HUE028793T2 - Több részbõl álló beadási forma, amely nukleinsavat tartalmazó mukoadhezív hatóanyagot tartalmaz és eljárás elõállítására - Google Patents

Description

TÖBB RÉSZBŐL ÁLLÓ BEADÁSI FORMA, AMELY NUKLEINSAVAT TARTALM AZÓ MUKOAOHZZfV HATÓANYAGOT TARTALMAZ ÉS ELJÁRÁS ELŐÁLLÍTÁSÁRA

The itivettiion relates to a multiparticulate ifettrnmeeuíieal fens, compsislag «meoadhesívely formulated mteleie add active mgpedient», and to apmeess for produciug fee pharmaceutical ferm.

Friar »rí WO 02/6414B describes íorentktkms comprising a mucopolysaccharide sud a process for producing feem. la tins case, a mucopolysaccharide, ma. h scans. sc formulated together wife sa adsorpUon enhancer. a .g. s chitosatt, and stfesixtuently provided ad äh a reciting soluble itt míestsoal juice, so feat she active ingredient cats be released m fee middle or Lover segments of fee small intestine, Example» of ««stable. coatings soluble in raKstmal juice are- stmome suty.h.0 eogolytners of fee type of Budragit® 1.., $, .1.)0(1-55. The formulations msy include cagreles, tablets stud grasssies,

Tdomer»*« ss an enzyme which, ist ceil divisions. c<.njtributes for DMA doubling, especially is fee mgkm· of-he chroxoosome ends The cacytse is therefore Intpomut for mannaming an ocas? chromosome struct ore. Telometase activity is repressed in ex-si adult body cetL. an elevated tdomemse activity beteg observed ttc-i only itt gères cells, but also in many tumour cell types. It is presumed feat teiomeewu plays sut important role itt the molecular control of tbc norma! life cycle of ceils until their genetically preosogmmmed cell death. The high telomerase activity, di tiering front normal cells, tn tumour cells is interpreted as a Sign that normal cell djvjstou control Isas gone astray. Telomerase and the .gene structures associated therewith are regained at; a starting poim for fee genetic feerapy oftnrnour-ceik. WO 99/35964 describes nucleic acid» for gene feetapy which cosnpme itt particular a tsbrtwmse gene promofer. litis DMA cars be coupled to hamrofogous genes such as, fee example, eytotoxin-oaoixiutgr genes. The ttucleic acid construct can lx; eosployed as acove, ingredsetd fcr transfection of rumour edls with elevated mfemsMB activity, The sx.peeku.on is that this will «fesbst tumour ceil. drvissoa and evert specifically kill these cells. The possibility of oral administration of the active ingredient types described itt WO 99/ÎS904, and of pharmaceutical forms derived fesmfmm. j.s msfttiorted. ín Í. Contr. Sol, VoL 19» pp. 151-165,. Repod er «/, 12903} describe "Chimsaa-based gastrointestinal delivery systems”, art oral administretroa foret for DMA eompkxcd wife elmossa. US 6,465,1)26 discloses mferopamefes of elmossa and gelatin which may comprise nuciese acid.

Roy at si {.1999} describes in Nature. Medicim. For. 5, AU. 4, ρρ. $87*3%. ‘Oral gem delivery wife ckk&amp;sm^DNA nenopnnielm gmmitm mmumhgia prot&amp;aim in- murim módé of pmnui o/fergy” oral adafe ntsitatlon <d"&amp; 1>NA active Ingredient itt unco The domrnant peanut «berge» eene tpCMV Antiul s present ott a plasmid ÖNA was formulated xsgnfeer wife dsttosatt .havntg an Mw of abottt 39(100Ô by· means of complex acerv&amp;tion to »anoparticks with a sire to fee möge not» HXi to 200 urn. These nnnopardeles were admmisteted orally to A.K.R/.l mice, whereupon it was possible to detect transduced gone espressxm in the intestinal epithelial cells. The mice treated in this way produced atlergco-speesfio secretory IgA antibodies artd serum ig02a antibodies and showed a seduced atiergett-mdsnxni anaphylaxis compared wife a control group.

Leoug et al ((9*98) tleserides in Jmtrnà of Comroihd Mßkme 3X pp. lêS-1.93 '^Md-p&amp;iyasukm mnosphereo m non-kml gene ûéiverv eehidaX’ gene transfer vehicles svhich bring about foreign gene exptes-slots la vivo m BALRfo mice· The nanosphsms were prtxiuced as UNA complexes with gdatm or ehitoasu having s aise m the range from 20(5 50 7*50 sm WO 02.-094993 describes fotmtsladatts of nudele acids, anohodies having speorfieny for DNA and ca-ionlc xnasronKnecuk complexes related thereto formulation takes piac* iß the (osra of nanop&amp;rticles. sud increased transfection mies atc demoted both. in. vrtro and In vivo. Ft>rmul«dom (hr oral ndmhastratkm with, delayed release of active ingredieut are «miuiouesi WO 03/(107913 describes ottà muhip&amp;rtieakae phatmaoeubcal fora» which comprise the sea ve iogreáií-o in she few of a multiplicity of so-called patches. A patch ta 3 dssc-shaped object made oh bkicompahble material having a diameter of (orna SOi) pnr to 5 nass sod a height of from 1ÔÔ to 1000· pm. The patch cotmm of two layers o:r sides, of one· s*de widch has only low permeability for water or body Holds, e.g. made of ethyieelhilosc. sod of a second side winch cotnpnses the active ingredient, e.g. a protein, a poSysaoefea-rida or a small molecule, which may its present ttt « mixture with evueoadhesive polymers, e.g. chltosnu, CMC. potyaervhe acid or pectin. The patches sac be compressed to forrt; a tablet or aise ha packed tote· 3 cttpatde winch is additionally equipped with 3 costing soluble in mtesomd juice The active ingredient preparations; may also in addition he combined with so-called enhancers assoit as fatty acids, fatty alcohols, esters, surface-active subs-aoces and protmt.se inhibitors. A; the site of action, e.g. in a particular segment of the intestine. the capsule dissolves and releases the patches. The released patches arc aide to adhere whit their ntneoadhesive side to the intestinal mucosa and those deliver the active sagredieat its a delayed n-atsner and directed towards the intestinal mucosa The second, only slsghtly permeable side of the peaches is intended, to prov.uk the active ingredient with a cert&amp;tn protection against chemical or 0 so ormuk inactivation from the side facing the intestinal lumen and aim tes prevent rite active ingredient escaping on this sitié. WO 01/092737 describes pH-sensitive polymers, based on amonie {lueth-actyitdc copolymers having a comparatively low molecular weight- Ms of 100Ö to SO (KICK The pH-seusihvc polyuters are also suitable inter alia for completing nucleic acids. The pH-seosdhe poivarért have cytotoxic properties only m high concentrations or not as all in rite region of pH 7.0 or slightly above, but have cytotoxic or haemolytic or ntembranolyth: effects itt vivo evet- in low eoneeruration below pH 6.5.

Problem and sakkt»« WO 951.-33964 describes nucleic acids and vectors relating to the human telomerase gene and the pre-meter of Shis gene. The mietete adds described tiietmo tnay be regarded as potential active ingredients for gene tivrspy of tntnonr cells. Oral admmisn&amp;tion of the active ingredient types described in WO 99.09964 ts suggested only very gesemily. There is a need for proposed fotmulaoons which allow a skilled person to transport active ingredients of tms type to the she of action in such a way that pou-xatufe inactivaiion. especially by nucleases, does not occur and a sufficient proportion of the active ingredient succeeds in dattsfecdog tits target cells. WO 02-094963. which was mentioned at site outset and which describes amtbody-DNA conjugate complexes Su utmoparnelcs, also gives only rather general hanta for the fonuulation ci otal pharmaceutical fotms, WO 03 007913 describes a posstb'c solution to the provision of oral pharmaceutical tonna which are released in the intestinal lumen and are intended to act there. One disadvantage of this solution may. inter alia, be regarded as bedug the elaborate construction and production of fite two-layer patch structures. It appears par-ic-rlany unfavourable for the drug form to be provided as capsule having a costing which is resistant to gastric juice anti soluble in Intestinal juice. With, a sise of distinctly more than 2.5 sum, it is to be feared that the therapeutic reproducibility will be inadequate. The tone for the capsule to pass through the stomach nmy vary widely. In any event, a.· delayed: onset of aption is- to fee expected, fr· addition, the capsule may «sdf dissolve rapidly or slowly aller partial dissolution of the coating. Tue two principles of coating and'capsule overlap fo a» unfimwahie way in. this case, so that the release of the patches must fee expected overall to fee uncontrolled.. The. capsule may, in a situation where it is .at least partly accessible to the intestinal juices, remain intact or else be substantially broken down .mechanically,: depending on the current intestinal contents- or intestinal peristalsis. There may fee on the out- hand a sudden release of large amounts of patches, or on the. other hand also an. unwanted delay of release, depending cm the disintegration or mechanical stress on the initially coated capsule, structuré,. An active-ingredient delivery-which can overall be controlled heuer would therefore he desirable.

The present invention relates to pharmaceutical forms-which can be-administered orally for nuclei» »erd active ingredient's, in particular for the purposes of gene therapy. A general, problem in this connection is to formulate the acti ve ingredient in a form which favours she transfection of living cells at the site-of action and, at the same time, ensure that the, active ingredient or at least a sufficient amount reaches the site of action in the form capable of -transfection. One of the problems of the invention was regarded as being to provide a pharmaceutical form which is. suitable for targeted and efficient release of nucleic acid active ingredients. The pharmaceutical form:is intended to provide high dosage reliability and be distributed well rathe intestinal lumen after a rapid passage through the stomach. The contained nucleic acid active ingredient is moreover intended to be protected substantially from physical, chemical -orancleolytic inactivation and to be released at the defined site of action in such a way that a large proportion of foe active ingredient can be absorbed by the body. The site •of release is intended to he variably and reliably adjustable depending on the therapeutic aim. The pharmaceutical font) is intended to comprise besides the DMA active ingredient only phmnacologieaHy acceptable, aontoxic- ingredients, so that no unwanted- -side - effects- are to be expected from the outset eves if intake of the pharmaceutical form is freque nt or regular.

The problem is solved fey a

Oral multiparticulate pharmaceutical form comprising pellets having an. average diameter in the mage from 50 to: 2-500' pm, which are composed of a) an «mer matrix layer comprising naaopamcles which comprise a nucleic add. active Ingredient, and are embedded into a matrix of a polymer having-a ntueoadhesive eiTect, where the matrix may optionally comprise further pharmaceutically «sun- excipients, b) an outer film coating consisting: essentially of an anionic polymer or copolymer which may optionally fee formulated with pharmaceutically usual excipients, especially plasticizers, characterized in.that the multiparticulate phaimaceutical forts is: formulated sc that foe contained pellets are released in the pH' range of the stomach, the outer coating is adjusted through the choice of foe átnőnie polymer or copolymer and its formulation with excipients and its: layer thickness: so that the: coating.dissolves -in pH. ranges from 4.D to 8,0 in the intestine within 15 to -SO mm so that: the active ingxedient-eontainmg, mneoadhesivo matrix layer is exposed and cart bind to the intestinal mucosa and release the active ingredient there, where the polymer having -a. mucoadhesive effect is chosen so that it exhibits a mueoadherive effect of at least η*. ~ I SO to 1000 raPa-s and a water uptake of from 1(): to 750% in 15 min in a range of Ή- 0,5 pH «sits relative to the pH at which the outer coating starts to dissolve, and the active ingredient content of the nanoparticles in the matrix layer Is a maximum of 4ö%· by weight of the- content of polymers having a mneoadhesive effect. &amp;mhsxilmetst of the invenüo»

Th« snventiou se bises so sus orsst reufeperueufese phssrssissecsstsciss form, in parsicsslssr isi s.he form of a tablet, wrtfe pellets» packed safe eapsaka, sachets os powders for rmtruaismion, comprising peiksix having <m •average m®. or average diameter -in. fee range írom $&amp; to .2500, preferably from ICO « .1000 pm, which are «omposed of 4} sa Ismer snatdx fey«« ctsnspisksg tsarsopattsclex which comprise « nucleic acid active ingredient, and are estsbesided safe a rn&amp;snx of a polymer having ;s mneoadhestve effect. where Sas? sast six sassy optionally cosoome further pharmaceutically asoai excipient*. %) an oases' Itha coating consisting essentially of an anionic polymer or copolymer which may optionally he formulated with pfcarmaceuocally usual excipient*. especially plaatfebmm.

