HRP20020804A2

HRP20020804A2 - Pharmaceutical preparations containing saccharose fatty acid esters for controlling the release of active ingredients

Info

Publication number: HRP20020804A2
Authority: HR
Inventors: Torsten Hoffman; Michael Pieroth; Gerhard Zessin; Karl-Friedrich Landgraf
Original assignee: Awd Pharma Gmbh & Co Kg
Priority date: 2000-03-08
Filing date: 2002-10-07
Publication date: 2004-12-31
Also published as: WO2001066081A2; WO2001066081A3; NO20024237D0; PL362547A1; AU2001250365A1; HRP20020804B1; HUP0204513A2; HK1054697A1; EP1267828B1; NZ521215A; SK13252002A3; EE200200504A; NO20024237L; PL202935B1; EP1267828A2; EA200200951A1; GEP20053455B; CZ20023009A3; CN1418091A; CN1212831C

Abstract

The invention relates to novel oral pharmaceutical formulations having a variably adjustable release effect . Said formulations contain one or several sucrose fatty acid esters as exclusive release control agents, in addition to one or several active ingredients. The invention also relates to a method for the production of the formulations by fusion granulation or fusion pelletizing . The novel pharmaceutical formulations range from quick release to delayed release medicament forms.

Description

Predmetna prijava odnosi se nove oralne farmaceutske pripravke s različito prilagodljivim svojstvima oslobađanja aktivnog sastojka u obliku zrnaca, peleta, tableta, tableta s premazom, mikrotableta, šećerom-premazanih tableta, kapsula ili terapijskih sustava, kao i na postupak za njihovu proizvodnju granulacije iz taljevine ili peletizacije iz taljevine. The application in question relates to new oral pharmaceutical preparations with different adaptive release properties of the active ingredient in the form of granules, pellets, tablets, coated tablets, microtablets, sugar-coated tablets, capsules or therapeutic systems, as well as to the process for their production of granulation from melt or pelletization from the melt.

Značajni ulogu u uporabi lijekova igra smanjivanje učestalosti uzimanja, u idealnom slučaju jedna doza na dan. A significant role in the use of medicines is played by reducing the frequency of taking them, ideally one dose per day.

Uzimanje jedne tablete u jutro ili navečer redovitije je od uzimanja nekoliko tableta tijekom dana. Takovo poboljšano pridržavanje terapije od strane pacijenta djelotvornije je za sam postupak liječenja. Osim toga, bolja tolerancija, koja je često povezana sa smanjivanom učestalosti uzimanja aktivnog sastojka ima pozitivan učinak na pacijenta. To je također povezano i sa duljim održavanjem, što je u tom slučaju potrebito, učinkovite koncentracije plazme te puno ujednačenije razine plazme, čime se izbjegavaju vršne vrijednosti koje nisu prihvatljive. Taking one pill in the morning or evening is more regular than taking several pills throughout the day. Such improved adherence to therapy by the patient is more effective for the treatment process itself. In addition, better tolerance, which is often associated with a reduced frequency of taking the active ingredient, has a positive effect on the patient. This is also related to the longer maintenance, which in this case is necessary, of effective plasma concentrations and much more uniform plasma levels, which avoids peak values that are not acceptable.

U iznimnim slučajevima, jedna doza dnevno može se postići i samo kinetičkim ili dinamičkim svojstvima aktivnog sastojka, poput, na primjer, duge eliminacije poluvijeka. Međutim, u većini slučajeva, učinkovite razine plazme koje se održavaju 12 do 24 sata omogućene su samo tehnološkim farmaceutskim mjerama poput, na primjer, zadržanim oslobađanjem aktivnog sastojka iz doze. In exceptional cases, one dose per day can be achieved only by kinetic or dynamic properties of the active ingredient, such as, for example, a long elimination half-life. However, in most cases, effective plasma levels that are maintained for 12 to 24 hours are made possible only by technological pharmaceutical measures such as, for example, sustained release of the active ingredient from the dose.

Čitav spektar rješenja namijenjenih ponajprije za ovu svrhu mogu se naći u literaturi, i pokazuju prednost ili nedostatke ovisno o kemijskim ili fizikalnim svojstvima aktivnog sastojka (članak: «Nedavni trendovi i napredak u zadržanoj ili kontroliranoj oralnoj isporuci nekih u vodi topljivih lijekova», Drug Development and Industrial Pharmacy 21 (9), 1037-1070 (1998)). A whole spectrum of solutions intended primarily for this purpose can be found in the literature, and they show advantages or disadvantages depending on the chemical or physical properties of the active ingredient (article: «Recent trends and progress in sustained or controlled oral delivery of some water-soluble drugs», Drug Development and Industrial Pharmacy 21 (9), 1037-1070 (1998)).

Stanje tehnike je također predstavljeno, na primjer, u jednom od nedavno objavljenih priručnika iz farmaceutske tehnologije (Voigt, R., Pharmazeutische Technologie, Ullstein Mosby Verlag 1993, str. 293 ff.). Prema njemu, učinak medicinskih tvari može se proširiti slijedećim mjerama: molekulske varijacije poput tvorbe estera ili soli, različite modifikacije aktivnog sastojka, veličina čestice, odabir pogodnog ekscipijensa i postupaka. Pojedinačne mogućnosti prikazane su primjerima kako slijedi: The state of the art is also presented, for example, in one of the recently published pharmaceutical technology handbooks (Voigt, R., Pharmazeutische Technologie, Ullstein Mosby Verlag 1993, pp. 293 ff.). According to him, the effect of medicinal substances can be extended by the following measures: molecular variations such as the formation of esters or salts, different modifications of the active ingredient, particle size, selection of suitable excipients and procedures. Individual possibilities are shown by examples as follows:

Oblici lijekova s polaganim oslobađanjem iz matrice Drug forms with slow release from the matrix

Karakterizirani su nerastvorljivom, po mogućosti poroznom strukturom od neprobavljivih masti, voska, polimera ili drugih anorganskih tvari koje mogu tvoriti matrice. Aktivni sastojak je uključen u rečenu strukturu. Oslobađanje aktivnog sastojka odvija se kroz difuziju, eroziju ili degradaciju matrice. They are characterized by an insoluble, preferably porous structure made of indigestible fats, waxes, polymers or other inorganic substances that can form matrices. The active ingredient is included in said structure. The release of the active ingredient takes place through diffusion, erosion or degradation of the matrix.

Oblici hidrokoloidnih lijekova s polaganim oslobađanjem Hydrocolloid drug forms with slow release

U ovom slučaju, medicinska tvar je usađena u hidrokolidnim matricama koje se sastoje, na primjer, od derivata celuloze. Nakon uzimanja, oblikuje se gel putem probavnih tekućina, a aktivni sastojak se difuzira (kroz gel) brže ili sporije ovisno o površini i viskoznosti gela. In this case, the medicinal substance is embedded in hydrocolloid matrices consisting, for example, of cellulose derivatives. After ingestion, a gel is formed by digestive fluids, and the active ingredient diffuses (through the gel) faster or slower depending on the surface and viscosity of the gel.

Oblici lijekova s polaganim oslobađanjem kontroliranim premazom (opnom) Forms of drugs with slow release controlled coating (membrane)

U ovom slučaju, čestice aktivnog sastojka ili oblika lijeka okružene su preprekom (barijerom). Difuzija kroz difuzijsku prepreku određuje kako brzo se oslobađa aktivni sastojak. In this case, the particles of the active ingredient or drug form are surrounded by an obstacle (barrier). Diffusion through the diffusion barrier determines how quickly the active ingredient is released.

Brzina difuzije može se povećati dodavanjem sredstva za plasticiziranje ili sredstava za tvorbu pora. The rate of diffusion can be increased by adding plasticizers or pore-forming agents.

Utjecaj specifične povrsine Influence of the specific surface

Kod aktivnih sastojaka s niskom topljivosti u vodi općenito postoji značajna ovisnost između brzine rastapanja i specifične površine. Definirana distribucija veličine čestice, pa tako i specifična površina čestica, može se uskladiti putem namjerne kristalizacije aktivnog sastojka, prosijavanjem ili mljevenjem. Veće čestice znače manju specifičnu površinu i sporije otpuštanje aktivnog sastojka. For active ingredients with low water solubility, there is generally a significant dependence between dissolution rate and specific surface area. A defined particle size distribution, and thus the specific surface area of the particles, can be matched through deliberate crystallization of the active ingredient, sieving or grinding. Larger particles mean a smaller specific surface area and slower release of the active ingredient.

Oblici lijekova koji kombiniraju postupke difuzije, erozije, razblaživanja Forms of drugs that combine the processes of diffusion, erosion, dilution

Također su poznati i oblici lijekova čije se dugotrajno oslobađanje aktivnog sastojka temelji na kombinaciji postupke difuzije, erozije i razblaživanja. There are also known forms of drugs whose long-term release of the active ingredient is based on a combination of diffusion, erosion and dilution procedures.

Naročito zanimljiv postupak, koji se može koristiti na različite načine u odnosu na oslobađanje aktivnog sastojka, jest taljenje granulata. Taljenje granulata ili termoplastična granulacija označava postupak u kojem se zrnca vezuju uporabom sastojka s niskim talištem i pod utjecajem toplinske energije (Lüdemann, J.; APV Course 231 17-18 lipanj, 1996). A particularly interesting procedure, which can be used in different ways in relation to the release of the active ingredient, is the melting of granules. Melting of granules or thermoplastic granulation refers to a process in which the granules are bonded using an ingredient with a low melting point and under the influence of thermal energy (Lüdemann, J.; APV Course 231 June 17-18, 1996).

