WO2019069108A1

WO2019069108A1 - Prolonged-release, gastroretentive, moulded, solid dosage form and process for the preparation thereof

Info

Publication number: WO2019069108A1
Application number: PCT/HU2018/050043
Authority: WO
Inventors: Ferenc FENYVESI; Gábor VASVÁRI; Ádám HAIMHOFFER; Ildikó BÁCSKAY; Miklós VECSERNYÉS; István BUDAI; Pálma FEHÉR; Zoltán UJHELYI; Judit VÁRADI
Original assignee: Debreceni Egyetem
Current assignee: Debreceni Egyetem
Priority date: 2017-10-04
Filing date: 2018-10-04
Publication date: 2019-04-11
Anticipated expiration: 2020-04-04

Abstract

The invention relates to prolonged-release gastroretentive, moulded, solid dosage form, which has a monolithic foam structure consisting of a gas phase and a solid phase comprising a solidified melt, wherein the gas phase is contained in the bubbles dispersed in the solid phase, and the solid phase comprises an active ingredient, at least one pharmaceutically acceptable hydrophilic polymeric component, at least one pharmaceutically acceptable hydrophobic component and optionally one or more additional pharmaceutically acceptable excipient(s), wherein the active ingredient is present optionally in the form of separate particles, and which is solid at 37°C and has a density of less than 1 g/ml. The invention further relates to a process for the preparation of a prolonged-release gastroretentive, moulded, solid dosage form of the invention, comprising the steps of: a) forming a melt from ingredients of the dosage form, which melt comprises the active ingredient in dissolved and/or in dispersed form, b) mechanically dispersing a gas in the mixture obtained in step a), and c) moulding and solidifying the foam obtained in step b). The invention further relates to the prolonged-release gastroretentive dosage form which can be prepared by the above process, and to a foamed melt and a process from the preparation thereof.

Description

PROLONGED-RELEASE, GASTRORETENTIVE, MOULDED, SOLID DOSAGE FORM AND PROCESS FOR THE PREPARATION THEREOF

The field of the invention The present invention relates to a prolonged-release gastroretentive dosage form prepared by foaming and moulding a melt, therefore it has a monolithic foam structure comprising cavities formed by dispersed gas. The invention further relates to a process for the preparation of said dosage form. The present invention further relates to a prolonged-release gastroretentive dosage form, which can be prepared by said process, as well as a mouldable foamed melt and a method for the preparation thereof.

The state of the art

Among prolonged release dosage forms gastroretentive floating tablets and capsules constitute a distinct group.

With their application gastric residence time of the dosage form can be elongated (gastroretention). By prolonging their residence time the drug concentration remains nearly constant for hours in the stomach content (Hong Wen, Kinam Park: Oral Controlled Release Formulation Design and Drug Delivery 2010, Chapter 12: Oral Targeted Drug Delivery Systems: Gastric Retention Devices. John Wiley & Sons, Inc.)

This approach can be useful, on the one hand, in gastric disorders (e.g. gastric ulcer or infections), since with higher local drug concentration a more effective therapy or treatment can be achieved. For example, metronidazole is often used in the therapy of gastric ulcer caused by Helicobacter pylori (Carla M. Lopesa, Catarina Bettencourta, Alessandra Rossib, Francesca Buttini, Pedro Barataa (2016): Overview on gastroretentive drug delivery systems for improving drug bioavailability. International Journal of Pharmaceutics 510:144-158). On the other hand, in the pharmaceutical field it may be a problem that certain drugs are poorly absorbed from the human gastrointestinal tract and the absorption efficiency is variable in the different intestinal segments. Anatomically, there is an intestinal segment, typically in the small intestine, where the absorption of the drug is most effective, this location is the absorption window of the drug (Alexander Streubel, Juergen Siepmann and Roland Bodmeier (2006): Drug delivery to the upper small intestine window using gastroretentive technologies. Current Opinion in Pharmacology 6:501-508).

If the active ingredient is transferred from the stomach at low and nearly equal doses towards the absorption window, it may be absorbed almost completely. In the case of a drug used in this manner, a therapeutically adequate drug concentration may be provided with a lower amount of the active ingredient.

Floating or buoyant dosage forms have been developed in the recent decades. Two subtypes are distinguished: floating forms based on gas generation, and non gas-generating systems.

Gas-generating tablets or capsules mostly float with the aid of carbon-dioxide. It is generated under the action of gastric acid, but the release of the gas is prevented by the drug formulation (bubbles are entrapped). These dosage forms are advantageous in that they can be manufactured with relatively high productivity and simple technology, but until gas generation starts and until enough gas is trapped, the dosage form is sunk to the bottom of the stomach. This lag time can be more than 5 minutes. There is a risk of premature transit to the small intestine, which might cause the failure of the dosage form (Sakonjan Treesinchai, Satit Puttipipatkhachorn, Tasana Pitaksuteepong, Srisagul Sungthongjeen (2016): Development of curcumin floating tablets based on low density foam powder. Asian Journal of Pharmaceutical Sciences, 11:130-131).

In the case of hydrodynamically balanced capsules, the air contained in the powder blend is entrapped by gelling agents. Water penetrates through the capsule shell into the powder blend and a viscous gel is formed, in which the air is entrapped in the form of small bubbles. The dosage form instantly floats, but the resulting gel is rather malleable and physically not particularly resilient, it can be smeared by the churning forces of the stomach. (F.A. Dorkoosha, M.P.M. Stokkelb, D. Bloke, G. Borcharda, M. afiee-Tehrania, J.C. Verhoef, H.E. Junginger (2004): Feasibility study on the retention of superporous hydrogel composite polymer in the intestinal tract of man using scintigraphy. Journal of Controlled Release 99: 199-206).

There is also a tablet formulation in which camphor as a sublimable substance was mixed into the powder blend, which was put into a vacuum oven after tablet compression and the sublimation of the camphor was done until reaching constant weight. Thus, small holes remained in the tablets having unchanged volume but smaller weight. The tablets were floating from the start and provided sustained release, but the sublimation of the camphor was complete after more than 8 hours. (Tack-Oon Oh, Ju-Young Kim, Jung-Myung Ha, Sang-Cheol Chi, Yun-Seok Rhee, Chun-Woong Park, Eun-Seok Park (2013): Preparation of highly porous gastroretentive metformin tablets using a sublimation method. European Journal of Pharmaceutics and Biopharmaceutics 83:460-467). This approach is not advantageous in industrial scale manufacturing. The process time for sublimation, and monitoring the sublimation process makes the manufacturing process difficult, and the tablet structure weakens and its strength is reduced, therefore, after pressing and sublimation, re-checking tablet hardness and friability may be necessary.

Foamed dosage forms, prepared by gas expansion in extrusion processes have also been published. (Almutairy et al.: „Development of a floating drug delivery system with superior buoyancy in gastric fluid using hot-melt extrusion coupled with pressurized C02" Pharmazie, 71, 128-133 (2016)). They show the advantage of floating from the start. It is a disadvantage, however, that the manufacturing process should be carried out in a high-pressure system or vessel, additionally this method is not suitable for continuous production. The obtained extrudates are cut into minitablets to investigate their dissolution characteristics. These minitablets, however, are not directly suitable for ingestion, due to the sharp edges and rough cutting surfaces. WO03/057197A1 also discloses dosage forms prepared by the gas expansion method, but mainly immediate release ("flash-dissolve") forms. In that specification, the sequential application of an extruder and an injection moulding device - until then not used successfully in the field of pharmaceutical technology - is disclosed to prepare foamed dosage forms. According to the description, the advantage of using an injection moulding device is the creation of an outer shell around the dosage form which provides or contributes to the hardness of the dosage form and protects against erosion; while disadvantages of the method in terms of manufacturing time and costs and environmental protection are also acknowledged. Besides the complexity of the technology, another disadvantage of this method is that the temperature applied during the injection moulding, which is approximately 90-120°C, leads to a high thermal load on the active ingredient.

We also highlight that none of the processes mentioned in the documents Dl and D2 can be used to produce encapsulated or blister packaged dosage forms, which are particularly preferred in case of light, oxygen or heat-sensitive active substances. Additionally, the processes are carried out under high pressure which can cause polymorph changes of crystalline drugs. The problem to be solved

Therefore there is a need of gastroretentive dosage forms, which float immediately in the stomach after swallowing, release the active substance over prolonged time and can be produced by simple technology. The solution of the problem

We have developed a solution in which a gastroretentive dosage form is prepared by foaming a melt and moulding the foamed melt. Foaming is carried out by mechanically dispersing a gas. Thus, the structure of the dosage form is a monolithic foam consisting of a gas phase and a solid phase comprising a solidified melt. The dosage forms of the present invention exhibit a hardness and strength at room temperature which is comparable to that of the tablets. Their apparent densities are smaller than that of the water and gastric juice, so it is their important feature that they float immediately. Due to their monolithic solid foam structure, their buoyancy is maintained until the end of the drug release period. The drug is released over a prolonged period of time, and during their manufacture there is no need for special conditions or for long waiting times. By adjusting the composition, the rate of drug delivery can be controlled. By using surface active and absorption enhancing additives, the bioavailability of the active ingredients can be improved. The production can be made continuous and is cost-effective. By the process according to the invention it is possible to prepare swallowable dosage forms, e.g. tablets, pastilles or capsules directly, under gentle temperature and pressure conditions. Brief description of the invention

The invention relates to prolonged-release gastroretentive, moulded, solid dosage form, which has a monolithic foam structure consisting of a gas phase and a solid phase comprising a solidified melt, wherein the gas phase is contained in the bubbles dispersed in the solid phase, and the solid phase comprises an active ingredient, at least one pharmaceutically acceptable hydrophilic polymeric component, at least one pharmaceutically acceptable hydrophobic component and optionally one or more additional pharmaceutically acceptable excipient(s), wherein the active ingredient is present optionally in the form of separate particles, and which is solid at 37°C and has a density of less than 1 g/ml.

