HRP920593A2

HRP920593A2 - New drug preparation

Info

Publication number: HRP920593A2
Application number: HR920593A
Authority: HR
Inventors: Lars-Erik Dahlinder; Mats Ove Johansson; John Anders Sandberg; John Albert Sjogren
Original assignee: Haessle Ab
Priority date: 1987-03-04
Filing date: 1992-09-29
Publication date: 1995-02-28
Also published as: HRP920593B1

Description

Područje izuma Field of invention

Predstavljeni izum se odnosi na nove farmaceutske preparate s kontroliranim oslobađanjem farmaceutski aktivnog spoja, na postupak za proizvodnju ovakvih preparata i na postupak za dobivanje kontroliranog oslobađanja farmaceutski aktivnog spoja. The present invention relates to new pharmaceutical preparations with controlled release of a pharmaceutically active compound, to a process for the production of such preparations and to a process for obtaining a controlled release of a pharmaceutically active compound.

Pozadina izuma Background of the invention

U medicinskom liječenju različitih bolesti, npr. kardiovaskularnih, gastrointestinalnih i kemoterapeutske bolesti, predstavlja prednost kada se u krvi postigne konstantna koncentracija lijeka koji se daje. Radi toga se zahtijeva kontrolirano oslobađanje lijeka iz farmaceutskih preparata. In the medical treatment of various diseases, for example, cardiovascular, gastrointestinal and chemotherapeutic diseases, it is an advantage when a constant concentration of the administered drug is achieved in the blood. For this reason, controlled drug release from pharmaceutical preparations is required.

Važno je da preparati s kontroliranim oslobađanjem isporučuju potrebnu količinu lijeka da bi se održavao odgovarajući i jednaki učinak tijekom cjelokupnog intervala terapeutskog doziranja. To obično znači da je lijek potrebno davati konstantnom brzinom da bi se postigle jednake koncentracije davanog lijeka u krvi, što je od posebnog značaja za lijekove koji imaju male terapeutske indekse, i.e. malu razliku između efektivne i toksične koncentracije. Odloženo i konstantno oslobađanje lijeka će također biti važno kod lijekova za lokalnu iritaciju kod kojih postoji potencijalan rizik prouzročavanja gastrointestinalnih poremećaja kada se daju u velikim lokalnim koncentracijama ili kod lijekova koji imaju kratko poluvrijeme eliminacije. U posljednjem slučaju rjeđe davanje i tako bolja prilagodba pacijenta (cf. Hayes R.B. et al. Clin. Pharm. Therap. (1977), 22, str. 125-130) se može postići preparatima s kontroliranim oslobađanjem u usporedbi s konvencionalnim oblicima doziranja. It is important that controlled-release preparations deliver the necessary amount of drug to maintain an adequate and equal effect throughout the entire therapeutic dosing interval. This usually means that the drug needs to be administered at a constant rate to achieve equal concentrations of the administered drug in the blood, which is of particular importance for drugs that have low therapeutic indices, i.e. little difference between effective and toxic concentration. Delayed and sustained drug release will also be important with local irritant drugs that have a potential risk of causing gastrointestinal disturbances when administered at high local concentrations or with drugs that have a short elimination half-life. In the latter case, less frequent administration and thus better patient compliance (cf. Hayes R.B. et al. Clin. Pharm. Therap. (1977), 22, pp. 125-130) can be achieved with controlled-release preparations compared to conventional dosage forms.

Lijek se može davati na kontrolirani način preko bilo kojeg načina davanja ali poželjno preparati moraju imati nešto zajedničkog, npr. da daju kontrolirano i reproduktivno oslobađanje lijeka i zbog reproduktivne apsorpcije, da nemaju toksične ili iritirajuće sastojke i da budu pogodni za lijekove visokih doza. The drug can be administered in a controlled manner via any method of administration, but preferably the preparations must have something in common, for example, that they provide a controlled and reproductive release of the drug and due to reproductive absorption, that they have no toxic or irritating ingredients and that they are suitable for high-dose drugs.

