Pričujoči izum spada v področje farmacevtske industrije in se nanaša na nov in izboljšan postopek za pripravo trdnih površinskih disperzij amorfnih, v vodnih medijih slabo topnih učinkovin in njihovo uporabo za pripravo trdnih doziranih oblik.The present invention is within the scope of the pharmaceutical industry and relates to a new and improved process for the preparation of solid surface dispersions of amorphous, water-insoluble substances and their use for the preparation of solid dosage forms.
Natančneje se izum nanaša na postopek za pripravo trdnih površinskih disperzij zlasti z uporabo mikrovalovne energije, kot tudi pri znižanem tlaku ter temperaturi, ki je nižja od temperature tališča učinkovine, pri čemer se izognemo uporabi okolju nezaželenih organskih topil. Poleg tega se izboljša hitrost raztapljanja učinkovin iz njihovih trdnih površinskih disperzij .More specifically, the invention relates to a process for the preparation of solid surface dispersions, in particular using microwave energy, as well as at reduced pressure and a temperature below the melting point of the active ingredient, avoiding the use of environmentally undesirable organic solvents. In addition, the rate of dissolution of the active substances from their solid surface dispersions is improved.
Tehnični problemA technical problem
Po znanih in v literaturi opisanih postopkih za pripravo trdnih površinskih disperzij so uporabljali organska topila, ki pa jih je pogosto težko ali celo nemogoče popolnoma odstraniti iz želene farmacevtske oblike.According to the known and described methods for preparing solid surface dispersions, organic solvents have been used, which are often difficult or even impossible to completely remove from the desired pharmaceutical form.
Zato obstaja stalna potreba za pripravo novega in izboljšanega postopka za pripravo trdne površinske disperzije amorfne učinkovine, s katerim bi želeno amorfno stanje v vodnih medijih netopne ali slabo topne učinkovine dobili iz njene kristalinične oblike na način, pri katerem ne bi bilo potrebno uporabiti organskih topil, zlasti kloriranih organskih ogljikovodikov, ki lahko v znatnem obsegu onesnažujejo okolje. Nadalje obstaja tudi potreba za izboljšanje hitrosti raztapljanja učinkovine iz njenih trdnih površinskih disperzij, katere bi bile primerne za pripravo trdnih dozirnih oblik.Therefore, there is an ongoing need to prepare a new and improved process for the preparation of a solid surface dispersion of an amorphous active ingredient in order to obtain the desired amorphous state in aqueous media of an insoluble or poorly soluble active ingredient from its crystalline form in a manner that does not require the use of organic solvents, in particular chlorinated organic hydrocarbons, which can significantly pollute the environment. Furthermore, there is a need to improve the rate of dissolution of the active substance from its solid surface dispersions, which would be suitable for the preparation of solid dosage forms.
Stanje tehnikeThe state of the art
Učinkovine, ki so zelo slabo topne v vodi, predstavljajo pri oblikovanju zdravil probleme zaradi nizke hitrosti raztapljanja. Primeri učinkovin, ki so zelo slabo topne v vodi so nekateri substituirani dihidropiridini, kot felodipin in nifedipin. Omenjeni dihidropiridini so znani kot antagonisti kalcija, ki se jih široko uporablja za zdravljenje kardiovaskularnih bolezni, kot so ishemične bolezni srca in arterielna hipertenzija. Eden izmed predstavnikov te skupine, felodipin, ima topnost le 0.5 mg/l v vodi pri sobni temperaturi. Ostali primeri učinkovin z zelo slabo topnostjo v vodi so aciklovir, fenofibrat in drugi.Substances which are very poorly soluble in water present problems in the formulation of drugs due to their low dissolution rate. Examples of substances that are very poorly soluble in water are some substituted dihydropyridines, such as felodipine and nifedipine. Said dihydropyridines are known as calcium antagonists, which are widely used to treat cardiovascular diseases such as ischemic heart disease and arterial hypertension. One representative of this group, felodipine, has a solubility of only 0.5 mg / l in water at room temperature. Other examples of substances with very poor water solubility are acyclovir, fenofibrate and others.
Hitrost in obseg absorpcije učinkovine pri sesalcih je odvisna od hitrosti raztapljanja, ta pa je odvisna od velikosti delcev učinkovine. Uporaba učinkovine z manjšo velikostjo delcev omogoča v terapiji nižja doziranja, kar pomeni seveda znižanje nezaželenih stranskih učinkov.The rate and extent of absorption of the active substance in mammals depends on the rate of dissolution, which depends on the size of the active substance particles. The use of a substance with a smaller particle size allows for lower dosages in therapy, which, of course, results in the reduction of undesirable side effects.
