-L-proline (international nonproprietary name, INN) is a competitive ACE inhibitor, which reduces arterial and venous vascular tone, total peripheral vascular resistance, cardiac pre- and post-load and increases cardiac output. The preparation of captopril is described in Hungarian patent no. 181,965. The content of the active substance in captopril tablets used for therapeutic purposes is 6.25-100 mg and the daily dose is 6.25-300 mg. Captopril is highly sensitive to oxidation and captopril disulfide is formed on the thiol group in the process of free radical oxidation. In solid pharmaceutical mixtures, the rate of decomposition increases during the drying stage in the production process and due to the presence of moisture in the mixture. When preparing captopril mixtures, special attention is directed towards the selection of a suitable auxiliary agent system and the production process, which would cause the breakdown and oxidation of the active substance to the smallest possible extent.

Oni koji poznaju ovu tehniku i bave se formuliranjem znaju da je kaptopril osjetljiv prema raspadu. Nekoliko patentnih specifikacija usmjereno je prema ovom problemu. Sukladno japanskom patentu br. 86 36,127 postojanost aktivnih tvari koje imaju tio-skupinu, uključujući kaptopril, može se povećati korištenjem askorbinske kiseline, natrijeva askorbata, eritrobinske kiseline ili njene natrijeve soli, natrijeva bisulfita, natrijeva sulfita i/ili natrijeva metabisulfita. Sukladno japanskom patentu br. 82 112,367 u otopinama koje su namijenjene injiciranju, postojanost kaptoprila može se povećati pomoću aminokiselina i njihovih soli. Japanski patent br. 94 32,776 odnosi se i na uporabu antioksidansa. Prema američkom patentu br. 5,158,777 savjetuje se istovremena uporaba dinatrijeva edetata i askorbinske kiseline. Međutim, uporaba gore navedenih oksidansa – s izuzetkom askorbinske kiseline – praćena je određenim rizikom jer navedene tvari često mogu izazvati alergijske simptome. Međutim, sukladno opisu američkog patenta br. 5,158,77 askorbinska kiselina gubi zadovoljavajući stabilizirajući učinak kada se rabi sama za sebe. Those who know this technique and deal with formulation know that captopril is susceptible to disintegration. Several patent specifications are directed towards this problem. According to Japanese patent no. 86 36,127 the stability of active substances having a thio group, including captopril, can be increased by using ascorbic acid, sodium ascorbate, erythrobic acid or its sodium salt, sodium bisulfite, sodium sulfite and/or sodium metabisulfite. According to Japanese patent no. 82 112,367 in solutions intended for injection, the persistence of captopril can be increased by amino acids and their salts. Japanese patent no. 94 32,776 also refers to the use of antioxidants. According to US patent no. 5,158,777 advises the simultaneous use of disodium edetate and ascorbic acid. However, the use of the above-mentioned oxidants - with the exception of ascorbic acid - is accompanied by a certain risk, because the substances mentioned can often cause allergic symptoms. However, according to the description of US patent no. 5,158,77 ascorbic acid loses its satisfactory stabilizing effect when used alone.

Sljedeći problem koji se javlja pri terapeutskoj uporabi kaptoprilskih smjesa je u tome što pojedinačne doze smjesa variraju u značajnoj mjeri te se pri kroničnom liječenju primjenljive doze mogu odrediti samo postupnim povećanjem doziranja. Da se postigne prilagodljivo doziranje farmaceutskih smjesa koje sadrže kaptopril koje se mogu jednostavno postaviti prema individualnim zahtjevima bolesnika, postoji snažna potreba za tabletama koje bi imale sadržaj aktivne tvari unutar širokog raspona s jedne strane i koje bi se mogle prelomiti u dva dijela (prepoloviti) s druge strane. Nepromjenljivo doziranje aktivne tvari zahtijeva da se načine smjese koje imaju različiti sadržaj aktivne tvari s identičnom postotnim sastavom s jedne strane, te s druge strane da cijepanjem smjese sadržaj aktivne tvari bude u svakom dijelu tablete bude jednak. Vrlo je važno da se postupkom proizvodnje osigura visoka homogenost aktivne tvari i pomoćnih sredstava u smjesi. The next problem that occurs in the therapeutic use of captopril mixtures is that the individual doses of the mixtures vary to a significant extent, and in chronic treatment the applicable doses can only be determined by gradually increasing the dosage. To achieve adaptive dosing of captopril-containing pharmaceutical compositions that can be easily tailored to individual patient requirements, there is a strong need for tablets that have active substance content within a wide range on the one hand and that can be broken into two parts (halved) with the other side. Invariable dosing of the active substance requires that mixtures with different contents of the active substance with an identical percentage composition be made on the one hand, and on the other hand, that the content of the active substance in each part of the tablet be equal by dividing the mixture. It is very important that the production process ensures high homogeneity of the active substance and auxiliary agents in the mixture.

Poznati postupci za proizvodnju farmaceutskih kompozita koji sadrže kaptopril posve odstupaju od gore navedenih zahtjeva. U europskoj patentnoj publikaciji EPA br. 288,732 opisane su kuglice koje sadrže kaptopril kojima se pune kapsule, a dobivaju se ekstruzijom i sferonizacijom. Takve kuglice sadrže 3-60% aktivne tvari i 5-50% karboksilne kiseline koja olakšava nastajanje kuglica. Known procedures for the production of pharmaceutical composites containing captopril completely deviate from the above requirements. In European patent publication EPA no. 288,732 describes beads containing captopril, which are used to fill capsules, and are obtained by extrusion and spheronization. Such balls contain 3-60% active substance and 5-50% carboxylic acid, which facilitates the formation of balls.

Priređivanje osmotskih kompozita za oralnu primjenu opisano je u PCT WO 91/01,130. Ovi kompoziti su dvoslojne tablete koje su prevučene polupropusnim slojem. Jedan sloj sadrži aktivnu tvar dok drugi sloj sadrži polimer koju bubri u vodi, pri čemu su u sloj koji sadrži aktivnu tvar načinjene rupice kroz koje može aktivna tvar prijeći u organizam. Preparation of osmotic composites for oral administration is described in PCT WO 91/01,130. These composites are two-layer tablets coated with a semi-permeable layer. One layer contains an active substance, while the second layer contains a polymer that swells in water, with holes made in the layer containing the active substance through which the active substance can pass into the body.

Priređivanje prevučenih tableta s postojanim otpuštanjem nultog reda opisano je u američkoj patentnoj specifikaciji br. 4 756 911. Jezgra tablete sadrži bar 70% aktivne tvari i 5-15% pomoćne tvari koja čini vodeno-koloidni gel, poglavito hidroksipropil metil celuloze, dok se prevlaka tablete sadrži od 4:1 – 1:4 smjese bar jednog hidrofilnog polimera i bar jednog hidrofobnog polimera. The preparation of zero order sustained release coated tablets is described in US Pat. 4 756 911. The core of the tablet contains at least 70% of the active substance and 5-15% of an auxiliary substance that forms a water-colloidal gel, mainly hydroxypropyl methyl cellulose, while the coating of the tablet contains a 4:1 - 1:4 mixture of at least one hydrophilic polymer and at least one hydrophobic polymer.

Priređivanje kompozita koji sadrže pomoćnu tvar od koje nastaje gel (npr. polimer koji sadrži laktamsku skupinu i polimer koji sadrži karboksilnu skupinu) i pomoćna tvar koja oslobađa plin (npr. natrijev hidrokarbonat) opisano je u europskoj patentnoj publikaciji br. EPA 669,129. The preparation of composites containing a gel-forming excipient (eg, a polymer containing a lactam group and a polymer containing a carboxyl group) and a gas-releasing excipient (eg, sodium bicarbonate) is described in European Patent Publication No. EPA 669,129.

