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EP-3622948-B1 - MULTILAYERED FORMULATIONS WITH DUAL RELEASE RATE OF ONE OR MORE ACTIVE PRINCIPLES

EP3622948B1EP 3622948 B1EP3622948 B1EP 3622948B1EP-3622948-B1

Inventors

  • PASOTTI, GINO
  • SPALLA, ANDREA
  • PENGO, SERGIO
  • SPALLA, LUCIANO

Dates

Publication Date
20260506
Application Date
20190903

Claims (13)

  1. Multilayered miniparticle having a particle size ranging from 200 µm to 850 µm for oral administration comprising from inside to outside: A) a core of an active substance; B) an inner film layer which is protective or for the modified release; C) a layer of at least an active substance which is equal to or different from the one in the core A); D) an outer film layer which more rapidly releases compared to the inner film layer which is protective or for the modified release B), wherein the active substance is selected in the group comprising thioctic or alpha lipoic acid, iron or a salt thereof such as ferrous fumarate or bisglycinate, vitamin C, folic acid.
  2. Multilayered miniparticle according to claim 1, wherein the core of active substance A) has a diameter of 188 µm - 630 µm in case the active substance is thioctic acid.
  3. Multilayered miniparticle according to claims 1-3, wherein the inner film layer B) which is protective or for the modified release is made of a substance or polymer selected in the group comprising ethyl cellulose, hydroxypropyl methyl ethyl cellulose phthalate (HPMCP), hydroxypropyl methyl ethyl cellulose acetate succinate (HPMCAS), ethylene-vinyl acetate, a polyacrylic acid derivative, acrylic derivatives: copolymers of acrylic acid/methyl metacrylate (i.e. EUDRAGIT), shellac, hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC).
  4. Multilayered miniparticle according to claims 1-3, wherein the core A) and the layer C) are made of thioctic acid.
  5. Multilayered miniparticle according to claims 1-4, wherein the outer film layer D) is made of a substance or polymer selected in the group comprising PCL-PVAc-PEG (i.e. Soluplus ® ), hydroxypropylmethyl cellulose (HPMC), polyethylene glycol (PEG), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), shellac, ethyl cellulose and acrylic derivatives: copolymers of acrylic acid/methyl metacrylate (i.e. EUDRAGIT).
  6. Process for preparing a multilayered miniparticle according to claims 1-5, comprising the following steps: i. sieving and sorting an active substance having varied particle size to obtain particles of active substance with defined particle size; ii. applying a solution of a polymer or film which is protective or for the modified release to each particle of active substance of step i. to obtain a core of active substance covered with a film layer which is protective or for the modified release; iii. forming a layer of at least an active substance which is equal to or different from the one present in the core, on the covered core of active substance of step ii.; iv. forming, on the layer formed at step iii, an outer film which releases more rapidly compared to the film layer which is protective or for the modified release of step ii.
  7. Process according to claim 6, wherein after each of step ii., and/or iii. and/or iv. there is another sieving and sorting step of the obtained material.
  8. Multilayered miniparticle according to claim 1 for oral administration comprising a further layer (E) an outer film layer which releases more rapidly than the inner film layer which is protective or for the modified release b).
  9. Multilayered miniparticle according to claim 8, wherein the core A) is of vitamin C, the layer C) is of folic acid, and the layer E) is of iron or a salt thereof such as ferrous fumarate or ferrous bisglycinate.
  10. Process for preparing a miniparticle according to claim 7, wherein after steps i., ii. and iii. it comprises the steps of: v. forming an outer film layer, on the layer formed at the previous step, which releases more rapidly compared to the film layer which is protective or for the modified release of step ii.
  11. Process according to claim 10, wherein after each step ii. and/or iii. and/or iv. and/or v. there is a step of sieving or sorting of the obtained material.
  12. Matrix comprising multilayered miniparticles according to claims 1-5, or 8-9.
  13. Formulation for oral use selected in the group comprising a sachet, a tablet, a capsule, a granulate, a vial, an extemporaneous suspension, which contains a set of multilayered miniparticles as defined in claims 1-5 or 8-9.

Description

FIELD OF THE INVENTION The present invention relates to multilayered miniparticles having a particle size ranging from 200 µm to 850 µm for oral use which allow both the slower release and the faster release of one or more active principles or active substances or matrices containing them, to a process for their preparation and to specific forms of administration for oral use containing them. STATE OF THE ART For a long time in the prior art modified release systems have been known constituted by a core comprising an inert material that is coated with a layer of the active ingredient or the active substance in turn covered with a layer of modified release membrane able to release the active ingredient/active substance to the stomach/small intestine or colon depending on the characteristics of the layer of the membrane used. Systems are also known as the Applicant's proprietory technology MATRIS® (Multiform Administration Timed Release Ingredients System, i.e. single matrix for the administration of active ingredients having a modified release and in different oral forms), for the controlled release of principles or active substances, without the use of neutral materials/inert materials. In this way, the concentration of the active ingredient/active substance in final form is considerably higher than the modified release forms known in the art. Said technology provides for covering each particle of the active ingredient with a suitable modified release membrane. The technology MATRIS® allows the controlled release of the active principle or active substance further to the total coverage of unpleasant tastes of the active ingredients and to provide any form of administration for oral use, such as, in additions to high concentration capsules, monodose sachets and tablets, also orosoluble, extemporaneous suspensions and monodose vials. MATRIS® overcomes the obstacle of the limited possibility of unitary administration of the active ingredients, due to the poor capacity of the capsule, particularly relevant problem with food supplements, whose dosage is very often higher than the one of drugs. MATRIS® also overcomes the problem of swallowing capsules for a better acceptance or compliance of the final user, especially in case of children and older people. Said technology also overcomes the disadvantages of the pellets that generally allow the release of limited amounts of active principle or substance since approximately 50% of their content is constituted by inert substances such as sugar and starch. In more recent times, however, there has been highlighted the problem of the need to provide a formulation having the same active ingredient or substance both with slow release and with fast release (so as to obtain for example a finished product with both a fast and a retard release of the active ingredient(s)). This is because for the treatment of specific diseases it is required a daily intake of two or more active substances in combination, or of the same active substance with different time releases or in different amounts. Therefore, to comply with this requirement in pharmaceutical technology and in the technology of supplements, individual forms for oral administration were made having a different content of active ingredient or dosage units also comprising two or more release forms even of different active principles. For example, compositions are known which comprise as dosage units a slow or controlled release formulation and another fast or immediate release formulation of topiramate and phentermine respectively (see for example US 2017/151179), in which the amounts of each active ingredient in the dosage form are chosen independently from one another and are specific for each active ingredient. In this regard, a tablet consisting of two parts having different active ingredients and different kinds of delivery (i.e. fast and slow), such as for example phentermine and topiramate, is also described in CN 106880640. Another example of tableted formulations, particulary for cardiovascular health (e.g., niacin and atorvastatin) are described in patent application WO 2009/033072 A1. In any case, these specific pharmaceutical forms tend to be rather voluminous in so far as they provide for the presence of the principles or active substances in combination with more excipients, thus said pharmaceutical forms are hardly swallowable or require to be divided and this has a negative impact on the administration and acceptance of these forms of administration by the users, as well as on the release times of the various active principles. There is also the disadvantage linked to the fact that the entire dosage unit after ingestion is located in only one point of the gastrointestinal tract, where the concentration of the released active principle/principles is very high, with risk of local irritations. In addition, it is possible that the entire dose ingested is arranged, during the journey in the gastrointestinal trac