(19) TZZ¥ _¥_T (11) EP 3 216 443 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 13.09.2017 Bulletin 2017/37 A61K 9/00 (2006.01) A47J 31/40 (2006.01) A47J 31/00 (2006.01) B65D 85/804 (2006.01) (21) Application number: 16000586.4 (22) Date of filing: 10.03.2016 (84) Designated Contracting States: (71) Applicant: Athenion AG AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 6304 Zug (CH) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (72) Inventors: Designated Extension States: • Brysch, Ekkehard BA ME 26316 Varel (DE) Designated Validation States: • Brysch, Wolfgang MA MD 13505 Berlin (DE) • von Wegerer, Jörg 13597 Berlin (DE) (54) BEVERAGE PREPARATION CAPSULE FOR DELIVERY OF A SOLUBILISATE (57) The present invention relates to a beverage pensing system. Poorly water-soluble dietary supple- preparation capsule for the delivery of a solubilisate, a ments or pharmaceutical active agents can be delivered beverage dispensing system configured for the use of in this new dosage form in order to increase the bioavail- such a beverage preparation capsule and a method for ability of these substances. preparing a beverage by means of such a beverage dis- EP 3 216 443 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 216 443 A1 2 Description bilayer of the cell membrane. Often the same or struc- turally related components are used for liposomes as [0001] The present invention relates to a beverage those known from the cell membrane, therefore display- preparation capsule for the delivery of a solubilisate, a ing similar physicochemical properties. There are also beverage dispensing system configured for the use of 5 multi-layered liposomes in which at least two liposomal such a beverage preparation capsule and a method for spheres are formed over one another, thus building a preparing a beverage by means of such a beverage dis- multispherical aggregate. When given in a lipophilic me- pensing system. dium these substances tend to build inversed spherical [0002] A broad variety of substances are known for structures where the lipophilic chain is oriented towards which potentially beneficial effects for the human health 10 the solution medium and the other layers are arranged have been found in in vitro experiments. The use of many accordingly. of them, however, has been seriously limited by the poor [0005] It is known for a long time that it is possible to bioavailability that can be achieved by application forms enclose substances inside such spherical structures. Dif- known in the state-of-the-art. In pharmacology, bioavail- ferent uses of such loaded spheres have been described ability is a parameter that indicates the fraction of an ad- 15 in the art, among them the usage as a dosage form for ministered dose of unchanged drug that finally becomes the application of lipophilic substances and/or for increas- available in the systemic circulation for the desired phar- ing the bioavailability of the enclosed substance. In mi- macological effects. This poor bioavailability is often due celles, the enclosed nonpolar substance concentrates in to apoor water solubility, respectively thelipophilic nature the interior space of the sphere toward which the nonpo- of the active agent to be administered. Hence the use of 20 lar chains of the amphiphilic molecules are oriented. In such substances as a dietary supplement or as a phar- liposomes, however, the interior space of the spheres is maceutically active agent is impaired when using stand- an aqueous, respectively hydrophilic medium. It can ard dosage forms. serve for packaging hydrophilic molecules. Poorly water- [0003] There is a variety of approaches for improving soluble, respectively lipophilic molecules, however, gath- the solubility of such agents and in many cases also their 25 er mostly in between the lipophilic structures of the lipo- bioavailabilityby using of solubilization techniques. Here- somal layers. in the solubility of an agent in a medium is augmented [0006] From empiric pharmacokinetic measurements by adding a third substance. These third substances are it is known that micelles as well as liposomes are ab- referred to as solubilizers (solubilizing agents), substanc- sorbed from the organism in the gastrointestinal tract to es that may for example build a complex with the sub- 30 a comparatively high degree, in particular from the intes- stance to be solubilized. Examples for such chelating tinal villi. Thus a substance packed in such a spherical agents are sodium benzoate and sodium salicylate. An- aggregate is absorbed to a much higher degree into the other mechanism of action of solubilizers is the augmen- systemic bloodstream into which a certain percentage of tation of the dissolving capacity of the solvent, for exam- the enclosed substance is released through different ple by disturbing the cluster structure of water. Examples 35 physiologic and non-physiologic mechanisms. Thus this for such structure breakers are glycerol (glycerin) and substance becomes bioavailable and can exert its ac- macrogols (polyethylene glycol, PEG). tions in the organism. If needed it can be transported via [0004] A third solubilization mechanism are micelle the cellular membrane to the interior of a cell. The trans- and liposome application technologies. They have won port, respectively the absorption rate over the cell mem- broad attention throughout the last decades. Herein the 40 brane is an intrinsic characteristic for each substance, substance to be delivered is enclosed in a spherical ag- depending on a variety of factors such as molecule size, gregate of surfactant molecules. These molecules are degree of lipophilicity and the presence of suitable trans- characterized by a polar head group and a long nonpolar porter molecules inside the cell membrane. In general, chain ("tail"). When given into an aqueous medium these lipophilic substances are transported more easily over molecules tend to associate by aggregating to spherical 45 the cell membrane because of the lipophilic nature of the structures by orienting the polar head group towards the lipid bilayer of the cell membrane. From liposomes it is surrounding medium and the nonpolar chain towards the also known that they are able to fuse with the cell mem- interior of the spheres. When these spheres consist of brane by invagination, thus delivering the enclosed sub- only one layer of such amphiphilic molecules they are stance to a considerable degree into the cytosol. Certain referred to as micelles. Depending on the nature of the 50 cell types, in particular phagocytes such as macrophag- amphiphilic molecule and the reaction conditions it is also es, monocytes and neutrophils, preferably ingest lipo- possible to form spheres with more than one layer. Herein somes which then may undergo metabolic digestion and a second layer is formed inside the outer layer of the thus deliver the enclosed substance to these cells. sphere, the nonpolar groups of this second layer being [0007] Liposomal applications have been widely dis- oriented towards the nonpolar groups of the outer layer, 55 cussed in medicine and pharmacology and many sophis- and the polar head groups being oriented towards the ticated technologies for their production have been de- interior of the sphere. Such aggregates are referred to veloped. Their use, however, is not very common. One as liposomes. In their structure they resemble the lipid reason are the relatively high production costs, another 2 3 EP 3 216 443 A1 4 reason are possible adverse side effects. In particular, and/or an inhomogeneous beverage. Another aspect is when parenterally applied, liposomes carry the risk of that the solubilization process often leads to a phenom- accumulating in the liver, the spleen and/or the bone mar- enon called zebra effect or striping caused by an incom- row. This problem occurs rather seldom in oral dosage pletedissolution of thesolubilisate (or other concentrate). forms. 5 Such a beverage is not particularly appealing for intake. [0008] Self-emulsifying drug delivery systems[0011] Therefore there is a need for new, respectively (SEDDS) are another approach to solubilize lipophilic alternative dosage forms of such solubilized substances compounds. They use to be isotropic mixtures of oils, for use as dietary supplement or pharmaceutically active surfactants, solvents and optionally cosolvents. Depend- agent that overcome the problems mentioned above. ing on the used components they may form solubilisates 10 [0012] Thus it is the task of this patent application to or stable oil-in-water (o/w) emulsions upon aqueous di- provide a consumer-friendly easy-to-handle and safe liq- lution and optionally gentle agitation. uid oral dosage form for dietary supplements or pharma- [0009] Another solubilization technique is the forma- ceutically active agents in need to be solubilized. tion of inclusion complexes of the substance to be solu- bilized with cyclodextrins such as α-, β- or γ-cyclodextrin 15 Description of the invention or cyclodextrin derivatives such as 2-hydroxypropyl-β- cyclodextrin, methyl-β-cyclodextrin or trimethyl-β-cyclo- [0013] Surprisingly, it was found that beverage prepa- dextrin. Typically, cyclodextrins are composed of 6 to 8 ration capsules containing such a solubilisate are able 1,4-linked α-D-glucopyranosides forming macrocycles. to solve these problems. Thus a water-soluble toroid (respectively cone-shaped 20 [0014] Thus the present invention refers to a beverage or bucket-shaped) structure is generated which is capa- preparation capsule containing a solubilisate of at least ble to host hydrophobic substances in its interior. The one pharmaceutically active agent and/or a dietary sup- interior space is considerably less hydrophilic than the plement. outside contacting the aqueous environment. Cyclodex- [0015] In particular, the present invention refers to a trins are produced from starch by enzymatic treatment.