Primjeri sustava za davanje lijeka za oralnu upotrebu s kontroliranim oslobađanjem lijeka su npr. tablete s usporenim oslobađanjem tipa netopive matrice, kao što je DurulesR, i osmotski aktivna tableta, OROSR. OROSR sustav je opisan u U.S. Patentu 4 036 227 i u dodatku British Journal of Clinical Pharmacology (1985), 19, 69S-76S od Theeuwes F et al. Sastoji se od jezgre, tablete koju čini supstancija lijeka kao glavni sastojak koji je okružen polupropusnom polimernom membranom kroz koju su probušeni mali otvori. DE-A-2030501 opisuje preparat tipa matrice koji sadrži amorfni silicij dioksid. Aktivni spoj se oslobađa difuzijom kroz matricu. Gornji primjeri su sustavi jedne jedinice sa svom supstancijom lijeka koncentriranom u jednoj jedinici, dok je ovaj izum na principu više jedinica. Examples of controlled-release oral drug delivery systems are, for example, insoluble matrix-type sustained-release tablets, such as Durules®, and the osmotically active tablet, OROSR. The OROSR system is described in the U.S. Patent 4,036,227 and in a supplement to the British Journal of Clinical Pharmacology (1985), 19, 69S-76S by Theeuwes F et al. It consists of a core, a tablet consisting of the substance of the drug as the main ingredient, which is surrounded by a semi-permeable polymer membrane through which small openings have been pierced. DE-A-2030501 describes a matrix-type preparation containing amorphous silicon dioxide. The active compound is released by diffusion through the matrix. The above examples are single unit systems with all the drug substance concentrated in one unit, while this invention is based on the principle of multiple units.

iz GB-A-154214 poznat je preparat koji sadrži organski noseći materijal za koji je aktivni spoj fizički ili kemijski vezan te staklasti materijal u kontaktu sa spomenutim nosećim materijalom. Staklo sadrži topive metalne ione. Oslobađanje lijeka je vođeno otapanjem metalnih iona iz staklenog materijala zahvaljujući postupku izmjene iona. Očigledno, staklo nije netopivi inertni spoj u preparatu. from GB-A-154214 a preparation is known which contains an organic carrier material to which the active compound is physically or chemically bound and a glassy material in contact with said carrier material. Glass contains soluble metal ions. Drug release is driven by the dissolution of metal ions from the glass material thanks to the ion exchange process. Obviously, glass is not an insoluble inert compound in the preparation.

Nekoliko prednosti sa depo-preparatima, koje obuhvaćaju veći broj malih jedinica, opisano je u literaturi. Tako je, na primjer, moguće dobiti reproduktivnost pražnjenja jedinica iz želuca u tanko crijevo kada su djelići manji od 1-2 mm (cf. Bogentoft C. et al: Utjecaj hrane na apsorpciju acetilsalicilne kiseline iz unutarnje obloženih oblika doziranja. Europ. J. Clin. Pharmacol. (1978), 14, 351-355). Disperzija po velikoj površini u gastrointestinalnom kanalu može dati veće ukupno reproduktivno vrijeme za prolaženje, što je prednost u procesu apsorpcije (cf. Edgar B. et al: Usporedba dva unutarnje obložena preparata acetil-salicilne kiseline praćenjem stalnih nivoa salicilne kiseline i njenih metabolata u krvi i urinu. Biopharmaceutics & Drug Disposition, (1984), 5, 251-260). Uz to, preparat s više jedinica je pogodniji od onog s jednom jedinicom lijeka kada se doza raspoređuje u unutrašnjosti organizma. Rizik od lokalne iritacije i akumulacije nekoliko doza zbog kontrakcije u kanalu za ulaz namirnica je također, smatra se, niži, (cf. McMahan F.G. et al: Gornje gastrointestinalne lezije nakon kalij kloridnih dopuna: Kontrolirana klinička proba The Lancet, Nov 13, 1059 -1061). Several advantages with depot preparations, which include a larger number of small units, have been described in the literature. Thus, for example, it is possible to obtain the reproducibility of emptying units from the stomach into the small intestine when the particles are smaller than 1-2 mm (cf. Bogentoft C. et al: The influence of food on the absorption of acetylsalicylic acid from internally coated dosage forms. Europ. J. Clin. Pharmacol. (1978), 14, 351-355). Dispersion over a large area in the gastrointestinal tract can give a longer total reproductive time to pass, which is an advantage in the absorption process (cf. Edgar B. et al: Comparison of two internally coated preparations of acetyl-salicylic acid by monitoring constant levels of salicylic acid and its metabolites in the blood and urine. Biopharmaceutics & Drug Disposition, (1984), 5, 251-260). In addition, a multi-unit preparation is more convenient than a single-unit drug when the dose is distributed inside the body. The risk of local irritation and accumulation of several doses due to contraction in the alimentary canal is also thought to be lower (cf. McMahan F.G. et al: Upper gastrointestinal lesions after potassium chloride supplementation: A controlled clinical trial The Lancet, Nov 13, 1059 - 1061).

