Multiparticle Pharmaceutical Dosage Form for a Low-Soluble Active Substances and Method for Producing Said Pharmaceutical Dosage Form

2:

• The pharmaceutical form as claimed in claim 1, characterized in that the active substance and the substance or substances forming the lipophilic matrix do not differ from each other in their water-solubility as defined in the German Pharmacopeia DAB 10 by more than ±50%, in their distribution coefficient defined in Annexe V to EU Directive No. 67/1548/EEC Point A.8 by more than ±60%, and/or in their HLB value as measured by Marszall's method by more than ±80%.

3:

• The pharmaceutical form as claimed in claim 1, characterized in that the mucoadhesive polymer and the substance or substances forming the lipophilic matrix either have the same ionic character, or—if they have opposite ionic characters—the mucoadhesive poly er is present in a form neutralized to an extent of at least 50%.

4:

• The pharmaceutical form as claimed in claim 1, characterized in that 80-100 wt-% of the lipophilic matrix is formed by a substance with an HLB value of 0-15 or by a mixture of substances with a mean HLB value of 0-15, and can contain 0-20 wt-% of pharmaceutically customary excipients, especially stabilizers, thickeners or adsorbents.

5:

• The pharmaceutical form as claimed in claim 1, characterized in that the substance or substances forming the lipophilic matrix belong to the group of oils, fats, mono-, di- or triglycerides, fatty acids, fatty alcohols, including their salts, ether derivatives, ester derivatives or amide derivatives, phospholipids, lecithins, emulsifiers, lipoids, fat-soluble vitamins or surfactants.

6:

• The pharmaceutical for as claimed in claim 1, characterized in that the lipophilic matrix contains one of the following lipid preparations:
• Imwitor 308 (glyceryl monocaprylate containing over 80% of the monoester), Imwitor 312 (glyceryl monolaurate containing over 90% of the monoester), Imwitor 491 [glyceryl monostearate (C16+C18) containing over 90% of the monoesters], Imwitor 900 P (glyceryl monostearate containing 40-55% of the monoester and 40-60% of C18 compound), Imwitor 900 K (glyceryl monostearate containing 40-55% of the monoester and 60-80% of C18 compound), Imwitor 742 (medium-chain C8 and C10 glycerides containing 45-55% of monoesters), Imwitor 928 (partial glycerides formed with saturated C10-C18 fatty acids of plant origin, where the main component is C12 compound and the monoester content is 34-36%), C8 and C10 glycerides, sodium caprylate or sodium caprate.

7:

• The pharmaceutical form as claimed in claim 1, characterized in that the active substance is soluble in the lipophilic matrix to an extent of at least 10%.

8:

• The pharmaceutical form as claimed in claim 1, characterized in that the amount of the inner matrix layer a) in the lipophilic matrix that contains the active substance is 5-60 wt-%.

9:

• The pharmaceutical form as claimed in claim 1, characterized in that the casing that disintegrates in the gastric pH range is a capsule, a tablet, a reconstitutable powder formulation or a sachet.

10:

• The pharmaceutical form as claimed in claim 1, characterized in that the properties of the outer coating are adjusted by the appropriate choice of the anionic polymer or copolymer and formulation or of its excipients with and of its layer thickness, in such a way that it—the outer coating—dissolves in the gut at a pH of 4.0-8.0 within 10-60 minutes, so that the lipophilic matrix embedded—with its active substance—in the mucoadhesive matrix layer is exposed, can bind to the intestinal mucosa and can release the active substance there;
• the mucoadhesive polymer is so chosen that, when the pH is within ±0.5 pH units from the pH value at which the outer coating begins to dissolve, it possesses a mucoadhesive action ηb of 150-1000 mPa·sec and a water absorption of 10-750% in 15 minutes, and the active substance constitutes at most 90 wt-% of the lipophilic matrix.

