SI8710407A - Process for obtaining solid pharmaceutical preparation with extended release of active compound - Google Patents

Abstract

Pripravek s podaljšanim sproščanjem aktivne spojine z zelo nizko topnostjo, ki vsebuje aktivno spojino raztopljeno ali dispergirano v pol-trdnem ali tekočem neionskem sredstvu za raztapljanje, pri čemer je masna količina sredstva za raztapljanje vsaj enaka masni količini aktivne spojine, kakor tudi postopek za njegovo pridobivanje.Prolonged-release preparation active compounds with very low solubility containing active the compound dissolved or dispersed in semi-solid or liquid non-ionic dissolving agent, at wherein the mass amount of the dissolving agent is at least equal to the mass of the active compound as well the process for obtaining it.

Description

AKTIEBOLAGET HASSLEACTIEBOLAGET HASSLE

Postopek za pridobivanje trdnega pripravka s podaljšanim sproščanjem aktivne spojineA process for the preparation of a solid sustained release preparation of the active compound

Področje tehnikeThe field of technology

Izum je s področja farmacevtskih tehnik, zlasti pa se nanaša na postopek za pridobivanje novega trdnega pripravka s podaljšanim sproščanjem aktivne spojine z zelo nizko topnostjo, zlasti substituiranih dihidropiridinov.The invention is in the field of pharmaceutical techniques, and in particular relates to a process for the preparation of a new sustained-release solid preparation of a very low solubility active compound, in particular substituted dihydropyridines.

Tehnični problemA technical problem

Z izumom rešujemo problem pridobivanja trdnega pripravka z zelo podaljšano biološko uporabnostjo in podaljšanim sproščanjem aktivne spojine, ki ima običajno zelo nizko topnost.The invention solves the problem of obtaining a solid preparation with very prolonged bioavailability and prolonged release of the active compound, which usually has very low solubility.

Zdravila z zelo slabo topnostjo v vodi predstavljajo pri formuliranju probleme zaradi svojega počasnega raztapljanja. Njihova učinkovitost je lahko zelo omejena s širokim obsegom variacij individualnih absorpcij, ki se lahko pojavijo. Primeri zdravil z zelo nizko topnostjo so nekatere substituirane dihidropiridinske spojine, kot sta nifedipin in felodipin. Omenjene dihidropiridine običajno klasificiramo kot antagoniste kalcija, ki se jih široko uporablja za zdravljenje kardiovaskularnih obolenj, kot sta ishemija srca in arterijska hipertenzija. Eden izmed omenjenih dihidropiridinov, felodipin, ima topnost le 0,5 mg/1 v vodi. Drugi primeri zdravil z zelo nizko topnostjo so griseofulvin, digoksin, oksazepam, fenitoin in ciklosporin.Drugs with very poor water solubility present problems with formulation due to their slow dissolution. Their effectiveness may be very limited by the wide range of variations in individual absorptions that may occur. Examples of very low solubility drugs are some substituted dihydropyridine compounds such as nifedipine and felodipine. These dihydropyridines are typically classified as calcium antagonists, which are widely used to treat cardiovascular diseases such as cardiac ischemia and arterial hypertension. One of the dihydropyridines mentioned, felodipine, has a solubility of only 0.5 mg / l in water. Other examples of very low solubility drugs are griseofulvin, digoxin, oxazepam, phenytoin and ciclosporin.

Stanje tehnikeThe state of the art

V predhodni literaturi je opisano nekaj načinov za povečanje absorpcije zdravila. En način je opisan v DE-A-3024858, kjer težko topen substituirani dihidropiridin nikar2 dipin uporabijo v njegovi amorfni obliki, da bi dosegli povečano absorpcijo aktivne spojine v črevesju. Drugi način je opisan v EP-A-47899, kjer zelo majhne kristale praktično netopnega dihidropiridina nifedipina uporabijo, da bi podaljšali biološko uporabnost. Te in druge metode so prav tako opisane v Techniques of solubilization of drugs, Ed.S.H.Yalkowsky, v Drugs and the pharmaceutical Sciences, Vol.12. Posebnega pomena za ta izum je, da lahko uporabimo površinska sredstva za raztapljanje, da bi povečali biološko uporabnost zdravila z zelo slabo topnostjo. Navedeno je, da lahko izboljšanje lastnosti absorpcije pripišemo naslednjim trem postopkom: (1) povečanemu omočenju, (2) povečani permeabilnosti membran in (3) solubilizaciji. Navedena publikacija opisuje nekaj primerov in služi kot dober prikaz stanja znanosti, ki se nanaša na topnost zdravil, zlasti da bi se povečala biološka uporabnost zdravil z zelo slabo topnostjo.Previous literature outlines several ways to increase drug absorption. One method is described in DE-A-3024858, where the hardly soluble substituted dihydropyridine nikar2 dipin is used in its amorphous form to achieve increased absorption of the active compound in the gut. The second method is described in EP-A-47899, where very small crystals of practically insoluble dihydropyridine nifedipine are used to prolong bioavailability. These and other methods are also described in Drug Solubilization Techniques, Ed.S.H.Yalkowsky, in Drugs and the Pharmaceutical Sciences, Vol.12. Of particular importance to the present invention is that dissolving surfactants can be used to increase the bioavailability of the drug with very poor solubility. It is stated that the improvement in absorption properties can be attributed to the following three processes: (1) increased wetting, (2) increased membrane permeability, and (3) solubilization. The cited publication describes some examples and serves as a good illustration of the state of the art relating to drug solubility, particularly to increase the bioavailability of drugs with very poor solubility.

Iz DE-A-3400106 so znani pripravki z nadzorovanim sproščanjem, ki vsebujejo en ali več naravnih, delno sintetičnih ali sintetičnih polimerov, eno ali več lipofilnih in/ali hidrofilnih topil ali gostil, skupaj z eno ali več farmacevtskimi aktivnimi spojinami. V primerih je opisana uporaba sredstva za raztapljanje v masni količini glede na aktivno spojino, kije znatno nižja od 1:1.DE-A-3400106 discloses controlled release preparations containing one or more natural, partially synthetic or synthetic polymers, one or more lipophilic and / or hydrophilic solvents or diluents, together with one or more pharmaceutically active compounds. In the examples, the use of a solubilizer in a mass by weight relative to the active compound which is substantially lower than 1: 1 is described.

