WO2023214018A1 - Gastro-retentive swellable sustained release composition - Google Patents

Abstract

The present invention relates to a gastro-retentive swellable sustained release composition comprising: a swellable active phase comprising at least one active ingredient and from 20% w/w to 98% w/w, preferably from 30% w/w to 95% w/w, of a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, said active phase being swellable at acidic pH; optionally a non-active phase; and at least one delayed and/or insoluble pH independent film coating phase, the percentages being calculated with respect to the total weight of the composition.; and to the use of a substituted acrylic acid copolymer swellable at acidic pH and soluble at pH above 5.5 alone as a matrix in a gastro-retentive sustained released pharmaceutical composition for increasing its gastric residence time to at least 12h, at least 24h, at least 48h, at least 72h, at least 3 days, at least 4 days, at least 7 days.

Description

GASTRO-RETENTIVE SWELLABLE SUSTAINED RELEASE COMPOSITION

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition for gastro-retentive swellable sustained release, methods of manufacture the same and uses thereof.

BACKGROUND OF THE INVENTION

Over the past few decades, many efforts have been made to improve the bioavailability of drug products after oral administration. A good example of this is the drug delivery systems for gastro-retentive drugs, which have emerged to improve the bioavailability and efficacy of drugs with a narrow absorption window in the gastrointestinal tract (Gl tract) and/or to promote local activity in the stomach and duodenum. Several strategies are used to increase gastric stay time, namely bio-adhesive or muco-adhesive systems, extensible systems, high density systems, floating systems, superporous hydrogels and magnetic systems.

Various pharmaceutical compositions formulated in the form of floating tablets are known in the state of the art. For example, floating tablets were obtained by acting on the density of the total composition, for example by varying the weight ratios between different excipients polymers such as carboxymethyl cellulose, ethyl cellulose, cross-linked povidone, or chitosan, a compound well known for its low density and muco-adhesive properties.

Another technical solution was to use, among the excipients, a porous mineral material such as calcium silicate, in which air was trapped in the pores, the tablets are then covered with a polymer such as hydroxypropyl cellulose or ethyl cellulose intended to retain air within the porous mineral matrix.

Gelatin capsules filled with an inert gas or with a substance containing inert gas bubbles were also used in the prior art.

Another technical solution was to implement hollow polycarbonate resin microspheres loaded with the active ingredient or hollow microspheres containing the active ingredient in the presence of Eudragit® S, which are perfect spheres from 500 to 1000 pm diameter capable of floating for more than twelve hours in an acidic medium in a 0.02% Tween-20 solution.

Another strategy was to obtain a decrease in the density of the tablet at the time of use, by the incorporation in the pharmaceutical composition of compounds capable of releasing a gas that remains, at least in part, trapped within this tablet and which will thus allow it to float on the surface of gastric juice, in the stomach.

Patent applications EP 0795324 and EP 0235718 disclose multilayer gastric pharmaceutical compositions comprising an active ingredient and hydrophilic polymers.

PCT Patent application No WO 98/47506 describes a gastric-residence pharmaceutical composition comprising an active ingredient of the benzamide family in combination with a hydrophilic polymer or porous mineral matrix and a carbon dioxide generating system. Such a pharmaceutical composition may be appropriate for low doses of the active ingredient, especially when the active ingredient dose in the tablet does not exceed 500 mg, as is generally the case for benzamides. On the other hand, a change in the dissolution profile of the active ingredient was observed for such compositions in comparison with conventional pharmaceutical compositions which did not contain a gas-generating system. In addition, the fact that the gas-generating system and the active ingredient are in the form of an intimate mixture is likely to favor interactions between the active ingredient and the other ingredients of the pharmaceutical composition, which may lead to at least partial chemical alteration of the active ingredient and consequently to a significant decrease in the therapeutic efficacy of the composition as well as long-term conservation problems.

ICHIKAWA et al. (1991 , Journal of Pharmaceutical Sciences, vol. 80, no. 11 , pages 1062- 1066) described a floating tablet consisting of a nucleus containing a prolonged-release pharmaceutical composition covered by a first layer comprising an effervescent couple, this first layer being itself covered with a polymer film capable of retaining a gas. The water or gastric juice penetrates through the outer polymer film and comes into contact with the effervescent couple which then generates the carbon dioxide. By releasing into the tablet, the carbon dioxide will inflate the tablet in the form of a “micro-balloon” capable of floating in the stomach. Such a tablet has the disadvantage of being difficult to industrialize and is also expensive to manufacture. In addition, coating the effervescent couple layer with the polymer film requires the use of solvents other than water, such as ethanol, dichloromethane or acetone, to prevent the effervescent couple from reacting at the time of manufacture.

In addition to the cost, the use of organic solvents is an important problem, since they have to be eliminated in the final stages of manufacture of the tablet, in order to meet the increasing administrative constraints required for a marketing authorization for a proprietary medicinal product.

The present invention addresses the many disadvantages identified above prior to the state- of-the-art gastric and floating compositions and provides a new pharmaceutical composition comprising at least one active phase comprising at least one active substance and one acrylic acid copolymer.

Thus, a first subject-matter of the invention consists of a gastro-retentive swellable sustained release composition as defined in the claims.

SUMMARY OF THE INVENTION

The present inventors have now found a way to design and produce a gastro-retentive swellable sustained release composition able to release for more than 12 hours, more than 24 hours, more preferably for days, an active ingredient exhibiting either a low or irregular bioavailability, due for example to slow dissolution, or either exhibiting a small absorption window, particularly at gastric level, or exerting a medicinal action at the gastric level.

A first object of the invention thus relates to a gastro-retentive swellable sustained release composition comprising:

- a swellable active phase comprising at least one active ingredient and from 20% w/w to 98% w/w, preferably from 30% w/w to 95% w/w, of a substituted acrylic acid copolymer soluble at pH above 5,5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, said active phase being swellable at acidic pH;

- optionally a non-active phase; and

- at least one delayed and/or insoluble pH independent film coating phase, the percentages being calculated with respect to the total weight of the composition.

