HUE024521T2

HUE024521T2 - Cineol új alkalmazási formái

Info

Publication number: HUE024521T2
Application number: HUE11003147A
Authority: HU
Inventors: Harald Dr Greve; Walter Dr Duchatsch
Original assignee: Maria Clementine Martin Klosterfrau Vertriebsges Mbh
Priority date: 2010-05-12
Filing date: 2011-04-14
Publication date: 2016-01-28
Also published as: MX2012013056A; ZA201208268B; WO2011141108A3; BR112012028868A2; RS53881B1; CA2798068C; PL2386296T3; GEP20156409B; EP2386296A3; EP2386296B1; DE102010022174A1; HRP20150230T1; WO2011141108A2; EP2386296A2; CA2798068A1; EA201100616A1; US20160000722A1; EA022173B1; SI2386296T1

Description

New spplesíioít for pfoao! iDescripfiors 11¾ present in^ofibn reiaíes toa dosage tea: es&ssinfeg clnegle embodied is: fos forte cí aóspsdte, fér tee perorai application, and: te $ method for fhe production thereof, m well as the urn thereof. in particular te the lets of human and veterinary medicine. FvOmmm, tee present: te^eitesdpeiates to 3 pitormaceuhoal or medio# protest comprising tee dosage teffo <teoy singdio^fe. I.S-Cteeo! belongs te tee bioyclic epoxy monsterpenes, more exactly to tee iimonene oxides. Synonymous deslgnsttons for ÍJ-efoeol, haying tee chemical! sum: formula CroHteS,: are sosafyptoi, iimorisne-lfooxibe:,: 1$^p®fy^eisfto<: *T exatecptep.ZálscIans. if te a odorless liquid having se afömate;, campteHike éi, with a melting pstet ni ««#:« boiling pofot st 1?8 te 1;?ΓΟ, which is insoluble is water,test is miscible with mosiof tes organic solvents.

Of cöorss, 1 ;8'díffiöie alsc occurs in other plants as tee main component of ebcaiyptus oil (eucalyptus oil contains up to 65% by weight of 1 te-eineteie), such as in mint., medicative sage... thyme, baste and In tea tree. Furthermore. 1 ,§-eineoto is also contained, for example, pepper, cannabis, oaiepA sage oil, myrtle si and ofoer essential ette

Technical 1 .S-efeeefe, *éisfe· $p$ggf %M. * peto®«te9d of Si# to §§M« is generally obtained by iractionafod diai lation of euealypipteCte

Ifocineoie is used m padssutar as an expaeforaniför bronchial; catarrhs, and other respiratory diseases, pgdominardiy m veterinary medicine, however, also as a fecrteg in the partem® iaddsby,: Furthermore. 1.8-emaote Is: used In dentistry «rite the revision of tobt

In a phystoidgibaf sense 1 .B-cineofe has an expectorant and oactehcidalelect in the upper and lower respiratory system, in particular fe tee lungs and tee sinuses,:It tertear Irtefofls certain nectefransmittom responsible; ter hatmwing: tee fefonoiaS: tohas, With: chronic ebstortelvs tong diseases; amd Pfspiteial, astern®,; teg: apnrfobaiton of sere t,S-sineote: may improve the kteg function, Due to corticosferoid-iiks effect it is used In tee case of severe respirefory diseases as a substitute for. or in oo-medioaiisrs with corticosteroids under systematic: application. 1,8-cteeole may generally be applied tepfeeliy, s.g Oy way of inhalation, or systematically, in particular in tee form of capsules.

As ® active Ingredient ijMbeoie also has expectorant and an?lhte§smmmpit effects, In the case; bf a systematic application. 1.8--cineols is slightly resorted, and then takes effect ones it reaches the respiratory organs via tee blood stream. I.S-cloeofe may, for and tough mtíct^.'teÍÉ'piss^s,^!íSöhte^.tofer^]^::pp£pgses te tee respiratory sptom. In this manner a blockage of tee secretory ducts Is prevented;, gfedebtivs coughing Is; facilitated, tee: function of the s!a in foe bronchia! tobes sod tee peso respon^bié for cianlng is: supported,. thus iteptovlhg veniaffon in the ;respifatofy system, ;!n tee ssm sf tee upper am,vays tte obsttoctfon: of nose hrsatelng ;te case of a osmmbh; cold!, and tee fesling of iighthesdadnass disappear.

For further details on the active togreosent l.8--ciosole reference may he made, for example. 1» toe Rgmpp Diopnary: si Chemistry. Georg Thieme V'erlag, Stuttgart/New Yom. 10* Edition, Volume !s 1996, page 752, keyword: "Ctoeokto as well as Itta literature died therein. CN 101 181 393 A describes the production of a gnanuists containing traditional Chinese medicinal components. sugar, eucalyptus 0¾ ginger tincture, and ephedrine. wherein the granulate is fiiad Into capsules.

Mterrnore, the scientific pulsation according to Chang etai>: Preparation of sigtnate complex sspsofes confetoirtg mfealyplus essential: pit and: its controlled release," Coffers- and SmMm & Bldntorfeces: 22 (2S931, :2§7-2S2 relates to the production of capsules üssed on an alpsfe icompfex, which are to contain eucalyptus oi

The appifeahfi own M W12909 §l| $£ III ifelafes to the use of a peroral moPOtofpene, and s respiratory therapeutic tor toe prophylactic, or Ésrapéuíto treatment: by way of Inhalation:,, !h particular a combination therapy of msplnafery diseases, such as hronchopuimonary diseases

Furtoeiimpfe:,. toe tsxfeobk excerpt according to “Fesfe ApneitormSG liiapseijf in::: Bmsr, & 'ft, Frőmming, Feme, C,;: :Phsrmaaeuiischs Technoiogte,“ 1993. Georg Interne Veriag, Siutigan, Volume 4; pages 324-335 relates to capsules that may foe used pharmaceutically in general.

Additionally, US 4 $MWM toitoes to a method fertoe prsdocherrof a gaiento teaiatioa, toe tnetosd composing toeptotoston of® ligáid mrxtore basing: an active ingredient arid a film-tonaing substance f ar this purpose, toe mixture Isto foe provided to droplets by TneSRS of spraying, and dried in order to obtain coated granulates, which win be subjected to subsequent iyophiiization.

Further, WO 9o/40Q?6 A1 relates to 3 method ito toe production of microspheres, or miorob-sads, wherein toe earner substance, as well as a precipitation agent are to be atomtoed, and brought into contact with each other.

Furtoennore. WÖ 2008/083032 A2 relates to a method tor toe production of polynuclear microcapsules, -wherein an aikexy silane is pcfemerssdis a multi-phase emulsion, to order to form a suspension: of the polynuclear microcapsutoson toss basis. mmmm?, m Wmmm H mm to a method tor the prpdpcfip Of: parties tor sss as·i pharmaceutical, whereto toe particles have a hydmphebic material, in pafticiar. whereto: hydrsphoiC: substances.: such as essential oils, are encapsulated to the particles with the aid of the nwtooct desprissb.

In the pdntod pufelicafophs DE 43 IS 5S4 C2, DE 41IS m S2, and W0 «835 A2, related to toe SsM.patent tomiiyv a combination therapy with peroral ly administered terpene compdhds, to particular 1,§*csnesle or menfePi and stso systsmicaly, :a patfeiisr psrpriiy adminisfered: corticosteroids, is described for the aoti-tofahtoistory treatment sf systemic, steroid-obligatory chronic bronchial asthma, whereto te use oi the perorafiv administered ferpsne compotmds is to reduce the requirement of systemic corrlcssteroids within the course of long-term therapy, for this purpose, preferably enteric-resistant, but smai: infest-ne-soiubie capsutes having the terpens based active ingredientare used.

For the systems application of 1 „S-cfesoie, various preparations: «to the marisét are available, ife particular based m capsules feat m snterlmresistant, feu}' small Intestine-soluble, wherein bath mono-preparations, arm so-eslied combinaloh preparations, containing 1 ,S-cirsQle in a complex mixture with a plurality' of additional terpenes, are available, or known. fesst of $m capsules available m the market, containing 1 J-drssole as the active ingredient, so not always generally comprise optimal tong-term slahifestisrr, m optimal prelection against the environment, in particular against air oxidation. Furthermore, a controlled release, or extended release, or delayed release: is not optimised, or not always possible with the capsule system containing cineoie known according: is prior art. Mm, an sptifepi dosing of the active ingredient is often not possible with the active ingredient capsules containing cineoie known according to prior art. Further, an optimal masking of taste and/or odar is oifers nof possible with the capsufe system containing dneoio known according: to: prior art. Additionaiiy, side effects may occur occasionally. In particular with the intake of higher dosages, such as stsmeobfeeiOn disorders, t« particular Indigestion, reflux, nausea, diarrhea, or Smile.

