WO2021229420A1

WO2021229420A1 - Solid oral compositions comprising composite monolithic matrices for chronotropic administration in the gastrointestinal tract of foods, diet supplements, nutraceuticals and medical devices

Info

Publication number: WO2021229420A1
Application number: PCT/IB2021/053984
Authority: WO
Inventors: Carlo Terruzzi; Fabio TERRUZZI; Alessia TERRUZZI
Original assignee: Giellepi S.P.A.
Priority date: 2020-05-14
Filing date: 2021-05-11
Publication date: 2021-11-18
Also published as: EP4149439A1; IT202000011053A1

Abstract

The present invention relates to solid oral controlled-release compositions comprising a core consisting of a monolithic matrix comprising a low-, medium- or high-viscosity hydroxypropyl methylcellulose, or a mixture thereof, anhydrous dicalcium phosphate or dicalcium phosphate monohydrate, methylcellulose, one or more superdisintegrant polymers and an outer coating of said core consisting of a layer comprising ethylcellulose or of a gastroresistant layer or of a layer comprising ethylcellulose which is coated in turn with gastroresistant polymers.

Description

SOLID ORAL COMPOSITIONS COMPRISING COMPOSITE MONOLITHIC

MATRICES FOR CHRONOTROPIC ADMINISTRATION IN THE

GASTROINTESTINAL TRACT OF FOODS. DIET SUPPLEMENTS,

NUTRACEUTICALS AND MEDICAL DEVICES

The present invention relates to solid oral controlled-release compositions comprising a core consisting of a monolithic matrix comprising a low-, medium- or high- viscosity hydroxypropyl methylcellulose, or a mixture thereof, anhydrous dicalcium phosphate or dicalcium phosphate monohydrate, a methylcellulose, one or more superdisintegrant polymers and an outer coating of said core consisting of a layer comprising ethylcellulose or of a gastroresistant layer or of a layer comprising ethylcellulose which is coated in turn with gastroresistant polymers.

Prior art

Having regard to the circadian rhythms of the body, the use of dietary supplements, nutraceuticals and botanical products requires a pre-established concentration of active ingredients which is available at the required times and at the specific absorption site. Disorders with a specific circadian cycle exhibit a marked change in symptoms, with peaks and troughs, during the day.

The design of compositions able to release a nutraceutical with timing suitable to ensure optimum treatment of symptoms involving circadian variations requires full understanding of the absorption, distribution, metabolisation and elimination thereof. Time-specific and site-specific release is achieved by exploiting variations in pH and/or the different transit times of the medicaments (nutraceuticals) in the gastrointestinal apparatus.

Gastric voiding times can be highly variable, depending on the type and amount of food eaten, and the fasting pH remains on average between 1.2 and 3.0. Transit times range from a few minutes to a few hours.

In the small intestine, the pH tends to approach neutrality, and the transit time is more constant (about 3 ± 1 hours), whereas in the colon, pH values can range from 5.5 to neutrality (pH 7.0-7.5), and transit times vary considerably from individual to individual, from a few hours to 24-48 hours.

Various controlled-release formulations based on monolithic, multi-particulate or multi-unit matrix or reservoir systems have been described. The technologies used comprise gastroresistant retard systems; slow-release systems (simple matrices); solely pH-dependent release systems; solely pH-independent release systems; pulsatile-release systems (an immediate-release portion combined with a slow, gradual controlled-release portion with a simple matrix); extended-release systems (simple extended-release matrices); and reservoir systems involving the use of containment polymers, acting as semipermeable membranes.

The known formulations, described, for example, in W0200610640, W02003101421, WO2009125981 and W02011106416, are mainly characterised by single-component systems wherein the release control effect is determined by a single type of excipient This can lead to low precision of release of the active ingredient in the site and over time, and high variability of release both in vitro and in vivo.

The common retard forms (gastroresistant and/or lag-time) can also exhibit erratic release in the gastrointestinal tract in the distal part of the ileum and/or the initial part of the colon, rapidly releasing tire active ingredient without homogeneous distribution thereof in the gastroenteric, ileocolonic and colonic tracts.

W0200400280, W02010100657, W0200658059 and W0200658059 report examples of matrices containing both a hydroxypropyl methylcellulose and an acrylic polymer. US20100285125 genetically indicates the possibility of obtaining a complex matrix containing different types of hydroxypropyl methylcellulose in a mixture with one or more enteric polymers. However, the formulations actually exemplified are characterised by hydroxypropyl methylcellulose acetate, succinate and phthalate matrices not mixed with acrylic polymers/copolymers and/or shellac. Moreover, the presence in the core of hydroxypropyl cellulose and superdisintegrants is not described. Description of the invention

It has now been found that the activity of nutraceuticals can be efficiently modulated by reducing their frequency of administration and controlling their release in particular sites of the gastrointestinal tract, using complex matrices consisting of a combination of polymers/materials with different characteristics.

