SI20625A

SI20625A - Matrix tablet enabling sustained release of gliclazide after peroral administration

Info

Publication number: SI20625A
Application number: SI200000203A
Authority: SI
Inventors: De Barochez Bruno Huet; Patrick Wuthrich; Louis Martin
Original assignee: Les Laboratoires Servier
Priority date: 2000-08-29
Filing date: 2000-08-29
Publication date: 2002-02-28

Abstract

The invention refers to a matrix tablet for sustained release of gliclazide which assures a continuous and constant release of the active ingredient after peroral administration irrespective of the variation of pH of the solvent medium.

Description

Matrična tableta, ki omogoča upočasnjeno sproščanje gliklazida po oralnem dajanjuA matrix tablet that allows slow release of gliclazide after oral administration

Predmetni izum sa nanaša na matrično tableto, ki omogoča upočasnjeno (retardirano) sproščanje gliklazida, neodvisno od spreminjanja pH medija za raztapljanje in zagotavlja enakomerne in konstantne nivoje v krvi po peroralnem jemanju (zaužitju) galenske oblike.The present invention relates to a matrix tablet that allows the retarded release of gliclazide independently of changing the pH of the dissolution medium and provides steady and constant blood levels after oral administration of the galenic form.

Gliklazid, spojina s formulo (I):Gliclazide, a compound of formula (I):

je derivat sulfonilsečnine z antidiabetičnimi lastnostmi pri dozah, ki jih običajno dajejo človeku.is a sulphonylurea derivative with antidiabetic properties at human-administered doses.

Gliklazid so doslej dajali oralno v obliki tablet z dozami po 80 mg. Povprečna običajna predpisana doza je dvakrat dve tableti dnevno, vendar pa lahko variira med 1 in 4 tabletami večkrat dnevno, v odvisnosti od resnosti diabetesa.So far, gliclazide has been administered orally as 80 mg tablets. The average usual prescribed dose is two tablets twice a day, but may vary between 1 and 4 tablets several times a day, depending on the severity of the diabetes.

Eden izmed ciljev predmetnega izuma je bil pridobiti oralno obliko, primerno za enkratno jemanje dnevno.To po eni strani omogoča za pacienta lažjo uporabo in po drugi strani boljšo prilagoditev terapiji.One object of the present invention was to provide an oral dosage form suitable for once daily administration. This, on the one hand, makes it easier for the patient to use and, on the other, better adapted to therapy.

Nadaljnji cilj izuma je bil, da bi imela ta oralna oblika upočasnjeno sproščanje. Oblika s takojšnjim sproščanjem namreč lahko privede pri nekaterih osebah do kratkotrajnih visokih koncentracij v krvi. Oblika z upočasnjenim sproščanjem pa omogoči, da se izognemo tem vršnim vrednostim v krvi in dosežemo enakomerno koncentracijo v krvi pri človeku. To omogoči zmanjšanje nezaželenih učinkov, ki bi se morebiti pojavili zaradi »vršnega efekta«, s spremljajočimi motnjami hidroelektrolitičnega in metaboličnega tipa, ki so v zvezi s spreminjanjem nivoja učinkovine v plazmi.It is a further object of the invention that this oral formulation would have a delayed release. Namely, immediate-release form can lead to short-term high blood concentrations in some subjects. The slow-release formulation, however, allows us to avoid these peaks in the blood and to achieve a steady concentration of blood in humans. This makes it possible to reduce the undesirable effects that may occur due to the "peak effect", with the accompanying hydroelectrolytic and metabolic-related disorders associated with changes in the level of the active substance in the plasma.

Glavni namen izuma pa je bil pridobiti oralno obliko, katere hitrost sproščanja učinkovine bi bila kontrolirana in ponovljiva. Dosedanja oblika dejansko kaže močno variabilnost glede raztapljanja učinkovine v odvisnosti od pH. Ta posebnost v zvezi s samim gliklazidom izzove probleme pri absorpciji učinkovine. Ta problem raztapljanja učinkovine, ki variira v odvisnosti od pH, ponazarja Slika 1 (v prilogi). Topnost je zelo šibka pri kislem pH in raste z naraščajočim pH.The main purpose of the invention, however, was to obtain an oral formulation whose rate of release of the active substance would be controlled and reproducible. The present formulation actually exhibits strong variability in the dissolution of the active ingredient as a function of pH. This particularity with respect to the gliclazide itself causes problems with the absorption of the active substance. This problem of dissolution of the active ingredient, which varies with pH, is illustrated by Figure 1 (in the annex). The solubility is very weak at acidic pH and grows with increasing pH.