A second object of the invention pertains to a method of manufacturing the gastro-retentive swellable sustained release composition of the invention, comprising the steps of: a) Providing at least one active ingredient;

Optionally dry and/or wet granulating at least one active substance and optionally pharmaceutically acceptable excipients to obtain at least one active ingredient; b) Providing a substituted acrylic acid copolymer soluble at pH above 5.5, alone and/or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients; c) Optionally film coating the at least one active ingredient with at least one delayed and/or insoluble pH independent film coating phase; d) Blending the optionally film coated active ingredient with the ingredients of step b), e) Tableting the blend obtained in step d), f) Optionally, film coating the obtained tableted blend obtained at step e) with at least one delayed and/or insoluble pH independent film coating agent; at least one of steps c) or f) being present.

A third object of the invention relates to the gastro-retentive swellable sustained release composition of the invention for use in the treatment of chronic diseases in humans or animals for example asthma, lung or liver diseases, hypertension, cancer or metabolic diseases such as for example obesity and/or diabetes.

Finally, one last object of the invention pertains to the use of a substituted acrylic acid copolymer soluble at pH above 5.5 alone as a swellable matrix in a gastro-retentive sustained released pharmaceutical composition for increasing its gastric residence time to at least 12h, at least 24h, at least 48h, at least 72h, at least 3 days, at least 4 days, at least 7 days.

FIGURES

Figure 1 : Photographs of a gastro-retentive swellable tablet after immersion in 250 ml of 0.1 N HCI at 37°C_sampling time T0+24hours (fig.1a) and T0+7days (fig.1b, fig.1c) presents a comparative of gastro-retentive swellable tablets before immersion and after sampling time T0+7days of immersion. Fig 1d presents the characteristics table of tablet thickness and tablet diameter for each sampling time.

Figure 2: In vitro dissolution profile of gastro-retentive swellable_tablets according to example 1. On the y-axis, percentage of active ingredient Metformin released. On the x- axis, time of release after contact of the tablets with an in vitro dissolution medium.

Figure 3: In vitro dissolution profile of gastro-retentive swellable sustained release tablets according to example 2. On the y-axis, percentage of active ingredient Esomeprazole released. On the x-axis, time elapsed after contact of the tablets with an in vitro dissolution medium. Figure 4: In vitro dissolution profile of gastro-retentive swellable_tablets according to example 3. On the y-axis, percentage of active ingredient Gliclazide released. On the x- axis, time of release after contact of the tablets with an in vitro dissolution medium.

Figure 5: In vitro dissolution profile of gastro-retentive swellable_tablets according to example 4. On the y-axis, percentage of active ingredient Fenofibrate released. On the x- axis, time of release after contact of the tablets with an in vitro dissolution medium.

Figure 6: In vitro dissolution profile of gastro-retentive swellable_tablets according to example 5. On the y-axis, percentage of active ingredient Metformin released. On the x- axis, time of release after contact of the tablets with an in vitro dissolution medium.

Figure 7: Schematic representation of different tablet dosage forms (double core tablet on fig 7a, bi-layer tablet on fig 7b and tri-layer tablets on fig 7c and 7d.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In the following, terms as used herein are defined in their meaning.

The use of the articles “a”, “an”, and “the” in both the description and claims are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The terms “comprising”, “having”, “being of”, “including”, and “containing” are to be construed as open terms (i.e., meaning “including but not limited to”) unless otherwise noted. Additionally, whenever “comprising” or another open-ended term is used in an embodiment, it is to be understood that the same embodiment can be more narrowly claimed using the intermediate term “consisting essentially of” or the closed term “consisting of”.

The term “about” or “ca.” has herein the meaning that the following value may vary for ± 10%, preferably ± 5%, more preferably ± 2%, even more preferably ± 1%.

Unless otherwise defined, “%” has herein the meaning of weight percent (wt%), also referred to as weight by weight percent (w/w%).

By “combination” or “in combination with,” it is intended to imply that the excipients or the active ingredients may be formulated together, either as an intimate mixture or not as long as they are part of the same final composition for administration.

The term “matrix” means a continuous polymeric network that is formed from the first contact with the biological liquid. The orally administered matrix composition is intended to ensure all or part of the sustained release of active substance(s) during the time after administration in humans or animals. Matrix forms are characterized by the formation of a continuous polymeric network from the first contact with the biological liquid. The most widely distributed matrix pharmaceutical form is in the form of a film coated core or film coated tablet.

The active substance is designated by their base form. However, in the meaning of the present disclosure, it includes also salts, isomers, tautomers thereof.

Herein after, the present disclosure is described in further detail and is exemplified.

The pharmaceutical composition

In a first aspect, the present disclosure relates to a gastro-retentive swellable sustained release composition comprising:

- a swellable active phase comprising at least one active ingredient and from 20% w/w to 98% w/w, preferably from 30% w/w to 95% w/w, of a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, said active phase being swellable at acidic pH;

- optionally a non-active phase, and

- at least one delayed and/or insoluble pH independent film coating phase, the percentages being calculated with respect to the total weight of the composition.

The gastro-retentive swellable sustained release composition according to the invention is a composition which is able to float very quickly when placed in gastric medium and is not erodible, allowing a residence in gastric medium for several days includes. In particular, this composition is deprived of any super-disintegrant, in particular it is deprived of crospovidone and/or croscarmellose. When placed in the gastric medium, the composition swells immediately, i.e. in less than 60 seconds, preferably less than 30 seconds, with a nonsignificant erosion allowing it to float.

The gastro-retentive swellable sustained release composition according to the invention presents a volume increase at least of 30% to 70%, preferably 40% to 60% after immersion in a gastric medium.

The gastro-retentive swellable sustained release composition according to the invention presents a swelled stable form when immersed in a gastric medium during at least 12h, at least 24h, at least 48h, at least 72h, at least 3 days, at least 4 days, at least 7 days. Said composition comprises at least one delayed and/or insoluble pH independent film coating phase. Said delayed and/or insoluble pH independent film coating phase is partially insoluble at gastric pH conditions, i.e. between pH 1.2 and 4.5, and helps to regulate the release of the active ingredient over time. Thus, this composition is intended in particular for long-acting release of the active ingredient administered orally. It also makes it possible to delay the administration of the composition up to a weekly administration and thus to enhance patient compliance.