Kod ovog postupka razlikujemo dva podtipa. Kod mokre granulacije, temperatura postupka je viša od tališta vezivnog sastojka. Tijekom granulacije, potonji ima oblik tekućine ili polukrutog sastojka. Kod taljenih granulata, sušenje je zamijenjeno hlađenjem. With this procedure, we distinguish two subtypes. In wet granulation, the process temperature is higher than the melting point of the binder. During granulation, the latter takes the form of a liquid or semi-solid ingredient. In the case of molten granulates, drying has been replaced by cooling.

Kod sinter granulacije, temperatura postupka ne doseže talište vezujućeg sastojka. U ovom slučaju, dolazi samo do lokalnog taljenja na površini čestica, tako da površine međusobno difuziraju (Voigt, R.; Lehrbuch der pharmazeutischen Technologie; Verlag Chemie, str. 159 (1984)). In sinter granulation, the process temperature does not reach the melting point of the binding ingredient. In this case, only local melting occurs at the surface of the particles, so that the surfaces mutually diffuse (Voigt, R.; Lehrbuch der pharmazeutischen Technologie; Verlag Chemie, p. 159 (1984)).

Sastojak s niskim talištem može biti aktivni sastojak ili ekscipijens. Točke taljenja tvari su, zbog stabilnosti, obično iznad 35ºC. Najčešće se koriste tvari s točkama taljenja u rasponu od 50-90ºC. A low melting point ingredient can be an active ingredient or an excipient. The melting points of the substance are, due to stability, usually above 35ºC. Most often, substances with melting points in the range of 50-90ºC are used.

Aktivni sastojci poznati kao lako spojive tvari su fenil salicilat, ibuprofen, α-lipoidna kiselina i meprobamat. Active ingredients known as easily conjugated substances are phenyl salicylate, ibuprofen, α-lipoid acid and meprobamate.

Kao lako spojivi ekscipijensi koriste se lipofilne, u vodi rastvorljive tvari koje bubre. Primjeri hidrofilnih tvari su makrogol, polividon i derivat polimetakrilne kiseline. Lipophilic, water-soluble, swelling substances are used as easily compatible excipients. Examples of hydrophilic substances are macrogol, polyvidone and polymethacrylic acid derivative.

Primjeri lipofilnih ekscipijensa koji se koriste su ugljikovodici (parafin), vosak, masti i masne kiseline. Examples of lipophilic excipients used are hydrocarbons (paraffin), wax, fats and fatty acids.

(Flanders, P; Dyer, G.A.; Jordan, D.; Drug Dev. Ind. Pharm. 13 (&), 1001-1022 (1987); Schaefer, T.; Holm, P.; Kristensen, H.G.; Drug Dev. Ind. Pharm. 16, 1249-1277 (1990); McTaggart, C.M. i sur.; Int. J. Pharm. 19, 139-148 (1984); Kinget, R.; Kemel, R.; Acta Pharm. Technol. 31, 57 (1985)). (Flanders, P; Dyer, G.A.; Jordan, D.; Drug Dev. Ind. Pharm. 13(&), 1001-1022 (1987); Schaefer, T.; Holm, P.; Kristensen, H.G.; Drug Dev. Ind. Pharm. 16, 1249-1277 (1990); McTaggart, C.M. et al.; Int. J. Pharm. 19, 139-148 (1984); Kinget, R.; Kemel, R.; Acta Pharm. Technol. 31, 57 (1985)).

Postupak granulacija iz taljevine obično se izvodi u granulatoru s fluidiziranim koritom, napravama s centrifugalnim fluidiziranim koritom ili mješalicama (mikserima) velike brzine i intenziteta. Uporaba potonjeg ima prije svega tehničke prednosti zato što se izbjegava skupi zračni tretman. U usporedbi s uobičajenim postupcima granulacije s uporabom organskih otapala, u ovom slučaju izbjegavaju se troškovi sprječavanja eksplozije i reciklaže otapala. Također nema ostataka od otapala u proizvodu. U usporedbi s vodenom granulacijom, izbjegnut je energetski zahtjevan postupak sušenja. U tom slučaju, preporučljiva je uporaba takozvanog The process of granulation from the melt is usually carried out in a granulator with a fluidized bed, devices with a centrifugal fluidized bed or mixers (mixers) of high speed and intensity. The use of the latter has above all technical advantages because expensive air treatment is avoided. Compared to conventional granulation processes using organic solvents, the costs of explosion prevention and solvent recycling are avoided in this case. There are also no solvent residues in the product. Compared to water granulation, the energy-demanding drying process is avoided. In this case, it is recommended to use the so-called

sustava s jednom posudom (one-pot system). one-pot system.

Postupak granulacije iz taljevine općenito se može predstaviti na sljedeći način: The melt granulation process can generally be presented as follows:

Miješanje Miješanje Mixing Mixing

Dodavanje veziva Zagrijavanje Addition of binder Heating

(kruto agregatno (solid aggregate

stanje) state)

Zagrijavanje dodavanje veziva Heating, adding a binder

(tekuće agregatno stanje) (current aggregate state)

Granulacija Granulacija Granulation Granulation

Hlađenje Hlađenje Cooling Cooling

Klasifikacija po izboru Klasifikacija po izboru Classification by choice Classification by choice

Vezivo koje se lako spaja može biti dodano u krutom ili tekućem obliku, tj. u rastaljenom stanju. A binder that is easy to join can be added in a solid or liquid form, i.e. in a molten state.

Ako se dodaje u obliku krutine, lako spojiva tvar se topi tijekom postupka, zbog čega je postupak također nazvan postupak taljenja. If it is added as a solid, the readily fused substance melts during the process, which is why the process is also called the melting process.

U potonjem postupku, ili se tekuće vezivo dodaje u krute sastojke, ili, u skladu s takozvanim postupkom fuzije, krutine se umiješaju u tekuće vezivo. U tu svrhu, zagrijavanje počinje prije dodavanja veziva. In the latter process, either the liquid binder is added to the solid ingredients, or, according to the so-called fusion process, the solids are mixed into the liquid binder. For this purpose, the heating starts before the binder is added.

Uvođenje energije kod mješalica velikog intenziteta moguće je na različite načine: The introduction of energy in high-intensity mixers is possible in different ways:

● mehaničkom energijom kroz miksere i sjeckalice ● mechanical energy through mixers and choppers

● toplinom kroz kontakt s oblogom ● by heat through contact with the coating

● IC ili mikrovalna radijacijska energija ● IR or microwave radiation energy

● Uvođenjem vrućeg zraka u korito s proizvodom ● By introducing hot air into the trough with the product

Veliki broj postupaka za proizvodnju takvih formulacija poznata je iz patentne literature. A large number of procedures for the production of such formulations are known from the patent literature.

Pripravke s kontroliranim oslobađanjem koji se mogu proizvesti granulacijom taljenja opisani su, na primjer, u DE 24 26 812, EP 351 580, EP 654 263, EP 672 416, EP 729 751 i WO 93/18753. Controlled release preparations which can be produced by melt granulation are described, for example, in DE 24 26 812, EP 351 580, EP 654 263, EP 672 416, EP 729 751 and WO 93/18753.

WO 93/18753 opisuje postupak u kojem se hidrofobne, voštane tvari netopive u vodi dodaju u već dobivene pelete u kasnijoj fazi proizvodnje, na temperaturi na kojoj se rečene tvari tale, što dovodi do oblaganja peleta. Ovaj postupak nazvan je «premazivanje vrućim taljenjem». WO 93/18753 describes a process in which hydrophobic, waxy substances insoluble in water are added to already obtained pellets at a later stage of production, at a temperature at which said substances melt, which leads to coating of the pellets. This process is called «hot melt coating».

Pod uvjetom da su svi početni materijali koji su uključeni u postupak termički stabilni pod uobičajenim uvjetima postupka, granulacija iz taljevine je zanimljiva alternativa drugim postupcima granulacije poput, primjerice granulacije uz uporabu organskog otapala ili granulacije uz uporabu vode. Provided that all starting materials involved in the process are thermally stable under normal process conditions, melt granulation is an interesting alternative to other granulation processes such as, for example, granulation with the use of an organic solvent or granulation with the use of water.

Peletizacija iz taljevine s tim u svezi predstavlja poseban oblik izvedbe postupka, u kojem se dobivaju granule izuzetno ujednačene veličine i okruglog oblika. In this regard, pelletizing from the melt represents a special form of performance of the procedure, in which granules of extremely uniform size and round shape are obtained.

Unatoč brojnim poznatim spojivim ekscipijensima, poznato je tek nekoliko ekscipijenata s stupnjevanom HLB (hydrophilic-lipophilic balance, hidrofilno-lipofilna ravnoteža) naročito prikladnih za postupke granulacije ili peletizacije iz taljevine. Despite the numerous known compatible excipients, only a few excipients with a graded HLB (hydrophilic-lipophilic balance) are known, particularly suitable for granulation or pelletizing processes from the melt.

Predstavnici nekoliko eksipijenata sa stupnjevanom HLB-om su hidrogenizirane jestive masnoće, koje nose zaštićeni naziv Gelucire, ili esteri sorbitol masne kiseline poznati kao Span. Međutim, čak niti oni ne pokrivaju široki opseg HLB-a od 1 do 16. Representatives of several excipients with graded HLB are hydrogenated edible fats, which carry the trademarked name Gelucire, or sorbitol fatty acid esters known as Span. However, even these do not cover the wide range of HLB from 1 to 16.