The mtrldparticukfe pharmaceutical torst is fortsnsHscd est fear she onntamsd petes are released is ih&amp; pH range of the stomach.

The term petes in iteeontext· of the mventto« incisées round to spherical -agglomerates which may alatt be referred so as mkfop&amp;meles, beads so- misthahleis, us long a* they hssve she structure ssnd ssxe described sa she inventer* she otiter coating ss adjusted by she choice of Use arnonie polymer or copolymer or sis. formulation with esespietiw ;sa;i it* fever dudmess so shat the coating dissolves so pH rangée from 4 0 so >1.0, preferably frosn 5,5, so 7.8, particularly preferably 5.S to 7.5, in the intestine «fehlst hi to 60, preferably irons 20 Jo 40 mm, so that she active iogfediem--eoataisiing muooasibeaive matrix lever iss exposed seid cats hsad Jo intestinal mucosa and .release the active isigredicot there. T he polymer or copolymer haváig a nmeoadhcaive dlect s» chosen so sasss is exhibits a mucoadhcsive effect of at leas! rw ~ 150 to 1000, preferably 1.50 so 600 tnPa « and :¾ wafer nplaise of irons 10 to 7SO, preferably 10 so 250., pstticulady preferably 10 so 160®* sn 15 sises, isi s range οί'*/- 0.5, preferably ;·' 0.3 pH units refed-ve to she pH as which she outer coasing stem so dissolve, and she active ingredient consent of the .matrix layer ss siót mam than 40, its particular inouï 0,001 to 15 or 0,0.1 to .1% by weight af the content of jmlymcts having a mucoadhesive· .effect.

The Inner matrix layer

The inner matrix layer acts a.s active ingrediens carrier. The «mer matrix layer additionally has the func-sksn of binding the active Ingrédient, by means of the contained mneoadhesive polymer, to she iaiestm&amp;l mucosa so shal she unlive ingrédient can erster the body tbereifom. The inner matrix layer additionally has the function of ptoleesitsg the active ingredient from physical, chemical or enzymatic inactivation.

The rosier matrix may additionally comprise phamiacensicai excipients, especially G-profeiu coupled receptors smd hgaads (see, tot example, WO 02/10240?, pp, 74-76), especially S-OH-DP/VI', aminokc&amp;nserin, atropine, fentaclsmol, ohdotpromaane, chlompmsshixen, chmseria cvssuopmdoiol, cyproheptadine, dotsperidono* eps-depi'ide, epi-nephritte, fcrsokkspasn, Osipesishixob Ihspisenssalsse, hssiopersdrsL hextxsyclnim, hsmbtscisp iodotnelatoain, ketansertn, lysergic acid derivatives, mesoridassae, mesrdsxigm, mmhoctramme, sisciSbyHcrgklu, melooioptamtde, misnsents. moimdonem, mascarhno, snsksxosx;, Hanelhvispsperone. rsot-epir-ephrsne, pergohde, phentolmniae, pinmaephie, PPHT-conmants, PPHT-rlxsdasnine, PPHT-Texas red, praaosrn, protnamuc, sxcfiprxfe, semtonis, ^epetotse, sssirnsxalrinc, sulphide, sumsshsphiss, sensiapitie and srifh^srimsxisfe.

The ismer mssfetx may sdditionaily esimprlse posetratien promoters, e.g. pkstfekets soeh as, for exssbjtle. tt Dutyi citrate, acetyl metyl citrate, durthyl sebacutt;, dibusyl sehaeaie, polymec* s:sse:h as eathonaee, chitosîtti, chuosatvcysteme, sodium càrbKtxywthyleedhiîose-, N-tttrsetbykted ehitman, jxdyx;affeophî)*eysteme, long-chssa fatty acids. the b esters s for example mono* ásd diglyeersdes} ásd their satis such as j auric acid, laurmsulphomc acid. pahrotlc acid, capryhc acid, eapric acid, oleic acid, acylcaralimesh chelating agents such as EDTÀ, salicylates, eyelixlexttfos, polyaerylic acids, bile soxis such as sholfo acid, choiyitaurtae, ehoiyharcosine, chettodeoxychoOe acid aad thmx salts seed as N'a choiate, Na dystochohtte, Na ttmrochofssi«, Ma. teumdihydrofusidate, Ms glycodlfeydro&amp;sidste, sutfaccuus arai emulsifiers suds us, m particular, polyethylene-<S6Ö 3 STtydroxystearaie (Sohtttxkl' HS 151, {Soiatol BSI5g polyxorbate SO (Txveen SO), polyoxyethylated easier cd (Cremophor El.}, polyoxyedtyletsc'polyoxypropyierie glycol (Pluroaic® Fh8), the toxin sonsfia occhxlcns toxi» (EOT), and vnmmsw such m vltsmss E {ttcmopheml} or Vitamin Bid.

Ptemaccudcal excipients, peaetratfoa promoters atxifor G-proteiu coupled receptors aud ligands are preferably aot. présem is the irmnr mao:tx layer or ax; present 1rs only small amounts, e,g, fisam D.ÖÍ to ICI, preferably Ö.Ö5 to 2, particularly·preferably 0.1 to 1% by weight.

AbudeR seid active ingredients

The matrix laves uompnwx nanopsrtieia? hamng a nucleic add active ingtedtem, The nucleic acid active mgmdtent has the task of «betting at the target sire dr vive atr Inleracixx· with the DMA of mammalian celts, itt ρ&amp;πχ dar human cells, which Rads so an altered DNA structure ta the cell or very generally so altered cell pro-petuev bt this conneetiosi, mention should primarily be made of so-called gene therapy, she amt of whtch o to repair defective gc.ae street nr es. iss genetically related disorders. This may sake site fours of, for example, innencation or switching-off of unwanted gene activities such as. for example, the ielomera.se activity m inmosur steih it may also take she form of a tessoratfou of gene activistes which are normally ore sem ht healthy cells, e,g, the p53 gene activity, &amp; tumour suppressor gesse, which has long been known and imensively researched. The invention accordingly relates to pharmaceutical tbsrss.s which ears be administered orally fot rsudeic acid active ingredients. in .particular for gene therapy.

Ilse nucleic acid active iagredimu may he a single- or doubk-strattded DMA fdeoxyribottucleic acid} or RM A. {ribonucleic acid} or a DMA-RNA chimera, st being possible for naturally occurring and.· or oon-natutally occurring synfoeitcaiiy modified nucleotides to be présem. The nucleic atsxi aelive ingredient may be in llneas or circular form,. It may take the, form of obgoaacleonde uaits. e.g. wsth a length of foxn 10 to 200 bases or base pairs- Is may also ink« the forts of longer units of. far ««staple, moee- than 200 to 100 0Ö0, .500 to 10 QOQ or 1000 to 50ÖÖ bases or base pairs. Besides the sequence acting as actual active ingredient, e.g. a nucleic acid sequence which ss present In the target ceil or is ns be supplemented, the nucleic acid neuve ingredient .may where appropriate also eomprne vector sequences winch arc not ordinarily present in the target cell and are not intended, to indexet with the latter.

Examples of known vector sysk.ms srk those which are boxed on double-stmnded DNA anti are derived Morn plasmids; or vectors based on vxral systems. Known examples arc recomb mam adeno-assixtlatcd viral vectors (rA.AV). Other do able-stranded vectors ntuy comprise prônante; of regulatory sequences írom cytomegaloviruses (CMV) or the SV4Q vhua. Otbet vectors, may be ne rued Irotn singte-rusnued DMA which can bn proieciet: front degradation with the aid of attached RM A elements Also known are xo-eahed RDO 3 astd RDO ii constructs ut which short DMA. pieces, e.g. 30 to «0 basex, are prnvsded. or. the ends with short RM A. pieces of Runt l to 4 basr». The huilMifc or the .nttele&amp;xe reslstttrtce can ixj .addnfonnlly iscres>xed by introducing non-oshaxlly ocemriag nucleotides into the RNA or £>NA, it is possible In fois connection for, for example, single oxygen atoms to be replaced by sulphur atoms, so thai phosphorus-sulp hur bridges are obtained (MSO). The diversity of nucleic acid fonns which are suitable as gene repair or gene replacement ve&amp;tors and which can be employed as active ingredients in the -context of the present iavention is described for example Nature Reviews Ybl. 4, 2ÖÖ3, pp. 679-(189, Li Liu et al Preference is gives to nucleic acid fragments wnieh comprise essentially only the nuclei«!· acid sequence acting as active ingredient and only small proportions of or no vector ΠΝΑ.

The nucleic acid active ingredient may he. present in a complex or conjugate, e.g, with cationic, polymers or proteins such as, for example, antibodies. The coxnpfoxarion or conjugate formation may take place reversibly or irreversibly covalently through chemical bridge bonding or non-covalenily via van der Waal's forces, ionic linkages, hydrophobic linkage: The molecules displayed besides the nucleic acid active ingredient in foe complex ox conjugate ihemselves display no therapeutic effect, however, and are thus to be regarded, as fonnulaaon aids and not as active ingredient or part of the active ingredient.

The nucleic acid active ingredient may. where appropriate, he formulated with the assistance of proteins or peptides. However, they themselves, however, display no therapeutic effect and are thus to h® regarded as formulation aids arid not as active ingredient or patt of the active ingredient.

The nucleic acid, may, for example as disclosed in WO 02/094983, be in the torn of a complex with an antibody wirich hinds specifically to the nucleic acid, and with &amp; cationic substance, it has been possible to show that this measure can contribute to an increased transfection rate bodrin vitro and in vivo. Possible and preferred in this connection are monoclonal IgG antibodies or IgM antibodies which act completely or else as fragments, Pc antibody fragments, Fab’ antibody fragments, F(a,b}'2 antibody fragments or half antibody fragments which, however, must in each ease comprise at least one anti-DNA binding site. Tire molecular ratio of nucleic add to auli'DNA antibody maybe for example from. 1:20 to 1:5, the nucleic acid active ingredient may be aimed-for example at the therapy of haemophilia and comprise a coagulation factor gene, e.g. the cDNA gene of human coagulation factor ÏX (see, for example, WO Ö3/Ö28Ő57 or Painter et si., Blood, 1989,73-(2), p. 438-445 oxYm -et- al, Froc Nad Acad Sei. DSA, 1992,89(8): pp, 3357-33.61). The nucleic acid active ingredient may, besicles. She therapeutically effective gene portion, also comprise an immimotokaunce'induemg gene such as, for: example, the Fas ligand. The coerpressed Fas ligand or Fas gene section can induce apoptosis ín T cells winch can, aber gene transfer into the target cells, be specifically activated. Vectors connected with apoptosis· -induction ia leukaemia cells can also be inferred from Walensky et at, 2004, ‘‘Activation of Apoptosis: ta Vivo by a Hydrocarbon-Staled ΒΉ3 HeEx", Science, 305, pp. 1466-1470.

Tire nucleic acid active ingredfont May comprise for example a gene section, especially the promoter region, of the huma» telomerase -gene. A suitable example is the gene therapy vector pGT62-ecdAopp described •is. WO 99--78954, or other vectors which can he inferred by « skilled person from WO 99/38964. Toe nucleic acid -active ingredient may comprise a tumour suppressor gene section, e,g, the'¢53 honour suppressor gene- of. fragments thereof. US. 6,451,5.93 BI describes principles for coastineiing expression vectors for gene therapy which are suitable for producing nucleic acid active ingredients lathe context of the invention,

Nsnoparrides

The pharmaceutical. form comprises nanopanlcles which may preferably have a size in the range from 20 to 1.000, preferably from 50 to 250, particularly preferably 80 to 220, in particular from 100 to 200 nm.

The nucleic acid present in the nanoparticles may preferably be present in the form of a complex with a cat ionic ««festaacè.

The oadosie substance msy be s cationic hpiá, a catiooic polypeptide aml/or a satiome polys»«?« Polybihyfeneimine $>r denvubves may aise be suitable.

Cationic lipids may be for exemple commercial mixtures of iN^Hl^-áloleyloxy^opylI-N-H-'N'· himefoylaounonram chloride {DOTMA.} and dioleylpbo^bastlyletbesekmme {DOPE}, Suitable exemples are als© H-{ 1 .-<2,3~ditdeyloxy)pogyi j-M-M-N-öimetbykismosiHSi. methyl ssxlphgte (ΙΧΧΓΛΕ). áfeieyiphosphafelylchoimes (DOPC). dioctedecylarntdoglyeyli^erinmeCDf^Sl.