Daljnje prednosti višestrukog jediničnog preparata je da se on može podijeliti u manje porcije od kojih sve imaju iste osobine apsorpcije. To omogućuje postizanje veće fleksibilnosti i selektivnost veličine doze. Further advantages of the multiple unit preparation is that it can be divided into smaller portions, all of which have the same absorption properties. This makes it possible to achieve greater flexibility and selectivity of dose size.

Pregled izuma Overview of the invention

Predstavljeni izum se odnosi na novi tip preparata koji daju kontrolirano oslobađanje jednog ili više farmaceutski aktivnih spojeva. The present invention relates to a new type of preparation that provides a controlled release of one or more pharmaceutical active compounds.

Preparat se sastoji od velikog broja malih netopivih malih dijelova, jezgri, koje su presvučene s farmaceutski aktivnim spojem. Jezgre imaju veličinu od 0,1 do 2 mm, poželjno od 0,1 do 0,5 mm, i sastoje se od netopivog inertnog materijala. Netopivi znači da je materijal netopiv u vodi, fiziološkim fluidima ili tekućinama koje se obično koriste za intravenoznu infuziju. Primjeri netopivih inertnih materijala su silicijdioksid, ili mali dijelovi plastičnih smola. Pogodni tipovi plastičnih materijala su farmaceutski prihvatljive plastike, kao što su polipropilen ili polietilen, poželjno polipropilen. Materijal jezgre treba imati standardnu veličinu i oblik, poželjno sferičan s ujednačenom površinom. Poželjno bi materijal jezgre trebao imati dovoljno veliku gustoću koja bi omogućila postupak za fluidiziranje. Dalje, važno je da materijal jezgre ima visoki stupanj čistoće, tj. da je oslobođen topivih kontaminirajućih spojeva. The preparation consists of a large number of small insoluble small parts, cores, which are coated with a pharmaceutical active compound. The cores have a size of 0.1 to 2 mm, preferably 0.1 to 0.5 mm, and consist of an insoluble inert material. Insoluble means that the material is insoluble in water, physiological fluids, or fluids commonly used for intravenous infusion. Examples of insoluble inert materials are silica, or small parts of plastic resins. Suitable types of plastic materials are pharmaceutically acceptable plastics, such as polypropylene or polyethylene, preferably polypropylene. The core material should have a standard size and shape, preferably spherical with a uniform surface. Preferably, the core material should have a high enough density to allow the fluidization process. Furthermore, it is important that the core material has a high degree of purity, i.e. that it is free from soluble contaminating compounds.

Farmaceutski aktivan spoj se nanosi na materijal jezgre štrcanjem iz otopine. Aktivni spoj pri tome formira kompaktni sloj na netopivoj jezgri. Upotrebljeni farmaceutski aktivni spojevi su spojevi s kardiovaskularnim, gastrointestinalnim ili kemoterapeutskim efektom, posebno adrenerički beta-blokirajući agensi i antibiotici. Primjeri pogodnih farmaceutski aktivnih spojeva koji se mogu nanijeti na materijal jezgre u soli alprenolola, metoprolola, kvinidina, magnezija i ampicilina. Dobiveni mali dijelovi ili slojevi imaju veličinu od 0,2 do 3,0 mm, poželjno od 0,3 do 1,0 mm. Moguće je, međutim, formirati preparate s kontroliranim oslobađanjem prema gornjoj metodi za većinu lijekova za koje se ovakav preparat zahtjeva, pod uvjetom da se mogu otapati u otapalu koji se može isušiti tijekom obrade. The pharmaceutical active compound is applied to the core material by spraying from a solution. The active compound forms a compact layer on the insoluble core. The pharmaceutical active compounds used are compounds with a cardiovascular, gastrointestinal or chemotherapeutic effect, especially adrenergic beta-blocking agents and antibiotics. Examples of suitable pharmaceutically active compounds that can be applied to the core material are alprenolol, metoprolol, quinidine, magnesium and ampicillin salts. The resulting small parts or layers have a size of 0.2 to 3.0 mm, preferably 0.3 to 1.0 mm. It is, however, possible to form controlled release formulations according to the above method for most drugs for which such a formulation is required, provided they can be dissolved in a solvent that can be dried during processing.