Kod konvencionalnih spojivih ekscipijenata, obično je moguće stupnjevati oslobađanje samo odabirom sredstva za polagano oslobađanje ili njegove količine. Često je moguće procesirati vezivo samo u kombinaciji s drugim vezivima koje se mogu spajati poput polietilen glikola, stoga što je njegov kapacitet tvorbe zrnaca sam po sebi nedostatan. Ova veziva dodatno zahtijevaju dodavanje maziva ili sredstava za oslobađanje iz matrice. Neki od njih imaju voštanu građu. With conventional compatible excipients, it is usually possible to grade the release only by selecting the slow release agent or its amount. It is often possible to process the binder only in combination with other crosslinkable binders such as polyethylene glycol, as its beading capacity is insufficient by itself. These binders additionally require the addition of lubricants or matrix release agents. Some of them have a wax structure.

Često je kod poznatih postupaka granulacije iz taljevine potrebno dobivene stvrdnute granule podvrgnuti detaljnom prosijavanju u svrhu smanjivanja veličine. Often, in known processes of granulation from the melt, it is necessary to undergo detailed sieving of the obtained hardened granules in order to reduce their size.

Kod postupka usporavanja oslobađanja premazivanjem, tanki premazi u nekim slučajevima su lako lomljivi, ali su također i relativno tanki, pa se često uočava oštećenje tankih premaza pri stlačivanju, osim ako se ne kompenzira relativno visokom vanjskom fazom. Ako je oštećen tanki premaz, povećava se intenzitet oslobađanja aktivnog sastojka iz tableta. To znači da oslobađanje aktivnog sastojka iz ovih tableta obično ovisi o sili stlačivanja. Kod ovog postupka, oslobađanje aktivnog sastojka se obično prilagođava preko količine raspršene tijekom proizvodnje. In the coating retardation process, the thin coatings are in some cases easily brittle, but they are also relatively thin, so compression damage to the thin coatings is often observed unless compensated by a relatively high external phase. If the thin coating is damaged, the intensity of release of the active ingredient from the tablet increases. This means that the release of the active ingredient from these tablets usually depends on the force of compression. In this process, the release of the active ingredient is usually adjusted via the amount sprayed during production.

Do promjene vezanih uz oslobađanje aktinog sastojka može doći tijekom skladištenja, ovisno o načinu tvorbe tankog premaza i poroznosti, primjerice zbog naknadnog otvrdnjavanja. Changes related to the release of the actin component may occur during storage, depending on the method of formation of the thin coating and porosity, for example due to subsequent hardening.

Jedan od ciljeva predmetnog izuma je dakle da omogući oralne farmaceutske pripravke s različito prilagodljivim svojstvima oslobađanja, drugim riječima od brzog do sporog oslobađanja. Kod oblika lijekova s promijenjenim ili polaganim oslobađanjem, namjena mu je da omogući proizvodnju kako lijekova koji se ne rastvaraju (tzv. "jednostruke jedinice"), kao i poželjnije brzo rastvorljivih lijekova s promjenjivim ili sporim oslobađanjem iz granula ("višestruke jedinice"). One of the objectives of the present invention is therefore to enable oral pharmaceutical preparations with differently adjustable release properties, in other words from fast to slow release. In the form of drugs with modified or slow release, it is intended to enable the production of both drugs that do not dissolve (so-called "single units"), as well as, preferably, fast-dissolving drugs with variable or slow release from granules ("multiple units").

Sljedeći cilj predmetnog izuma je da omogući postupke za proizvodnju takovih pripravaka s polaganim oslobađanjem, a posebice granulacijom iz taljevine ili peletizacijom iz taljevine. A further aim of the present invention is to enable processes for the production of such preparations with a slow release, and in particular by granulation from the melt or pelletizing from the melt.

Predmetni izum omogućava inovativne orlane farmaceutske pripravke koje imaju svojstva promjenjivo prilagodljivog oslobađanja, te osim jednog ili više aktivnih sastojaka sadrže jedan ii više saharoznih estera masnih kiselina kao isključivih sredstava za kontrolu oslobađanja. The subject invention enables innovative organic pharmaceutical preparations that have the properties of variable and adaptive release, and besides one or more active ingredients, they contain one or more sucrose esters of fatty acids as exclusive agents for release control.

Inovativne farmaceutske pripravke uključuju oblike lijekova kod kojih je (brzina) oslobađanja u rasponu od brzog do sporog. Innovative pharmaceutical preparations include drug forms in which the (rate) of release ranges from fast to slow.

Farmaceutske pripravke iz predmetnog izuma mogu se primjenjivati u obliku granula, peleta, tableta, tableta s tankim premazom, mikrotableta, tableta sa šećernim premazom, kapula i terapijskih sustava. Pharmaceutical preparations from the present invention can be applied in the form of granules, pellets, tablets, tablets with a thin coating, microtablets, tablets with a sugar coating, capsules and therapeutic systems.

Začudo, saharozni esteri masnih kiselina u stanju su kontrolirati oslobađanje aktivnog sastojka na željeni način, a povrh toga i poboljšati tehnološka svojstva u proizvodnji formulacija iz predmetnog izuma granulacijom iz taljevine ili peletizacijom iz taljevine. Surprisingly, sucrose esters of fatty acids are able to control the release of the active ingredient in the desired way, and on top of that, to improve the technological properties in the production of the formulations of the present invention by melt granulation or melt pelletization.

Saharozni esteri masnih kiselina su, između ostalog, također prikladni za granulaciju aktivnog sastojka bez dodavanja drugih ekscipijensa. Time se omogućava smanjivanje bruto težine u usporedbi s drugim postupcima, kod kojih se mora koristiti mnoštvo veziva ili spojivih sredstava za usporavanje otpuštanja. Sucrose esters of fatty acids are, among other things, also suitable for granulating the active ingredient without adding other excipients. This allows for a reduction in gross weight compared to other processes, where multiple binders or coupling agents must be used to slow down the release.

Saharozni esteri masnih kiselina, naročito stearati, s niskim HLB mogu se koristiti istodobno kao podmazivači ili sredstva za oslobadjanje iz matrice. Sucrose esters of fatty acids, especially stearates, with low HLB can be used simultaneously as lubricants or matrix release agents.

Saharozni esteri masnih kiselina su anionski surfaktanti koji se sastoje od mono-, di-, tri- ili poliestera saharida kao hidrofilne komponente i od zasićenih ili nezasićenih masnih kiselina kao lipofilne komponente. Moguće je promjenom stupnja esterifikacije i svojstava masnih kiselina proizvesti saharozne estere masnih kiselina s različitim HLB vrijednostima, što utječe na biofarmaceutska svojstva, a naročito na oslobađanje aktivnog sastojka, postojanost dobivene farmaceutske pripravke kao i njezina tehnološka svojstva. Sucrose esters of fatty acids are anionic surfactants consisting of mono-, di-, tri- or polyester saccharides as a hydrophilic component and saturated or unsaturated fatty acids as a lipophilic component. By changing the degree of esterification and the properties of fatty acids, it is possible to produce sucrose esters of fatty acids with different HLB values, which affects the biopharmaceutical properties, especially the release of the active ingredient, the stability of the obtained pharmaceutical preparation as well as its technological properties.

Oni su neotrovni, biorastvorivi, bez okusa i mirisa, te postojani pri skladištenju. They are non-toxic, biodegradable, tasteless and odorless, and stable during storage.

Saharozni esteri masnih kiselina s talištem > 30oC su u krutom agregatnom stanju pri sobnoj temperaturi i imaju HLB u rasponu od 1 - 16. Sucrose esters of fatty acids with a melting point > 30oC are in a solid aggregate state at room temperature and have an HLB in the range of 1 - 16.

Saharozni esteri masnih kiselina također se prodaju na tržištu pod nazivom šećerni esteri ili esteri tršćanog šećera, od strane društva Mitsubishi (zaštićeni žig Ryoto), Gattefosse, Sisterna i drugi. Sucrose esters of fatty acids are also marketed as sugar esters or cane sugar esters by Mitsubishi (trademark Ryoto), Gattefosse, Sisterna and others.

Saharozni esteri masnih kiselina poznati su u literaturi; na primjer, koriste se prema US 4 844 067 za poboljšanje površine svilenih vlakana, a u WO 93/17677 za poboljšanje okusa u farmaceutskim pripravcima. Sucrose esters of fatty acids are known in the literature; for example, they are used according to US 4 844 067 to improve the surface of silk fibers, and in WO 93/17677 to improve the taste of pharmaceutical preparations.

Glavno područje uporabe je u prehrambenoj industriji. Saharozni esteri masnih kiselina koriste se primjerice za poboljšanje miješanja sastojaka žvakaćih guma, za sprječavanje nehomogenosti i denaturacije gotovih napitaka, kod rafinacije šećera, kao bjelila (bijela boja - whiteners) kondenziranog mlijeka i kave. The main area of use is in the food industry. Sucrose esters of fatty acids are used, for example, to improve the mixing of chewing gum ingredients, to prevent inhomogeneity and denaturation of finished beverages, in sugar refining, as whiteners for condensed milk and coffee.