V medicinskem zdravljenju različnih obolenj, npr. na kardiovaskularnem, gastrointestinalnem in kemoterapevtskem področju, je koristno, da zagotovimo v krvi konstantno koncentracijo zdravila, ki ga dajemo. Zaradi tega je zahtevano podaljšano sproščanje zdravila iz farmacevtskega pripravka.In the medical treatment of various diseases, e.g. in the cardiovascular, gastrointestinal and chemotherapeutic fields, it is advantageous to ensure that the blood is given a constant concentration of the drug being administered. Therefore, prolonged release of the drug from the pharmaceutical preparation is required.

Pomembno je, da pripravek s podaljšanim sproščanjem oddaja potrebno količino zdravila, tako da se vzdržuje ustrezen in enak učinek tekom celotnega intervala terapevtskega doziranja. To običajno pomeni, da se mora zdravilo dostavljati s konstantno hitrostjo, da bi v krvi dobili enake koncentracije zdravila, ki ga dajemo. To je še zlasti pomembno za zdravila, ki imajo majhen terapevtski indeks, oz. majhno razliko med efektivno in toksično koncentracijo. Zadržano in konstantno sproščanje zdravila bo prav tako pomembno za zdravila z lokalno iritacijo, ki imajo potencialno nevarnost za povzročitev gastrointestinalnih motenj, kadar jih dajemo v velikih lokalnih koncentracijah ali za zdravila, ki imajo kratek razpolovni čas eliminacije. V zadnjem primeru lahko dobimo s pripravki s podaljšanim sproščanjem redkejše dajanje in tako boljšo prilagoditev pacienta v primerjavi z običajnimi oblikami doziranja (ef. Hayes R.B. et al. Ciin. Pharm. Ther. (1977), 22, str. 125-130).It is important that the sustained release formulate the required amount of drug in order to maintain an adequate and equal effect throughout the therapeutic dosing interval. This usually means that the drug must be delivered at a constant rate in order to obtain the same concentrations of the drug being administered in the blood. This is especially important for medicines that have a low therapeutic index, or. little difference between effective and toxic concentration. The sustained and constant release of the drug will also be important for topical irritants that have the potential to cause gastrointestinal disorders when administered at high local concentrations or for drugs with short elimination half-lives. In the latter case, sustained release preparations can be used to give less frequent administration and thus a better adjustment of the patient compared to conventional dosage forms (ef. Hayes R.B. et al. Ciin. Pharm. Ther. (1977), 22, pp. 125-130).

Zdravilno obliko s podaljšanim sproščanjem običajno dajemo po oralni poti. Za pripravke je želeno, da dajo podaljšano in reproduktivno sproščanje zdravila in da zaradi reproduktivne absorpcije nimajo toksičnih ali iritirajočih konstituent in da so primerni tudi za zdravila v visokih dozah. Primerno dosežemo podaljšano sproščanje z nadzorovanim raztapljanjem in/ali difuzijo zdravila iz dozirne oblike. Za te namene uporabljamo nekaj materialov, npr. voske, maščobne materiale, polimere, naravne, sintetične in polsintetične gumije. Med gumiji tvori hidroksipropil metilceluloza (HPMC) pomemben razred zaradi svojih lastnosti pH-neodvisnosti, kakor tudi zaradi svojega polsintetičnega izvora. Prikaz celuloznih etrov in hidrofilnih matric za oralne dozirne oblike z nadzorovanim sproščanjem je podal Alderman D.A. Int. J. Pharm. Tech. & Prod. Mfr (1984), 5(3) 1-9. Kemijska obdelava HPMC, da bi dobili želeno konstitucijo in uporaba teh kvalitet je opisana v US 3 087 790, US 4 226 849, US 4 357 469 in US 4 369 172. SE-A-8008646 opisuje kombinacijo HPMC in hidroksipropilceluloze, ki se uporablja za nadzorovanje hitrosti sproščanja farmacevtsko aktivne spojine.The sustained release dosage form is usually administered by the oral route. The preparations are desirable to give a prolonged and reproductive release of the drug and to have no toxic or irritant constituents due to reproductive absorption and are also suitable for high-dose drugs. Prolonged release by controlled dissolution and / or diffusion of the drug from the dosage form is suitably achieved. We use some materials for these purposes, e.g. waxes, fatty materials, polymers, natural, synthetic and semi-synthetic rubbers. Among the gums, hydroxypropyl methylcellulose (HPMC) is an important class because of its pH-independent properties as well as its semi-synthetic origin. The presentation of cellulose ethers and hydrophilic matrices for controlled release oral dosage forms was provided by Alderman D.A. Int. J. Pharm. Tech. & Prod. Mfr (1984), 5 (3) 1-9. The chemical treatment of HPMC to obtain the desired constitution and the use of these qualities is described in US 3 087 790, US 4 226 849, US 4 357 469 and US 4 369 172. SE-A-8008646 describes the combination of HPMC and hydroxypropyl cellulose used for controlling the release rate of a pharmaceutically active compound.

Kadar uporabljamo hidrofilno matrico, tvori topni polimer želatinsko plast okoli tablete po izpostavitvi tablete gastrointestinalnim tekočinam ali slini. Sproščanje zdravila je omejeno s hitrostjo penetracije vode v nastali gel in difuzije zdravila skozi nastali gel (Bamba et al. Int.J.Pharm. (1979), 2, 307). Erozija strukture gela je prav tako pomemben mehanizem sproščanja zdravila iz sistema. Da bi se tableta zaščitila pred hitrim raztapljanjem, se morajo uporabljeni polimeri hitro hidratizirati. (Alderman, 1984).When using a hydrophilic matrix, the soluble polymer forms a gelatin layer around the tablet after exposure of the tablet to gastrointestinal fluids or saliva. The release of the drug is limited by the rate of water penetration into the resulting gel and the diffusion of the drug through the resulting gel (Bamba et al. Int.J.Pharm. (1979), 2, 307). Erosion of the gel structure is also an important mechanism of drug release from the system. In order to protect the tablet from rapid dissolution, the polymers used must be rapidly hydrated. (Alderman, 1984).