In particular, it has been found that the use of a hydroxypropyl methylcellulose with low, medium, or high viscosity, and in particular the combination of at least two hydroxypropyl methylcelluloses having different viscosities, methylcellulose, dicalcium phosphate (dibasic calcium phosphate or monohydrogen calcium phosphate) with superdisintegrant copolymers (such as croscarmellose sodium, sodium starch glycolate and crosslinked polyvinylpyrrolidone), allows the preparation of formulations that overcome the limitations of the previously known formulations.

The solid oral controlled-release nutraceutical compositions according to the invention comprise one or more active ingredients in a core, and an outer coating of said core, wherein: a) the core consists of:

(i) a monolithic matrix containing one or more active ingredients, a low-, medium- or high-viscosity hydroxypropyl methylcellulose or a mixture thereof, methylcellulose (MC), dicalcium phosphate and at least one or more superdisintegrant polymers/copolymers; or

(ii) a composite monolithic matrix as defined in point (i), adjacent to an immediate-release layer comprising the same active ingredient as contained in the monolithic matrix; b) the coating consists of a layer comprising hydroxypropyl methylcellulose and/or ethylcellulose, or of a gastroresistant layer or of a layer comprising ethylcellulose which, in turn, is coated with gastroresistant polymers.

The core can consist of a composite monolithic matrix (i) or a bi-layer system consisting of a composite monolithic matrix (i) adjacent to an immediate-release layer comprising the same active ingredient(s) as the monolithic matrix.

The gastroresistant coating can be the conventional type, and typically comprises methacrylic acid copolymers soluble at pH ≥ 5.5, pH≥ 6.0 or pH ≥ 7.0. Examples of said copolymers are available on the market (Eudragit, Eudraguard). Preferred is the combination of polymethacrylate L100 with polymethacrylate S100 at the ratio of 1:10- 10:1 (preferably 1:1), soluble at pH ≥ 6.0, pH≥ 7.0; or L 100/55 soluble at pH ≥ 5.5; or Eudraguard, shellac; or cellulose acetate phthalates/succinates.

In the compositions according to the invention, hydroxypropyl methylcelluloses constitute 1 to 40% of the weight of the core, methyl celluloses constitute 0.1 to 10% of the weight of the core, dicalcium phosphate constitutes 1 to 40% of the weight of the core, and the polymer/copolymer and/or mixture of superdisintegrants constitutes 0.1 to 20% of the weight of the core.

Hydroxypropyl methylcelluloses having a viscosity ranging between 3.0 and 280,000 mPa.s 2% in H₂O at 20°C are available on the market under various tradenames

(such as Methocel or Hypromellose) K3LV, K100 LV, K250, K750, K1500, K4M, K15M, K35M, K100M and K200M.

The core preferably contains two hydroxypropyl methylcelluloses having different viscosities, more preferably a hydroxypropyl methylcellulose having a viscosity ranging between 3 and 5000 mPa.s 2% in H₂O at 20°C, and a hydroxypropyl methylcellulose having a viscosity ranging between 13500 and 280000 mPa.s 2% in H₂O at 20°.

The hydroxypropyl methylcellulose and/or ethylcellulose is present in the corecoating layer in percentages ranging from 1% to 20% of the weight of the core; preferably

5%.

The matrix core can comprise conventional excipients such as diluents (microcrystalline cellulose, starches, sugars), binders (PVP, starches, cellulose, dextrins, maltodextrins, low-viscosity cellulose), glidants (colloidal silicas, talc), sliding agents (talc), lubricants (Mg stearate, fumaryl stearate, stearic acid, glyceryl behenate) and other functional excipients (waxes, polycarbophil, carbomer, glycerides).

The matrix is prepared by processes of partition and direct compression, dry granulation, compacting, wet granulation, melting and extrusion.

The resulting matrix/mini-matrix can then be coated with a gastroresistant film containing pH-dependent polymers that prevent release for at least 2 hours under pH conditions < 1.2-5.5. The following can be used for this purpose: pH-dependent methacrylic acid copolymers soluble at pH ≥ 5.5 (L 100-55/L 30 D-55); pH-dependent methacrylic acid copolymers soluble at pH 6.0-7.0 (L 100/L 12.5); pH-dependent methacrylic acid copolymers soluble at pH ≥ 7.0 (S 100/S 12.5/FS 30D); shellac; cellulose acetate phthalate; cellulose succinate, methacrylic acid copolymers and starches (Eudraguard Control, Protect, Natural, GRS, Biotic).