Iherefere, the present Invention is based on the object of providing m eUclenf dosage form for ί,δ-elheole as the active ingredient, which is intended for tire peroral application:, as well as a respective melhod for the production of said dosage form, fey means of which the disadvantages and side Sleets described above, occurring in connection with prior art, are at ieasf partially avoided, or at least partially diminished. in particular, fee present invention::! based on the object of providing an eleien! dosage form for f ,8-efeeoie as the acbve ingredient, for the perorat application, which enables an Imoroved release profile, anp/or an improved long-term: stabilization m terms of the active ingredient. In: psrfcafar, the protection of the active ingredient sgamst the environment, particular against sxidahon with air oxygen, is also to be improved, 3od addionaiiy so unproved dossng and/or handing of the active ingredient, in particular also within fee scope of the production: process tor the dosage form, is to fee ensured.

In order to solve the problems: described above, the pfsserit feventtors mcomineuds - according to a first aspect of fee Invention - a dosage form containing dnesie for the peroral: application to the form of capsules according to claim: 1i; additional, parficuiahy preferred,, and/or advantageous embodiments e! said aspect of the muentfen are the object: of the respective suts-eialms in this regard.

An addionei object of the present invention - according to a second sspeci of the invention: - is a method for the production of the dosage form containing cineoie according toffee present invention according to claim S: additional, pasfeifsriy preferred, and/or advantageous embodiments of said aspect of the invention: are fee object of the respective: sub-claims in fess regard.

Yet: another object of tha present Invention ~ according to a third aspect of the invention: - is the use: of fee dssap fomn containing: cineols according to the present invention according to claim: 11;; additional garbeeisriy preferred, and/or advantageous embodiments of said aspect of fee invention m fee object cf the respective suhtoaims in this regard ,

RnaSiy. another object öt íné present invention ~ according to a fourth aspect oi the: invention - is a pharmaceutical or medical iPhxfect according: to claim £4; addifisnai, psrticulady istenest, andfor advsr iiapous embodiments at said aspect oh fee Invention are fee obtest si fee respective sub-claims in Ms nsgarfe it Is undemtoed feat pa^coiar iesigns and embodiments described cnty toüm®ásm· «St an aspect #fee inventton, also apply «lit regard fe fee olher aspects of fee invention, without this being expfessiy described fetife ail rslative;,: or prcentep, in parfeiar weightfeased amount spctfcations stated below» lit should se noted feat said specfiieaitecs are: to ihe selected, or esrnhfeei, respectively,: by fee person sfcisd in fee art within fee scope si is cofepoaiion according to feehhverfeon sutfe feat m fee sum - epbonaiiyiinclodiing any apldnali components, or active ingredients, or additives, or pap, In particfear those dsifeed below - should always: result in or 1iS$ by weight, However, this goes without saying: for fee person stíled In fee: art

As to fee rest fee person skilled in the art knows that -- based on the application, or on a case-by-case basis - deviations may be made from the amount specifications below w-feout depffe: fee scope of fee present invention.

The applicant has now ourpi ,siugiy found trial feu problem ctoscrlDec. edOs—u, on wl-cn Ide ρτeso,, invenuon a based:.; may be so.ved in that fee active ingredient 1,8-cfeeoie is being provided within fee scope si a capsute-ln-capsute system, wherein the active ingredient Ϊ ,8-efesc'le is present in inner capsules or said cspsuie-in-capsule system such feat fee 1,8-cineoie may be released in a controied: or extended: manner after a systemic sppiieslon.

The Ofejefeufe fee presbrtt feyendpn:- according to á ϋ§| aspect off fee present invenlipn - is therefor® a dosage fenn containing: cfeeoie for fee: general applcaiisn jrtfee hm of a capsule,, fefeteeis fee dosage fenn is embodied as s capsole-in-capsuie sysferfe wherein feecspsuteeomapsute system: has sn outer capsule fextedpr dapsoiei: wife an outer capsote shell, and s plurality of inner capsules finisher capsuiesj located: insidefeifee spier capsule, wherein fee inner capsules am completely surrounded by fee capsule shot at fee order capsule, and the inner capsules are gmbPdSedias inisrQcapsuies:, esch ccniaimng fee active ingredient 1.&cinsoie, and

Wherein the inner capsules: comprise 1,8~c,;rseote, together wife at: least one physifeopcsiy aecept^sfe earner fexcipiemj feat Is miscibfe wife I.S-cinsois. or soluble therein, and is listed at 20*0 and at atmospheric pressure, wherein fee carrier is selected from fee group Gí tsgíyoeddes,

Tbd ptessht invention is connected wife a piarsir of advantages, impmvemente,, mid speoiaies, which set: fee present Invention apart írom prior art:

On one hand, fee dosage form according te fee invention based on the capsuie-in-capsuie system described above enables a sonireiied, in parfesiar also extended, or delayed release» Such that lor example, ills: possible to provide fee amount oi td-feneoie & be applied ter daily desing irt a single administration, while wife: conventionsi etneoia active ingredient capsules multiple administrate distributed over fete :dsy <m repteréé On fee ter te, fee dosage te according to the Invention enables an eicient longterm stabliaslsh dffee active ingredient lys-oineoie, in particular also against exidafifen, mg, fey means of sir eyyoen,: in particular fte active ingredient 1 .8-oineoie is protected ftom the environment in sn efferent manner such fet ice storage ImeS; are sígslfeaaöy sxtended as okossá its fenvenibnai eineole capsules,. Furthermore, Örs dosage form: according to the Invention soniáning clneoie ais© scabies m impnfe taste and/or odor mashing ot Ihé active: ingredient. As; to the rest; the dosing and mixing is optimised both daring tee production of tee capsules. and wir tee application thereof, with regard; to the active ingredient Fsriiwmo®, any andadired accessary symptoms or fesffects, in pafefe stpiafteW^^isorders. smte as indigestion. acidosis, reilux. etc., ere stpifioafdJy reduced, or even completely avoided

Sssed on the dosage fever containing dneole according to the invention on the basts of tee capsute-in-capsule system described above, the active ingredient 1,8-cineoie is effectively stabilized during tee storage thereof, and protected from environmental «femes. Os tee oteerfeamt, I peü an appfeiion term, wtedh enables a confeobed refers, or drug refsass with» tea scope of a so-caltó oonfroSed release efteefe is partólar. Iprig-tem;:, or extended release preparations may ba provided in this manner, which; release tee sete® ingredient i ;tecteedte over a; longer period of dtp in precisely fiotrfe&lled amourfe, te particular, selectively rétessé the active agent at tee site: of action. in psteeuiar, it has been tesen tete consideration; ter the Örst te within: tee scope of tee present; tevsife, and has been successfully achieved iter tee first fee to deliver 1 .S-ctesols te s mioro-encapsuiahon in tee manner mentioned above, and to design tee cspsuiedn-pagsule system on tee basis of the microeapsoias obtained in this manner, which enables m optimal active ingredient dosing and active Ingredient appiicstesa of t&cinecfe ~ accompsoied by the advantages described above.

According to prior art, ihewever. providing tee active ingredient 1,8-cineoie in a micro-encapsulated term within tee scope or a capsuie-in-capsuie system has eunshby neither been considered, m could such micfo-encspsulation have been realized, In parrlcmar, a has not oeen achieved in poor art thus far to micro-encapsulate 1.8-cineole in an efferent manner, which has been seeeessfeify achieved within ÉéiS0^#És-j^^Í^«^tet^-8mev'l|fe-ys^ «selected In this manner.