Hitrost absorpcije zdravila s slabo topnostjo iz intenstinalnega trakta v obtok je ozko vezana na hitrost raztapljanja. Glede na to, da ima majhna hitrost raztapljanja običajno za rezultat nizko biološko uporabnost, je težko zmanjšati hitrost absorpcije, t.j. podaljšati trajanje brez istočasnega zniževanja biološke uporabnosti.The rate of absorption of the drug with poor solubility from the intestinal tract into circulation is closely related to the rate of dissolution. Given that low dissolution rate usually results in low bioavailability, it is difficult to reduce the rate of absorption, i.e. extend the duration without simultaneously reducing bioavailability.

Opis rešitve tehničnega problema z izvedbenimi primeriDescription of solution to a technical problem with implementation examples

Predmet tega izuma je zagotoviti pripravek zdravila z zelo nizko topnostjo, ki kaže podaljšano in skoraj konstantno hitrost absorpcije zdravila tekom dolgega časovnega obdobja, ob istočasnem vzdrževanju visoke stopnje biološke uporabnosti. Ta cilj smo dosegli z uporabo sredstva za raztapljanje, ki ga zmešamo z zdravilom z zelo nizko topnostjo. Primerna sredstva za raztapljanje v smislu izuma so navedena spodaj. Aktivno spojino prednostno raztopimo ali dispergiramo v sredstvu za raztapljanje. Zmes aktivne spojine (zdravila) in sredstva za raztapljanje lahko razredčimo z vodo ali intestinalnim sokom brez znatnega obarjanja raztopljenega zdravila. V raztopini se zdravilo nahaja vključeno v strukturo micela, ki se tvori s pomočjo sredstva za raztapljanje. Z drugimi sredstvi za raztapljanje ali so-topili lahko razredčevanje privede do obarjanja zdravila. Zmes zdravila in sredstva za raztapljanje vnesemo v farmacevtsko formulacijo, kar omogoča podaljšano sproščanje.It is an object of the present invention to provide a very low solubility drug preparation which exhibits a prolonged and almost constant rate of absorption of the drug over a long period of time while maintaining a high level of bioavailability. This was achieved by using a dissolving agent mixed with a very low solubility drug. Suitable solubilizers of the invention are listed below. The active compound is preferably dissolved or dispersed in a solvent. The mixture of active compound (drug) and solubilizer can be diluted with water or intestinal juice without significant precipitation of the dissolved drug. In the solution, the drug is contained included in the structure of the micelles formed by the dissolving agent. With other solvents or co-solvents, dilution may cause the product to precipitate. The mixture of the drug and the dissolving agent is introduced into the pharmaceutical formulation, allowing prolonged release.

Zdravila, primerna za pripravke s podaljšanim sproščanjem v smislu izuma, so spojine, ki se odlikujejo z zelo nizko topnostjo oz. pod 0,1 mas.% v vodi. Poleg tega se jih da solubilizirati v sredstvih za raztapljanje ali v kombinaciji sredstev za raztapljanje in vode. Primeri zdravil, primernih v smislu izuma, so nekateri substituirani dihidropiridini, kot je nifedipin in felodipin. Felodipin je etil metil ester 4-(2,3dihidrofenil)-l,4-dihirdo-2,6-dimetil-3,5-piridindikarboksilne kisline. Nifedipin je dimetil ester l,4-dihidro-2,6-dimetil-4-(2-nitrofenil)-3,5-piridindikarboksilne kisline. Oba, felodipin in nifedipin sta praktično netopni spojini in zaradi tega sta zelo primerna za solubilizacijo. Drugi primeri zdravil z zelo nizko topnostjo so griseofulvin, digoksin, oksazepam, fenitoin in ciklosporin.The medicaments suitable for the sustained release formulations of the invention are compounds which are characterized by very low solubility and / or solubility. less than 0.1% by weight in water. In addition, they can be solubilized in dissolving agents or in a combination of dissolving agents and water. Examples of the drugs of the invention are some substituted dihydropyridines, such as nifedipine and felodipine. Felodipine is 4- (2,3-dihydrophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridindicarboxylic acid ethyl methyl ester. Nifedipine is 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinedicarboxylic acid dimethyl ester. Both felodipine and nifedipine are practically insoluble compounds and are therefore well suited for solubilization. Other examples of very low solubility drugs are griseofulvin, digoxin, oxazepam, phenytoin and ciclosporin.

Sredstva za raztapljanje, primerna za pripravke v smislu izuma, so pol-trdna ali tekoča ne-ionska površinsko aktivna sredstva, zlasti tista, ki vsebujejo polietilenglikole kot estre ali etre. Običajno jih izberemo med polietoksiliranimi maščobnimi kislinami, hidroksiliranimi maščobnimi kislinami in maščobnimi alkoholi. Zlasti primerno je, da sredstvo za raztapljanje izberemo v skupini, v kateri so polietoksilirano ricinovo olje, polietoksilirano hidrogenirano ricinovo olje, polietoksilirane maščobne kisline iz ricinovega olja ali polietoksilirane maščobne kisline iz hidrogeniranega ricinovega olja. Tržno dostopna sredstva za raztapljanje, ki jih lahko uporabimo, so znana pod trgovskimi imeni Cremophor, Myrj, Polyoxyl 40 stearat, Emerest 2675, Lipal 395 in HCO 50. Posebno prednostno sredstvo za raztapljanje je Cremophor^ RH 40 (BASF).Solvents suitable for the compositions of the invention are semi-solid or liquid non-ionic surfactants, in particular those containing polyethylene glycols as esters or ethers. They are usually selected from polyethoxylated fatty acids, hydroxylated fatty acids and fatty alcohols. It is particularly appropriate to select the dissolving agent in the group consisting of polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acids of castor oil, or polyethoxylated fatty acids of hydrogenated castor oil. The commercially available dissolving agents that can be used are known by the trade names Cremophor, Myrj, Polyoxyl 40 stearate, Emerest 2675, Lipal 395 and HCO 50. A particularly preferred dissolving agent is Cremophor ^ RH 40 (BASF).