Slojevi prema izumu su kompaktni, što znači da je njihova poroznost manja od 15 postotaka. The layers according to the invention are compact, which means that their porosity is less than 15 percent.

Slojevi su presvučeni polimernom membranom koja modificira i kontrolira oslobađanje lijeka. Polimerna membrana može oslobađati lijek prema različitim profilima oslobađanja, npr. u ovisnosti o pH, unutarnje obloge, neovisno o pH, sa ili bez vremenskog zastoja. Najznačajnija primjena je kontrolirano oslobađanje neovisno o pH u opsegu pH od 1 do 8. Primjeri pogodnih polimernih materijala su etil celuloza, hidroksipropilmetil celuloza, hidroksipropil celuloza, hidroksipropilmetil ftalat (npr. HP 55), acetat ftalat celuloze, EudragitR RL, EudragitR RS. Etil celuloza se može upotrijebiti sama ili u kombinaciji s npr. polimerom topivim u vodi kao što je hidroksipropilmetil celuloza da bi se podesila permeabilnost presvučenog sloja. The layers are coated with a polymer membrane that modifies and controls the release of the drug. The polymer membrane can release the drug according to different release profiles, eg pH-dependent, inner coating, pH-independent, with or without a time lag. The most significant application is pH-independent controlled release in the pH range of 1 to 8. Examples of suitable polymeric materials are ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl phthalate (eg HP 55), cellulose acetate phthalate, Eudragit® RL, Eudragit® RS. Ethyl cellulose can be used alone or in combination with, for example, a water-soluble polymer such as hydroxypropylmethyl cellulose to adjust the permeability of the coated layer.

Etil celuloza je dostupna s različitim stupnjevima viskoziteta. U niže danim primjerima, upotrijebljene su kvalitete etil celuloze sa 10, 50 ili 100 cps, ali su također pogodni i drugi tipovi etil celuloze. Ethyl cellulose is available with varying degrees of viscosity. In the examples below, 10, 50, or 100 cps grades of ethyl cellulose were used, but other types of ethyl cellulose are also suitable.

EudragitR je trgovačko ime za veliki broj supstancija za oblaganje filmom na bazi akrilne smole koje proizvodi Rohm Pharma. Npr. Eudragit RL i RS su kopolimeri sintetizirani iz estera akrilne i metakrilne kiseline s niskim sadržajem kvaterernih amonijevih skupina. Molarni odnos ovih amonijevih skupina prema neutralnom ostatku (estera (met)akrilne kiseline je 1 : 20 za EudragitR RL i 1: 40 za EudragitR RS, što rezultira u različitim karakteristikama permeabilnosti. Druge varijante Eudragita, koje se mogu upotrijebiti, su Eudragit L, Eudragit S i Eudragit E. EudragitR is the trade name for a large number of film coating substances based on acrylic resin produced by Rohm Pharma. For example Eudragit RL and RS are copolymers synthesized from acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. The molar ratio of these ammonium groups to the neutral residue ((meth)acrylic acid ester) is 1:20 for EudragitR RL and 1:40 for EudragitR RS, which results in different permeability characteristics. Other variants of Eudragit that can be used are Eudragit L, Eudragit S and Eudragit E.

Polimernoj otopini se mogu dodati pigmenti i/ili plastifikatori radi poboljšanja tehničkih osobina membrane ili modificiranja karakteristika oslobađanja. Primjeri plastifikatora, koji se mogu upotrijebiti, su citratni esteri, acetilirani monogliceridi i glicerintriacetat. Pigments and/or plasticizers can be added to the polymer solution to improve the technical properties of the membrane or to modify the release characteristics. Examples of plasticizers that can be used are citrate esters, acetylated monoglycerides and glycerin triacetate.

Novi preparat ima nekoliko prednosti, npr. mali dijelovi, koji sadrže visoki postotak aktivnog sastojka nisu zaprljani topivim inertnim spojevima, što je slučaj kada su jezgre, npr. laktoze ili šećera, presvučene terapeutski aktivnim spojem. Ovo je naročito važno kod korištenja preparata za parenteralno davanje. The new preparation has several advantages, e.g. small parts, which contain a high percentage of the active ingredient, are not contaminated with soluble inert compounds, which is the case when cores, e.g. lactose or sugar, are coated with a therapeutically active compound. This is especially important when using preparations for parenteral administration.