Zato je bilo pomembno ustvariti za to učinkovino novo galensko obliko, ki omogoča tako sproščanje gliklazida, ki ni odvisno od pH topilnega medija.Therefore, it was important to create a novel galenic form for this active substance, which allows the release of gliclazide, which is independent of the pH of the solvent medium.

Predmetni izum opisuje zlasti hidrofilno matriko za dajanje po oralni poti (zaužitje), ki omogoča upočasnjeno in kontrolirano sproščanje učinkovine, gliklazida, brez vpliva pH na kinetiko in vitro raztapljanja navedenega matriksa.The present invention particularly describes a hydrophilic matrix for oral administration (ingestion), which enables the sustained and controlled release of the active substance, gliclazide, without affecting the pH of the in vitro dissolution kinetics of said matrix.

Ta oblika za upočasnjeno sproščanje gliklazida, ki je koristna za zdravljenje diabetesa, zagotavlja enakomernejše nivoje v plazmi, kot tudi manjše variacije Cmaks-Cmin· Hitrost sproščanja mora biti ponovljiva in v korelaciji s koncentracijami v krvi, ki jih zasledimo po dajanju.This sustained release formulation of gliclazide, which is useful for the treatment of diabetes, provides more consistent plasma levels as well as smaller variations of Cmax-Cmin. · The rate of release should be reproducible and correlate with blood levels observed after administration.

Med mehanizmi, ki se jih da uporabiti za kontrolo difuzije topne učinkovine, je treba poudariti glavnega, in sicer difuzijo učinkovine skozi gel, tvorjen po nabrekanju hidrofilnega polimera v stiku s tekočino - topilom (in vitro), ali gastro-intestinalno tekočino (in vivo).One of the mechanisms that can be used to control the diffusion of a soluble substance is the major one, namely the diffusion of the active ingredient through a gel formed after swelling of a hydrophilic polymer in contact with a liquid-solvent (in vitro) or gastro-intestinal fluid (in vivo) ).

Opisani so številni polimeri, ki naj bi omogočali tvorbo takega gela. Glavni so celulozni derivati, zlasti celulozni etri kot hidroksipropilceluloza, hidroksietilceluloza, metilceluloza, hidroksipropilmetilceluloza, in med različnimi tržnimi kakovostmi teh etrov tisti s precej veliko viskoznostjo. Pripominamo, da opisani sistemi teoretično ne dopuščajo, da bi v kinetični enačbi za sproščanje (učinkovine) dosegli red nič.A number of polymers have been described to allow such a gel to be formed. The main cellulose derivatives, especially cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, and among the different market qualities of these ethers, those with a fairly high viscosity. We note that the systems described do not theoretically allow us to reach zero in the kinetic release equation.

Običajno uporabljani postopki za izdelavo takih matričnih tablet so bodisi direktno stiskanje po mešanju različnih ekscipientov (dodatkov, polnil) in učinkovin(e), bodisi mokro granuliranje.Commonly used processes for making such matrix tablets are either direct compression after mixing of various excipients (additives, fillers) and active ingredients (s), or wet granulation.

Matrična tableta gliklazida, ki je opisana v predmetnem izumu, združuje na izviren način najmanj en polimeren derivat celuloze in glukozni sirup (hidrolizat koruznega amidona), kar omogoči v popolni meri upočasnjeno in kontrolirano sproščanje učinkovine.The gliclazide matrix tablet described in the present invention combines in an original way at least one polymeric cellulose derivative and glucose syrup (corn amidon hydrolyzate), enabling the active agent to be completely slowed down and controlled.

Kontrolirano sproščanje je linearno v teku več kot osem ur in je tolikšno, da se 50% celotne množine gliklazida sprosti med 4 in 6 urami. Po drugi strani pa matrična tableta po izumu omogoči upočasnjeno sproščanje gliklazida, kar vodi do nivojev v krvi človeka med 400 in 700 ng/ml, največ 12 ur po enkratnem oralnem dajanju tablete z dozo 30 mg gliklazida, in do nivojev v krvi med 250 in 1000 ng/ml po dajanju ene tablete z dozo 30 mg gliklazida dnevno.Controlled release is linear for more than eight hours and is such that 50% of the total amount of gliclazide is released between 4 and 6 hours. On the other hand, the matrix tablet of the invention provides a slow release of gliclazide, leading to levels in human blood of between 400 and 700 ng / ml, up to 12 hours after a single oral administration of a 30 mg gliclazide tablet, and to blood levels between 250 and 1000 ng / ml after administration of one 30 mg gliclazide tablet daily.