At a third stage, a core coating can be applied which is alternative and/or additional to and beneath the gastroresistant coating with pH-independent polymers (ethylcellulose or hydroxypropyl methylcellulose with different viscosities), which act as membranes delaying the passage of the ingredient loaded into the matrix/mini-matrix core following contact with biological fluids (Nutrateric, Surelease, NS Enteric).

The matrix is coated with an amount of polymer sufficient to guarantee that it remains intact in gastric and enteric juices for at least 2-4 hours before the release of the active ingredient from the core (lag time). To reduce the impact of variable gastric voiding times, a further (pH-dependent) gastroresistant coating can be applied outside the (pH-independent) matrix core and outside the (pH-independent) cellulose film coating, to further delay contact between the biological fluids and the modified-release core (extended release).

In this way the system prevents early release during the stomach-jejunum transit time, initiating the modulated-release programme lasting up to 24 hours and ensuring homogeneous distribution of the active ingredient in the duodenum, ileum and distal ileum and in the ascending, transverse and descending tracts of the large intestine.

The use of a combination of hydroxypropyl methylcelluloses, methylcelluloses, dicalcium phosphate and superdisintegrant polymers with different rheological/functional characteristics (viscosity/swelling properties) allows the release to be modulated for between 4 and 24 hours. If desired, a modified-, controlled-release core can be combined with an immediate-release layer (bi-layer and/or tri-layer matrix/mini-matrix); a system thus designed gives results of “therapeutic equivalence” or different levels of therapeutic efficacy.

Examples of active ingredients which can be advantageously formulated according to the invention comprise red yeast rice, curcumin, probiotics, lactoferrin, lipoic acid, mineral salts and menthol.

The formulations according to the invention are particularly suitable to optimise the absorption, release site and effect of nutraceuticals which have an unfavourable profile in terms of compliance because of the large number of daily administrations, and the side effects.

The invention is described in detail in the examples below.

EXAMPLE 1

16.65 kg of red rice is loaded into a granulator with 7 Kg of dicalcium phosphate, 500 g of methylcellulose and 3 Kg of microcrystalline cellulose.

The mixture is granulated with a 5% solution of PVP (200 g). The granulate is dried, and 8.3 Kg of hydroxypropyl methylcellulose (HPMC K100lv), 8.3 Kg of hydroxypropyl methylcellulose (HPMC K4M) and 1.1 Kg of hydroxypropyl methylcellulose (HPMC K100M) are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 100 g of magnesium stearate, 100 g of talc, 100 g of crospovidone and 100 g of croscarmellose are then added in sequence. The mixture is then homogenised for at least 15 minutes.

This mixture will form part of the first, controlled-release layer of the tablet.

16.65 g of red rice is loaded into a second granulator, and 2.5 Kg of dicalcium phosphate, 1 Kg of microcrystalline cellulose, 1.16 Kg of crospovidone, 1.16 Kg of croscarmellose, 100 g of magnesium stearate and 100 g of talc are added. The mixture is then homogenised for at least 15 minutes.

This mixture will form part of the second, immediate-release layer of the tablet.

The two separate mixtures are then compressed to obtain a double-layer tablet weighing 681.2 mg.

The resulting tablets are then film-coated with a solution/suspension based on 1.7 Kg of HPMC 5 premium, 800 g of talc, 230 g of titanium dioxide and 150 g of triethyl citrate, to obtain a tablet with a mean weight of 710 mg.

The tablets were subjected to disintegration and dissolution tests; when subjected to the dissolution test at pH ≥ 6.4 they exhibited the following release profile: not more than 60% after 60 minutes, at pH 7.2 not more than 70% after 240 minutes, and not more than 80% after 480 minutes; the value must be > 80% after 24 hours.

EXAMPLE 2

20 Kg of lactoferrin is loaded into a granulator with 4 Kg of dicalcium phosphate, 1 Kg of methylcellulose, 5 Kg of microcrystalline cellulose, 100 g of crospovidone and

100 g of croscarmellose.

The mixture is granulated with a 5% solution of PVP (200 g). The granulate is dried, and 8 Kg of hydroxypropyl methylcellulose (HPMC K4M) is then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; 150 g of magnesium stearate and 200 g of talc are then added in sequence. The mixture is then compressed to obtain a tablet weighing 386.5 mg. The resulting tablets are then film-coated with a gastroresistant solution/suspension containing 3.2 Kg of shellac (amounting to 800 g of a 25% solution), 650 g of talc, 300 g of titanium dioxide, 150 g of triethyl citrate and 1.45 Kg of HPMC E 5 premium, to obtain a tablet with a mean weight of 420 mg.