Kapsule s postojanim otpuštanjem sadrže polučvrsto punjenje, koje se sastoji iz bar jednog glicerida masne kisleine i/ili estera polietilenglikola, opisane su u američkom patentu br. 5,433,951. Sustained-release capsules containing a semi-solid filling consisting of at least one fatty acid glyceride and/or polyethylene glycol ester are described in US Pat. No. 5,433,951.

Sažetak izuma Summary of the invention

Cilj ovoga izuma je dobivanje tableta kaptoprila koje su visoko postojane i pokazuju visoku homogenost aktivne tvari i pomoćnih tvari. The aim of this invention is to obtain captopril tablets that are highly stable and show high homogeneity of the active substance and excipients.

Gore navedeni cilj ostvaren je odabirom posebne kombinacije punilo/vezujuća tvar i specifičnog odnosa punila i vezujuće tvari. The above-mentioned goal was achieved by choosing a special combination of filler/binder and a specific ratio of filler and binder.

Sukladno ovom izumu, dobivene su tablete kaptoprila koje sadrže punilo i vezujuću tvar, sredstvo koje izaziva raspad, tvar za podmazivanje i glidantno sredstvo pri čemu je težinski odnos punila (laktat i mikrokristalna celuloza) 1,5:1 - 1:1 dok je ukupna količina navedene smjese 60-80% ukupne težine tablete. According to this invention, captopril tablets containing a filler and a binding agent, a disintegrating agent, a lubricating agent and a glidant agent were obtained, wherein the weight ratio of the filler (lactate and microcrystalline cellulose) is 1.5:1 - 1:1, while the total the amount of the specified mixture 60-80% of the total weight of the tablet.

Prema ovom izumu, definiran je i postupak za priređivanje tableta kaptoprila koje sadrže punilo i vezujuću tvar, sredstvo koje izaziva raspad, tvar za podmazivanje i glidantno sredstvo, koje sadrže kao punilo i vezujuću tvar 1,5:1 – 1:1 smjesu laktoze i mikrokristalne celuloze, a količina navedene smjese je 60-80% težine prema ukupnoj težini tableta. According to this invention, a process for the preparation of captopril tablets containing a filler and a binding agent, a disintegrating agent, a lubricating agent and a glidant agent, which contain as a filler and a binding agent a 1.5:1 - 1:1 mixture of lactose and microcrystalline cellulose, and the amount of the mixture is 60-80% of the total weight of the tablet.

Detaljan opis izuma Detailed description of the invention

Ovaj izum temelji se na spoznaji da se tablete kaptoprila koje su osobito postojane mogu prirediti postavljanjem odnosa laktoze i mikrokristalne celuloze u tabletama na vrijednost između 1,5:1 i 1:1. This invention is based on the knowledge that captopril tablets which are particularly stable can be prepared by setting the ratio of lactose to microcrystalline cellulose in the tablets to a value between 1.5:1 and 1:1.

Gore navedena spoznaja time je više iznenađujuća budući da se na temelju stanja tehnike očekuje da se visoka postojanost kaptoprila može postići korištenjem sustava pomoćnih tvari koji imaju najmanji sadržaj vlage i najmanju sposobnost vezanja vlage. The above knowledge is therefore more surprising since, based on the state of the art, it is expected that a high stability of captopril can be achieved by using excipient systems that have the lowest moisture content and the lowest moisture binding ability.

Prema komparativnim eksperimentima koji su opisani u ovom izumu može se vidjeti da se povećanjem sadržaja mikrokristalne celuloze koja ima visoku sposobnost vezanja vlage, također povećava sposobnost vezanja vlage tablete. Također je nađeno, na neočekivani način, kada se koristi razmjerno uski raspon odnosa laktoza/mikrokristalna celuloza, količina kaptoprilskog disulfida koji je nastao u tabletama pokazuje minimum i dobivene su tablete visoke stabilnosti. According to the comparative experiments described in this invention, it can be seen that increasing the content of microcrystalline cellulose, which has a high moisture binding capacity, also increases the moisture binding capacity of the tablet. It was also found, unexpectedly, that when a relatively narrow range of lactose/microcrystalline cellulose ratios was used, the amount of captopril disulfide formed in the tablets showed a minimum and tablets of high stability were obtained.

Ukupni sadržaj laktoze i mikrokristalne celuloze tableta kaptoprila ovoga izuma je težinski 60-80% , poželjno 65-75% , osobito težinski 70% , u odnosu prema ukupnoj težini kompozita. The total content of lactose and microcrystalline cellulose of the captopril tablets of this invention is 60-80% by weight, preferably 65-75%, especially 70% by weight, in relation to the total weight of the composite.

Sadržaj aktivne tvari sukladno ovom izumu je poželjno 5-150 mg. Veličina čestica 90% aktivne tvari je poželjno 3-80 µm i početno sadržaj kaptoprilskog disulfida je poželjno manji od težinskih 0,3% . The content of the active substance according to this invention is preferably 5-150 mg. The particle size of 90% of the active substance is preferably 3-80 µm and the initial captopril disulfide content is preferably less than 0.3% by weight.

Laktoza se koristi poželjno u obliku lakoza-monohidrata. Vrijednosti količine i % koje su navedene u ovoj patentnoj specifikaciji odnose se na laktoza-monohidrat. Lactose is preferably used in the form of lactose monohydrate. The quantity and % values stated in this patent specification refer to lactose monohydrate.

Poželjno je koristiti laktoza-monohidrat koji je priređen sušenjem raspršivanjem i koji ima prosječnu veličinu čestica 50-200 µm, posebice 80-160 µm. It is preferable to use lactose monohydrate which has been prepared by spray drying and which has an average particle size of 50-200 µm, especially 80-160 µm.

Veličina čestica 90% mikrokristalne celuloze koja se koristi u kompozitima ovog izuma je 20-150 µm, posebice 50-100 µm. The particle size of the 90% microcrystalline cellulose used in the composites of this invention is 20-150 µm, especially 50-100 µm.

Kompoziti ovog izuma mogu sadržavati tvar koja se raspada, poželjno kukuruzni škrob, karboksimetilni škrob, djelomično hidrolizirani škrob, karboksimetilnu celulozu ili umreženi polivinil pirolidon. Količina navedene tvari koja se raspada je poželjno težinski 1-20% , posebice težinski 5-15%, što je odnos prema ukupnoj težini kompozita. The composites of this invention may contain a degradable substance, preferably corn starch, carboxymethyl starch, partially hydrolyzed starch, carboxymethyl cellulose or cross-linked polyvinyl pyrrolidone. The amount of the said substance that decomposes is preferably 1-20% by weight, especially 5-15% by weight, which is the ratio to the total weight of the composite.

Kompoziti ovog izuma mogu sadržavati kao tvar za podmazivanje poželjno stearin, magnezijev stearat, kalcijev stearat, natrijev stearin fumarat i hidrogenirano dabrovo ulje. Količina glidantnog sredstva je težinski 0,2-3% , poželjno težinski 0,5-2%, što je odnos prema ukupnoj težini kompozita. The composites of this invention may preferably contain stearin, magnesium stearate, calcium stearate, sodium stearin fumarate and hydrogenated beaver oil as a lubricant. The amount of gliding agent is 0.2-3% by weight, preferably 0.5-2% by weight, which is the ratio to the total weight of the composite.

Kompoziti ovog izuma sadrža kao glidantno sredstvo poželjno silika-gel. Količina pomoćne tvari je težinski 0,2-1% , poželjno težinski 0,4-0,5%. The composites of this invention preferably contain silica gel as a gliding agent. The amount of auxiliary substance is 0.2-1% by weight, preferably 0.4-0.5% by weight.

Pomoćne tvari – sredstvo koje se raspada, glidantno sredstvo i tvar za podmazivanje zadovoljavaju kriterije koji su opisani u Farmakopeji (npr. USP 23 ili VII. Madžarska farmakopeja). Auxiliary substances - disintegrating agent, glidant agent and lubricating agent meet the criteria described in the Pharmacopoeia (eg USP 23 or VII. Hungarian Pharmacopoeia).