In the dosage form of the invention, the pharmaceutically acceptable hydrophobic component is preferably present in an amount of 1-50 wt% based on the total weight of the composition. More particularly, the amount of said component is 2-35 wt%, preferably about 2-20 wt%, more preferably 3-20 wt% based on the total weight of the composition.

The pharmaceutically acceptable hydrophobic component preferably has a melting range within the temperature range of 25-90°C. The pharmaceutically acceptable hydrophobic component(s) can be selected from the group consisting of: fatty acids, fatty alcohols, fatty acid esters, including pharmaceutically acceptable waxes, fats, cholesterol, polymers and copolymers of caprolactone and lactic acid, and pharmaceutically acceptable paraffins.

More particularly, the pharmaceutically acceptable hydrophobic component(s) can be selected from the group consisting of: lauric acid, myristic acid, stearic acid; myristyl, cetyl, cetylstearyl, and stearyl-alcohol; palmitic acid, solid paraffin, glyceryl distearate (Precirol AT05), glyceryl dipalmitostearate (Biogapress Vegetal BM297ATO), glyceryl behenate, glyceryl monostearate, hard fat (Adeps Solidus 50), hydrogenated vegetable oils, carnauba wax, white and yellow beeswax, ceresin, cholesterol, polycaprolactone, polylactic acid, poly(lactic-co-glycolic acid). Preferred are the fatty acids having 10-26 carbon atoms and their mixtures, particularly the following ones: lauric acid, myristic acid, stearic acid or palmitic acid or their mixtures.

Preferred are the fatty alcohols having 10-26 carbon atoms and their mixtures, particularly the following ones: cetyl, cetylstearyl and stearyl alcohol and/or their mixtures.

Preferred are the esters of the above mentioned fatty acids and fatty alcohols, and the mixtures thereof, particularly the pharmaceutically acceptable waxes, such as carnauba wax or white and yellow beeswax.

Furthermore, preferred are the glyceryl monoesters, particularly glyceryl behenate, glyceryl monostearate and their mixtures.

A further preferred group of the hydrophobic components consists of: stearic acid; cetyl, cetyl stearyl and stearyl alcohol; and white and yellow beeswax.

The dosage form according to the invention is a gastroretentive, moulded, solid dosage form, more particularly a moulded tablet, a moulded pastille for swallowing or a dosage form moulded directly into a capsule or a blister and solidified therein. The dosage form according to the invention is suitable for swallowing directly (without further processing, e.g. coating). However, we do not exclude the possibility of additional processing, e.g. coating.

The gastroretentive dosage form according to the invention is preferably a capsule. In another preferred embodiment, the gastroretentive dosage form according to the invention is in a blister-moulded form.

In the prolonged-release gastroretentive dosage form of the invention, the pharmaceutically acceptable hydrophilic polymeric component is preferably present in an amount of 10-95 wt% based on the total weight of the composition. More preferably, the amount of said component is 20-90 wt%, 30-75%, or about 40-80 wt% based on the total weight of the composition.

The pharmaceutically acceptable hydrophilic polymeric component preferably has a melting range within the temperature range of 40-80°C.

The pharmaceutically acceptable hydrophilic polymeric component(s) is/are preferably selected from the group consisting of: polyethylene glycols, stearoyl macrogolglycerides, copovidone, povidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, dextrans, poloxamers, ethylene glycol and vinyl alcohol graft copolymer, methacrylic acid-ethyl acrylate copolymer, ethyl vinyl acetate, ethylene glycol palmitostearate, polyoxyethylene stearates; macrogol cetostearyl, lauryl, oleyl, stearyl ethers. Preferred are the polyethylene glycols (macrogols), or the conjugates of macrogols, such as their fatty acid esters, alcohol ethers, furthermore the conjugates of fatty glycerides and macrogol. More preferred are the grades of PEG with a molecular weight of 1000 to 8000 g/mol, and the stearoyl macrogolglycerides.

The gastroretentive dosage form according to the invention contains at least one active ingredient, preferably selected from the group consisting of: furosemide, famotidine, ranitidine, metronidazole, captopril, levodopa, atenolol, metoprolol succinate, verapamil, prazosin, diazepam, tramadol, baclofen, isradipine, curcumin, quercetin, silymarin, ubidecarenone, chrysin, diosmin, hersperidin, oxerutin, Ginkgo biloba dry extract, and mixtures thereof.

The gastroretentive dosage form according to the invention preferably contains about 1-50 wt% of a pharmaceutically acceptable hydrophobic component having a melting range within the temperature range of 25-90°C, and is a capsule or is in a blister-moulded form. The gastroretentive dosage form according to the invention preferably contains about 1-50 wt% of a hydrophobic component selected from the group consisting of: fatty acids, fatty alcohols, fatty acid esters, including pharmaceutically acceptable waxes and fats, cholesterol, polymers and copolymers of caprolactone and lactic acid, and pharmaceutically acceptable paraffins; and is a capsule or is in a blister-moulded form.

The gastroretentive dosage form according to the invention preferably contains about 1-50 wt% of a pharmaceutically acceptable hydrophobic component having a melting range within the temperature range of 25-90°C, and about 10-95 wt% of a hydrophilic polymeric component having a melting range within the temperature range of 40-80°C, and is a capsule or is in a blister- moulded form.

The gastroretentive dosage form according to the invention particularly preferably contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG4000 and about 2-10 wt% of stearic acid.

The gastroretentive dosage form according to the invention particularly preferably contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG4000 and about 2-10 wt% of stearic acid, and is a capsule or is in a blister-moulded form.

In the gastroretentive dosage form according to the invention, the optional additional pharmaceutically acceptable excipient(s) is/are selected from the group consisting of: foam modifiers, nonionic surfactants, solubility enhancers.

The monolithic foam structure of prolonged-release gastroretentive dosage form according to the invention is characterized in that it contains substantially spherical or deformed spherical bubbles, and cavities formed by merging of bubbles.

The cavities formed by merging of bubbles are channel-like, the bubbles and cavities are homogeneously distributed and are not open to the outside world, and the outer surface does not form a structurally distinct shell. As the cavities are not open to the outside world, the outer surface of the dosage form is smooth.

In the dissolution test for solid dosage forms, the prolonged-release gastroretentive dosage form according to the invention floats from the start of the test, and maintains its buoyancy until the end of the drug release period, and the duration of the drug release period is at least 3 hours, preferably at least 5 hours. (The dissolution tests are carried out in accordance with pharmacopoeia regulations, see Ph. Hg. VIII^th edition, Volume IV.A, 2.9.3. Dissolution test for solid oral dosage forms). The prolonged-release gastroretentive dosage form according to the invention has a breaking strength typically of at least 15 Newtons, preferably at least 30 Newtons.

The microscopic, preferably electron microscopic image of the surface obtained by splitting the prolonged-release gastroretentive dosage form according to the invention is characterized in that the bubbles can be distinguished from the solidified melt and the optional granules of the active ingredient can be distinguished from the solidified melt and from the bubbles.

The average diameter of the bubbles in the prolonged-release gastroretentive dosage form according to the invention is preferably 5-500 μιη, more preferably 5-300 μιη or 50-300 μιη.

The invention further relates to a process for the preparation of a prolonged-release gastroretentive, moulded, solid dosage form, comprising the steps of: a) forming a melt from the active ingredient, at least one pharmaceutically acceptable hydrophilic polymeric component, at least one pharmaceutically acceptable hydrophobic component, and optionally one or more additional pharmaceutically acceptable excipient(s), which melt comprises the active ingredient in dissolved and/or in dispersed form, b) mechanically dispersing a gas in the mixture obtained in step a), and c) moulding and solidifying the foam obtained in step b).

Preferably, step a) of the process comprises: i) melting the at least one pharmaceutically acceptable hydrophilic polymeric component and the at least one pharmaceutically acceptable hydrophobic component, ii) dispersing the active ingredient in the melt obtained in step i), and optionally adding one or more additional excipient(s) in step i) and/or in step ii) and/or after dispersing the active ingredient in a separate step iii).

The temperature in step a) is preferably about 50-100°C, more preferably 50-80°C, typically 50- 70°C. The gas used in step b) of the process is air or inert gas (e.g. nitrogen, carbon dioxide, argon).

The temperature in step b) is generally 40-100°C, preferably 40-70°C, or 50-100°C, preferably 50- 70°C.

In step c) of the process, solidification of the foamed melt may comprise cooling, but it may also be sufficient to allow the foamed melt to cool (for example at room temperature). In the process of the invention, the blending and melting of the ingredients, the dispersion of the gas and the moulding and solidification of the foamed melt are substantially carried out at the same pressure. When gas is introduced in step b), the excess pressure applied for the introduction of the gas is preferably up to about 400 kPa, more preferably at most about 150 kPa, more preferably at most about 100 kPa or 50 kPa.

The process is preferably carried out substantially at atmospheric pressure; more particularly, the pressure during the process is preferably about 101-250 kPa, more preferably about 101-200 kPa, particularly preferably about 101-150 kPa.

The invention further relates to a prolonged-release gastroretentive, moulded, solid dosage form, which can be prepared by the process described above.

The foamed melt obtained in step b) is stable and mouldable; it can be regarded as an intermediate of the dosage form.

The invention further relates to a mouldable foamed melt, which comprises dispersed gas in a melt comprising an active ingredient, at least one pharmaceutically acceptable hydrophilic polymeric component, at least one pharmaceutically acceptable hydrophobic component, and optionally one or more additional pharmaceutically acceptable excipient(s), wherein the active ingredient is present optionally in the form of separate particles, and which has a density lower than 1 g/ml.

The invention further relates to a process for the preparation of the mouldable foamed melt described above, comprising the steps of: a) forming a melt from the active ingredient, the at least one pharmaceutically acceptable hydrophilic polymeric component, the at least one pharmaceutically acceptable hydrophobic component, and optionally one or more additional pharmaceutically acceptable excipient(s), which melt comprises the active ingredient in dissolved and/or in dispersed form, b) mechanically dispersing a gas in the mixture obtained in step a).