When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH ≥ 6.4, they exhibited release below 10%; when subjected to the dissolution test at pH ≥ 7.2, they exhibited the following release profile: not more than 20% after 60 minutes, not more than 60% after 240 minutes, and not more than 80% after 480 minutes; the value must be ≥ 90% after 24 hours.

EXAMPLE 3

20 Kg of Bifidobacterium longum is loaded into a granulator with 20 Kg of dicalcium phosphate, 2 Kg of methylcellulose, 6.65 Kg of microcrystalline cellulose, 150 g of crospovidone and 150 g of croscarmellose.

10 Kg of hydroxypropyl methylcellulose (HPMC K4M) and 1 Kg of hydroxypropyl methylcellulose (HPMC K100M) are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained, and 150 g of magnesium stearate and 250 g of talc are then added in sequence.

The mixture is homogenised for at least 20 minutes, followed by compression to obtain a tablet weighing 603.5 mg.

The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 750 g of polymethacrylate (Eudraguard Biotic), 500 g of talc, 200 g of titanium dioxide and 200 g of triethyl citrate, to obtain a tablet with a mean weight of 620 mg.

When subjected to disintegration and dissolution tests at pH 1.2, the tablets remain intact for at least 2 hours, with release below 1%; when subjected to the dissolution test at pH ≥ 6.4, they exhibited release below 1%; when subjected to the dissolution test at pH ≥ 7.2, they exhibited the following release profile: not more than 60% after 60 minutes, not more than 75% after 240 minutes, and not more than 85% after 480 minutes; the value must be > 90% after 24 hours.

EXAMPLE 4

4 Kg of hydroxypropyl methylcellulose (HPMC K15M) and 4 Kg of hydroxypropyl methylcellulose (HPMC KIOOM) are added in sequence to the same system.

The mixture is homogenised for at least 20 minutes, followed by compression to obtain a tablet weighing 573.5 mg.

The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 750 g of polymethacrylate (Eudraguard Biotic), 500 g of talc, 200 g of titanium dioxide and 200 g of triethyl citrate, to obtain a tablet with a mean weight of 590 mg.

When subjected to disintegration and dissolution tests at pH 1.2, the tablets remain intact for at least 2 hours, with release below 1 %; when subjected to the dissolution test at pH ≥ 6.4, they exhibited release below 1%; when subjected to the dissolution test at pH ≥ 7.2, they exhibited the following release profile: not more than 60% after 60 minutes, not more than 75% after 240 minutes, and not more than 85% after 480 minutes; the value must be > 90% after 24 hours.

EXAMPLE 5

13.75 Kg of Mg-K salts are loaded into a granulator with 10 Kg of dicalcium phosphate, 2 kg of methylcellulose and 2.3 Kg of microcrystalline cellulose.

10 Kg of hydroxypropyl methylcellulose (HPMC K 4M) and 2.5 Kg of hydroxypropyl methylcellulose (HPMC K100M) are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained; 150 g of magnesium stearate, 250 g of talc, 125 g of crospovidone and 125 g of croscarmellose are then added in sequence.

The mixture is then homogenised for at least 25 minutes. This mixture will form part of the first, controlled-release layer of the tablet, weighing 412 mg.

13.75 Kg of Mg-K salts are loaded into a second granulator, and 4 Kg of calcium phosphate, 750 g of microcrystalline cellulose, 1.25 Kg of crospovidone, 1.25 Kg of croscarmellose, 150 g of magnesium stearate and 250 g of talc are added. The mixture is then homogenised for at least 15 minutes. This mixture will form part of the second, immediate-release layer of the tablet, weighing 214 mg. The two separate mixtures are then compressed to obtain a double-layer tablet weighing 650 mg.

The resulting tablets are then film-coated with a solution/suspension based on 1.5 Kg of polymethacrylate (Eudraguard Control), 500 g of talc, 200 g of titanium dioxide and 200 g of triethyl citrate, to obtain a tablet with a mean weight of 649.5 mg.

EXAMPLE 6

3.75 Kg of lipoic acid is loaded into a granulator with 125 g of microcrystalline cellulose, 100 g of dicalcium phosphate and 100 g of methylcellulose.

250 g of hydroxypropyl methylcellulose (HPMC K4M), 125 g of hydroxypropyl methylcellulose (HPMC K15M), 30 g of crospovidone and 30 g of croscarmellose are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained, and the mixture is then granulated with an aqueous solution containing 150 g of polyvinylpyrrolidone (5%).

After drying, 10 g of colloidal silicon dioxide, 30 g of magnesium stearate and 15 g of talc are added in sequence. The mixture is then homogenised for at least 15 minutes.