11:

• The pharmaceutical form as claimed in claim 1, characterized in that the film-applied outer coating is cellulose glycolate (Duodcell®), cellulose acetate phthalate (CAP, “Cellulosi acetas” as per European Pharmacopeia, cellulose acetate phthalate as per TNT, or Aquateric®), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxy propyl methyl cellulose phthalate (HPMCP, HP50, HP55), hydroxy propyl methyl cellulose acetate succinate (HPMCAS-LF, -MF -HF), polyvinyl acetate phthalate (PVAP or Sureteric®), vinyl acetate-vinylpyrrolidone copolymer (PVAc or Kollidon® VA64), a 9:1 vinyl acetate:crotonic acid copolymer (VAC:CKA or Kollicoat® VAC) and/or shellac.

12:

• The pharmaceutical form as claimed in claim 1, characterized in that the film-applied outer coating consists of a (meth)acrylate copolymer containing 5-60 wt-% of monomers with anionic groups,

13:

• The pharmaceutical form as claimed in claim 1, characterized in that the layer thickness of the outer coating is from 20 to 200 μm.

14:

• The pharmaceutical form as claimed in claim 1, characterized in that the inner layer a) contains an efflux pump inhibitor and/or a penetration promoting agent.

15:

• The pharmaceutical form as claimed in claim 1, characterized in that the mucoadhesive polymer is a chitosan, a (meth)acrylate copolymer consisting of 20-40 wt-% of methyl methacrylate and 60-80 wt-% of methacrylic acid, and or a cellulose, a cross-linked or non-cross-linked polyacrylic acid, a lectin, a sodium alginate and/or a pectin.

16:

• The pharmaceutical form as claimed in claim 15, characterized in that the matrix formed by the mucoadhesive polymer comprises a chitosan which is used jointly with an acid or a buffer system which is present in the matrix or in or on a core to which the matrix is applied.

17:

• The pharmaceutical for as claimed in claim 16, characterized in that the matrix formed by the mucoadhesive poly er comprises a chitosan and is adjusted to pH 5.0-5.5 by means of an acid or a buffer system, and it is combined with a film-applied outer coating which begins to dissolve at pH 6.0-8.0.

The pharmaceutical form as claimed in claim 1, characterized in that there is a separating layer applied between the inner layer a) and the film-applied outer coating layer b).

19:

• The pharmaceutical form as claimed in claim 1, characterized in that the active substance formulated in the lipophilic matrix is chosen from the group of Classes II and IV of the Bio-Pharmaceutical Classification System (BCS) of Prof Amidon and/or from the group of antiandrogens, antidepressants, antidiabetics, antirheumatics, glucocorticoids, cytostatics, antimigraine drugs, neuroleptics, antibiotics, estrogens, vitamins, pyschopharmaceuticals, ACE inhibitors, beta-blockers, calcium channel blockers, diuretics, cardiac glycosides, antiepileptics, diuretics/antiglaucoma agents, uricostatics, H2 receptor blockers and virostatics.

20:

• The pharmaceutical form as claimed in claim 1, characterized in that the active substance formulated in the lipophilic matrix is bicalutamide, anastrozole, glimepiride, nilutamide, bromocriptine, ketotifen, letrozole, naratriptan, ganciclovir, orlistat, mesoprostol, granisetron, pioglitazone, lamivudine, rosiglitazone, zidovudine, enalapril, atenolol, nadolol, felodipine, bepridil, furosemide, digoxin, digitoxin, carbamazepine, acetazolamide, allopurinol, cimetidine, ranitidine or oxcarbazepine.

22:

• The process for the preparation of a multiparticle pharmaceutical form as claimed in claim 2, characterized in that steps a) and b) are carried out as follows
• a) the inner matrix layer is made by preparing an emulsion, dispersion or solution of the active substance with the one or more substances for the lipophilic matrix and possibly with other pharmaceutically customary excipients, by intensely mixing the constituents in water and preparing an oil-in-water system with an average particle size of at most 60 μm,
• b) prepellets are prepared by spraying the oil-in-water system obtained in step a) onto the mucoadhesive polymers which may also contain admixtures of pharmaceutically customary excipients, where the ingredients are present in the form of a micronized powder, by rotary agglomeration, extrusion or granulation.