U proizvodnji jela od žitarica, saharozni esteri masnih kiselina koriste se primjerice kao stabilizatori, za poboljšanje teksture, za sprječavanje zgrušavanja i ljepljenje. Kod mliječnih proizvoda (koriste se) za stabiliziranje emulzije i sprječavanje degradacije bjelančevina. Saharozni esteri masnih kiselina poboljšavaju svojstva kristalizacije, učinkoviti su emulzifikatori te sprječavaju viskoznost u proizvodnji masti i ulja. In the production of cereal dishes, sucrose esters of fatty acids are used, for example, as stabilizers, to improve the texture, to prevent coagulation and sticking. With dairy products (they are used) to stabilize the emulsion and prevent protein degradation. Sucrose esters of fatty acids improve crystallization properties, are effective emulsifiers and prevent viscosity in the production of fats and oils.

US 3 896 238, US 4 150 114 i US 4 046 886 navode uporabu saharozni esteri masnih kiselina u kombinaciji s alkil sulfoksidom ili oksidima fosfora u farmaceutskim spojevima za poboljšanje penetracije aktivnog sastojka kroz kožu. US 3 896 238, US 4 150 114 and US 4 046 886 state the use of sucrose esters of fatty acids in combination with alkyl sulfoxide or phosphorus oxides in pharmaceutical compounds to improve the penetration of the active ingredient through the skin.

Konkretni navedeni primjeri saharoznih estera masnih kiselina su: saharozni monooktanoat, monolaureat, monopalmitat, monostearat i di- i triesteri recenih spojeva. Concrete examples of sucrose esters of fatty acids are: sucrose monooctanoate, monolaureate, monopalmitate, monostearate and di- and triesters of said compounds.

JP 81 75 437 opisuje uporabu saharoznih estera masnih kiselina s HLB-om u rasponu od 1 - 5 kao osnova supozitorija. JP 81 75 437 describes the use of sucrose esters of fatty acids with HLB in the range of 1 - 5 as the basis of suppositories.

WO 88/06880 opisuje uporabu saharoznih estera masnih kiselina kod lokalne primjene, korištenjem smjese mono- i dialkil estera saharoze s HLB-om u rasponu od 8 - 16 za poboljšanje penetracije kroz kožu. WO 88/06880 describes the use of sucrose esters of fatty acids for topical application, using a mixture of sucrose mono- and dialkyl esters with an HLB in the range of 8-16 to improve penetration through the skin.

Poželjna je uporaba saharoze kokoata, saharoze ricinoleata, sahridnog laureata i saharidnog stereata. The use of sucrose cocoate, sucrose ricinoleate, saccharide laureate and saccharide stearate is preferred.

Saharozni esteri masnih kiselina u znatnoj se mjeri rabe i u kozmetičkim proizvodima (FR 2 241 605, JP 81 24 034, JP 81 55 306). Sucrose esters of fatty acids are also widely used in cosmetic products (FR 2 241 605, JP 81 24 034, JP 81 55 306).

DE 40 03 844 opisuje farmaceutske spojeve koji, uz aktivi sastojak ciklosporin, sadrže i saharozni monoester masne kiseline i rastvarač ili nosač. DE 40 03 844 describes pharmaceutical compounds which, in addition to the active ingredient ciclosporin, also contain sucrose monoester of a fatty acid and a solvent or carrier.

Takovi spojevi omogućavaju smanjivanje doze ciklosporina potrebite za postizanje učinkovite terapije, pa time smanjuju i neželjene nuspojave. Such compounds make it possible to reduce the dose of ciclosporin needed to achieve effective therapy, thus reducing unwanted side effects.

Za ovu svrhu naročito prikladni saharozni monoester masne kiseline su: Sucrose monoesters of fatty acids that are especially suitable for this purpose are:

C6-14 - saharozni monoester masne kiseline i C8-18 - saharozni monoester masne kiseline. C6-14 - sucrose monoester of fatty acid and C8-18 - sucrose monoester of fatty acid.

WO 93/00093 opisuje inovativnu formulaciju za diltiazem sa sporim oslobađanjem u obliku sferoida koji su sastavljeni od aktivnog sastojka, navlaživača i polimernog premaza za kontrolu oslobađanja. Navlaživači koji se rabe su saharozni monoester masne kiseline. Konkretno usporavanje oslobađanja postiže se koroz polimer. U tom slučaju, navlaživač se procesira s aktivnim sastojkom postupkom protiskivanja ili postupkom granulacije s organskim otapalima. Proizvodi dobiveni protiskivanjem premazuju se konvencionalnim polimerima. WO 93/00093 describes an innovative formulation for slow release diltiazem in the form of spheroids which are composed of an active ingredient, a humectant and a polymer coating to control the release. The moisturizers used are sucrose monoester of fatty acids. Concrete slowing down of the release is achieved by the corrosion polymer. In this case, the moisturizer is processed with the active ingredient by extrusion process or granulation process with organic solvents. Products obtained by extrusion are coated with conventional polymers.

Primjeri navedenih navlaživača su također i C12-20 - esteri masne kiseline aharoze ili ksiloze. Examples of the mentioned humectants are also C12-20 - fatty acid esters of acharose or xylose.

DE 198 40 152 opisuje formulaciju sa sporim oslobađanjem koja uključuje kalcijev valporat, barem jedan akrilni polimer i barem jedan ester šećera, a tražena kontrola oslobađanja postiže se uporabom akril polimera. Navedeno je kako ester šećera sam po sebi tek neznatno usporava oslobađanje. DE 198 40 152 describes a slow release formulation comprising calcium valporate, at least one acrylic polymer and at least one sugar ester, the desired release control being achieved by the use of an acrylic polymer. It has been stated that the sugar ester itself only slightly slows the release.

Prikladnost saharoznih estera masne kiseline u farmaceutskim pripravcima predmetnog izuma kao jedinog sredstva za kontrolu oslobađanja tim više čudi jer su saharozni esteri masne kiseline poznati relativno dugo vrijeme, a s druge strane, od sada je omogućena proizvodnja oralnih farmaceutskih spojeva s različito prilagodljivim svojstvima oslobađanja aktivnog sastojka na jednostavan način. The suitability of sucrose fatty acid esters in the pharmaceutical preparations of the present invention as the only means of controlling the release is all the more surprising because sucrose fatty acid esters have been known for a relatively long time, and on the other hand, it is now possible to produce oral pharmaceutical compounds with differently adaptable release properties of the active ingredient on simple way.

Saharozni esteri masne kiseline korišteni prema predmetnom izumu su saharozni esteri sa zasićenim ili nezasićenim masnim kiselinama ili njihovim smjesama. Posebice su prikladne C12-22 - masne kiseline. Sucrose fatty acid esters used according to the present invention are sucrose esters with saturated or unsaturated fatty acids or their mixtures. C12-22 - fatty acids are especially suitable.

Poželjna je uporaba stearata saharoze, palmitata saharoze, laureata saharoze, behenata saharoze i oleata saharoze s HLB-om u rasponu od 1-16. The use of sucrose stearate, sucrose palmitate, sucrose laureate, sucrose behenate and sucrose oleate with HLB in the range of 1-16 is preferred.

Točka taljenja ili područje taljenja saharoznih estera masne kiseline koji se rabe prema predmetnom izumu je u rasponu od 30 - 200oC. The melting point or melting range of sucrose fatty acid esters used according to the present invention is in the range of 30-200oC.

Poželjna je uporaba saharoznih estera masne kiseline s točkom taljenja ili područjem taljenja u rasponu od 40 - 150oC. The use of sucrose fatty acid esters with a melting point or melting range in the range of 40 - 150oC is preferred.

Bitna prednost predmetnog izuma je da se tražena svojstva oslobađanja novih farmaceutskih spojeva mogu kontrolirati vrstom i omjerom uporabljenih saharoznih estera masne kiseline, ili parametrima proizvodnog postupka. An important advantage of the present invention is that the required properties of the release of new pharmaceutical compounds can be controlled by the type and ratio of the sucrose fatty acid esters used, or by the parameters of the production process.

Poželjna je uporaba saharoznih estera masne kiseline s niskim HLB za postizanje sporog oslobađanja. The use of low HLB fatty acid sucrose esters is preferred to achieve slow release.

Saharozni esteri masne kiseline s visokim HLB prikladni su za brzo ili promjenjivo oslobađanje. High HLB fatty acid sucrose esters are suitable for rapid or sustained release.

Saharozni esteri masne kiseline mogu se nalaziti u farmaceutskim pripravcima iz predmetnog izuma u omjeru 1% - 95% težine tvari koja se granulira (unutarnja faza). Poželjna je uporaba u omjeru 5% - 50% težine. Osim saharoznih estera masne kiseline, moguće je da unutarnju fazu čini samo aktivni sastojak ili smjese aktivnih sastojaka s jednim ili više farmaceutski uporabljivih ekscipijenata. Sucrose fatty acid esters can be found in the pharmaceutical preparations of the subject invention in a ratio of 1% - 95% of the weight of the substance to be granulated (internal phase). It is preferable to use it in a ratio of 5% - 50% by weight. In addition to sucrose fatty acid esters, it is possible that the internal phase consists only of the active ingredient or mixtures of active ingredients with one or more pharmaceutically usable excipients.

Sljedeće utjelovljenje predmetnog izuma omogućava premazivanje granula i peleta, koje u granulama ili sadrže ili ne sadrže saharozne estere masne kiseline u granulama, sa saharoznim esterima masnih kiselina. The following embodiment of the subject invention enables the coating of granules and pellets, which either contain or do not contain sucrose esters of fatty acids in the granules, with sucrose esters of fatty acids.