Tablete koji su u skladu s ovim izumom mogu se prirediti poželjno takozvanom izravnom tehnologijom stlačivanja koja ima prednost što je uklonjen stupanj sušenja. Prema ovom postupku prije stupnja tabletiranja prašak aktivne tvari je homogeniziran u čvrstom stanju s pomoćnim tvarima, koji omogućuju pogodnu stlačivost kompozita. Tablets according to the present invention can preferably be prepared by the so-called direct compression technology, which has the advantage that the drying step is eliminated. According to this procedure, before the tableting stage, the powder of the active substance is homogenized in a solid state with auxiliary substances, which enable a suitable compressibility of the composite.

Postojanost tableta kaptoprila ovoga izuma je vrlo dobra. Ako se razlomi u dva ili četiri dijela, standardno odstupanje sadržaja aktivne tvari u tako dobivenim dijelovima je bolja od odgovarajućih vrijednosti poznatih kompozita. The stability of captopril tablets of this invention is very good. If it is broken into two or four parts, the standard deviation of the content of the active substance in the parts thus obtained is better than the corresponding values of known composites.

Daljnje pojedinosti ovog izuma mogu se naći u primjerima koji slijede koji ne ograničuju doseg zaštite. Further details of the present invention can be found in the following non-limiting examples.

U komparativnom primjeru 1 ispitan je učinak odnosa laktoza-monohidrata i mikrokristalne celuloze na stlačivost praškastih mješavina. Izmjerene vrijednosti su u skladu s činjeničnim stanjem tehnike i pokazuju da se povećavanjem količine mikrokristalne celuloze koja se rabi kao suho vezivo, praškasta smjesa može lakše stlačiti tj. korištenjem identične sile tlačenja povećava se sila lomljenja tableta i mrvljivost se smanjuje. In comparative example 1, the effect of the ratio of lactose-monohydrate and microcrystalline cellulose on the compressibility of powder mixtures was tested. The measured values are in accordance with the actual state of the art and show that by increasing the amount of microcrystalline cellulose used as a dry binder, the powder mixture can be compressed more easily, i.e. using the same compression force, the tablet breaking force increases and the crumbliness decreases.

U komparativnom primjeru 2 ispitan je učinak odnosa laktoze i mikrokristalne celuloze na sposobnost vezanja vlage u tabletu. Rezultati su u skladu s činjeničnim stanjem tehnike i pokazuju da se pri čuvanju uz vlažnost 75% i povećanju količine mikrokristalne celuloze koja ima veću sposobnost vezanja vlage (veći ravnotežni sadržaj vlage) povećava sposobnost vezanja vlage u tabletama. In comparative example 2, the effect of the ratio of lactose and microcrystalline cellulose on the ability to bind moisture in the tablet was tested. The results are in accordance with the actual state of the art and show that when stored at a humidity of 75% and increasing the amount of microcrystalline cellulose, which has a greater ability to bind moisture (higher equilibrium moisture content), the ability to bind moisture in tablets increases.

U komparativnim primjerima 3 i 4 ispitan je utjecaj odnosa laktoze i mikrokristalne celuloze na postojanost sadržaja aktivne tvari u tabletama. Glede stanja tehnike, rezultati su iznenađujući i pokazuju na neočekivan način da pri čuvanju tableta uz relativnu vlažnost 75%, oksidacija kaptoprila – tj. sadržaj kaptoprilskog disulfida u tabletama – pokazuje minimum za odnos laktoza-monohidrata i mikrokristalne celuloze u intervalu 1,5:1 – 1:1. Na temelju prošlih tehnika, valjalo bi očekivati da tablete koje imaju najmanju količinu mikrokristalne celuloze budu najpostojanije. Niz eksperimenata međutim pokazuje da ako se odnos laktoza-monohidrata i mikrokristalne celuloze postavi u razmjerno uskom rasponu, količina disulfida koja nastaje u tabletama smanjuje se na minimum i ova vrijednost je manja od sadržaja disulfida u tabletama kaptoprila koju dozvoljava farmakopeja (npr. USP 23). In comparative examples 3 and 4, the influence of the ratio of lactose and microcrystalline cellulose on the stability of the content of the active substance in the tablets was tested. Regarding the state of the art, the results are surprising and show in an unexpected way that when storing tablets with a relative humidity of 75%, the oxidation of captopril - i.e. the content of captopril disulfide in the tablets - shows a minimum for the ratio of lactose-monohydrate and microcrystalline cellulose in the interval 1.5:1 – 1:1. Based on prior art, tablets having the least amount of microcrystalline cellulose should be expected to be the most stable. However, a series of experiments shows that if the ratio of lactose monohydrate and microcrystalline cellulose is set in a relatively narrow range, the amount of disulfide formed in the tablets is reduced to a minimum and this value is lower than the content of disulfide in captopril tablets allowed by the pharmacopoeia (e.g. USP 23). .

U primjerima 5-8 opisano je priređivanje tableta kaptoprila u skladu s ovim izumom, s promjenjivim sadržajem. Examples 5-8 describe the preparation of captopril tablets according to the present invention, with variable content.

U komparativnom primjeru 9 definirano je standardno odstupanje individualnog sadržaja aktivne tvari u tabletama koje su industrijski proizvedene i standardno odstupanje pojedinačnog sadržaja aktivne tvari u tabletama koje su podijeljene u dva ili četiri dijela. Eksperimentalni rezultati pokazuju da ukoliko se tablete kaptoprila razlome u dva ili četiri dijela, standardno odstupanje sadržaja aktivne tvari navedenih tableta je vrlo povoljno. Sukladno tome, farmaceutski kompozit ovoga izuma može se poželjno koristiti jer takvi kompoziti zadovoljavaju posebnim zahtjevima pri terapiji kaptoprilom, tj. kada je potrebno uskladiti pojedinačnu dozu za bolesnika njenim povećanjem, tablete koje su načinjene u skladu s ovim izumom mogu se pouzdano razlomiti u dva ili četiri dijela zbog manjeg standardnog odstupanja sadržaja aktivne tvari dijelova tablete. In comparative example 9, the standard deviation of the individual content of the active substance in industrially produced tablets and the standard deviation of the individual content of the active substance in tablets that are divided into two or four parts are defined. Experimental results show that if the captopril tablets are broken into two or four parts, the standard deviation of the active substance content of the said tablets is very favorable. Accordingly, the pharmaceutical composite of this invention can preferably be used because such composites meet the special requirements of captopril therapy, i.e. when it is necessary to adjust the individual dose for the patient by increasing it, the tablets made in accordance with this invention can be reliably broken into two or four parts due to a smaller standard deviation of the active substance content of the tablet parts.

U komparativnom primjeru 10 određen je sadržaj disulfida u uzorcima koji su podvrgnuti ispitivanju postojanosti. Tablete koje sadrže 12,5 mg kaptoprila pakirane su u hladne mjehuriće koji su načinjeni u PVC/PDVC plastičnoj foliji i zatvorene aluminijskom folijom. Tablete ovog izuma uspoređene su s tabletama koje imaju odnos laktoza/mikrokristalna celuloza izvan dosega ovog izuma, dok su inače identičnog sastava. Tablete zatvorene u mjehurićima čuvane su na 40°C uz relativnu vlažnost 75% tijekom 3 mjeseca. Nakon ovog vremena sadržaj kaptoprilskog disulfida u tabletama ovog izuma povećava se od početne vrijednosti od 0,31% do 3,32%, dok je u referentnim tabletama sadržaj kaptoprilskog disulfida povećan od 0,30% do 5,04%. In comparative example 10, the content of disulfide was determined in the samples subjected to the stability test. Tablets containing 12.5 mg of captopril are packed in cold blisters made in PVC/PDVC plastic foil and closed with aluminum foil. The tablets of this invention were compared with tablets having a lactose/microcrystalline cellulose ratio outside the scope of this invention, while otherwise having an identical composition. Tablets sealed in blisters were stored at 40°C with a relative humidity of 75% for 3 months. After this time, the captopril disulfide content in the tablets of this invention increases from the initial value of 0.31% to 3.32%, while in the reference tablets the captopril disulfide content increases from 0.30% to 5.04%.