This mixture will form part of the first, controlled-release layer of the mini-tablet.

3.75 Kg of lipoic acid is loaded into a second granulator and granulated with an aqueous solution containing 10 g of polyvinylpyrrolidone. After drying, 335 g of crospovidone, 335 g of croscannellose, 30 g of magnesium stearate and 75 g of talc are added and mixed homogeneously.

The mixture is then homogenised for at least 20 minutes. This mixture will form part of the second, immediate-release layer of the mini-tablet.

The two separate mixtures are then compressed to obtain a 5 mm double-layer mini-tablet weighing 94.5 mg.

The resulting mini-tablets are then film-coated with a solution/suspension containing 750 g of HPMC E5 Premium, 200 g of talc and 100 g of triethyl citrate, to obtain a mini-tablet with a mean weight of 105 mg.

When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release ≤ 1%; when subjected to the dissolution test at pH ≥ 6.4, the tablets exhibited a release not exceeding 50% after 60 minutes; when subjected to the dissolution test at pH ≥ 7.2, they exhibited the following release profile: not more than 70% after 60 minutes; not more than 80% after 240 minutes, not more than 90% after 480 minutes; the value must be > 90% after 24 hours.

EXAMPLE 7

1.56 Kg of curcumin is loaded into a granulator with 500 g of microcrystalline cellulose, 1 Kg of dicalcium phosphate and 225 g of methylcellulose.

225 g of hydroxypropyl methylcellulose (HPMC K4M), 225 g of hydroxypropyl methylcellulose (HPMC K15M), 20 g of crospovidone and 20 g of sodium amidoglycolate are then added in sequence. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained. 13 g of magnesium stearate and 22.5 g of talc are then added in sequence. The mixture is then homogenised for at least 15 minutes.

This mixture will form part of the first, controlled-release layer of the mini-tablet. 1.56 Kg of curcumin is loaded into a second granulator.

500 g of microcrystalline cellulose, 225 g of lactose monohydrate, 225 g of crospovidone, 225 g of croscannellose, 13 g of magnesium stearate and 27 g of talc are added and homogeneously mixed.

The two separate mixtures are then compressed to obtain a 4 mm double-layer mini-tablet weighing 65.9 mg.

The resulting mini-tablets are then film-coated with a solution of 14.9 g of HPMC 5 premium, 165.6 g of talc, 29 g of triethyl citrate and 200 g of shellac (25%), to obtain a mini-tablet with a mean weight of 70 mg.

When subjected to the dissolution test at pH 1 and the dissolution test at pH ≥ 6.0, the tablets exhibited the following release profile: not more than 60% after 60 minutes, not more than 75% after 240 minutes, and not more than 85% after 480 minutes; the value must be ≥ 90% after 24 hours.

EXAMPLE 8

3.125 Kg of curcumin is loaded into a granulator with 500 g of microcrystalline cellulose, 1 Kg of dicalcium phosphate and 225 g of methylcellulose.

225 g of hydroxypropyl methylcellulose (HPMC K4M), 225 g of hydroxypropyl methylcellulose (HPMC K 200M), 20 g of crospovidone and 20 g of croscarmellose are then added in sequence. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained. 13 g of magnesium stearate and 22.5 g of talc are then added in sequence. The mixture is then homogenised for at least 15 minutes.

3.125 Kg of curcumin is loaded into a second granulator.

500 g of microcrystalline cellulose, 225 g of lactose monohydrate, 225 g of crospovidone, 225 g of croscarmellose, 13 g of magnesium stearate and 27 g of talc are added and homogeneously mixed.

The two separate mixtures are then compressed to obtain a 4 mm double-layer mini-tablet weighing 97.155 mg.

The resulting mini-tablets are then film-coated with a solution of 15.5 g of HPMC 5 premium, 40 g of talc, 29 g of triethyl citrate, 200 g of polymethacrylate (Eudraguard Biotic) and shellac (25%), to obtain a mini-tablet with a mean weight of 100 mg.

EXAMPLE 9

16.65 Kg of red rice (1.5%) is loaded into a granulator with 6.5 Kg of dicalcium phosphate, 1 Kg of methylcellulose and 3 Kg of microcrystalline cellulose.

1.1 Kg of hydroxypropyl methylcellulose (HPMC K100lv ), 1.1 Kg of hydroxypropyl methylcellulose (HPMC K 200M), 10 g of crospovidone and 10 g of croscarmellose are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained, and 100 g of magnesium stearate and 100 g of talc are then added in sequence.