Cationic polypeptides are preferably synthetically prepared homopolymem of ankso setds with caborn« side groups. Mention should be made of-poly-iyema«, poiy-argmme, poiy-emiädöß· stxd golyTdsIiáke, The elms lesgtbs tsey vary fen a few tmits op so large salts, e.g, 3 to.20, 10 to 30, 50 to 100 or op to 5ÖÖ or up to Î000 ataiso.acids, it xs also possible to employ safe-rally eccttrrlng proteins having predom.ka.ody ctdiooic. properties sttch os, for example, histone protems.

Preference is given, in relation to other substances with comparatively little pharmacological exprimas, to |tneth}&amp;crylate copolymers hccense they have bees safely used for decades in medicaments admisbfered orally. The cationic polymer may therefore preferably be a lketb)scrylatc copoiyeter, in pariiexdar « fmeth}acryiaîe copolymer which has tertiary or quaternary ammo groups. The glass transition temperature f ISO 11357-2, s-xbseens-n 3.3.3} of the cationic frneshkeryiate copolymer is preferably In the rattge from 40 to hlPC, and she molecular weight Mw (weight average) ia from 1,00 000 to 200 000 (the molecular weight: Mw can be dmernnoed tor example by gel permeation chromatography or by a scattered hght method (see, for example. H,F. Mark et «1,, Encyclopedia, of Polymer Science and Engineering, 2nd Bdhfett, Vol, 10, pttges 1 et setp, J, Wiley. 1289), To improve the excretion vk The kidney or the biliary tract, preference is gives to cationic itneshkeryktc copoiytners having a low molecular weight Mw, e,g. having an Ms of 50 001) or less. 3000 to 40 000,10 000 to 30 000 or 15 000 to 25 000.

The molecular weight Mw (wesgh; average) can he determined lbs example by vocosneSry or gel exclusion chromatography iGPCy Vfesnetric values (limiting mcoshy number) ean he dctemxhxsd in eldoro-form or ttt DMf -dtmethyiferntamide} at ET C and should preferably be in the rattge from 10 to 20. preferably 11 to 15 η,.,,,., (cm'. g). Viscosity numbers can he measured for example as specified in ISO 1620 -6.

Ear-seder preference is given lo a (tnelh)acryiale copolymer whtch 1« composed of ike-radical polymerised units of 20-.)0% by weight methyl nrsthseryiats, 20-305¾ by weight butyl, methacrylate sud 00-40% by weight dinwthyiatshxxethyl methacrylate. The (methacrylate copolymer can itt particular he employed in mietooxaed ferns with averttge psssllele sires offert 10 so 30 urn, A spxxofsenlly rtxifohk commercial (meth)actyisle copolymer having tertiary amino groups Is composed for example of 2S% by weight methyl methacrylate., 25% by weight butyl methacrylate and 50% by weight disscthykminocthyl methacrylate (EudragitW El00). A r-sicrooised fort» (EudraghT) E FÖ, -powder) h&amp;ving as average parSxde of hots 10 tit 20 s-s s.s particularly preferred. lids kort can he processed pafllcskrly well tn nucleic add-eon-aining nsnopakdes The result in this case Is at» evidently particularly favourable complex formation, tvhtch ;uay cotjiribot« to increased trendedre?- rates, with the nadexc acid nxolccxtles, hknogaxdidss comprising txudete seid aedvo logrcdfent and otfisaje mû aafeafe <*feb)a«ry|at« copnlymers

The reduction rains of the respective nucleic sekk for the forget cell type ean be further optxmtxcd by addmg. m rite preparation of me »anoparticlss comprising nucleic seid active mgrediest and caîï<mic (meth}aawiate «opol-ymcr, is addition ars «mi« imethkcrylsk copolymer m proportions of'from OJ m 40, 1rs partie.«s«!' ; ht 50. psrncukrdy preferably 2 to 25% by weight based on -he nucleic seid active ingredient and tbc cat kmc (meth)acryiat£ copolymer; The wotopartieles «t Sises be checked for their tra-msfeettos rat®· m as is via» assay wirb a ceil culture-of the target cell type, where available« os wish a call, type which, is at kast similar er reacts similarly, it ts possible is this way to adj^tsrt. a suitable hskttee between the hisdisg forces of the nucleic add is the complex and its release from the complex into the being cell. If the bmdms effect due it1 the catjsmk (tseihlacryiatc eopolytoer aksne is initially too strong« so that the ixaosfeetion she of the mtsíetc acid is uttsaosfactoriSy low, the hknlntg effect eats be weakened by adding the amortie Proethjaeryiate copolymer «red the Srnosfsctton rate reaches as oputmtm which is spéciik fer the rtudeic acid etnployed and for the target cell type, "fins mode of formulation, has the advatthtge that both the cstiomo sod the amonk (meshkíctykte copolymer are pharmacologically acceptable, so that, scarcely aay or so side «fleets am to be expected.

Suitable and preferred amortie (metntncryUue copolymers are site sente types winch can also be used for the cuter coating, t.e, imeihkterykte copolymer? having a costteut of mortotners having antonio groups of from 5 io 60% by weight ( t-udragkh types X., S. L100-55, FS). Irt many cases, a surprising increase itt the s.r;msfeenor< rates can be achte ved by employing anionic fmeth}&amp;crylate copolymers ctxnposed of 2(1 to 33% by weight methacsrylic add and/or acrylic acid, 5 to 30% by weight methyl acrylate and 20 to 40% by weight ethyl acrylate arid snore than 10 to 30% by weight butyl methssrylak and where: appropriate 0 to 10% by weight ihtthet tmmmm. capable tsf virtylie copolymsrlmktm where dte propotaions of the monomers add up to 11X1% by weight, with the proviso that the glass transition kmpemhue of the ocpolyrtw tseeordbsg to ISC) 11352-2, subsection 3.3.3 (taklpoirtt retnpernsure is from 55 to ?(FC,

The abovetnenttoned copolymer Is composed írt particular of kee- tadieal polymerized noils of 20 to 33« preferably 25 to 32, particularly preferably 28 to 31% by weight methnerylie acid or acryke add, wttb prsscosace for ssrcthtresylic acht, 3 to 30, preferably 10 to 23, particularly preferably 15 to 25% by wdghi toothy! tserylsse, 20 to 40, preferably 25 to 35, particularly preferably 18 to 228¾ by weight ethyl acrylate, end more fura) 10 to 30, preferably 15 io 25, particularly preferably '18 to 223( by weight butyl methacrylate, where the monomer composition Is chosen so that the glass transition temperature of the copolytner is from· 55 to 70*€> preferably 59 to 6&amp;, particularly preferably 60 to <15%;,

To improve the excretion via she kidney or the biliary tract, attsomc {methiaeryl&amp;le copolymers inwing a low molecular weighs are preferred, e.g. prefetred having an Mw of 50 000 or teas, 5090 to 40 000. 10 000 io 30 000. or IS 0(8) So 25 000.

The molecular weighs Mse (weight average) cats be determined for example by seseotnetry or gel exclusion eln-omaksgreplty (OXC). Vtscometdc vahsss (limiting sdseosiiy mmkm} cm be determined in chloroform or in DMf (dintethylfcsrtnasside} td 23*€ and should preferably be in the rattge .from 10 to 20, preferably 11. to 15 s"em5/g), Viseoshy ssmbers can be measured 1er example as specified in ISO 1628-5, Λη*οτηο Cmethjaaylam· «polymer« having &amp; ktw molecular weighs. are pH-sensitlve polymers wiskh. la she sagiors of pH ?.C) or slightly above , bays cytotoxic properties otsly Is high eoacsntmtions,; «r not st all, bst below pH b. 5 bave haemoiyiie and membtanolytic effects eves bt low mwmtsmm in vivo, Tb« polymers cssn serve as meatelamrs ol: the femding srrstsgrb between nucleic seid active tegtsdieut and cationic <tneth)acryiats copolymer kt the nauopsr-kdes aas, st the same osar, have a beneficial influence oss -.he toros let:-lot: sa-es. The ptoporsioa. of anionic .{methiaorytese copolymers having &amp; low molecular weight in Ike .oanopardoles eau contribute1 in particular to intracellular release of the nucleic add active ingredient sfset uptake into endosomss through their subsequent dmabdsrarion or lysis.

Anksnfeimetktecryiste eopoiynsers having a low muleeuiar weight for nmmmspmi&amp;tàm la ts preferred emlxxiimeat, anémie {«aablaorykte copolymers having a low mo.lecalar weight, e,g, having m M,y of $$000 sa kas. SOUCI to 41)1)00, 10 MO to 30 000 or 15 MO. to 15000, ate applied by nanoeac&amp;psulaiion as shell to uaneparocles which «emprise the nucleic add active Ingrediens sod oarksnie polymer, preferably a cationic fmcthkwtykste oopoiymer. Ike proportion of atssooie (iactlt}aerylste copolymers having: a low siokesrlar weight oh sh« surface of Ike aaaopssttkles cos contribute 1st particular so intracellular release of the rsnelek add act ive ingredient alter uptake ksto endosomes through their subsequent destabilisation or lysis, la addition, the taxádé add &amp;div« mgredkut sx lseket protected in she interior font mscieoiylie degra-daîson. so that more acsive Ingrediens can reach she targes site.

Proportions of active ingredient

Iks proportion ofnanepaructes in the matrix layer is preferably not mom -ban 40, in particular 0.001 to 15 or 0,05 to 5% by weight of the content of polymer having a amcoadhesive effect, The proportion of the tsuelelc add acav« ingrediem in the nanoparfccies cast be for example tom 11st 50, pre&amp;mhlv 2 to 2S% by weighs. lYepnmksu of aanepastieles I'be preparation of nanopar&amp;tes is known. Known methods are coacenmses, complex: ibrmation, ernnl-sión pstasipissitlosr, evaporation of the organ!« solvers!: conscrit hum a water-ireoil emulsion, resuitiag ist nanoparticles in she aqueous phase. Evaposotioss of the organic solvent costsetst from m oikiswwater emulsion, resulting »· uanofsarticies 1st the aqueous phase, teong et ai. 1190¾} describe? the preparation of nanopaniclea ist Jommi of Controlled Mdmw Id. pp. I83~i93 ’‘DNA pafyeMan mmspheres ox mn-virol gene delivery vehicles”. lief et si (1999) describes she prepamSton of naaopartfeies· in Mséwv Medicine, Vei 5, Na. 4, pp.. 3ë?~39f “Ümt gene didivery wir h chitomn-ÙNA mnopmnioles gmemfes immunologie pr&amp;bieme in murim model ifpearms ûiiergf\ klitriiteiteispsstkfbd is a bstundary layer poiymerteatio® srattbod (see. ibr exempte, Choturtard F. et ai,, Pfsarm Res,, 1994, June 11(6): 869-844). .Nsmoestpsnles cerr be gaserated by dispetsing natKtpamctea as involute le eo-tsplexes in sgueossa mediam, ssstd emulsifying She dispersion in ars organic solvent. The dispersion 1rs an organic solvent comprises tbs example &amp; (sseskkcryhste copolymer. Os evaporation of the organ.ks solversb the inseshlecryisste copolymer preoipiiases and fonás a shell around ske nanoparteles. Encapaniatson of the oanoparticies Is advantageous because ass addiusmai pmseebost of the complexed rsudetc aetd acsive iugrediast is ensured durirtg she absosyssost ptoeessea by she euteroeytrs ssstd sixs liver,

Polymers hating ss ntneoadhesive effect

The matrix layer further comprises polymers having a sHstcdstlhdsive elïkot. Suitable polymem having a· mucoasdteaive effect are- in ptss'slcstlar e ohitosaa (cbltosan sod tietisysives, chltosaos), (meth)teylate· copolymers ceaedstfeg of 20-45% by »«sight methyl mefeacrylate· sad 55 to $i}% by weight metbsmyiie acife celluloses·, especially medryloeOfeoses. such ss Na earboxymrefeyicellufose (e.g. Blaaose® or MethoceM). .ibefereose b .gives, is tuladea to other substances »ids comparatively little pharmacological experietsoe, to· imeth)aarylate copolymets because they have beets safety used for decades is medicaments adomustered orally.