Primjer 11 pokazuje da tablete kaptoprila ovog izuma pokazuju osobito visoku postojanost u pakiranju tipa “hladnog mjehurića” koje osigurano od vlage. Example 11 shows that the captopril tablets of the present invention exhibit particularly high stability in a "cold blister" package that is protected from moisture.

Primjer 1 Example 1

(komparativni primjer) (comparative example)

(Učinak odnosa laktoza-monohidrata i mikrokristalne celuloze na stlačivost praškastih smjesa) (The effect of the ratio of lactose-monohydrate and microcrystalline cellulose on the compressibility of powder mixtures)

Sadržaj (mg/tableta) (g/5000 tableta) Contents (mg/tablet) (g/5000 tablets)

[image] Komponente su prosijane kroz sito 0,5 mm i zatim homogenizirane u Lödige 5M ultrabrzom mješaču, uz miješanje 5 minuta. Homogenizirana praškasta smjesa je stlačena u tablete na Fette E XI tipe ekscentričnog stroja za tabletiranje korištenjem probojaca za tabletiranje s ravnim rubom pod silom tlačenja od 5 kN, 10 kN i 15 kN. Određena je sila lomljenja (Schleuniger 4M mjerni uređaj), mrvljivost (uređaj za mjerenje mrvljivosti Roche-ova tipa, 100 r.p. 4 minute) i vrijeme raspadanja na 37°C u destiliranoj vodi (Erweka uređaj za mjerenje raspada). [image] The components were sieved through a 0.5 mm sieve and then homogenized in a Lödige 5M ultra-fast mixer, mixing for 5 minutes. The homogenized powder mixture was compressed into tablets on a Fette E XI type eccentric tabletting machine using flat edge tablet punches under compression forces of 5 kN, 10 kN and 15 kN. The breaking force (Schleuniger 4M measuring device), friability (Roche-type friability measuring device, 100 r.p. 4 minutes) and disintegration time at 37°C in distilled water (Erweka disintegration measuring device) were determined.

Rezultati su prikazani u tablici 1. The results are presented in Table 1.

Tablica 1. Table 1.

Rezultati ispitivanja koja su provedena s tabletama The results of tests carried out with tablets

[image] [image]

Gore navedeni podaci pokazuju da se promjenom odnosa laktoze i mikrokristalne celuloze u korist mikrokristalne celuloze poboljšava stlačivost praškaste smjese (povećavaju se vrijednosti sile lomljenja koje odgovaraju vrijednosti sile stlačivanja, dok se mrvljivost smanjuje) i vrijeme raspadanja tableta je vrlo dobro (kraće od jedne minute). Ako smjesa sadrži laktozu i mikrokristalnu celulozu u približno jednakim količinama (pokus br. 1/3) mrvljivost je manja od 0,5% i to je karakteristično svojstvo tableta koje imaju odličnu mehaničku snagu. The above data show that by changing the ratio of lactose and microcrystalline cellulose in favor of microcrystalline cellulose, the compressibility of the powder mixture is improved (the breaking force values corresponding to the compressive force values increase, while the crumbliness decreases) and the tablet disintegration time is very good (less than one minute). . If the mixture contains lactose and microcrystalline cellulose in approximately equal amounts (experiment no. 1/3), the friability is less than 0.5% and this is a characteristic property of tablets that have excellent mechanical strength.

U gore navedenim podacima pokus br. 1/3 odgovara sastavu ovog izuma. In the above data, experiment no. 1/3 corresponds to the composition of this invention.

Primjer 2 Example 2

(komparativni primjer) (comparative example)

(Učinak odnosa laktoza-monohidrata i mikrokristalne celuloze na količinu apsorbirane vlage tableta) (Effect of the ratio of lactose monohydrate and microcrystalline cellulose on the amount of absorbed moisture in tablets)

Sadržaj (mg/tableta) (g/1000 tableta) Content (mg/tablet) (g/1000 tablets)

[image] [image]

Opažanja: Observations:

* = hidrogenirano dabrovo ulje * = hydrogenated beaver oil

** = koloidni silika-gel ** = colloidal silica gel

Tablete su priređene primjenom metode i opreme koji su opisani u primjeru 1; veličina šarže: 1000 tableta. Tablete su stlačene uporabom tabletnog probojca promjera 12 mm pod silom tlačenja 20 kN. The tablets were prepared using the method and equipment described in example 1; batch size: 1000 tablets. The tablets were compressed using a tablet punch with a diameter of 12 mm under a compression force of 20 kN.

Sposobnost vezanja vlage određena je stavljanjem tableta u kondicionirani prostor (LABORMIM, LP-23) s relativnim sadržajem vlage 75% (relativna vlažnost od 75% postignuta je zasićenom otopinom amonijeva sulfata; fluktuacija temperature i vlažnosti kontrolirana je termometrom-higrometrom – “LOMBIK HÖMÉRÖ és ÜVEGIPARI MÜSZERGYÄRTÓ SZÖVETKEZET” tipa 06912). Tijekom dvotjednog vremena temperatura je fluktuirala između 39,7°C i 40,4°C dok je vlažnost varirala između 73% i 88%. The ability to bind moisture was determined by placing the tablets in a conditioned space (LABORMIM, LP-23) with a relative humidity of 75% (a relative humidity of 75% was achieved with a saturated solution of ammonium sulfate; temperature and humidity fluctuations were controlled by a thermometer-hygrometer – “LOMBIK HÖMÉRÖ és ÜVEGIPARI MÜSZERGYÄRTÓ SZÖVETKEZET” type 06912). During the two-week period, the temperature fluctuated between 39.7°C and 40.4°C, while the humidity varied between 73% and 88%.

Vezanje vlage tableta mjereno je nakon vremena od 1, 2, 4, 8 i 14 dana. Količina vezane vlage mjerena temeljem povećanja težine tablete (SARTORIUS A 200 S analitička vaga) i izračunato prema sljedećoj jednadžbi: The moisture binding of the tablets was measured after 1, 2, 4, 8 and 14 days. The amount of bound moisture measured based on the increase in tablet weight (SARTORIUS A 200 S analytical balance) and calculated according to the following equation:

[image] [image]

gdje je: where is:

[image] = težina uzorka prije smještaja u kondicionirani prostor [image] = weight of the sample before placement in the conditioned space

[image] = težina uzorka nakon vađenja iz kondicioniranog prostora. [image] = sample weight after removal from the conditioned space.

No u kondicionirani postor nisu stavljene samo tablete, već također i komponente od kojih su načinjene tablete i određena je sposobnost vezanja vlage kaptoprila (aktivna tvar) i pomoćnih sredstava u vremenima koja su gore navedena. However, not only tablets were placed in the conditioned post, but also the components from which the tablets were made, and the moisture binding capacity of captopril (active substance) and auxiliary agents was determined at the times stated above.

Rezultati su prikazani u tablicama 2 i 3. The results are presented in tables 2 and 3.