Iz farmacevtskega stališča pomeni zmanjšanje velikosti delcev relativno netopne učinkovine večjo hitrost raztapljanja in praviloma večjo biološko uporabnost.From a pharmaceutical point of view, reducing the particle size of a relatively insoluble active ingredient means a greater dissolution rate and, as a rule, greater bioavailability.
Nizka biološka uporabnost v vodnih raztopinah relativno slabo topnih učinkovin je bila in ostaja problem farmacevtske industrije, ker je hitrost raztapljanja lahko omejujoč proces absorpcije v vodnih raztopinah slabo topne učinkovine iz zdravilne oblike. V tem primeru lahko fizikalno kemijske parametre, ki kontrolirajo hitrost raztapljanja, uporabimo v znani NoyesWhitneyevi enačbi, ki pravi, da je hitrost raztapljanja direktno proporcionalna velikosti površine, iz katere se učinkovina raztaplja, povečamo pa jo z drobljenjem učinkovine.Low bioavailability in aqueous solutions of relatively poorly soluble active substances has been, and remains, a problem for the pharmaceutical industry, since the rate of dissolution may be a limiting process of absorption in aqueous solutions of poorly soluble active substance from the pharmaceutical form. In this case, the physicochemical parameters controlling the rate of dissolution can be used in the known NoyesWhitney equation, which states that the rate of dissolution is directly proportional to the size of the surface from which the substance dissolves and is increased by fragmentation of the active substance.
To lahko dosežejo na konvencionalen način z enostavno mehansko mikronizacijo učinkovine, kateri pa običajno sledi aglomeracija mikroniziranih delcev, kar lahko izniči učinek mikronizacije. Zmanjšanje velikosti delcev se lahko doseže tudi z drugimi v literaturi opisanimi metodami, kot so evtektične zmesi, precipitati, trdne raztopine, kompleksi.This can be achieved in a conventional manner by simple mechanical micronisation of the active ingredient, which is usually followed by agglomeration of the micronized particles, which can counteract the micronization effect. Particle size reduction can also be achieved by other methods described in the literature, such as eutectic mixtures, precipitates, solid solutions, complexes.
Izbor posameznega postopka za spreminjanje hitrosti raztapljanja učinkovine je odvisen od strukture molekule posamezne učinkovine.The choice of a particular process for varying the rate of dissolution of an active substance depends on the structure of the molecule of each active substance.
Znano je, da se nekatere v vodi netopne učinkovine v solvent depozitih na amorfnem silicijevem dioksidu kot nosilcu hitreje raztapljajo kot same mikronizirane učinkovine.It is known that some water-insoluble substances in solvent deposits on amorphous silica as a carrier dissolve faster than the micronized substances themselves.
Velikost površine amorfnega silicijevega dioksida je kontrolni faktor za povečano hitrost raztapljanja adsorbiranih učinkovin (glejte Monkhouse D.C. in Lach J.L., J.Pharm.Sci. 61, 1430-1435, 1972 in J.Pharm. Sci. 61, 14351441, 1972).The size of the amorphous silica surface is a control factor for the increased rate of dissolution of the adsorbed substances (see Monkhouse D.C. and Lach J.L., J.Pharm.Sci. 61, 1430-1435, 1972 and J.Pharm. Sci. 61, 14351441, 1972).
Sistem solvent deposit je trdna disperzija, ki se pripravi z nanašanjem učinkovine iz raztopine učinkovine v organskem topilu na površino nosilca, kot silicijevega dioksida ali drugega primernega nosilca. To stopnjo se običajno pripravi z odparevanjem organskega topila, ki se ga uporabi za raztapljanje, ter porazdelitev in nanašanje učinkovine na površino nosilca, kar je opisano v članku J.Kerč in drugi, Acta Pharm.Jug.41, 259-265, 1991 in v Acta Pharm. 43, 113-120, 1993 istih avtorjev. Stopnje, ki vplivajo na kvaliteto trdne disperzije so izbor organskega topila ali zmesi organskih topil, hitrost ter popolna odstranitev organskega topila. Pomanjkljivost tega postopka predstavlja uporaba organskih topil, zlasti kloriranih ogljikovodikov, ki lahko v znatni meri onesnažujejo okolje.The solvent deposit system is a solid dispersion that is prepared by applying an active substance solution in an organic solvent to the surface of a carrier, such as silica or another suitable carrier. This step is usually prepared by evaporation of the organic solvent used for dissolution and the distribution and application of the active ingredient to the surface of the carrier, as described in J. Kerch et al., Acta Pharm.Jug.41, 259-265, 1991 and in Acta Pharm. 43, 113-120, 1993 by the same authors. The levels that affect the quality of the solid dispersion are the selection of the organic solvent or mixtures of organic solvents, the rate and complete removal of the organic solvent. The disadvantage of this process is the use of organic solvents, especially chlorinated hydrocarbons, which can significantly pollute the environment.
