Gastroretentive formulations

Abstract

The present invention relates to the field of gastroretentive formulations, in particular to solid gastroretentive formulations such as tablets, as well as their method of manufacture.

Description

[0001] TITLE

[0002] GASTRORETENTIVE FORMULATIONS

[0003] TECHNICAL FIELD

[0004] The present invention relates to the field of gastroretentive formulations, in particular to solid gastroretentive formulations such as tablets, as well as their method of manufacture.

[0005] PRIOR ART

[0006] When developing a pharmaceutical formulation containing an active ingredient, the aim is generally to be able to control the location, the rate and the onset of release of the active ingredient, and to reduce frequency of administration.

[0007] For instance, certain active ingredients should preferably be released for prolonged time in specific gastrointestinal locations to ensure absorption and bioavailability. An approach to ensure prolonged release is to use extended release formulations. However, the localized release is not always guaranteed, since the digestive system is constantly moving and continues to propel the content throughout the gastrointestinal tract.

[0008] Therefore, an effective solution to prolong the retention of pharmaceutical formulation in the Gl tract is to design appropriate delivery systems that reside for prolonged time in the stomach while ensuring controlled release of the ingredients. The state of art teaches different formulations that may aid the retention of pharmaceutical formulations in the stomach, which are known as gastroretentive formulations.

[0009] For instance, it is known to provide formulations that when exposed to gastric liquid can swell on one hand and on the other hand can generate gas in situ. The result is a low density and floating on top of the gastric fluid and therefore, longer retention in the stomach. Such formulations have traditionally been made using wet granulation techniques to provide bulk formulation which is subsequently pressed and compacted into a tablet. Such tablets however tend to erode and disintegrate in the stomach because the structural integrity imparted by the mere pressing is easily disrupted after a prolonged exposure to liquid. As a consequence, the tablet rapidly crumbles. When the tablet crumbles, the rate of release of the drug and the retention time within the stomach are necessarily affected.

[0010] One known strategy is described in EP 3 463 313 A1 , where in some embodiments, a method of manufacturing an elongate member for use in a gastric residence system, comprises extruding the elongate member by co-extruding at least two regions comprising a carrier polymer-agent blend, wherein each region of carrier polymer-agent blend is separated from an adjacent region of carrier polymer-agent blend by a linker region. The carrier polymer may comprise a gum.

[0011] EP1213014A2 discloses a controlled-release dosage form for a pharmaceutically active agent comprises a core, in which the agent is dispersed, surrounded by a diffusion-limiting sleeve. The agent is released at a zero-order or approximately linear rate because the release rate of the agent will be governed entirely by erosion from exposed core surfaces, the surface area of which does not change substantially during the release process. Such a product may be made by coextruding the core and sleeve material and slicing the extrudate. The agent may be combined in the core with a matrix material such as PEG, PVOH, PVP, HPMC acetate succinate or polysorbate, whereas the outer coating or sleeve may be made from polymethacrylate or ethylcellulose.

[0012] There exists need to provide a pharmaceutical formulation, as well as methods for their manufacture, that demonstrates a structural integrity when exposed to gastric juice, which can uphold a given rate of release even after prolonged periods in gastric juice and which may be manufactured in a continuous manner (as opposed to batch manufacturing).

[0013] SUMMARY OF THE INVENTION

[0014] It is thus a first object of the present invention to provide a solid gastroretentive dosage form comprising at least one active ingredient and an extruded drug delivery system, said drug delivery system comprising a mixture of a swelling sub-system and a gas generating subsystem, wherein the swelling sub-system comprises a. a first polysaccharide capable of forming a hydrogel network when dissolved in an aqueous liquid, and wherein the first polysaccharide preferably has a molecular weight of more than 50 kDa, b. a second polysaccharide capable of increasing viscosity when dissolved in an aqueous liquid, wherein the second polysaccharide is chosen from natural gums, and preferably has a viscosity of at least 800 cP (when measured at 1 % by weight in water and at a shear rate of 0.1 s'1and 25°C), wherein the gas generating sub-system comprises c. a gas forming agent capable of releasing a gas when in contact with an aqueous liquid, optionally a pH-regulating agent, wherein the swelling sub-system is formed by mixing a) of the first and second polysaccharide with an aqueous liquid, allowing a hydrogel comprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient such as ferrous fumarate or metformin, to form an intermediate composition, and subsequently at least partially dehydrating said hydrogel comprised in the intermediate composition.

[0015] It is thus a second object of the present invention to provide a process for the manufacture of a solid gastroretentive dosage form such as the solid gastroretentive dosage form according to the first object of the invention, comprising at least one active ingredient such as ferrous fumarate or metformin ,and an extruded drug delivery system, said drug delivery system comprising a mixture of a swelling sub-system and a gas generating sub-system, comprising the steps of:

[0016] • providing a swelling sub-system by: o mixing the first and second polysaccharide with an aqueous liquid and allowing a hydrogel comprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, to form an intermediate composition, and subsequently o at least partially dehydrating said hydrogel comprised in the intermediate composition.

[0017] It is thus a third object of the present invention to provide a use of an extruded drug delivery system in a solid gastroretentive dosage form such as according to the first object of the invention, comprising said extruded drug delivery system and at least one active ingredient, such as ferrous fumarate or metformin, wherein said extruded drug delivery system comprises a mixture of a swelling sub-system and a gas generating sub-system, wherein the swelling sub-system comprises a fist polysaccharide capable of forming a hydrogel network when dissolved in an aqueous liquid, and wherein the first polysaccharide preferably has a molecular weight of more than 50 kDa, a second polysaccharide capable of increasing viscosity when dissolved in an aqueous liquid, wherein the second polysaccharide is chosen from natural gums, and preferably has a viscosity of at least 800 cP, wherein the gas generating sub-system comprises a gas forming agent capable of releasing a gas when in contact with an aqueous liquid, optionally a pH-regulating agent, wherein the swelling sub-system is formed by mixing a) of the first and second polysaccharide with an aqueous liquid, allowing a hydrogel comprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, which active ingredient is preferably ferrous fumarate or metformin, to form a intermediate composition and subsequently at least partially dehydrating said hydrogel comprised in the intermediate composition.

[0018] Further embodiments of the invention are laid down in the dependent claims.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,

[0021] Fig. 1 shows a uniform distribution embodiment of a tablet according to the present disclosure;

[0022] Fig. 2 shows a non-uniform distribution embodiment of a tablet (100) according to the present disclosure, having a core region (101) as well as a shell region (102).

[0023] Fig. 3 shows a cumulative release graph. In abscissa, time is expressed in hours; in ordinate, cumulative release is expressed in percentage of the overall amount of active ingredient. Three comparative examples of commercially available tablets are compared with a tablet according to the present disclosure. The graph of figure 3 relates to the following composition: HPMC 7 wt%, XG (xanthan gum) 2 wt%, NaHCCh 2.5 wt%, NaOH 1.3 wt%, FeFum (iron fumarate) 5 wt%. In this case, it is noted that while the commercially available tablets release 50% of the overall amount of active principle in less than 3 hours, the tablet of the present disclosure takes substantially 5 hours to release 50% of the overall amount of the active ingredient. It is thus apparent that the release of active ingredient is significantly slower with respect to the comparative tablets. Longer release timings may be achieved. Embodiments that release 50% of the overall amount of active principle at least after 3,75 hours, or at least after 4 hours, or at least after 4,5h hours can be achieved. When considering the timings related to a release of 70% of the overall amount of active principle, it can be noted that the comparative tablet having the longer release time takes about 4 hours to release the 70% of the overall amount of active principle; in contrast, the tablet according to the present disclosure takes about 10 hours to release such 70%. Embodiments that release 70% of the overall amount of active principle at least after 8 hours, preferably at least after 9 hours, more preferably after at least 10 hours can be achieved. From the above it is thus apparent that the tablet according to the present disclosure is characterized by a release of active principle which is significantly longer with respect to that of the comparative commercial tablets.