Aktivno spojino, pomešano s sredstvom za raztapljanje, vnesemo v različne vrste znanih sistemov za nadzorovano sproščanje, npr. v sistem hidrofilnega gela, v sloje prevlečene z membrano za nadzorovanje hitrosti, ki so lahko s prevleko za zadrževano difuzijo ali dezintegrirajočo prevleko, ali v tablete z inertno porozno matrico. V smislu izuma je raztopljeno zdravilo prednostno v kombinaciji s sistemom hidrofilnega gela, oz. hidrofilno matrico, npr. HPMC. Ta oblika mehanizma nadzorovanega sproščanja je primeren način, da nadzorujemo sproščanje micela zdravila in sredstva za raztapljanje. Tehnične lastnosti so dobre, prav tako pa je dobro tudi obnašanje in vivo. Med različnimi testiranimi hidrofilnimi materiali je najboljši material za tvorbo gela HPMC, hidroksipropil metilceluloza. Drugi primeri primernih spojin, ki izzovejo sproščanje aktivne spojine iz sistema hidrofilnega gela, so guar gumi, ksantan gumi, karboksipolimetilen, različni celulozni materiali, npr. natrijeva karboksimetilceluloza in hidroksipropilceluloza, laktoza in aluminijev silikat.The active compound mixed with the dissolving agent is introduced into various types of known controlled release systems, e.g. into a hydrophilic gel system, into layers coated with a rate control membrane, which may be coated with a sustained diffusion or disintegrating coating, or into tablets with an inert porous matrix. According to the invention, the dissolved drug is preferably in combination with a hydrophilic gel system, or. hydrophilic matrix, e.g. HPMC. This form of controlled release mechanism is a convenient way to control drug release and dissolution agents. The technical characteristics are good and the behavior in vivo is also good. Among the various hydrophilic materials tested, the best HPMC gel forming material is hydroxypropyl methylcellulose. Other examples of suitable compounds that cause the release of the active compound from the hydrophilic gel system are guar gum, xanthan gum, carboxypolymethylene, various cellulosic materials, e.g. sodium carboxymethylcellulose and hydroxypropylcellulose, lactose and aluminum silicate.

Pripravek v smislu izuma vsebuje 20-80 mas.%, prednostno 30-50 mas.% sistema hidrofilnega gela.The composition of the invention comprises 20-80% by weight, preferably 30-50% by weight of the hydrophilic gel system.

Največji del sistema hidrofilnega gela ima viskoznost pod 100 mPa.s. Zlasti je prednostno, da uporabimo HPMC z vsebnostjo hidroksipropoksila od 4-12 mas.%, zlasti okoli 8,5 mas.% in viskoznostjo nižjo od 100 mPa.s, npr. 6,15 in/ali 50 mPa.s. Viskoznost merimo s standardizirano metodo opisano npr. v United States Pharmacopeis XXI, 1985, str. 672.The largest part of the hydrophilic gel system has a viscosity below 100 mPa.s. It is particularly advantageous to use HPMC having a hydroxypropoxyl content of 4-12% by weight, in particular about 8.5% by weight and a viscosity of less than 100 mPa.s, e.g. 6.15 and / or 50 mPa.s. Viscosity is measured by a standardized method described e.g. in United States Pharmacopeis XXI, 1985, p. 672.

Končni pripravek je npr. v obliki želirane tablete. S pozornim izborom polnil in vezivnih sredstev, kot tudi materialov za tvorbo gela, lahko pripravek proizvajamo v tržno sprejemljivi obliki, npr. kot tableto ali trdo želatinsko kapsulo, ki obsega granulat, ki tvori gel, ki kaže nepričakovano dobro absorpcijo aktivne spojine, kot tudi podaljšano trajanje delovanja. V pripravku v smislu izuma razmerja med aktivno spojino in sredstvom za raztapljanje variirajo v obsegu od 1:1 do 1:10, prednostno v obsegu od 1:2 do 1:6.The final preparation is e.g. in the form of a gel tablet. By carefully selecting fillers and binders as well as gel forming materials, the preparation can be manufactured in a commercially acceptable form, e.g. as a tablet or hard gelatin capsule comprising a gel-forming granulate showing unexpected good absorption of the active compound as well as a prolonged duration of action. In the composition of the invention, the ratios of the active compound to the dissolving agent vary in the range of 1: 1 to 1:10, preferably in the range of 1: 2 to 1: 6.

Prav tako lahko v smislu izuma uporabimo tudi druge tipe pripravkov z nadzorovanim sproščanjem, npr. tablete z inertno porozno matrico; kapsule, ki obsegajo granule s prevleko za zadržano difuzijo ali dezintegrirajočo prevleko.Other controlled release formulations can also be used in the invention, e.g. tablets with an inert porous matrix; capsules comprising granules with sustained diffusion or disintegrating coating.

Tablete z inertno porozno matrico dobimo z mešanjem zdravila in sredstva za raztapljanje z v vodi netopnimi polimeri ali voski in s polnili in vezivi. Kot primerne polimere za zadrževanje difuzije lahko uporabimo polivinilacetat, polivinilklorid, etilcelulozo, parafin in acetat ftalat celuloze. Polnila in veziva so trdna, praškasti nosilci, kot je laktoza, saharoza, sorbitol, manitol, škrob, amilopektin, derivati celuloze, želatina in drugi primerni nosilci. Zmes omočimo s topilom, npr. vodo ali etanolom ali raztopino, ki sestoji npr. iz vode in polimera, npr. polivinil pirolidona. Prav tako lahko dodamo tudi maziva, npr. magnezijev stearat, kalcijev stearat, natrijev stearil fumarat in polietilenglikolni vosek. Zmes nato oblikujemo v tablete.Tablets with an inert porous matrix are obtained by mixing the drug and the dissolving agent with water-insoluble polymers or waxes and with fillers and binders. Polyvinyl acetate, polyvinyl chloride, ethyl cellulose, paraffin and acetate phthalate cellulose may be used as suitable polymers for diffusion retention. Fillers and binders are solid, powdered carriers such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin and other suitable carriers. The mixture is wetted with a solvent, e.g. water or ethanol or a solution consisting e.g. from water and polymer, e.g. polyvinyl pyrrolidone. Lubricants can also be added, e.g. magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. The mixture is then formulated into tablets.