Lastnosti nosilcev imajo velik vpliv na hitrost raztapljanja dispergirane učinkovine. Za dosego zvišanja hitrosti raztapljanja učinkovine morajo biti nosilci hidrofobni z lastnostjo hitrega raztapljanja, biti morajo netoksični in farmakološko inertni, kemično kompatibilni z učinkovino in ne smejo tvoriti močno vezanih kompleksov z učinkovino.The properties of the carriers have a great influence on the dissolution rate of the dispersed active ingredient. In order to achieve an increase in the rate of dissolution of the active substance, the carriers must be hydrophobic with rapid dissolving properties, must be non-toxic and pharmacologically inert, chemically compatible with the active substance, and must not form strongly bound complexes with the active substance.
Za pripravo trdnih disperzij je poznana in uporabljana tudi talilna metoda. Veliko pomanjklivost te metode pomeni uporaba visoke temperature, ki je običajno vsaj enaka ali višja od temperature tališča učinkovine, v postopku priprave trdne disperzije, kajti mnoge učinkovine termično niso stabilne in pri tališču delno ali povsem razpadejo.The melting method is known and used to prepare solid dispersions. The great disadvantage of this method is the use of a high temperature, usually at least equal to or higher than the melting point of the active ingredient, in the process of solid dispersion preparation, since many of the active ingredients are not thermally stable and partially or completely decompose at the melting point.
Uporaba mikrovalovne energije v hitro rotirajočih mešalcih je znana pri pripravi oziroma sušenju granulatov (Doelling M.K. in Nash R.A., Pharm.Res. 9, 1493-1501, 1992, Gaillard C. in drugi, Eur.J.Pharm. Biopharm. 38, 16368, 1992, Mesiha M. in drugi, Pharm. Res. 5, Suppl. S 252, 1988).The use of microwave energy in fast-rotating mixers is known for the preparation or drying of granules (Doelling MK and Nash RA, Pharm.Res. 9, 1493-1501, 1992; Gaillard C. et al., Eur.J.Pharm. Biopharm. 38, 16368 , 1992, Mesiha M. et al., Pharm. Res. 5, Suppl. S 252, 1988).
Mikrovalovno energijo so uporabili tudi pri sušenju filmske obloge tablet (Joshi H.M. in drugi, J.Pharm. 51, 19-25, 1989, Joshi H.N. in Τορρ E.M., Pharm. Res. 5, Suppl. S252, 1988), pelet (Vertommen J. in drugi,Microwave energy has also been used in drying the film coating of tablets (Joshi HM and others, J.Pharm. 51, 19-25, 1989; Joshi HN and Τορρ EM, Pharm. Res. 5, Suppl. S252, 1988), pellets (Vertommen J. and others,
J.Pharm.Belg. 48, 158, 1993), pri pripravi hidrogelov (Maue V.R. in Moll F., Dtsch. Apoth. Ztg. 129, 1035-1038, 1989) in emulzij (Maue R. in Moll F., Acta Pharm. Technol. 33, 225-230, 1987).J.Pharm.Belg. 48, 158, 1993), in the preparation of hydrogels (Maue VR and Moll F., Dtsch. Apoth. Ztg. 129, 1035-1038, 1989) and emulsions (Maue R. and Moll F., Acta Pharm. Technol. 33, 225-230, 1987).
Konno T. in drugi opisuje v Chem. Pharm. Buli. 34, 301-307, 1986, pripravo trdne disperzije aspirina, fenacetina in derivatov benzojske kisline pri znižanem tlaku z uporabo medicinskega oglja ali magnezijevega aluminijevega silikata kot nosilcev.Konno describes T. et al. In Chem. Pharm. Buli. 34, 301-307, 1986, the preparation of a solid dispersion of aspirin, phenacetin and benzoic acid derivatives under reduced pressure using charcoal or magnesium aluminum silicate as carriers.