[0024] Figure 4 shows a variation of cumulative release in accordance with different types of formulation for a prolonged-release tablet 100 of the present disclosure. Figure 4 relates to tablet 100 where XG (Xanthan Gum) 2 wt% and FF (iron fumarate, or ferrous fumarate) 5 wt%, or XG 5 wt% and FF 5 wt%, or XG 2 wt% and FF 11.9 wt%, or XG 5 wt% and FF 11.9 wt% are in a homogenous mixture. All the mixtures always contain HPMC 7 wt%, NaHCOs 2.5 wt%, and NaOH 1.3 wt%. Figure 4 shows that for a given amount of Ferrous Fumarate as active principle, the cumulative release below 12h, in particular below 10h, or below 8h, increases with the increase of XG. Increasing the amount of Ferrous Fumarate as active principle, produces a cumulative release below 12h, in particular below 10h, or below 8h, which is increased with respect to the cumulative release obtainable with Ferrous Fumarate at 5 wt%. Figure 5 shows a relation of a mass increase factor with the amount of gum, in particular of Xanthan gum and FF. Again, Figure 5 relates to a tablet 100 where the ingredients are in a homogenous mixture. Examples considered in Figure 5 contain XG 2 wt% and FF 5 wt%, XG 5 wt% and FF 5 wt%, XG 2 wt% and FF 11.9 wt%, XG 5 wt% and FF 11.9 wt%. All the mixtures always contain HPMC 7 wt%, NaHCOs 2.5 wt%, and NaOH 1.3 wt%. Mass increase factor is given as follows:

[0025] MtI Mt=o, wherein:

[0026] Mtis the mass of the tablet at a given time t of exposition to a fluid;

[0027] Mt=o is the mass of the tablet at a time 0, before it is exposed to a fluid.

[0028] At time 0, the above ratio is 1 ; the ratio increases with time, and this implies that the prolonged-release tablet of the present disclosure progressively swells. At 2 hours, 4 hours, 7 hours it becomes evident that a higher percentage of gum, in particular Xanthan gum, corresponds to a corresponding increase of the mass increase factor. Increasing the content of FF from 5 wt% to 11.9 wt%, keeping the content of XG at 2 wt% and 5 wt% reduces the swelling with respect to the embodiments with FF 5 wt%.

[0029] Figure 6 shows a relation of a mass increase factor with the amount of FF. Figure 6 shows the behaviour of swelling of three embodiments with XG at 5 wt% and with FF at 0 wt%, 5 wt% and 11.9 wt%. All the mixtures always contain HPMC 7 wt%, NaHCOs 2.5% wt%, and NaOH 1 .3 wt%. The bars of the graph of Figure 6 clearly show that increasing the amount of FF (or, in some cases, of the active principle) while keeping constant the amount of XG causes a reduction of the mass increase factor.

[0030] Figure 7 shows a viscosity [Pa s] over shear rate [1 / s] graph, for embodiments of homogeneous distribution prolonged-release tablet 100, with formulations including XG 2 wt% and FF 17.1 wt%, XG 2 wt% and FF 11.9 wt%, and XG 2% and FF 5 wt%. All the formulations always contain HPMC 7 wt%, NaHCOs 2.5 wt%, and NaOH 1.3 wt%

[0031] Figure 8 shows a viscosity [Pa s] over shear rate [1 / s] graph, for embodiments of homogeneous distribution prolonged-release tablet 100, with formulations including XG 2 wt% and FF 5 wt%, XG 5 wt% and FF 5 wt% and XG 6.5 wt% and FF 5 wt%. All the formulation always contain HPMC 7 wt%, NaHCOs 2.5 wt%, and NaOH 1.3 wt%

[0032] Figure 9 shows a cumulative release graph which shows a comparison between a first embodiment of prolonged release tablet 100 with homogeneous mixture of components and a second embodiment of prolonged release tablet 100 with a core-shell distribution. From the above graph it is apparent that the core-shell embodiment shows a release which is significantly retarded with respect to the homogeneous mixture embodiment. Such retard is particularly evident up to 16h from the contact with the liquid (gastric acid) and as long as the time proceeds, it decreases. Studies performed by the Applicant show that between 3 and 6 hours, reaching a same amount of cumulative release (~ 15 % to ~ 35 %) is retarded of at least 1.5 hours or at least 1.75 hours or at least 2 hours.

[0033] Figure 10 shows a cumulative release graph which shows a comparison between a first embodiment of prolonged release tablet 100 with homogeneous mixture, a second specific embodiment of prolonged release tablet 100 with a non- homogeneous distribution (cylindrical core-shell having the core loaded with the active ingredient and both ends exposed to the outer environment, see Fig. 2), and a third specific embodiment of prolonged release tablet 100 with an inverted non-homogeneous distribution (cylindrical core-shell having the shell loaded with the active ingredient and both ends exposed to the outer environment, in Fig. 2). From the above graph it is apparent that the second specific embodiment shows a prolonged and constant release which is significantly longer and more linear with respect to the homogeneous distribution embodiment and the third specific embodiment. Such prolonged and more constant release is particularly evident up to 26h from the contact with the liquid (gastric acid) and as long as the time proceeds. The graph of figure 10 shows that some designs of a core-shell tablet may achieve a determined cumulative release, e.g. 50%, faster than a homogeneously designed tablet.

[0034] Fig. 11 shows an embodiment of a tablet (100) according to the present disclosure, having a core region (101) with a cruciform cross-section as well as a shell region (102).

[0035] Fig. 12 shows SEM images of successively enlarged portions of a drug delivery system obtained according to the present invention, where HPMC 7 wt%, XG 5 wt%, NaHCOs 2.5 wt%, NaOH 1.3 wt%, FF 2.5 wt%, and water 81.7 wt% were combined to form a hydrogel and then dehydrated (top row), as well as SEM images of successively enlarged portions of a drug delivery system obtained by dry mixing the same ingredients and by compressing them (bottom row). As can be seen, the internal morphology is very different due to the hydration / dehydration and the drug delivery system obtained according to the present invention forms a more porous and homogenous phase whereas the dry mixed and compacted drug delivery system forms an agglomerate of caked heterogenous particles.

[0036] Fig. 13 shows storage modulus G’ [Pa] and loss modulus G” [Pa] over time [s] at different temperature [°C], for embodiments of homogeneous distribution prolonged-release tablet 100, with formulations including HPMC 7 wt%, XG 3.5 wt%, FF 5.0 wt, NaHCOs 2.5 wt%, and NaOH 1.3 wt%. For the measurements a plate-plate geometry with 20 mm diameter was used and the gap was set to 1 mm. The angular frequency was kept constant at 1 rad / s and the oscillatory shear strain was set to 0.1 %. It can be observed that G’ increased and G” decreased with increasing temperature (from 25°C to 37 °C), indicative of the formation of a hydrogel network with more pronounced solid-like properties (G’ » G”).

[0037] Figure 14 shows the normalized cumulative release of several Fe fumarate formulations over time (7 hours) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and carrageenan at 2 % by weight as second polysaccharide (triangles), as well as comparative formulations incorporating a single polysaccharide - carrageenan - at 2 % by weight (stars) and at 9 % by weight (lozenges).

[0038] Figure 15 shows the normalized cumulative release of several Fe fumarate formulations over time (24 hours) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and carrageenan at 2 % by weight as second polysaccharide (triangles), as well as comparative formulations incorporating a single polysaccharide - carrageenan - at 2 % by weight (stars) and at 9 % by weight (lozenges). Figure 16 shows the mass increase of several Fe fumarate formulations over time when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and carrageenan at 2 % by weight as second polysaccharide, as well as a comparative formulation incorporating a single polysaccharide - carrageenan - at 2 % by weight and 9 % by weight.

[0039] Figure 17 shows the flotation behaviour of several Fe fumarate formulations over time when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Pictures are shown for formulations incorporating a single polysaccharide - carrageenan - at 2 % by weight and 9 % by weight.

[0040] Figure 18 shows the flotation behaviour of several Fe fumarate formulations over time when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C or in water at pH = 7 at 37°C. Pictures are shown for formulations incorporating hydrogen carbonate (Form. 1) - as well as formulations incorporating no hydrogen carbonate (Form. 2).

[0041] Figure 19 shows the flotation behaviour of a Fe fumarate formulation over time when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Pictures are shown for a formulation incorporating no second polymer -xanthan gum and did include only HPMC as first polysccharide.

[0042] Figure 20 shows the drying behaviour of a Fe fumarate formulation, whereby a crust of crystalline hydrogen carbonate is formed on the surface of the dried formulation, which did not include a second polymer, in this case, xanthan gum and did include only HPMC as first polysccharide.

[0043] Figure 21 shows the normalized cumulative release of several Fe fumarate formulations over time (7 hours) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and xanthan gum at 5 % by weight as second polysaccharide (lozenges) or at 2 % by weight as second polysaccharide (squares), as well as comparative formulations incorporating a single polysaccharide - xanthan gum - at 9 % by weight (triangles).

[0044] Figure 22 shows the mass increase of several Fe fumarate formulations over time when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and xanthan gum at 5 % by weight as second polysaccharide (lozenges) or at 2 % by weight as second polysaccharide (squares), as well as comparative formulations incorporating a single polysaccharide - xanthan gum - at 9 % by weight (triangles).