Omjer saharoznih estera masne kiseline u premazu je 1%-60% težine, a poželjno je od 3%-20% težine, računajući od oblika lijeka s premazom. The proportion of sucrose fatty acid esters in the coating is 1%-60% by weight, and preferably 3%-20% by weight, counting from the form of the drug with the coating.

Saharozni esteri masne kiseline mogu se rabiti sami ili, gdje je to prikladno, u kombinaciji s drugim spojivim ekscipijensima. U nekim slučajevima, dodavanje jednog ili više ekscipijenata poput plastifikatora je korisno za postupak. Sljedeća prilagodba oslobađanja aktivnog sastojka moguće je umetanjem tzv. porifikatora (pore formers), to jest ekscipijensa s posebnim svojstvima poput, primjerice, karakteristične topivosti ili sposobnosti bubrenja (swellability), tijekom postupka granulacije iz taljevine ili peletizacije iz taljevine. Sucrose fatty acid esters can be used alone or, where appropriate, in combination with other compatible excipients. In some cases, the addition of one or more excipients such as plasticizers is beneficial to the process. The following adjustment of the release of the active ingredient is possible by inserting the so-called porifiers (pore formers), that is, excipients with special properties such as, for example, characteristic solubility or swelling ability (swellability), during the process of granulation from the melt or pelletization from the melt.

Oralni farmaceutski pripravci predmetnog izuma mogu sadržavati aktivne sastojke u rasponu od u vodi lako topivih do praktično u vodi netopivih spojeva. Oral pharmaceutical preparations of the present invention may contain active ingredients ranging from easily water-soluble to practically water-insoluble compounds.

Za tu svrhu prikladni su aktivni sastojci sljedećih indikacijskih skupina, pri čemu sljedeći popis nije konačan: Active ingredients from the following indication groups are suitable for this purpose, with the following list not being exhaustive:

Analeptici/antihipoksemici (poput kofeina); anlagetici/antireumatici (poput diklofenaka, morfija, tramadola, tilidina, flupirtina); antialergici (poput azelastina, pseudoefedrina); antiaritmici (poput kvinidina, dizopiramida, diltiazema, verapamila); lijekovi protiv demencije (nootropici) (poput piracetama, nicergolina, ksantinonikotinata, pentifilina, vinkamina); antidijabetici (poput glibenklamida); antiemetici/lijekovi protiv vrtoglavice (poput betahistin dimezilata, dimenhidrinata); antiepileptici (poput karbamazepina, valproične kiseline, dihidrat kalcijevog valproata, retigabina); antihipertensivi (poput talinolola, fosinoprila, doksazosina, metroprolola, nifedipina); antihipotenzivi (poput norfenefrin HCl, dihidroergotamin mezilata); bronhospazmolitici/antiastmatici (poput salbutamola, terbutalin sulfata, teofilina); diuretici (poput furosemida, piretanida); sredstva za stimulaciju protoka krvi (poput buflomedila, naftidrofurila, pentoksifilina); sredstva za lijecenje ožilja (poput glicerol trinitrata, izosorbid mononitrata, izosorbid nitrata, molsidomina); sredstva za snižavanje razine lipida (poput bezafibrata, fenofibrata, ksantinola); sredstva protiv migrene (poput sumatriptana); sredstva za opuštanje mišića; sredstva protiv parkinsonove bolesti, te druga sredstva protiv ekstrapiramidalnih poremećaja (poput levodopa/benserazida, levodopa/karbidopa); psihoaktivni lijekovi (poput amitriptilin HCl, venlaksafin HCL, tioridazin HCl, litijev karbonat, litijev acetat); tioktična kiselina ili R-tioktična kiselina i njezine soli, poput dekslipotama. Analeptics/antihypoxemics (like caffeine); analgesics/antirheumatic drugs (such as diclofenac, morphine, tramadol, tilidine, flupirtine); antiallergic drugs (such as azelastine, pseudoephedrine); antiarrhythmics (such as quinidine, disopyramide, diltiazem, verapamil); anti-dementia drugs (nootropics) (such as piracetam, nicergoline, xanthine nicotinate, pentyphylline, vincamine); antidiabetics (such as glibenclamide); antiemetics/anti-vertigo drugs (such as betahistine dimesylate, dimenhydrinate); antiepileptics (such as carbamazepine, valproic acid, calcium valproate dihydrate, retigabine); antihypertensives (such as talinolol, fosinopril, doxazosin, metoprolol, nifedipine); antihypotensives (such as norphenephrine HCl, dihydroergotamine mesylate); bronchospasmolytics/antiasthmatics (such as salbutamol, terbutaline sulfate, theophylline); diuretics (such as furosemide, piretanide); blood flow stimulants (such as buflomedil, naftidrofuril, pentoxifylline); means for treating veins (such as glycerol trinitrate, isosorbide mononitrate, isosorbide nitrate, molsidomine); lipid-lowering agents (such as bezafibrate, fenofibrate, xanthine); anti-migraine agents (such as sumatriptan); muscle relaxants; agents against parkinson's disease, and other agents against extrapyramidal disorders (such as levodopa/benserazide, levodopa/carbidopa); psychoactive drugs (such as amitriptyline HCl, venlaxafine HCL, thioridazine HCl, lithium carbonate, lithium acetate); thioctic acid or R-thioctic acid and its salts, such as dexlipotam.

Poželjno je da farmaceutski pripravci predmetnog izuma sadrže flupirtin, tramadol, nifedipin, karbamazepin, kalcijev valproat ili retigabin. Preferably, the pharmaceutical preparations of the present invention contain flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine.

Farmaceutski pripravci iz predmetnog izuma mogu se po ovom izumu proizvoditi granulacijom iz taljevine ili peletizjom iz taljevine. According to this invention, pharmaceutical preparations from the present invention can be produced by melt granulation or melt pelletization.

To podrazumijeva zagrijavanje smjese aktivnog sastojka i jednog ili više saharoznih estera masne kiseline, a kada je to prikladno i s drugim ekscipijensima, uz miješanje u mješalici velike brzine. Zagrijavanje se izvodi grijaćim oblogama, mikrovalovima, energijom radijacije ili drugim načinom uvođenja energije u mješalicu. This involves heating a mixture of the active ingredient and one or more sucrose fatty acid esters, and when appropriate with other excipients, while mixing in a high-speed mixer. Heating is performed with heating pads, microwaves, radiation energy or another way of introducing energy into the mixer.

Granulacija započinje kada se dostigne točka taljenja konkretno uporabljenog saharoznog estera masne kiseline u smjesi, ili se njegova površina omekša ili pak djelomično rastali. Pojačana aglomeracija i s njom povezano trenje povećavaju potrošnju energije motora koji pogoni mješalicu. Granulacija se obično zaustavlja kada potrošnja energije počne rasti eksponencijalno. Nakon toga, vruće rastaljene granule se izbace iz mješalice i ohlade u tankim slojevima na sobnoj temperaturi ili se hlade u mješalicama prikladnim hlađenjem (na primjer, obloge za hlađenje), po mogućnosti uz miješanje. Granulation begins when the melting point of the specifically used sucrose ester of fatty acid in the mixture is reached, or its surface softens or partially melts. Increased agglomeration and the associated friction increase the energy consumption of the motor that drives the mixer. Granulation usually stops when energy consumption begins to increase exponentially. After that, the hot molten granules are ejected from the mixer and cooled in thin layers at room temperature or cooled in the mixers by suitable cooling (for example, cooling jackets), preferably with stirring.

Prema predmetnom izumu također postoji mogućnost da se saharozni esteri masne kiseline dodaju u rastaljenom stanju. According to the present invention, it is also possible to add sucrose fatty acid esters in a molten state.

Začudo, ovo ima za posljedicu veoma usku distribuciju veličine zrnaca. Granule ili pelete imaju, ovisno o načinu upravljanja postupkom, gotovo zaobljenu i glatku površinu. Surprisingly, this results in a very narrow grain size distribution. Granules or pellets have, depending on the method of managing the process, an almost rounded and smooth surface.

Također je moguće koristiti druge naprave sa grijanjem, poput granulatora s fluidiziranim koritom ili rotacijskog granulatora. It is also possible to use other devices with heating, such as a granulator with a fluidized bed or a rotary granulator.

Granule proizvedena na taj način mogu se, ukoliko je to potrebito, razvrstavati prosijavanjem, po mogućnosti pomiješani s ekscipijensima vanjske faze i na primjer stlačiti u tablete ili pakirati u kapsule. Granules produced in this way can, if necessary, be sorted by sieving, preferably mixed with excipients of the external phase and, for example, pressed into tablets or packed into capsules.

Ekscipijensi vanjske faze koji se mogu rabiti su uobičajeni farmaceutski raspršivači (dezintegratori) ili pomoćna sredstva za raspršivanje, punjači, sredstva za oslobađanje kalupa i slično. Obično je moguće izbjeći uporabu sredstva za oslobađanje iz kalupa ako se već koriste stearati saharoze s niskim HLB-om zato što su stearati saharoze s niskim HLB-om sami po sebi dobra sredstva za oslobađanje iz kalupa. External phase excipients that can be used are conventional pharmaceutical disintegrants or dispersion aids, fillers, mold release agents, and the like. It is usually possible to avoid the use of a mold release agent if low HLB sucrose stearates are already used because low HLB sucrose stearates are good mold release agents in their own right.