As explained above, fete active tegasdierd 1:;8-C!naoie is provided within tee settee of the present Invenitee ®ihte tee scope of a eapsule-in-oapsuie system, which has an outer capsule (e.xtenor capsule) with an outer capsule shell, end a plurality of Inner espsuies Interior capsules) located; inside of the outer capsule, whemin the inner capsules ar® completely surroundod by tee outer papsuie, and the Inner capsaies are embodied as. micrecapsulss, each comamlrig the active ingredient 1 f8~clnsole,

The term micro^hcapsuiafidrt, as ssed; according to tee invention, denotes, in psrfeniar, the sheathing;, embedding, ate: of tee acffve: ingredient fe.S-cineofe by means of ® suitable: ospsote, shall, & matbxtestenab as defined In further detaii below. With; mlcre-: encapsnlaPen, mlorocapsufes of deiinsd; size and; sice distefenben: m bfssted:, as; explained ibelow. For tels purpose;, generally core/sheli encapsulation. and matrix encapsulation are differentiated, iterdingiy, within tee scope ef tee present levente, tee mmcapsfemay he present eter» tee term of matrix capsules;, or te, the rerm or core/shell capsules. According to a proterred embodiment of tee Invention tee terser capsules are present in the term of matrix capsules Equally, within the scope of tee present invention it -s also possible te combine tee matrix capsules and the core/sheil capsules within a capsuleen-capsure system with each other. A matrix encapsulation is manner Irt which ιΐ is distributed across me entire microcapsute or microbead. preferably' in a homogenous and/or uniform distribution, whereas in ease of a core/sheli eneepsuisuon: 8¾ aetive ingraien|fs toeateo in the interior, or in the hollow space, of a capsule shell Idairix capsules are uíí^eesí m oadfefear, if a contnuiec, In particular extended and/or continuous release of the encapsufafel active ingredient. over a defined: period of time is to occur, wherein different release rates, máim different release profiles may fee adjusted fey means of the suitable selection of the matrix materials and of fee capsufe sizes, wile core/shefi encapsulations enable particularly short-term releases, or even releases over a very long period of time. in particular, the interior capsules of fee dosage form according to the invention have a capsule shell, or a capsule matrix, which encloses fee asffve irppdleoteipptefe|c:

For this reason, the capsule shell, or the capsule matrix material of fee interior capsules may generally fee identical or different with regard to the capsufe she!! material of the exterior capsule. Preferably, the capsule shell or capsule matrix material of the interior capsules is embodied differently with regard to fee capsule shell material of the exterior capsule, in particular, the capsule shell, or cepsuie matrix, materia! of the interior capsules may comprise at least one pharmacologically acceptable polymer, or consist of fee seme. According fo the invention synthetic, natural, and/or nature-identical polymers and poiymehzaiss are preferablyesed fer this purpose. Partisj^fe preferred, fee capsule shell of fee interior capsules may comprise at issstdne pharmacologically acceptable polymer, or may consist of the same, which is selected fi'cm the group of jAj pdiysacchafides:, in canicular spsafes, cellulose, and cellulose derivatives, onltosans, starch, and starti denvatives, Spr-agar, carrageens, pectins, gaiactemannas, § uarap,: dgxffaos, xanfeenfe giacans, and gum: Arabic: proteins,, in partieuisr gelatin: arid csseihsfes; |G| popaciMes, in padioufar ihomd and copdlymprs of iacfic acid: ID} ammo resins; {£}; polypefejacrylafes; fffj pslpreas:; :|@j pdiyslectfelytes, or poiyeleetroiyfe complexes;, {{f waxes; $). paraffins; (<| epildids and hydroccisids,, in particular based on: polysaccharide and/or protein; as well as fee: mixtures: arid odmfeinafions thereof; ite particular preferably seieefed from: fee group of ,|A| pplysaccfearides, in particular alginates, cefeiosa, and: pellulpse derivai#:. obifosáhs,, starch:,, and starch derivatives, agar-agar, camsgeshfe psoifes:, gaiacfomannas, guaran,, dax&ans,: xanfeans. giucans, and gum: Arabic:;: i$f proteins, in particular §slstin: and caseinates; .f C$ polyiactdes, in particular homo and copolymers of lactic acid: as well: as·the mixtures and combinations thereof. in general, fee inferior capsules of the dosage form according ·& fee: invention may fee. produced fey means: of droplet forming methods, interfasiaf golycondensafen methods, ihterfspis): pslysddiom mefeods, solvent evaporation methods, spray drying methods, or phase: separation mefeods, preferably by means of drsplef: forming mefeods., Axordingito the invenion: interior capsules are preferred, wh:ifeh::are available fey means, of the droplet forming mefeods; said interior capsules supply the best results wifeift fee seopeef fee· present: invention. Further details wife regsffelte fee :piodudori: method of fee Capsutes ars provided below.

Generally, fee dismste, in parScular the average diamiStereifes interior capsules, is smeller fey at least onsiofbsr si magnitude than fee diameter, In parfipy lar than fee average diameter,, felfed: exterior capsule.: in general the ratio of the diameter, in particular of the average diameter, o? the interior capsules to the diameter, in particular the average diameter, of die exterior capsule ;s alleast 1:2, in particular at least. 1:5, preferably at least 1:10, particularly preferred at least 1:15. most particularly preferred at least 1:20:

Commonly, fee ratio of the diameter, in particular of the average disovafer; of the interior capsules to the diameter, in particular is average diameter, of the e^por capsale Is gp to 1:100.000, In particular up to 1:50,000, preferably up to 1:15,000, particularly preferred up to 1:10,000, most parliaiarly preferred up to 1:5,000.

In general, the raSo of the diameter. In pameuiar of die average diameter, of the interior capsules to die diameter, in particular the average diameter, of the exterior capsule varies within die range of 12 to 1:100,000, in particular in the range of 1:5 to 1:00,000, preferably in the range of 1:10 to 1:15,000, particularly preferred in the range of 1:15 to 1:10,000. most particularly preferred in die range of 1.20 to 1:5,000.

The diameter, in particular the average diameter, of die interior capsules may vary within prosd ranges. Commonly, the diameter, in parleeiar fee ¾v(é^^i0*^(.«if¾8te^r':εapsöfes may vary withfe fee ranpof 0,1 pi to 10 mm, fee range of 1 pm to 8 mm, preferably within fee range of § pm to 7 mm, particuiariy preferred within fee range of 10 pm to 5 mm, most particularly preferred within fee range of 25 um to 4 mm, stiff more preferred within fee range of 50 urn to 3 mm.

For Ihfepipse, fee iÉ^FSái^siii^pete%'M(i«í:'3'TO*0a®^i grain

The diameter,. In particular fee average diameter, of the exterfef eapute may also vary to broad ranges. Cdmmoaiy, fee diameter, m partisuter fee average diameter, of dre exterior capsule varies ssfeln fee range of 50 ramie 100 mim, to particular vyifein fee range of 1:00 \m to ?5 mm, preferably within fee range of 2S0: pi to: 10 fern, particularly preferred within fee range of 500 jam is 50 mm. most: particularly preferred, wifein lito range of ?5δ μι® to 30 ;mfe:,: síi more preferred within fee m§é-ef1,000 pan to 25 mm feexplafeed: above, the eapsulsfevcapsule system aedtedlpg: te fes fevention comprises a plurality ot interior picracapsufes iecated In one exterior :eapsu!e, in particular, fee exterior eapsufe may contain at least two Interior capsules, in particular st feast live Inferior capsules, preferably sí least ten interior capsules, particularly preferred: at least fifteen Interior capsules, most parlsuiarly preferred at least twenty intersor capsules:. Commonly, fee exterior capsute may contain dp to 10.000 interior capsules, in pardcofer up to 5,000 inferior capsules, prfeetebiyipto 1 ,.090 interior capsules, prfeferiy preferred: yp to,SS0interior capsules, :msst: pardcularty furred1 up to 100 mlenor capsules. :With regard: te the: active: fegradlenii J-cinsote, fee: dosage: toon, or fee inferior may optain 1,8-

Ciheoi as the sole: active ingredient,: ar - according to ap alfernefive, hut less preferred embodiment ~ may contain: the active: ingredient IjiS-olnedle «ÍÉ: áí least one addionalsaetive ingredient,: preferably seteeted: from ferpenes, According to fetelhvention:* is preferred, f tee dosap fertft, ar the Inferior capsules according: to: fee invention oantaintecontsin: p-cineoie as tire sole active ingredient. £m$m te fee invention fee imebor capsoies rnm IT-ciRsoie &§Λττ* at leastone actsjpiabfe -ssafer (excipient} that is miscíhfe Λ 1.8-cineole, or soluble therein, and: felfesid at 2irC and at. atmospheric pressure. The carrier, or excipient: respectively, bseflis ph^a^isgíca^ilneieettve, but tos a preferably tooganoes mixture or soiuifen fegatber wife fee active ingredient Ι,δ-cineoie. in this manner a micro-encapsulation of the active ingredient 1 ,8-cineole is achieved within the scope of fee present invention, #5¾ -miid otherwise m he possible using eonventfepf mimstoapsuifefen methods.