[0045] Figure 23 shows the normalized cumulative release of several Fe fumarate formulations over time (7 hours) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and xanthan gum at 2 % by weight as second polysaccharide (squares), or carrageenan at 2 % by weight as second polysaccharide (triangles), as well as incorporating MC at 7 % by weight as first polysaccharide and carrageenan at 2 % by weight as second polysaccharide (semi-filled hexagons).

[0046] Figure 24 shows the normalized cumulative release of several Fe fumarate formulations over time (24 hours) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and xanthan gum at 2 % by weight as second polysaccharide (squares), or carrageenan at 2 % by weight as second polysaccharide (triangles), as well as incorporating MC at 7 % by weight as first polysaccharide and carrageenan at 2 % by weight as second polysaccharide (semi-filled hexagons).

[0047] Figure 25 shows rheological behaviour of hydrogels (HPMC7%-XG2% I MC / %-Carr2% I HPMC7%-Carr2%) incorporating hydroxypropylmethyl cellulose (HPMC) or methyl cellulose (MC) as the first polysaccharide at 7% by weight and xanthan gum (XG) or carrageenan (Carr) as a second polysaccharide at 2% by weight, in particular shear storage modulus (G1) and shear loss modulus (G") when measured by oscillatory shear rheometry in the linear viscoelastic regime. Figure 26 shows the normalized cumulative release of several metformin formulations over time (7 hours) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC at 7 % by weight as first polysaccharide and xanthan gum (XG) at 5 % by weight as second polysaccharide (triangles), as well as incorporating MC at 7 % by weight as first polysaccharide and carrageenan (Carr) at 2 % by weight as second polysaccharide (half-filled triangles).

[0048] Fig. 27 shows the mass increase of metformin formulations over time (7 h) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC or MC at 7 % by weight as first polysaccharide and xanthan gum at 5 % by weight or carrageenan at 2% by weight as second polysaccharide.

[0049] Fig. 28 shows the mass increase of ferrous formate formulations over time (7 h) when placed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Data is shown for formulations according to the present invention, incorporating HPMC or MC at 7 % by weight as first polysaccharide and xanthan gum or carrageenan at 2 % by weight as second polysaccharide.

[0050] DESCRIPTION OF PREFERRED EMBODIMENTS

[0051] It is thus a first object of the present invention to provide solid gastroretentive dosage form comprising at least one active ingredient and an extruded drug delivery system, said drug delivery system comprising a mixture of a swelling sub-system and a gas generating subsystem, wherein the swelling sub-system comprises a. a first polysaccharide capable of forming a hydrogel network when dissolved in an aqueous liquid, and wherein the first polysaccharide preferably has a molecular weight of more than 50 kDa, b. a second polysaccharide capable of increasing viscosity when dissolved in an aqueous liquid, wherein the second polysaccharide is chosen from natural gums, and preferably has a viscosity of at least 800 cP (when measured at 1 % by weight in water and at a shear rate of 0.1 s’1), wherein the gas generating sub-system comprises c. a gas forming agent capable of releasing a gas when in contact with an aqueous liquid, optionally a pH-regulating agent, wherein the swelling sub-system is formed by mixing a) of the first and second polysaccharide with an aqueous liquid, allowing a hydrogel comprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, to form a intermediate composition and subsequently at least partially dehydrating said hydrogel comprised in the intermediate composition.

[0052] The term "hydrogel" relates to materials in which the storage modulus (G1) is greater than the loss modulus (G") at a frequency of 10 rad / s, as measured by oscillatory shear rheometry in the linear viscoelastic regime.

[0053] The hydrogel comprising a hydrogel network to be formed by mixing the first and second polysaccharide with an aqueous liquid such as an aqueous buffer liquid preferably exhibits a viscosity in the range of 0.1 - 10 kPa*s at by / bt = 0.1 s’1, when measured on a strain- controlled shear rheometer (MCR 502; Anton-Paar) equipped with a Peltier stage, a parallel plate geometry (PP20, Anton Paar) and plate temperature of 25 °C. The rotational shear rate measurements (by / bt = 0.1-100 s-1) were performed at 25 °C.

[0054] The present invention relates to a solid gastroretentive dosage form. The term gastroretentive is meant to express that the solid dosage form, which may for example be a tablet, is retained in the stomach after ingestion for a longer period than a solid dosage form that is not designed to be retained in the stomach.

[0055] A solid gastroretentive dosage form according to first object of the present invention will be retained, because of an increase in mass and volume, for at least 30 minutes, or at least 1 hour, or at least 2 hours, or at least 4 hours, or at least 7 hours, or at least 24 hours in an aqueous liquid. A solid gastroretentive dosage form according to first object of the present invention may be capable of instant release or of prolonged release of the active ingredient, and in particular may, in some embodiments capable of instant release of a first active ingredient and of prolonged release of a second active ingredient, for example in the case where more than one active ingredient is comprised in the solid gastroretentive dosage form according to first object of the present invention.

[0056] In a preferred embodiment, the solid gastroretentive dosage form according to first object of the present invention is a prolonged release solid gastroretentive dosage form, which in particular is configured for a 50% release of said active ingredient after at least 3 hours, preferably after at least 3,5 hours, preferably after at least 4 hours, more preferably after at least 4,5 hours, and / or for a 70% release of said active ingredient after at least 6 hours, preferably after at least 7 hours, preferably after at least 8 hours, preferably after at least 9 hours, more preferably at least after at least 9.5 hours, in particular when release of said active ingredient from the solid gastroretentive dosage form is measured at 37°C in aqueous hydrochloric acid having a pH of 1.

[0057] The first polysaccharide is capable of forming a hydrogel comprising a hydrogel network when dissolved in an aqueous liquid. It is noted that the term hydrogel network refers to a molecular network in which the polymer molecules of the first polysaccharide (and in some cases, with the second polysaccharide) cross-link to form a network.

[0058] The second polysaccharide is capable of increasing the viscosity when dissolved in an aqueous liquid. It is noted that in some embodiments, the second polysaccharide may also have form hydrogels comprising a hydrogel network, in particular in combination with the first polysaccharide, when dissolved in an aqueous liquid.

[0059] The first polysaccharide preferably has a molecular weight of more than 50 kDa and / or less than 1500 kDa, and more preferably may have a molecular weight of between 100 and 1000 kDa, even more preferably of between 500 and 900 kDa, most preferably between 600 and 800 kDa. In a preferred embodiment, the first polysaccharide may be a cellulose ether such as for example hydroxypropylmethyl cellulose, and have a molecular weight of more than 100 kDa and / or less than 1500 kDa, and more preferably may have a molecular weight of between 100 and 1000 kDa, even more preferably of between 500 and 900 kDa, most preferably between 600 and 800 kDa. In a preferred embodiment, the first polysaccharide may alternatively be a chitosan, which preferably has a molecular weight of less than 500 kDa, a molecular weight of between 10 and 500 kDa, even more preferably of between 30 and 450 kDa, most preferably between 40 and 400 kDa.

[0060] Without wishing to be bound to a particular theory, it is believed that the swelling sub-system of first and second polysaccharide in the drug delivery system, among others, is responsible for the advantages of the present invention such as the mechanical stability and prolonged swelling and tunable release kinetics. When the first and second polysaccharide are hydrated and dissolve in an aqueous liquid, a hydrogel is formed in which the molecular polysaccharide chains of the polysaccharide can interact between each other or in some cases with the polysaccharide chains of the other polysaccharide, forming a hydrogel network made of at least one polysaccharide or of both polysaccharides. This hydrogel network is mostly conserved, even after the thus obtained hydrogel is dehydrated, only to swell back to its hydrated form once the drug delivery system is in contact with gastric juice. The creation of said hydrogel network can be favored by the addition of the second polysaccharide, which on one hand increases the viscosity of the aqueous mixture when the mixture of polysaccharides is processed. In one embodiment, both polysaccharides can form a hydrogel comprising a hydrogel network may in particular form a hydrogel network where the molecular polysaccharide chains of one polysaccharide cross-link with the molecular polysaccharide chains of the other polysaccharide. It is noted that the crosslinking may preferably a non-covalent cross-linking such as via hydrogen bonding, van-der- Wals interaction, hydrophobic interaction, or ionic interaction.