Na ovaj način moguće je proizvesti, primjerice, pripravke s brzim oslobađanjem ili promjenjivim do sporim oslobađanjem (jednostruka ili višetruka jedinica), ovisno o farmaceutskoj namjeni. In this way, it is possible to produce, for example, preparations with fast release or variable to slow release (single or multiple units), depending on the pharmaceutical purpose.

Začudo, također je uočeno kako su saharozni esteri masne kiseline prikladni kao ekscipijensi za premazivanje s vrelom taljevinom. Surprisingly, sucrose fatty acid esters have also been found to be suitable excipients for hot melt coating.

U tom smislu, određena količina saharoznih estera masne kiseline istog ili drugačijeg tipa ponovno se dodaje već proizvedenim i skrutnutim granulama, pa se smjesa još jednom zagrijava preko točke taljenja ili omekšavanja dodanog saharoznog estera masne kiseline. U tom slučaju, granule su premazane taljevinom saharoznog estera masne kiseline. In this sense, a certain amount of sucrose fatty acid esters of the same or different type is again added to the already produced and solidified granules, and the mixture is once again heated above the melting or softening point of the added fatty acid sucrose ester. In this case, the granules are coated with a sucrose fatty acid ester melt.

Premazivanje se također može odvijati u nazočnosti plastifikatora. Coating can also take place in the presence of plasticizers.

Također je moguće premazati granule bez saharoznog estera masne kiseline ili čiste aktivne sastojke na gore opisni način. It is also possible to coat granules without sucrose fatty acid ester or pure active ingredients in the manner described above.

Prednosti rečenog postupka su da se premazivanjem postiže primjerena kontrola oslobađanja, naročito usporavanje oslobađanja, čak i relativno malim omjerom saharoznog estera masne kiseline. S druge strane, na taj se način zaglađuje površina granula ili peleta. The advantages of the said procedure are that adequate control of the release is achieved by coating, especially the slowing down of the release, even with a relatively small ratio of sucrose ester of fatty acid. On the other hand, the surface of the granules or pellets is smoothed in this way.

Sljedeća prednost je da se ovim postupkom mogu proizvesti enterični premazi na jednostavan način. To znači da je moguće znatno odgoditi oslobađanje aktivnog sastojka u kiselom pH omjeru zbog praktične netopivosti saharoznog estera masne kiseline u vodenoj i kiseloj sredini. Another advantage is that this process can produce enteric coatings in a simple way. This means that it is possible to significantly delay the release of the active ingredient in an acidic pH ratio due to the practical insolubility of the sucrose ester of a fatty acid in an aqueous and acidic environment.

Vezano uz gore navedeno, praškasti premaz poseban je tip premazivanja s vrućom taljevinom. Jedna pretpostavka (ovog postupka) jest da se saharozne estere masne kiseline u slobodnom protoku odmjerava/dozira prikladnim postupkom praškaste isporuke, poput punjača praška, a druga je uvođenje plastifikatora, poput trietil citrata, u početne sirovine. Related to the above, powder coating is a special type of hot melt coating. One assumption (of this process) is that the free-flow sucrose fatty acid esters are metered/metered by a suitable powder delivery process, such as a powder filler, and another is the introduction of a plasticizer, such as triethyl citrate, into the starting materials.

Ovaj postupak odlikuje se znatnim uštedama vremena i troškova, a u usporedbi s konvencionalnim vodenim procesima premazivanja nisu potrebni postupci sušenja. This process is characterized by significant time and cost savings, and compared to conventional aqueous coating processes, no drying processes are required.

Farmaceutski pripravci dobiveni na takav način naročito su prikladni za aktivne sastojke osjetljive na vodu, poput Na valproata. Pharmaceutical preparations obtained in this way are particularly suitable for active ingredients sensitive to water, such as Na valproate.

Namjena sljedećih primjera jest ilustracija područja predmetnog izuma bez ograničavanja. The following examples are intended to illustrate the scope of the subject invention without limitation.

Primjer 1: Example 1:

Tramadol klorovodik s 50% stearata saharoze s HLB-om 1 Tramadol hydrochloride with 50% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

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Početne sirovine se zagrijavaju uz miješanje u mješalici velikog intenziteta Aeromatic-Fielder tip GP1 uz odgovarajuću temperaturu obloge. Kada se dostigne određena temperatura proizvoda, započinje proces granulacije. Nakon što se potrošnja energije motora mješalice poveća i dođe do naglog porasta temperature proizvoda, granulacija se zaustavlja i proizvod izbacuje, prosijava kroz sito s mrežicom 1,4 mm i hladi na sobnoj temperaturi. The initial raw materials are heated with mixing in a high-intensity mixer Aeromatic-Fielder type GP1 with an appropriate coating temperature. When a certain product temperature is reached, the granulation process begins. After the energy consumption of the mixer motor increases and there is a sudden rise in the temperature of the product, the granulation is stopped and the product is thrown out, sieved through a sieve with a mesh of 1.4 mm and cooled at room temperature.

Analiza: Oslobađanje aktivnog sastojka Analysis: Release of the active ingredient

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Vidi Dodatak 1 u svezi oslobađanja aktivnog sastojka. See Appendix 1 regarding the release of the active ingredient.

Primjer 2: Example 2:

Flupirtin maleat s 30% stearata saharoze s HLB-om 1 Flupirtine maleate with 30% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

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Proizvodnja se odvija jednako kao i u Primjeru 1. Production takes place in the same way as in Example 1.

Primjer 3: Example 3:

Nifedipin s 30% stearata saharoze s HLB-om 1 Nifedipine with 30% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi dodatak 2 u svezi oslobađanja aktivnog sastojka. See appendix 2 regarding the release of the active ingredient.

Primjer 4: Example 4:

Nifedipin s 30% palmitata saharoze s HLB-om 1 Nifedipine with 30% sucrose palmitate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi Dodatak 3 u svezi oslobađanja aktivnog sastojka. See Appendix 3 regarding the release of the active ingredient.

Primjer 5: Example 5:

Tablete izrađene od taljenih granula nifedipina s 30% stearata saharoze s HLB-om 5 Tablets made of fused nifedipine granules with 30% sucrose stearate with HLB 5

Formula: Formula:

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Parametri granulacije: Granulation parameters:

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Parametri za izradu tableta ("tabletizacije"): Parameters for making tablets ("tabletization"):

Granule su potom stlačene zaobljenim strojem za tabletiranje, promjera oruđa 6 mm, srednje zaobljenog, u tablete bruto težine 71,4 mg. The granules were then compressed with a rounded tabletting machine, tool diameter 6 mm, medium rounded, into tablets with a gross weight of 71.4 mg.

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Vidi Dodatak 4 u svezi oslobađanja aktivnog sastojka. See Appendix 4 regarding the release of the active ingredient.

Primjer 6: Example 6:

Tablete izrađene od taljenih granula nifedipina s 50% stearata saharoze s HLB-om 9 i 2,5% stearata saharoze s HLB-om 1 Tablets made from fused granules of nifedipine with 50% sucrose stearate with HLB 9 and 2.5% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

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Granule su stlačene zaobljenim strojem za tabletiranje, promjera oruđa 6 mm, srednje zaobljenog, u tablete bruto težine 100 mg. The granules were compressed with a rounded tableting machine, tool diameter 6 mm, medium rounded, into tablets with a gross weight of 100 mg.

[image] [image]

Vidi Dodatak 5 u svezi oslobađanja aktivnog sastojka. See Appendix 5 regarding the release of the active ingredient.

Primjer 7: Example 7:

Karbamazepin s 10% stearata saharoze s HLB-om 1 Carbamazepine with 10% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi Dodatak 6 u svezi oslobađanja aktivnog sastojka. See Appendix 6 regarding the release of the active ingredient.

Primjer 8: Example 8:

Karbamazepin s 30% stearata saharoze s HLB-om 9 Carbamazepine with 30% sucrose stearate with HLB 9

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi Dodatak 7 u svezi oslobađanja aktivnog sastojka. See Appendix 7 regarding the release of the active ingredient.

Primjer 9: Example 9:

Karbamazepin s 50% behenata saharoze s HLB-om 3 i 2,5% trietil citrata Carbamazepine with 50% sucrose behenate with HLB 3 and 2.5% triethyl citrate

Formula: Formula:

[image] [image]

Parametri: Parameters:

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Početne sirovine karbamazepin i trietil citrat miješaju se u mješalici velikog intenziteta Aeromatic-Fielder tip GP1. Nakon jednosatnog miješanja, dodaje se behenat saharoze B-370, te se smjesa uz miješanje zagrijava uz temperaturu obloge od 50oC. Kada se dostigne određena temperatura proizvoda pri kojoj se uočava povećanje (potrošnje) energije, granule se prosijavaju kroz kroz sito s mrežicom 1,4 mm i hlade na sobnoj temperaturi. The starting raw materials carbamazepine and triethyl citrate are mixed in a high-intensity mixer Aeromatic-Fielder type GP1. After stirring for one hour, sucrose behenate B-370 is added, and the mixture is heated with stirring at a coating temperature of 50oC. When a certain temperature of the product is reached, at which an increase (consumption) of energy is observed, the granules are sieved through a sieve with a mesh of 1.4 mm and cooled at room temperature.