Korištenjem malih dijelova niske gustoće, npr. silicij dioksida kao materijala za jezgru, moguće je dobiti slojeve (granule) visokih koncentracija aktivnog spoja, što je prednost kod preparata s visokim doziranjem, npr. magnezij klorida. By using small parts of low density, for example silicon dioxide as a material for the core, it is possible to obtain layers (granules) of high concentrations of the active compound, which is an advantage in preparations with high dosage, for example magnesium chloride.

Prednost s novim preparatom je ta da je obično potreban manje polimeran materijal da bi se postiglo odgođeno oslobađanje lijeka kada se na netopivu jezgru nanosi aktivni spoj u usporedbi s preparatima koji imaju jezgru od topivog materijala presvučeni aktivnim spojem (cf. Crtež 1). Preparat prema izumu može se davati na različite načine, npr. oralno ili parenteralno. Primjer intravenoznog davanja je uređaj za intravenozno davanje lijeka opisan u EP-B1-59694. An advantage with the new formulation is that less polymeric material is usually required to achieve sustained drug release when an active compound is applied to an insoluble core compared to formulations having a soluble material core coated with an active compound (cf. Figure 1). The preparation according to the invention can be administered in different ways, for example orally or parenterally. An example of intravenous administration is the device for intravenous drug administration described in EP-B1-59694.

Kada se koriste presvučeni slojevi aktivnog spoja prema ovom izumu za oralnu primjenu, moguće je oblikovati preparatu obliku granula koje su pune i čvrste želatinozne kapsule, pune i čahure ili oblikuju u tablete, a da još uvijek daju željeni profil koncentracije u krvi i trajanje efekta nakon davanja. When using the coated layers of the active compound according to the present invention for oral administration, it is possible to form the preparation in the form of granules that are full and solid gelatin capsules, full and capsules or formed into tablets, while still providing the desired blood concentration profile and duration of effect after giving.

Kada se mali slojevi tabletiraju, oni se miješaju s aditivima koji sadrže npr. mikrokristalnu celulozu, kao što je AvicelR, koji poboljšava osobine tabletiranja i olakšava dezintegraciju tablete da bi se oslobodili individualni slojevi. When the small layers are tableted, they are mixed with additives containing, for example, microcrystalline cellulose, such as AvicelR, which improves the tableting properties and facilitates the disintegration of the tablet to release the individual layers.

Izumom je omogućeno dobivanje smanjene frekvencije doziranja a da se pritom ima gotovo konstantna koncentracija lijeka u krvi tijekom čitavog perioda sve dok se ne da slijedeća doza. Često je s novim preparatom dovoljna samo jedna doza dnevno. The invention makes it possible to obtain a reduced dosing frequency while having an almost constant concentration of the drug in the blood during the entire period until the next dose is given. Often, with a new preparation, only one dose per day is sufficient.

Postupak za proizvodnju preparata s kontroliranim oslobađanjem predstavlja daljnji aspekt izuma. Farmaceutski aktivni spoj se topi u pogodnoj otopini, npr. metilen oksidu, etanolu, izopropil alkoholu ili vodi i štrca preko jezgri od netopivog materijala u tornju za presvlačenje ili poželjno u fluidiziranom sloju i otopina se osuši. Dobiveni slojevi se potom presvlače s gore opisanim polimernim slojem. Polimerna smjesa se topi u otopini kao što je etanol, izopropil alkohol i/ili metilen klorid. [trcanje se može vršiti u tornju za presvlačenje, ali se poželjno vrši u fluidiziranom sloju. Etil celuloza se također može nanijeti iz vodene disperzije (lateksa). A process for the production of a controlled release preparation represents a further aspect of the invention. The pharmaceutical active compound is dissolved in a suitable solution, eg, methylene oxide, ethanol, isopropyl alcohol or water and injected over a core of insoluble material in a coating tower or preferably in a fluidized bed and the solution is dried. The resulting layers are then coated with the polymer layer described above. The polymer mixture is dissolved in a solution such as ethanol, isopropyl alcohol and/or methylene chloride. [Running can be done in a dressing tower, but is preferably done in a fluidized bed. Ethyl cellulose can also be applied from an aqueous dispersion (latex).

Preparat prema izumu je naročito pogodan kada se traži kontrolirano i konstanto oslobađanje terapeutski aktivnog spoja. Postupak za kontrolirano oslobađanje terapeutski aktivnih spojeva je daljnji aspekt izuma. The preparation according to the invention is particularly suitable when a controlled and constant release of a therapeutically active compound is required. A method for the controlled release of therapeutically active compounds is a further aspect of the invention.