According to the invention, the swellable active phase is coated with the at least one delayed and/or insoluble pH independent film coating phase, or only the at least one active ingredient, preferably under the form of granules or microgranules, is coated with the at least one delayed and/or insoluble pH independent film coating phase.

In a specific embodiment, the whole active phase is coated with the at least one delayed and/or insoluble pH independent film coating phase. In another embodiment, in the active phase, the active ingredient is under the form of granules or microgranules which are coated with the at least one delayed and/or insoluble pH independent film coating phase.

Delayed and/or pH independent film coating phase

The at least one delayed and/or pH independent film coating phase is partially insoluble at gastric pH conditions and comprises a delayed and/or pH independent film coating phase and excipients chosen among plasticizers, anti-tacking agents, pore-forming agents, emulsifiers, muco-adhesive agents.

The delayed and/or pH independent film coating phase is chosen among the film coating agents insoluble in aqueous medium (independent pH solubility) and, in particular, the at least one delayed film coating agent is chosen from the list consisting of substituted acrylic acid copolymers, cellulose phthalate acetate, polyvinyl acetophthalate (OPADRY® OY A or equivalent), hydroxypropyl cellulose succinate (AQOAT® or equivalent), and mixtures thereof. The cellulose phtalate substances may be chosen from among the phthalates of hydropropylmethylcellulose (also known as hypromellose phthalate), the substituted acrylic acid copolymers are chosen from ethyl acrylate and methyl methacrylate copolymer (Eudragit® NE and/or NM), ammonio methacrylate copolymer type A or B (Eudragit® RL and/or RS), ethylcellulose polymers, polydimethylsiloxanes (PDMS) and its derivatives, and mixtures thereof.

Since the composition is swellable, in order to avoid a break in the film coating when in contact with gastric juice, the at least one delayed and/or pH independent film coating phase may comprise a plasticizer. Examples of plasticizers usually used in coating films are triethyl citrate (TEC), dibutyl sebacate (DBS), polyethylene glycol, polysorbate and mixtures thereof.

Conventionally, the at least one delayed and/or insoluble pH independent film coating phase may comprise anti-caking agents such as talc, glycerol monostearate and/or emulsifiers such as polysorbate.

To regulate the release of the active ingredient, the at least one delayed and/or pH independent film coating phase may also comprise pore-forming agents which allow formation of channels that ensure the release mechanism of the active ingredients while maintaining the integrity of this coating. Examples of pore-forming agents usually used in coating films are colloidal silica, polyethylene glycol, polyols such as mannitol, and saccharides such as lactose, carbonate or bicarbonate such as calcium bicarbonate.

To avoid the release during gastric emptying, the delayed and/or insoluble pH independent film coating agent may also comprise muco-adhesive agents.

The swellable active phase

As mentioned above, to allow the swellability and floatation of the composition according to the invention, the active phase forms a matrix which comprises at least one active ingredient and from 20% w/w to 98% w/w, preferably from 30% w/w to 95% w/w, of a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients.

The use of a substituted acrylic acid copolymer soluble at pH above 5.5 as a matrix including the active ingredient which is swellable at gastric pH conditions, makes it possible to obtain a composition which expands and floats without using gas generating agents and which is not erodible. The swelling of the matrix makes it possible to reduce sufficiently the density of the pharmaceutical composition including it. Further, its swelling rate is fast enough for the pharmaceutical composition to float rapidly when contacting the gastric fluid causing the increasing gastric residence time of said pharmaceutical composition. Since the substituted acrylic acid copolymer is not soluble at gastric pH conditions, it would not erode, and would float during several days.

The particularity of this invention is that the active phase, thanks to its matrix of substituted acrylic acid copolymer, allows to remain at the gastric level by floating without using components generating off-gas as the prior art. Thus, chemical alterations due to interactions between gas-generating system and active ingredient, decrease of the therapeutic efficacy of the pharmaceutical composition and stability issues encountered with the gas-generating system are avoided with the present invention. In an embodiment, the active phase is deprived of any gas generating components. In another embodiment, the total composition is deprived of any gas generating components.

In a particularly preferred embodiment, the substituted acrylic acid copolymer soluble at pH above 5.5 is chosen from anionic copolymers of acrylic acids such as Methacrylic Acid - methacrylate Copolymer (1 :1) and its derivatives (for example marketed under the trademark Eudragit® L100-55), Methacrylic Acid - Methyl methacrylate Copolymer (1 :1) and its derivatives (for example marketed under the trademark Eudragit® L100), Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2) and its derivatives (for example marketed under the trademark Eudragit® S100), Methacrylic Acid - Ethyl acrylate Copolymer (1 :1) and mixtures thereof. Methacrylic Acid - Ethyl acrylate Copolymer (1 :1) and Methacrylic Acid - Ethyl acrylate Copolymer (1 :1) Type A refer to the same copolymer.

The substituted acrylic acid copolymer is present in an amount from 20% w/w to 98% w/w in the pharmaceutical composition. The large quantity of this substituted acrylic acid copolymer guarantees a robust, inflating and resistant structure of the pharmaceutical composition. In particular, the substituted acrylic acid copolymer is present at a quantity in the active phase from 30% to 95 % w/w.

According to the invention, a cellulose derivative may also be present in the active phase. The cellulose derivative is chosen from a list consisting of ethylcellulose, methylcellulose, microcrystalline cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloe, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium caroboxymethylcellulose.

The cellulose derivative may be present in an amount of between 5% w/w and 70% w/w.

The cellulose derivative is often use in the pharmaceutical field for tablet compression, especially for direct compression.

In an embodiment the active phase may further comprise at least one pharmaceutically acceptable excipient chosen conventionally used in the formation of matrix for dosage form such as a lubricant, a diluent insoluble in the acid medium, a colorant, etc. Preferably, said excipient is in solid form. The lubricant may be added to improve powder flow and reduce friction and adherence, or to reduce ejection forces, to prevent tooling damage and tablet defects during compression of a pharmaceutical composition. For example, the lubricant may be magnesium stearate or talc. The insoluble diluent in the gastric pH conditions may be for example Microcrystalline cellulose (AVICEL®; VIVAPUR®... etc.), Calcium hydrogen Phosphate dihydrate (EMCOMPRESS®... etc.). Active ingredient

In the present invention, “active ingredient” is used to designate the active substance alone, or granules comprising the active substance and granulating excipients.