Opis rešitve tehničnega problema z izvedbenimima primeromaDescription of the solution of a technical problem with two examples
Izum temelji na nalogi pripraviti trdne površinske disperzije amorfnih v vodnih medijih slabo topnih učinkovin na način, s katerim bi se izognili uporabi znanih postopkov za spremembo kristaliničnih oblik učinkovin v njihovo amorfno oziroma mikrokristalinično obliko, ki uporabljajo organska, okolje onesnažujoča topila ali drugih postopkov, ki uporabljajo prekomerno toplotno ali mehansko energijo, poleg tega pa bi se tudi izboljšala hitrost raztapljanja učinkovin iz njihovih trdnih površinskih disperzij. Te farmacevtske oblike bi bile primerne za pripravo trdnih doziranih oblik za peroralno uporabo, to je tablet, kapsul, granulata, pripravkov s podaljšanim sproščanjem, pripravkov s kontroliranim sproščanjem in pripravkov z zadržanim sproščanjem učinkovine.The invention is based on the task of preparing solid surface dispersions of poorly soluble amorphous substances in aqueous media in such a way as to avoid the use of known processes for converting crystalline forms of active substances to their amorphous or microcrystalline form using organic, environmentally polluting solvents or other processes which they use excessive thermal or mechanical energy and would also improve the rate of dissolution of the active substances from their solid surface dispersions. These pharmaceutical formulations would be suitable for the preparation of solid dosage forms for oral administration, i.e., tablets, capsules, granules, sustained release preparations, controlled release preparations and sustained release formulations.
Ta smoter izuma dosežemo z obdelavo kristaliničnih v vodnih medijih slabo topnih učinkovin in nosilca (adsorbenta) pri znižanem tlaku in še zlasti z uporabo mikrovalovne energije , pri čemer dobimo učinkovino v amorfni obliki v trdni površinski dišperziji.This object of the invention is achieved by treating crystalline, water-soluble crystalline substances and the adsorbent carrier under reduced pressure, and in particular by using microwave energy, to obtain the active substance in amorphous form in solid surface dispersion.
Lastnosti nosilcev imajo velik vpliv na karakteristiko hitrosti raztapljanja dispergirane učinkovine.The properties of the carriers have a great influence on the dissolution rate of the dispersed active ingredient.
Kot nosilec (adsorbent) uporabimo najbolje porozni ali neporozni amorfni silicijev dioksid ali drug primeren hidrofilni nosilec.The most porous or non-porous amorphous silica or other suitable hydrophilic carrier is used as the adsorbent.
Amorfni silicijev dioksid deluje kot nosilec amorfne, v vodnih medijih slabo topne učinkovine in hkrati zaradi hidrofilnih lastnosti izboljša omočljivost učinkovine pri raztapljanju.Amorphous silica acts as a carrier of an amorphous, poorly soluble substance in aqueous media and at the same time improves the wettability of the active substance upon dissolution due to its hydrophilic properties.
Kot nosilec lahko uporabimo najbolje porozni silicijev dioksid, ki ima specifično površino od 6 do 1000 m2/g, prednostno od 100 do 600 m2/g in povprečno velikostjo por od 2 do 40 nm, prednostno od 5 do 20 nm ali neporozni silicijev dioksid s specifično površino od 50 do 500 m2/g, prednostno od 200 do 400 m2/g. Kot nosilce lahko uporabimo še naravne polimerne snovi, kot so škrob ali modificirani škrobi, celuloza ali mikrokristalna celuloza, polsintetske polimerne snovi, kot so derivati naravne celuloze in sicer metilceluloza, etilceluloza, hidroksietilceluloza, hidroksipropilceluloza, hidroksipropilmetilceluloza, natrijeva karboksimetilceluloza, zamrežena natrijeva karboksimetilceluloza in različne sintetske polimerne snovi, kot so polivinilpirolidon, zamreženi polivinilpirolidon in drugi, ter kombinacije teh.As a carrier, porous silica having a specific surface area of from 6 to 1000 m2 / g, preferably from 100 to 600 m2 / g and an average pore size of from 2 to 40 nm, preferably from 5 to 20 nm, or non-porous silicon, can be used dioxide having a specific surface area of 50 to 500 m2 / g, preferably 200 to 400 m2 / g. As carriers, natural polymeric substances such as starch or modified starches, cellulose or microcrystalline cellulose, semi-synthetic polymeric substances such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropylcellulose, carboxymethylcellulose synthetic polymeric substances such as polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and others, and combinations thereof.
Kot v vodi slabo topne aktivne učinkovine lahko uporabimo antagoniste kalcija , izbrane iz skupine dihidropiridinov, ki obsegajo felodipin, nifedipin, amlodipin, nimodipin, nitrendipin, nilvadipin in nikardipin, poleg tega še aciklovir, fenofibrat in druge v vodnih raztopinah netopne ali slabo topne učinkovine.As water-insoluble active ingredients, calcium antagonists selected from the group of dihydropyridines comprising felodipine, nifedipine, amlodipine, nimodipine, nitrendipine, nilvadipine, and nicardipine, in addition acyclovir, fenofibrate, and other insoluble or water-insoluble solutions, may be used.