Tise polymer having e mscoedhesive «Seat ta choses so that it displays a water tspiske of from 10 to ?50%< preferably Kl so .250, particularly preferably 10 to 100% is 15 min st a range of +/- 0,5, preferably */-0,3 pH units relative to the pH at which the eater coating starts to dissolve,

Mettsoresrten? et' the mucoadhesiv« properties A s-fecble measurement method for characterizing mucoadhcrive properties is conialned ia //«p mä CfeOb (1900) (see Bäum EÆ cmd Gtdk> J.M, Ή Stmph Mheéíogknd Mmhedibr the in Fiteo Assnxxment of Mmin-Poiytmf BimMexlve Bond StrengthPhermn key, f(5), 491 (/Sfefel The method is baaed ο» fee assumption thai: the viscosity (s), dynamic viscosity or viscosity coeffedent) of a mixture of polymers noth taocia is different from Use total of the viscosities of she individual components. The relationship applying is

OnUsaa; «r tefy-m* was .-i»w ·" OmwiB + Ossiyisst * :fe« wko« % stiäxuis for fee difference. A higher % tseasS greaser mscoudhesive properties. Ilse- Individual ceas-x-aoais are initially measured fest their vrseosity using &amp; rotational vrseirmeter. A 0,5% strength tw/wt aqueous sokfeon of the mueoadheaive polymer and » 15% strength solution of pomme gassHc; macis ate employed. To determine the ataeoadhesive properties η** rattern and polymer arc measured-alone sod mixed in the stated concentrations»

The polymer having mueoadhesive effect is chosen so that is exhibits a mueoadhesive effect measured as viscosity % of feemt 1.50 to 1000, preferably 150 to 000, tstFa-s in &amp; range of·!·/- Ô.5, preferably· ·!·/· 0,3 pH units relative so she p.H at, whseb the outer coating stem to dissolve. M^telSLä^^yaM.uptake

The hydtation of polymers is bs-vd ot> she aifefey of the polymer to take up wafer. Polymers swell owing to this wafer uptste. This is concerned wife: sa imbalance hetawa-fee-ehembai potential of the: water ta the polymer and fee water ist she surrounding medium. Th« water is takes op. owing to the ostssoiic pressure of tbs polymer, aatii an. equilibrium is reached between Hs« fester sad fee outer phase- The polymer is the« 100% .hydrated. Polymers having a few average molecular weight are then is the Iona of a solution. A gel is produced wish polymers having s higher molecular weight or erossliuked. polymer«. The wafet uptake and) fee equilibrium ss set tip may ataount tor twaorpic to up to 10 times the inherent wesgbt, cmrespoadtng to 1000-3·« si'she polymer wshglis. MSHfeHIHSife

Measaremesn of she pcsceotsge water upteke is familiar to few skilled person, A. suitable method is described for exmnple is fee Lehrbuch der pinsrm&amp;sæifeschs« Tessfesokigie/Hnfeslf Voigt, Bssafe: Verlag Chemie, 5th completely revised edstlsa. 19M, page 151, 7 .7,6 méat "Äufeaegvesstsfegeif1\ Tiro method makes srso of the so-called Essim. apparatus, its which s glass suedes tliter fonsrcl Is eesnected. by tfefesg so a.gmdaaied pipette. The pspetfe is mmtmi exactly hmrjxrmtkly ist such a way that it is -at fee aaste level, as fee glass frit A water uptake of .1003¾ is defined is the present esse as a water uptake· of I ml of water pm 1 g of polymer having a moceadhesrve effect in 1.5 mfe.

The esmparsti vely rapid water uptake or hydration sad fee higis degree -of hydration ensure, at fee time at W'kkh fee outer cesssfing «bars To dissolve, &amp; raprd pmtserion of the aedve fegsoilicaf and a dsreot hisdiug to the istestmal mucosa,. Bissdlng of fee active ingredient m the mucoadhesive matrix should he only small. $0 thsf the active ingmdtesl east pas dbesîly frets the mtosbna! omsoss. isse the body,

The mucoadhosive effoet k pH'-depeodess: for MJÿ mucoadherive polymers. The pM la the mtrix cas be specifically eosiooikd through the addition of an ttciíh cd a base or of a butter system, The Toner matrix-may comprise sa polymer having a ntutmdhesive effect far example a ehitosan which is employed together with its acetate bailer svaem. The acetate/Ns acetate buffet, e.g. adjusted to pH 5.0 to S.S ess be present as an additive in the matrix or ire applied hr a core esta which the mstnx Is applied, is: is passible 1» this way to employ elmossa also it:· coinhinstfos with Him coalings which start to dissolve at higher pH values, e,g, pH 6.0 so 8.Ö. Dosprte she high surrounding pH. she lose pH k maintained ta the miœoenvuonmeni of the matrix. H is thus possible to atllixe the mueosdhesive properties of the polymer itt a pH range in which it would otherwise have tio roucosdhesive elfe or sot to tins exteat This has the advantage-that a cettain protection against aoefessea whose pH optimum :,s is higher pH rstrges ca» he achieved. The same principle eao also be applied is the converse manner by raising the pH of she matrix, by adding g bass, sad eomhisdog with a film coating which dissolves at lower pH values.

Examples of lire sc ice bos of ssilsbk- moiosohestoe polymers

The soleoiios of statable tmicoadhesive polymers is based on their tnocotxihesive properties and their water uptake capacity. The polymers should have a tnueoadhetsive effect of as least gs, ™ 150 to 1000 mFa-s and a water uptake of from 10 to 750% to I S mla ia the. respective pH range-. The following table gives ta list by way of example..

Chitos&amp;o. is suitable for example for use In a autyoottdtag pH region of pH 5.5 (duodenum) or at .another surrounding pH tegktn (ileum or colon) as long as the matrix pH region has been adjusted, e.g. with the aid of a buffer system, to the reg lot:, around pH 5.5.

The {tneih)aerylate copolymer listed its the table is more sui table for a pH .region of pH 72 than for a pH region, around pH 5.5.

Na alginate is suitable for iho pH region around pH. 5.5 hoi not for pH 7,2,

Ha a^oxymeStyicellnlose aod crPSslielsxl polysefyfe acid .sm suitable over s wide pH range bos» 5,5 to 72.

* ::: (uíeíhjasryHse copolymer composed of 20% by weight methyl methacrylate artd ?>% by weight, methacryke &amp;e;d

The ou ter coating of anionic (meth>aerylate copolymers

The order coating of art tonic polymers or copolymers serves as coating resistant to gastrin juke in order to protest the meter matrix, layer foam gastric jukes* The outer coating additionally aots to protect the. active ingredient from aoeleolytie ettayroes until the time when the coating teaches a section of the intestine f duódé- asm, jejunum, ileum or colon) where à starts so dissolve. The orner ousting ww in this esse in ptóonla? for so-called "gastrointestinal targeting”, i.e. the targeted release «f she loner tnairy; layer sí She sections of she intelme ddermiasd by the pH' prevstil&amp;g there. For shore to be no impediment s» delivery of fee tasser matrix layer. the (mdh}acrylme copolymer of the carer eoeiing should exhibit minimal or only slight interactions with •the active ingredient or the mneoadhesive polymer of she inner matrix layer.

Suitable .auionie polymers mà copolymers are cellulose glycolate (Dnodoell®), eeáhdose acetate phth&amp;iatc tCA?, Celluiosi seeses, Phifer, cellulose acetate phfeaktes, M£, Aquateriofefe cellulose seetsfe sacexoate (CAS), cellulose acetste trimellste (CAT), hyfexwypw^yknefeykelfelose phthalatc HiPMCF, HP50, HPSS), hyhroxypropyhncfeyfeelhsfese acetate suceksste (M.PMCA3 -LP, -MF, -MF), posy vinyl acetate phshalate IfVAP, Satetede®h vinyl aoe&amp;te-vmyipymdidone copolymer (PVAc, Kolildon® VA64}> vinyl acsta-tetotefenâc sad 9:1 copolymer (YACtCRA, Kfellsccetfe1 VAC) anfebr sheilsc, The polymers and copolymers mentioned caa in assay cases he formulated ist a perfectly sasislhc-fety way to allow pH-spéciik- dissoiudos to be achieved.

The outer Bm coating psrtinalarty prídarahiy nemim essentially of {oreife}acrykte copolymers havmg it cornent of monomers having aaionk; groups of fasor 5 to 60% by weight, which may optimally he formulated wrth pkaanaoeotiartly »sasi exetptems, especially plasticisers, Compared wish the polymers mentioned st the outset the jussaié CmeŐs)«serylate copolymers meatioaed make it. possible withm the scope of tbs mvartion in many esses for the pH--sped fk: adjurt-neu; of the dissolution pH to he adjusted eves more accurately -aad reproducibiy, The handling and application is also usually regarded as less elaborate

The fmoth)acrylate copolymer for the outer coating preferably eoasisfs of 40 to 95, preferably 45 to 90, lu particular 30 to % by weight of fee-radical poiymermed Cr to Ch-sikyl esters of aorylk; or rnefhaeryhe acid and may comprise 5 to 60, preferably 8 io 40, ia particular 20 to 35% by weight (methacrylate monomers ts.ivtag an aruome group. •The--mentioned--uotthaily add: op to 100% by weight. However, if is possible is addition, without this leading' ta sa impairment or alteration of feu essestial properties,ihr small surnoms la the regain of &amp;om 0 to 10, e.g. l to 5¼ by weight of lasher m«®» capable of vinylic, copolymerimrioa, such as, for example, kydrmyethyi mefeacrylateor hydroxyefeyl acrylate, to b« praseat

Ci- ta Ch-fekyl estem of acrylic at methaeryhc aad use m particular methyl methacrylate, ethyl, ssuthsorylsslo, butyl metbserykte, methyl acrylate, ethyl acrylate and butyl sctylaie, A im«th}scrylate raoaoaser having sa anionic gmup aery he lor «sumpfe acrylic acid, but preferably methaerylic acid.

Also suitable tue uaiosfe; (meshjaerylate copolymers composed of 40 to 00% by weight methserylic acid and 69 to 40% by weight andhyi methacrylate or 60 to 40% by we%ht ethyl serylute {Budrsgii® L or Ehámgit® LÍÖ0-55 types). The ghisa bousition featpursturu (ISO 11357-2. sabseedea 3,3.3) of dm type is m the tsnge from 103 to ! 60*C. and the molecular weigh! Mw is 1Ö0 000 to 300 900 (feu molecular wight Mw can- he deteaaiaed for example by gel'pennestioa dsrosraiograpky or by a sconerecl light nretbod (see, for osan^le, H.F, Mark e( at, Fpeyplopedta of .Folyam- Scieuou safe Engfeeeriog, 2.od Fdil.ioa, Vol. 10, pages .1 at seq., J, Wiley, 1989).

HgdmgfeH L is o copolymer of 59% by weight methyl methacrylate nod 50% by weight arofeueryhc seife This (nr«th>serykte copolymer is pardeukdy suitable for dissohrtka in pH ranges mound pH 6.0 to 6,5 tjoto- műn).

Emfeagihlb LKKF-.5S is s eopolyster of $$% by w-dgia ethyl acrylate aud 50% by weight· methseryke a«*4 Ehdtsagit® L3ÖÖ-5S is a éí^ssmm eomprismg .30% by weight Eedtagit® L 160-55. This {meth>srylme copolymer is pametdatiy sstteble for dlssolutiots iupíT mages Mourn! pH 5,5 te> 6,0 fduodems®},

Likewise suitable tsre tmlottic trueshkcrylate copolymers composed of 20 sa 40% hy weiglw tsmthmtrylic actd sob §0 to 005¾ by weight methyl metbserylsm tBudtagrttl? S type)., This fmethhscrylate copolymer is particularly suitable for dissolution m pH ranges aronu-i pH 0.5 to 7 0 (jejunum or ; leu® ), The glass transition tempe®®®· of ibis type ss m the range fsura )40 to .18<HC. ansi the molseuiar weight M* is IÖ0-00Ö so 150000. .Particularly smtable- tynedtlaetylste copoiyraers a® dtose eomastsag <ή 10 to 30% fey weight: methyl methacrylate, 50 to ?0% by weight ttteihyi acrylate sad S te 15% by weight nsethaerylic add.