The active phase may contain a single active ingredient or several active ingredients in combination, the active ingredient or ingredients may be of any kind. The active ingredients may be small molecules or biologies. However, the particular gastro-retentive properties of the pharmaceutical composition according to the invention make it particularly suitable for the use of active(s) ingredient(s) with low or irregular bioavailability, due for example to slow dissolution. Indeed, such active ingredients, when they are included in conventional non- gastro-retentive compositions, are released for a limited time into the cavity of the stomach, then pass quickly into the intestinal tract. Thus, in the case of active ingredients whose target sites are located at the gastric level i.e. in the stomach or in the upper part of the small intestine, conventional pharmaceutical compositions do not allow a bioavailability of the active ingredient sufficient to saturate these sites of such a nature as to permit optimal therapeutic action of said active ingredient.

Further, the particular gastro-retentive properties of the pharmaceutical composition according to the invention make it particularly suitable for the use of active ingredient(s) with small absorption window and/or local action. Indeed, a pharmaceutical composition according to the invention, thanks of its gastro-retentive properties, allows the release of the active(s) ingredient(s) comprised in the active phase at the gastric level, to the target sites of the latter, for a long period of time in order to saturate the target sites for a much longer time than non-gastro-retentive compositions of the prior art.

In addition, a release of the total quantity of the active(s) ingredient(s) at gastric level virtually excludes, or at least substantially diminishes, a deviation of the metabolic pathways that is observed with non-gastro-retentive compositions of the prior art. For example, with the non-gastro-retentive compositions of the prior art a significant quantity of the active(s) ingredient(s) is released downstream of the gastric level, i.e. the lower part of the small intestine to the colon, the active(s) ingredient(s) being then transformed by different metabolic pathways from the initially targeted metabolic pathways.

Therefore, in an embodiment, the at least one active ingredient is chosen from all active ingredients exhibiting a low or irregular bioavailability, due for example to slow dissolution, or exhibiting a small absorption window, preferably at the gastric level, i.e in the stomach or in the upper part of the small intestine, or exerting a medicinal action at the gastric level. In a specific embodiment, the at least one active ingredient or active substance is chosen from the non-limitative list of small molecules comprising: antibiotics, preferably cephalosporin such as cefaclor or ciprofloxacin, antiviral agents, preferably acyclovir or inosine or pranobex or tribavirine or vidarabine or zidovudine, gastric antisecretory, preferably metoclopramide, proton pump inhibitors, preferably omeprazole or esomeprazole or lansoprazole or rabeprazole or pantoprazole or mixtures thereof, histamine type 2-receptor antagonists, preferably ranitidine or cimetidine, selective 5-HT2 serotonin receptor antagonists, preferably ketanserin, anticonvulsants, preferably valproic acid or carbamazepine, calcium inhibitors, preferably verapamil or nifedipine or nicardipine or amlodipine or nitrendipine, diuretics, preferably furosemide, antiarrhythmic, preferably dihydroquinidine, mineral supplements, preferably potassium, antidiabetic agents, preferably metformin, antidiarrheal agents, preferably loperamide, anti-inflammatory drugs, preferably etodolac or ketoprofen or ibuprofen, hormones, preferably estrogens such as oestradiol and progestins such as progesterone, antihormones, preferably flutamide, antiparkinsonians, preferably levodopa or levodopa/carbidopa, antihypertensives, preferably methyldopa, alpha-blockers, preferably alfusozine, beta-blockers, preferably acebutolol, prostaglandins analogues preferably misoprostol, and neuroleptics preferably butyrophenones such as penfluridol or phenothiazines.

In a preferred embodiment, the at least one active ingredient or active substance is chosen from the list consisting of omeprazole or esomeprazole or lansoprazole or rabeprazole or pantoprazole or metformin or a mixture thereof.

The at least one active substance or active ingredient may also be a biologic, preferably protein and/or peptide, for example Insulin. In one embodiment, these active ingredients are associated with chronic diseases where the oral route is preferred. Chronic diseases may be defined as a long-term disease which is progressive i.e. that will worsen, or cause more symptoms. Chronic diseases may be in humans or animals, such as diabetes, asthma, lung or liver diseases, hypertension, cancer or obesity.

In a particular case where the active ingredient is unstable in acid medium, for example with a pKa less than 6.0, as it is the case for the proton pump inhibitors chemical class, it will be necessary to first protect active ingredient through preparations capable of protecting them from degradation in acidic medium, for example by coating the active ingredient with an entero-soluble polymer film coating or by obtaining microemulsions MICROGIX® according to the Galenix Patent no. FR 285 1918, before formulating them in the pharmaceutical composition of the invention. Therefore, in an embodiment, the at least one active ingredient of the active phase is in the form of micro-granules containing said at least one active ingredient. Said micro-granules are mixed with substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, before being compressed. The compressed form is then coated with a delayed and/or insoluble pH independent film coating phase.

In another embodiment, the at least one active ingredient is capable of ionizing mainly in the gastrointestinal tract.

In certain aspects, the quantity of the at least one active ingredient is at least 2% w/w, preferably from 3% w/w to 80% w/w, and more preferably from 5% w/w and 70% w/w of the active phase.

The non-active phase:

The gastro-retentive swellable sustained release composition according to the invention may also comprise a non-active phase. This non active phase isolates the active phase from its external environment by playing the role of taste masking agent and/or sustained release agent, etc. This non-active phase can be composed in different ways depending on the main required function. The non-active phase may comprise: a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, and/or a cellulose derivative, and optionally pharmaceutically acceptable excipients, and/or a diluent and optionally pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients may be lubricants, sweeteners, anti-caking agents, colorants, taste-masking agents, etc.