According te the invention fee carrier, or excipient, respectively', is selected from the group of triglycerides, ptotiiar|: preferred from medium-dhsin feglycsfldes pCT}, particularly triglycerides having Csröt? iat|í acid residues.

According to the invention ft is preferred, if the carrier or excipient, respectively, is :ufed at a 1,8-cineofefcarrfer proportion within the i^nge of 1,888:1 "teltljtPi m parfiooiar 105:1 to 1:108,. preferably 50:1 to 1:5¾ parscPiady: preferred 18:1 Is 1::18, most: padicpiady preferred: Sri to 1:2, shit more preferred Sill to 1:1; in this mannar f pfbcuiariy good: misro-ebeapsulafion of the adive: ingredient 1 ,δ-cineöie fe achieved.

The term oils, as ussd acdsring to lbs invention: for the sapfers, or excipients mentioned adorn ts: a; eoltofe nsfes for ikpdx, which are not miscibfe wife: wafer The fsmvistty <$&,, as used according to the invention in this context, dsrsfees specraf fats, M. mixtures of My acid fegSycshdss, which are liquid a; room femperafere (in particular 20*C) and at atmospheric pressure; in pedicular said term dehpfes ftp esfers of the Ifivaicnt: alcohol glycerin }pfepene-i2;Miei) Λ feree.: mostly diterfe predominsady even-numbered; and uhhranched slpafic mdnosafeoxyiic: acids, the so-called fatty acids:. Compounds of das type are also ©ailed triglycerides fseesrdmg fe the recommendaticn. of iCFACf tisbylglysermss}, Thgiyceddes, also synonymously denoted as glycerol femesfer, are ah© the triple glycerin fmr§ fereé sold msiecuSes, wherein the pe%- “Pf refers to three acyl acid tssidpos,1 which are esferlted yafe: glycerin.

Especially medium-chain triglycerides, as biibgf aswdfe$ % lie invention as carriers, or excipients for the arise ingredient I,S-Cneofeto m particular sembsynfeefic.: neutal glycerin esters of satuft^d, censrsliy iUhdfeihched monocarboxylic :seids of average chain length fee, feChc}. In particular, fee to: medium chain fegiycerisss denotes fee msdores of triglycerides of saturated fatty acids, mamiy csprylic acid |oofeholc add);, aod©apflc add fdscanoic acid}. Generally, médium: chain triglycerides may be 'produced from oil. which is extracted from ids solid and dried par, of the endosperm o? Cocos tofera L, and/or from the dried endosperm of E!mm0mmm$M§· For further toils regserdfeg the top: medium: clsalh triglycerides, reference: may be made, far example, to feonographfe Ph, Eur,, 6* Edition, basic worKs 2088, pages 4224 to 4226, as: well as the Magsamé for Nuirfeohs! Science, volume: TS, issue: '% 1 §?3,. paps 6 ff., I), Sailer of al. IMs&eip Tf^toe - Attoe Tfepfeipfe und Aswemfer^i

The active Ingredient content (i.e. the 1,8-crneoi content) of tire dosageform according to the mvenbon may equally vary within broad limits: commonly, the dosage form acoonfing: te: fee Invention atoms the asfer© ingredient: 1,S-sinto in sbsoiufe amounts ism 18 to íiöOQ; mg, i psrticuiaf 25 to ?§δ ms:,, preferably 58 fa 580 r% pariiouSafiy preferred M is 308 mgi Ih igetferal, fee dosage form: according fe fee feventldn contfens die active ingredient tS-csnsefe fe ttom® emodnis of 1,81 to 58¾ by :«eight, In ;pariicular 81 to 85¾ by weight., :ptefer#ly 1 % 89% by weight,: particoferiy preferred 5 to 98% by weight.

Wlfoirs $3$ scope# És písstelfovenilsn ie; dosage fess. according teteissenfe is gepratty present In m enfeteteiterfo smafi: irtefesstóisíe le, %« dogags%m·$$$$$-'%&.mm entecm^istarif, ll srt iniesfinersefoble manner. ín this signer it Is asüÉ ii a sysfemfo sppi^lion isst te active Ingredient set released, until ítls;isö3te::sí te sete! resorption location. Late smalt fetestfoss. For this purpose, ®e exterior capsule, and/or the small infeslne-soiufeieferm:, a^d inay ^mie?'sfe^ fee stepped wits an etete teslant smali iintelas-'Sdiabfe ending or shell, Such enterteesistsnt, but small Itesfe-satefa coating or shaft materials am town as MkM the person skied ün te art feffgg putpose, for exáteífe^ ps^iac^fc aid polymers, in particular mefoaerylic acid/othyi aerate capoipers $&$ EudraglUj aaaf fee utilize# ferfotee? te#is regarding the tetecrylfe acid/ofoyf acrylate ccpoiymers allied for Ibis purpose, reiecence m$: Is mads, for example, fo: fsfonsgraphie Pth Eur,, P Edition, basic wrote 2008.. pages 3215 to 321:7, Assn aifernatfos, according to a preferred embodiment of the inversion, a mixture of oleic acid, stearic add, and ethyl cellulose may also Is cited: for Ibis purpose as the eiterteedslte emeli intteina-soiubie ceadr^ or caslrig, respectively.

Additional advantageous properties, aspects. and ebaraterislips ofiepissent invention: are obvious-frem te following descrípíisnef an axgidplaivennbodimentllitisiratelin me fpre, it shows:

Fig, a schematic sectloeai: mm iacross a dosap: form containing: cteoie escoof n§ to te itnvendonteteding to an embodiment df foe present invention.

Tbs only figure shows a dosage feme i containing cihesle, intended for fee: perofa! appilcsifon, embodied: in te form of a capsule, according to an embodiment os foe present invention. As seen from te illustration in foe figure, tedosage form 1 is embodied as a bdpA-in-capsuie system, wherein foe eapste-fo-capsufo system has one outer capsule /exterior capsule) 2, having an outer capsule shell, 3nd a piuratity of inner capsules Interior capsules) 3 looted inside of te outer capsule, wherein the inner cepsuies 2 are completely surrounded by the capsule shell of foe outer capsule 2, and the Inner capsules 3 are embodied as mlcrocapsuies. each containing the active ingredient 1,8-cteoie.

For further details regarding foe embodiment iestrated m foe illustration of the figure, reference may be made to the statements made-above for foe purpose In reference to: te lustration of foe figure.

Another object of the present invention - according to a second aspect of foe present invention -: Is a method for foe production of a dosage form containing cteole, as deserted above, wherein: initially mlorocapsutss sm produced, each containing the aefiye: Ifepsdient Ifhcteofe, fogefoer with at least one physiologically acceptable carrier (excipient) that is miscible with 1.8-cteofe, or soluble therein, and is liquid at 20eC and at atmospheric pressure, wherein foe carrier is selected from foe group of triglycerides, and wherein subsequently a plurality of foe microcapsules previously produced are completely surrounded by an outer capsule shell and is combined and/or joined into a cspsuie-in-capsuie system, with foe microcapsules being foe Inner eapsotes interior cepsuies).

As described or infonpr ospsdids:; mspsíáteíy, may be carried: out by means of droplet forming teisds, interfecisl piyeorsdensation method# Itefociaf poiyaPitipb methods, solvent. evaporation msihdde, spray drying: methods, or phase separation: methods. in a mmm preferable according: fo foe inveohfen, a: droplet forming method is utilized: for foe prodscta of fee írteKs^stfe, The as such te fee person sfeiiedfe the art but have thus far not been applied for either fee active fngradleof lifFoiftesie,. sr in the context of the total method seeording fa fee invention in combination with the rest of fie process steps,

Thus far in ^ art, l;a panelon of p caf^oteoo^psdis system containing igmeote, vlh ndefocapsuies centeining 1 J-cineoie as the ffter capsules: ptefisr capsules) has not bees successfully achieved, sines T:.gteinssfe is hot sassy processed ifemegenousty into respective pÉrooápSpíes without any problems., in pafecufar due to its relatively high melting point of+1 5‘C.