Izum je detaljno opisan u slijedećim primjerima: The invention is described in detail in the following examples:

PRIMJERI EXAMPLES

Primjer 1 Example 1

Jezgra Core

Metoprolol fumarat 1440g Metoprolol fumarate 1440g

Metilen klorid 9618g Methylene chloride 9618g

Etanol 95% 3888g Ethanol 95% 3888g

SiO2 (0,15-0,25 mm) 375g SiO2 (0.15-0.25 mm) 375g

Polimerni sloj Polymer layer

Etil cleuloza 10 cps 265,6g Ethyl cellulose 10 cps 265.6g

Hidroksipropilmetil celuloza 58,4g Hydroxypropylmethyl cellulose 58.4g

Acetiltributilcitrat 36,0g Acetyltributylcitrate 36.0g

Metilen klorid 6241g Methylene chloride 6241g

Izopropil alkohol 1544g Isopropyl alcohol 1544g

U granulatoru s fluidiziranim slojem metoprolol futnarat je štrcan preko jezgri silicij dioksida iz 95% etanola. 400 g tako oblikovanih slojeva (frakcija 0,4 - 0,63 mm) je presvučeno polimernom otopinom koja je sadržavala etil celulozu 10 cps, hidroksipropilmetil celulozu i acetiltributilcitrat, štrcanjem otopine spomenutih supstancija u metilen kloridu i izopropil alkoholu. Presvučeni slojevi su potom punjeni u čvrste želatinozne kapsule. In a fluidized bed granulator, metoprolol futnarate was sprayed over silica cores from 95% ethanol. 400 g of layers formed in this way (fraction 0.4 - 0.63 mm) were coated with a polymer solution containing ethyl cellulose 10 cps, hydroxypropylmethyl cellulose and acetyltributylcitrate, by spraying a solution of the mentioned substances in methylene chloride and isopropyl alcohol. The coated layers are then filled into solid gelatin capsules.

Primjeri 2-3 i Referentni 1 Examples 2-3 and Reference 1

[image] [image]

Polimerni slol Polymer layer

400 g granula (frakcija 9m4 - 0,5 mm) kao gore, presvučene su s preparatom koji obuhvaća 400 g of granules (fraction 9m4 - 0.5 mm) as above, are coated with a preparation that includes

[image] [image]

Metoprolol sukcinat je ištrcan preko jezgri silicij dioksida, stakla i natrij klorida, respektivno, iz otopine 95 % etanola i metilen klorida. Oblikovani slojevi su presvučeni s polimernom otopinom koja sadrži etil celulozu 10 cps i acetiltributilcitrat otopljen u metilen kloridu i izopropilalkoholu putem štrcanja. Crtež 1 ilustrira kumulativno oslobađanje metoprolol sukcinata tijekom 20 sati. Kako se može vidjeti sa crteža, kontrolirano i skoro konstantno oslobađanje aktivnog spoja je postignuto kada je aktivni spoj nanesen na silicij dioksidnu ili staklenu jezgru, dok topiva jezgra natrij klorida rezultira u značajno visokoj početnoj brzini oslobađanja, što je također ilustrirano na Crtežu 2 (Referentni 2 niže), gdje je topivi kalij klorid upotrijebljen kao materijal za jezgru. Metoprolol succinate was spread over silica, glass and sodium chloride cores, respectively, from a solution of 95% ethanol and methylene chloride. The molded layers were coated with a polymer solution containing ethyl cellulose 10 cps and acetyl tributyl citrate dissolved in methylene chloride and isopropyl alcohol by spraying. Figure 1 illustrates the cumulative release of metoprolol succinate over 20 hours. As can be seen from the figure, a controlled and almost constant release of the active compound is achieved when the active compound is coated on a silica or glass core, while the soluble sodium chloride core results in a significantly high initial release rate, which is also illustrated in Figure 2 (Ref. 2 below), where soluble potassium chloride was used as the core material.

Referentni 2 Reference 2

Jezgra Core

[image] 400 g granula prema Referentnom primjeru 2 je presvučeno s preparatom koji obuhvaća [image] 400 g of granules according to Reference Example 2 are coated with the preparation comprising

Polimerni sloj Polymer layer

[image] [image]

Granule su oblikovane kao što je opisano u prethodnim primjerima. The granules were shaped as described in the previous examples.