Badragii# FS type is a copolymer of 25% fey weight methyl tuechacrylete, 655¾ by weight methyl acrylate ami 3.0% by weight tnethacrylie acid. Eudregit® FS K) D is a dtspersioa compnsisg 30% by weight of the FS type copolymer. Td-s (me-h'saerylate copolymer is parikoterly suitable for dissolution itt pH ranges srouad pH 7.0 to 7.-¾ (ileum or etrbti}.

Addmoaaïly· suitable is a capolymet composed af 7-6 to 34% by weight metkacrylk; add axtd/or sen-lie acid, 20 to 69% by weight methyl gory late and 0 to 40% by weight ethyl acrylate stiddr, wbe®-appropriate 0 to 10% by-weight further mooome® capable of vinylic eopolymerisukay scab the proviso that the glass- transition tompomute of the copolymer according. to ISO 103570, suhseettoa 3.3,3, is not more than 60:'C, This {tnethjacrylate copolymer is particularly suitable, beeattse of its good elongation at break properties, fot compressiag pellets te tablets,

Additionally suitable are copolymers eorapo.scd of 2d to 3354 by weight meth&amp;cryhc -mié -aa-d% serylie add, 5 to 30% by weight methyl actyi&amp;ts stud 20 to 40% by weight ethyl acrylate and store. then U! to 30% by weight butyl methacrylate anti where appropriate 0 to 10% by weight .further moaoroers capable -of vinylic eogoiymeHaatkm. where the proportions of the monomers add ap to 100% by weight, wsth the proviso that the glass transition. tetuperaone of the copolymer according to ISO l}337-2, suhseettoa 3.3.3 (midpoint tempera®® 7^-), is 55 to ?(fC. Copolymers of this type are particularly suitable, because of its good mechanical properties, for eotrtpressmg pellets to tablets.

The sboveutenhoned copolymer is composed in particular of free-radical polymerized units of 20 to 33. ptefemhiy 25 to 32, particularly preferably 2§ to 3154 by weigh! otethacrylie odd or acrylic acid, witlt preference for methaetybe seid, 5 to 30, preferably IÔ to 28, particularly preferably 15 to 2554 by weight methyl acrylate, 2.0 I« 40, pre usably 23 te 3 $, particularly preferably i 5 to 22% by weigh! eibyl acrylate, and store than lb to 3(K preferably 15 to 25, partictskrly preferably 1-5 to .22% fey weight butyl methacrylate, where the atonouter composition is chosen so that the glass feansition temperature of the copolymer is (rent 53 to 70*0, preferably St to 55. padienieuiy preferably 66 to 65*11.

It is also possible to employ mixtures of the copolymers matisioncd in order so adjust spec dk' rekase profiles or release sites,

Glass transition temperature «μ in fids comtecíám m particular the midpoint temperature Γ** sccorásng to ISO 11357-2, subsection 3.3.3. Measutument takes place without adder! ptagtacteer, with residual monomer contests (REMO) of less thos 1ÔÔ· ppta, whh a heating ma of iöeCüsm and undor a rútságért sttsiosghere. "Hu; copolymer preferably consists esscadafiy to exclusively of 90. 95 or 99 to 100% by weight of the monomers methaerylie acid, methyl aerylals, ethyl .acrylate and huiyl methitcrylate la the mages of smmnv» indicated above,

However, It is possible, without this necessarily leading to so impairment of the esseatia! properties, fot smell, amounts ta fite rastge irma 0 to 10, e,g, 1 to 5% by weight of fmther motsotners capable of vinylic copolymeriseatkra addrnennlly to be present» such as. for example, methyl methacrylate, batyl acrylate, hydraxycthyl methacrylate» Ytny^iyrRthdone, visylmtdenk acid, styrene, vinyl alcohol,, vinyl 'acetate smd-'er derivatives theteaf.

The copolymer? are obtained in a manner known per se by free-radical bulk, solution, bead or emulsion polymerizsuoa. They must before pmcosshtg be brought- to the particle six« range rtf the: invention by settable grinding, drying or spraytag processes. This can take place by simple crushing of as traded and corded pellets or hot cut.

The use of powders may be .advantageous especially on. mixture wiki other powders or liquids, Suitable apparatuses for producing powders are familiar :m the skilled person, e.g. air jet mills, pinned disc mills, ouraparönent-milH. It is possible whore appropriate to Include appropriate sieving steps, A suitable mill for industrial large quantifies is, for example» an opposed jet mill (Multi Ho, 4208} operated'wiih a gauge pressure of shout'd bar,

Copolymer preparation

All the (methjacrylshs copolymers .mentioned can be obtained by free-radical polymetizsumt of the tno&amp;emcrs In the presence of polymerisation Initiators and molecular weight regulators by means ofhlock, bead or emulsion polymerisation. and discharge of the polymer (see. for example, EE 0 ?Ô4 307 A3, Bf ö 704 20¾ A2 or WO 03/093732). The fmsth}serylate copolymers can be prepared in s manner known per se by free-radical emulsion polymerization in aqueous phase in the presence of preferably átnőnie emuhdlen, for example by the process described in DE-C 3 135 073. Further prep&amp;onion processes which are also suitable in principle .are group transfer polymerisation (GTP;· or atom transfer radical polymerisation (ATRP) (see, tor example, Matyiassewxki, K. el: al., Cnem. Rev, 2001» 181, 2921-299(1). The resulting polymer xtrnemms are random copolymers or block copolymers, fæfæmm.M given to emulsion polymeriaotlon m tbc presence of from * to 15% by wight motatkr weight regulators-, ms. emulsifier comerst in the songe from 1).1 to 2% by weight, a polymerisation initiator quantity in the range from 0 02 to 0.43¾ by weight and at temperatures from 65 to 90*6.'. Preference is gown to an emulsifier mixture, pmterably composed of sodium hairy! sulphate, e.g. 0.1 so 0.35« by weighs, and polyoxyethylene-20 sorbitan .monooleate, e,g. 0,4 to 1,5% by xvslght, Esntieuisidy suitable initiators am sodium peroxesissolphxtc or ammonium peroxodisulphate. it is possible iti this wsty to prepare fot example s dispersion with a solids corttont of iront 28 to 405¾ by weight, and io isolate the copolymer by spray drying sir by coagulation a«d expuleios of the water la m extruder, The polymer k .shhseqimtttiy· dissolved, preferably ts-ss organic solvent, padiad by multiple dndysk agamat water, and pmfhrably frees« dried

Example« wfeíoh may Ire mentioned of ptdymstixatson «ammrs are: aæo. compounds such s®· 2^^-820^(jaofeoryroöiöífe> or 2»2>»a®öb{^2s4~dkoetfey5vai«gr«eifeiie}> mdos sysfotns such as, for ««ample, the combinaison. of tertiary aminos with peroxides or preferably petmhks (ef is this, cowmsim for e&amp;ampl« H. Rsoek-Fumiptn, Tfe. Völker, "Acryh «ad MethncryhwbasdnrtgesY Sptiagse, Iteideliwrg, 1967 or Kirk-Otfemar, Encyclopedia. of Chemical Technology, Voi. 1, pages 38$ at ssq.., 3. Wil«y, fiese York, !$?$). Examples, of settable peroxide polymarizatiot· mitiators are dtkutcyl peroxide, tert-butyl peroctoate, tethbutyl psmononaaoate, dfoycksksxyl peeoxyfoembortate, dihcnxoyl peroxide »r2,3“bis{iertfos:ityiper&amp;xy}hotatw.

The polymmaatio» cs» also preferably he .earned oat with a mixture of different polymerisation initiators differing m half lile, for example dikaroyl rw-rcfode sod 2,2-hk{terî-butylpcKtxy)bna»e, at order to keep she. flow of dee radicals -comtant· during the polymentmEort and at ditfemri polymerisation temperatures. The employed smmmta of polymérisation initiator are generally from 0,01 to a maximum. of 1.% by weight based ott tbc tttosemer .mixture.

The molecular weights Μ w css be adjusted by txdymeneixg the monomer to lx ίο re so the presence id' owfoeulsr weight regulators. Suitable molecular weigh; regulators are is particular mereapi&amp;ns such ax, for exemple, »-butyl mercaptan, n-dodccyi mercaptan, 2~s»ercaptoethsno) or 2-eihyihexyl thioglycoiate, the snoiaevdsr weight regulators, generally feei&amp;g employed m amount» offres» 0-05 to 15% by weight based os the monomer mixture, preferably m amouefe of fixes 0,1. to 105¾ by weight and particularly 'preferably in amounts of frost 2 to I llI: by weigh; os the monester ssixtxax; tef, for example R Raueh-Puntig&amp;tn, Th. Volker, 'Àetyl-und Menhacryt Verbindungen'', Springer, Heidelberg, 1967; Houbett-Weyi, Methoden der organische» Chenue, Vol. XÏV/1, page 56, Georg Thiotse, Heidelberg, 1961 or Kirk-Othtaec, Beoyelopedia of Chemical Technology, Yol, i , pages 296 et ses,, I, Wiley, blew York, I97ST The molecular weight regelet»? preferably employed is rt-dodoeyl mercaptan or 2-erhyii;exyl thioglyeolate. EthylSexyi thloglycolale Iras the advantage that the hydrophobic tty of the Imeshjseryfeie copolymer cart be isflucuced, because she regulator is incorporated terminally into the molecule. Preferred artKsums employed are 5 io 15% by weight dodecyl memapfea or 2 to 10% by weight 2-esfeylbexyl thioglyoolste.

Organic solution

The itnethj&amp;cryiate copoiyrners mentioned can he. provided in the torsa of an organic solution, e.g. I» a concentration, of feots iil io 30% by weighs. Solvents which may be used are, for exemple, acetone, Isopropanol or ethnnoi or mixture theteof, which may where appropriate compose water in proportions tsp to «bout 10% by weight. However, aqueous dispersions are preferred.

Dispersions

The {meth)acrylste copolymers tnentioned coo be produced and used as emulsion polymers, pmfemhly in the form of a ii) to 50 pestent by weight, itt particular 20 to 40 percent strength aqueous dispersion. A solids corsent of 1K>% by weight its preferred as commercial fortn, Partial ueutrahtmtloa of the rnefhaeryiie acid nshts can be ctlspeswed with for processing; ;t is, hower er, possible, for example to ats extent of up to 5 or H) tsol%, if stabdixstion or thickenirtg of she coating compctsttton dispersion is desired. The weight average sfee ef tire la rex panicles is usually foes« 40 to 1Ö0 stm, ptxtforsbly SO to 7Ô mi, thus ettsuring. s visoosi.ty of below 1000 mPa-s which is fexxturahle for proeesstng.

Wife higher dsgteos of nenîralkahe»,, mg, 18 so 50 mol%* or gpmpfein ««utmlimtioa Ét b possible to convert. the copolymer so to a dissolved state. fe order to prepare a solution of the atuomc copolymer, it· is usually necessary to n.csnmiize the acidic groups partly or completely. The anionic copolymer may for example he stirred gradually into water its a. -Saal eonesmuation of fesm t to 40% by weighs sad at the same time he partly or completely steutrsiixed by adding a hasis substance such as» for example, NaOH, KÖH, mnntommn hydrasMa or organic bases tsssk as, for example. triethtosohsmme. It is also possible to employ s powder of the copolymer so which a has«, mg. M'aOH, has bee» added during its pmparatbn for the purpose of ipartial) neutralisation, «ο litas fee-powder is a polymer which is already (pertly) acmmiked. The pH of the solution is usually above 4, e,g, tern 4 to about ?.

The dispersa?» csss for example also be spray shied or fessxe dried m a soasmer known per se aad be provided in the -form of a mdtapersshle powder (see:, for. example, BP-A 0 262 326). Alternative processes ate ffs&amp;ae drying or coagulation and squeezing eut of the. water is an extruder -with subsequent granulation (see, for example, EF-A Ô 683 028), is has sorpnsisgiy bees found that copolymer dispersions from spray- or üeere-dried and tedispersed powdm exhibit increased shear stability. This is advantageous is particular m the case of spray application. This advantage is pemcularly evident when the copolymer present ist the dispersion, is partly- neutralised fe the extent of 2 to 19 moi% «based or; the acidic groups preset« is the copolymer). Partial neutralization by adding bfeOH is preferred for this -purpose. As amemc· esmdsiftet is preferably present is sox .amount of from 0,1 to 2% bv weight Sodium lauryi sulphate is particularly preferred us ss.muisdser, Iääm

The fever thickness of the outer coating is preferably in the range from 20 to 289, preferably from· 58 to 120 μ a:·.