Da dosežemo stabilno farmacevtsko obliko v smislu izuma je potrebno masno razmerje med učinkovino in nosilcem v območju od 1 : 20 do 8 : 10, najbolje v območju od 1 : 10 do 5 : 10.In order to achieve the stable pharmaceutical form of the invention, a weight ratio of the active ingredient to the carrier is required in the range of 1: 20 to 8: 10, preferably in the range of 1: 10 to 5: 10.
Zlasti prikladen postopek za pripravo trdne površinske disperzije amorfne, v vodnih medijih slabo topne učinkovine temelji na uporabi mikrovalovne energije, s katero se kristalinična oblika učinkovine spremeni v amorfno obliko. V skladu s tem postopkom izbrano učinkovino in ustrezen nosilec homogeno premešamo, pri čemer dobljeno fizikalno zmes toplotno obdelujemo v mikrovalovni pečici z energijo od 200 W do 24000 W. V skladu s postopkom v smislu izuma dobimo amorfno obliko izbrane učinkovine v njeni trdni površinski disperziji, ne glede na izbor uprabljene polimorfne kristalinične oblike izhodne učinkovine.A particularly convenient process for preparing a solid surface dispersion of an amorphous, poorly soluble substance in aqueous media is based on the use of microwave energy, which transforms the crystalline form of the active ingredient into an amorphous form. In accordance with this method, the selected active ingredient and the corresponding carrier are homogeneously mixed, whereby the resulting physical mixture is thermally treated in a microwave oven with an energy of 200 W to 24000 W. irrespective of the choice of the polymorphic crystalline form of the starting material used.
Drug prikladen postopek za pripravo trdne površinske disperzije amorfne, v vodnih medijih slabo topne učinkovine temelji na spremembi kristalinične učinkovine v amorfno pri znižanem tlaku. V skladu s tem postopkom izbrano učinkovino in ustrezen nosilec homogeno premešamo in pri tem dobljeno fizikalno zmes v vakuumskem sušilniku segrevamo pri temperaturi nižji od tališča učinkovine in pri tlaku med 0,005.105Pa do 0,1.10^Pa. Območje temperature, pri kateri poteka sprememba, je odvisno od fizikalno kemijskih lastnosti v vodnih medijih slabo topne izbrane učinkovine in je odvisno od njenega tališča. Učinkovina pri znižanem tlaku sublimira in se preko plinaste faze nalaga na površini nosilca v amorfni obliki. Tudi v skladu s tem postopkom v smislu izuma dobimo amorfno obliko izbrane učinkovine v njeni trdni površinski disperziji, ne glede na izbor uporabljene polimorfne kristalinične oblike izhodne učinkovine.Another suitable method for preparing a solid surface dispersion of an amorphous, poorly soluble in aqueous media is based on the change of the crystalline substance to amorphous under reduced pressure. In accordance with this method, the active ingredient and the corresponding carrier are stirred homogeneously, heating the resulting physical mixture in a vacuum dryer at a temperature lower than the melting point of the active substance and at a pressure between 0.005.105 Pa and 0.1.10 ^ Pa. The temperature range at which the change occurs depends on the physicochemical properties of the poorly soluble substance in the aqueous media and depends on its melting point. At reduced pressure, the active substance sublimates and is deposited over the gaseous phase on the carrier surface in an amorphous form. Also, in accordance with this process of the invention, the amorphous form of the active ingredient in its solid surface dispersion is obtained, regardless of the choice of the polymorphic crystalline form of the starting material used.
Pri obeh postopkih uporabimo kot izhodno spojino kristalinično in fino presejano učinkovino, v danem primeru pa uporabimo tudi fino presejan nosilec, ki ju nato dobro premešamo v fizikalno zmes, ki jo nato toplotno obdelujemo dalje v skladu z izbranim postopkom.In both processes, the crystalline and finely screened active ingredient is used as the starting compound, and optionally a finely screened carrier is used, which is then well mixed into a physical mixture, which is then further heat treated in accordance with the chosen process.
Znano je, da na zvišano hitrost raztapljanja učinkovine vpliva površina nosilcev, kot silicijevega dioksida, na katerih je adsorbirana učinkovina.It is known that the increased rate of dissolution of the active substance is affected by the surface of the carriers, such as silica, on which the active ingredient is adsorbed.