Primjer 10: Example 10:

Tablete izrađene od taljenih granula karbamazepina s 30% stearata saharoze s HLB-om 9 Tablets made of fused granules of carbamazepine with 30% sucrose stearate with HLB 9

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

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Granule su stlačene bez drugih dodataka zaobljenim strojem za tabletiranje, promjera ravnog oruđa 13 mm, u tablete bruto težine 571 mg i tvrdoće 25N. The granules were compressed without any other additions by a rounded tableting machine, with a flat tool diameter of 13 mm, into tablets with a gross weight of 571 mg and a hardness of 25N.

[image] [image]

Vidi Dodatak 8 u svezi oslobađanja aktivnog sastojka. See Appendix 8 regarding the release of the active ingredient.

Primjer 11: Example 11:

Karbamazepin s 20% stearata saharoze s HLB-om 2 Carbamazepine with 20% sucrose stearate with HLB 2

Formula: Formula:

[image] [image]

Parametri: Parameters:

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Primjer 12: Example 12:

Kalcijev valproat dihidrat s 35% kalcijev hidrogen fosfata i 30% stearata saharoze s HLB-om 1 Calcium valproate dihydrate with 35% calcium hydrogen phosphate and 30% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

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Proizvodnja se odvija jednako kao i u Primjeru 1, uz pocetno uvodjenje aktivnog sastojka kalcij valproat dihidrata s kalcij hidrogen fosfatom. Production takes place in the same way as in Example 1, with the initial introduction of the active ingredient calcium valproate dihydrate with calcium hydrogen phosphate.

[image] [image]

Vidi Dodatak 9 u svezi oslobađanja aktivnog sastojka. See Appendix 9 regarding the release of the active ingredient.

Primjer 13: Example 13:

Tablete izrađene od taljenih granula kalcijevog valproat dihidrata i 30% stearata saharoze s HLB-om 1 Tablets made of fused granules of calcium valproate dihydrate and 30% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

[image] [image]

Granule su stlačene duguljastim strojem za tabletiranje, duljine oruđa 23 mm, a sirine 9 mm, u duguljaste tablete bruto težine 951 mg i tvrdoće 65 N. The granules were compressed by an oblong tableting machine, tool length 23 mm and width 9 mm, into oblong tablets with a gross weight of 951 mg and a hardness of 65 N.

[image] [image]

Vidi Dodatak 10 u svezi oslobađanja aktivnog sastojka. See Appendix 10 regarding the release of the active ingredient.

Primjer 14: Example 14:

Tablete izrađene od taljenih granula kalcijevog valproat dihidrata i 30% stearata saharoze s HLB-om 9 Tablets made of fused granules of calcium valproate dihydrate and 30% sucrose stearate with HLB 9

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

[image] [image]

Granule su stlačene duguljastim strojem za tabletiranje, duljine oruđa 23 mm, a širine 9 mm, u duguljaste tablete bruto težine 951 mg i tvrdoće 50 N. The granules were compressed by an oblong tableting machine, tool length 23 mm and width 9 mm, into oblong tablets with a gross weight of 951 mg and a hardness of 50 N.

[image] [image]

Vidi Dodatak 11a u svezi oslobađanja aktivnog sastojka. See Appendix 11a regarding the release of the active ingredient.

Vidi Dodatak 11b za usporedbu oslobađanja aktivnog sastojka iz formulacija s kalcijevim valproatom u pH 3.0. See Appendix 11b for a comparison of active ingredient release from calcium valproate formulations at pH 3.0.

Vidi Dodatak 11c za usporedbu oslobađanja aktivnog sastojka iz formulacija s kalcijevim valproatom u pH 6.8. See Appendix 11c for a comparison of active ingredient release from calcium valproate formulations at pH 6.8.

Primjer 15: Example 15:

Retigabin s 20% stearata saharoze s HLB-om 1 Retigabine with 20% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

[image] [image]

Vidi Dodatak 12 u svezi oslobađanja aktivnog sastojka. See Appendix 12 regarding the release of the active ingredient.

Primjer 16: Example 16:

Retigabin s 20% stearata saharoze s HLB-om 2 Retigabine with 20% sucrose stearate with HLB 2

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

[image] [image]

Vidi Dodatak 13 u svezi oslobađanja aktivnog sastojka. See Appendix 13 regarding the release of the active ingredient.

Primjer 17: Example 17:

Retigabin s 20% stearata saharoze s HLB-om 1 i 10% stearata saharoze s HLB-om 9 Retigabine with 20% sucrose stearate with HLB 1 and 10% sucrose stearate with HLB 9

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi Dodatak 14a u svezi oslobađanja aktivnog sastojka. See Appendix 14a regarding the release of the active ingredient.

Vidi Dodatak 14b za usporedbu oslobađanja aktivnog sastojka iz pripravaka s retigabinom u 0.1N HCl. See Appendix 14b for a comparison of active ingredient release from formulations with retigabine in 0.1N HCl.

Vidi Dodatak 14c za usporedbu oslobađanja aktivnog sastojka iz pripravaka s retigabinom u puferu s pH 6.8. See Appendix 14c for a comparison of active ingredient release from formulations with retigabine in pH 6.8 buffer.

Primjer 18: Example 18:

Tablete izrađene od taljenih granula s retigabinom, 20% stearata saharoze s HLB-om 1 i 10% natrijeve kroskarmeloze Tablets made of fused granules with retigabine, 20% sucrose stearate with HLB 1 and 10% croscarmellose sodium

Formula: Formula:

[image] [image]

Parametri granulacije: Granulation parameters:

[image] [image]

Parametri izrade tableta ("tabletizacije"): Parameters of tablet production ("tabletization"):

[image] [image]

Smjesa za tabletiranje stlačena je u tablete okruglim strojem za tabletiranje, promjera oruđa 9 mm, kosine 45o i polumjerom zaobljenosti R13. The mixture for tableting was compressed into tablets by a round tableting machine, tool diameter 9 mm, slope 45o and radius of roundness R13.

[image] [image]

Vidi Dodatak 15 u svezi oslobađanja aktivnog sastojka. See Appendix 15 regarding the release of the active ingredient.

Primjer 19: Example 19:

Retigabin s 7% stearata saharoze s HLB-om 1 Retigabine with 7% sucrose stearate with HLB 1

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Početne sirovine zagrijavaju se miješanjem u posebnom spremniku obloženim PTFE-om (politetrafluoetilen) u mješalici velikog intenziteta Aeromatic-Fielder tip GP1 uz temperaturu obloge od 50oC. Nakon što se potrošnja energije motora mješalice ponovno poveća, pelete se vade i u tankim slojevima hlade na sobnoj temperaturi. The initial raw materials are heated by mixing in a special container lined with PTFE (polytetrafluoroethylene) in a high-intensity mixer Aeromatic-Fielder type GP1 with a lining temperature of 50oC. After the power consumption of the mixer motor increases again, the pellets are removed and cooled in thin layers at room temperature.

[image] [image]

Vidi Dodatak 16 u svezi oslobađanja aktivnog sastojka. See Appendix 16 regarding the release of the active ingredient.

Primjer 20: Example 20:

Retigabin s 20% stearata saharoze s HLB-om 11 Retigabine with 20% sucrose stearate with HLB 11

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Proizvodnja se odvija jednako kao i u Primjeru 19. Production takes place in the same way as in Example 19.

[image] [image]

Vidi Dodatak 17 u svezi oslobađanja aktivnog sastojka. See Appendix 17 regarding the release of the active ingredient.

Primjer 21: Example 21:

Retigabin s 20% stearata saharoze s HLB-om 16 Retigabine with 20% sucrose stearate with HLB 16

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi Dodatak 18 u svezi oslobađanja aktivnog sastojka. See Appendix 18 regarding the release of the active ingredient.

Primjer 22: Example 22:

Retigabin s 16% stearata saharoze s HLB-om 15 Retigabine with 16% sucrose stearate with HLB 15

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Vidi Dodatak 19 u svezi oslobađanja aktivnog sastojka. See Appendix 19 regarding the release of the active ingredient.

Primjer 22: Example 22:

Tablete retigabina Retigabine tablets

Formula za taljene granule: Formula for molten granules:

[image] [image]

Parametri: Parameters:

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Formula za premaz Coating formula

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Taljene granule iz 5 raznih serija se sastave i prskaju u rotacijskom granulatoru s dovodom zraka na 50oC, na 300 opm u suspenziji Eudragita L 30 D-55, talka i trietil citrata u 536 g destilirane vode. Proizvod se potom suši sve dok temperatura ne padne na 33oC. Molten granules from 5 different batches are assembled and sprayed in a rotary granulator with air supply at 50oC, at 300 rpm in a suspension of Eudragit L 30 D-55, talc and triethyl citrate in 536 g of distilled water. The product is then dried until the temperature drops to 33oC.

Granule premazane na takav način homogeniziraju se s 30% po težini mikrokristalne celuloze i 5% natrijeve kroskarmeloze (težinski) 10 minuta u Turbula mješalici. Granules coated in this way are homogenized with 30% by weight of microcrystalline cellulose and 5% of croscarmellose sodium (by weight) for 10 minutes in a Turbula mixer.

Smjesa za tabletiranje stlači se u duguljaste tablete, 17 x 8 mm, konveksnim oruđem i prosječne tvrdoće 87 N. The mixture for tableting is pressed into oblong tablets, 17 x 8 mm, with a convex tool and an average hardness of 87 N.

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Vidi Dodatak 20a u svezi oslobađanja aktivnog sastojka u 0.1N HCl. See Appendix 20a regarding the release of the active ingredient in 0.1N HCl.