Production «Τ &amp;. multiparticulate pharmaceutical ferns.

The invention additionally -relates to a process for producing ss rnuMpamculafe p)mœ*aeemkai&amp;sm. by it) fortauiatiag a nucleic. aeid active ingredient wife excipients in a manner hnowu per se to nanopaætieies, b) producing an inner malm layer comprising the nucleic acid active ingredient m the form of nanopardefes and a polymer having a mucoadbmue effect and, where appropriate, further pharmaceutically usual excipients by moans of spray application onto a eom or- by mtugglomeration, precipitation or spray processes without a cere and subsequently c) applying an outer fiirn coating consisting essentially of ati anionic polymer, which may optionally he .fermnkkd 'with pharmaceutically usual excipients, «spec tally phtsfiefeers, by spray application so that active ifigindieuf'crsataining enveloped pellets are obtamed, and d) processing the msmthig pellets by means of phantnaoeuncally usual excipients and at a manner known per se to a irmitipaHicuiate pharmaceutical fonn. in particular to peilet-contaming tablets, mmitablets. capsules, s&amp;che-s or powders for reconstitution. which ate formulated so feat the contained pellets are released at die pH tätige of the stomach.

The pelleting can lake place onto active fegmdteat-fiec heads (amqiareilles), or eore-frcc pellets enn be produced.

Firstly, active ingredient-containing. nanopsrticks are produced.

Subsequently, tbc hmer maSxk layer is pmdanaá «mb or without core, Thus s$s yet tmcoated, rounded fayercan be referred to as pre-pellet (pellet coreL iS: is possible by m» of a fkidked feed process to apply a sofatto» or suspension of the moeoadbekvo polymer eoropdsmg the ussreptsruefes havtsg the osoleic acid settle ingredient to planets© pellets- or oik«' suitable earner materials, with evaporation- of the solvent or suspending agent. The production ptooess cart be followed by a drying step.

The nuclei« acid active meredtem is tat reduced is she form of nanopartkies having the polymer Slaving a macoadhepive effect into an organic soke»; or into wtwr, and mixed hi order to ensure satisfactory vpmyablhfy of the mixture, is is usually necessary to formak-e s mixture of low viscosity. it may be beneficial for Shis purpose to employ she polymer having a mecoadhesive effect us comparatively low concentrations, e.g. from .1 to a maximum of 10, preferably 2 to 5k by wight AddMoa of &amp; dstergem, ®.g. two», its eoitcentrelioos of from 0.1 to SIX preferably 0.5 to 10% by weight may moreover be- advantageous to reduce the. surface testslot·.

Besides the active ingrédient it is possible for further pharmaceutical excipients to be present: bashers such as cellulose and its derivatives, polyvittyîpjmoUéoae (FVPg hmneetassx, diskfegratiort promoter, lubricants·, dnunfegmts, (saethyacryktes, starch and its derivatives* 'sugars, solohtlixms or others.

Appropriate application process«« are disclosed for exaiuple k Bauer, Lchmam, Osierwskl, Rothgang, ’'Überxogette Amteifonnea" Wisseftschnllllelis Votitegsgesellsclsait mbH Stuttgart, chapter 7, pp, 165-196.

Details ere furthermore disclosed to the skilled person from textbooks. See, for example.

~ Voigt, R. Lehrbuch der phwxsraaeufisdam Technologie; Verlag Chemie Wahrheit» « BeerfieM

Beash/Llorrda - Basel

Sucker, H., Fuchs. P., Speiser, P.: Pharmaxeutiscbe Techaoktgi», öeorg Tfefetse Verlag Stuttgart (1991), in particular chapters 15 and i b, ρρ. 625-642, - Gesattm, A>, R> (Editor?, Remington's Pkumaeeímcál Sciences, Maok Publishing Co., Pás ton Petm-syh-mia (1965(, chapter 8 k pp. 1567-1573. - List, F.H. 0962): Arasetiomrenishre, Wissenschaftliche VerkpgeseHschsB mbH, Stuttgart,

The inner matrix can .also be produced will-out tbc assistance of an mert core (rmupirredles}. The ingredients of the inner matrix may in this caw he rounded to ns yet unseated pellets spre-pellets) of defined ske, e,g, SO to 160(1 pm, by processes such as retaggiomeraheta, preetpiisikisi or spray processes, especially ultrasound fhxldked spray process««. This has the advantage dsat the entire core volume is available for loading with active ingredient. The loading with active ingredient can thus be increased further compared with the enfnodimeni: having a» mort· com.

After production of the inner matrix cores (or of the pre-pellets > they see in tarn provided, preferably in the spray process, with the outer coaling, to result in finished pellets. The pellets tire produced by spray application from organic solution, or preferably from aqueous dispersions. It is decisive for implementation irt this ease that uniform, pore-free coatings are pnxkeed.

Xbihkât

The pellets can lie provided additionally with pigmented coatings which, however, must not ktlueuee the dissokakm pH, Suitable examples are coalings composed of pigmented hyxiroxypmpylmelftyicelklose or other polymers which are soluble in water or rapidly dikttiegtme m water.

Fharmnueatleally «suas excipients

Usnal exetplems cor additives cas B® added t© dt« fen&amp;niatioos of the inveatim dadog production, U is, of coarse, always necessary for ail the snbs&amp;isfces employed ίο be kokokmically acceptante sad nseabte io particular sh medieameats without" » risk for patients.

The amcsimra employed and lise ose of the usual additives- -ht medioameat. coatittga or layerings are isœiiiar to the skilled parson, Possible- examples of usual additives ate plasdessers, telesse agents, pigments, stabibnem, asbomdams, pore dormers* panemsskm .promoters, glass agents, munsrbdug substances, delergouts, hthricartls or ilavourfags. They serve as processing aids aad sre iutesuied to ensure a reliable mâ reproducible production process ássd good ioug-term storage stability, or they achieve additional advartîageom properstes Is the phatmaeeesjcal loros, They -are «aided to the polymer preparatkmx befere She processing sad may itiflecece the pcnecabilisy of the coatkgs» it being possible to mlliae this where appropriate os sddidooai cotdro).-párámé-ser, V Release agoras. .Release agents usually have lipophilic properties sod am usually added so the spray suspeushms, They prevent agglomeration of the cors? dunng the film costing. Tale, Mg stearate or Ca stearate, ground silica, kaolin or noulom«: etaolsifters having an HT.8 of between 3 and b are preferably employed The ostial amounts empfeyed id'ideas«·: agent ;n -he coating agetits and binders of the intention am between O.S io 10()¾¾ by weighs baaed oh r&amp;e copolymer. * Figments

Figments mcompatrhte wirh ihe coating- agest art; $n partimiiar those pigmcatS: which,, if added directly to the ímeíhíacrylde cop;dynwr dispersion, e.g. by stirring in, ist the usual amounts used of, for example, 20 to 400% by v eight based cm the dry' weight offne tmeihlacrylat«; copolymer load to desiabds ration of She dispersion, congelation, to signs of mlwmog«:ndty itt similarly wiwsmed effects The pigments to be used are moreover of comae uotntoxtc and suitable for pharmaceutical purpose?. Concerning this, see also, for example: .Deutsche Forschungsgemeinschaft, Farhstoß<\ßt' twrwoxmmy/, Harald (Soldi Verlag KG, ISoppard (1978); Deutsche Lebsrfsmittslrimdschau 74, No, 4, p. 1.56 i 1.978): .ArimeirniStelikrbsS-oflverordaong AmFsfbV of 3-5.08,1580, Figments incotnpaubic with Sim coaling agent may he fer example alumina pigments. Examples of incotnp&amp;tihSe gigámmá are orange yellow, eoefunea! red lake, eolotsred pigments based os alumina or azo dyes, snlphonic acid dyes, orange yellow S (El 10., CX 15085, FDM? Yellow 5), laéogo carmine (El 33, Ci. 73015. FD&amp;C Blue 3}, snrtraxhw (B 102, C'.L 19140. FDEC Yellow $), pencéús 4E CE 125, Ci, 16255, FD&amp;C Codaneai Red Â), «ghnohne yellow ÇE 104-, CX 471)05, FD&amp;C Yellow Kl), eryihrosme (Bl.27, Ci. 45430, FP&amp;C Red $), axoruhme (F 122, Ci- M72Ö, DD&amp;C Onsnolsnsei, amaranth í£ 122, Cd. 16185. FD&amp;C Red 2), acid hrdlisnl: green IE 142, CM. 44000, FD&amp;C Green S).

TkeE numbers mdieatsd tor dm pigments-relate-to a» EU smmbedng. Cosoerslsg fess, sea also ‘TNmtsoho For-sehmtgsgesmlnschsfL Farbstoffe* the Lshensn-kdnl, Hamid Soldi Verlag KG, Bopp&amp;txi (1978); Deutsche Le-bnassnmhrnodsehsu 74. No. 4, p, 15b (1978);

Ar^ehuittellarbstoftwtrordsusig AtnFarhV of 25,08.1980. Tite FB&amp;C numbers relate Io she approval in Food, Drugs and Cosmetics by the U.S. Food and Drug Administration. (FDA), described irt: ILS. Food ássd Drug Ad~ miötetmiöH, Center for Food Safety and Applied Netedoss, Office of Cosmetics ami Ccslors: Code of Federal. Regulations - Title 21 Color Additive Regnhtthms Fart §2,, listing of Certified Froviskamlly listed- Colors and b peer fkai to ns í CFE fart :¾¾ « IHasncteem

Furihet abdstlves may also fee pSaaoeäsers. The «sual smatmfet are feetwee» Ô and S£t, preferably 2 to 3¾ in ptstuetda? 5 te 10% by weight

Pla&amp;ncs'trm may influence tb« funetioosbty of the polymer layer, depending on the type (lipophilic or hydrophilic) and added itatom«, Kïmimzm» acfeie»e through. physical ißÄSw with the polymers a rciloeakjn its she glass tmnxlftnn sernperaWfe and ρρ»* illat fomstion, depending on the added amount Suitable substances usually have a molecular weighs of between 100 atsd 20 000 and comprise one ot more hydrophilic gtmtgs ist she molecule, e.g. hydroxyl, ester or amioo groups, bxatnpjes of suitable plasticizers are alkyl citrates, aivcerol esters, alky; phtkslates. alkyl seh&amp;cates. sucrose esters, sorfeilen esters, diethyl sebacaie, dibutyi sefescate and polyethylene glycols 200 to 12 OoO. Preferred pkisilerœrs aas rnethyi eiímte (TEC? end acetyl trlethyi «amte (ΑΤΒ€ρ Menően should additionally he mad® of esscfs winch are usually Hí yod a; room Uonnersture, such as c irrstes, pMhakttea, sebacstes ot castor oil, Esters of citric tieid and sehaese acid tecs pteferahly used

Addition of, pisstiesxor m the formulation can take place in a known toaot;er, directly, in aqueous solution or síiét therm«! ptetmstsma of the mixmm. Is is also possible to employ mixtures of jdaslldaeta.

Production of otrdidpartk'.slaiv pharsssmttiiaf forets

The active |ag??edie®5x«onlamiug costed pellets eatt he processed by means of plsarmaeentieally nattai eseuneots and nj a manner known per se to multiparticulate phartnacectie&amp;i fonás, in particular to pellet-containing tablets, minùabkos, capsules, sachets or powders for reconstitution, which are formulated such that she contain«! pellets are released in the pH range of the stomach. The preparation as multiparticulate pharmaceutical tom places a high dosage reliability offers the advantage of good dismbodoa of the pelles? In the intestinal lamm. The multiparticulate pitarmacensical form of the ttwetttiott may additionally also comprise different pellet type;; with iliffereet active Ingredients and/or different pellet structure; iahlSllSS^

The pmduetbfi. of mtdtípsrtteuiaíe phamtstmitieai forms fey cotnpmsaitm of s phanmcetiticslly usual biitder with active ingnsliem-containing particles xs described lor example itt Beckett es «I. 11996), '’Comptasse»*}, of eotenemoamdpellets to disintegmisg tablets^ ïntermtiomÎ Jourmi of Phamm&amp;Uics i4$, pp. /,1-22, ásd is WO 96/01624, frits coatings of active htgredieut-'Cesnalsiog pellets are normally applied is dusdtaed bed apparatuses. Film formers am eonnaity mixed with plasticizers aod release agents by a suitable process. Is is possible is this ease tot rite fibs former to be in the Ibrsn of a solution or suspension. The excipients for fUm formation may likewise be dissolved o? suspended. Organic or aqueous solvents or dispersing agent? cats be used. Stabilizers can he used additionally to stabilize the dispersion (example: Tween Sit or other suitable emulsifiers or stabilisers).