[0061] Thus, the sub-system of the extruded drug delivery system is obtained, simply put, when a mixture of a first polysaccharide and a second polysaccharide are combined, in presence of an aqueous liquid so that a hydrogel forms and dehydrating the hydrogel. While the ratio between the aqueous buffer liquid and the mixture of first polysaccharide and second polysaccharide is not particularly limited, it is of course chosen such that the initial hydration can be achieved, and the ratio between the aqueous buffer liquid mixture of first polysaccharide and second polysaccharide is preferably at least 1 :10 by weight. In an alternative embodiment, the first polysaccharide and second polysaccharide may be formed into a hydrogel in an extruder, and is subsequently extruded from said extruder or may be gelled or formed into a hydrogel via (co-)extrusion in a different mixing device such as for example a mixer such as for example a static mixer. When the first polysaccharide and a second polysaccharide are mixed, in presence of an aqueous liquid, the first polysaccharide and the second polysaccharide form a hydrogel comprising a hydrogel network of first polysaccharide and eventually of second polysaccharide, which positively contributes to the advantages of the present invention. When said hydrogel is at least partially dehydrated, it may be dehydrated to a moisture content of less than 10 weight percent, 5 weight percent, 3 weight percent, 1 weight percent, or to a moisture content between 0.1 and 10 weight percent, between 0.1 and 5 weight percent, between 0.1 and 3 weight percent, between 0.1 and 1 weight percent. Moisture content may be determined, for example, via thermogravimetric measurement.

[0062] While (co-)extrusion allows to provide an extruded solid gastroretentive dosage form, the extruded solid gastroretentive dosage form may be subsequently be shaped, such as for example, via moulding, into a suitable oral dosage form such as a tablet or pill of a given shape or size. Alternatively, the extruded solid gastroretentive dosage form may be further processed, such as for example, via chopping the strand of extruded solid gastroretentive dosage form, into a suitable oral dosage form. Thus, the oral dosage form may be provided as segments of extruded strands of solid gastroretentive dosage form. Specific types of molding processes that may be further used for manufacturing the solid gastroretentive dosage form of the present disclosure include compression molding, rotational molding, injection molding, blow molding, core loss molding, transfer molding, and overmolding.

[0063] Specific types of molding processes that may be used for manufacturing the prolonged- release tablet 100 of the present disclosure include compression molding, rotational molding, injection molding, blow molding, core loss molding, transfer molding, overmolding.

[0064] After a hydrogel comprising a hydrogel network is formed, it is subsequently at least partially dehydrated, or stated alternatively, it is dried.

[0065] While the hydrogel may be dehydrated at any time, it is preferably dehydrated after extrusion, e.g. after exiting an extruder die. It may, however, also be dried after the extruded drug delivery system is moulded, since moulding may be facilitated by a moist (and thus malleable) drug delivery system.

[0066] The extrusion may be effected via any means suitable, such as for example means of an extrusion manufacturing process, or by means of a 3D-printing manufacturing process. In a preferred embodiment of the solid gastroretentive dosage form the solid gastroretentive dosage is an oral dosage form, in particular is a tablet and more particularly is an uncoated tablet. The tablet may not be coated, because the swelling system and the gas-generating system are then immediately activated when in contact with the gastric juice. The tablet may be provided in the form of a tablet consisting of homogenous mixture of the constitutive ingredients of the drug delivery system or may be provided in the form of a tablet consisting of separate regions, where at least one region may be formed of a homogenous mixture of the constitutive ingredients of the drug delivery system, and where the remaining regions may be formed of a different mixture.

[0067] It is understood that the first and second polysaccharide are combined with an aqueous liquid in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, meaning that all constitutive ingredients of the drug delivery system may be combined at once to form a homogenous mixture without negatively impacting the functioning of the drug delivery system.

[0068] The extruded drug delivery system also comprises a gas generating sub-system, which comprises a gas forming agent capable of releasing a gas when in contact with an acidic aqueous liquid, and optionally a pH-regulating agent. The gas forming agent may be any suitable gas forming agent. For example, the gas forming agent may rely on a chemical reaction to generate a gas or may rely on the desorption of a previously adsorbed gas.

[0069] The pH-regulating agent is suitable to modify the pH of the system, avoiding premature gas formation and may further regulate the water solubility of the active principle. It is understood that the overall amount of the pH-regulating agent may be varied according to the specific type of active principle. For instance, NaOH may be used as pH-regulating agent. Preferably, pH-regulating agent comprises, but not limited to, acetic acid, sodium acetates, calcium acetate, lactic acid, propionic acid, malic acid, fumaric acid, ascorbic acid, sodium ascorbate, calcium ascorbate, sodium lactate, potassium lactate, calcium lactate, citric acid, sodium citrates, potassium citrates, calcium citrates, tartaric acid, phosphoric acid, sodium phosphates, potassium phosphates, calcium phosphates, magnesium phosphates, adipic acid, sodium adipate, succinic acid, triammonium citrate, diphosphates, sodium carbonates, sodium carbonate, sodium hydrogen carbonate, sodium sesquicarbonate, potassium carbonates, magnesium carbonate, sodium sulphates, sodium hydroxide, potassium hydroxide, gluconic acid, glucono-delta lactone, potassium gluconate, calcium gluconate. When the extruded drug delivery system is extruded, it is extruded in the form of the hydrated intermediate composition comprising the hydrogel, which intermediate composition is subsequently dehydrated (as is the hydrogel in it) to form the extruded drug delivery system. While the extrusion may take place, in principle at any temperature that is not detrimental to the functioning of the drug delivery system, the extrusion is preferably made between 4°C and 80°C, and more preferably between 15° and 60°C, or between 30° and 60°C.

[0070] When the intermediate composition is extruded, it is extruded in the form of intermediate composition (i.e. when the hydrogel is formed) to be subsequently dehydrated to form the extruded drug delivery system. The hydrated intermediate composition, or stated alternatively, the hydrogel that is formed when the constituent ingredients of drug delivery system are combined, may have a moisture content of about between 20 % and 95 %, preferably 40 % and 95 %, more preferably 62 % and 92 %. The moisture content may be determined via thermogravimetric measurements.

[0071] The solid gastroretentive dosage includes an extruded drug delivery system, which is obtained among others, by forming a hydrogel comprising a hydrogel network, and dehydrating it. Therefore, after dehydration, the extruded drug delivery system comprises the first polysaccharide in an amount of between 2 wt% and 55 wt% or between 4 wt% and 50 wt% or between 7 wt% and 45 wt%, and / or the second polysaccharide in an amount of between 2 wt% and 50 wt% or between 3.5 wt% and 45 wt% or between 5 wt% and 40 wt%; and / or the gas-forming agent in an amount of between 1 wt% and 40 wt%, or between 2 wt% and 35 wt%, or 3 wt% and 30 wt%, and / or the pH-regulating agent, if present, in an amount of 0.2 wt% and 30 wt%, or between 0.5 wt% and 25 wt%, or between 1 wt% and 20 wt%; and / or the at least one active ingredient, if present, in an amount of between 0.1 wt% and 70 wt%, or between 0.1 wt% and 60 wt%, or between 0.1 wt% and 50 wt%.

[0072] The at least one active ingredient may be, for example ferrous fumarate or metformin, but may equally be any other active ingredient that is to be released in the stomach, preferably over a prolonged period, or stated alternatively, where the cumulative release of the active ingredient after 2 hours does not exceed 10, 15, 20 or 30 % by weight of the total amount of active ingredient of the solid gastroretentive dosage form of the present invention, when measured at 37°C in aqueous hydrochloric acid having a pH of 1 . The first polysaccharide and the second polysaccharide are formed to a hydrogel together in the presence of an aqueous liquid and can bind water molecules in the process. The presence of the gas generating sub-system and optionally the presence of the active ingredient does not influence the formation of the hydrogel network, as mentioned before. The pH-regulating agent and gas forming agent are homogenously dispersed in the composite gel network as it forms.

[0073] The first polysaccharide and the second polysaccharide are combined with an aqueous liquid. Said aqueous liquid may be aqueous buffer liquid or may be water. Preferably, albeit in a non-limiting extent, the water is ultrapure water (UPW) or high-purity water (HPW); such water is water that has been purified to stringent specification for the purposes of eliminating all contamination elements, including organic and / or inorganic compounds, dissolved and particulate matters, volatiles and non-volatiles, dissolved gases.

[0074] In a preferred embodiment of the solid gastroretentive dosage form the intermediate composition comprises the first polysaccharide in an amount of between 1 wt% and 15 wt%, preferably between 3,5 wt% and 12 wt%, when forming of the hydrogel comprising the hydrogel network in the presence of an aqueous liquid.

[0075] In a preferred embodiment of the solid gastroretentive dosage form the intermediate composition comprises the second polysaccharide in an amount of 1 wt% and 15 wt%, preferably between 1 ,5 wt% and 12 wt%, when forming of the hydrogel comprising the hydrogel network in the presence of an aqueous liquid.

[0076] In a preferred embodiment of the solid gastroretentive dosage form the intermediate composition comprises the gas forming agent in an amount of between 0.5 wt% and 11 wt%, preferably between 1 wt% and 10,5 wt%, when forming of the hydrogel comprising the hydrogel network in the presence of an aqueous liquid.