Brief description of the drawings:

Figure 1 presents the dissolution profiles of the dosage forms of Examples 1-5.

Figure 2 presents the dissolution profiles of the dosage forms of Examples 6-9.

Figures 3-11 present electron microscopic image of the surface obtained after splitting the dosage forms of the examples, namely: On Figure 3, a representative picture of the composition of Example 1 can be seen with 30x magnification,

On Figure 4, a representative picture of the composition of Example 2 can be seen with 18x magnification,

On Figure 5, a representative picture of the composition of Example 3 can be seen with 20x magnification,

On Figure 6, a representative picture of the composition of Example 4 can be seen with 20x magnification,

On Figure 7, a representative picture of the composition of Example 5 can be seen with 40x magnification,

On Figure 8, a representative picture of the composition of Example 6 can be seen with 30x magnification,

On Figure 9, a representative picture of the composition of Example 7 can be seen with 40x magnification,

On Figure 10, a representative picture of the composition of Example 8 can be seen with 30x magnification,

On Figure 11, a representative picture of the composition of Example 9 can be seen with 40x magnification.

On Figure 12 the Micro-CT picture of the composition of Example 3 can be seen. Definitions and abbreviations of terms used in the present application

In the present application, gastroretentive dosage form refers to such a dosage form, which is able to stay in the stomach for a long time and to provide a prolonged release of the active ingredient therein.

In the present application, apparent density refers to the ratio of the mass of the dosage form to the volume filled by it.

In the present application, monolithic solid foam refers to a solid foam structure composed of a single, coherent block. In this structure the bubbles and any active ingredient particles that are optionally present, are surrounded by a homogeneous mixture of excipients solidified from a melt.

In the present application, "bubble" refers to a cavity formed by the gas dispersed in the melt, thus containing the gas, surrounded by the melt, including the cavities constituted by the trapped gas bubbles surrounded by the solidified - i.e. solid phase - melt. In general, therefore, any cavities surrounded by the melt are included, irrespective of their shape. When we refer to their shape, we use a corresponding expression, e.g. "spherical or spheroidal bubbles" and "short channel-like cavities".

Preferably, the solidified (solid phase) melt and the bubbles containing the gas phase form a closed cell foam. The melt and the bubbles dispersed therein, containing the gas phase, are together designated as foamed melt, and in solid state they are designated as solidified foamed melt or solid foam.

Cavity refers to a space (hole) in a liquid or solid condensed phase material which is not filled by the condensed phase.

The fact that a dosage form "floats" or "is buoyant" in a fluid, preferably in a body fluid, especially in the gastric juice, means that it does not sink down due to its density - which is not greater than, preferably is smaller than that of the fluid - since the buoyancy exerted on it is not smaller, preferably is greater than the gravitational force exerted on it. Therefore, in the stomach, the dosage form is preferably located on the surface of the stomach contents, and optionally the flow of body fluid cannot convey it from the stomach to the intestine. This can be expected in humans if after the dosage form is taken, the treated person maintains his upper body in a vertical or at least tilted position (standing or sitting position, but not lying), thus, the stomach sphincter, which regulates the conveyance of the food into the small intestine, is in the lower anatomical position.

In the present application, by fatty acids we refer to aliphatic, saturated or unsaturated, monovalent carboxylic acids of 8 to 26 carbon atoms. In the present application, by fatty alcohols we refer to aliphatic, saturated or unsaturated, monovalent alcohols of 8 to 26 carbon atoms.

In the present application, by melting range we refer to that the material does not have a melting point specific to a given pressure and temperature, but the transition from solid phase to liquid phase falls within a temperature range. Within this range, the material is present in a semi-solid or partially molten state. Below the lower point of the melting range the material is solid and above its upper point it is liquid.

In the present application, "moulded dosage form" refers to a dosage form which is prepared by pouring a melt into a mould, more particularly by moulding substantially at ambient pressure; injection-moulded products are not considered as belonging to this category. In the present application, "blister" refers to a pharmaceutical packaging made of plastic or metal (e.g. aluminium) comprising preformed cavities. In the present application, "room temperature" generally refers to 20-25°C. Where more accurate knowledge of the temperature may be important, the temperature used is given (for example, the texture analysis tests were carried out at 22°C).

Detailed description of the invention The gastroretentive dosage form according to the invention is a dosage form prepared by foaming a melt and moulding the foam. The structure of the dosage form therefore is a monolithic foam consisting of a gas phase and a solid phase comprising a solidified melt, in which the gas phase is contained in the bubbles dispersed in the solid phase, and the solid phase contains an active ingredient and pharmaceutically acceptable excipients, in which the active ingredient is present optionally in the form of separate particles.

It is not difficult for a person skilled in the art to recognize or to determine this structure. The structure can be checked for instance by splitting the dosage form or by preparing a section and the obtained surfaces and sections can be examined with e.g. (transmission or scanning) electron microscopy or with different types of optical microscopy (bright or dark field illumination microscopy, cross-polarized light illumination microscopy or stereomicroscopy). On the microscopical images, the cavities created in the melt by the dispersed gas phase can be easily distinguished from the solidified melt, and the granules of the active ingredient that are optionally present can be easily distinguished from the solidified melt and from the gas bubbles.

Particularly, the margins of the cavities can be recognized on the electron microscopic pictures and can be easily distinguished from the surrounding solidified melt and, if the active ingredient was added in solid form, from the particles (typically crystals) of the active ingredient. Owing to dispersing gas into the molten material the shape of the cavities is typically spherical or deformed sphere or spheroidal, on the sectional image or fracture surface it is circular or very similar to that, possibly elliptical-shaped. Cavities formed by the merging of bubbles may also be present. The cavities formed by merging of bubbles have short channel-like appearance, and they are assumed to originate from mechanically dispersing gas in the melt. The inner surface of the cavities are typically smooth, uneven surface can possibly be seen as well, as a result of the solidified but once fluid melt. The solidified melt forms one single phase in which the granules of the active ingredients (if they are present) and the cavities created by the dispersed gas are distributed randomly. Particles of the active ingredient can vary in shape, but can be easily distinguished from the melted and solidified carrier and from the cavities created by the dispersed gas. On the electron microscopical images, the granules are markedly light in colour. It is not typical that any of the interfaces in the melt is enriched in solid particles. If the active ingredient is used in non- solid form (whose state of matter is liquid or which is dissolved in a solvent), only one continuous and solid phase and the cavities can be seen on the electron microscopic pictures.

In the foam the entrapped bubbles form typically closed cells and thus they typically contain the gas from the foaming step.

The foam structure of prolonged-release gastroretentive dosage forms according to the present invention is characterized by its homogenous appearance and by the presence of essentially spherical or deformed spherical bubbles, and additionally short channel-like cavities (supposedly created by the merging of some bubbles). The bubbles and the cavities are typically not opened to the outside world. This provides smooth outer surface to the dosage form. The structure of the foam is homogeneous and the smooth outer surface does not from a shell with different properties (e.g. different density, different mechanical properties, such as hardness) compared to the inner part.

As mentioned before, due to the fact that in the solidified melt the cavities were created as a result of dispersing gas bubbles in the liquid phase, they are typically spherical or (due to deformation) very similar, spheroidal or possibly elliptical in shape. The short and channel-like cavities formed by merging of bubbles typically have spheroidal and cylindrical parts as well. Therefore, the sectional views of these bubbles and cavities are typically circular or deformed circular, so the sectional views of the dosage forms are characterized by the presence of circular or deformed circular outlines. It is not difficult for a person skilled in the art to recognize this structure based on the microscopical pictures. If desired, quantification of this feature is possible by determining the similarity of the outlines of the bubbles with respect to a circle (roundness), e.g. according to the following calculation and relationship.

For this method we start from the microscopical, for instance, scanning electron microscopical (SEM) pictures of the fracture surface of the samples. For calculating the roundness, the diameter of the inscribed circle of the cavity is divided by the diameter of its circumscribed circle (according to the guidelines of ISO 1101 for„roundness"). If the sectional view shows a circular cavity, this ratio will be 1. The more diverging from the circle the shape of the sectional view of the cavity, the smaller the value will be under 1. The value of the quotient obtained based on the calculation mentioned above, which is characteristic to the shapes of the cavities (more precisely of their sectional view) and which is used in the present description as a possible characterization to the roundness, is at least 0.35, preferably at least 0.65, at least 0.75, at least 0.85 or at least 0.95 in the case of at least 80% of the bubbles. The roundness is preferably at least 0.75 in the case of at least 80% of the bubbles. The roundness is more preferably at least 0.75 in the case of at least 95% of the bubbles. Particularly preferably the roundness is at least 0.85 in the case of at least 95% of the bubbles. It is required for the dosage form to be solid at body temperature. The preserved solid state at body temperature provides floating/buoyancy property and resistance for the dosage form against the grinding and churning movements of the stomach.

The gastroretentive dosage form according to the invention is intended to be administered to mammals, typically to humans, so by body temperature typically 37°C is meant. The dosage form must therefore be solid at 37°C. The dosage form is solid, preferably at 42°C, more preferably even at 45°C as well.

The dosage form has a breaking strength at 22°C of at least 15, preferably at least 30, more preferably at least 45 Newtons.

The gastroretentive dosage form according to the invention has an apparent density below 1 g/ml, preferably about 0.5-0.95 g/ml, typically about 0.6-0.95 g/ml, more particularly about 0.70- 0.92 g/ml. The apparent density lower than that of the stomach content ensures the floatation of the dosage form with zero lag time.

In the foam structure of the gastroretentive dosage form according to the invention the average diameter of the bubbles, which can be characterized, e.g. by measuring the diameters of the section of the bubbles seen on the fractural surface, is preferably 5-500 μιη, more preferably about 5-300 μιη or 50-300 μιη. The small - preferably homogenously dispersed - bubbles favour the fact that the dosage form maintains its initial structure and properties (especially the apparent density below 1 g/ml) during its erosion.