Examples of release agents am glvcencl monostetuate or other suitable fatty add dersvatsvew. silica derivatives or talc. Examples of plasticisers are propylene glycol, phthaistes, polyethylene glycols, sefeaesstes or citrates, attd other aubstanoes ntentlottesl is the Iheraltrte, A separating layer cart fee applied between active iogtedlent -ootuaining anti Intestine-soluble copolytaer layer stnti serves to stepsrate active Ingredient and coating material for the purpose of preventing interactions.

Tass layer may consist «f meri film formers- ic.jp 11TMC, MFC oc (metb laetytie aeM. copolymers) or» for example, ude or another suitable pharmaceutical Ass». F ts likewise possible tt>· »se combinations of film formers aud talc or sitmlar stsbsr&amp;oees. ír is also possible to apply a septsmmg layer composed of partially or completely ncmratiæsd (moth)soryiain copolymer dispersions.

Toe sepamtirtg lavór may also consist of the xattw or a different mueoadhedve polymer as m toe urtder!·· yiag matrix layer, Fossibie x»tsras«o«s or incompatibilities· of tite active iagmdleal ot of fits tmeoadlmstve polymer with the űlru-íbrruiog {mmhl&amp;seyfate copolymer layer csa ho countered in this way.

Mixtures for producing tablets composed of mated particles ate prepared by nnaisg the pellets «iris suitable binders for «ablating.. if necessary adding dtstntitgratbn~pmmntittg substances-and if necessary adding lubrscauts, The mixing can take place in satiable machines. Unsuitable mrxers are those: leading to damage to the coated parádés, «.g. ploughshare mixers. To achieve: suitable shun disliuegration times it may be necessary to add the excipients to the coated pamoles itt a spécibe sequence. It Is possible by premising: with the coated particle with the lubricant or mould telesse· agent magnesium stesnste for its surface to be rendered hydrophobic-and thus adhesion So be avoided.

Mixtures suitable for tabletirtg: normally eotnprise 3 to 151¾ by weight of &amp; disintegration aid. e.g. iSoliiáos CL and. for example·, 0.1 to 1% by weighs of a lubricant and mould release agent suds as magnésium stearate. The proportion of binder lx detomtiaed by she required proportion of coated· particles.

Examples of typical binders are Celiaesose#. aticmctrystitlfine cellulose» ealeiem phosphates, tudlpresshk, lactose or other castable sugars, ealeium sulphsies or starch derivatives, Substances of ion· balk density are preferred.

Typtest! disintegration· aids {dishkegoxuts} .are crossttnked stanch derivatives or cellulose derivatives* attd etossnoked polyvkyipyrrolldoee. Cellulose derivatives are .kkewtse suitable. It is possible to dispense with the use of disintegration skis through selection-of a suitable: hinder.

Tip;«; hthricanis ;trtd mould release agents «tu magnesium stearates or ether suitable salts of fatty acids or substances detailed in the llterantre for ibis purpose íe.g. lantié add, ealeium stearate, tale, etc.), It: is possfcle to dispense with the use of a lubricant and mould ««lease age«tt to the mixture on use cf suitable machine* (c,g. tablet press with external lubrication}.·«»· suitable formulations. lus possible where appropriate to add tm .aid to the ntkntre to improve the flow (e,g, colloidal silks derivatives, tgic,.eie,},

Tbo sahleliog can take place on usual tablet presses, eccentric or rotary tablet presses, with compressive lorces in the range from 5 to dO k.N, preferably 10-20 kX Tee tablet presses can be equipped with systems lor external Móricaikat. Special systems for die rilling, which avoid die riliiog by means of impeller peddles* ate employed, where appropriate.

As alternative to conspmssed tablets or nkuitaidels, it is also possible for the: acti ve ksgrmileno-cxwtaimag costed pellets to be processed to any other orally administered multiparticulate pharmaceutical .loan. The costed pellets can, for example, be -packed Into capsules. e,g, gelatin capsules, or formulated to sachets or powders for reconstitution.

Advantageous affects of the kmtoiíon

The pharmaceutical hum of the invention Is sdfsihlo ihr targeted and efficient release of nucleic acid am- tive fegcediestfe, The phttrouteetdical form exhibits a high -dosage reliability m4 Ärilsm«s well. at äse stomach and in the isuestfeal honen. The contained oocieie acid activa rágcsálom is moreover substantially protected from physical er xmelmlytlc inactivation sad can fee released at ára defined site of actress hr such, a way shat &amp; high proportion of she activa ingredient can ba taken up fey the body. The pharmaceutical .ferns therefore- makes do with, kss activa ingredient, because only a little of the active ingrédient is lost,· Th« risk of skie effects is reduced ovtsoad by the ttngereti. delivery. The site of action can be adjusted variably, depending m the therapeutic arm. The. timing of the active ingredient uptake can feus be better costtiolled. Because fee pharmaceutical fenn is lor oral «se is is accepted bstter overall by patienta (patient «otnptiaoce) «ompared wife other «dtnimsSxatK<n fern«., A targe camber of nocisic seid active ingredients can fens be made avail able for oral use. The risks of administration see alien less than with parenteral administration in psrrienlar, Theorems of afenrmsmstion can also fee kept low because ho skilled staff are necessary for fee admtuistrstion.

Lipophilic matrix

An special aspect of the invention emerges whet; the active segrefeem is incotporated in fee form of mmopartioi.es toto a lipophilic matrix: which has a malting point above 3?°C* preferably above 45*C, pmkulatly preferably preferably above SS'C, and the acine mgrsiient -cotttsntfeg lipophilic tnstnx is incorporated in«; fee matrix composed offen polymer having a mueoadhesive effect. The aim of fommiaiioo in the lipophilic matrix is to improve the solubility and fee bioavailability of fee nedve ingredient, preferably of sparingly or slightly soluble active ingredients las defused it; DAB 10, 200s}. Λ lipophilîc matrix means irt the contest of fee invention a substance or &amp; mixtum of cubar&amp;nces in which the seovs: Ingredient cats, be dissolved, suspended or smulstiutd. Use substance os fee substance» of the lipophilie matrix are dirik cm from the usual pharmaceutical excipsettts ami fee polytner having a mucoadhesive effect, Tire .substance or the substances of fee hpopfeáic matrix preferably have a hydrophobic ox else amphiphilic character. The fepophihe matrix: might also be referred te as antplnpbilk mattis or as bpottfel matrix..

The llpopltibc matrix. tatty consis t, of a single sufesutnee, e.g, of a lipid, or of a mixture of substances, e,g. of a nnxiurc of Holds In the case of mixtures, the properties, described hereinafter for watet solubilities according to DAB H). partition t oei'ikiems and/or ΓΠ..Β vaines are cskul&amp;ted itt each ease from the arlthme-ic mean of tire parts by weight, and the values of the substances of the-mixture. The snaploysd substances mum not h&amp; toxic.

Lipophilic mstrix/poiymers having a mueoadfeesive effeet

It· a pteiewed emberibe cot. possible interactions of the lipophilic matrix with the polymer having a mneoadhesive effect arc taken into account in order to avoid uncottfeoUahle isueractions, fee sobs tance ce the substances which fern; the lipophilie matrix* -and fee polymer having a. ttmeesefeesive effect should preferably tot her have fee same tome properties. I.c. both should have toncortlattily either at least predominantly cationic or coneor&amp;atitly anionic character. In fee event that substances havmg opposed sonic properties are selected, the polymer having a mneoadhexive effect shc-nid preferably he present In at least SO, particularly preferably 100%, nvutrahrad fotrn. The neumrikstioo can ttske ple.ee fey adding acid or base in a knows manner.

Substance er substances fur assembling tire lipophilie tuas rix

The lipophilie taalnx preferably consosts of SO to IÛÜ, preferably Iti) to IDO* particularly -preferatily .100% fey weight of a stfestatree or of a rtnxture of substances feeving t-.n (averaged t HLB of front 0 to 15, preferably 2 to Id consists. The lipophilie matrix may compnse Ö to 20, preferably' 0 in 1(1% by weight of -p&amp;artasceutie&amp;Uy usual excipients, especially stabil leers, thickeners or adsorbents, li is particularly preferred for no pharmaceutically pssai e&amp;efpjenta to be presets,

Tb« substance or the substances which fona the lipophilie nsatttx may .fer example belong to the group of oil®, fais, sasaid, di- or triglycérides» fàtty acids, laity alcohols. especially CT to -€»> fatty aek) a«d/öí a C§ to Cj§ alcohol iaclttdmg their salts*. ether, «stör or astride derivatives, phospholipids, lecithins. cumdsitdets, lipoids, lipid-soluble vttamms or suriaetauts.

Ik; lipophilic matrix may -cotspme for example ose of ike (ollow-iag lipid prepartttfons; fluswotor 30S) glyceryl monocaptylate having a monoeste cotacst of > 80%, (Imwitot 312} glyceryl utotsolsuralcs .having a monoester cement of > $Ô%, (îmwstor 491) glyearoi mosostetstes (Ct*. + Ctg.) having- a monomer coateot of > 90%, (tmwitw 900 F) glycerol snottostearale having a. monoester contest of 40-353¾ aad a Cfo cornent of 40-60¾¾. (fmwtior 900 K) glycerol aïoaosieàntte, having .a monoestef coateat of 40-53% sad a €$* ootnem: of 40-30%, timwlter 742} medmm ehmft-imgth 0« sad glycerides having a mmtoester emtt-eat of 45-5551 (îavvaer 920) parttal glycerides of saturated vegetable €srC;s fatty adds having a mattt coolest of €«, ask having a mootsester contest of 34-36%, C* aad €% glycerides, Na c-aptykte or Isa eaprkte.

The lipophilic tnatrsx may cotapme for example ont of ke following lipid prepararroris; fats such, as mono-* dl-, triglycerides of saturated sod ussstssatcd fatty adds aad mixtures thereof, ïa particular glycerol stearic seid estet, glycetol pshollie acid ester, glycerol tsyristse acid ester, glyceroipaktritk; aokl sieano acid ester, glycerol l&amp;am acid ester, glycerol capryiic acid ester, glycerol oleic acid ester, sxaurples of these esters are Imwiror® -3M, -312, -491, -742, >90(1, -9:3¾, -9M. aad Gelueim# 44/.14, -50/13, Oeleol, Cotapmoi £: Aft.), öyn&amp;sa;r 114, Softisan. Witcpsol, D vase el 212, coconut fat, oils sock as, for example, easier oil, sesasne oil, sunflower oil, cottonseed oil, «om oil. -almond oil, peanut eil, olive oil, eocormt oil, carrot oil, wheat gertn oil walnut oil, stern! oils such as isopropyl mymhtie, isopropyl palmitafe, isopropyl stearate, mechuro chain-length mgiyceddott (Mlgiyol#},