The mixture is then homogenised for at least 20 minutes. This mixture will form part of the first, controlled-release layer of the tablet

16.65 Kg of red rice (1.5%) is loaded into a second granulator, and 2.5 Kg of lactose monohydrate, 1 Kg of microcrystalline cellulose, 1.16 Kg of crospovidone, 1.16 Kg of croscarmellose, 100 g of magnesium stearate and 100 g of talc are added.

The mixture is then homogenised for at least 15 minutes. This mixture will form part of the second, immediate-release layer of the tablet.

The two separate mixtures are then compressed to obtain a double-layer tablet weighing 522.4 mg.

The resulting tablets are then film-coated with a solution/suspension containing

1.66 Kg of HPMC E5 Premium, 800 g of talc, 200 g of titanium dioxide and 100 g of triethyl citrate, to obtain a tablet with a mean weight of 550 mg.

When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; at pH ≥ 6.4 they exhibited release ≤ 10% after 60 minutes; at pH 7.2 release ≤ 50% after 60 minutes; release ≤ 60% after 240 minutes, and not more than 80% after 480 minutes; the value must be > 90% after 18 hours.

EXAMPLE 10

20 Kg of lactoferrin is loaded into a granulator with 900 g Kg of dicalcium phosphate, 100 g of methylcellulose and 4 Kg of microcrystalline cellulose.

1.1 Kg of hydroxypropyl methylcellulose (HPMC K100lv , 1.1 Kg of hydroxypropyl methylcellulose (HPMC K 200M), 10 g of croscarmellose and 10 g of crospovidone are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained, and 150 g of magnesium stearate and 200 g of talc are then added in sequence. The mixture is then homogenised for at least 15 minutes. The mixture is then compressed to obtain a tablet weighing 379 mg.

The resulting tablets are then film-coated with a solution/suspension containing 700 g of Nutrateric, 280 g of talc, 300 g of titanium dioxide and 150 g of triethyl citrate, to obtain a tablet with a mean weight of 380 mg.

When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; at pH ≥ 6.4 they exhibited release below 10%; when subjected to the dissolution test at pH ≥ 7.2, they exhibited the following release profile: not more than 20% after 60 minutes, not more than 60% after 240 minutes, and not more than 80% after 480 minutes; the value must be ≥ 90% after 18 hours.

EXAMPLE 11

20 Kg of Bifidobacterium longum is loaded into a granulator with 2 Kg of dicalcium phosphate, 250 g of methylcellulose and 7.425 Kg of microcrystalline cellulose.

4.5 Kg of hydroxypropyl methylcellulose (HPMC K 100 lv), 4.5 Kg of hydroxypropyl methylcellulose (HPMC K200M), 10 g of crospovidone and 10 g of croscarmellose are added in sequence to the same system.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained, and 150 g of magnesium stearate and 250 g of talc are then added m sequence.

The mixture is homogenised for at least 20 minutes, followed by compression of the mixture to obtain a tablet weighing 390.95 mg.

The resulting tablets are then film-coated with a solution/suspension containing 700 g of Nutrateric, 305 g of talc, 200 g of titanium dioxide and 200 g of triethyl citrate, to obtain a tablet with a mean weight of 405 mg.

When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; at pH ≥ 6.4 they exhibited release ≤ 10% after 60 minutes; at pH 7.2, release ≤ 60% after 60 minutes; release ≤ 60% after 240 minutes, and not more than 80% after 480 minutes; the value must be > 90% after 18 hours.

EXAMPLE 12

20 Kg of Bifidobacterium longum is loaded into a granulator with 2 Kg of dicalcium phosphate, 215 g of methylcellulose and 7.425 Kg of microcrystalline cellulose. 5.5 Kg of hydroxypropyl methylcellulose (HPMC K 100 lv), 3.5 Kg of hydroxypropyl methylcellulose (HPMC K200M), 10 g of crospovidone and 10 g of croscarmellose are added in sequence to the same system.

The mixture is homogenised for at least 20 minutes, followed by compression of the mixture to obtain a tablet weighing 390.95 mg. The resulting tablets are then film- coated with a solution/suspension containing 840 g of Nutrateric, 200 g of talc, 200 g of titanium dioxide and 200 g of triethyl citrate, to obtain a tablet with a mean weight of 405 mg.

EXAMPLE 13

13.75 Kg of Mg-K salts is loaded into a granulator with 10 Kg of dicalcium phosphate, 2 Kg of methylcellulose and 2.25 Kg of microcrystalline cellulose.

5 Kg of hydroxypropyl methylcellulose (HPMC K100lv), 5 Kg of hydroxypropyl methylcellulose (HPMC K 200M), 10 g of croscarmellose and 10 g of sodium starch glycolate are then added in sequence.