However, The applicants completely surprisingly and unexpdteiy feond feat fee production misroeapsaies containing 1,$-cfeeole, in particular as: hmt sap^ies fintensr capsules) <$. a eaptls>m'eap«ie system, may be carried oat successfully, if fee production of the mterosspspfes is earned out in fee presence of a carrier, or excipient, respectively, as described above, for the 1,8-cineois he. fee micro^npspsgiafsa of a mixture, or a solution of 1,8-cineote, and a carrier, or excipient, resgeeSvefy, of the type msnssned above , is earned sat lbs pis&idtisrs of capsules) containing 1 ,8teinasSe is cafeed oof within fee seeps of fee present invention by means of a droplet forming method:;, wherein a micTocapsuie forming base matériát fg.g. feginate) is provided In droplets in fee presence of 1£-o!neö!e. and optlonaiiy at least one physiofegicaiiy acceptable carrier (excipient) feat is miscible with 1.8-dngoie, or soluble therein, and is Siqutd at 20*C and at afeicspharie pressure, in gadioufar as deserfeed above, and is soldi Usd into mlofooapsolss containing 1 fprferfeer dafeifs regarding fee carrier, sr excipnt, respectively, reference: may be made to fee istafemefes made above in order to avoid unnecessary repetitions.

Wiiih fee scope: of fee production method according fe fee invention, the process step of fee micro-encapsulation of fee active mpÉehi Ifecfeecte may be carried out, in particular, as fellows: the: active ingredient hfecinsois is brought fete contact wife the csrrisr. or excpanf described shove, and is feorougiy, or homogenously mixed. The resulting: mixture orseiutian: of 1 Jmioeote, and fee earner, -or excipient, is then subsequently subject: to mimofenoapsuiatlon:.

For This purpose, fee liquid of 1 Jkrteeteefearrisr, or excipient, to be mícrcteoeapsuiated, together wife: fee capsule forming mágiái (eg. alginates), may be fed to a: suitable nosaie head; under pressure, and may be made:into mlcrospheres in dropiets by means of said noaale head, which may he carried out. fer example, by means of suitable virgfen,; due to which the liquid stream exiting from fee neaife head Is constricted into inmvHual segments, or spheres, sod separated, vfesch subsequently, in parteiar due te; fee surface tension, assume fee shape of spheres, andiaos then solidified: in a suitable medium feg. & suitable ico sslubeoi k misyofencapsuialpn rrsfehods feet rnayibe tetilteedifer this purpose: is described, for example, In FR 2 S45 43§ A1, or in ER 8 381 883 if ,belonging to the same pteot faiy, tea irsspecliVe disclosure content of which is hereby iricteded by reference, fececrbteg to said feefesd microcapsates based on aiginaie are: pmvidedby a droplet: terming method;. which may he, used in the case of fes :piasoht invention speclfieeiiy for fee micrbtehsapsuiatlcn of fee 1,S^lneolefeamer mixture described: above. For this: purpose^, the alginate droplets charged wife: fee active ingredient 1 íMeslé are sbfKlied in a suitable ion liquid; fe,g. calcium chloride solution). & fos fessem,: the árögifet %mii^:-*^Í8É':áss<«M.MMIpíéicS'oói $ foe míerooapsufos, or fos ínferkrcapsufes;, m 'NO §3?82?35 Mi end DE 41 25 133 A1. iss equally suitable, foe respective disclosure content sí which & hereby included: by iBfetóáaá^ M sáá method micreeagsuies based m atp# wherein for íns paposé áigfoate based on atgfoste, already eerdairiíng: the described mixture, m produced: írom droplets of ars alpsíe sóialöri discharged írom; 3 soeele by meahs o# solidifying foe Iropfotsty means# plapihq said droplets info m m sotodon, and optionally fey means of subsequent washing oflbe e^íRafo sphere: reaped &m «aid ion solution, wherein the aígfosfosísSofen droplets may be separated by means of vibration excitation, and the droplets are essentially freeiy movable until the desired soliditioation takes place in foe ion solution.

The disclosure content of all previously mentioned printed publications mentioned in the context with micro-encapsulation is tsereby inetedpd by rsforsoss; such foat for further details regarding foe prodaotiso of foe pcrocapsuies to be produced according to foe method according: to foe invention reference may be made to foe printed publications mentioned above

The method of micro-encapsulation is also carried out in a manner generally known to die person skilled in foe art, however. padfeuladypt55?jeed that a and spseácaSly excipients, er earrisrs as described above is utilised for the iivvXliw w encspsu&son.

Subsequent to the process steps of foe production of foe active ingredient roicrocapsuies containing 1,8-cineole, the attachment of the exterior sheii, or exterior layer onto each, or around e plurality of miciocapsuies produced In foe manner is then carried out. This is a process: step: that is generally W&m to foe -p&m skied: fo foe art such iat fodder details fo ids regard my be omitted.

Wifo regard: fo fcrihsr defoiis oh foe method asssrdmg: to foe invention, reference may be made to foe statements mede above regarding foe dosage form ascsfofog to foe invention, which apply accordingly regarding foe method according to: foe invention, m order to avoid unnecessary repetition,

Another abject o:f fo«: presentlnvenfiori - aeedrding: to a third aspect bí tse present Invention - is a: dosage form containing oineele accordlpgilo the present invention torosé fofodman medicine and: in «efoÉáry foédidifie.

The dbjeot df the present foysritiprt is therefore sdosdpform confining: cinaals for foe prophylactic endfor therapeutic treatment of Irifiammstory.; infection exacerbating, or allergenic diseases of foe human or animal body. Equally, foe dosage fsnrv according to the fpyentíon may also fee deed fér the production of a pharotaoeeiicsj: for the prophylactic and/or foerspéúfid: troatfodnt of Inlaroroaisry, infection exacerbating, or sitergenic diseases of the human or animal body.

Equally, foe dosage form containing: cineöfo according: fo foe haverien rosy also be used for foe prephytafofo sndfor therapeutic treabnent of autoimmune diseases of the human or animal body.

FbriMroiore, foe dosage form containing cjnsole :8sceiidipgi fo foe invention may alsó :he used for foe prophylactic snd/or foerapeubc: frsaimsnt o? the: common chid and the la, as well as diseases and: infections related to foe same, in padfouiar iSifeohdhsfof ifoe upper sod lower resplrafoty systems, in peicular rhinis,: sinusitis, arid: bronchopulmonary diseases.

Further, :Éé Sör® eorSfefefeg cineote sw^· to tirfevegÉfe *®%· aÉSfeíü used sor fee pröífeyiacife and/or feerapsutio h particular of örcnctenlmonary diseases, fegsrhefesr bfonchiils; bmnchisf asfema, má chronic oifeifucfee pulmonary disease p8PD|. in this contest oeybedlcsiísu fepther wife pfeer fearapSúics, 0 pharmteuifeis, É páöiöiJiar ööfióöSism^s, is also possible,

Equally,; fee dosage farm cofeaififeg cineofe according \o fee;invention ma# also be mad; fer ti® pe#j|acilc and/or fesrapsulic treatment of infefamslsry diseases; sí fee blary trsct, in particular chotecystiilS: and cholangitis. ;Fu|hetmore;f fee dosage fen® ephteinmg cioeole according to; fee famtommy slop; bp used for fee |i^|tec::i^^"^sp6iic treatment of Mammafery feteses of fee urinary tract ecftestioh system, in; particular gio®arufeneghn% ppfeoepbitis, cystitis, arid

Wmm-

Also, fee dosage form containing cineoie according to IP mmmt may equally be used for fee prophylactic and/or therapeutic treatment of iffeaesmafery isespeef ise colon, in particular Crehn’s disease and colitis ulcerosa.