In the present application, homogenous distribution refers to the fact that in the distribution of the bubbles in the dosage form there is no gradient in any direction of the space. Based on our findings there is no gradient outwards from the inside of the dosage form either, therefore the outer smooth surface does not form a structurally distinct shell with different (higher) density or significantly different mechanical properties (e.g. hardness) compared to the inner parts.

In a preferred embodiment, the average diameter of the bubbles in the gastroretentive dosage form according to the invention is about 5-500 μιη, the dosage form is solid at 42°C and below and has a breaking strength at 22°C of at least 15 Newtons, furthermore its density is about 0.5- 0.95 g/ml.

In another preferred embodiment, the average diameter of the bubbles in the gastroretentive dosage form according to the invention is typically about 50-300 μιη, the dosage form is solid at 45°C and below and has a breaking strength at 22°C of at least 30 Newtons, its density is about 0.6-0.95 g/ml.

In another preferred embodiment, the roundness of the bubbles in the sectional view of the gastroretentive dosage form according to the invention is at least 0.65 in the case of at least 80% of the bubbles, the average diameter of the bubbles is typically about 5-500 μιη, the dosage form is solid at 42°C and below, and has a breaking strength at 22°C of at least 15 Newtons, furthermore its density is about 0.5-0.95 g/ml.

In another preferred embodiment, the roundness of the bubbles in the sectional view of the gastroretentive dosage form according to the invention is at least 0.75 in the case of at least 80% of the bubbles, the average diameter of the bubbles is typically 50-300 μιη, the dosage form is solid at 45°C or below, and has a breaking strength at 22°C of at least 45 Newtons, furthermore its density is about 0.6-0.95 g/ml.

The monolithic solid foam structure of the dosage form makes it possible for the dosage form to stay afloat on the top of the stomach content during the whole time of the drug release, while the dosage form erodes (e.g. by dissolution, friction or by cracking). This can be checked, for instance, during dissolution tests by visual inspection.

The gastroretentive dosage form according to the invention is prolonged release type, which means that it releases the active ingredient into the body during a prolonged period of time compared to an immediate-release dosage form by staying in the stomach for a longer time.

The duration of the complete drug release period for the dosage form is at least 3 hours, preferably at least 5 hours, more preferably at least 7 hours, particularly preferably at least 10 hours.

The buoyancy of the dosage form is maintained until the end of the drug release period, furthermore it is also possible that the total amount of the active ingredient is released before complete erosion (i.e. after complete drug release the remnant of the dosage form composed of excipients, typically mainly fat-soluble excipients, may remain buoyant or float before its complete erosion.) The dosage form releases the active ingredient preferably during its whole lifespan, namely preferably releases the active ingredient during at least 80%, preferably at least 90%, more preferably about 100% of its floating duration.

In a preferred embodiment, the average diameter of the bubbles in the gastroretentive dosage form according to the invention is about 5-500 μιη, the dosage form is solid at 42°C and below and has a breaking strength at 22°C of at least 15 Newtons, furthermore its density is about 0.5- 0.95 g/ml, and the drug release period is at least 5 hours.

In another preferred embodiment, the roundness of the bubbles in the sectional view of the gastroretentive dosage form according to the invention is at least 0.75 in the case of at least 80% of the bubbles, the average diameter of the bubbles is typically 50-300 μιη, the dosage form is solid at 42°C and below and has a breaking strength at 22°C of at least 30 Newtons, its density is about 0.6-0.95 g/ml, and the drug release period is at least 5 hours.

In another preferred embodiment, the roundness in the sectional view of the gastroretentive dosage form according to the invention is at least 0.75 in the case of at least 95% of the bubbles, the average diameter of the bubbles is typically 50-300 μιη, the dosage form is solid at 45°C or below and has a breaking strength at 22°C of at least 45 Newtons, its density is about 0.6-0.95 g/ml and the drug release period is at least 7 hours.

In a preferred embodiment, the average diameter of the bubbles in the gastroretentive dosage form according to the invention is about 5-500 μιη, the dosage form is solid at 42°C and below and has a breaking strength at 22°C of at least 15 Newtons, furthermore its density is about 0.5- 0.95 g/ml, and the drug release period is at least 5 hours and the drug release period is at least 80% of the floating time.

In another preferred embodiment, the roundness of the bubbles in the sectional view of the gastroretentive dosage form according to the invention is at least 0.75 in the case of at least 95% of the bubbles, the average diameter of the bubbles is typically 50-300 μιη, the dosage form is solid at 45°C and below and has a breaking strength at 22°C of at least 45 Newtons, its density is about 0.6-0.95 g/ml and the drug release period is at least 7 hours and the drug release period is at least 90% of the floating time.

The dosage form according to the invention is suitable for swallowing directly (without further processing, e.g. coating). However, we do not exclude the possibility of additional processing, e.g. coating. The dosage form according to the invention may be a dosage form moulded directly into a capsule shell or a blister and solidified therein, a pastille for swallowing or a tablet with various shapes.

Application of capsule shell in the case of light-sensitive active ingredients provides a simple option for instant protection against light, it also protects from other environmental effects (such as air and humidity), additionally aids the swallowing of the dosage form, the different colour of the capsule body and cap makes another opportunity to distinguish between product with the same active ingredient but with different strengths as well; therefore the gastroretentive dosage form according to the invention is preferably encapsulated. More particularly, the gastroretentive dosage form according to the invention is preferably a prolonged release hard capsule. The capsule according to the invention contains a foamed melt moulded directly into a capsule shell and solidified therein. The shell of the capsule may be made e.g. form gelatine, HPMC, pullulan or from other polysaccharides.

Application of a blister is advantageous in that the filling is fast and can be inserted into the continuous process: the production of the dosage form can be continuously followed by moulding it into its primary packaging. Instant protection against light and environmental effects is also realized in this case as well. We also mention that due to the appropriate hardness and the preferably applicable components the dosage form does not stick to the primary packaging material, no lubrication is needed, because the components provide enough lubrication on the plastic or metallic blisters. Therefore, in another preferred embodiment, the dosage form according to the invention is a blister-moulded dosage form, particularly a dosage form moulded directly into a blister and solidified therein.

Components of the product

One of the main components of the dosage form is a pharmaceutically acceptable hydrophilic polymer. This component provides for the elimination of the dosage form the stomach by dissolution. Furthermore, this component, due to its polymeric nature, is characterized by having a melting range. The melting range is preferably within the temperature range of 40-80°C.

Examples of hydrophilic components include: polyethylene glycols (PEGs), also called macrogols, stearoyl macrogolglycerides, copovidone, povidone, polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, dextrans, poloxamers, ethylene glycol and vinyl alcohol graft copolymer, methacrylic acid-ethyl acrylate copolymer, ethyl vinyl acetate, ethylene glycol palmitostearate, polyoxyethylene stearates; macrogol cetostearyl, lauryl, oleyl, stearyl ethers, and their mixtures. Preferred are polyethylene glycols (macrogols) and their conjugates, such as fatty acid esters, alcohol esters, furthermore the conjugates of fatty glycerides and macrogol. More preferred are the grades of PEG with a molecular weight between 1000 and 8000 g/mol and the stearoyl macrogolglycerides. Particularly preferred is PEG 4000. The amount of the component mentioned above in the dosage form is generally about 10-95 wt%, or 20-90 wt% or 30-75%, typically about 40-80 wt% based on the total weight of the composition. The optimal amount of the component mentioned above depends on the physicochemical properties and the amount of the other components, particularly of the active ingredient.

In a preferred embodiment, the dosage form contains 10-95 wt% of polyethylene glycol, more preferably 40-80 wt% of polyethylene glycol, particularly preferably 45-70 or 55-70 wt% of polyethylene glycol.

In another preferred embodiment, the dosage form contains 10-95 wt% of PEG4000, more preferably 40-80 wt% of PEG4000, particularly preferably 45-70 or 55-70 wt% of PEG4000.

In another preferred embodiment, the dosage form contains 10-95% of stearoyl macrogolglyceride, more preferably 35-85 or 40-85 wt% of stearoyl macrogolglyceride, particularly preferably 35-70 or 45-70 wt% of stearoyl macrogolglyceride.

The gastroretentive dosage form contains a pharmaceutically acceptable hydrophobic component as well; one of the roles of this component is to slow down the release rate of the active ingredient from the dosage form. Surprisingly, we have found that the pharmaceutically acceptable hydrophobic component plays vital role in the foaming as well. More particularly, the hydrophobic component plays a role in the stabilization of the gas-melt interfacial surface and contributes to lower the density below 1 g/ml and thereby to the buoyancy on the surface of the gastric juice. Preferably the hydrophobic component has a melting range, which is preferably within the temperature range of 25-90°C, more preferably within 40-80°C. The hydrophobic components may be, for example: fatty acids, fatty alcohols, fatty acid esters, fats or their mixtures. Further examples are cholesterol, polymers and copolymers of caprolactone and lactic acid and pharmaceutically acceptable paraffins. A specific group of the fatty acid esters are the pharmaceutically acceptable waxes.

The fatty acids and fatty alcohols contain at least 8, preferably 8-26 carbon atoms, their aliphatic chains may be saturated or unsaturated, but the saturated fatty acids and fatty alcohols are preferred due to their higher melting ranges. The fatty acid esters may be the glycerol esters (preferably mono- or diesters) of the fatty acids mentioned above; additionally the esters of fatty acids with fatty alcohols and the mixtures occurring in the nature containing typically such components, also known as waxes, are also contemplated. The pharmaceutically acceptable waxes are well known to those skilled in the art, such examples are carnauba wax and white or yellow beeswax.

By the term fats we mean triesters of fatty acids and glycerol, additionally natural mixtures are included as well, if pharmaceutically acceptable.

The pharmaceutically acceptable paraffins contain aliphatic hydrocarbons, typically having at least 8 carbon atoms, generally having about 8-40 carbon atoms, typically in the form of a mixture. The aliphatic hydrocarbons may be saturated or unsaturated, straight or branched-chained. The pharmaceutically acceptable paraffins are well known to those skilled in the art, such examples are solid paraffin and ceresin.