Kapsule, ki obsegajo granule z lastnostmi podaljšanega sproščanja, dobimo z izdelavo jedra materiala, ki sestoji iz zdravila in sredstva za raztapljanje skupaj s polnilom. Površino jeder nato prevlečemo z v vodi netopnimi polimeri ali voski za zadržano difuzijo. Granule nato polnimo v trdne želatinske kapsule. Material jeder lahko npr. pripravimo z mešanjem zdravila in sredstva za raztapljanje s skrbno izbranimi polnili, kot so laktoza, sorbitol, škrob, derivati celuloze in druga primerna polnila. Zmes omočimo s topilom, npr. vodo ali etanolom ali raztopino, ki sestoji npr. iz vode in polimera, npr. polivinilpirolidona. Maso oblikujemo v granule, npr. z ekstrudiranjem in sferonizacijo. Površine oblikovanih jeder prevlečemo z raztopino, ki sestoji iz topila npr. metilen klorida in/ali izopropilalkohola in polimerov, ki so netopni v vodi npr. etil celuloze. Granule polnimo v trde želatinske kapsule.Capsules comprising granules with prolonged-release properties are obtained by producing a core of material consisting of a drug and a dissolving agent together with a filler. The surface of the cores is then coated with water-insoluble polymers or waxes for retained diffusion. The granules are then filled into solid gelatin capsules. The core material may e.g. are prepared by mixing the drug and the dissolving agent with carefully selected fillers such as lactose, sorbitol, starch, cellulose derivatives and other suitable fillers. The mixture is wetted with a solvent, e.g. water or ethanol or a solution consisting e.g. from water and polymer, e.g. of polyvinylpyrrolidone. The mass is formed into granules, e.g. by extrusion and spheronization. The surfaces of the formed cores are coated with a solution consisting of a solvent, e.g. methylene chloride and / or isopropyl alcohol and water-insoluble polymers e.g. ethyl cellulose. The granules are filled into hard gelatin capsules.

PRIMERIEXAMPLES

Izum je ponazorjen z naslednjimi primeri:The invention is illustrated by the following examples:

PRIMER 1EXAMPLE 1

S felodipin 10S felodipine 10

Cremophor RH 40 90 kalcijev fosfat 250 hidroksipropilmetilceluloza 2910 6 mPa.s 250 ksantan gumi 25 guar gumi 25 natrijev stearil fumarat 13Cremophor RH 40 90 calcium phosphate 250 hydroxypropyl methylcellulose 2910 6 mPa.s 250 xanthan gum 25 guar gum 25 sodium stearyl fumarate 13

Pripravek po primeru 1 oblikujemo v tablete s hidrofilnimi matricami, ki vsebujejo 10 mg felodipina/tableto. Tablete pripravimo na naslednji način:The preparation of Example 1 was formulated into hydrophilic matrix tablets containing 10 mg felodipine / tablet. The tablets are prepared as follows:

Felodipin raztopimo v Cremophoru RH 40 in dobljeno raztopino previdno pomešamo z nosilnim materialom, HPMC, ksantan gumijem, guar gumijem in kalcijevim fosfatom. Zmes granuliramo z etanolom in posušimo. Dodamo natrijev stearil fumarat kot mazivo in tablete pripravimo s stiskanjem v stroju za tabletiranje.Felodipine is dissolved in Cremophor RH 40 and the resulting solution is carefully mixed with the carrier material, HPMC, xanthan gum, guar gum and calcium phosphate. The mixture was granulated with ethanol and dried. Sodium stearyl fumarate is added as a lubricant and the tablets are prepared by compression in a tablet machine.

PRIMER 2 gEXAMPLE 2 g

felodipin felodipine 10 10 Cremophor RH 60 Cremophor RH 60 90 90 aluminijev silikat aluminum silicate 100 100 parafin paraffin 80 80 hidroksipropilceluloza hydroxypropylcellulose 7,4 7.4 natrijev stearil fumarat sodium stearyl fumarate 5,0 5.0

Pripravek po primeru 2 oblikujemo v tablete z nadzorovanim sproščanjem tipa inertne porozne matrice, ki vsebujejo 10 mg felodipina na tableto. Tablete pripravimo na naslednji način:The preparation of Example 2 is formulated into controlled release tablets of inert porous matrix type containing 10 mg felodipine per tablet. The tablets are prepared as follows:

Felodipin raztopimo v Cremophor-u RH 60 in dobljeno raztopino previdno pomešamo z aluminijevim silikatnim nosilnim materialom in s parafinom. Zmes granuliramo z raztopino hidroksipropilceluloze v etanolu in posušimo. Kot mazivo dodamo natrijev stearil fumarat in tablete pripravimo s stiskanjem v stroju za tabletiranje. Nadzorovano sproščanje felodipina dosežemo glede na rezultate in vitro, 50 % se ga sprosti po 2 h, 100 % pa se ga sprosti po 6 h.Felodipine is dissolved in Cremophor RH 60 and the resulting solution carefully mixed with aluminum silicate carrier material and paraffin. The mixture was granulated with a solution of hydroxypropylcellulose in ethanol and dried. Sodium stearyl fumarate is added as a lubricant and tablets are prepared by compression in a tablet machine. Controlled release of felodipine is achieved according to in vitro results, 50% is released after 2 h and 100% is released after 6 h.