Doziranje enote zdravila lahko variira v odvisnosti od starosti in mase pacienta ter narave in resnosti diabetesa. Na splošno pa je razvrščeno med 30 in 120 mg za enkratno jemanje dnevno. Odstotek gliklazida v matrični tableti znaša med 12 in 40 % celotne mase tablete. Po prednostni varianti izuma vsebuje navedena tableta dozo 60 mg gliklazida. Posebno prednostna izvedba izuma je priprava tablet z dozami po 30 mg gliklazida. Pri teh zelo prikladnih primerih izuma ustreza enkratna dnevna doza, ki je v območju 30 do 120 mg, jemanju 1 do 4 tablet z dozami po 30 mg, ali pa 1 do 2 tablet z dozami po 60 mg. Matrična tableta, kot jo opisuje prijaviteljica, daje po eni strani na voljo oralno obliko, ki se jo da dajati enkrat dnevno, po drugi strani pa na presenetljiv in zlasti ugoden način zmanjša množino učinkovine v vsaki tableti, brez modifikacij ali sprememb koncentracij gliklazida v plazmi. Dosedanja formulacija je vsebovala dozo 80 mg gliklazida.The unit dosage may vary depending on the age and weight of the patient and the nature and severity of the diabetes. However, it is generally graded between 30 and 120 mg once daily. The percentage of gliclazide in the matrix tablet is between 12 and 40% of the total weight of the tablet. According to a preferred embodiment of the invention, said tablet contains a dose of 60 mg gliclazide. A particularly preferred embodiment of the invention is the preparation of tablets with doses of 30 mg gliclazide. In these very convenient embodiments, a single daily dose in the range of 30 to 120 mg is appropriate, taking 1 to 4 tablets of 30 mg or 1 to 2 tablets of 60 mg. The matrix tablet as described by the applicant provides, on the one hand, an oral formulation which can be administered once daily, and on the other hand, in a surprising and particularly advantageous manner, reduces the amount of the active ingredient in each tablet, without modifications or changes in plasma concentrations of gliclazide. . The formulation so far contained a dose of 80 mg gliclazide.

Specifična kombinacija zgoraj opisanih sestavin nadalje presenetljivo omogoči izključitev vpliva pH na kinetiko raztapljanja navedenega matriksa in vitro, čeprav topnost učinkovine variira v odvisnosti od samega pH. To je ponazorjeno na Sliki 2 (v prilogi), ki kaže, da je tako sestavljen matriks neobčutljiv na spremembe pH v območju 6.3 do 7.4 črevesnega medija. Tako v območju pH od 6 do 8 in ustrezno coni dviga krivulje na Sliki 1 (v prilogi) ugotavljamo, da je profil sproščanja učinkovine v teku 0 do 12 ur identičen, ne glede na pH topilnega medija matrične tablete, ki obdaja navedeno učinkovino.The specific combination of the ingredients described above further surprisingly makes it possible to exclude the influence of pH on the dissolution kinetics of said matrix in vitro, although the solubility of the active substance varies depending on the pH itself. This is illustrated in Figure 2 (annexed), showing that the matrix thus assembled is insensitive to pH changes in the range 6.3 to 7.4 of the intestinal medium. Thus, in the pH range 6 to 8 and corresponding to the curve lift zone in Figure 1 (in the annex), we find that the release profile of the active substance over the course of 0 to 12 hours is identical, regardless of the pH of the solvent medium of the matrix tablet surrounding the active ingredient.

Tako je s karakteristično kombinacijo najmanj enega polimernega derivata celuloze in glukoznega sirupa prijaviteljica ustvarila hidrofilni matriks, ki je na izumiteljski ravni po sestavi in po delovanju, saj namreč omogoča, da se učinkovina, ki jo vsebuje, to je gliklazid, sprošča upočasnjeno in kontrolirano, ne glede na pogoje pH topilnega medija.Thus, by characterizing a combination of at least one polymeric cellulose derivative and glucose syrup, the applicant has created a hydrophilic matrix which, at the inventive step, is by composition and by action, since it allows the active ingredient contained, that is, gliclazide, to be slowed down and controlled, regardless of the pH conditions of the solvent medium.