Dosage form of the gastro-retentive swellable sustained release composition:

In an embodiment, the pharmaceutical composition is an oral dosage form intended for oral administration to humans and animals. Preferably, the oral dosage form is a tablet. It is indeed generally observed that a conventional tablet only resides in the stomach cavity for a time varying from 1 to 3 minutes, beyond which this tablet crosses the pylori and then passes through the small intestine and passes through the intestinal tract to the colon. To the contrary, a tablet according to the present invention swells and floats at the level of gastric juice in the stomach for hours, such as at least 24 hours, and even for days, such as at least 7 days. Therefore, the pharmaceutical composition according to the invention may be a daily release tablet, a 48h release tablet, a 72h release tablet, a twice weekly release tablet, a once weekly release tablet. The present invention is thus very useful for treating chronic disease since it enhances the treatment observance.

According to a preferred embodiment, the gastro-retentive swellable sustained release composition according to the invention is a tablet.

Said tablet is a double core tablet, a bi-layer tablet or a tri-layer tablet.

The tablet according to the invention is sufficiently large to prevent the passage of the pylorus. The tablet has a size such that its larger dimension is at least 12 mm, preferably from 13 mm to 20 mm, even more preferably from 14 mm to 18 mm.

The tablets according to the invention are described below in reference to figure 7.

As illustrated in figure 7a, the tablet may be a double core tablet. The active phase 2 is under the form of a core which is surrounded by a non-active phase 1 .

The non-active phase is a phase which does not include any active ingredient, i.e. which is a mixture of excipients, as defined above.

As illustrated in figure 7b, the tablet is a bi-layer tablet. A non-active layer 11 (as defined above) is stacked on an active layer 12 comprising a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients. In said active layer the active ingredient is in the form of granules or microgranules. In one embodiment, the bi-layer tablet is coated with at least one delayed and/or insoluble pH independent film coating phase (not represented). In another embodiment, the granules or microgranules of active ingredient are coated with at least one delayed and/or insoluble pH independent film coating phase (not represented), the bi-layer tablet is not coated.

As illustrated in figure 7c, the tablet is a tri-layer tablet. A non-active layer 21 is sandwiched between two active layers 22, each active layer 22 comprising a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients. In said active layer 22 the active ingredient is in the form of granules or microgranules. In said embodiment, both active layers 22 are identical or are different. In one embodiment, the tri-layer tablet is coated with at least one delayed and/or insoluble pH independent film coating phase (not represented). In another embodiment, the granules or microgranules of active ingredient are coated with at least one delayed and/or insoluble pH independent film coating phase (not represented), the tri-layer tablet is not coated.

As illustrated in figure 7d, the tablet is a tri-layer tablet. An active layer 24 is comprising in between two non-active layers 23, the active layer 24 comprising a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients. In said active layer 24 the active ingredient is in the form of granules or microgranules. In said embodiment, both non-active layers 23 are identical or are different. In one embodiment, the tri-layer tablet is coated with at least one delayed and/or insoluble pH independent film coating phase (not represented). In another embodiment, the granules or microgranules of active ingredient are coated with at least one delayed and/or insoluble pH independent film coating phase (not represented), the tri-layer tablet is not coated.

In a specific embodiment, the active phase tablet is composed of an internal active phase surrounded by an external active phase. The internal active phase comprising at least one active ingredient and a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and the external active phase comprising at least one active ingredient, pharmaceutically acceptable excipients, such as disintegrating agents, pore forming agents, etc. In such an embodiment, the active ingredient of the internal active phase is granulated or included in micro-granule and coated with at least one delayed and/or insoluble pH independent film coating phase as described above.

This specific embodiment allows a bimodal release of the active ingredient.

In this embodiment the active ingredient of the external active phase will be immediately released (fast disintegrating phase), which thus allows the release of a high concentration of the active ingredient at gastric level. Thus, the target sites at the gastric level will be quickly saturated. Then the active ingredient present in the internal active phase will be sustained released which means that a smaller amount of the active ingredient will be released slowly in order to maintain the saturation status of the target sites for a long period of time. The at least one active ingredient of the active phase of the inner core may be the same as the at least one active ingredient of the external phase or may be different.

In an embodiment, the at least one active ingredient of the active phase is a proton pump inhibitor chosen from the list consisting of omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, and mixtures thereof.

Methods for preparing the pharmaceutical composition

In a second aspect, the present invention relates to a method of manufacturing the gastro- retentive swellable sustained release composition of the invention, wherein it comprises the steps of: a) Providing at least one active ingredient;

Optionally dry and/or wet granulating manufacturing process at least one active substance and optionally pharmaceutically acceptable excipients to obtain at least one active ingredient; b) Providing a substituted acrylic acid copolymer soluble at pH above 5.5, alone and/or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients; c) Optionally film coating the at least one active ingredient with at least one delayed and/or insoluble pH independent film coating phase; d) Blending the optionally film coated active ingredient with the ingredients of step b), e) Tableting the blend obtained in step d), f) Optionally, film coating the obtained tableted blend at step e) with at least one delayed and/or insoluble pH independent film coating phase; at least one of steps c) or f) being present.

In step (d), the blending means that the at least on active ingredient and substituted acrylic acid copolymer soluble at pH above 5.5, alone and/or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients are intimately blended. The intimate blending and the sufficient quantities of the substituted acrylic acid copolymer allows the formation of a stable continuous network or a matrix.

Step e) can be carried out by direct compression or by a step of dry or wet granulation and then a compression in order to obtain a tablet.

In certain aspects, the method further comprises a step of adding an excipient such as magnesium stearate and/or talc after step (d) and before step (e). Said excipient may be present in a total amount between 0.5% and 2.5% w/w of the active phase, preferably between 0.75% w/w and 2.25% w/w of the active phase. Indeed, these excipients are lubricants that improve powder flow and reduce friction and adherence, or reduce ejection forces, prevent tooling damage and tablet defects during compression of a pharmaceutical composition.

In specific embodiments, the at least one active ingredient provided in step a) is in the form of granules and/or micro-granules containing said at least one active ingredient. Said at least one active ingredient in form of granules and/or micro-granules being optionally coated with at least one delayed and/or insoluble pH independent film coating phase capable of modulating the active ingredient release as defined above. The film coating may be so as to separate the swellable active phase from the optional non-active phase, or to separate the at least one active ingredient from the rest of the swellable active phase.