As examples for the pharmaceutically acceptable hydrophobic components the followings can be mentioned: lauric acid, myristic acid, stearic acid; myristyl, cetyl, cetylstearyl and stearyl-alcohol; palmitic acid, solid paraffin, glyceryl distearate (Precirol AT05), glyceryl dipalmitostearate (Biogapress Vegetal BM297ATO), glyceryl behenate, glyceryl monostearate, hard fat (Adeps Solidus 50), hydrogenated vegetable oils, carnauba wax, white and yellow beeswax, ceresin, cholesterol, polycaprolactone, polylactic acid, poly(lactic-co-glycolic acid).

Preferred are the fatty acids having 10-26 carbon atoms and their mixtures, particularly the following ones: lauric acid, myristic acid, stearic acid or palmitic acid or their mixtures.

Preferred are the esters formed from the fatty acids and fatty alcohols mentioned above, and their mixtures, particularly the pharmaceutically acceptable waxes, such as carnauba wax or white and yellow beeswax.

Furthermore, preferred are the glycerol monoesters, particularly the glyceryl behenate, glyceryl monostearate and their mixtures.

A further preferred group of the hydrophobic components consists of: stearic acid; cetyl, cetyl stearyl and stearyl alcohol; and white and yellow beeswax. In the dosage form of the invention, the hydrophobic component is generally present in an amount of 1-50 wt%, more particularly 2-35 wt%, preferably about 2-20 wt%, more preferably 3- 20 wt%, based on the total weight of the composition. Regarding that this component has an important role to slow down the release of the drug from the dosage form, its optimal amount greatly depends on the properties of the active ingredient. Generally, the more hydrophilic the active ingredient, the greater amount of hydrophobic component should be used. If the effectiveness of the foaming is not appropriate, it is also suggested to increase the amount of this component. Hydrophobic component is necessary to achieve foaming and to reach appropriate density, even if it would not be necessary for other reasons.

In a preferred embodiment, the dosage form contains 1-20 wt%, more preferably 2-10 wt% hydrophobic component selected from the followings: fatty acids, fatty alcohols, fatty acid esters and fats, or their mixtures, polymers and copolymers of caprolactone and lactic acid, pharmaceutically acceptable waxes and paraffins, and cholesterol.

In another preferred embodiment, the dosage form contains 1-20 wt%, more preferably 2-10 wt% hydrophobic component selected from the followings: stearic acid, cetyl, cetylstearyl and stearyl-alcohol, furthermore white or yellow beeswax, and their mixtures. In another preferred embodiment, the dosage form contains 1-20 wt%, more preferably 2-10 wt% of stearic acid.

In another preferred embodiment, in the dosage form according to the invention the hydrophilic polymeric component is selected from polyethylene glycols, conjugates of macrogols, conjugates of glycerides and macrogol, and their mixtures, and the hydrophobic component is selected from stearic acid; cetyl, cetylstearyl or stearyl alcohol; and white or yellow beeswax, and their mixtures.

In another preferred embodiment, in the dosage form according to the invention the hydrophilic polymeric component is selected from polyethylene glycols, conjugates of macrogols, and conjugates of glycerides and macrogol, and the hydrophobic component is stearic acid.

In another preferred embodiment, in the dosage form according to the invention the hydrophilic polymeric component is selected from the grades of PEG with a molecular weight between 1000 and 8000 g/mol and stearoyl macrogolglycerides, and the hydrophobic component is stearic acid.

With respect to the aforementioned hydrophilic and hydrophobic components of the dosage form, it is mentioned that preferably such components are chosen which are solid at body temperature. Nevertheless, such components may also be used which melt or soften at body temperature (for example: the hydrophobic Hard Fat, type 50) if the resulting dosage form possesses the desired features, among others, it is solid at body temperature. It is not difficult for the person skilled in the art to ascertain that optionally what ratio of such components with lower melting points complies with the desired features mentioned above.

As active ingredient, any drug substance may be used which is not sensitive to heat (more particularly to the temperature used during the production, particularly the temperature used for melting) and does not react with the other components. As active ingredient mainly small molecules are considered, regarding the fact that larger biomolecules are typically sensitive to heat. The active ingredients are typically solid and often crystalline.

The dosage form - taking into account the above mentioned limitations - can be preferably used to achieve modified-release with a wide range of active ingredients. It is reasonable to use this dosage form in the case of active ingredients which have a higher bioavailability in a gastroretentive form. Examples for active ingredients are: furosemide, famotidine, ranitidine, metronidazole, captopril, levodopa, atenolol, metoprolol succinate, verapamil, prazosin, diazepam, tramadol, baclofen, isradipine etc. Active ingredients can be natural in origin, especially flavonoids. Examples for active ingredients with natural origin: curcumin, quercetin, silymarin, ubidecarenone, chrysin, diosmin, hesperidin, oxerutin, Ginkgo biloba dry extract (extraction solvent: 60w/w% acetone) etc.

The dosage form is particularly suitable in the case of such active ingredients that have good absorption rates in the stomach or in the proximal part of the duodenum (drugs with narrow absorption window). Examples for these active ingredients are: furosemide, captopril, levodopa, atenolol, metoprolol succinate, verapamil, prazosin, diazepam, tramadol, baclofen, isradipine.

The dosage form is particularly suitable in the case of such active ingredients which are used for the treatment of gastric disorders such as reflux disease, gastric ulcer, hyperacidity or bacterial infection. Examples for these active ingredients are: famotidine, ranitidine and metronidazole. A particularly preferred active ingredient is metronidazole. The active ingredient can be a mixture of multiple drugs if it is pharmaceutically reasonable to administer a combination of certain drugs.

The applicable ratio of the active ingredients depends on the physicochemical properties of the active ingredients and on the quality and ratio of other components, while the applied amount is mainly determined by the target dose and the amounts of the other components are adjusted to this dose. Typically, the active ingredient is present in at most 50 wt% of the dosage form. The applied amount of the active ingredient is not more than 1000 mg in a single dose of the dosage form.

In the case of metronidazole, the amount of the active ingredient is at most 50 wt%, preferably about 25-35 wt%. In a particularly preferred embodiment, the dosage form contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG 4000 and about 2-10 wt% of stearic acid.

In another particularly preferred embodiment, the dosage form contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG 4000 and about 2-10 wt% of stearic acid, and the average diameter of the bubbles in the structure of the dosage form is typically 5-500 μιη, the dosage form is solid at 42°C and below, and has a breaking strength at 22°C of at least 15 Newtons, furthermore its density is about 0.5-0.95 g/ml and the drug release period is at least 5 hours.

In another particularly preferred embodiment, the dosage form contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG 4000 and about 2-10 wt% of stearic acid, the roundness of the bubbles in the sectional view of the dosage form is at least 0.75 in the case of at least 95% of the bubbles, the average diameter of the bubbles is typically 50-300 μιη, the dosage form is solid at 45°C and below and has a breaking strength at 22°C of at least 45 Newtons, its density is about 0.6-0.95 g/ml, the drug release period is at least 7 hours, and the drug release period is at least 80% of the floating time. Besides the active ingredient and the components mentioned above, the dosage form may contain other excipients as well, which may further influence, for example, the structure, the disintegration time and/or the dissolution profile. Such excipients are well known to those skilled in the art.

As excipients, for instance, foam modifiers can be used, which influence the foam generation, the sizes of the bubbles. These excipients can be, for example, biologically acceptable alcohols, namely ethyl alcohol and glycerol, but even small amounts of water as well. The amount of ethyl alcohol or glycerol is typically at most 50 ml/kg, preferably 5-25 ml/kg. The amount of water is at most 100 ml/kg, preferably 0-75 ml/kg, particularly preferably 0-25 ml/kg. In practice, typically the aqueous solutions of the above mentioned alcohols are used, the applied concentration is typically between 10 and 90 vol%, preferably 20-80 vol%, particularly preferably 30-75 vol%. The above mentioned foam modifier only modifies the foam generation, but does not substitute the hydrophobic component. Foaming, carried out by mechanically dispersing a gas, is essentially determined by the presence of the hydrophilic and hydrophobic component, their ratio can be optimized, and the structure of the generated foam can be further modified with the foam modifiers mentioned above.

In another particularly preferred embodiment, the dosage form contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG 4000 and about 2-10 wt% of stearic acid, furthermore 5- 15 ml/kg of ethanol or glycerol and 0-10 ml/kg of water.

In another particularly preferred embodiment, the dosage form contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG 4000 and about 2-10 wt% of stearic acid, additionally 5- 15 ml/kg of ethanol or glycerol and 0-10 ml/kg of water, and the average diameter of the bubbles is about 5-500 μιη, the dosage form is solid at 42°C and below and has a breaking strength at 22°C of at least 15 Newtons, furthermore its density is about 0.5-0.95 g/ml, and the drug release period is at least 5 hours. In another particularly preferred embodiment, the dosage form contains about 25-35 wt% of metronidazole, about 55-70 wt% of PEG 4000 and about 2-10 wt% of stearic acid, additionally 5- 15 ml/kg of ethanol or glycerol and 0-10 ml/kg of water, the roundness of the bubbles in the sectional view of the dosage form is at least 0.75 in the case of at least 95% of the bubbles and the average diameter of the bubbles is about 50-300 μιη, the dosage form is solid at 45°C and below and has a breaking strength at 22°C of at least 45 Newtons, its density is about 0.6-0.95 g/ml, the drug release period is at least 7 hours, and the drug release period is at least 90% of the floating time.

Moreover, e.g. non-ionic surfactants can also be used, e.g. caprylocaproyl polyoxylglycerides (Labrasol^®), tocopherol polyethylene glycol succinate ester, polysorbates. As a result, the wetting rate of the solid foam structure of the obtained dosage form increases and thereby the dissolution rate of the active ingredient increases. The applied amount of the surfactant is typically at most 3 wt%, preferably 0.5-2.5 wt%.