Equally, fee dosage form prMnfeg: eineofe according to fee invento may also fee used for fee prophylactic sndtor therapeutic treatment of inf emfeafery or allergenic skin disease, in particular eczemas end dermatitis

Further, fee dosage form containing dineeie accsrdfeg to the Invention may else be used for fee prophylactic and/or therapeutic treatment of feeernaioid diseases ;fee, ifeenmafeid, fecmmatisrfe as well; as aStferseases of fee feeumafold morphogenetic region^,

Ffeslfe fee dosage form pnfelnfeg cineple according to the inyentiarv may also be used fer fee prophylactic and/or feetspeqflo treatment of systemic coildCfeercid^cbiigafery disease |e. all diseases, which must be treated wife systernicaiiy admfeisferes coiiicostaroidsi, This may fee: explained by means efifee codfeoaleroidalipbarmasoiogfeaf eiscfeahesS: profile of Id-feheoie. fe&h ail used fegefeer wife atteastiose addfeditaiifegiipferfid ahdfer pharfeteUScaf is possible, feilfefe fee; scope of fee use «xordin§ to the1 invente fee dosage fórra Cgrifelnfeg cineola i$ commcniy pdfeinisfered In such amounts thstvftfecfeeole IS ádmfeísisrsd in daily dosage» cl 50 fe 3,000 mg/diefe, in gsicular 100 to 1000 mg/iem, preferably Mi do 1,000 mg/dserg, and/or feat fee 1,8-cineofe is prepared tor administrate of s daily dosage of 50 is 3.0S0 feg/disfe, In particular 100 to 5.000 mg/d!sm:; preferSbiy 200 In 1,000 mptre®. ;For lurfesr details regarding the use according to fesfeverta, ieiSrshca msy be made to fee statements feeds shove regarding the dosage ferm according :fe fee invention, and fee fedduete method according fe: the: invention, in order to avoid unnecessary rppeiloo; which eppiy accordingly with regard in fee use according tc the invention,

Finaiiy, anofeer cfeíecí of ippsepf invention ~ according to a fourth ascsct of the present invention - is a pharfeaceeiicai or medical product comphsrng fee teapfer® oontafeing eirfeole described; shove according to fee Invention.

Within the scope of the pharmaceutics! or medics! product according to the invention, the pharmaceutical or medical product is prepared, s* parfeuiar tor administration of 1 tb-cioepteM a daiiy dosage of 50 to TOGO mg/dim, in particular 100 to g,0SG mgMiem. preferably 200 to 1,000 mg/oiem.

For further details regarding the piharmaceuiica! or medical product according to ire Inuptlom reference may be mads to the statements made above regarding the desage iormaocsrding to the invention, the production method according to the invention, and the use according to the invention, in order to avoid unnecessary repsÉiem which apply accordingly with regard to the use according to the invention.

Further embodiments, modifications, and variations, as well as advantages of the present invention are obvious and realisable by the person skied in She art without any problems horn reading the description, without departing lorn the scope of the present invention.

Tha present invention h'wm- illustrated has*!: m the Mowing exemplary embodiments, which, however, do set Smi the present invention in any manner.

Sxemoiarv embodiments:

Frodbdfion of a dosaee form accordion to theibvenfion A dosage form according to M invention based on soapstfeiinreepsuie sptshr is produced as follows: initially, a homogenousmixture Posed on 1.8-cineeféénd medium chain:trigperidesk produced ata

Based on said 1:,Sreinools/tngiycsrids mixture, matrix microcapsules based on atpata are subsequently obtained according to the method :sbd:: devise of FR 2 645 436 At, which contain the sdiiya Íftgmdtó i jmpsrde, by means of the droplet forming method described therein. : For this purpose,: no aqueous sodium agnate soldto, coniathing the 1,8-cineo!eArigtyserida mixture described; shove. is produced, optisodiiy together with common additives, and said: aqueous sodium adnata solution containing 1,8-eineme is subsequently added Into a: Pross-ilnKed solution containing csteum chloride by means of dfeptefs, in a pceraliy known manner, which further may also within common additives (e g. surfactants, etc}.

This: results in matrix m«rocapsutes containing %$<md as the active ingredient, with, alginate as the matnx material. The miorocapsulss obtain in this mariner :ars subsequently puriedi,, and: qpfeaiiy isolated:.:

As an ahsmative tp ?8# mode of bpersbsn described above, initially pure matrix; mirwrapsules: based os algipais $& Fmtrlx silofocapsuies, which ere produce# wifhbut ths active way also be produced according to FR 2 64S 43§ At, which subsequently nns inserted into a solution based on the: %|*oiheoíeftfíg!ycéridé mixture: described 3bsve. and ere charged with Issameihfita manner,

The matrix rnfcrccapsuies charged wish: the :aciive agent 1 .Nihecle oinaioed in Éis manner are subsequently further processed into te: sspsnlenmoapsuie system m a mermer genoraiiy known,: th that each piuraly όί the mSerc&apsdiss described above is surrounded by sn exterior she!!, F!na!!y,:: the exterior shell is equipped with ah enterimresistshbIbut sma!i: inlestioé'-solubie coating. For this purpose, fmoíhíaoíyiö acid pbiymerS,: In particuisf methactyiic aeidiieihyl acrylate coppiymors fe.g, iudragit®?. may ;be obiiaed. ..½ an aitamabve, however, ® mixture o? oleic: acid, steeds aoid, and ethyl cellulose may alaO: be ufedfor this purpose. 1¾ dosage form according: te fee iwfp. containing 1 ,&-cfoecjie se w mim mgrísdJent based orr a eapsuie-imcapsule system ss described above is utilized wsfeih fee scope of fee treatment ef asfefea in cö^eáes^ön: wife ccsticosteroids.

CtemfeSíciaiiv available capsules enfefefoing semi; as s comparison. each containing 2Q8 :rn§ eí |,3-dne^: psísapsiSe, wherein fee commercially swsiiabis capsules heve a liquid nucleus containing IS-sinede, and an safer, enteric-resistant, but small imestine-solubie shell layer.

Wifoln fee scope si tee tdmfcai application observations, 15 fost parsons each are Seated with esmteercally avalahfo eapsuies containing 1^δίη§δΐ& Λ :|^^ admíresöeööns of 200 mgidefe on one hand, and wife tie dosage forrwsosprbing to fee invention wife» & W '®$ém onse, on foe ofeerhand,Aleratfera?^of cnty 4 days wife (rise of FsV;, decrease of fespifafory resistance, raw) i$ equally Improved, and in all cases the daily corticosteroid requirement may be reduced by approximately 5D% to 60% due to an increased stabilisation of tie bronchial asthma. Within the scope of fee dosage form according to fee Invention fee only once a day administration wife an effective dosage reduced by 100 rng/drem has fee same effect as fee triple administration of 200 mg/diern each with commercially aveiiabfe capsules, which do not contain the active ingredient in a microencapsulated form. A long-term therapy with 1,8-clneole is tolerated significantly better wife the capsule-isvcapsufe system according to fee invention, in particular fee side effects thereof, such as stomachfcolcn disorders, in particular indigestion, acidosis, and reflux, are significantly reduced.

The storage stability under standardised storage conditions Is also Improved by more fear; 70%, and thereby optimized, in the case of the dosage form: according to foe invention as opposed to the commercially available capsules containing 1 .S-cineole.

Within the scope o? foe product-on meted according to fee invention fee adjustment; pi; the active ingredient amount per capsule is ferfesr significantly improved, and thereby opifemisd, m opposed fee production of cammemialy available espsufes contsining íveléseié.

As a result fee dosage form according fo fee invention based on tee; espsuie-in-eapsufe system containing 1.8-clneole leads to an improvement andi dpffmteaiien wife regard: fo foe producibifffy and; the application properties, of capsule systems oontsihfeg 1,8-cineoie,

Addif i^cjiicaLagjicalfon ebseryations

The dosap form i j-sinecie as an active ingredient based on s sapsui^in-capsufe system as: described above is utilized within fee scope of tee treatment of Cretin's disease and colitis ulcerosa In co-msdreaiicn wife soicosterslds.

Again, csmmerciaiiy avslable capsules contateshg 1 J-eineole serve as a compatisom, each confeinfe| 280 mg of tartós per capsule,, wherein fee commercially available capsules; have a liquid nucleus: containing 1 ,δ-eineeia., and: an eufoq, entenc-reslstant, but small thtesfinfesdluble shell layer:

Wlfein lie sccpe-of the clinical application obssmaldns:, 12 test persons; each are: treated wife commercially available capsules containing one hand,: and wife fee dosage form according to fee Invention wife; a one-time administration of 500 mgfdrera once, on tie other head.

Dee to the inflammatory component, Crohn's disease and colitis ulcerosa may also be stated within fee scope of the clinics: application analogous fo the therapy of bronchia! asthma, using tee same fforapy regime.