The cellulose derivative, and optionally pharmaceutically acceptable excipients of step b) are as described above.

In an embodiment, the at least one active ingredient is chosen from all active ingredients exhibiting a low or irregular bioavailability, due for example to slow dissolution, or exhibiting a small absorption window, preferably at gastric level, or exerting a medicinal action at the gastric level.

In an embodiment, the at least one active ingredient is chosen from the list consisting of antibiotics, antiviral agents, gastric antisecretory, proton pump inhibitors, histamine type 2- receptor antagonists, selective 5-HT2 serotonin receptor antagonists, anticonvulsants, calcium inhibitors, diuretics, antiarrhythmic, mineral supplements, antidiabetic agents, antidiarrheal agents, anti-inflammatory drugs, hormones, antihormones, antiparkinsonians, antihypertensives, alpha-blockers, beta-blockers, prostaglandins analogues and neuroleptics.

In an embodiment, the at least one active ingredient is chosen from the list consisting of cephalosporin such as cefaclor and its salts or ciprofloxacin, acyclovir or inosine or pranobex or tribavirine or vidarabine or zidovudine, metoclopramide, omeprazole or esomeprazole or lansoprazole or rabeprazole or pantoprazole or mixtures thereof, ranitidine or cimetidine and salts thereof, ketanserin, valproic acid and its derivates or carbamazepine, verapamil or nifedipine or nicardipine or amlodipine or nitrendipine, furosemide, dihydroquinidine, potassium, metformin and its derivatives, loperamide, etodolac or ketoprofen or ibuprofen, estrogens such as oestradiol and progestins such as progesterone, flutamide, levodopa or levodopa/carbidopa, methyldopa and its salts, alfusozine and its salts, acebutolol, misoprostol, butyrophenones such as penfluridol, phenothiazines, preferably omeprazole or esomeprazole or lansoprazole or rabeprazole or pantoprazole or mixtures thereof or metformin and its derivatives.

In an embodiment, the quantity of the at least one active ingredient is at least 2% w/w, preferably from 3% to 80% w/w, and more preferably from 5% w/w to 70% w/w of the active phase.

In an embodiment, the substituted acrylic acid copolymer soluble at pH above 5.5 is chosen from anionic copolymers of acrylic acids such as Methacrylic Acid - methacrylate Copolymer (1 :1) (Eudragit® L100-55 and its derivatives), Methacrylic Acid - methyl methacrylate Copolymer (1 :1) (Eudragit® L100 and its derivatives), Methacrylic Acid Methyl - Methacrylate Copolymer (1 :2) (Eudragit® S100 and derivatives) and mixtures thereof.

In an embodiment, the amount substituted acrylic acid copolymer is from 30 to 95 % w/w.

In another embodiment, the cellulose derivative is chosen from a list consisting of ethylcellulose, methylcellulose, microcrystalline cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloe, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium caroboxymethylcellulose, and mixtures thereof.

In an embodiment, the optionally pharmaceutically acceptable excipients are chosen among lubricant such as magnesium stearate or talc or colloidal silica, an insoluble diluent in the gastric pH such as Microcrystalline cellulose or Calcium hydrogen Phosphate dihydrate, a binder such as povidone or copovidone, a colorant and mixtures thereof.

In an embodiment, the delayed and/or pH independent film coating phase is chosen among the film coating agents insoluble in aqueous medium, preferably the at least one delayed film coating agent is chosen from the list consisting of substituted acrylic acid copolymers, cellulose phthalate acetate, polyvinyl acetophthalate (OPADRY® OY A or equivalent), hydroxypropyl cellulose succinate (AQOAT® or equivalent), and mixtures thereof. The cellulose phtalate substances may be chosen from among the phthalates of hydropropylmethylcellulose (also known as hypromellose phthalate), the substituted acrylic acid copolymers are chosen from ethyl acrylate and methyl methacrylate copolymer (Eudragit® NE and/or NM), ammonio methacrylate copolymer type A or B (Eudragit® RL and/or RS), ethylcellulose polymers, polydimethylsiloxanes (PDMS) and its derivatives, and mixtures thereof.

In an embodiment, the at least one delayed and/or insoluble pH independent film coating phase comprises excipients chosen among plasticizers (triethyl citrate, dibutyl sebacate, polyethylene glycol...), anti-tacking agents (talc, magnesium stearate...), pore-forming agents, emulsifiers (polysorbate ...), muco-adhesive agents.

Use

The present invention also relates to the pharmaceutical composition as described above for use in the treatment of chronic diseases in humans or animals. Chronic diseases may be defined as a long-term disease which is progressive i.e. that will worsen, or cause more symptoms. Chronic diseases may be in humans or animals, such as diabetes, asthma, lung or liver diseases, hypertension, cancer or obesity.

In an embodiment, the pharmaceutical composition is administered twice weekly, preferably once weekly.

In an embodiment, the present invention relates to a method of treating chronic diseases in humans or animals comprising the step of providing an effective amount of the gastro- retentive swellable sustained release composition of the invention, and administering to the human or animal said composition.

In another embodiment, the present invention relates to the use of a gastro-retentive swellable sustained release composition of the invention in the manufacture of a medicament for treating chronic diseases in humans or animals.

According to another aspect, the invention relates on the use of a substituted acrylic acid copolymer soluble at pH above 5.5 as a swellable matrix in a gastro-retentive sustained released pharmaceutical composition for increasing its gastric residence time to at least 12h, at least 24h, at least 48h, at least 72h, at least 3 days, at least 4 days, at least 7 days.

EXAMPLES

Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.

Example 1 : Gastro-retentive swellable tablet according to the invention with Metformin Hydrochloride as active ingredient.