Tablica 2 Table 2

Vlaga koju veže tableta, w/w % Moisture bound by tablet, w/w %

[image] [image]

Tablica 3 Table 3

Vezanje vlage aktivne tvari i pomoćnog sredstava (w/w %) Moisture binding of active substance and auxiliary agents (w/w %)

[image] [image]

Gore navedeni podaci pokazuju da se povećanjem količine mikrokristalne celuloze u tabletama povećava sadržaj vezane vlage što je u skladu s činjenicom da tijekom držanja u kondicioniranom prostoru laktoza-monohidrat ne veže vlagu dok je vezanje vlage mikrokristalne celuloze iznad 1 w/w %. Budući da je visoka sposobnost vezanja vlage mikrokristalne celuloze poznata iz prošlih tehnika, sposobnost vezanja vlage tableta u skladu je s očekivanim rezultatima. The above data show that by increasing the amount of microcrystalline cellulose in tablets, the content of bound moisture increases, which is in accordance with the fact that during storage in a conditioned space, lactose monohydrate does not bind moisture, while the moisture binding of microcrystalline cellulose is above 1 w/w %. Since the high moisture binding capacity of microcrystalline cellulose is known from the prior art, the moisture binding capacity of the tablets is in accordance with the expected results.

U gore navedenim podacima smjesa br. 2/3 odgovara ovom izumu. In the above data, mixture no. 2/3 corresponds to this invention.

Primjer 3 Example 3

(komparativni primjer) (comparative example)

(Učinak odnosa laktoza-monohidrata i mikrokristalne celuloze na stabilnost kaptoprila) (The effect of the ratio of lactose-monohydrate and microcrystalline cellulose on the stability of captopril)

U ovom eksperimentu sadržaj aktivne kaptoprilske tvari u tabletama karakteriziran je određivanjem sadržaja katoprilskog disulfida u tabletama prije i nakon smještaja u kondicionirani prostor (uvjeti su identični onima koji su opisani u primjeru 2). Količina kaptoprilskog disulfida u tabletama određena je sukladno HPLC metodama koje su opisane u USP 23. Pri mjerenju, uz VARIAN MODEL 5000 Liquid Chromatograph, korišten je PYE UNICAM LC-3 UV detektor i HEWLETT-PACKARD HP 3394A integrator. Sadržaj disulfida u tabletama izražen je u težinskim postocima normalnog sadržaja kaptoprila u tabletama. Rezultati su prikazani u tablici 4. In this experiment, the content of the active captopril substance in the tablets was characterized by determining the content of captopril disulfide in the tablets before and after placement in the conditioned space (the conditions are identical to those described in example 2). The amount of captopril disulfide in the tablets was determined according to the HPLC methods described in USP 23. During the measurement, in addition to the VARIAN MODEL 5000 Liquid Chromatograph, a PYE UNICAM LC-3 UV detector and a HEWLETT-PACKARD HP 3394A integrator were used. The content of disulfide in the tablets is expressed in weight percentages of the normal content of captopril in the tablets. The results are shown in table 4.

Tablica 4 Table 4

Količina katoprilskog disulfida u tabletama, izražen težinskim postocima prema normalnom sadržaju kaptoprila u tabletama (w/w %) The amount of captopril disulfide in the tablets, expressed as a percentage by weight of the normal content of captopril in the tablets (w/w %)

[image] [image]

Prema gore navedenim podacima čini se da povećanjem sadržaja mikrokristalne celuloze u tabletama (tj. smanjenje sadržaja laktoze) količina kaptoprilskog disulfida koji nastaje u tabletama prolazi minimalnom vrijednošću tj. raspad smjese (nastajanje disulfida) najmanje je u točno određenom odnosu laktoza-monohidrata i mikrokristalne celuloze. Ovaj rezultat eksperimenta je iznenađujući jer u skladu s nalazom postojećih tehnika veću brzinu oksidacije kaptoprila, tj. nastajanje veće količine kaptoprilskog disulfida, valja očekivati u sustavima koji imaju veći sadržaj vlage, tj. veći sadržaj mikrokristalne celuloze. According to the above data, it seems that by increasing the content of microcrystalline cellulose in the tablets (i.e. reducing the lactose content), the amount of captopril disulfide formed in the tablets passes the minimum value, i.e. the disintegration of the mixture (formation of disulfide) is at least in the exact ratio of lactose-monohydrate and microcrystalline cellulose . This result of the experiment is surprising because, in accordance with the findings of existing techniques, a higher oxidation rate of captopril, i.e. the formation of a larger amount of captopril disulfide, should be expected in systems with a higher moisture content, i.e. a higher content of microcrystalline cellulose.

Primjer 4 Example 4

(komparativni primjer) (comparative example)

Da bi se odredio preciznije optimalni odnos, u ovom nizu eksperimenata određena je stabilnost sadržaja kaptoprila tableta korištenjem odnosa laktoza/mikrokristalna celuloza koji su blizu onom koji je procijenjen pogodnim sukladno eksperimentima 2 i 3. Sastav tableta postavljen je na vrijednosti koje su između onih za eksperimente 2/2 i 2/4. Korišteni sastavi prikazani su u tablici 5. Stabilnost je određena prije i nakon perioda od 2, odnosno 4 tjedna, mjerenjem sadržaja kaptoprilskog disulfida u tabletama sukladno HPLC metodi koja je opisana u poglavlju “Captopril Tablets” u USP 23. Pri mjerenju, uz VARIAN MODEL 5000 Liquid Chromatograph, korišten je PYE UNICAM LC-3 UV detektor i HEWLETT-PACKARD HP 3394A integrator. Sadržaj disulfida u tabletama izražen je u težinskim postocima normalnog sadržaja kaptoprila u tabletama. Rezultati su prikazani u tablici 5. In order to determine more precisely the optimal ratio, in this series of experiments the stability of the captopril tablet content was determined using lactose/microcrystalline cellulose ratios close to those judged suitable according to experiments 2 and 3. The composition of the tablets was set to values that were between those of the experiments 2/2 and 2/4. The compositions used are shown in table 5. The stability was determined before and after a period of 2 and 4 weeks, respectively, by measuring the content of captopril disulfide in the tablets in accordance with the HPLC method described in the chapter "Captopril Tablets" in USP 23. When measuring, with VARIAN MODEL 5000 Liquid Chromatograph, PYE UNICAM LC-3 UV detector and HEWLETT-PACKARD HP 3394A integrator were used. The content of disulfide in the tablets is expressed in weight percentages of the normal content of captopril in the tablets. The results are shown in table 5.

Tablica 5 Table 5

Sastav (mg/tableta) (g/1000 tableta) Composition (mg/tablet) (g/1000 tablets)

[image] [image]

Opažanja: Observations:

* = hidrogenirano dabrovo ulje * = hydrogenated beaver oil

** = koloidni silika-gel ** = colloidal silica gel

Tablete su priređene primjenom metode i opreme koji su opisani u primjeru 1; veličina šarže: 1000 tableta. Tablete su stlačene uporabom tabletnog probojca promjera 12 mm pod silom tlačenja 12 kN. The tablets were prepared using the method and equipment described in example 1; batch size: 1000 tablets. Tablets were compressed using a tablet punch with a diameter of 12 mm under a compression force of 12 kN.

Sposobnost vezanja vlage određena je stavljanjem tableta u kondicionirani prostor (LABORMIM, LP-23) na 40°C s relativnim sadržajem vlage 75% (relativna vlažnost od 75% postignuta je zasićenom otopinom amonijeva sulfata; fluktuacija temperature i vlažnosti kontrolirana je termometrom-higrometrom – “LOMBIK HÖMÉRÖ és ÜVEGIPARI MÜSZERGYÄRTÓ SZÖVETKEZET” tipa 06912). Tijekom dvotjednog vremena temperatura je fluktuirala između 39,6°C i 40,5°C dok je vlažnost varirala između 72% i 78%. The ability to bind moisture was determined by placing the tablets in a conditioned space (LABORMIM, LP-23) at 40°C with a relative humidity of 75% (a relative humidity of 75% was achieved with a saturated solution of ammonium sulfate; temperature and humidity fluctuations were controlled by a thermometer-hygrometer - "LOMBIK HÖMÉRÖ és ÜVEGIPARI MÜSZERGYÄRTÓ SZÖVETKEZET" type 06912). During the two-week period, the temperature fluctuated between 39.6°C and 40.5°C, while the humidity varied between 72% and 78%.