Inthis case the same positive clinical affect pay be:Viewed'wife fee dcsap farm apördiítg to the invmdion át the íovyef dosage, which is reflected in the feet that the frequency of bowdf moveifsanis is reduced by apóst halt TP dosage of the systemic corticosteroids may also be reduced by about 18% te 78%. Within fee Step of tee dosage form aecotding to invention the once daily administration of an estiva dosap reducedpy 180 mgtetem; brings about the some affect, as the tepid dosap öf 200 mptiemeacb in pmmoreiaiiy avalfabfe capsuias, which cte not contain the active ingredient in a ndero-encapsulated term.

Ctemprabte fesuife are atso obtained with the therapy of systemic eomsssterotiPhligstGry rheumatic or rheumatoid diseases: ih §# ease, the dosage of the systemic ooftipsterdids may also PfeduPd by apm»Wy :50% te 70%, wherein in ibis regard the once •daily administration of so active dosage reduced by 180: mg/diem also brings shoot fee same effect, as fee tdpte dosage of 288 mg/diem each in commercially availahie capsofes, which do not eantainfee active ingredienfin a ffiterop®apsulated term.

Claims

Öd ALKALMAZÁSI FORMÁI SZABADALMI IGÉNYPONTOK

1, Cineoit tartalmazó dózisforma peroráks alkalmazáshoz kapszula tormájában.. ahol a dözistorrna: fendsiteként vart megvalősílvs,; M a kagszuis-e tsaptóáta rendszernek mt'W kösse kapszulája (kinti (exteriőr) kapszulái ep külső kapszula héjjal, és rendelkezik belső kapszulák [benti (interior) kapszula] sokaságát, amelyek a külső kapszulán belöl helyezkednek el, ahoi a belső kapszulák teljes mértékben körül vannak véve a külső kapszula kapszula-bájával és a belső kapszulák úgy vannak megvalósítva., mint mikrokapszulák.. ahol mindegyikük tartalmazza m 1,8»oineoi aktív alkotórészt, és ahol a belső kapszulák tartalmaznak t;iS-slbeöit tegalábő egy Szlötogtátfag elfogadható hordozóval (kötőssyaggaif egyBto amely összekeverhető 1,8-cineoilaí, vagy oldódik benne, és folyadék formájú 20-C bőmérsékleten és atmoszferikus nyomásnál ahol ez a hordozó a trlglícerldek közül választható ki.
2, Az 1:, igénypont szerint; dózisforma, mat jellemezve, hop a beiső kapszulák magbslső/héj (core/sheíi) kapszulák formájában vannak jelen, és/vagv a belső kapszuláknak olyan kapszula héja vagy kapszula máirixa van, amely tepsi mértékben magában fogtállá az aktív álkölörészt P/vagy 8: belső kapszulák kapszula bej vagy a kapszula mátrix anyaga lehat azonos vagy lehet kűtönbözi a külső kapszula kápszaíá bej; anyagához viszonyítva, és előnyösen különböző,
3, Az i vagy 2. igénypont szerini dtesförme, azzal felieméivé; hop a belső kapszulák kgpöznts héj vagy kapzuis mátrix anyaga feimáz; legalább egy gyógyászstüag elfogadható polimert, vagy állhat Is ebből; ezek elsősorban szintetikus, természetes vagy temvészeiazonos polimerek vagy pokrnerizátumok, amelyek lőieg a következek köpi választhatók ki: (A) peiiszsöhapöok, elsősorban aiglnátok. cellulóz és cellulóz származékok, kitozánok, ksmérryM és keményítő származékok, agam sgar. karragánek. pekiinek, galaktomannánok, guar-gumík. dextránok, xantánok. glukánok és gumlarábikunr (8) fehérjék, elsősorban zselatin és kazeinátok; (C) pöÉaktidbk, elsősorban: a fejsav homo- és kopolimegeí; (D) amino-gyanták;: ||) pc^rmeíphsiek; (F) pdíkarhamfdok, (G) poilafekiroüiok vagy poMsktrolit komplexek; fi) viaszok; (!) paraffinok; (új kollsdsk és bldrokosoíőök, különösen poiiszadmrid- és/vsp fehérje alapúak; valamint mindezek keverékei és kombinációi, amelyek elsesorbsn a következők közül választhatók ki: (A) poílszacharidofc, elsősorban aiglnátok, cellulóz és cellulóz származékok, kitelnek, keményítő és keményítő származékok, ágai-agsp, ixarragéáek,, pektlrte, galiitomsrmánek, gesn-gumik, dexáénok, xantánok, glukánok ás gumiarábikum; (B) fehérjék, elsősorban zselatin és kazsinstok; (C) polllakiidok, elsősorban a tejsav homo- és kcpoílmerjel; valamint mindezek keverékei és kombinációi. A M1-3. igénypontok bármelyike szedni doteferma, azssl jéáonrsíve, épp a belső kapszól^ cseppesskeképzö eljárások, határfelületi poiikorrdenzádós sprásek; határfelületi poiladdiciös epteok, oidószer-bepádásl eljárások, pefmstszárítási eljárások: vagy fáz-sszeparáclés eljárások révén álnak rendelkezésre, előnyösen cseppecskeképp fdropiebfermfcg} eljárások révén, és/vagy a belső kapszulák átmérője, előnyösen átlagos átmérője legalább egy nagyságrenddel kisebb, mini a külső kapszula átmérője, elsősorban átlagos átmérője.
5. Az 1-4. igénypontok bánnelylke szeÉi dősslbrma, azzal jéiiemszve, hogy a hányaáósa: a belső kapszulái íátméfSlénsk. elsősorban az átlagos átmérőjénél:, a külső kapszula átmérőjéhez, elsősorban átlagos átmérőjéhez viszonyítva legalább 1:2. eisősbfban Isgiáhh 1:¾ sihyősen legalább Ilii, különösen előnyösen legalább Idő, leginkább előnyösen legalább í;20, és/vagy a hányadosa a belső kapszula átmérőjének, elsősorban az átlagos ámferőjénsk, a külső kapszula átnfertphez, elsősorban átlagos átmérőjéhez viszonyítva Isgtsljsbb 1:100000, elsősorban iegfisljebö 1:500D0: előnyösen legfeljebb 1:16000, különösen előnyösen tggfepbh 1:10000, leginkább előnyösen legfeljebb 1:6000, és/vagy a hányadosa a belső kapszula áíméröpesk, etsősaíbap az átlagos áhnétijéneit, a külső kapszula átmérőjéhez, elsősorban átlagos átmérőjéhez viszonyítva változik az 1:2 és 1:100000 közti tartományban, elsősorban az 1:5 és 1:50000 közt! tartományban, előnyösen az 1:10 és 1:15000 közti tartományban, löinösen előnyösen az 1:15 és 1:10000 Közti tartományban, leginkább előnyösen az 1:20 és 1:5000 közti tartományban.