Tablets presenting the composition as mentioned in Table A were prepared:

Table A

The tablet is obtained by direct compression according to the following steps:

1 . Providing metformin hydrochloride and Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Type A which are sieved,

2. Blending in a powder blender,

3. Adding Silica colloidal anhydrous and magnesium stearate which is sieved in the powder blender in order to obtain a final blend,

4. Direct compression using a tablet press machine,

5. Blending Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1), Polysorbate 80, Triethyl citrate, Glycerol monostearate and calcium bicarbonate,

6. Film coating the tablet forms obtained at step 4.

Film coated monolithic tablets with an average mass of 618 mg per unit are obtained. The tablets tested are tablets obtained in a 12 mm diameter compression format. The breaking strength of the tablets is approximately 150 Newtons. The tablets of the above pharmaceutical composition were immersed in a hydrochloric acid I sodium chloride medium adjusted to a pH of 1.2 in a conventional paddle in vitro dissolution apparatus type II, the paddle speed being set at 75 rpm and the volume of the medium being 1000 ml, at a temperature of 37°C.

The dissolution profile of the tablet was measured in an in vitro dissolution medium. Results are given in Figure 2. On the y-axis, percentage of Metformin active ingredient released. On the x-axis, time of release after contact of the tablets with an in vitro dissolution medium. The tablet was still floating after 7 days and only 80% of the active ingredient were released after 48h.

Example 2: Sustained-release tablet according to the invention with esomeprazole as active ingredient.

Table B

Composition according to table B presented in the form of monolithic tablets of average mass 1545 mg per unit.

The tablet is obtained by direct compression according to the following steps:

1. Providing Esomeprazole granule, Methacrylic Acid - Ethyl Acrylate Copolymer (1:1) Type A, microcrystalline cellulose, calcium hydrogen phosphate and colloidal anhydrous silica which are sieved,

2. Blending altogether in a powder blender,

3. Adding magnesium stearate and talc which is sieved in the powder blender in order to obtain a final blend,

4. Final blend tableting using a tablet press machine,

5. Film coating with a suspension comprising methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Dispersion, Polysorbate 80, Triethyl citrate, Glycerol monostearate, Calcium bicarbonate and purified water, in a pan coating machine.

The tablets were obtained with a compression format of 13 mm diameter.

According to this method of preparation, the Esomeprazole magnesium tri-hydrate , which is sensitive to degradation in an acidic environment, is protected thanks to the use of the MICROGIX® technology according to the Galenix patent n° FR 285 1918 dated 06th March 2003.

This granule was then used as active ingredient of the active phase. It was blended with the other ingredients of the swellable active phase, the substituted acrylic acid copolymer, the diluent agent, the flow agent, the lubricant and the release agent before being tableted. The obtained tablets were film coated with a delayed and/or insoluble pH independent film coating. This film coating confers "partial" delayed release properties because only the pores generated by calcium bicarbonate in an acid medium are solubilized in an acid medium and allow the regulation of the release of the active ingredient over time. Dissolution profile is presented in Figure 3.

Example 3: Gastro-retentive swellable tablet according to the invention with Gliclazide as active ingredient.

Tablets presenting the composition as mentioned in Table C were prepared:

Table C

The tablet is obtained by dry granulation manufacturing process according to the following steps:

1. Providing Gliclazide, microcrystalline cellulose and magnesium stearate which are sieved,

2. Blending in a powder blender,

3. Granule by “slugging” method the Gliclazide blend,

4. Adding with the calibrated Gliclazide granule, Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Type A, ethyl cellulose, microcrystalline cellulose, magnesium stearate , talc and silica colloidal anhydrous which is sieved in the powder blender in order to obtain a final blend,

5. Final blend tabletting using a tablet press machine Monolithic tablets with an average mass of 1000 mg per unit are obtained.

The tablets tested are tablets obtained in a 13.5 mm diameter tablet format prepared by dry granulation. The thickness of the tablets is approximately 8.3mm.

The tablets of the composition according to table C were immersed in 250 ml of 0.1 N HCI at 37°C. The lag time before tablet flotation is less than 30 minutes. In 0.1 N HCI medium, the tablets floated after 2 hours with an important increase of the tablet volume. The tablet thickness increases from approximately 8.3mm to approximately 15.1 mm.

The tablets of the above pharmaceutical composition were immersed in a hydrochloric acid I sodium chloride medium adjusted to a pH of 1.2 in a conventional paddle in vitro dissolution apparatus type II, the paddle speed being set at 75 rpm and the volume of the medium being 1000 ml, at a temperature of 37°C.

The dissolution profile of the tablet was measured in an in vitro dissolution medium. Results are given in Figure 4. The y-axis represents the percentage of active ingredient Gliclazide released. The x-axis represents the time elapsed after contact of the tablets with the in vitro dissolution medium. Only 30% of the active ingredient was released at 24 hours.

Example 4: Gastro-retentive swellable tablet according to the invention with Fenofibrate as active ingredient.

Tablets presenting the composition as mentioned in Table D were prepared: Table D

The tablet is obtained by dry granulation manufacturing process according to the following steps:

1. Providing Fenofibrate, microcrystalline cellulose and magnesium stearate which are sieved,

2. Blending in a powder blender,

3. Granule by “slugging” method the Fenofibrate blend, 4. Adding with the calibrated Fenofibrate, granule, Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Type A, ethyl cellulose, microcrystalline cellulose, magnesium stearate , talc and silica colloidal anhydrous which is sieved in the powder blender in order to obtain a final blend,

5. Final blend tabletting using a tablet press machine

Monolithic tablets with an average mass of 750 mg per unit are obtained.

The tablets tested are tablets obtained in a 12 mm diameter tablet format prepared by dry granulation. The thickness of the tablets is approximately 7.8mm.

The tablets of the composition according to table D were immersed in 250 ml of 0.1 N HCI at 37°C. The lag time before tablet flotation is less than 30 minutes. In 0.1 N HCI medium, the tablets floated after 2 hours with an important increase of the tablet volume. The tablet thickness increases from approximately 7.8mm to approximately 13.5mm.

The tablets of the above pharmaceutical composition were immersed in a hydrochloric acid I sodium chloride medium adjusted to a pH of 1.2 in an in vitro dissolution apparatus type III, the agitation rate being set at 15 dips per minute (dpm) and the volume of the medium being 250 ml, at a temperature of 37°C.

The dissolution profile of the tablet was measured in an in vitro dissolution medium. Results are given in Figure 5. The y-axis represents the percentage of active ingredient Fenofibrate released. The x-axis represents the time elapsed after contact of the tablets with an in vitro dissolution medium. Only 3% of the active ingredient was released at 48 hours.