Vidi Dodatak 20b u svezi oslobađanja aktivnog sastojka u puferu s pH 7.5, 1,7% Texapona. See Appendix 20b regarding the release of the active ingredient in the pH 7.5, 1.7% Texapon buffer.

Primjer 24: Example 24:

Vruće premazivanje taljenih granula s retigabinom s 10% stearata saharoze s HLB-om 1 Retigabine Hot Coated Molten Granules with 10% Sucrose Stearate with HLB 1

Formula za taljene granule: Formula for molten granules:

[image] [image]

Parametri: Parameters:

[image] [image]

Taljene granule retigabina se zagrijavaju uz miješanje u mješalici velikog intenziteta Aeromatic-Fielder tip GP1 uz temperaturu obloge od 52oC. Stearat saharoza S-170 dodaje se pri temperaturi proizvoda od 30oC, a granulacija se nastavlja još 7 minuta i pri tom je uključena sjeckalica (3 000 opm). Premazane granule se otklone i prosiju kroz sito s mrežicom 1,4 mm. Molten granules of retigabine are heated with stirring in a high-intensity mixer Aeromatic-Fielder type GP1 with a coating temperature of 52oC. Sucrose stearate S-170 is added at a product temperature of 30oC, and granulation continues for another 7 minutes with the chopper (3,000 rpm) turned on. The coated granules are removed and sieved through a sieve with a mesh of 1.4 mm.

- Rezultati distribucije veličine čestica - Particle size distribution results

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Vidi Dodatak 21a u svezi oslobađanja aktivnog sastojka u 0.1N HCl. See Appendix 21a regarding the release of the active ingredient in 0.1N HCl.

Vidi Dodatak 21b u svezi oslobađanja aktivnog sastojka u puferu s pH 7,5, 2,5% Texapona. See Appendix 21b regarding the release of the active ingredient in a pH 7.5, 2.5% Texapon buffer.

Primjer 25: Example 25:

Dexlipotam (trometamolna sol R'-tioktične kiseline) s 22,7% stearata saharoze s HLB-om 15 Dexlipotam (trometamol salt of R'-thioctic acid) with 22.7% sucrose stearate with HLB 15

Formula: Formula:

[image] [image]

Parametri: Parameters:

[image] [image]

Claims

1. An oral pharmaceutical preparation with differently adjustable release properties, characterized by the fact that one or more sucrose esters are used as the only release control agent, apart from one or more active ingredients.

2. A pharmaceutical preparation according to Claim 1, characterized in that (the subject pharmaceutical preparation) is a drug form with a (speed range) of release from fast to slow.

3. Pharmaceutical preparation according to Claim 1, characterized in that the release properties can be controlled through the type and ratio of sucrose esters of fatty acids, and through the process parameters of the manufacturing process.

4. A pharmaceutical preparation according to Claim 1, characterized in that it comprises single-unit or multi-unit pharmaceutical forms.

5. Pharmaceutical preparation according to Claims 1 and 4, characterized in that it is in the form of oral dosage forms such as granules, pellets, tablets, coated tablets, microtablets, sugar-coated tablets, capsules or special therapeutic systems.

6. Pharmaceutical preparation according to Claim 1, characterized in that the active ingredient(s) are included in a matrix composed of sucrose esters of fatty acids and/or are coated with sucrose esters of fatty acids.

7. Pharmaceutical preparation according to Claim 6, characterized in that the granules or pellets containing the active ingredient or mixtures of active ingredients and sucrose esters of fatty acids can be additionally coated with sucrose ester of fatty acids.

8. Pharmaceutical preparation according to Claim 6, characterized in that the granules or pellets without sucrose esters of fatty acids are coated with sucrose esters of fatty acids.

9. Pharmaceutical preparation according to Claim 1, characterized in that the sucrose esters of fatty acids used consist of mono-, di-, tri- or sucrose polyesters with medium to long chain saturated and/or unsaturated fatty acids.

10. Pharmaceutical preparation according to Claim 9, characterized in that it is preferable to use sucrose with C12-22 - fatty acids as sucrose esters of fatty acids.

11. Pharmaceutical preparation according to Claims 1 and 9, characterized in that the HLB of the sucrose esters of fatty acids used is in the range from 1 to 16.

12. Pharmaceutical preparation according to Claims 1 and 9, characterized in that the sucrose esters of fatty acids used have a melting point or melting range in the temperature range from 30 to 200oC.

13. Pharmaceutical preparation according to Claim 12, characterized in that the sucrose fatty acid esters used have a desirable melting point or melting range in the temperature range from 40 to 150oC.

14. Pharmaceutical preparation according to Claim 1, characterized in that sucrose esters of fatty acids are present in the granules in a weight ratio of 1% to 95%.

15. Pharmaceutical preparation according to Claim 14, characterized in that sucrose esters of fatty acids are present in the granules in a preferred weight ratio of 5% to 50%.

16. Pharmaceutical preparation according to Claims 1 and 8, characterized in that the sucrose esters of fatty acids in the coating are in a weight ratio of 1% to 60%, in relation to the form of the drug with the coating.

17. Pharmaceutical preparation according to Claim 16, characterized in that the sucrose esters of fatty acids in the coating are present in a preferred weight ratio of 3% to 20%, in relation to the form of the drug with the coating.

18. Pharmaceutical preparation according to Claim 1, characterized in that, in addition to sucrose esters of fatty acids, other excipients may additionally be present.

19. Pharmaceutical preparation according to Claim 18, characterized in that fillers, soluble binders, disintegration aids, flow regulators, mold release agents, coating agents and/or other common excipients can be used as excipients.

20. Pharmaceutical preparation according to Claim 18, characterized in that it is possible to further modify the release of the active ingredient by including pore forming agents (porifiers) during the process of granulation from the melt or pelletization from the melt.

21. Pharmaceutical preparation according to Claim 1, characterized in that active ingredients ranging from easily water-soluble to practically water-insoluble active ingredients can be used as active ingredients.

22. Pharmaceutical preparation according to Claims 1 and 21, characterized in that the active ingredients can be used for the following indications: analeptics/anahypoxemics; analgesics/antirheumatic drugs; antiallergens; antiarrhythmics; anti-dementia drugs; antidiabetics; antiemetics/anti-vertigo drugs; antiepileptics; antihypertensives; antihypotensives; bronchospasmolytics; antiasthmatics; diuretics; means for stimulating blood flow; hypnotics/sedatives; means for the treatment of scars; migraine relievers; migraine relief; muscle relaxants; means against parkinson's disease, and psychoactive drugs.

23. Pharmaceutical preparation according to Claims 1 and 21, characterized in that it contains the following active ingredients: caffeine; diclofenac; morphine; tramadol; tilidine; flupirtine; azelastine; pseudoephedrine; quinidine; disopyramide; diltiazem; verapamil; piracetam; nicergoline; xanthine nicotinate; pentiphylline; vincamine; glibenclamide; betahistine; dimesylate; dimenhydrinate; carbamazepine; valproic acid; calcium valproate dihydrate; retigabine; talinolol; fosinopril; doxazosin; metoprolol; nifedipine; norepinephrine HCl; dihydroergotamine mesylate; salbutamol; tetrabutaline sulfate; theophylline; furosemide; piretanide; buflomedil; naphthydrofuryl; pentoxifylline; glycerol trinitrate; isosorbide mononitrate; isosorbide dinitrate; molsidomine; bezafibrate; fenofibrate; xanthinol; sumatriptan; levodopa; benzerazid; carbidopa; amitriptyline HCl; venlaxafine HCl; thioridazine HCl, lithium carbonate; lithium acetate; thioctic acid or R-thioctic acid and its salts, such as dexlipotam.

24. Pharmaceutical preparation according to Claims 1 and 21, characterized in that it primarily contains flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine.

25. Pharmaceutical preparation according to Claim 24, characterized in that the granules, apart from the active ingredient retigabine, contain sucrose esters of fatty acids in a weight ratio of 1 to 95%.

26. Pharmaceutical preparation according to Claim 25, characterized in that the granules contain, in addition to the active ingredient retigabine, sucrose esters of fatty acids in a preferred weight ratio of 5 to 50%.

27. Process for the production of a pharmaceutical preparation according to Claim 1, characterized in that the process in question is melt granulation or melt pelletization.

28. Process for the production of a pharmaceutical preparation according to Claim 27, characterized in that the starting materials are heated in a suitable device with stirring or in a fluidized bed to a temperature at which softening, partial surface melting or melting of sucrose esters of fatty acids occurs, and cooling after the formation of granules .

29. Process for the production of a pharmaceutical preparation according to Claim 28, characterized in that the melted sucrose esters of fatty acids are added to the heated powder of the active ingredient in a suitable device.

30. A process for the production of a pharmaceutical preparation according to Claims 28 or 29, characterized in that a high-speed mixer, a fluidized bed device or a rotary granulator is used as a preferred suitable device.

31. Process for the production of a pharmaceutical preparation according to Claims 1, 7 or 8, characterized in that the granules or pellets are primarily coated by a hot melt coating process or a powder coating process.

32. Process for the production of a pharmaceutical preparation according to Claim 31, characterized in that sucrose ester (esters) of fatty acids are used alone or in combination with plasticizers in hot melt or powder coating processes.

33. Process for the production of a pharmaceutical preparation according to Claim 32, characterized in that triethyl citrate, acetyltriethylcitrate, triacetin or dibutyl sebacate are used as plasticizers.