Felodipin, kot predstavnik skupine antagonistov kalcija, je praktično netopen v vodi (vodotopnost je 0.5 mg/l pri sobni temperaturi) z nizko hitrostjo raztapljanja. Iz člankov J.Kerča in drugih v Acta Pharm. Jugosl.41 (1991) 259, Acta Pharm.43 (1993) 113 in Procc. 11th Pharm.Technol.Conference, Vol.2, 1992, 282 so opisani primeri zvišanja topnosti in hitrosti raztapljanja.Felodipine, as a representative of the calcium antagonist group, is practically insoluble in water (water solubility is 0.5 mg / l at room temperature) with a low dissolution rate. From the articles by J. Kerch and others in Acta Pharm. Yugoslavia.41 (1991) 259, Acta Pharm.43 (1993) 113 and Procc. 11th Pharm.Technol.Conference, Vol.2, 1992, 282 describes examples of solubility and solubility enhancement rates.
Vendar ti opisani rezultati še vedno niso bili zadovoljivi.However, these results were still not satisfactory.
Ugotovili smo, da se hitrost raztapljanja felodipina in drugih v vodnih medijih slabo topnih učinkovin znatno zviša iz trdne površinske disperzije amorfne, v vodnih medijih slabo topne učinkovine, pripravljene po postopku v skladu s smotrom izuma, zlasti z uporabo mikrovalovne energije. Pomembno zvišanje hitrosti raztapljanja amorfne učinkovine je bilo opazno tudi iz trdnih površinskih disperzij, pripravljenih v skladu s postopkom pri znižanem tlaku, medtem ko smo metodo solvent deposition uporabili kot primerjalno metodo, ob oporabi metilenklorida kot organskega topila, pri pripravi trdnih površinskih disperzij.It has been found that the rate of dissolution of felodipine and others in the aqueous media of poorly soluble substances is significantly increased from the solid surface dispersion of an amorphous, in aqueous media, the poorly soluble substances prepared by the process according to the invention, in particular using microwave energy. A significant increase in the rate of dissolution of the amorphous substance was also observed from solid surface dispersions prepared according to the reduced pressure process, while the solvent deposition method was used as a comparative method using methylene chloride as an organic solvent in the preparation of solid surface dispersions.
Na sliki 1 je ponazorjen termogram, dobljen z diferenčno dinamično kalorimetrijo (Differential scanning calorimetry-DSC) trdnih površinskih disperzij felodipina, s katerim smo spremljali spremembo kristaliničnega felodipina v homogeni fizikalni zmesi z nosilcem poroznim amorfnim silicijevim dioksidom v amorfno obliko učinkovine s pomočjo mikrovalovne energije v mikrovalovni pečici. Fizikalna zmes je vsebovala 20 mas.% felodipina in 80 mas.% nosilca. Kot je razvidno iz slike je bil v 15 min. ves kristalinični felodipin spremenjen v amorfnega.Figure 1 illustrates a thermogram obtained by Differential Scanning Calorimetry (DSC) of solid surface dispersions of felodipine, which monitored the change of crystalline felodipine in a homogeneous physical mixture with a carrier of porous amorphous silica into an amorphous form of the active ingredient microwave ovens. The physical mixture contained 20 wt% felodipine and 80 wt% carrier. As can be seen in the picture it was in 15 min. all crystalline felodipine converted to amorphous.
Slika 2 ponazarja rentgenske praškovne difraktograme trdnih površinskih disperzij felodipina, ki potrjuje amorfno stanje felodipina pri pripravi njegovih trdnih površinskih disperzij z amorfnim silicijevim dioksidom kot nosilcem in ob uporabi mikrovalovne energije.Figure 2 illustrates X-ray powder diffractograms of solid surface dispersions of felodipine, confirming the amorphous state of felodipine in the preparation of its solid surface dispersions with amorphous silica as a carrier and using microwave energy.
Slika 4 ponazarja DSC termograme trdnih površinskih disperzij felodipina, pripravljenih z metodo solvent deposition in z metodo pri znižanem tlaku. Rentgenski praškovni difraktogram na sliki 5 trdnih površinskih disperzij felodipina ob uporabi amorfnega silicijevega dioksida kot nosilca ponazarjata spremembo kristalinične strukture felodipina v mikrokristalinično oziroma v amorfno stanje v trdnih površinskih disperzijah, pripravljenih po postopku pri znižanem tlaku (vakuum) ali v skladu s postopkom z uporabo metode solvent deposition. Pri znižanem tlaku felodipin sublimira na površino nosilca v amorfnem stanju.Figure 4 illustrates DSC thermograms of solid surface dispersions of felodipine prepared by the solvent deposition method and the reduced pressure method. The X-ray powder diffraction pattern in Figure 5 of solid surface dispersions of felodipine using amorphous silica as a carrier illustrates the change in the crystalline structure of felodipine to microcrystalline or amorphous state in solid surface dispersions prepared by the process under reduced pressure (vacuum) or in accordance with the method solvent deposition. At reduced pressure, felodipine sublimates to the carrier surface in an amorphous state.