PRIMER 3 felodipinEXAMPLE 3 felodipine

Cremophor RH 40 polivinilpirolidon mikrokristalna celuloza koruzni škrob laktoza etilceluloza hidroksipropilmetilceluloza 2910 6 mPa.sCremophor RH 40 polyvinylpyrrolidone microcrystalline cellulose corn starch lactose ethylcellulose hydroxypropylmethylcellulose 2910 6 mPa.s

100100

66.5 6266.5 62

29.5 157 36 1229.5 157 36 12

Želatinske kapsuleGelatin capsules

Pripravek po primeru 3 oblikujemo v kapsule z nadzorovanim sproščanjem, ki vsebujejo 20 mg felodipina na kapsulo. Kapsule pripravimo na naslednji način:The preparation of Example 3 was formulated into controlled release capsules containing 20 mg felodipine per capsule. The capsules are prepared as follows:

Felodipin raztopimo v Cremophor-u in dobljeno raztopino previdno pomešamo z nosilcem, polivinilpirolidonom, celulozo, koruznim škrobom in laktozo. Zmes omočimo z vodo in sferoniziramo. Dobljene granule posušimo in presejemo, uporabimo frakcije od 0,71-1,12 mm. Jedra prevlečemo z etilcelulozo raztopljeno v zmesi metilen klorida in etanola. Prevlečene granule polnimo v trde želatinske kapsule.Felodipine is dissolved in Cremophor and the resulting solution carefully mixed with carrier, polyvinylpyrrolidone, cellulose, corn starch and lactose. The mixture is wetted with water and spheronized. The obtained granules were dried and sieved using fractions of 0.71-1.12 mm. The cores were coated with ethylcellulose dissolved in a mixture of methylene chloride and ethanol. The coated granules are filled into hard gelatin capsules.

PRIMER 4 gEXAMPLE 4 g

nifedipin 20nifedipine 20

Cremophor RH 40 50 hidroksipropilmetilceluloza 2910 50 mPa.s 70 hidroksipropilmetilceluloza 2910 6 mPa.s 160 mikrokristalna celuloza 6 laktoza 56 aluminijev silikat 94 natrijev stearil fumarat 10Cremophor RH 40 50 hydroxypropyl methylcellulose 2910 50 mPa.s 70 hydroxypropyl methylcellulose 2910 6 mPa.s 160 microcrystalline cellulose 6 lactose 56 aluminum silicate 94 sodium stearyl fumarate 10

Pripravek po primeru 5 oblikujemo v tablete s hidrofilnimi matricami, ki vsebujejo 20 mg nifedipina na tableto. Tablete pripravimo na isti način, kot je opisano v primeruThe preparation of Example 5 was formulated into hydrophilic matrix tablets containing 20 mg nifedipine per tablet. The tablets are prepared in the same manner as described in the example

1.1.

Trenutno smatramo kot najboljši način izvedbe izuma primer 5.Currently, Case 5 is considered the best way of carrying out the invention.

REFERENČNI PRIMER AREFERENCE EXAMPLE A

Naslednji primer ponazarja referenčno tableto, ki jo uporabljamo pri preučevanjih in vivo gThe following example illustrates the reference tablet used in in vivo studies of g

felodipin 25 laktoza 250 metilceluloza 0,5 polivinilpirolidon 1,5 magnezijev stearat 3felodipine 25 lactose 250 methylcellulose 0.5 polyvinylpyrrolidone 1.5 magnesium stearate 3

Pripravek po referenčnem primeru A oblikujemo v običajne tablete, ki se hitro raztapljajo in ki vsebujejo 25 mg felodipina na tableto. Tablete pripravimo na naslednji način:The preparation of Reference Example A is formulated into conventional, rapidly dissolving tablets containing 25 mg felodipine per tablet. The tablets are prepared as follows:

Felodipin mikroniziramo in pomešamo z laktozo in metilcelulozo. Zmes granuliramo z vodo in posušimo. Dodamo polivinilpirolidon in magnezijev stearat in maso stisnemo v tablete.Felodipine is micronized and mixed with lactose and methylcellulose. The mixture was granulated with water and dried. Polyvinylpyrrolidone and magnesium stearate are added and the mass is compressed into tablets.

REFERENČNI PRIMER B felodipin metilceluloza manitol polivinilpirolidon mikrokristalna celuloza etilceluloza N 10 polietilenglikol 6000REFERENCE EXAMPLE B felodipine methylcellulose mannitol polyvinylpyrrolidone microcrystalline cellulose ethylcellulose N 10 polyethylene glycol 6000

870870

41,841,8

Pripravek po referenčnem primeru B oblikujemo v kapsule z nadzorovanim sproščanjem, ki vsebujejo 10 mg felodipina na kapsulo. Kapsule pripravimo na naslednji način:The preparation of Reference Example B is formulated into controlled release capsules containing 10 mg felodipine per capsule. The capsules are prepared as follows:

Felodipin mikroniziramo in previdno pomešamo z nosilcem, manitolom, metilcelulozo, polivinilpirolidonom in celulozo. Zmes omočimo z vodo in sferoniziramo. Dobljene granule posušimo in presejemo, uporabimo frakcije od 0,71-1,12 mm. Jedra prevlečemo z etilcelulozo in polietilenglikolom raztopljenim v zmesi metilen klorida in izopropil alkohola. Prevlečene granule polnimo v trde želatinske kapsule.Felodipine is micronized and carefully mixed with vehicle, mannitol, methylcellulose, polyvinylpyrrolidone and cellulose. The mixture is wetted with water and spheronized. The obtained granules were dried and sieved using fractions of 0.71-1.12 mm. The cores were coated with ethylcellulose and polyethylene glycol dissolved in a mixture of methylene chloride and isopropyl alcohol. The coated granules are filled into hard gelatin capsules.

Biofarmacevtske študijeBiopharmaceutical studies

FelodipinFelodipine

Na priloženi sliki 1 so ponazorjene povprečne vrednosti (nmol/1) v krvi za pripravek po primeru 1, 4 in referenčnem primeru A. Enkratno dozo 20 mg felodipina za pripravek z nadzorovanim sproščanjem v smislu izuma smo dali 6 zdravim moškim prejemnikom. Koncentracije felodipina v plazmi smo primerjali s koncentracijami v plazmi po enkratni dozi tablete, ki se hitro raztaplja in ki vsebuje 25 mg felodipina. Kot lahko vidimo, so dali pripravki v smislu izuma nižje pike koncentracij v krvi. medtem koje tableta, ki se hitro raztaplja, dala neželeno visok pik.Figure 1 shows the mean (nmol / l) in blood for the preparation of Example 1, 4 and Reference A. A single dose of 20 mg felodipine for the controlled release preparation of the invention was administered to 6 healthy male recipients. Plasma concentrations of felodipine were compared with plasma concentrations following a single dose of rapidly dissolving tablet containing 25 mg of felodipine. As can be seen, the compositions of the invention have given lower blood concentration points. meanwhile, which the rapidly dissolving tablet gave an unwanted high pixel.