Surprisingly, we have found that the application of the surfactants mentioned above, without the use of a hydrophobic component, did not result a foam with suitable density. The foamability and the appropriate (below 1 g/ml) density is essentially achieved by the presence of the hydrophilic and hydrophobic components, the surfactants only modify the structure as described above. Additionally, solubilizing agents, e.g. cyclodextrins can also be used, even in the form of cyclodetrine-drug complexes.

The preparation process

The gastroretentive dosage form of the present invention is prepared by forming a melt from the ingredients of the dosage form, in which the active ingredient is dissolved and/or dispersed, and mechanically foaming the melt and pouring the foam into moulds and solidifying it (by cooling or by allowing it to cool).

By the term melt comprising the active ingredient in dissolved and/or in dispersed form we mean a mixture which contains ingredients other than the active ingredient in a molten or liquid state and the active ingredient is dispersed in this melt. Depending on the composition or the state of matter of the active ingredient (liquid, solution or solid material) the active ingredient can be completely or partially dissolved, the undissolved fraction remains solid, typically in crystalline form in the melt.

The melt comprising the active ingredient in dissolved and/or in dispersed form can be prepared in one single step by mixing and heating all the ingredients (including the active ingredients and excipients as well). In spite of the simplicity of the method, it has the disadvantage of having a notable heat load on the active ingredient, therefore this method cannot be used in the case of heat sensitive active ingredients, and in some cases (depending on the composition) mixing of the ingredients properly can be difficult. The melt comprising the active ingredient in dissolved and/or in dispersed form is preferably prepared in a multi-step process, namely i) firstly forming a melt from a pharmaceutically acceptable hydrophilic polymeric component and a pharmaceutically acceptable hydrophobic component, and optionally one or more additional excipient(s) and ii) dispersing the active ingredient in the obtained melt, and optionally adding simultaneously one or more additional excipient(s), and optionally iii) mixing the obtained mixture with one or more additional excipient(s).

The essence of the multi-step process is therefore that firstly a melt is formed from a hydrophilic polymeric component and a hydrophobic component, into which the active ingredient (in pure or dissolved form) is dispersed. The excipients - depending on their properties - can be added in step i) at melt formation, or in step ii) together with the active ingredient, or posteriorly, after adding the active ingredient in a separate step iii). For example, the liquid surfactants can be added simultaneously with the active ingredient or directly at the initiation of the melting. The ethanol and glycerol is conveniently added to the melt simultaneously with the active ingredient, or can be added after mixing the active ingredient in a separate step iii). Ethanol and glycerol also provide the opportunity to add and disperse a pre-dissolved active ingredient into the melt. This method is conveniently used in the case when the dose of the active ingredient is small. Small amounts are necessary for the therapy from such active ingredients like prazosin, isradipine or baclofen. It is not difficult for a person skilled in the art to determine in which sub-step it is convenient to add the optional additional excipient(s). An advantage of the multistep process is that there is less heat load on the active ingredient and it is easier to disperse the (typically solid) active ingredient in a previously formed molten liquid phase.

In step i) the ingredients are heated to a temperature above the temperature needed to their complete melting, expediently with mild agitation. This step can be preferably carried out in the apparatus, in which the foaming is carried out in a later step, but applying slower speed of agitation compared to the later foaming step. In the apparatus, built and designed by the inventors and used for the examples, the mixing is carried out with the speed of about 50-300 rpm. Applying more powerful agitation is not expedient, since prefoaming can occur, which is unfavourable for the addition of the remaining excipients. It is not difficult for a person skilled in the art to optimize the intensity of agitation.

The temperature used for the melting is usually 50-100°C, typically about 50-70°C.

In step ii) the active ingredient or optionally one or more additional excipient(s) is/are mixed into the melt. Due to the addition, the temperature of the mixture decreases (unless the added excipients are preheated). If the melt starts to solidify, heating is used again. In this step, the temperature is preferably kept above about 50°C, typically kept at about 50-70°C.

Optionally, after dispersing the active ingredient, in a step iii) one or more additional excipient(s) is/are mixed into the melt, while stirring and maintaining the temperature.

In the next step, the mixture is foamed by mechanically dispersing air or other inert gas (e.g. nitrogen, carbon-dioxide, argon) in the melt. Inert gas is used expediently in those cases when the active ingredient is sensitive to air (oxygen). Furthermore, various gases are suitable to the change the foam and its size distribution due to the changes in interfacial tension. Besides the given composition, the main factors determining the efficacy of the foaming are the viscosity of the mixture (depending strongly on temperature) and the way of mixing (this includes the type and geometry of the mixing element, and the intensity of the mixing).

The optimal temperature range used for foaming is determined by the viscosity of the melt. For the foaming, the melt should be viscous enough to entrap the bubbles of air or inert gases during mixing. This state can be checked by visual observation, it is unnecessary to know or determine the actual viscosity. The upper limit of the applicable temperature is determined by the efficacy of bubble entrapment and optionally the heat sensitivity of the active ingredient. The lower limit of the applicable temperature is determined by the mixability and the flowability of the final foam. The temperature-viscosity relationship varies depending on the composition, a person skilled in the art can determine the optimal temperature for a given composition. The temperature used for foaming is generally about 40-100°C or 50-100°C, typically about 40-70°C or 50-70°C. It is possible to set the same temperature for melting as used for later foaming, but it may be desirable to apply a higher temperature for melting (to accelerate the process). The foaming is preferably carried out at a temperature close to the solidification point.

For foaming, it is convenient to use a mixing element with a similar geometry of a whisk used in food industry, for example a multiple wire mixer. The optimal value of the mixing speed is greatly influenced by the geometry of the mixing element. The mixing speed is generally about 500-5000 rpm. In the apparatus, built and designed by the inventors and used specially for this purpose, the speed is typically about 500-2000 rpm in this step.

Foaming can be carried out, for example with a roto-stator mixer which is capable to disperse bubbles in the material intended to be foamed by high shear forces. In this case the gas is introduced directly under the mixing element thus the motion of the melt sucks the gas into the mixing element where it is dispersed into bubbles. It is preferable to introduce preheated gas, because cold gas can cool the system resulting in the solidification of the melt.

The optimal duration of the foaming step depends on the resultant of the factors listed above, and it is typically 0.5-20 minutes, preferably 0.5-10 minutes, more preferably 0.5-5 minutes. Too long mixing might deteriorate the foam structure, "break down" the foam.

Optimizing foaming conditions is a routine task for a person skilled in the art. At the end of foaming when the foam reaches its maximal volume (may be checked visually) the agitation is stopped and the foamed mixture is poured into moulds. The moulding step is therefore a separate step from the foaming step (as opposed to extrusion or injection moulding techniques where foam formation and moulding is carried out concomitantly).

The mould can be suppository-shaped, or a capsule shell or a metal mould at room temperature containing voids of various shapes and sizes. The foam can be also moulded into hard capsule shell having appropriate size (e.g. size 00 or 000) or plastic or aluminium blisters.

After cooling, preferably after cooling to room temperature the products are removed by opening the mould.

If capsule shells are used, the product is left in the capsule shells. During capsule filling it is possible to "overfill" the capsule bodies and the excess material is cut off before closing the capsule. In this case, the capsule also contains some gas (air), but this is not disadvantageous from the viewpoint of the dosage form (the shell quickly disintegrates in the stomach and the solid monolithic foamed dosage form is released).

If blister, e.g. plastic or aluminium blister is used, the product is left in the blister. We have found that in this case the foam completely fills blister cavities and solidifies without contraction (this is not characteristic to any known blistered product).

We can use a cooling system to aid the solidification of the foamed melt, but it can be enough to allow the foamed melt to cool down on its own. Based on our experiments the pre- and aftercooling of the mould or capsule shell is not necessary if the temperature of melted and foamed material is higher than the solidification point by a few Celsius degree. This way the foamed melt stabilizes quickly in the moulds or capsule shells without phase separation, and the distribution of the gas bubbles remains random. Preferably, to solidify the foamed and moulded melt, it is allowed to cool to room temperature on its own.

We have found that the structure of the foam is stable enough to remain unchanged during moulding. Considerable change in the volume does not occur, the bubbles do not expand or release from the system (slight changes might occur due to the difference in the temperature). Without wishing to be bound by any theory, we assume that such type of change occurs in the structure of the foam which results in the coalescence (merging) of some bubbles. This coalescence may also originate from dispersing the gas mechanically, since the high rotation speed of the mixing element may create transitional channels of gas behind the wires, these channels may separate into individual cells. Cells may merge together or break into smaller cells due to the heavy agitation. Coalescence in the resting foam that is ready to be moulded becomes the dominant process. Coalescence can be facilitated by the addition of aqueous glycerol or ethanolic solution or pure alcohol alone. The presence of these cavities or short channels created by the merging of some bubbles can be seen on the MicroCT picture (see Figure 12). This change essentially does not cause changes in the volume of the foam, and substantially does not alter the dissolution properties or the hardness of the dosage form.

The process is carried out essentially at constant pressure, preferably at atmospheric pressure. Excess pressure is applied, if desired, to introduce gas into the system (depending on the type of mixing) at the value of at most about 400 kPa, preferably at most about 150 kPa, more preferably at most about 100 kPa or 50 kPa. This pressure is significantly lower than the pressure used in an extruder or injection moulding apparatus (which is about 4-40 MPa); it serves only to introduce gases and not suitable to dissolve/press gas into the melt.

The process is preferably carried out at atmospheric pressure; more particularly, the pressure during the process is preferably about 101-250 kPa, more preferably about 101-200 kPa, particularly preferably about 101-150 kPa. The presence of greater pressure than the atmospheric pressure is essentially related to the gas introduction, it is present at the site of the gas introduction, and away from this site the pressure gradually decreases to the atmospheric pressure is the system.

Regarding the fact that there is no substantial pressure change, the foam, during moulding and solidification, preserves its density obtained at the end of the foaming step. This has the advantage (besides the fact that high pressure apparatuses are not needed), that the structure of the foam is stable, as described above. In addition, in case of crystalline active ingredients, no polymorphic changes occur.