Polimerni derivat celuloze uporabljen v tej hidrofilni matriki, je celulozni eter z veliko viskoznostjo. Prikladno je celulozni eter hidroksipropilmetilceluloza, prednostno pa zmes dveh hidroksipropilmetilceluloz z različnimi viskoznostmi. Druga sestavina, ki nastopa v sestavi navedene matrike, je glukozni sirup; prikladno uporabimo maltodekstrin, ki ustreza glukoznemu sirupu z vrednostjo dekstroznih ekvivalentov (DE) med 1 in 20. Povezava teh dveh kategorij spojin omogoča po eni strani pridobivanje pripravka, v katerem je profil sproščanja učinkovine neobčutljiv na spreminjanje pH topilnega medija, po drugi strani pa doseganje popolne kontrole nad kinetiko sproščanja. Odstotek polimernega derivata celuloze je med 10 in 40% celotne mase tablete, in po posebno prednostni varianti znaša med 16 in 26% celotne mase tablete. Odstotek glukoznega sirupa znaša med 2 in 20% celotne mase tablete, prednostno med 4 in 10 % celotne mase tablete.The cellulose polymer derivative used in this hydrophilic matrix is a high viscosity cellulose ether. Suitably cellulose ether is hydroxypropylmethylcellulose, and preferably a mixture of two hydroxypropylmethylcelluloses with different viscosities. Another ingredient that forms part of said matrix is glucose syrup; it is convenient to use maltodextrin corresponding to glucose syrup with a dextrose equivalents (DE) value of between 1 and 20. The connection of these two categories of compounds enables, on the one hand, the preparation of a composition in which the release profile of the active ingredient is insensitive to changing the pH of the solvent medium and, on the other, complete control over the release kinetics. The percentage of the cellulose polymer derivative is between 10 and 40% of the total weight of the tablet, and in a particularly preferred embodiment, is between 16 and 26% of the total weight of the tablet. The percentage of glucose syrup is between 2 and 20% of the total weight of the tablet, preferably between 4 and 10% of the total weight of the tablet.

Možno je dodajati različne ekscipiente za dokončno oblikovanje pripravka. Izmed običajno uporabljanih razredčil uporabimo prednostno dihidrat kalcijevega hidrogenfosfata, ki omogoča doseganje boljše sipkosti granul in njihovo lažje stiskanje. Vrhu tega lahko dihidrat kalcijevega hidrogenfosfata zadržuje kinetiko raztapljanja, ta značilnost pa omogoča uporabo manjših množin hidroksipropilmetilceluloze za kontrolo profila raztapljanja učinkovine. Odstotek dihidrata kalcijevega hidrogenfosfata znaša med 35 in 75% celotne mase tablete in prednostno med 45 in 60% celotne mase tablete. Med mazalnimi sredstvi naj kot primer navedemo magnezijev stearat, stearinsko kislino, glicerol behenat ali natrijev benzoat, med drsnimi sredstvi pa prednostno uporabljamo brezvodno koloidno kremenico.Different excipients can be added to complete the formulation. Of the commonly used diluents, calcium hydrogen phosphate dihydrate is preferably used, which enables better granularity of the granules and their easier squeezing. On top of this, calcium hydrogen phosphate dihydrate can retain the dissolution kinetics, and this feature allows the use of smaller amounts of hydroxypropylmethylcellulose to control the dissolution profile of the active substance. The percentage of calcium hydrogen phosphate dihydrate is between 35 and 75% of the total weight of the tablet and preferably between 45 and 60% of the total weight of the tablet. Magnesium stearate, stearic acid, glycerol behenate or sodium benzoate should be mentioned as lubricants, and anhydrous colloidal silica is preferably used as a sliding agent.

Predmetni izum se nanaša tudi na izdelavo te matrične tablete. Vlažno granulacijo dosežemo s pomešanjem učinkovine, glukoznega sirupa in dihidrata kalcijevega hidrogenfosfata, in sledečim omočenjem te zmesi. Ta prva stopnja omogoči, da se okoli učinkovine ustvari hidrofilno okolje, ki je ugodno za njeno dobro raztapljanje, in prav tako pridobivanje čim enakomernejše enkratne doze. V drugi stopnji pa predhodno dobljeno granulo pomešamo s celuloznim etrom. Po želji lahko celulozni eter granuliramo direktno z učinkovino v prvi stopnji. Zatem zmes namažemo z dodatkom koloidne kremenice in magnezijevega stearata. Končni namazani sestavek nato stiskamo.The present invention also relates to the manufacture of this matrix tablet. Wet granulation is achieved by mixing the active ingredient, glucose syrup and calcium hydrogen phosphate dihydrate, and then wetting the mixture. This first step enables the hydrophilic environment to be created around the active substance, which is favorable for its good dissolution and also to obtain a uniform single dose as evenly as possible. In the second stage, the previously obtained granule is mixed with cellulose ether. If desired, the cellulose ether can be granulated directly with the active substance in the first step. The mixture is then coated with the addition of colloidal silica and magnesium stearate. The final lubricated composition is then compressed.