Vezanje vlage tableta mjereno je nakon vremena od 4 tjedna. Količina vezane vlage mjerena je temeljem povećanja težine tablete (SARTORIUS A 200 S analitička vaga) i izračunata prema sljedećoj jednadžbi: The moisture binding of the tablets was measured after a time of 4 weeks. The amount of bound moisture was measured based on the increase in tablet weight (SARTORIUS A 200 S analytical balance) and calculated according to the following equation:

[image] [image]

gdje je: where is:

Rezultati su prikazani u tablici 6. The results are shown in table 6.

Tablica 6 Table 6

[image] [image]

Rezultati ovih eksperimenata u potpunosti potvrđuju podatke koji su dobiveni prema primjeru br. 3. Dakle, povećanjem sadržaja mikrokristalne celuloze u tabletama (tj. smanjenjem sadržaja laktoze) količina nastalog disulfida u tabletama nakon odstojavanja dosiže minimalnu vrijednost i pri određenom odnosu laktoza-monohidrat:mikrokristalna celuloza raspad tablete (nastajanje disulfida) pokazuje minimum. Rezultati ova dva niza eksperimenata su iznenađujući i neočekivani jer temeljem prošlih tehnika valjalo bi očekivati znatniju oksidaciju kaptoprila (tj. nastajanje veće količine kaptoprilskog disulfida) u sustavu s većim sadržajem vlage. Normalno je očekivati da što je veći sadržaj mikrokristalne celuloze to će biti veći raspad kaptoprila i nastat će veća količina kaptoprilskog disulfida. Međutim, ako je odnos laktoze i mikrokristalne celuloze između 1,5:1 i 1:1, dolazi do iznenađujućeg dodatnog učinka. The results of these experiments fully confirm the data obtained according to example no. 3. Therefore, by increasing the content of microcrystalline cellulose in the tablets (i.e. by reducing the lactose content), the amount of disulfide formed in the tablets after standing reaches a minimum value and at a certain ratio of lactose-monohydrate: microcrystalline cellulose, the disintegration of the tablet (formation of disulfide) shows a minimum. The results of these two series of experiments are surprising and unexpected because, based on past techniques, one should expect a more significant oxidation of captopril (ie formation of a larger amount of captopril disulfide) in a system with a higher moisture content. It is normal to expect that the greater the content of microcrystalline cellulose, the greater the breakdown of captopril and the greater the amount of captopril disulfide will be. However, if the ratio of lactose to microcrystalline cellulose is between 1.5:1 and 1:1, a surprising additional effect occurs.

Primjer 5 Example 5

Tablete koje imaju sadržaj aktivne tvari od 12,5 mg Tablets with an active substance content of 12.5 mg

Veličina šarže: 2 milijuna tableta (140 kg) Batch size: 2 million tablets (140 kg)

Korištene tvari: Substances used:

Komponenta Količina, kg Component Quantity, kg

kaptopril (veličina čestica: 90% između 3,5 i 46,9 µm) 25,00 captopril (particle size: 90% between 3.5 and 46.9 µm) 25.00

laktoza-monohidrat 52,50 lactose monohydrate 52.50

mikrokristalna celuloza 45,00 microcrystalline cellulose 45.00

kukuruzni škrob 15,00 corn starch 15.00

hidrogenirano dabrovo ulje 1,40 hydrogenated beaver oil 1.40

koloidni silika-gel 0,70 colloidal silica-gel 0.70

magnezijev stearat 0,40 magnesium stearate 0.40

Gore navedene tvari – izuzev magnezijeva stearata – pomiješane su u mješaču 450 litara tijekom 20 minuta, nakon čega je dodan magnezijev stearat i nastavljeno je miješanjem još 2 minute. Tabletiranje je izvršeno u Fette Perfecta 2000 stroju za tabletiranje (43 mjesta za stlačivanje) korištenjem ravno obrubljenih probojaca pri 40 okretaja u minuti. Snaga lomljenja tableta je 35-45 N, vrijeme raspada iznosi 2-3 minute, aktivna tvar je otopljena unutar 5 minuta pri brzini 100% i relativnoj standardnoj devijaciji (RSD) sadržaja pojedinačne aktivne tvari od 3,7%. Nakon čuvanja tableta 3 mjeseca na 40°C u staklenom spremniku koji je zatvoren polietilenskim poklopcem sadržaj nastalog kaptoprilskog disulfida bio je 1,6%, dok su snaga lomljenja, vrijeme raspada i brzina otapanja aktivne tvari ostali praktički nepromijenjeni. Prema gore navedenim podacima priređene su tablete koje sadrže kaptopril sukladno ovom primjeru, pri čemu su ispunjeni zahtjevi Farmakopeje (USP 23, Captopril Tablets). The above substances - with the exception of magnesium stearate - were mixed in a 450 liter mixer for 20 minutes, after which magnesium stearate was added and mixing was continued for another 2 minutes. Tableting was carried out in a Fette Perfecta 2000 tableting machine (43 compression sites) using flat edge punches at 40 rpm. The breaking force of the tablets is 35-45 N, the disintegration time is 2-3 minutes, the active substance is dissolved within 5 minutes at a speed of 100% and the relative standard deviation (RSD) of the individual active substance content is 3.7%. After storing the tablets for 3 months at 40°C in a glass container closed with a polyethylene lid, the content of the formed captopril disulfide was 1.6%, while the breaking strength, disintegration time and dissolution rate of the active substance remained practically unchanged. According to the above data, tablets containing captopril were prepared in accordance with this example, meeting the requirements of the Pharmacopoeia (USP 23, Captopril Tablets).

Primjer 6 Example 6

Tablete sa sadržajem aktivne tvari 25 mg Tablets with an active substance content of 25 mg

Veličina šarže: 100,000 tableta (14 kg) Batch size: 100,000 tablets (14 kg)

Korištene tvari: Substances used:

Komponenta Količina, kg Component Quantity, kg

kaptopril (veličina čestica: 90% između 5,5 i 69,6 µm) 2,50 captopril (particle size: 90% between 5.5 and 69.6 µm) 2.50

laktoza-monohidrat 4,90 lactose monohydrate 4.90

mikrokristalna celuloza 4,90 microcrystalline cellulose 4.90

kukuruzni škrob 1,50 corn starch 1.50

hidrogenirano dabrovo ulje 0,10 hydrogenated beaver oil 0.10

koloidni silika-gel 0,07 colloidal silica gel 0.07

magnezijev stearat 0,04 magnesium stearate 0.04

Gore navedene tvari – izuzev magnezijeva stearata – pomiješane su u mješaču 50 litara tijekom 20 minuta, nakon čega je dodan magnezijev stearat i nastavljeno je miješanjem. Tabletiranje je izvršeno u Manesty B3B stroju za tabletiranje sa 16 mjesta za stlačivanje, korištenjem ravno obrubljenih probojaca pri 30 okretaja u minuti. Snaga lomljenja tableta je 40-55 N, vrijeme raspada iznosi 2-3 minute, otapanje aktivne tvari je 100% unutar 10 minuta. Relativna standardna devijacija (RSD) pojedinačnih tableta je 1,9%. Nakon čuvanja tableta 3 mjeseca na 40°C u staklenom spremniku koji je zatvoren polietilenskim poklopcem sadržaj nastalog kaptoprilskog disulfida bio je 1,5%, dok su snaga lomljenja, vrijeme raspada i brzina otapanja aktivne tvari ostali praktički nepromijenjeni. Prema gore navedenim podacima priređene su tablete koje sadrže kaptopril sukladno ovom primjeru, pri čemu su ispunjeni zahtjevi Farmakopeje (USP 23, Captopril Tablets). The above substances - with the exception of magnesium stearate - were mixed in a 50 liter mixer for 20 minutes, after which magnesium stearate was added and mixing was continued. Tableting was carried out in a Manesty B3B tableting machine with 16 compression sites, using straight-edged punches at 30 rpm. The breaking force of the tablets is 40-55 N, the disintegration time is 2-3 minutes, the dissolution of the active substance is 100% within 10 minutes. The relative standard deviation (RSD) of individual tablets is 1.9%. After storing the tablets for 3 months at 40°C in a glass container closed with a polyethylene lid, the content of the formed captopril disulfide was 1.5%, while the breaking strength, disintegration time and dissolution rate of the active substance remained practically unchanged. According to the above data, tablets containing captopril were prepared in accordance with this example, meeting the requirements of the Pharmacopoeia (USP 23, Captopril Tablets).