The mixture is then homogenised for at least 15 minutes. This mixture will form part of the first, controlled-release layer of the tablet.

13.75 Kg of Mg-K salts are loaded into a second granulator, and 4 Kg of lactose monohydrate, 750 g of microcrystalline cellulose, 1.25 Kg of crospovidone, 1.25 Kg of croscarmellose, 150 g of magnesium stearate and 250 g of talc are added.

The mixture is then homogenised for at least 20 minutes. This mixture will form part of the second, immediate-release layer of the tablet.

The two separate mixtures are then compressed to obtain a double-layer tablet weighing 598.2 mg.

The resulting tablets are then film-coated with a solution/suspension containing 2.4 Kg of polymethacrylate (Eudraguard Control), 350 g of talc, 200 g of titanium dioxide and 200 g of triethyl citrate, to obtain a tablet with a mean weight of 630 mg.

When subjected to disintegration and dissolution tests at pH 1, the tablets remain intact for at least 2 hours, with release below 1%; at pH ≥ 6.4 they exhibited release ≤ 5% after 60 minutes; at pH 7.2 release ≤ 45% after 60 minutes; release ≤ 60% after 240 minutes, and not more than 85% after 480 minutes; the value must be > 90% after 18 hours.

EXAMPLE 14

7.5 Kg of lipoic acid is loaded into a granulator with 325 g of microcrystalline cellulose.

1 Kg of dicalcium phosphate, 225 g of methylcellulose, 250 g of hydroxypropyl methylcellulose (HPMC K 100 lv), 125 g of hydroxypropyl methylcellulose (HPMC K15M), 30 g of crospovidone and 30 g of croscarmellose are then added in sequence.

The ingredients are mixed until a homogeneous dispersion of the active ingredient in the matrix is obtained, and the mixture is then granulated with an aqueous solution containing 150 g of polyvinylpyrrolidone (5%).

After drying, 30 g of magnesium stearate, 10 g of talc and 10 g of colloidal silicon dioxide are added in sequence. The mixture is homogenised for at least 15 minutes, followed by compression to obtain a 5 mm mini-tablet weighing 96.9 mg.

The resulting mini-tablets are then film-coated with a solution/suspension containing 630 g of HPMC E5 Premium, 20 g of talc, 100 g of titanium dioxide and 60 g of triethyl citrate, to obtain a mini-tablet with a mean weight of 105 mg.

When subjected to disintegration and dissolution tests at pH 1, the mini-tablets remain intact for at least 2 hours, with release below 1%; at pH ≥ 6.4 they exhibited release ≤ 10% after 60 minutes; at pH 7.2, release ≤ 60% after 60 minutes; release ≤ 70% after 240 minutes, and not more than 85% after 480 minutes; the value must be > 90% after 18 hours.

EXAMPLE 15

3.125 Kg of curcumin is loaded into a granulator with 325 Kg of microcrystalline cellulose.

1 Kg of dicalcium phosphate, 225 g of methylcellulose, 225 g of hydroxypropyl methylcellulose (HPMC K 100 lv), 225 g of hydroxypropyl methylcellulose (HPMC K15M), 20 g of crospovidone and 20 g of sodium starch glycolate are added in sequence to the same mixture.

The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrix is obtained.

13 g of magnesium stearate and 47 g of talc are then added in sequence. The mixture is then homogenised for at least 15 minutes.

The mixture is then compressed to obtain a 4 mm diameter mini-tablet weighing

91 mg.

The resulting tablets are then film-coated with a solution/suspension containing 710 mg of polymethacrylate (Eudraguard Control), 10 g of talc, 75 g of titanium dioxide and 15 g of triethyl citrate, to obtain a mini-tablet with a mean weight of 100 mg.

EXAMPLE 16

6.250 Kg of curcumin is loaded into a granulator with 500 g of microcrystalline cellulose.

1 Kg of dicalcium phosphate, 225 g of methylcellulose, 225 g of hydroxypropyl methylcellulose (HPMC K 100 lv), 225 g of hydroxypropyl methylcellulose (HPMC K15M), 20 g of crospovidone and 20 g of croscarmellose are added to the same mixture.

The mixture is then compressed to obtain a 4 mm diameter mini-tablet weighing

91 mg.

The resulting tablets are then film-coated with a solution/suspension containing 834 mg of polymethacrylate (Eudraguard Control), 90 g of talc, 75 g of titanium dioxide and 15 g of triethyl citrate, to obtain a mini-tablet with a mean weight of 90 mg.

The following tables summarise the qualitative and quantitative compositions of

Examples 1-16.