Naslednji Primeri izum pojasnjujejo, nikakor pa ne omejujejo.The following Examples illustrate the invention but are by no means limiting.

Pripravo tablet s upočasnjenim sproščanjem, namenjenih za oralno dajanje, izvedemo po naslenjem proizvodnem postopku:The preparation of slow-release tablets for oral administration is carried out following the inheritance of the manufacturing process:

STOPNJA A:LEVEL A:

Pomešanje gliklazida, maltodekstrina in dihidrata kalcijevega hidrogenfosfata, zatem pa omočenje te mešanice s prečiščeno vodo. Pripravljeno vlažno maso nato granuliramo, sušimo in zatem kalibriramo, da dobimo granulo s fizikalnimi lastnosti, ki omogočajo dobro zapolnitev matrice hitre tabletirne stiskalnice.Mixing gliclazide, maltodextrin and calcium hydrogen phosphate dihydrate and then wetting this mixture with purified water. The prepared wet mass is then granulated, dried and then calibrated to obtain a granule with physical properties that allow the matrix of the rapid tablet press to be filled well.

STOPNJA B:LEVEL B:

Pomešanje granule, dobljene pri stopnji A, s hidroksipropilmetilcelulozo.Mixing granules obtained in step A with hydroxypropylmethylcellulose.

STOPNJA C:STAGE C:

Namazanje mešanice, dobljene pri stopnji B, s koloidno kremenico in magnezijevim stearatom.Lubrication of grade B mixture with colloidal silica and magnesium stearate.

STOPNJA D:STAGE D:

Stiskanje namazane mešanice, dobljene pri stopnji C, na rotacijskem tabletirnem stroju, da dobimo tablete s trdoto, merjeno z diametralnim drobljenjem, okoli 6 do 10 daN.Compression of the lubricated mixture obtained at step C on a rotary tabletting machine to obtain tablets with a hardness measured by diametrical crushing of about 6 to 10 daN.

Primer 1:Example 1:

Primer 1 kaže vpliv maltodekstrina na kinetiko sproščanja in vitro. Množina maltodekstrina variira od 7,5 do 15 mg na tableto, kar predstavlja 4 do 10% celotne mase tablete. Množina hidroksipropilmetilceluloze ostaja konstantna in množino razredčila, dihidrata kalcijevega hidrogenfosfata, nastavimo tako, da dobimo tablete s konstantno maso 160 mg. Izdelava poteka po delovnem postopku, opisanem v stopnjah A do D.Example 1 shows the influence of maltodextrin on the kinetics of in vitro release. The amount of maltodextrin varies from 7.5 to 15 mg per tablet, representing 4 to 10% of the total weight of the tablet. The amount of hydroxypropylmethylcellulose remains constant and the amount of diluent, calcium hydrogen phosphate dihydrate, is adjusted to give tablets of a constant weight of 160 mg. Production is carried out according to the working procedure described in steps A to D.

Tabela 1: Formulacija tablete (enote) (v mg na tableto) in značilnostiTable 1: Tablet (unit) formulation (in mg per tablet) and characteristics

Šarži (partiji) Batch (lot) Sestavine Ingridients LP1 LP1 LP2 LP2 Gliklazid Gliclazide 30 30 30 30 Dihidrat kalcijevega hidrogenfosfata Calcium hydrogen phosphate dihydrate 87,4 87,4 79,9 79.9 Maltodekstrin (*) Maltodextrin (*) 7,5 7.5 15 15 Hidroksipropilmetilceluloza Hydroxypropylmethylcellulose 34 34 34 34 Magnezijev stearat Magnesium stearate 0,8 0.8 0,8 0.8 Koloidna kremenica Colloidal flint 0,32 0.32 0,32 0.32 Končna masa The final mass 160 160 160 160 Učinkovina, raztopljena v 8 urah (%) Active ingredient dissolved in 8 hours (%) 73 73 84 84

(*) Množina maltodekstrina ustreza 6 do 12% množine granuliranega materiala (učinkovina + dihidrat kalcijevega hidrogenfosfata + maltodekstrin).(*) The amount of maltodextrin corresponds to 6 to 12% of the amount of granular material (active substance + calcium hydrogen phosphate dihydrate + maltodextrin).