Rezultati testov raztapljanja (hitrosti sproščanja) so ponazorjeni na sliki 3. V ta namen smo uporabili metodo veslastega mešala (Paddle Method) na Aparatu 2 po USP XXI, s katerim smo določili hitrost raztapljanja felodipina iz trdnih površinskih disperzij. Kot medij smo uporabili 900 ml prečiščene vode pri temperaturi 37 C, hitrost vrtenja veslastega mešala je bila 100 vrt/min. Vzorci so vsebovali 10 mg felodipina in smo jih nanesli na površino medija za raztapljanje. Količino raztopljenega felodipina smo določili spektrofotometrično pri 240 nm (Aparat UV VIS spektrometer Perkin Elmer ZDA). Takoj po odvzemu alikvotnega vzorca smo dodali enako koločino medija za vzdrževanje konstantnega volumna.The results of the dissolution tests (release rates) are illustrated in Figure 3. To this end, we used the Paddle Method on Apparatus 2 according to USP XXI to determine the dissolution rate of felodipine from solid surface dispersions. 900 ml of purified water at 37 C was used as the medium, the rotational speed of the paddle mixer was 100 rpm. The samples contained 10 mg of felodipine and were applied to the surface of the dissolution medium. The amount of dissolved felodipine was determined spectrophotometrically at 240 nm (UV VIS Spectrometer Perkin Elmer USA). Immediately after the aliquot sample was taken, the same volume of medium was added to maintain a constant volume.
Na sliki 3 je ponazorjena hitrost raztapljanja trdnih površinskih disperzij felodipina, pri čemer je razvidno znatno povišanje hitrosti raztapljanja amorfnega felodipina (nastalega v mikrovalovni pečici v času 15 min.) iz njegovih trdnih površinskih disperzij v primerjavi s trdno disperzijo felodipina, pripravljeno z metodo solvent deposition, medtem ko je iz slike 6 tudi razvidno delno povišanje hitrosti raztapljanja amorfnega felodipina z metodo pri znižanem tlaku v primerjavi z metodo solvent deposition.Figure 3 illustrates the dissolution rate of the solid surface dispersions of felodipine, showing a significant increase in the dissolution rate of the amorphous felodipine (generated in a microwave over 15 min) from its solid surface dispersions as compared to the solid dispersion of the felodipine method. , while Figure 6 also shows a partial increase in the dissolution rate of amorphous felodipine by the reduced pressure method compared to the solvent deposition method.
V skladu s postopkom v smislu izuma predstavlja uporaba mikrovalovne energije, kot tudi postopek pri znižanem tlaku za pripravo trdnih površinskih disperzij v vodnih medijih slabo topnih učinkovin, kot felodipina, dragoceno izboljšavo, s katero se izognemo uporabi okolju nezaželenih organskih topil, poleg tega pa tudi prekomerne termične in mehanske energije. Še zlasti je pomembno izboljšanje hitrosti raztapljanja učinkovine iz trdnih površinskih disperzij, pripravljenih s postopkom uporabe mikrovalovne energije, ker je znano, da povišana hitrost raztapljanja vpliva tudi na absorpcijo učinkovin iz trdnih dozirnih oblik.According to the process of the invention, the use of microwave energy, as well as the process of reduced pressure for the preparation of solid surface dispersions in aqueous media of poorly soluble substances, such as felodipine, is a valuable enhancement to avoid the use of environmentally undesirable organic solvents, and excessive thermal and mechanical energy. It is particularly important to improve the rate of dissolution of the active ingredient from solid surface dispersions prepared by the microwave energy process, since it is known that the increased dissolution rate also affects the absorption of active ingredients from solid dosage forms.
V ta namen lahko uporabimo trdne površinske disperzije amorfnih v vodnih medijih slabo topnih učinkovin za pripravo trdnih dozirnih oblik za peroralno uporabo, to je tablet, kapsul, granulata ter pripravkov s podaljšanim, pripravkov s kontroliranim in pripravkov z zadržanim sproščanjem učinkovine. Za pripravo trdnih dozirnih oblik lahko poleg trdne površinske disperzije v vodnih medijih slabo topnih učinkovin uporabimo še druge nosilne snovi in ekscipiente, znane v farmaciji za pripravo trdnih dozirnih oblik, ter njihove kombinacije.For this purpose, solid surface dispersions of aqueous amorphous, poorly soluble substances in aqueous media can be used for the preparation of solid dosage forms for oral use, i.e., tablets, capsules, granules and prolonged, controlled and sustained release formulations. For the preparation of solid dosage forms, other carriers and excipients known in the pharmaceutical industry for the preparation of solid dosage forms, and combinations thereof, may be used in addition to solid surface dispersion in aqueous media of poorly soluble substances.