[0077] In a preferred embodiment of the solid gastroretentive dosage form the intermediate composition comprises the pH-regulating agent in an amount of between 0, 1 wt% and 20 wt%, or between 0.1 wt% and 13 wt%, or between 0,3 wt% and 6 wt%, or between 1 wt% and 3,5 wt%, when forming of the hydrogel comprising the hydrogel network in the presence of an aqueous liquid.

[0078] In a preferred embodiment of the solid gastroretentive dosage form the intermediate composition comprises the at least one active ingredient, if present, in an amount of between 0.1 wt% and 50 wt%, or of between 0.1 wt% and 40 wt%, or of between 0.1 wt% and 30 wt%, or of between 0.1 wt% and 18 wt%, based on the weight of the intermediate composition, when forming of the hydrogel comprising the hydrogel network in the presence of an aqueous liquid. It is understood that the remainder (of 100 wt%) is the aqueous liquid, for example water.

[0079] In a preferred embodiment of the solid gastroretentive dosage form the intermediate composition has a viscosity in the range of 0.1 - 10 kPa*s at by / bt = 0.1 s’1, when measured on a strain-controlled shear rheometer (MCR 502; Anton-Paar) equipped with a Peltier stage, a parallel plate geometry (PP20, Anton Paar) and plate temperature of 25 °C.

[0080] In a preferred embodiment, said ultrapure or high-purity water has a conductivity of less than 1.3pS / cm, a total organic carbon (TOC) of less than 0.5mg / l, bacteria less than 10CFU / 100ml, endotoxins less than 0.25 Ell / rnl and nitrates or aluminum of less than, respectively 0.2ppm and 10ppb. Preferably nitrates and aluminum are totally absent.

[0081] In a preferred embodiment, the first polysaccharide may be at least one of the following agents:

[0082] - pectins,

[0083] - starch,

[0084] - cellulose derivatives, such as cellulose ethers, preferably comprising at least one among methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose, and microcrystalline cellulose polysaccharides.

[0085] - chitosan.

[0086] In a preferred embodiment, the first polysaccharide is a cellulose ether, and preferably is hydroxypropylmethyl cellulose (HPMC). In a more preferred embodiment, the hydroxypropylmethyl cellulose (HPMC) has a molecular weight of between 100 and 1500 kDa. In a more preferred embodiment, the hydroxypropylmethyl cellulose (HPMC) has a viscosity of between 3000 to 5600 cP when measured at a concentration of 2% in water.

[0087] In a preferred embodiment, the first polysaccharide is a chitosan. In a more preferred embodiment, the chitosan has a viscosity of between 20 to 300 cP when measured at a concentration of 1 % in 1% acetic acid (aq.). In a preferred embodiment, the second polysaccharide gum is chosen from alginic acid, alginates, agar, gellan gum, karaya gum, locust bean gum, tara gum, gum arabic, gum tragacanth, xanthan gum, A-carrageenan, guar gum, gum ghatti, xanthan gum, carrageenan derivatives, and mixtures thereof, and preferably is xanthan gum. Especially when the second polysaccharide is xanthan gum, physical instabilities (e.g., precipitation or phase separation of swelling or gas-forming agents) may be prevented.

[0088] In a preferred embodiment of the solid gastroretentive dosage form according to the present invention, the first polysaccharide is a cellulose ether, preferably is methyl cellulose (MC) or hydroxypropylmethyl cellulose (HPMC), and the second polysaccharide is a xanthan gum (XG) or a carrageenan (Carr).

[0089] In a preferred embodiment of the solid gastroretentive dosage form according to the present invention, the first polysaccharide is a cellulose ether, preferably is methyl cellulose (MC) or hydroxypropylmethyl cellulose (HPMC), and the second polysaccharide is a xanthan gum (XG) or a carrageenan (Carr), and preferably the first polysaccharide is comprised in an amount by weight that is higher than an amount by weight the second polysaccharide.

[0090] In a more preferred embodiment, of the solid gastroretentive dosage form according to the present invention, the first polysaccharide is a cellulose ether, such as methyl cellulose (MC) or hydroxypropylmethyl cellulose (HPMC), and is comprised in the intermediate composition in an amount of between 1 wt% and 15 wt%, preferably between 3,5 wt% and 12 wt%, more preferably between 5 and 10 wt%; and the second polysaccharide is a xanthan gum (XG) or a carrageenan (Carr) and is comprised in the intermediate composition in an amount of 1 wt% and 15 wt%, preferably between 1 ,5 wt% and 12 wt%, more preferably between 1 ,5 wt% and 7,5 wt%.

[0091] In a preferred embodiment, the second polysaccharide is a xanthan gum and has a viscosity of between 800 to 200 000 cP when measured at a concentration of 1 % in water at a shear rate of 0.1 s’1.

[0092] The active ingredient may be a drug, in particular a prescription medicament, or a supplement. A prescription drug or prescription medicament is a pharmaceutical drug that is dispensed only to subjects provided with a medical prescription.

[0093] Prescription drugs differ from over-the-counter drugs; over-the-counter drugs can be obtained without a prescription.

[0094] Prescription drugs are subject to a prescription e.g. for reducing the risk of misuse, drug abuse.

[0095] An active ingredient may be an antibiotic (e.g. penicillins, macrolides, fluoroquinolones, oxazolidolones, monobactams, quinolones, tetracyclines, aminoglycosides, glycopeptides, streptogramins, cephalosporins, carbapenems, sulfonamides, rifamycins), an antiviral (e.g. human-derived nAbs, animal-derived nAbs, recombinant human receptors, CRISPR), an anti-inflammatory (e.g. NSAIDs, SAIDs), a sedative (e.g. flurazepam, midazolam, clonazepam, phenobarbital), an anesthetic (e.g. propofol, ketamine, methohexital, benzydamine), an anti-hypertensive, a depressant drug, a pre-medication drug, an anticholinergic (e.g. scopolamine, solifenacine, triesifenidile), a neurotransmitter, a cholinergic, a chemotherapy agent for cancer (e.g., small molecules and biologies, such as adalimumab, abatacept, infliximab), a bronchodilator (e.g. tipotropium, ipratropium bromide), a central nervous system stimulant, an anticoagulant, a diuretic, an hormone, for instance a corticosteroid, a peptide, for instance semaglutide agonist (GLP-1) or insuline, or an antidiabetic (e.g. metformin).

[0096] An active ingredient may be a supplement, in particular a dietary supplement, is a manufactured product intended to supplement person or animal diets. Supplement can provide nutrients extracted from food sources (animal, vegetal) or that may be synthetically manufactured. Non limiting examples of supplements, include vitamins, minerals, fibers, fatty acids, amino acids and sugars.

[0097] In a preferred embodiment of the solid gastroretentive dosage form according to the invention, the solid gastroretentive dosage form consists essentially of a homogenous mixture of active ingredient, first polysaccharide, second polysaccharide and gas generating sub-system and optionally of the active ingredient. The homogenous mixture is characterized in that the constituent ingredients of the dosage form are uniformly distributed throughout the volume of the extruded dosage form. In the embodiment shown in Figure 1 there is no distinction of concentration among the aforementioned elements between a peripheral portion of the tablet and a central portion of the tablet.

[0098] In a preferred embodiment of the solid gastroretentive dosage form according to the invention, the solid gastroretentive dosage form comprises a core region and a shell region, and wherein the core and shell region are preferably co-extruded, said core region having two exposed opposite end surfaces and a lateral surface extending between said opposite end surfaces, wherein the lateral surface is covered, at least partially or entirely, by a shell region, preferably wherein one of the core and shell region comprises the swelling subsystem and gas generating sub-system without active ingredient, and the other of the core and shell region comprises the at least one active ingredient.

[0099] In a preferred embodiment of the solid gastroretentive dosage form according to the invention, when the solid gastroretentive dosage form comprises two or more active ingredients, the solid gastroretentive dosage form comprises a core region and a shell region, and wherein the core and shell region are preferably co-extruded, said core region having two exposed opposite end surfaces and a lateral surface extending between said opposite end surfaces, wherein the lateral surface is covered, at least partially or entirely, by a shell region, preferably wherein one of the core and shell region comprises the swelling sub-system and gas generating sub-system with one or more active ingredient, and the other of the core and shell region comprises the remaining active ingredient(s).

[0100] In a preferred embodiment of the solid gastroretentive dosage form according to the invention, when the solid gastroretentive dosage form comprises two or more active ingredients, the solid gastroretentive dosage form comprises a core region and a shell region, and wherein the core and shell region are preferably co-extruded, said core region having two exposed opposite end surfaces and a lateral surface extending between said opposite end surfaces, wherein the lateral surface is covered, at least partially or entirely, by a shell region, preferably wherein one of the core and shell region comprises the swelling sub-system and gas generating sub-system with one or more active ingredient, and the other of the core and shell region comprises the swelling sub-system and gas generating sub-system with the remaining active ingredient(s).