Površina pod krivuljo koncentracija v krvi (AUC) od časa 0 do neskončnosti je bila:The area under the blood concentration (AUC) curve from time 0 to infinity was:

Pripravek Preparation Doza mu His dose AUC/doza nmol.hAl.mu AUC / dose nmol.hAl.mu referenčni A reference A 25 25 7,2 7.2 primer 1 case 1 20 20 8,8 8.8 primer 4 Example 4 20 20 7,4 7.4

Kot lahko vidimo iz te tabele, biološka uporabnost felodipina pri pripravkih z nadzorovanim sproščanjem ni zmanjšana.As can be seen from this table, the bioavailability of felodipine in controlled release preparations is not reduced.

Na priloženi sliki 2 so ponazorjene povprečne (nmol/1) vrednosti v plazmi za pripravke po primeru 3 in referenčnem primeru B. Enkratno dozo 20 mg felodipina v pripravku z nadzorovanim sproščanjem v smislu izuma smo dali 5 zdravim moškim prejemnikom. Koncentracije felodipina v plazmi smo primerjali s koncentracijami v plazmi po enkratni dozi običajnih pripravkov z nadzorovanim sproščanjem, oz. brez sredstva za raztapljanje, ki vsebujejo 10 mg felodipina. Kot lahko vidimo, je dal pripravek v smislu izuma nizek pik koncentracije v krvi in znatno razširjeno biološko uporabnost. Referenčni primer je pokazal, da v plazmi ne moremo detektirati koncentracij, kar jasno kaže na potrebo po sredstvu za raztapljanje v kolikor je želen učinek nadzorovanega sproščanja.The accompanying Figure 2 illustrates the mean (nmol / l) plasma values for the preparations of Example 3 and Reference B. One single dose of 20 mg felodipine in the controlled release preparation of the invention was administered to 5 healthy male recipients. Plasma concentrations of felodipine were compared with plasma concentrations following a single dose of conventional controlled-release preparations, respectively. free of solvents containing 10 mg felodipine. As can be seen, the preparation of the invention gave a low peak in blood concentration and significantly increased bioavailability. The reference example showed that no concentrations could be detected in the plasma, clearly indicating the need for a solubilizer if the controlled release effect was desired.

NifedipinNifedipine

Na priloženi sliki 3 so ponazorjene srednje vrednosti (nmol/1) koncentracije v plazmi za pripravek po primeru 5 in referenčni pripravek, ki vsebuje nifedipin, Adalat* 10 mg (Bayer) (referenčni C). Adalat^ je pripravek s hitrim sproščanjem, ki se nahaja na tržišču. Enkratno dozo 20 mg nifedipina pripravka z nadzorovanim sproščanjem v smislu izuma smo dali 6 zdravim moškim prejemnikom. Koncentracije nifedipina v krvi smo primerjali s koncentracijami v krvi po dajanju enkratne doze referenčnega pripravka, ki je vseboval 10 mg nifedipina. Kot lahko vidimo, je dal pripravek v smislu izuma nižji pik koncentracije v krvi, medtem ko je dal referenčni primer neželjeno visok pik kljub dejstvu, da je bila doza prepolovljena. Ne moremo videti nikakršnega znatnega zmanjšanja biološke uporabnosti, kadar primerjamo referenčni pripravek C s primerom 5.Figure 3 shows the mean (nmol / l) plasma concentrations for the preparation of Example 5 and the reference preparation containing nifedipine, Adalat * 10 mg (Bayer) (reference C). Adalat ^ is a marketed quick release preparation. A single dose of 20 mg nifedipine controlled release preparation of the invention was administered to 6 healthy male recipients. Nifedipine blood concentrations were compared with blood concentrations after administration of a single dose of a reference preparation containing 10 mg nifedipine. As can be seen, the preparation of the invention gave a lower peak of blood concentration, while giving the reference case an undesirably high peak despite the fact that the dose was halved. No significant decrease in bioavailability can be seen when comparing the reference preparation C to Example 5.

Površina pod krivuljo koncentracija v krvi od časa 0 do neskočnosti je bila:The area under the curve of blood concentration from time 0 to infinity was:

PripravekPreparation

Doza mgDose mg

AUC/doza nmol.hil.mg'¹ AUC / dose nmol.hil.mg ' ¹

Adalat^, Bayer primer 5Adalat ^, Bayer Case 5

46,546.5

36,036,0

DiskusijaDiscussion

Gornji primeri in priložene slike 1, 2 in 3 ponazarjajo prednosti pripravka z nadzorovanim sproščanjem v smislu izuma v primerjavi s konvencionalnimi pripravki ali pripravki z nadzorovanim sproščanjem brez sredstva za raztapljanje, pri čemer vsi vsebujejo isto aktivno spojino. Z raztapljanjem aktivne spojine z zelo nizko topnostjo je mogoče dobiti tableto, ki ima bolj konstanten profil koncentracije v krvi in brez kakršnihkoli neželenih visokih pikov. Prav tako dobimo učinek tekom podaljšanega časovnega obdobja. Pogosto prihaja do zmanjšanja biološke uporabnosti, kadar formuliramo zdravila z zelo nizko topnostjo. Ta izum pa med drugim zagotavlja tehniko za pripravo pripravka z nadzorovanim sproščanjem zdravila z zelo nizko topnostjo z zgoraj omenjenimi prednostmi in brez kakršnegakoli pomembnega zmanjšanja biološke uporabnosti.The above examples and the attached figures 1, 2 and 3 illustrate the advantages of the controlled release formulation of the invention over conventional or controlled release formulations without dissolving agent, all containing the same active compound. By dissolving the very low solubility active compound, it is possible to obtain a tablet that has a more constant concentration profile in the blood and without any unwanted high peaks. We also have an effect over an extended period of time. Bioavailability is often reduced when very low solubility formulations are formulated. The present invention, among other things, provides a technique for the preparation of a controlled release preparation of very low solubility drug with the aforementioned advantages and without any significant reduction in bioavailability.