The apparatus

The process can be carried out in any apparatus that is suitable for heating to the desired temperature, regulating the temperature and mechanically foaming.

The process is preferably carried out in an apparatus which is equipped with a thermostat, a mixing element and an outlet plug. The mixing element must be capable to disperse air or inert gases. If air is dispersed, the apparatus may be an open system. If an inert gas is to be dispersed in the melt, the apparatus must be equipped with a suitable inlet opening as well, to introduce gas, and in this setup the apparatus is a closed system. Preferably the mixing element used is a whisk type element. In this setup the gas is introduced from the top of the vessel. Furthermore, roto- stator mixing elements may also be applied. In this setup, gas (either air or inert gas) is introduced under the mixing element. (In this case, there is a need for sufficient pressure to introduce the gas, as described above.) The outlet plug has to be wide enough so that it does not destroy the structure of the foam. The apparatus, constructed by the inventors and used for the preparation of the formulations of the examples contains a thermostatic tank which is a jacketed vessel, in which jacket a helical coil heat exchanger is placed to allow the circulation of the thermostating fluid, preferably water.

The top of the apparatus is open and a mixing element is placed from the top into the interior of the tank. The mixing element is a whisk type element consisting of four wires, which is completely submerged into the thermostatic tank through the opening on the top. The wires are located at the same distance from each other on the shaft of the stirrer. We have found that the efficacy of the foaming is increased if the mixing element is not centrally located but is asymmetrically positioned relative to the axis of rotation of the tank. The mixing element is connected to a variable speed electric motor having a speed range of 50-4000 rpm.

The bottom of the thermostatic tank is equipped with an outlet plug to discharge the product. The bottom of the thermostatic tank and the plane of the plug is at the same level to prevent material deposition.

When designing and building the outlet opening, we have surprisingly found that it was unnecessary to cover the entire opening with a heat-exchanger to prevent plug formation. It was enough to heat the upper one-quarter of the opening.

We note that the units of the apparatus are well-known in themselves, and are wildly used in the field of chemical industry, their functional formation, the selection of their constituting materials and their dimensioning are routine tasks for a person skilled in the art, and therefore their detailed description is not disclosed herein.

Characterization of the product

The final product was characterized by following methods. Density measurements

The apparent density of the gastroretentive dosage form according to the invention can be determined by simply measuring the mass if the exact volume of the mould is known (for example in the case of capsules). For instance, the average volume of the body of the capsule (into which the foamed melt is later filled) can be determined by filling it with a material with a known density. It is a criterion to use a material which does not hydrate or shrink the wall of the capsule. After closing the capsule with a cap, the total weight can be measured and the available volume for the foamed melt can be calculated in the hard capsule. If the exact volume is not known, pycnometer can be used to determine the apparent density. For this measurement, a liquid is used in which the dosage form does not dissolve or dissolves only with a negligible dissolution rate, for example, liquid paraffin. Submersion of the samples can be achieved using a metal sinker with a known volume. In this case, the volume of the displaced liquid is equal to the sum of the predetermined volume of the sinker and the volume of the sample. Dissolution tests

The dissolution tests were carried out in accordance with the regulations of the Hungarian Pharmacopoeia (see Ph. Hg. VIII^th edition, Volume IV.A, 2.9.3. Dissolution test for solid oral dosage forms), as detailed below.

The tests were performed in 900 ml of pH: 1.2 hydrochloric acid, sodium chloride solution as prescribed in the Hungarian Pharmacopoeia, for 10 hours (600 minutes) by rotating paddle method. Samples were automatically collected into 20 ml test tubes and were diluted ten times with distilled water, and were filtered through 0.25 micron syringe filters. For metronidazole, the detection was done spectrophotometrically at 278 nm.

Dissolution tests were also used to the check the floatability and determine the floating time of the dosage forms. The dosage forms of the present invention float throughout their lifespan, i.e., in the drug dissolution test from the start, until complete drug release.

Electron microscopic imaging

Electron microscopic pictures were captured to investigate the foam structure. Pictures were captured with a Hitachi TM3030Plus Tabletop Microscope, under vacuum, with 5 kV acceleration voltage, with a magnification range between 18 and 40x magnification. Samples were bended to break them and the fracture surface was recorded in scanning mode. The sizes of the bubbles were measured by GIMP 2.0 software, measuring the diameter of 100 bubble cross-sections, and the average size and the standard deviation were calculated using MS Excel. The software of the microscope allowed different minimal magnifications for the different samples. It was aimed to capture the total fracture surface within the whole field of view, but it was only available at 18x or 20x magnifications.

MicroCT imaging

MicroCT picture was captured by the following method. Following the foaming step, as a part of the required sample preparation, a polyethylene tube (inner diameter: 5.0 mm, wall thickness: 0.5 mm) was merged into the fresh foam and the tube was allowed to be completely filled with the foam. After closing the free end of the tube, it was removed from the vessel and the foam inside was allowed to cool and solidify in horizontal position. The sample was later cut into 5-6 mm long cylinders. Samples were scanned using a Skyscan 1172 X-ray microtomograph (Bruker μ( ). Scanning was carried out at a resolution of 4.86 μιη isometric voxel size (70 kV, 124 μΑ). Average scan duration was 25 min. After the acquisition, raw images were reconstructed by using N econ software (v.1.7.1.6., Bruker μ(ΖΤ).

Texture analysis

To characterize the dosage form, texture analysis was carried out on dry and wet samples. The tests carried out were based on the pharmacopoeia regulations, see Ph. Hg. VII Ith edition, Volume I., 2.9.8 (Resistance to crushing of tablets) but with a different and better resolution method, the so called texture analysis. For the tests, Brookfield CT3 texture analyser was used. During the tests both dry samples and wet samples - that had been placed into the dissolution media and taken out at different times - were investigated to determine the resistance of the foams when they are placed in an aqueous environment (for instance gastric juice).

During measurements the samples were placed on a sample holder metal plate lying on their side and were compressed with a probe (plexi cylinder, diameter: 50.8 mm, height: 20 mm). The maximum compression force was 45 N (4500 grams) in each test. At room temperature (22°C), the dry samples did not break or crack. Based on these results we can only state that the moulded solid dosage form has a breaking strength of at least 45 Newtons.

Adding 20 drops of 5 m/m% Sicovit Tartrazine solution to the 900 ml solution of hydrochloric acid and sodium chloride made visible the diffusion pathway of the water within the foam. Samples were left in the dissolution vessel for 60, 180, 300 and 600 minutes simulating the gastric environment. Samples were removed carefully from the medium with a plastic sieve cloth, and after removing as much excess water as possible, texture analysis was done as described above.

An alternative investigating method for physical characterization is the Resistance to crushing of tablets, which gives the minimum crushing force needed to break or crush the dosage form. Examples

The following examples are meant to illustrate the present invention. Table 1: Compositions and densities of the formulations of Examples 1-5

The formulations of examples 1-5 were prepared in the apparatus detailed above with the following protocol.

The total mass of the mixtures that were foamed was 40 grams. The temperature of the thermostat was set to 65°C and after weighing PEG4000 and stearic acid according to the ratios presented in Table 1, they were loaded without premixing into the thermostatic tank, which already contained the mixing element. After complete melting (checked visually) the total amount of Labrasol and metronidazole was added. The mixing speed was set to 300 rpm, the thermostat temperature was set to 53°C. Dispersing was continuous until the temperature in the jacket reached 53°C. Dispersing was continued for 5 more minutes, in order to equalize the temperatures. Foaming was done thereafter, by setting the mixing speed to 2000 rpm. Gas was continuously dispersed into the viscous melt and the foaming was easy to follow visually. After reaching the maximal volume of the foam, the mixing was stopped and the foamed product was discharged continuously through the outlet opening into size 00 hard gelatine capsules and were allowed to cool therein. The final products were characterized by the tests described above. The density values are presented in Table 1. Dissolution profiles are depicted in Figure 1.

As to the main features of the products, we note the following.

The composition of Example 1 was the sample that produced the fastest dissolution rate, with the apparent density of 0.89 g/ml after foaming. However, in the acidic medium it eroded very soon, after 60 min it was found to fall into fragments, and after 180 minutes some of the samples were completely dissolved. Specifically, the lifespan of this dosage form, during which it floated and released its drug content was 180±20 minutes. The electron microscopic image of the surface, after splitting the samples is shown in Figure 3. The size of the bubbles was found to be 254±83 microns.

For the composition of Example 2, after 60 minutes the dosage form still had a non-wetted inner core, after 180 minutes, however, there were samples which were split and eroded. Nevertheless, they still contained solid and dry cores. After 300 minutes the dosage form was completely wetted, and had no hard and resistant inner core. The floating time of these dosage forms were 6 hours±30 mins. During this time the active ingredient was completely released. The electron microscopic image of the surface after splitting the samples is shown in Figure 4. The size of the bubbles was found to be e 193±63 microns.

For the composition of Example 3, during 180 minutes, the solid foam had a well detectable inner part that was crushable when applying external compression forces. At the end of the dissolution tests significant signs of erosion and complete wetting were seen, while it was still floating. Complete drug release was found after 10 hours. The electron microscopic image of the surface after splitting the samples is shown in Figure 5. The size of the bubbles was found to be 231±113 microns.

For the composition of Example 4, during 300 minutes, the solid foam had a well detectable inner part that was crushable when applying external compression forces. Signs of erosion was visible after 600 minutes, the sample was completely wetted but it more or less retained its shape. The samples remained floating even at the end of the dissolution test. 85% of the drug was released within 600 minutes. The electron microscopic image of the surface after splitting the samples is shown in Figure 6. The size of the bubbles was found to be 67±25 microns. The composition of Example 5 provided the second fastest drug release, and the total amount of the active ingredient was released within 7 hours. However, it was challenging to create a foam because of the low stearic acid content of 2.5%. At the beginning of the foaming step the foam formation was not stable, the volume of the foam slowly increased. When the melt was somewhat foamy, stirring of the foam into the lower regions of the melt was possible. This was observed by visual tracking. The lifespan of this dosage form, during which it floated, was 6 hours ± 30 minutes. The electron microscopic image of the surface after splitting the samples is shown in Figure 7. The size of the bubbles was found to be 318±172 microns.