Slika 3 predstavlja krivulji kinetike raztapljanja za obe uporabljeni formulaciji. Slika 3 (v prilogi): predstavlja kinetiko raztapljanja in vitro za šarži LP1 in LP2 Množina maltodekstrina pri konstantni masi hidroksipropilmetilceluloze vpliva na sproščanje učinkovine v času, daljšem od 4 ur. S povečevanjem množine maltodekstrina lineariziramo krivuljo raztapljanja.Figure 3 represents the dissolution kinetics curves for the two formulations used. Figure 3 (annexed): presents the dissolution kinetics of in vitro dissolution of LP1 and LP2 batches The amount of maltodextrin at a constant mass of hydroxypropylmethylcellulose affects the release of the active substance over a period of more than 4 hours. By increasing the amount of maltodextrin, we linearize the dissolution curve.

Primer 2:Example 2:

Primer 2 kaže vpliv hidroksipropilmetilceluloze na kinetiko sproščanja in vitro. Množina hidroksipropilmetilceluloze variira od 26 do 42 mg, kar predstavlja 16 do 26% celotne mase tablete.Example 2 shows the effect of hydroxypropylmethylcellulose on the kinetics of in vitro release. The amount of hydroxypropyl methylcellulose varies from 26 to 42 mg, representing 16 to 26% of the total weight of the tablet.

Izdelava poteka po delovnem postopku, opisanem pri stopnjah A do D.Production is carried out according to the work procedure described in steps A to D.

Tabela 2: Formulacija tablete (enote) (v mg na tableto)Table 2: Tablet (unit) formulation (in mg per tablet)

Šarži (partiji) Batch (lot) Sestavine Ingridients LP3 LP3 LP4 LP4 Gliklazid Gliclazide 30 30 30 30 Dihidrat kalcijevega hidrogenfosfata Calcium hydrogen phosphate dihydrate 79,87 79.87 94,91 94.91 Maltodekstrin (*) Maltodextrin (*) 7,01 7.01 7,97 7.97 Hidroksipropilmetilceluloza Hydroxypropylmethylcellulose 42 42 26 26 Magnezijev stearat Magnesium stearate 0,8 0.8 0,8 0.8 Koloidna kremenica Colloidal flint 0,32 0.32 0,32 0.32 Končna masa The final mass 160 160 160 160 Učinkovina, raztopljena v 4 urah (%) Active ingredient dissolved in 4 hours (%) 35 35 52 52

(*) Množina maltodekstrina ustreza 6% množine granuliranega materiala (učinkovina + dihidrat kalcijevega hidrogenfosfata + maltodekstrin).(*) The amount of maltodextrin corresponds to 6% of the amount of granular material (active substance + calcium hydrogen phosphate dihydrate + maltodextrin).

Slika 4 (v prilogi) predstavlja krivulji kinetike raztapljanja za obe uporabljeni formulaciji.Figure 4 (annexed) represents the dissolution kinetics curves for the two formulations used.

Slika 4: Kinetika raztapljanja in vitro za šarži LP3 in LP4.Figure 4: In vitro dissolution kinetics for LP3 and LP4 batches.

Množina hidroksipropilmetilceluloze v hidrofilnem matriksu močno vpliva na sproščanje učinkovine.The amount of hydroxypropylmethylcellulose in the hydrophilic matrix greatly affects the release of the active substance.

Primer 3:Example 3:

Primer 3 kaže vpliv kakovosti hidroksipropilmetilceluloze na kinetiko sproščanja in vitro. V vsaki šarži je celotna masa hidroksipropilmetilceluloze konstantna, variiramo pa relativne množine hidroksipropilmetilceluloz z različnimi viskoznostmi, kar omogoča pripravo šarže s počasnim raztapljanjem (LP5) in šarže s hitrim raztapljanjem (LP7) z ozirom na referenčno šaržo (LP6).Example 3 shows the effect of hydroxypropylmethylcellulose quality on in vitro release kinetics. In each batch, the total weight of hydroxypropylmethylcellulose is constant, and the relative amounts of hydroxypropylmethylcellulose vary with different viscosities, allowing the preparation of slow-dissolving (LP5) and rapid-dissolving (LP7) batches with respect to the reference batch6.