Primjer 7 Example 7

Tablete sa sadržajem aktivne tvari 50 mg Tablets with an active substance content of 50 mg

Veličina šarže: 50 000 (14 kg) Lot size: 50,000 (14 kg)

Korištene tvari: Substances used:

Komponenta Količina, kg Component Quantity, kg

kaptopril (veličina čestica: 90% između 2,3 i 36,5 µm) 2,50 captopril (particle size: 90% between 2.3 and 36.5 µm) 2.50

laktoza-monohidrat 5,85 lactose monohydrate 5.85

mikrokristalna celuloza 3,90 microcrystalline cellulose 3.90

kukuruzni škrob 1,50 corn starch 1.50

hidrogenirano dabrovo ulje 0,14 hydrogenated beaver oil 0.14

koloidni silika-gel 0,07 colloidal silica gel 0.07

magnezijev stearat 0,04 magnesium stearate 0.04

Gore navedene tvari – izuzev magnezijeva stearata – pomiješane su u mješaču 50 litara tijekom 20 minuta, nakon čega je dodan magnezijev stearat i nastavljeno je miješanjem još 2 minute. Tabletiranje je izvršeno u Manesty BB3B stroju za tabletiranje sa 27 mjesta za stlačivanje, korištenjem ravno obrubljenih probojaca pri 30 okretaja u minuti. Snaga lomljenja tableta je 45-65 N, vrijeme raspada iznosi 2-3 minute, otapanje aktivne tvari je 100% unutar 10 minuta i relativna standardna devijacija (RSD) pojedinačnih tableta je 3,7%. Nakon čuvanja tableta 3 mjeseca na 40°C u staklenom spremniku koji je zatvoren polietilenskim poklopcem sadržaj nastalog kaptoprilskog disulfida bio je 1,7%, dok su snaga lomljenja, vrijeme raspada i brzina otapanja aktivne tvari ostali praktički nepromijenjeni. Prema gore navedenim podacima priređene su tablete koje sadrže kaptopril sukladno ovom primjeru, pri čemu su ispunjeni zahtjevi Farmakopeje (USP 23, Captopril Tablets). The above substances - with the exception of magnesium stearate - were mixed in a 50 liter mixer for 20 minutes, after which magnesium stearate was added and mixing was continued for another 2 minutes. Tableting was carried out in a Manesty BB3B tableting machine with 27 compression sites, using straight-edged punches at 30 rpm. The breaking force of the tablets is 45-65 N, the disintegration time is 2-3 minutes, the dissolution of the active substance is 100% within 10 minutes and the relative standard deviation (RSD) of individual tablets is 3.7%. After storing the tablets for 3 months at 40°C in a glass container closed with a polyethylene lid, the content of the formed captopril disulfide was 1.7%, while the breaking strength, disintegration time and dissolution rate of the active substance remained practically unchanged. According to the above data, tablets containing captopril were prepared in accordance with this example, meeting the requirements of the Pharmacopoeia (USP 23, Captopril Tablets).

U tabletama odnos laktoze i mikrokristalne celuloze je 1,5:1. In tablets, the ratio of lactose and microcrystalline cellulose is 1.5:1.

Primjer 8 Example 8

Tablete sa sadržajem aktivne tvari 100 mg Tablets with an active substance content of 100 mg

Veličina šarže 500 000 tableta (140 kg) Lot size 500,000 tablets (140 kg)

Korištene tvari: Substances used:

Komponenta Količina, kg Component Quantity, kg

kaptopril (veličina čestica: 90% između 4,3 i 65,3 µm) 25,00 captopril (particle size: 90% between 4.3 and 65.3 µm) 25.00

laktoza-monohidrat 52,50 lactose monohydrate 52.50

mikrokristalna celuloza 45,00 microcrystalline cellulose 45.00

kukuruzni škrob 15,00 corn starch 15.00

hidrogenirano dabrovo ulje 1,40 hydrogenated beaver oil 1.40

koloidni silika-gel 0,70 colloidal silica-gel 0.70

magnezijev stearat 0,40 magnesium stearate 0.40

Gore navedene tvari – izuzev magnezijeva stearata – pomiješane su u mješaču 450 litara tijekom 20 minuta, nakon čega je dodan magnezijev stearat i nastavljeno je miješanjem još 2 minute. Tabletiranje je izvršeno u Manesty BB3B stroju za tabletiranje sa 35 mjesta za stlačivanje, korištenjem ravno obrubljenih probojaca promjera 12 mm pri 30 okretaja u minuti. Snaga lomljenja tableta je 70-90 N, vrijeme raspada iznosi 1,5-3 minute, otapanje aktivne tvari je iznad 90% unutar 10 minuta i relativna standardna devijacija (RSD) sadržaja aktivne tvari pojedinačnih tableta je 3,7%. Nakon čuvanja tableta 3 mjeseca na 40°C u staklenom spremniku koji je zatvoren polietilenskim poklopcem sadržaj nastalog kaptoprilskog disulfida bio je 1,7%, dok su snaga lomljenja, vrijeme raspada i brzina otapanja aktivne tvari ostali praktički nepromijenjeni. Prema gore navedenim podacima priređene su tablete koje sadrže kaptopril sukladno ovom primjeru, pri čemu su ispunjeni zahtjevi Farmakopeje (USP 23, Captopril Tablets). The above substances - with the exception of magnesium stearate - were mixed in a 450 liter mixer for 20 minutes, after which magnesium stearate was added and mixing was continued for another 2 minutes. Tableting was carried out in a Manesty BB3B tableting machine with 35 compression sites, using straight edge punches of 12 mm diameter at 30 rpm. The breaking force of the tablets is 70-90 N, the disintegration time is 1.5-3 minutes, the dissolution of the active substance is above 90% within 10 minutes and the relative standard deviation (RSD) of the active substance content of individual tablets is 3.7%. After storing the tablets for 3 months at 40°C in a glass container closed with a polyethylene lid, the content of the formed captopril disulfide was 1.7%, while the breaking strength, disintegration time and dissolution rate of the active substance remained practically unchanged. According to the above data, tablets containing captopril were prepared in accordance with this example, meeting the requirements of the Pharmacopoeia (USP 23, Captopril Tablets).

U tabletama odnos laktoze i mikrokristalne celuloze bio je 1,16:1. In the tablets, the ratio of lactose and microcrystalline cellulose was 1.16:1.

Primjer 9 Example 9

Određivanje standardnog odstupanja sadržaja aktivne tvari u tabletama sukladno ovom izumu polovljenjem i dijeljenjem tableta u četvrtine Determination of the standard deviation of the active substance content in tablets according to this invention by halving and dividing the tablets into quarters

Ispitivanje je provedeno korištenjem lomljenjem tableta koje imaju sadržaj aktivne tvari 25 mg. Da se primijeni doza od 12,5 mg , odnosno 6,25 mg, bolesnici moraju tijekom liječenja prelomiti tablete u dva ili četiri dijela. The test was carried out by breaking tablets containing 25 mg of active substance. To apply a dose of 12.5 mg or 6.25 mg, patients must break the tablets into two or four parts during treatment.