TABLE 2 - Mini-tablets of Examples 6-8

Lipoic acid 8 minitabs 5 mm= 500 mg Curcumin 10 minitabs 4 mm =100

TABLE 4 - Mini-tablets of Examples 14-16

Lipoic acid 8 minitabs 5 mm= 500 mg Curcumin 10 minitabs 4 mm= 100 mg.

COMPARATIVE EXAMPLE

The dissolution profile of the isradipine formulations exemplified in US20100285125 was compared with the formulations according to the invention containing the same active and other ingredients in the same amounts, but adding superdisintegrants and methylcellulose to the core.

The compositions of the formulations examined are reported below. The amounts are expressed in mg.

Table 5

Table 6

Table 7

The tables below show the dissolution profiles of the formulations reported above. The formulations according to the invention clearly exhibit a burst-effect-free release with high homogeneity of behaviour on the profiles thereof (low RSD values) compared with the formulations according to US20100285125

Table 8 - Dissolution profiles F1-F4 US20100285125

Table 9 - Dissolution profiles F5-F8 Invention

Table 10 - Dissolution Profiles F9-F11 US20100285125

Table 11 - Dissolution profiles F12-F13 Invention

Table 12 - Dissolution profiles F16-F18 US20100285125

Table 13 - Dissolution profiles F19-F21 Invention

Claims

1. A controlled-release solid oral composition comprising one or more active ingredients in a core and an outer coating of said core, wherein:

5 a) the core consists of:

(i) a monolithic matrix containing one or more active ingredients, a low-, medium- or high-viscosity hydroxypropyl methylcellulose or a mixture thereof, methylcellulose (MC), dicalcium phosphate and at least one or more superdisintegrant polymers/copolymers;

10 or

(ii) a composite monolithic matrix, as defined in point (i), adjacent to an immediate-release layer comprising the same active ingredient as the monolithic matrix; b) the coating consists of a layer comprising hydroxypropyl methylcellulose

15 and/or ethylcellulose or a gastroresistant layer or a layer comprising ethyl cellulose which is coated in turn with gastroresistant polymers.

2. A composition according to claim 1 wherein the core consists of a monolithic matrix as defined in claim 1, point (i).

3. A composition according to claim 1 wherein the core consists of a monolithic 20 matrix as defined in claim 1, adjacent to an immediate-release layer comprising the same active ingredient as the monolithic matrix.

4. A composition according to any one of claims 1 to 3 wherein the coating consists of a layer comprising ethylcellulose.

5. A composition according to any one of claims 1 to 3 wherein the coating consists 25 of a layer comprising hydroxypropyl methylcellulose and/or ethylcellulose coated with gastroresistant polymers.

6. A composition according to any one of claims 1 to 3 wherein the coating consists of a gastroresistant layer.

7. A composition according to one or more of claims 1 to 6 wherein the acrylic/methacrylic polymer or copolymer is selected from amino alkyl methacrylate copolymers soluble up to pH 5.0, methacrylic acid copolymers soluble at pH ≥ 5.5, methacrylic acid copolymers soluble at pH 6.0-7.0; and pH-dependent methacrylic acid

5 copolymers soluble at pH ≥ 7.0.

8. A composition according to one or more of claims 1 to 7 wherein the gastroresistant coating comprises pH-dependent methacrylic acid copolymers soluble at pH ≥ 5.5; pH-dependent methacrylic acid copolymers soluble at pH 6.0-7.0; pH- dependent methacrylic acid copolymers soluble at pH ≥ 7.0; methacrylic acid polymers

10 and starches, shellac; cellulose acetate phthalate; and cellulose succinate.

9. A composition according to one or more of claims 1 to 8 wherein the hydroxypropyl methylcelluloses having a viscosity of between 3 and 280,000 mPa.s 2% in H₂O at 20°C constitute 1 to 40% of the weight of the core.

10. A composition according to one or more of claims 1 to 9 wherein dicalcium 15 phosphate constitutes 0.1 to 2% of the weight of the core.

11. A composition according to one or more of claims 1 to 10 wherein methylcellulose constitutes from 0.1 to 20% of the weight of the core.

12. A composition according to one or more of claims 1 to 8 wherein the superdisintegrant polymers are selected from crospovidone, croscarmellose and sodium

20 starch glycolate in a percentage ranging from 0.1 to 20% of the weight of the core.

13. A composition according to one or more of claims 1 to 10 wherein hydroxypropyl methylcellulose and/or ethyl cellulose are present in percentages ranging from 1 to 20% of the weight of the core.

14. A composition according to one or more of claims 1 to 11 wherein the active 25 ingredient is selected from red yeast rice, curcumin, probiotics, lactoferrin, lipoic acid, mineral salts and menthol.