Izum pojasnjujejo, vendar v ničemer ne omejujejo naslednji izvedbeni primeri.The invention is explained, but in no way limited by the following embodiments.
PRIMER 1EXAMPLE 1
Priprava trdne površinske disperzije amorfnega felodipinaPreparation of solid surface dispersion of amorphous felodipine
1.0 g kristaliničnega felodipina presejemo skozi sito z velikostjo zank 0.100 mm in ga mešamo z magnetnim mešalom 1 uro z 5.0 g poroznega silicijevega dioksida (Kieselgel KG 100- firme Merck Nemčija).Sift 1.0 g of crystalline felodipine through a sieve with a mesh size of 0.100 mm and mix it with a magnetic stirrer for 1 hour with 5.0 g of porous silica (Kieselgel KG 100 by Merck Germany).
Pri tem dobljeno fizikalno zmes nato segrevamo v mikrovalovni pečici 15 minut pri moči 500 W, pri čemer dobimo želen naslovni pripravek.The resulting physical mixture is then heated in a microwave for 15 minutes at a power of 500 W to give the desired title preparation.
PRIMER 2EXAMPLE 2
Priprava trdne površinske disperzije amorfnega felodipinaPreparation of solid surface dispersion of amorphous felodipine
1.0 g kristaliničnega felodipina in 5.0 g poroznega silicijevega dioksida (Kieselgel KG 100-Firme Merck Nemčija) presejemo skozi sito z velikostjo zank 0.100 mm in ju mešamo 1 uro z magnetnim mešalom. Pri tem dobljeno fizikalno zmes nato segrevamo 15 minut v vakuumskem sušilniku pri temperaturi 100°C in tlaku 0.01.105 Pa, pri čemer dobimo želen naslovni pripravek.1.0 g of crystalline felodipine and 5.0 g of porous silica (Kieselgel KG 100-Firm Merck Germany) were sieved through a sieve with a mesh size of 0.100 mm and stirred for 1 hour with a magnetic stirrer. The resulting physical mixture was then heated in a vacuum oven at 100 ° C and a pressure of 0.01.105 Pa for 15 minutes to give the desired title preparation.
tovarna farmacevtskih mičnih izdelkov, d.d.Pharmaceutical Mills Factory, d.d.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9500059ASI9500059A (en) | 1995-02-23 | 1995-02-23 | PROCEDURE FOR THE PREPARATION OF SOLID SURFACE DISPERSIONS OF AMORPHIC, IN AQUATIC MEDIA Mild soluble substances and their use |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9500059ASI9500059A (en) | 1995-02-23 | 1995-02-23 | PROCEDURE FOR THE PREPARATION OF SOLID SURFACE DISPERSIONS OF AMORPHIC, IN AQUATIC MEDIA Mild soluble substances and their use |
| Publication Number | Publication Date |
|---|---|
| SI9500059Atrue SI9500059A (en) | 1996-08-31 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI9500059ASI9500059A (en) | 1995-02-23 | 1995-02-23 | PROCEDURE FOR THE PREPARATION OF SOLID SURFACE DISPERSIONS OF AMORPHIC, IN AQUATIC MEDIA Mild soluble substances and their use |
| Country | Link |
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| SI (1) | SI9500059A (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8389006B2 (en) | 2001-06-22 | 2013-03-05 | Bend Research, Inc. | Pharmaceutical compositions of adsorbates of amorphous drug |
| US9023393B2 (en) | 2003-08-04 | 2015-05-05 | Bend Research, Inc. | Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials |
| US9486410B2 (en) | 2002-02-01 | 2016-11-08 | Bend Research, Inc. | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8389006B2 (en) | 2001-06-22 | 2013-03-05 | Bend Research, Inc. | Pharmaceutical compositions of adsorbates of amorphous drug |
| US8703199B2 (en) | 2001-06-22 | 2014-04-22 | Bend Research, Inc. | Pharmaceutical compositions of adsorbates of amorphous drug |
| US9486410B2 (en) | 2002-02-01 | 2016-11-08 | Bend Research, Inc. | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials |
| US10357455B2 (en) | 2002-02-01 | 2019-07-23 | Bend Research, Inc. | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials |
| US9023393B2 (en) | 2003-08-04 | 2015-05-05 | Bend Research, Inc. | Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials |
| USRE47033E1 (en) | 2003-08-04 | 2018-09-11 | Bend Research, Inc. | Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials |
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