The products of examples 1-5 are solid at room temperature. Their strength is maintained at a compression force of 45N (4500 grams), they do not break, they do not crack.

Table 2: Compositions and densities of the preparations of Examples 6-9

The formulations of examples 6-9 were prepared with the same protocol as mentioned for Examples 1-5, with the difference that 5 minutes after dispersing the active ingredient the aqueous solutions of the alcohols were added in a manner that 1 ml of foam modifier (30 vol% ethanol, 30 vol% glycerol or 70 vol% glycerol) was added to a mixture having 40 g total weight. The duration times and temperatures used were the same as those mentioned above.

The final products were characterized by the tests described above. The density values are presented in Table 2. Dissolution profiles are depicted in Figure 2.

In connection with the effect of the foam modifiers we mention the followings.

Generally, both alcohols increased the average bubble sizes and decreased the density. In the case of Example 6, 1 ml of 30 vol% ethanol was added to the 40 grams of the composition of Example 3, i.e. 7.5 ml/kg of pure ethanol and 17.5 ml/kg of water were added, in this way the average bubble size increased from 231±113 μιη (measured in Example 3) to 303±170 μιη, and the density decreased from 0.82 g/ml to 0.71 g/ml compared to Example 3. In the case of Examples 7-9, the composition of Example 4 was modified by adding ethanol and water in the amount of 7.5 ml/kg and 17.5 ml/kg, then by adding 7.5 ml/kg of glycerol and 17.5 ml/kg of water, finally by adding 17.5 ml/kg of glycerol and 7.5 ml/kg of water. The average diameters of the bubbles increased from 67±25 μιη to 134±55 μιη, 180±99 μιη and 197±84 μιη respectively, the densities decreased from 0.93 g/ml to 0.79 g/ml, 0.71 g/ml and 0.78 g/ml respectively.

The electron microscopic image of the surface after splitting the samples, is shown in Figures 8-11. The electron microscopic pictures show that the ethanolic aqueous solution does not significantly influence the distribution of the bubbles, only their sizes were increased. The glycerol-water mixture has probably inhibited the solidification of the foamed melt, because on the periphery of the dosage form smaller bubbles, while in the central region larger bubbles were recorded.

Based on the results of the dissolution tests (Figure 2) it can be seen that both alcohols decreased the dissolution rates of the active ingredient form the dosage form. This effect is surprising, since these alcohols are known in pharmaceutics as pore formers, and it was expected that the active ingredient would be dissolved faster through the channels they create.

The preparations of examples 6-9 floated on the top of the dissolution media until the end of the dissolution test (10 hours). In the case of Example 6, only 87% of the active ingredient was released in 10 hours. In the case of Examples 7-9 only 67%, 73.5% and 74.4% of the active ingredient was released in 10 hours, this means that the dissolution retarding effect of the 30% or 70% glycerol solution is lower compared to that of the ethanolic solution. We assume that the explanation for this is that glycerol is a much more hygroscopic substance than ethanol, it simply increases water permeation into the dosage form, favouring its hydration.

The formulations according to Examples 6-9 are solid at room temperature, at 20-25°C. Their strength is maintained at a compression force of 45N (4500 grams), they do not break, they do not crack.

Dosage forms of Examples 1-9 are solid at 37°C. Table 3: Compositions of the preparations of Examples 10-12

The compositions of Examples 10-11 were prepared with the same protocol as mentioned for Examples 1-5.

In the case of Example 10, we have found that foaming was successful at the beginning of the foaming step but later the mixing element broke the foam. By optimizing the duration and the intensity of the mixing it is assumed that proper foamed dosage form could be prepared. In further experiments, more suitable wax concentration and jacket temperatures could probably be found that could lead to better foam formation.

In Example 11, the foam generation was slower, the foam remained stable for longer time, but finally the mixing element also broke down the foam.

For the preparation of Example 12 the same protocol as mentioned for Examples 1-5 was used, with the only difference that the heating of the thermostat (temperature of the jacket) was set to 47°C. Similarly to Example 11, the foam generation was slow but the foamed melt was stable enough to be moulded. However, the foam was too viscous to completely fill the cavities of the mould, so determination of the apparent density was not possible in this case.

In further experiments, more suitable stearoyl macrogol-glyceride concentration could probably be found that could lead to better foam formation.

Claims

1. Prolonged-release gastroretentive, moulded, solid dosage form, which has a monolithic foam structure consisting of a gas phase and a solid phase comprising a solidified melt, wherein the gas phase is contained in the bubbles dispersed in the solid phase, and the solid phase comprises an active ingredient, at least one pharmaceutically acceptable hydrophilic polymeric component, at least one pharmaceutically acceptable hydrophobic component and optionally one or more additional pharmaceutically acceptable excipient(s), wherein the active ingredient is present optionally in the form of separate particles, and which is solid at 37°C and has a density of less than 1 g/ml.

2. The prolonged-release gastroretentive dosage form according to claim 1, wherein the pharmaceutically acceptable hydrophobic component is present in an amount of 1-50 wt% based on the total weight of the composition.

3. The prolonged-release gastroretentive dosage form according to claim 1 or 2, wherein the pharmaceutically acceptable hydrophobic component has a melting range within the temperature range of 25-90°C.

4. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 3, wherein the pharmaceutically acceptable hydrophobic component(s) is/are selected from the group consisting of: fatty acids, fatty alcohols, fatty acid esters, including pharmaceutically acceptable waxes, fats, cholesterol, polymers and copolymers of caprolactone and lactic acid, and pharmaceutically acceptable paraffins.

5. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 4, wherein the pharmaceutically acceptable hydrophobic component(s) is/are selected from the group consisting of: stearic acid; cetyl, cetyl stearyl and stearyl alcohol; and white and yellow beeswax.

6. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 5, which is a capsule.

7. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 6, which is in a blister-moulded form.

8. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 7, wherein the pharmaceutically acceptable hydrophilic polymeric component is present in an amount of 10-95 wt% based on the total weight of the composition.

9. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 8, wherein the pharmaceutically acceptable hydrophilic polymeric component has a melting range within the temperature range of 40-80°C.

10. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 9, wherein the pharmaceutically acceptable hydrophilic polymeric component(s) is/are selected from the group consisting of: polyethylene glycols, stearoyi macrogolglycerides, copovidone, povidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl alcohol- polyethylene glycol graft copolymer, dextrans, poloxamers, ethylene glycol and vinyl alcohol graft copolymer, methacrylic acid-ethyl acrylate copolymer, ethyl vinyl acetate, ethylene glycol palmitostearate, polyoxyethylene stearates; macrogol cetostearyl, lauryl, oleyl, stearyl ethers.

11. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 10, wherein the active ingredient is selected from the group consisting of: furosemide, famotidine, ranitidine, metronidazole, captopril, levodopa, atenolol, metoprolol succinate, verapamil, prazosin, diazepam, tramadol, baclofen, isradipine, curcumin, quercetin, silymarin, ubidecarenone, chrysin, diosmin, hersperidin, oxerutin, Ginkgo biloba dry extract, and mixtures thereof.

12. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 11, wherein the additional pharmaceutically acceptable excipient(s) is/are selected from the group consisting of: foam modifiers, nonionic surfactants, solubility enhancers.

13. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 12, whose monolithic foam structure is characterized in that it contains substantially spherical or deformed spherical bubbles, and cavities formed by merging of bubbles.

14. The prolonged-release gastroretentive dosage form according to claim 13, wherein the cavities formed by merging of bubbles are channel-like, the bubbles and cavities are homogeneously distributed and are not open to the outside world, and the outer surface does not form a structurally distinct shell.

15. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 13, which, in the dissolution test for solid dosage forms, floats on the surface of the release medium from the start of the test, and maintains its buoyancy until the end of the drug release period, and the duration of the drug release period is at least 3 hours, preferably at least 5 hours.

16. The prolonged-release gastroretentive dosage form according to any one of claims 1 to 15, wherein the average diameter of the bubbles is 5-500 μιη.

17. Process for the preparation of the prolonged-release gastroretentive dosage form according to any one of claims 1 to 16, comprising the steps of: a) forming a melt from the active ingredient, the at least one pharmaceutically acceptable hydrophilic polymeric component, the at least one pharmaceutically acceptable hydrophobic component, and optionally one or more additional pharmaceutically acceptable excipient(s), which melt comprises the active ingredient in dissolved and/or in dispersed form, b) mechanically dispersing a gas in the mixture obtained in step a), and c) moulding and solidifying the foam obtained in step b).

18. The process according to claim 17, wherein step a) comprises: i) melting the at least one pharmaceutically acceptable hydrophilic polymeric component and the at least one pharmaceutically acceptable hydrophobic component, ii) dispersing the active ingredient in the melt obtained in step i), and optionally adding one or more additional excipient(s) in step i) and/or in step ii) and/or after dispersing the active ingredient in a separate step iii).

19. Prolonged-release gastroretentive, moulded, solid dosage form, which can be prepared by the process of claim 17 or 18.

20. Mouldable foamed melt, which comprises dispersed gas in a melt comprising an active ingredient, at least one pharmaceutically acceptable hydrophilic polymeric component, at least one pharmaceutically acceptable hydrophobic component, and optionally one or more additional pharmaceutically acceptable excipient(s), wherein the active ingredient is present optionally in the form of separate particles, and which has a density lower than 1 g/ml.

21. Process for the preparation of the mouldable foamed melt of claim 20, comprising the steps of: a) forming a melt from the active ingredient, the at least one pharmaceutically acceptable hydrophilic polymeric component, the at least one pharmaceutically acceptable hydrophobic component, and optionally one or more additional pharmaceutically acceptable excipient(s), which melt comprises the active ingredient in dissolved and/or in dispersed form, b) mechanically dispersing a gas in the mixture obtained in step a).