Tabela 3: Formulacija tablete (enote) (v mg na tableto)Table 3: Tablet (unit) formulation (in mg per tablet)

Šarže (partije) Batch (lot) Sestavine Ingridients LP5 LP5 LP6 LP6 LP7 LP7 Gliklazid Gliclazide 30 30 30 30 30 30 Dihidrat kalcijevega hidrogenfosfata Calcium hydrogen phosphate dihydrate 83,64 83.64 83,64 83.64 83,64 83.64 Maltodekstrin (*) Maltodextrin (*) 11,24 11,24 11,24 11,24 11,24 11,24 Hidroksipropilmetilceluloza 4000 mPas Hydroxypropyl methylcellulose 4000 mPas 24 24 16 16 8 8 Hidroksipropilmetilceluloza 100 mPas Hydroxypropyl methylcellulose 100 mPas 10 10 18 18 26 26 Magnezijev stearat Magnesium stearate 0,8 0.8 0,8 0.8 0,8 0.8 Koloidna kremenica Colloidal flint 0,32 0.32 0,32 0.32 0,32 0.32 Končna masa The final mass 160 160 160 160 160 160 Učinkovina, raztopljena v 4 urah (%) Active ingredient dissolved in 4 hours (%) 33 33 46 46 58 58

(*) Množina maltodekstrina ustreza 9% množine granuliranega materiala (učinkovina + dihidrat kalcijevega hidrogenfosfata + maltodekstrin).(*) The amount of maltodextrin corresponds to 9% of the amount of granular material (active substance + calcium hydrogen phosphate dihydrate + maltodextrin).

Slika 5 (v prilogi) predstavlja krivulje kinetike raztapljanja za vse tri uporabljene formulacije.Figure 5 (annexed) presents dissolution kinetics curves for all three formulations used.

Slika 5 (v prilogi): Kinetika raztapljanja in vitro za šarže LP5 do LP7Figure 5 (annexed): In vitro dissolution kinetics for batches LP5 to LP7

Te krivulje jasno kažejo, da na kinetiko raztapljanja učinkovine ne vpliva samo celotna množina hidroksipropilmetilceluloze, vključene v hidrofilni matriks, ampak prav tako kakovost uporabljene hidroksipropilmetilceluloze.These curves clearly show that the dissolution kinetics of the active substance is not only affected by the total amount of hydroxypropylmethylcellulose incorporated into the hydrophilic matrix, but also by the quality of the hydroxypropylmethylcellulose used.

Kinetiko gliklazida v plazmi smo merili pri 12 osebah po enkratnem dajanju tablete LP6. Srednja koncentracija v plazmi je podana na Sliki 6.Plasma gliclazide kinetics were measured in 12 subjects after single administration of the LP6 tablet. The mean plasma concentration is given in Figure 6.

Slika 6 (v priogi): Kinetika gliklazida v plazmiFigure 6 (in priority): Klinics of gliclazide in plasma

Srednja vrednost za koncentracije gliklazida (v pg/mL) v krvi po oralnem dajanju tablete po izumu z doziranjem 30 mg gliklazida pri 12 zdravih prostovoljcih.Mean for gliclazide concentrations (in pg / mL) in blood after oral administration of the tablet of the invention with a dosage of 30 mg gliclazide in 12 healthy volunteers.

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Ta krivulja kaže profil raztapljanja matričnega tipa (kontinuirno sproščanje učinkovine) z monofazno kinetiko plazme.This curve shows the dissolution profile of the matrix type (continuous release of the active substance) by single-phase plasma kinetics.

Primer 4:Example 4:

Primer 4 kaže, da je kinetika sproščanja in vitro pri tableti z dozo po 60 mg podobna, kot pri tableti z dozo 30 mg (šarža LP6) za matrične tablete, dozirane na identičen način s hidroksipropilmetilcelulozo in maltodekstrinom.Example 4 shows that the in vitro release kinetics of a 60 mg tablet are similar to that of a 30 mg tablet (LP6 batch) for matrix tablets dosed identically with hydroxypropylmethylcellulose and maltodextrin.