Shôït-ohâia aliphatic and aromatic carboxylic esters such aa, for exasnple, dihutyl pMr&amp;iate, diethyl, sehacate, dibatyf sebaeaie, tributyi citrate, acetyl trsbutyl citrate,, glycerol triacetate, waxes such as, for example, oanauha wets, beeswax., wool was glycerol behenk- add ester, fatty seid amide® sued as, ibr example, stemmsde, pfosskasride, lataarsride, aliphatic, long-chain carboxylic- sekk sodr as, for example, stearic sold, palmitic- acid, lauric add, aiyristio acid, oleic acid, capryiic acid, iiaoieic acid, linoienic acid. And, for example, their Ma, Ál and Mg stdis, fatty alcohols such as, lor example, stearyl alcohol, found alcohol, cetyl alcohol, myristm alcohol, glycerol formal, W/O etttuMfite such as, for exstspfo, cholesterol, glycerol nxasostarats, ethylene glycol monostetute, sorbite moaookate (Spaa# SO), sorhitsn monepaltmttde· (Spas® 4()), sodblttta mostolaumte (Spas® 20), sorbitaa mmosmm&amp; (Spas# SO), sorbite trioleate (Span® S3), sorbite triskstate (Span® 65), stabdsa sesguiofeates (Arktcei# S3), Ca, Ai, Mg siestale, potexyotkylese xothifan kistearate -(Twees® 65), polyoxyethylene sorhitas trioleate (Twees# 65), uokorïie OAV «mulsrftm sack ss, for example, roaorogol stearate 4M (ChresKiphoî# A), roserogol lautyl ether, polyedryicac glycol 2(r aorb-itas monels»*», sorbitaa monotearslc- sorhihat mosopalatilatc, sorbista aiosKsdtec, atacrogol 1500 glycerol ttmehmieam, mactogol glycerol hydtoxystearatc (CteorophorS· AH), taacrogol (00(5 giyeettd stoaolstarste, monosterate, moBoolcate. sucsx>se monesterate. Foiysorkste 69 δ8), pulymycthykne moaostcsrsfo (Myii 4¾ poiysorbxfe 80 (fmm Φ. SO), polysorbaie 40 (Tweenfo 40), pet$$;<sxbm 20 {Tmm® 20}., poioxamcr 407 ΙΕχΡοΙΦ F 127), pötoxämur ISS (Lutroi# F 6%), prdyoxyailtyieue: rieÙKskafe (Cmmophm# ELK polyoxyethylene 5 steasyi smarofe, sorbe Ô/W etordsifiers such iss-, for exanqsie, cetybaearyl sulphate {l^aett«^ E), M&amp; htmyl sulphate (Texapos# ZX Ma giyencholai«, hndurogdma, ktephlphilfo «malÄscs huch m> for «x&amp;mpk,. «gg phosphatidylcholine íegg tóthmX soya phoapharidyicholiac (soya iecifofo), behxsx;, suJphqhstamcs, eeratskles (sphingomyelin ), vitamins such as, for example, retinol tsitarttin A), cixjfee&amp;leifecol ivitsmia f>), eiplxwtoeopherol and alpha-tocopherol asetstc (yhsrtks B), phylloqu tuons (viiatmo K), farther exskpfoms are galketohpiris such as, for example, monogsiactoayi diacylglycérol, digalactcsyl dlacylglytterol, trigalsektsyl diecyl giyeerol and aromatic oik sack as, for example, aniseed oil, etkonella oil, euealypms oil, lennel otfe.eamoatik oik cardamom oil, pine needle ssd, .caraway oil, dwarf pme oil, lévesxler oil mMoil, mascai oil, clove oil, peppermint oil rosemary oil, sage ail and kapertes such as, for example, menthol, linalool, l,4fremeok pysxthdn, bemerd, sudesmoi, .phytol,. .tnanord, atmdiraehtiu, nimfetn,

Ids content of the active ingredient-containing lipid matrix m she inner matrix layer a} can be front 1 so SO, preferably K> k> 20% fey weight.

The lipophilic· matrix ptefomfeiy comprise« si less! 50% by weight glycerol moneeaprylat®, ap to 10% by weight Mo eholais, up to 10% by weight tocqphsrol stseolttste, I to 5% by weight of an efflux psunp inhibitor in she esse where the active ingredient ts s substrate stf tire PgP efflux putnp, e,g, Solutol MS IS, a triglyceride, in particular hiasearas.e, wish the components adding rsp so .100%, This lipophihe matrix nan be incorporated directly hue the mucoadherivu polymer or be .emulsified in water and- hscesporated into the ttxteosxlhesive polymer. la the laster ease, the aqueous phase may comprise: a weak sek! such as, lor example, citric acid. Process

The invention·also·roiatcs to a process for prosiuehsg ss srirsisipssrsienhke phamsisceutietsl fostyx with the steps a) ' production of tire txuive fogrodierst-eosrsxisrhrg lipophilic· matrix by suspending the nanoparticka comprising tlx; nucleic acid active ingredient wxth dm substancefs) which form she lipophilic matrix and, schere appropriate, ferdtet plumtiaceutieally usual excipients by vigorously mixing or melting the iogmdients. b) production of pre-pellets (pellet cores} by spray application of tlx; mncoadhestvcpolymer mixed with the active ingredient-containing· lipophilic matrix otxo a core or by rot&amp;gglemeratien, precipitation or spray processes without a core, c) production of pellets by sprsy applies; too of s coating of the strfortie polymer os' copolymer, whseh may optionally comprise admixtures of phatmaccuticaily usual exetptettis, especially plasticisers and telesse eget;is, from a dispersion ot organic sotutsox otxo the pro·· pellets from step by ¢) pnxkx'hoo of X meltspaxtlcolsk; pharmaceutical form by filling or incorporatmg the pellets from step e) ;n a tnsnnet keoon per se, where appropriate with use of pharmaccnocslly xsu&amp;i excipients, ia particular by processmg to pellet-containing tsblets, mmttafete, cepstdes, sachets or powders for reconstitution. Froferrtsd process

Froctîss steps a) aad b) ere preferably eturkoi out as folxnvs; &amp;} pmdoctsos of the Imssc matrix layer by papering. m -emuMm or suspension of the- uenoparttciss comprising ihr: mteletc aojd. active ingredient wish the substancefs} for &amp;e lipophilic matrix, and. where appropriate fonher pksrnaceuheshy usual exciptents by vigorously mtxbtg the ingredients tß water and producing au od»m~water prapsratioji having sa average particle sixe of not more Ősart.00, preferably not more ihass 20 pas» b) production of pre-pellets hy spray application of the oil-m-water préparais» tern step a) oate the mucoatfoesive -polymer -which may optionally compose adnsixtures of further pharmaceutically usual excipients, where she ingredients are hi she form of s enornnixed powder, e.g. having an average particle sire of foam H) us 100 gem, by rotaggiomeration, extrusion or gramilatton,

EXAMPLES

The examples illustrate procedures typical for the investioti 2 mg· of BN A {mtetem acid active ingredient}, e<g. a-gene therapy vector composed of double-stranded piavmid DNA havmg, for· example. 5000 to ih 000 hiwe pairs, comprising a gesse which is so be expressed so humas- cells and intended to haw a fnem-ieusk' effect, is dsssos red iss 4 mi of phosphate heifer of pH 7.4, and mixed with 2 mi of a mouse monoclonal «nn-hutnan BN A IgM solution {! ragud) sail incubated at 57SC for 1 hour; Thee I. mi of Upofectitt5*5 or preferably 3 mi (l mg/ml) of modified BttdragitS B {(:meth>a«ryfote copolymer of 25% by weight methyl methacrylate. 255® by weight butyl rnettesiryiass aad 50% by weight rhmedtyiammoethyl methacrylate, lose molecular weight. reaally eliminated Mw ·* 2.1 000} ate· mixed and kept si 37*C tvoh slow vtsrrsttg for about 20 -minutes. The pH is measured after rhis time and adjusted so 7.4 with 0,00 IN RCi, Vigorous mixing, e,g, on a vortex, results -m onaopatticles with an average diameter of about-2SÖ rust on. use of Lspofeotisr® and of about: 15i) artt ors rase of modified Eudrsgifeb B, The suspension of the nanopantcies is pun fled hy dtsiysns. The susperision can be farther processed directly, or sise ».asiopsrücks oars lse separated by freesse shyistg, bxampica NapopMid^^^

It is foetid so prelimmury tests with suitable human ceil cultures fost an optimal transfection rate: for the nucleic·' aeM active ingredient ears .be achieved when a proportion of, for example, 105¾ of the anionic {»t«tb)actyl8te copolymer Budragtt<Si i, (modified} is; added to she canonic Endnsgit\§> E {modified}.· 2 mg of DNA (sucle:c acid active ingredient t, e.g. a gene therapy vector composed cd double-stranded plassnid DMA havmg, for exantple, 3o00 to f 0 Ö00 basse pasta, comprising is gene which is to he expressed in hntnatt ceils asxl intended to have a therapeutic effect, is dissolved in 4 mi of phosphate buffer of pH ? 4V and mixed with .3 ml of a -mouse mtmtxslonai ami- .human BN A -%M -solution. {1. mg/ml) and -i-nenhated- at $?*G for 1 hour. That LI. ml, 4 ml (I mg/ml) of modified Endrsgit® B{{meth}«cry.iatecopolymer of 25% by weight me-dtyl methaorylate, 25% by weight butyl srsethac?yht.m and 50% by weight dimmhylammocthyi methasuylam, low moleciihsr weighs, reaaily eliminated Mw ebtntt 21000} and 0.4 sal. (1 mghul). of rnssihfssd lndr%it<^ L (copolysster of 50% hy -weight-methyl meötacryhtk ;md 50% by weight mmbaoryhc mod, tew molecular we^rt, renaliv ehminated Mw «= 21 000} are mixed and kegs at 3?4C wish slow ssirdng for about 30 adsmtes, Vigorraa mixing·, e.g, on &amp; vortex, results -tu oaae*parä:ica with an average dissaseter of about 25Ô am. The sstspertaion of the ntmopartieles is ptmtied by dialysis.. The .«pension am he farther processed directly* or the stmteparbeles casr he separated by Sees® dry ittg, .SmrkfespiäiiMjMtsabiliekt.ihMb^ 2 mg of DNA (nucleic edd active mgxediern), e.g. a yeas therapy vector composed of dcvihtevdrmwed placard PNA having, for example, 30(1(5 to 10 00(5 base pairs, composing a gen« which is to be expressed rn bamatr cells and irrtespkd ίο have a thnrapeutie ellhet, is dissolved 1rs 4 r»l of Doibeeco phosphate b»Herr of pH 7.4, and nnsed with 3 ml of a messe monoclonal snti-humaa DNA IgM solution (1 mg/mi) and incubated as 37*€ for 1 hour, Tires 4 ml (1 mglml) of modiSsd EydrsgiPb £ ((medfiscryiate eopoiymor of 250¾ by weight methyl methacrylate, 255¾ by weight butyl tnathaeryiafo and 50% by weight siktethylammostthyl methacrylate, low ntokenlax weight, renally eüxahtated Mw ^ 21 000} are mixed aod kept at 37%' with stow at irt ing for akxu 00 minutes, The pH Is measured aller this nme and adjusted to 7.4 with ö.Oö iH HCl. 1 ml of a solution (1 mgfinl} of modified Xiudragidib L f(meds)acry;iate copolymer of 50% by weight meshy! methacrylate smti 50% by wetghi metitaerytic seid, low molecular weight, remtliy eliminated, M%v ~ about 21 000) irs phosphate buffer (pH 7.4, 0,5 mg/mi) is admixed, and the resulting Mex-ltke buffer rftspsrstos is wtihaddmoo of s 0.001 M eltdc acid «»til pil 5.(1 is reached. The soxpeasie» of the sanopartic lea .is purified by-dialysis. The suspension cast be further pnxessed directly, ot the enveloped ttaa opart tel es can he separated by keexe drying. iHpioaki ikâ?Thll%.L.2pLll«%.StÀ.ini%LE!Mn%Hy^^ iisiil

Preparstkm of a utseosdhsslve substitut:: 4 .g of -chitosan acetate are dissolved, in 20 g of water. Then, while stinting rapidly, 2 g of citric tserd môuobydrate are added, A pH of $.2 is set. T hee, 0,4 g of Na dhtieesnate ate. added to the dear, yellowish viscous solution otimoed, The suspensions fiom Example 1,2 or 2 are mixed into this solution "with slow aiming.

Production of pre-pellets

The mixed suspension is spsxtyesi using a Saidixed bed apparatus (Micro-Lab fiom Htittling) at. a spray rate of 5-8 g/minkg, onto 40 g of neutral pellets having a dtasteter of about 400-500 pm with an inlet ait temperature of 30*€. The diet air is sa this ease set at 35-45 saVk·. The yield la this cuss is 85-9(5%,

OSOddCJ bsàE&amp;o.3àjfââM3>sli^.

Pre-pellets produced as :n Example 4 are costed in a livid;red bed ρηχόν* wttit h'ndrsgh® I. 12.S i(tneth)&amp;crylate copolymer of 50% by weight methyl methsetylate sad 5(58¾ by weight nuUhaorylic ante, Mw --shont 2ÔÔ 000, 12,5% strength organic solution in isopmpanolkcmone 3:2), The appheatiou of polymer amounts io 40% by weight based ou the core weight 'the sttspensiost ihr coating consista of:

Btidmgii® L 12,5 53.5%

Trietityl citrate 1,33%