[0101] In another preferred embodiment of the solid gastroretentive dosage form according to the invention, the core region comprises the active ingredient and the shell region comprises the at least one swelling sub-system and gas generating sub-system without active ingredient. In this case, the swelling sub-system and gas generating sub-system without active ingredient in the shell region can modulate the release of active ingredient by opposing the release from the core region where the shell region covers the core region.

[0102] In another preferred embodiment of the solid gastroretentive dosage form according to the invention, the shell region comprises the active ingredient whereas the core region comprises the at least one swelling sub-system and gas generating sub-system without active ingredient.

[0103] In a preferred embodiment of the solid gastroretentive dosage form according to the invention, when the solid gastroretentive dosage form comprises two or more active ingredients, and comprises a core region and a shell region, the core and shell region comprises the swelling sub-system and gas generating sub-system with a first active ingredient or a subset of the two or more active ingredients, and the other of the core and shell region comprises the remining active ingredient or remaining the subset of ingredients.

[0104] In a preferred embodiment of the solid gastroretentive dosage form according to the invention, the solid gastroretentive dosage form comprises a first layer and one or more further layers, preferably two or more further layers, and wherein the layers are preferably (co-)extruded, said first layer having one or more, preferably three or four, exposed opposite end surfaces and two lateral surfaces extending between said opposite end surfaces, wherein the lateral surfaces are covered, at least partially or entirely, by a the one or more further layers, preferably wherein one of the first or further layers region comprises the swelling sub-system and gas generating sub-system without active ingredient, and the other of the first or further layers comprises the at least one active ingredient. In one embodiment, the solid gastroretentive dosage form comprises a first central layer and two or more further layers, wherein the layers are preferably (co-)extruded, said first central layer having three or four, exposed opposite end surfaces and two lateral surfaces extending between said opposite end surfaces, wherein one lateral surfaces is covered, at least partially or entirely, by one of the two further layers, wherein the other one of the two further lateral surfaces is covered, at least partially or entirely, by the other of the two further layers, and the two further layers comprise the extruded drug delivery system without the active ingredient and the central layer comprises the active ingredient. EXPERIMENTS

[0105] Materials

[0106] Hypromellose (HPMC, Sigma-Aldrich, Hydroxypropylmethylcellulose 2910)

[0107] Methyl cellulose (MC, Sigma-Aldrich, Ref. M0512)

[0108] Xanthan Gum (XG, Jungbunzlauer, Lot: 2548360)

[0109] K-carrageenan (Carr, Sigma-Aldrich, Ref. 22048)

[0110] Milli-Q (mQ, Merck)

[0111] Sodium hydrogen carbonate (NaHCOs, Fisher Chemical)

[0112] Sodium hydroxide (NaOH, Sigma-Aldrich)

[0113] Acetic acid 99.7% (AA, Sigma-Aldrich)

[0114] Chitosan (low molecular weight, Sigma-Aldrich)

[0115] Ferrous Fumarate (FeFum / FF, Dr. Paul Lohmann)

[0116] Metformin hydrochloride (Metformin, Sigma-Aldrich, Ref. PHR1084)

[0117] Example 1

[0118] 500 mg Xanthan gum (XG), 700 mg hydroxylmethylcellulose (HPMC) and 250 mg sodium hydrogen carbonate (NaHCO3) were carefully weighted and combined with 3550 mg ultrapurified water (mQ) in a first 10ml syringe. In a second 10ml syringe, 3250 mg 1 M NaOH solution and 500 mg ferrous fumarate (FeFum) were sequentially added to 1250 mg mQ. Excess air was removed by centrifugation.

[0119] The syringes were sealed and stored at specific temperature (e.g, 25 °C) on a stirring plate overnight to solubilize the polymers.

[0120] The next day, both syringes were centrifuged to remove residual air entrapped in the solution. Subsequently, the two syringes were connected via a female-to-female luer lock and thoroughly mixed until a hydrogel formed.

[0121] The polymer formulation was stored at a specific temperature (e.g,. 4 °C) for at least 12h prior use.

[0122] The thus obtained formulation exhibited a viscosity in the range of 0.1 - 10 kPa*s at by / bt = 0.1 s’1, specifically of about 4.24 kPa*s, when measured on a strain-controlled shear rheometer (MCR 502; Anton-Paar) equipped with a Peltier stage, a parallel plate geometry (PP20, Anton Paar) and plate temperature of 25 °C. The rotational shear rate measurements (by / bt = 0.1-100 s’1) were performed at 25 °C. Hydrated intermediate tablets were manufactured by means of an extrusion-based method. Briefly, the prepared hydrogels were forced through a die of the desired cross section at a specific temperature (e.g., 25°C) to obtain intermediate hydrated tablets of predetermined mass and shape.

[0123] Following extrusion, the intermediate hydrated tablets were placed in an oven at specific temperature (e.g., 41 °C) to allow gelation and formation of hydrogel network. Moreover, the intermediate tablets were dehydrated and dried for approximately 24 hours (e.g., until solvent content 0.1-10%). The samples were stored at 25°C until further use.

[0124] Example 2

[0125] For the preparation of a solid gastroretentive dosage form comprising a core region and a shell region, two separate hydrated formulations can be used.

[0126] Hydrated formulation #1 : (as described in Example 1).

[0127] Hydrated formulation #2:

[0128] 600 mg Chitosan was added to 4400 mg 0.2M acetic acid solution in a first 10ml syringe. In a second 10ml syringe, 400 mg HPMC was added to 4600 mg 0.2M acetic acid solution. Excess air was removed by centrifugation. The syringes were sealed and stored at specific temperature (e.g, 25 °C) on a stirring plate overnight to solubilize the polymers. The next day, both syringes were centrifuged to remove residual air entrapped in the solution. Subsequently, the two syringes were connected via a female-to-female luer lock, thoroughly mixed and then sonicated (e.g., 3 hours at 25°C at 40kHz) until a hydrogel formed. The polymer formulation was stored at a specific temperature (e.g,. 4 °C) for at least 12h prior use. Formulation #2 exhibited a viscosity in the range of 0.1 - 10 kPa*s at by / bt = 0.1 s’1, specifically of about 9.91 kPa*s, when measured on a strain-controlled shear rheometer (MCR 502; Anton-Paar) equipped with a Peltier stage, a parallel plate geometry (PP20, Anton Paar) and plate temperature of 25 °C. The rotational shear rate measurements (by / bt = 0.1-100 s'1) were performed at 25 °C.

[0129] Core-shell hydrated intermediate tablets were manufactured by means of a (co-)extrusion- based method. Briefly, the prepared hydrogel formulation #1 and #2 were forced through a die of the desired cross section at a specific temperature (e.g., 25°C) to obtain intermediate hydrated tablets of predetermined mass and shape.

[0130] Following extrusion, the intermediate hydrated core-shell tablets were placed in an oven at specific temperature (e.g., 41 °C) to allow gelation and formation of hydrogel network. Moreover, the intermediate tablets were dehydrated and dried for approximately 24 hours (e.g., until solvent content 0.1-10%). The samples were stored at 25°C until further use.

[0131] Example 3 - Swelling characterization

[0132] Dissolution media (250 mL 0.1 M HCI solution) was pre-heated for 15 mint at 37°C in 600 mL beakers. Post-processed tablets were then immersed in the beakers containing dissolution media and then placed in an incubator (Minitron, INFORS HT, Bottmingen, Switzerland) equipped with a shaking plate configured at 53rpm and 37°C. At each time point (0.5h, 1 h, 2h, 4h, 7h, and 24h), tablets were carefully removed from the beakers and weighted. After determination of the tablet mass, tablets were returned to the acid buffer.

[0133] The mass increase factor (MIF), was calculated using the following formula:

[0134] MIF = mt / mt=o where mtis the mass of the tablet at time t, and mt=o is the mass of the post-processed tablet (after the intermediate tablets were dehydrated).