Claims (12)

Patentni zahtevkiPatent claims 1. Postopek za pridobivanje trdnega pripravka s podaljšanim sproščanjem aktivne spojine z zelo nizko topnostjo, označen s tem, da aktivno spojino raztopimo ali dispergiramo v pol-trdnem ali tekočem ne-ionskem sredstvu za raztapljanje v vsaj enakih masnih deležih glede na aktivno spojino, nakar zmes vnesemo v primeren sistem za nadzorovano sproščanje aktivne spojine in oblikujemo farmacevtsko enotsko dozo.A process for the preparation of a solid sustained release preparation of a very low solubility active compound, characterized in that the active compound is dissolved or dispersed in a semi-solid or liquid non-ionic solvent for dissolving in at least equal parts by weight relative to the active compound, the mixture is introduced into a suitable controlled release system of the active compound and a pharmaceutical unit dose is formulated. 2. Postopek po zahtevku 1, označen s tem, da ne-ionsko sredstvo za raztapljanje izberemo izmed estrov in/ali etrov polietilenglikola.Process according to claim 1, characterized in that the non-ionic solvent is selected from polyethylene glycol esters and / or ethers. 3. Postopek po enem ali več zahtevkih 1 in 2, označen s tem, da ne-ionsko sredstvo za raztapljanje izbermo izmed polietoksiliranih maščobnih kislin, hidroksiliranih maščobnih kislin ali maščobnih alkoholov.Process according to one or more of Claims 1 and 2, characterized in that the non-ionic solubilizer is selected from polyethoxylated fatty acids, hydroxylated fatty acids or fatty alcohols. 4. Postopek po enem ali več zahtevkih 1 in 3, označen s tem, da ne-ionsko sredstvo za raztapljanje izberemo izmed polietoksiliranega ricinovega olja, polietoksiliranega hidrogeniranega ricinovega olja, polietoksilirane maščobne kisline iz ricinovega olja ali polietoksilirane maščobne kisline iz hidrogeniranega ricinovega olja.Process according to one or more of Claims 1 and 3, characterized in that the non-ionic solvent is selected from polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil or polyethoxylated fatty acid hydrochloric acid. 5. Postopek po zahtevku 4, označen s tem, da so ne-ionska sredstva za raztapljanje estri maščobnih kislin hidrogeniranega ricinovega olja z oksietiliranim glicerinom, zlasti z zmesjo trihidroksistearatnega estra etoksiliranega glicerola in majhnih količin makrogol trihidroksistearata in ustreznih prostih glikolov.Process according to claim 4, characterized in that the non-ionic fatty acid esters for dissolving the fatty acid esters of hydrogenated castor oil with oxyethylated glycerin, in particular a mixture of ethoxylated glycerol trihydroxystearate ester and small amounts of macrogol trihydroxystearic glycerol. 6. Postopek po zahtevku 1, označen s tem, da so razmerja med aktivno spojino in sredstvom za raztapljanje v obsegu od 1:1 do 1:10, prednostno v obsegu od 1:2 do 1:6.Process according to claim 1, characterized in that the ratios between the active compound and the solvent are in the range 1: 1 to 1:10, preferably in the range 1: 2 to 1: 6. 7. Postopek po enem ali več zahtevkih od 1 do 6, označen s tem, da je topnost spojine v vodi od 1:1000 ali manj, masno, in da se aktivna spojina raztaplja v neionskem sredstvu za raztapljanje ali v kombinaciji vode in ne-ionskega sredstva za raztapljanje.A process according to one or more of claims 1 to 6, characterized in that the solubility of the compound in water is 1: 1000 or less, by weight, and that the active compound is dissolved in a non-ionic solvent or in combination with water and ionic dissolving agent. 8. Postopek po enem ali več zahtevkih od 1 do 7, označen s tem, da aktivno snov izberemo izmed enega ali več substituiranih dihidropiridinov, zlasti nifedipina in/ali felodipina.Process according to one or more of Claims 1 to 7, characterized in that the active substance is selected from one or more substituted dihydropyridines, in particular nifedipine and / or felodipine. 9. Postopek po kateremkoli izmed zahtevkov 1 do 8, označen s tem, da obsega sistem za nadzorovano sproščanje inertne porozne matrice, prevleke za upočasnjeno difuzijo ali dezintegrirajoče prevleke.A method according to any one of claims 1 to 8, characterized in that it comprises a controlled release system for an inert porous matrix, slow diffusion coatings or disintegrating coatings. 10. Postopek po kateremkoli izmed zahtevkov 1 do 9, označen s tem, da je sproščanje aktivne snovi nadzorovano s sistemom hidrofilnega gela, zlasti sistemom, v katerem znaša komponenta, ki tvori sistem hidrofilnega gela 20-80 mas.% pripravka.The method according to any of claims 1 to 9, characterized in that the release of the active substance is controlled by a hydrophilic gel system, in particular a system in which the component forming the hydrophilic gel system is 20-80% by weight of the preparation. 11. Postopek po patentnem zahtevku 11, označen s tem, da je komponenta, ki tvori sistem hidrofilnega gela, hidroksipropil metilceluloza, zlasti sisteme, v katerih je hidroksipropil v razmerju od 4 do 12 mas. % samega pripravka.Process according to claim 11, characterized in that the component forming the hydrophilic gel system is hydroxypropyl methylcellulose, in particular systems in which hydroxypropyl is in the ratio of 4 to 12 wt. % of the preparation itself. 12. Postopek po zahtevku 10, označen s tem, da vsebuje sistem hidrofilnega gela karboksipolimetilen.12. The process of claim 10, wherein the hydrophilic gel system comprises carboxypolymethylene.