Tijekom ispitivanja standardno odstupanje sadržaja aktivne tvari cijelih tableta određeno je mjerenjem pojedinačnog sadržaja aktivne tvari 10 tableta i izračunato je relativno standardno odstupanje sadržaja aktivne tvari (RSD). Nakon toga je 10 tableta oba kompozita razlomljeno rukom u dva dijela te je određeno relativno standardno odstupanje težine i sadržaja aktivne tvari raspolovljenih tableta mjerenjem alternativno težine i sadržaja kaptoprila raspolovljenih tableta u desnoj, odnosno lijevoj ruci. Preostale raspolovljene tablete su zatim podijeljene u dva dijela te je određeno relativno standardno odstupanje mjerenjem alternativno težine i sadržaja akptoprila četvrtina tableta koje su preostale u desnoj, odnosno lijevoj ruci. During the test, the standard deviation of the active substance content of the whole tablets was determined by measuring the individual active substance content of 10 tablets and the relative standard deviation of the active substance content (RSD) was calculated. After that, 10 tablets of both composites were broken into two parts by hand, and the relative standard deviation of the weight and active substance content of the halved tablets was determined by alternately measuring the weight and captopril content of the halved tablets in the right and left hand. The remaining halved tablets were then divided into two parts and the relative standard deviation was determined by measuring alternately the weight and actopril content of the quarter tablets that remained in the right and left hand.

Sadržaj kaptoprila cijelih, raspolovljenih tableta i četvrtina tableta određen je sukladno poglavlju “Captopril tablets” prema USP 23 mjerenjem pojedinačnog sadržaja aktivne tvari tableta kaptoprila pomoću HPLC. The captopril content of whole, halved tablets and quarter tablets was determined in accordance with the chapter "Captopril tablets" according to USP 23 by measuring the individual content of the active substance of captopril tablets using HPLC.

Rezultati su prikazani u tablici 7. The results are shown in table 7.

Tablica 7 Table 7

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Gore navedeni podaci pokazuju da raspolavljanjem i dijeljenjem tableta u četiri dijela, standardno odstupanje težine i sadržaja aktivne tvari polovina tablete i četvrtina manja od 15% dozvoljene granice za standardno odstupanje sadržaja aktivne tvari. Sukladno tome, tablete ovoga izuma mogu se poželjno koristiti u terapeutskoj praksi ako se tablete podijele u dva ili četiri dijela da se postavi optimalna doza pri liječenju. The above data show that by halving and dividing the tablet into four parts, the standard deviation of the weight and content of the active substance of half of the tablet and a quarter is less than 15% of the permissible limit for the standard deviation of the content of the active substance. Accordingly, the tablets of the present invention can preferably be used in therapeutic practice if the tablets are divided into two or four parts to set the optimal dose in treatment.

Primjer 10 Example 10

(komparativni primjer) (comparative example)

U komparativnom primjeru 10 tablete koju su u skladu s ovim izumom (primjer 2, br. 2/3) uspoređene su s onima koje imaju odnos laktoza/mikrokristalna celuloza izvan dosega ovog izuma: inače je sadržaj aktivne tvari (12,5 mg) i ostalih komponenti identičan. Tablete su pakirane u “mjehuriće” (udubljenja koja su načinjena od PVC/PVDC plastične folije i zatvorena aluminijskom folijom). Uzorci su podvrgnuti ispitivanju postojanosti i mjeren je sadržaj disulfida. Tablete su pakirane u “mjehuriće” i čuvane na 40°C uz relativnu vlažnost 75% tijekom 3 mjeseca. Određen je sadržaj kaptoprilskog disulfida prije i nakon čuvanja. Rezultati su prikazani u tablici 8. In a comparative example, 10 tablets according to this invention (example 2, no. 2/3) were compared with those having a lactose/microcrystalline cellulose ratio outside the scope of this invention: otherwise, the content of the active substance (12.5 mg) and other components identical. Tablets are packed in "blisters" (indentations made of PVC/PVDC plastic film and closed with aluminum foil). The samples were subjected to a stability test and the disulfide content was measured. The tablets were packed in "bubbles" and stored at 40°C with a relative humidity of 75% for 3 months. The captopril disulfide content was determined before and after storage. The results are shown in Table 8.

Tablica 8 Table 8

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Primjer 11 Example 11

Ispitivanje stabilnosti tableta ovog izuma (sadržaj aktivne tvari 12,5 mg) koje su pakirane u vodonepropusne “hladne mjehuriće”. Stability testing of the tablets of this invention (active substance content 12.5 mg) which are packed in waterproof "cold blisters".

Tablete ovoga izuma (primjer 2, br. 2/3: sadržaj aktivne tvari 12,5 mg) stavljene su u udubljenja koja su načinjena od aluminijske folije koja je kombinirana s plastikom (Al/PE/PVC) uporabom odgovarajućih strojeva za pakiranje. Udubljenja su zatvorena aluminijskom folijom. Tablets of this invention (example 2, no. 2/3: active substance content 12.5 mg) were placed in recesses made of aluminum foil combined with plastic (Al/PE/PVC) using suitable packaging machines. The recesses are closed with aluminum foil.

Tablete su čuvane na 40°C (±2°C) uz relativnu vlažnost 75% tijekom 3 mjeseca nakon čega je određen sadržaj kaptoprilskog disulfida u tabletama HPLC metodom, sukladno USP 23. The tablets were stored at 40°C (±2°C) with a relative humidity of 75% for 3 months, after which the content of captopril disulfide in the tablets was determined by the HPLC method, in accordance with USP 23.

Rezultati su prikazani u tablici 9. The results are shown in table 9.

Tablica 9 Table 9

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Može se vidjeti da se sadržaj kaptoprilskog disulfida u tabletama povećava vrlo malo, daleko ispod dozvoljene granice, čak i ako su čuva u agresivnim uvjetima. It can be seen that the content of captopril disulfide in the tablets increases very little, far below the permissible limit, even if they are stored under aggressive conditions.

Claims

1. Captopril tablets containing a filler and binder, a disintegrant, a lubricant and a glidant, characterized in that the filler and binder are a mixture of a 1.5:1 to 1:1 weight ratio of lactose and microcrystalline cellulose and the total amount of the mentioned mixture is 60-80% by weight of the total weight of the tablets.

2. Tablets according to claim 1, characterized in that the total amount of the mixture of lactose and microcrystalline cellulose is 67-75% by weight based on the total weight of the tablet.

3. Tablets according to claim 2, characterized in that the total amount of the mixture of lactose and microcrystalline cellulose is 69-70% by weight based on the total weight of the tablets.

4. Tablets according to any one of claims 1-3, characterized in that the disintegrating agent is corn starch, carboxymethyl starch, partially hydrolyzed starch, carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone, and the amount is 1-20% by weight based on the total weight of the tablet.

5. Tablets according to any one of claims 1-3, characterized in that the lubricating substance is stearin, magnesium stearate, calcium stearate, sodium stearyl fumarate or hydrogenated beaver oil, in an amount of 0.2-3% by weight based on the total weight of the tablet.

6. Tablets according to any one of claims 1-3, characterized in that the glidant is colloidal silica gel in an amount of 0.2-1% by weight based on the total weight of the tablet.

7. Tablets according to any of claims 1-3, characterized in that the average particle size of lactose monohydrate is 50-200 µm.

8. Tablets according to claim 7, characterized in that the average particle size of lactose monohydrate is 80-160 µm.

9. Tablets according to any one of claims 1-3, characterized in that 90% of the microcrystalline cellulose has an average particle size of 50-150 µm.

10. Tablets according to claim 9, characterized in that the microcrystalline cellulose has an average particle size of 50-100 µm.

11. Process for preparing captopril tablets containing a filler and a binding agent, a disintegrating agent, a lubricating agent and a glidant agent, indicated by the fact that a 1.5:1 - 1:1 mixture of lactose and microcrystalline cellulose is used, and the amount of the of the mixture is 60-80% by weight of the total weight of the tablets.

12. The method according to claim 11, characterized in that lactose, microcrystalline cellulose, a disintegrant, a lubricant and/or a glidant defined according to claims 2-10 are used.