[0135] Example 4 - Characterization of the release kinetic of ferrous fumarate

[0136] Dissolution media (250 mL 0.1 M HCI solution) was pre-heated for 15 mint at 37°C in 250 mL reagent bottles. Post-processed tablets were immersed in the bottles containing the dissolution media and then placed in an incubator (Minitron, INFORS HT, Bottmingen, Switzerland) equipped with a shaking plate configured at 53rpm and 37°C. Subsequently, 2 mL supernatant was collected at specific time points: 0.5h, 1 h, 2h, 4h, 7h, 12h, 26h and 72h. Shortly before characterization, samples were diluted following the dilution factor described in below. Iron calibrators (0, 1.25, 2.5, 3.75 and 5 ppm) were then prepared from a Tritisol iron standard solution and adjusted with HCI 32% (w / v) to reach pH 1. Dilution factors: The iron content of each sample was characterized using an atomic absorption spectrometer (AAS, AA240FS, Varian, acquired by Agilent technologies, Santa Clara, USA). Normalized cumulative release was calculated as follow:

[0137] Normalized cumulative release [%] = xt / xt=72 where xtis the total mass of elemental iron solubilized in the buffer at time t, and xt=72 is the mass of elemental iron solubilized in the buffer after 72 hours.

[0138] Comparative Example 5

[0139] A formulation incorporating carrageenan as the sole polysaccharide was provided by mixing 9% by weight of carrageenan, 2.5% by weight of sodium bicarbonate, 1.3% by weight of sodium hydroxide, 5% by weight of iron fumarate and 82.2 % by weight of water. The mixture displayed essentially a liquid state at 25°C, and did not form a hydrogel unless being cooled after being heated to a temperature of more than 80°C to solubilize the carrageenan. At this temperature, though, the sodium bicarbonate prematurely decomposed by releasing carbon dioxide. To form dosage forms for evaluation, the hot liquid was poured into appropriate molds and left to solidify and then dried. As can be seen in Figure 14 and 15, the thus obtained dosage form of carrageenan displayed burst-like release, when immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, when compared to formulations that included a first (7% by weight of HPMC) and second polysaccharide (2 % by weight of carrageenan), which displayed a rather constant release profile.

[0140] Another formulation incorporating carrageenan as the sole polysaccharide was provided by mixing 2% by weight of carrageenan, 2.5% by weight of sodium bicarbonate, 1.3% by weight of sodium hydroxide, 5% by weight of iron fumarate and 89.2 % by weight of water. The mixture displayed essentially a liquid state at 25°C, and did not form a hydrogel unless being cooled after being heated to a temperature of more than 80°C to solubilize the carrageenan. At this temperature, though, the sodium bicarbonate prematurely decomposed by releasing carbon dioxide. To form dosage forms for evaluation, the hot liquid was poured into appropriate molds and left to solidify and then dried. To evaluate the erosion and swelling properties of said dosage form, a single dosage form was immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. As can be seen in Figure 14 and 15, the thus obtained dosage form of carrageenan displayed burst-like release, when immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, when compared to formulations that included a first (7% by weight of HPMC) and second polysaccharide (2 % by weight of carrageenan). As can be seen in Figure 16, the formulations incorporating carrageenan as the sole polysaccharide at 9% displayed quick disintegration (*), and the formulations incorporating carrageenan as the sole polysaccharide at 2% displayed premature erosion (loss of mass), when immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, when compared to formulations that included a first (7% by weight of HPMC) and second polysaccharide (2 % by weight of carrageenan). As can be seen in Figure 17, the formulations incorporating carrageenan as the sole polysaccharide at 9% displayed quick disintegration in aqueous solution of hydrochloric acid having a pH of 1 at 37°C, and the formulations incorporating carrageenan as the sole polysaccharide at 2% displayed premature erosion (loss of mass).

[0141] Example 6 - Influence of sodium bicarbonate (NaHCCh)

[0142] A formulation incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and xanthan gum (XG) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 5% by weight of XG, 2.5% by weight of sodium bicarbonate (NaHCOs), 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 79.2 % by weight of water, and subsequently drying the thus obtained hydrogel (Form. 1).

[0143] Another formulation without sodium bicarbonate (NaHCOs), incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and xanthan gum (XG) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 5% by weight of XG, 1.3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 81.7 % by weight of water, and subsequently drying the thus obtained hydrogel (Form. 2).

[0144] The thus obtained solid formulation was immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, as well as in water having a pH of 7 at 37°C.

[0145] As can be seen from the photographs provided in Figure 18, the formulation without sodium bicarbonate (NaHCOs) did not float in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C that simulates gastric acid, whereas the same formulation with sodium bicarbonate (NaHCOs) did float. Also, the formulation with sodium bicarbonate (NaHCOs) did not float in water having a pH of 7 at 37°C.

[0146] Example 7 - Influence of second polymer (XG) A formulation incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and no xanthan gum (XG) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 2.5% by weight of sodium bicarbonate (NaHCCh), 1.3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 84.2 % by weight of water, and subsequently drying the thus obtained hydrogel.

[0147] The thus obtained solid formulation was immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, to evaluate the behaviour of said formulation. As can be seen in Figure 19 and 20, the formulation loses floatation within 0.5 h and further leads to the formation of crystal crust on the outside of the formulation during the drying step, because in the absence of XG, the NaHCOs is not efficiently retained in the formulation. As a consequence, upon contact with gastric juice, the released carbon dioxide could not be retained in the bulk of the formulation and floating (and therefore g astro retention) becomes impossible.

[0148] Example 8 - Influence of first polymer (HPMC)

[0149] A formulation incorporating no hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and xanthan gum (XG) as a second polysaccharide was provided by mixing 9% by weight of XG, 2.5% by weight of sodium bicarbonate (NaHCOs), 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 82.2 % by weight of water, and subsequently drying the thus obtained hydrogel (HPMC0-XG9).

[0150] An alternative formulation incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and xanthan gum (XG) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 5% by weight of XG, 2.5% by weight of sodium bicarbonate (NaHCOs), 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 79.2 % by weight of water, and subsequently drying the thus obtained hydrogel (HPMC7- XG5). The same formulation was also provided with 2% by weight of XG (HPMC7-XG2) and 82.2 % by weight of water instead.

[0151] The thus obtained solid formulations were immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, to evaluate the behaviour of said formulation.

[0152] As can be seen in Figure 21 , the inclusion of a first polymer, in this case HPMC, together with the second polysaccharide, in this case XG, leads to a more linear release (i.e constant) of the iron fumarate, whereas in formulations with only second polysaccharide, in this case xanthan gum (and no HPMC), exhibit a delayed release in the aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Furthermore, as can be seen in Figure 22, the mass increase (i.e. swelling) of the formulations is enhanced by the inclusion of the first polysaccharide, in this case HPMC, when compared to formulation using xanthan gum as the sole polysaccharide.

[0153] Example 9 - Varying first and second polysaccharide

[0154] Formulations incorporating hydroxypropylmethyl cellulose (HPMC) or incorporating methyl cellulose (HPMC) as the first polysaccharide, and incorporating carrageenan (Carr) or incorporating xanthan gum (XG) were provided by mixing 7% by weight of HPMC or MC, 2% by weight of carrageenan or xanthan gum, 2.5% by weight of sodium bicarbonate, 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 82.2 % by weight of water. As can be seen in Figure 23 and 24, the thus obtained dosage forms displayed a rather constant release profile, when immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C. Furthermore, the mass increase displayed by such formulations when immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C is shown in Fig. 28, where it can be seen that each combination of first and second polysaccharide displayed a mass increase over the entire measurement period of 7 hours.

[0155] Example 10 - Rheology

[0156] A hydrogel (HPMC7-Carr2) incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and carrageenan (Carr) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 2% by weight of carrageenan, 2.5% by weight of sodium bicarbonate (NaHCCh), 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 82.2 % by weight of water, and the rheology properties thereof were measured, in particular shear storage modulus (G1) and shear loss modulus (G") by oscillatory shear rheometry in the linear viscoelastic regime.

[0157] Another hydrogel (MC7-Carr2) incorporating methyl cellulose (MC) as the first polysaccharide and carrageenan (Carr) as a second polysaccharide was provided by mixing 7% by weight of MC, 2% by weight of carrageenan, 2.5% by weight of sodium bicarbonate (NaHCCh), 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 82.2 % by weight of water, and the rheology properties thereof were measured, in particular shear storage modulus (G1) and shear loss modulus (G") by oscillatory shear rheometry in the linear viscoelastic regime.

[0158] Another hydrogel (HPMC7-XG2) incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and xanthan gum (XG) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 2% by weight of XG, 2.5% by weight of sodium bicarbonate (NaHCOs), 1 .3% by weight of sodium hydroxide (NaOH), 5% by weight of iron fumarate and 82.2 % by weight of water, and the rheology properties thereof were measured, in particular shear storage modulus (G1) and shear loss modulus (G") by oscillatory shear rheometry in the linear viscoelastic regime.

[0159] As can be seen in Fig 25, in all formulations the shear storage modulus (G1) was larger than the shear loss modulus (G"), which is characteristic of a hydrogel, over nearly the entire frequency range, and in particular at 10 rad / s. All formulations formed hydrogels displayed shear-thinning behaviour (not shown).