Primjeri 4-6 Examples 4-6

Jezgra Primjer Core Example

[image] 400 g granula prema primjerima 4 - 6 presvučeno je preparatom koji obuhvaća [image] 400 g of granules according to examples 4 - 6 are coated with a preparation that includes

Polimerni sloj Polymer layer

granulati prema primjerima granulates according to the examples

[image] [image]

Preparati su formulirani kako je gore opisano. U priloženoj Tablici 1 dano je oslobađanje metoprolol sukcinata tijekom 20 sati. Svi preparati su dali kontrolirano oslobađanje lijeka tijekom dugačkog perioda vremena. The preparations were formulated as described above. The attached Table 1 shows the release of metoprolol succinate over 20 hours. All preparations provided controlled drug release over a long period of time.

Primjer 7 Example 7

Jezgra Core

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Polimerni sloj Polymer layer

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Magnezij klorid (MgCl2) je štrcan preko jezgri silicij dioksida iz 99,5 % otopine etanola 400 g slojeva, koji su tako oblikovani, presvučeno je etil celulozom 50 cps iz otopine metilen klorida i izopropil alkohola da bi se dobile granule Magnesium chloride (MgCl2) was sprayed over silica cores from a 99.5% ethanol solution 400 g layers, which were thus formed, were coated with ethyl cellulose 50 cps from a solution of methylene chloride and isopropyl alcohol to obtain granules

koje sadrže 347 mg/g magnezij klorida (MgCl2). Oslobađanje lijeka in vitro je bilo 38 % nakon 1 h, 58 % nakon 2 h i 82 % nakon 6 sati. which contain 347 mg/g of magnesium chloride (MgCl2). Drug release in vitro was 38% after 1 h, 58% after 2 h and 82% after 6 h.

Primjer 8 Example 8

Jezgra Core

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Polimerni sloj Polymer layer

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Ampicilin - Na je štrcan preko jezgri od stakla i otopine etanol/voda. 500 g ampicilin-Na slojeva je nakon toga presvučeno s polimernom otopinom etil celuloze 100 cps u metilen kloridlizopropil alkoholu. Poslije 40 minuta in vitro otapanja 50% sadržaja lijeka je bilo oslobođeno iz slojeva. Ampicillin - Na was sprayed over glass cores and an ethanol/water solution. 500 g of ampicillin-Na layers were then coated with a polymer solution of ethyl cellulose 100 cps in methylene chloride lysopropyl alcohol. After 40 minutes of in vitro dissolution, 50% of the drug content was released from the layers.

Primjer 9 Example 9

Jezgra Core

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Polimerni sloj Polymer layer

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Aditivi za tablete Additives for tablets

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Prevlaka za tablete (12.500 tableta) Cover for tablets (12,500 tablets)

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Metoprolol sukcinat je štrcan preko jezgri silicij dioksida prema postupku opisanom u prethodnim primjerima. 400 g tako dobivenih slojeva (frakcije 0,4 - 0,63 mm) je presvučeno gore opisanim polimernom otopinom. Presvučeni slojevi metoprolol sukcinata su pomiješani s aditivima u jednakim količinama i nakon dodavanja Mg-stearata 0,1 %, suha smjesa je komprimirana u tablete. Konačno, tablete su presvučene u tornju za presvlačenje s gore opisanom polimernom otopinom. Metoprolol succinate was sprayed over the silica cores according to the procedure described in the previous examples. 400 g of the thus obtained layers (fractions 0.4 - 0.63 mm) were coated with the polymer solution described above. The coated layers of metoprolol succinate were mixed with additives in equal amounts and after adding Mg-stearate 0.1%, the dry mixture was compressed into tablets. Finally, the tablets are coated in a coating tower with the polymer solution described above.

Vrlo mali dijelovi, 0,15 - 0,25 mm, gustog SiO2 upotrijebljenog kao materijal za jezgru, omogućava visoki sadržaj lijeka u malim slojevima koji su oblikovani (0,4 - 0,63 mm) i tako je smanjena veličina finalnog proizvoda. The very small parts, 0.15 - 0.25 mm, of dense SiO2 used as the core material, enable a high drug content in the small layers that are formed (0.4 - 0.63 mm) and thus the size of the final product is reduced.