Tabela 4: Formulacija tablete (enote) (v mg)Table 4: Tablet (unit) formulation (in mg)

Šarža (partija) LP8 Batch (lot) LP8 Sestavine Ingridients Gliklazid Gliclazide 60 60 Dihidrat kalcijevega hidrogenfosfata Calcium hydrogen phosphate dihydrate 53,64 53.64 Maltodekstrin (*) Maltodextrin (*) 11,24 11,24 Hidroksipropiimetilceluloza Hydroxypropymethylcellulose 34 34 Brezvodna koloidna kremenica Anhydrous colloidal silica 0,32 0.32 Magnezijev stearat Magnesium stearate 0,8 0.8 Končna masa The final mass 160 mg 160 mg Učinkovina, raztopljena v 4 urah (%) Active ingredient dissolved in 4 hours (%) 45 45

Slika 7 (v prilogi): Kinetika raztapljanja in vitro šarže LP8Figure 7 (annexed): In vitro dissolution kinetics of LP8 batch

Claims

PATENT APPLICATIONS

A matrix for slow release of gliclazide, characterized in that it contains at least a combination of a polymeric cellulose derivative and glucose syrup, said combination providing control of prolonged release of gliclazide and insensitivity of the kinetics of dissolution of the gliclazide to pH variations.

Gliclazide matrix tablet according to claim 1, characterized in that the polymeric cellulose derivative consists of at least one hydroxypropylmethylcellulose,

Gliclazide matrix tablet according to any one of claims 1 and 2, characterized in that the polymeric cellulose derivative consists of a mixture of two hydroxypropylmethylcelluloses with different viscosities.

Gliclazide matrix tablet according to any one of claims 1 to 3, characterized in that the polymeric cellulose derivative consists of a mixture of hydroxypropylmethylcellulose with a viscosity of 4000 mPas and hydroxypropylmethylcellulose with a viscosity of 100mPas.

Gliclazide matrix tablet according to claim 1, characterized in that the glucose syrup consists of maltodextrin.

Gliclazide matrix tablet according to any one of claims 1 to 4, characterized in that the percentage of polymeric cellulose derivative is in the range of 10 to 40% of the total weight of said tablet.

Gliclazide matrix tablet according to any one of claims 1, 2, 3, 4 and 6, characterized in that the percentage of polymeric cellulose derivative is in the range of 16 to 26% of the total weight of said tablet.

Gliclazide matrix tablet according to any one of claims 1 and 5, characterized in that the percentage of glucose syrup is in the range of 2 to 20% of the total weight of said tablet.

Gliclazide matrix tablet according to any one of claims 1, 5 and 8, characterized in that the percentage of glucose syrup is in the range of 4 to 10% of the total weight of said tablet.

Gliclazide matrix tablet according to claim 1, characterized in that calcium hydrogen phosphate dihydrate is used as a diluent.

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Gliclazide matrix tablet according to any one of claims 1 and 10, characterized in that the percentage of diluent is between 35 and 75% of the total weight of said tablet.

Gliclazide matrix tablet according to any one of claims 1, 10 and 11, characterized in that the percentage of diluent is between 45 and 60% of the total weight of said tablet.

Gliclazide matrix tablet according to claim 1, characterized in that the amount of gliclazide is between 12 and 40% of the total weight of said tablet.

Gliclazide matrix tablet according to any one of claims 1 and 13, characterized in that it contains a total amount of gliclazide 30 mg.

Gliclazide matrix tablet according to any one of claims 1 and 13, characterized in that it contains a total amount of gliclazide 60 mg.

Gliclazide matrix tablet according to claim 1, characterized in that the percentages of the polymeric cellulose derivative and glucose syrup provide a constant release profile of the gliclazide at a dissolution pH varying between 6 and 8.

Gliclazide matrix tablet according to claim 1, characterized in that the percentages of the polymeric cellulose derivative and glucose syrup allow the release of 50% of the total amount of the gliclazide over a time interval of 4 to 6 hours.

18. The gliclazide matrix tablet according to claim 1, characterized in that the percentages of the polymeric cellulose derivative and glucose syrup allow the delayed release of the gliclazide, leading to levels in human blood in the range of 400 to 700 ng / ml_, for a maximum of 12 hours after a single oral administration to humans .

A method for preparing a matrix tablet according to claim 1, characterized in that a simultaneous wet granulation and direct compression technique is used, comprising the following steps:

degree Α):

mixing gliclazide, maltodextrin and calcium hydrogen phosphate dihydrate, then wetting this mixture with purified water to obtain a wet mass, which is granulated, dried and then calibrated to obtain a granule with physical properties that allow the rapid press of the matrix to be filled;

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mixing the granules obtained in step A) with hydroxypropylmethylcellulose; grade C):

spreading the mixture obtained in step B) with colloidal silica and magnesium stearate; grade D):

compressing the lubricated mixture obtained in step C) on a rotary tabletting machine to obtain tablets with a hardness measured by diametrical crushing of about 6 to 10 daN.

A gliclazide matrix tablet according to claim 1, characterized in that it is useful in the treatment of diabetes.