[0160] Example 11 - Active ingredient metformin

[0161] A formulation incorporating hydroxypropylmethyl cellulose (HPMC) as the first polysaccharide and xanthan gum (XG) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 5% by weight of XG, 2.5% by weight of sodium bicarbonate (NaHCOs), 1.3% by weight of sodium hydroxide (NaOH), 1 % by weight of metformin hydrochloride and 83.2 % by weight of water, and subsequently drying the thus obtained hydrogel (HPMC7%-XG5%).

[0162] An alternative formulation incorporating methyl cellulose (MC) as the first polysaccharide and carrageenan (Carr) as a second polysaccharide was provided by mixing 7% by weight of HPMC, 2% by weight of Carr, 2.5% by weight of sodium bicarbonate (NaHCOs), 1.3% by weight of sodium hydroxide (NaOH), 1 % by weight of metformin hydrochloride and 86.2 % by weight of water, and subsequently drying the thus obtained hydrogel (MC7%-Carr2%).

[0163] The thus obtained solid formulations were immersed in an aqueous solution of hydrochloric acid having a pH of 1 at 37°C, to evaluate the behaviour of said formulation. As can be seen in Figure 26, the inclusion of a first polymer, in this case HPMC or MC, together with the second polysaccharide, in this case XG or Carr, leads to a linear release (i.e constant) of the metformin hydrochloride. Furthermore, as can be seen in Figure 27, the formulations have a good swelling behaviour and it was observed that they maintained flotation for 7 hours and beyond (pictures not shown).

[0164] LIST OF REFERENCE SIGNS tablet core region shell region

Claims

CLAIMS1. A solid gastroretentive dosage form comprising at least one active ingredient and an extruded drug delivery system, said drug delivery system comprising a mixture of a swelling sub-system and a gas generating subsystem, wherein the swelling sub-system comprises a. a first polysaccharide forming a hydrogel network when dissolved in an aqueous liquid, and wherein the first polysaccharide is chosen from cellulose ethers such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose, microcrystalline cellulose polysaccharides, and preferably has a molecular weight of more than 50 kDa, b. a second polysaccharide capable of increasing viscosity when dissolved in an aqueous liquid, wherein the second polysaccharide is chosen from alginic acid, alginates, agar, gellan gum, karaya gum, locust bean gum, tara gum, gum arabic, gum tragacanth, xanthan gum, A-carrageenan, guar gum, gum ghatti, xanthan gum, and carrageenan derivatives,, and preferably has a viscosity of at least 800 cP, when viscosity is measured in water at 1 % by weight of the second polymer and at a shear rate of 0.1 s-1and 25°C, wherein the gas generating sub-system comprises c. a gas forming agent releasing a gas when in contact with an aqueous liquid, optionally a pH-regulating agent, wherein the swelling sub-system is formed by mixing a) of the first and second polysaccharide with an aqueous liquid, allowing a hydrogel comprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, which active ingredient is preferably ferrous fumarate, to form an intermediate composition, and subsequently at least partially dehydrating said hydrogel comprised in the intermediate composition.

2. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the first polysaccharide is methyl cellulose orhydroxypropylmethyl cellulose (HPMC).

3. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the second polysaccharide gum is xanthan gum.

4. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the gas forming agent comprises at least one carbonate or hydrogenocarbonate, preferably at least one among a sodium carbonate, a calcium carbonate, a magnesium carbonate, a potassium carbonate.

5. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the pH-regulating agent, said pH-regulating agent comprising at least one among acetic acid, sodium acetates, calcium acetate, lactic acid, propionic acid, malic acid, fumaric acid, ascorbic acid, sodium ascorbate, calcium ascorbate, sodium lactate, potassium lactate, calcium lactate, citric acid, sodium citrates, potassium citrates, calcium citrates, tartaric acid, phosphoric acid, sodium phosphates, potassium phosphates, calcium phosphates, magnesium phosphates, adipic acid, sodium adipate, succinic acid, triammonium citrate, diphosphates, sodium carbonates, sodium carbonate, sodium hydrogen carbonate, sodium sesquicarbonate, potassium carbonates, magnesium carbonate, sodium sulphates, sodium hydroxide, potassium hydroxide, gluconic acid, gluconodelta lactone, potassium gluconate, calcium gluconate.

6. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the solid gastroretentive dosage is an oral dosage form, in particular is a tablet and more particularly is an uncoated tablet.

7. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the solid gastroretentive dosage form consists essentially of a homogenous mixture of active ingredient, first polysaccharide, second polysaccharide and gas generating sub-system and optionally of the active ingredient.

8. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the solid gastroretentive dosage form comprises, or essentially consists of, at least two regions, wherein a first region comprises a mixture of said first polysaccharide, second polysaccharide and gas generating sub-system without active ingredient, and wherein a second region comprises the active ingredient.

9. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the solid gastroretentive dosage form comprises, or essentially consists of, a mixture of said first polysaccharide, second polysaccharide and gas generating sub-system and active ingredient.

10. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the intermediate composition comprises, or essentially consists of, the first polysaccharide in an amount of between 1 wt% and 15 wt%, preferably between 3,5 wt% and 12 wt%; the second polysaccharide in an amount of 1 wt% and 15 wt%, preferably between 1 ,5 wt% and 12 wt%; the gas forming agent in an amount of between 0.5 wt% and 11 wt%, preferably between 1 wt% and 10,5 wt%; the pH-regulating agent in an amount of between 0,1 wt% and 20 wt%, or between 0.1 wt% and 13 wt%, or between 0,3 wt% and 6 wt%, or between 1 wt% and 3,5 wt%; the at least one active ingredient, if present, in an amount of between 0.1 wt% and 50 wt%, or of between 0.1 wt% and 40 wt%, or of between 0.1 wt% and 30 wt%, or of between 0.1 wt% and 18 wt%.11 . The solid gastroretentive dosage form according to any one of the preceding claims, wherein the solid gastroretentive dosage form comprises a core region and a shell region, and wherein the core and shell region are coextruded, said core region having two exposed opposite end surfaces and a lateral surface extending between said opposite end surfaces, wherein the lateral surface is covered by a shell region, preferably wherein one of the core and shell region comprises the swelling sub-system and gas generating sub-system without active ingredient, and the other of the core and shell region comprises the at least one active ingredient.

12. The solid gastroretentive dosage form according to any one of the preceding claims, wherein the core region has a circular, oval, cruciform, stellate, triangular, square or polygonal cross-section and / or wherein the shell region portion has a circular, oval, cruciform, stellate, triangular, square or polygonal cross-section, and preferably wherein the core region has a cruciform crosssection and the shell region has a circular cross-section.

13. A process for the manufacture of a solid gastroretentive dosage form according to any one of claims 1 to 12, comprising at least one active ingredient and an extruded drug delivery system, said drug delivery system comprising a mixture of a swelling sub-system and a gas generating subsystem, comprising the steps of: providing a swelling sub-system by: mixing the first and second polysaccharide with an aqueous liquid and allowing a hydrogel comprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, and subsequently at least partially dehydrating said hydrogel.

14. Use of an extruded drug delivery system in a solid gastroretentive dosage form according to any one of claims 1 to 12, comprising at least one active ingredient, wherein the extruded drug delivery system comprises a mixture of a swelling sub-system and a gas generating sub-system, wherein the swelling sub-system comprises a fist polysaccharide forming a hydrogel network when dissolved in an aqueous liquid, and wherein the first polysaccharide is chosen from cellulose ethers such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose, microcrystalline cellulose polysaccharides, and preferably has a molecular weight of more than 50 kDa, a second polysaccharide increasing viscosity when dissolved in an aqueous liquid, wherein the second polysaccharide is chosen from alginic acid, alginates, agar, gellan gum, karaya gum, locust bean gum, tara gum, gum arabic, gum tragacanth, xanthan gum, A-carrageenan, guar gum, gum ghatti, xanthan gum, and carrageenan derivatives, and preferably has a viscosity of at least 800 cP, when viscosity is measured in water at 1 % by weight of the second polymer and at a shear rate of 0.1 s-1and 25°C, wherein the gas generating sub-system comprises a gas forming agent releasing a gas when in contact with an aqueous liquid, optionally a pH-regulating agent, wherein the swelling sub-system is formed by mixing a) of the first and second polysaccharide with an aqueous liquid, allowing a hydrogelcomprising a hydrogel network to form, in the presence b) of the gas generating sub-system, and optionally in the presence of c) the active ingredient, which active ingredient is preferably ferrous fumarate, and subsequently at least partially dehydrating said hydrogel.

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