0. M t-S. Igéhypoüfsk bármelyike szennit dSzisfbrme, szxái jellemezve, hegy a belső kapszulák átmérőié, eísősörbah átlagos átmérője változik a 0,1 pm és 10 mm közti tartományban, elsősorban az 1 pm ás 8 mm közti tartományban, előnyösen az 5 pm és 7 mm közti tartományban, különösén: előnyösen a 10 pm és 5 mm közti tartományban. Igen különösen előnyösen a 25 pm és 4 mm közti tartományban, még ennél Is előnyösebben az 50 pm és 3 mm közti tartományban, és/vagy a belső kapszuláknak egymodusé szémssemérefe ésftagy méreteloszlása van, és/vsgy a Kíiiső kapszulák átmérője, elsősorban stiagos átmérőié változik az 50 pm és 100 mm közti tartományban, elsősorban a 100 μ-m és 75 mrn közti tartományban, előnyősén a 250 pm és §Ö mm közti tartományban, különösen előnyösen az 500 pm és 50 mm közti tsrtomárfybar:, még különösen előnyösebben a 750 pro és 30 mm közti tartományban, és még ennél is előnyösebben az 1000 pm és 25 mm közti tartományban, és/vagy a külső kapszula tartalmaz legalább két belső kapszulát, elsősorban legalább őt belső kapszulát, előnyösen legalább tíz belső kapszulát, különösen elönyoseo legalább tizenöt belső kapszulát, még érmét IS előnyösebben legalább húsz belső kapszulát,: és/vagy á külső kapszula tartalmaz legfeljebb lOöQO belső kapszulát, elsőserbair lég^efebHOQ belső kapszulát, előnyösen legfeljebb 1000 belső kapszulát, különösen előnyösen legfeljebb 500 belső Kapszulát, még ennél is előnyösebben legfeljebb 100 belső Kapszulát. T. Az 1-S. Igénypontok bármelyike szerint· dózistorina, aszal jellemezve, hogy a öoásforma és/vagy á belső kapszulák tártsímazrsáK iS-eínesíl, mint egyedüli aktív alkotórészt, vagy a: dőziéfcrma és&agy á belső kapszulák az l,8>drtecst legalább égy további áHv aíketópásszáfegyőtt: tartalmazzák,: amely tpáhlí skliy alkotórész előnyősén a térpéPék közül választható k| és a belső kapszulák az 1 ,8mieéotl legalább egy flziblőgiaitág elfogadható hmdbzöval fkstőányagpli legyei: tartalmazzák, amely összekeverhető I.SdneoUai, vagy oldódik benne, és folyadék formáié 20yC hőmérsékleten és atmoszfefikus nyomásnál, ahol ez a hordozó a közepes iáncméretö trlgiíoeridek ímeibm-chaln triglyvígrbS ki, ahol a legelőnyösebbek s Ce-Cr;: zsirsavgyökkel bíró trigtteertöek:,; és/vagy elsősorban előnyös: p, ha a hordozó olyan: íjrörtetihordoző arányban vm hasznosévá, amely az 1080:1 és 1:1000 közti íarfenfenyban:, elsősorban a l:p:1 és i;;10ö közti: tarikn^ybmi, előnyösen: az 50 i és 1 50 közti tartományban, különösen előnyösen a 10:1 és 1:10 közti tartományban, ennél Is előnyösebben az 5:1 és 1:2 közű tartományban, és m%ennéi is előnyösebben a 3:1 és: 1:1 közti tartományban van.
8. Az 1-7. igénypontok bármaiy<ke szermii dozisíorma azzal Jellemezve» hegy a Uőzlslbrma az i j-plneoi aktív aikoföfeszt Itt mg és 1800 mg közti,:elsősorban 25 mg es 750 mg közti. előnyösen 50 mg és S0Ö'«§ közti: és Különösen előnyösen ?5 mg és: 300 mg közti abszb|t mennyiségben isnalrnazzs, és/vagy s dózisforma az I.S-cineol aktív alkotórészi 0,01 tömeg % és §9 tömeg % közti, elsősorban |,1 tömeg: % és §5 tőhleg: %; 18¾ előnyösen 1 tömeg % és §8 tömeg % közt; és köooősan előnyösen S tömeg % és 80 tömeg 35 közli: felaiv ménnylségb^^^Éazzs^ösÁsgy a dozisferma gyomorban ellenálló (enterie-reslálBnll, vékonybélben: oldódó fsroslí isUestine-soiublef tormában van jelen, és/vagy a öőzisiorma gyomorban ellenálló,, de a vékonybéle# olőhstő módon van kivitelezve, különösen ahol a Külső kapszule és/vagy a belső Kapszulák gyomorban ellenálló, de a vékonybélben oldható formában vannak, előnyösen ahol ezek előnyösen el vannak látva egy gyomorban ellenálló, vékonybélben oldható: bevonadat: vagy hop!. 9 Eprasólosoit tartalmazó, 1-3. igénypontok bármelyike szerinti cózlsibrrns előállítására. ak#kpdülssj mikrokapszuiákat ilíunk si, smelysk mtndegpe teámat 1B~cíneoí aktív! $gy tzísíógiailag elfogadható hdidozSyei fköíőanysggá!) együtt, ssi% .ősszeteeífeálÉ vagy oldódik kenne, és folyadék formájú 201¾ hőmérsékleten és atmoszferikus nyomásnál, #¢1 «z a hordozó 8; thgiieetkfek: közöl váísszíbafa ki ahol szí koptden az eiözÉsg: eiöélíMt mikrokapszufák: sokasága teljes mértékben kori vas véve egy Külső kapszölabélak ás kombinálva van egy kspszula-a-kspszulában rendszerrel és/vagy hozzá van kapcsolva egy kapszuiS'edrspszeiában rendszerhez olyan módon, hogy a mikrokapszulák lösznek a belső kapszulák (benti kapszulák). % A §; igénypont: szerinti épm azzal jslfemezaa, bogy a mikrdkapszolák eioéííitásét cseppscskeképzi siférásofe: hatarfeiűieü polikoridenzációs eljárások, határfelület; poiladdiciós eljárások, oldószer-bepádási eljárások, permefszarííési elírások vagy feasszsparáeiés éprasok fém. bájtjuk végre, előnyösen oseppecskeképzc {ctroplet-fprmihf) eíjlraspk fá«, és/vagy a mikrokapszelSkat ósegpeoéksképző Idföpiétdonmlg) sptások: revárí alakífok ki, ahol a mtekapzülá'hépző aisparsyagof cseppecskékben szolgáltatjuk llhcioaó! és egy hardőző (kötőanyag) tetenlÉében, és a kapod terméket: 1,8-cineoit ímtsimsző míkrekapszvilákké szi!áfdl|dl, 1Í, Μ M. Igénypontok bShoelyike: szskfeü dőzlsíorma a&éifeazásra az ember! vágy Illái lesi. gyidiádéssinak, fertőzés-súlyosbodásainak vagy allergée betegségeinek megelőző vagy terápiás kezelésében, 12. A 11 igabyp# szedői oöziéforma. ahol m emberi vagy állal lest gyuifeáásá, íeflszes-sólpsbodlsaí és aPrgéa betegségei aikövelkezök kézi kerülhetnek ki: eufeimm# betegségek; nnogfazrás (&mm bőid) esMoenza 0% valamint az ezekkel Kapcsolatba hozható betegségek és fertőzések, különösen a ?«;$·:> és alsó légül rendszerek, fedezései, úgymint: a nátha (rhinitis), öff-mélékürog'gyöltadás; poosis) és a igét és tüdő betegesei (teebopglmonary diseases);, tegzes! betegségek, elsősorban a légutak: és a tüdő betegségei, főleg s hörghurut (bronchitis), hörgő asztma (bronchial asthms), és krónikus sizéraeos tudoxssgségek: jekronic obstructive gelrnsnary disease (iDPGjj: & epetraktus gpladésas betegségei,: elsősorban az epehólyag-gyulladás (cholecystitis) és az egevezet^gyslla#? (eheísngis|; a hegy# gyűjtőrendszer gyuléóasos betegségei, elsősorban az érgemplyi vesegyiiabés (gísmer^osephntisp vesemedeoee'gyulfeóás |pye!enepi#isk hégyssőgyaliadás (urethra#); a végbe! és vastagbél gyulladásos: betegségei,, elsősorban a Crohmtéle betegség és a vasíagbéifekéiy (colitis uieerosa); gyulladásos vagy süergéo bőrbetegségek, elsősorban az ekcéma #s· a borgysiladás (bermottíls): reuma-szerű betegségek, elsősorban a reuma, valamint a reumával: kspcsolalos morfológiai pofét (rheumatoid: morphogebeüo region) betegsége!: szisztémás keóiköszterbid-elkőtslezetí betegségek (oortisosterb^obligatory disease), ásössrbsn olyan betegségek, omslyak kortikoszteroidok rendszeres bevezetésével kezelhetők: 13. A.11. vsgy: 12. igénypont szenntitddz-slorrne,: éhéi: az hBmlneo! 18 mg imp és 3S86 mgfespkSztt, elsősorban tÖO mgtnap ó§: 28Ö0 hígfhaplípzi, előnyösen 200 mgtnap iés ISOÖiőgíhap kőzfí neplőózísfean var? bovezéíya.; ahef az l.S^esot M mgtnap és: 3600 mgíaap közi, efsősorbao iM mgthap és 2É50 mgthp közti,: eidvösén 290 mgrn# és tOOO mg/nap közi napl! dózis: bevezetéshez van szoigáitatya.
14. Gyógyászat! yagy orvosi termék, ahol ez olyan dbzisformaból áii. amely tanalmaz az 1-13. igénypontok bármelyike szerinti oioplt, lő. A14, igénypoht ézérlbfí gpgyászaíi vpy orvos! Pmék, ahol: ez a győgpszati: vsgy orvost femnák !S0: mg#p és 3000: mgtnap klzi, éísosoüan IÜ8 mgtoás és: 2009 mglbiap ko^l, előnpsen: 2tM) mgfeap és: fg$ mgáiap közti napi dózis i ,δ-clnéöl; bevezetéséhez van szo|[é!íabfa.