Tablica 1 zbrojeno prikazuje podatke o oslobađanju lijeka prema primjerima 1 - 6 i 9 i referentnim primjerima 1 i 2. Table 1 summarizes the drug release data according to examples 1 - 6 and 9 and reference examples 1 and 2.

Biofarmaceutske studije Biopharmaceutical studies

Oralna primjena ovog izuma (Primjer 9) je ilustrirana na crtežu 3. Više jedinični sustav je primijenjen na metoprolol sukcinat radi pronalaženja preparata za doziranje jednom dnevno s profilom jednake koncentracije u krvi tijekom 24 sata. An oral application of the present invention (Example 9) is illustrated in Figure 3. A multi-unit system was applied to metoprolol succinate to find a once-daily dosage formulation with an equal 24-hour blood concentration profile.

Jedna doza od 190 mg metoprolol sukcinata (ekvivalentno s 200 mg metoprolol tartarata) u preparatu s kontroliranim oslobađanjem prema ovom izumu je dana desetorici zdravih muških primatelja. Koncentracije u krvi metoprolola su uspoređivane s koncentracijama u plazmi poslije jednostruke doze tablete s usporenim oslobađanjem (DurulesR) bazirane na principu netopive matrice koja sadrži 200g metoprolol tartarata. Kao što se može vidjeti, preparat prema izumu dao je skoro konstantnu koncentraciju metoprolola u krvi, dok su tablete s matricama dale neželjeni visoki pik koncentracije u krvi tijekom prvih sati nakon davanja. A single dose of 190 mg of metoprolol succinate (equivalent to 200 mg of metoprolol tartrate) in the controlled release formulation of this invention was administered to ten healthy male recipients. Metoprolol blood concentrations were compared with plasma concentrations after a single dose of a sustained-release tablet (DurulesR) based on the principle of an insoluble matrix containing 200g of metoprolol tartrate. As can be seen, the preparation according to the invention gave an almost constant concentration of metoprolol in the blood, while the matrix tablets gave an undesired high peak of the concentration in the blood during the first hours after administration.

Smatra se da je najbolji način izvođenja izuma za sada primjer 9. Example 9 is considered to be the best mode of carrying out the invention for the time being.

Tablica 1 Kumulativno in vitro oslobađanje metoprolola u fosfatnom puferu Table 1 Cumulative in vitro release of metoprolol in phosphate buffer

na pH 6.8. Metoda: USP aparat No. II, rotacija na 100 opm at pH 6.8. Method: USP apparatus No. II, rotation at 100 rpm

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Claims

1. Controlled release layers with a membrane that controls drug release, characterized in that they contain one or more pharmaceutically active compounds applied to a compact core of insoluble material, wherein the active compound forms a compact layer on the insoluble core, and this compact layer is further coated polymer membrane for controlled release.

2. Layers according to claim 1, characterized in that the size of the small parts in the core material is from 0.1 to 2 mm, and the size of the core coated with a pharmaceutical active compound is from 0.2 to 3.0 mm.

3. Layers according to claim 2, characterized in that the core material has a size of 0.1 to 0.5 mm, and said core material coated with a pharmaceutical active compound has a size of 0.3 to 1.0 mm.

4. Layers according to claim 1, characterized in that the core material is silicon dioxide.

5. Layers according to claim 1, characterized in that the core material is small parts of glass.

6. Layers according to claim 1, characterized in that they contain a pharmaceutically active compound for which immediate drug release is not desired.

7. Layers according to claim 1, characterized in that the pharmaceutical active compound should be administered orally or parenterally.

8. Layers according to claim 1, characterized in that the pharmaceutical active compound is used in the cardiovascular, gastrointestinal or chemotherapeutic field.

9. Layers according to claim 1, characterized in that the pharmaceutically active compound is a salt of an adrenergic beta-blocking agent.

10. Layers according to claim 1, characterized in that the pharmaceutical active compound is an antibiotic.

11. Method for obtaining layers for the production of products with controlled release, indicated by the fact that the pharmaceutical active compound dissolved in the solution is applied to a core of insoluble material with a size of 0.1 to 2 mm, the solvent is dried and the layers are coated with a compact layer of the active compound and with a size of 0.2 to 3.0 mm are shaped in this way, after which the obtained layers are further coated with a polymer membrane for controlled release.

12. A method for obtaining a controlled release of a therapeutically active compound, characterized in that the preparation according to claim 1 is given to a recipient in which a controlled release of the said therapeutically active compound is required.