Example 5: Gastro-retentive swellable tablet according to the invention with Metformin as active ingredient.

Tablets presenting the composition as mentioned in Table E were prepared:

Table E

The tablet is obtained by direct tableting manufacturing process according to the following steps:

1. Providing Metformin, Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Type A, ethyl cellulose and microcrystalline cellulose which are sieved,

2. Blending in a powder blender,

3. Adding magnesium stearate, talc and silica colloidal anhydrous which is sieved in the powder blender in order to obtain a final blend,

4. Final blend tabletting using a tablet press machine

Monolithic tablets with an average mass of 1000 mg per unit are obtained.

The tablets tested are tablets obtained in a 13.5 mm diameter tablet format prepared by direct tabletting. The thickness of the tablets is approximately 8.6mm.

The tablets of the composition according to table E were immersed in 250 ml of 0.1 N HCI at 37°C. The lag time before tablet flotation is less than 30 minutes. In 0.1 N HCI medium, the tablets floated after 2 hours with an important increase of the tablet volume. The tablet thickness increases from approximately 8.6mm to approximately 12.6mm.

The tablets of the above pharmaceutical composition were immersed in a hydrochloric acid I sodium chloride medium adjusted to a pH of 1.2 in a conventional paddle in vitro dissolution apparatus type II, the paddle speed being set at 75 rpm and the volume of the medium being 1000 ml, at a temperature of 37°C.

The dissolution profile of the tablet was measured in an in vitro dissolution medium. Results are given in Figure 6: The y-axis represents the percentage of active ingredient Metformin released. The x-axis represents the time elapsed after contact of the tablets with an in vitro dissolution medium. Only 80% of the active ingredient was released at 18 hours.

Example 6: Gastro-retentive swellable tablet according to the invention with Esomeprazole as active ingredient.

Tablets presenting the composition as mentioned in Table F were prepared: Table F

The tablet is obtained by a tableting manufacturing process of Gastro-resistant delayed coated pellets according to the following steps:

1 . Providing Esomeprazole Gastro-resistant coated pellet and colloidal anhydrous silica which are sieved,

2. Blending in a powder blender,

3. Adding Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Type A, ethyl cellulose, microcrystalline cellulose, magnesium stearate and talc which is sieved in the powder blender in order to obtain a final blend,

4. Final blend tabletting using a tablet press machine

Monolithic tablets with an average mass of 545 mg per unit are obtained.

The tablets tested are tablets obtained in a 12 mm diameter tablet format prepared by dry granulation. The thickness of the tablets is approximately 6.5mm.

The tablets of the composition according to table F were immersed in 250 ml of 0.1 N HCI at 37°C. The lag time before tablet flotation is less than 30 minutes. In 0.1 N HCI medium, the tablets floated after 2 hours with an important increase of the tablet volume. The tablet thickness increases from approximately 6.5mm to approximately 10.6mm.

The tablets of the above pharmaceutical composition were immersed in a hydrochloric acid I sodium chloride medium adjusted to a pH of 1.2 in an in vitro dissolution apparatus type III, the agitation rate being set at 15 dips per minute (dpm) and the volume of the medium being 250 ml, at a temperature of 37°C.

The dissolution profile of the tablet was measured in an in vitro dissolution medium. About 20% of the active ingredient was released at 5 days.

Example 7: Gastro-retentive swellable tablet according to the invention with Trimetazidine as active ingredient.

Tablets presenting the composition as mentioned in Table G were prepared:

Table G

The tablet is obtained by dry granulation manufacturing process according to the following steps:

1. Providing Trimetazidine, microcrystalline cellulose, povidone, talc and magnesium stearate which are sieved,

2. Blending in a powder blender,

3. Granule by “slugging” method the Trimetazidine blend,

4. Adding with the calibrated Trimetazidine, granule, Methacrylic Acid - Ethyl Acrylate Copolymer (1 :1) Type A, ethyl cellulose, microcrystalline cellulose, magnesium stearate , talc and silica colloidal anhydrous which is sieved in the powder blender in order to obtain a final blend,

5. Final blend tabletting using a tablet press machine

Monolithic tablets with an average mass of 1000 mg per unit are obtained.

The tablets tested are tablets obtained in a 13.5 mm diameter tablet format prepared by dry granulation. The thickness of the tablets is approximately 8.7mm. The tablets of the composition according to table G were immersed in 250 ml of 0.1 N HCI at 37°C. The lag time before tablet flotation is less than 30 minutes. In 0.1 N HCI medium, the tablets floated after 2 hours with an important increase of the tablet volume. The tablet thickness increases from approximately 8.7mm to approximately 14.1mm.

The tablets of the above pharmaceutical composition were immersed in a hydrochloric acid I sodium chloride medium adjusted to a pH of 1.2 in an in vitro dissolution apparatus type III, the agitation rate being set at 15 dips per minute (dpm) and the volume of the medium being 250 ml, at a temperature of 37°C.

The dissolution profile of the tablet was measured in an in vitro dissolution medium. Only 76% of the active ingredient was released at 24 hours.

Claims

1. A gastro-retentive swellable sustained release composition comprising:

- a swellable active phase comprising at least one active ingredient and from 20% w/w to 98% w/w, preferably from 30% w/w to 95% w/w, of a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, said active phase being swellable at acidic pH;

- optionally a non-active phase; and

- at least one delayed and/or insoluble pH independent film coating phase, the percentages being calculated with respect to the total weight of the composition.

2. The gastro-retentive swellable sustained release composition according to claim 1 , wherein the swellable active phase and the optional non active phase, is coated with the at least one delayed and/or insoluble pH independent film coating phase, or only the at least one active ingredient, preferably under the form of granules or micro-granules, is coated with the at least one delayed and/or insoluble pH independent film coating phase.

3. The gastro-retentive swellable sustained release composition according to claim 1 or claim 2, wherein the delayed film coating agent is chosen among the film coating agents insoluble in aqueous medium and in particular the at least one delayed film coating agent is chosen from the list consisting of substituted acrylic acid copolymers, cellulose phthalate acetate, polyvinyl acetophthalate, hydroxypropyl cellulose succinate, and mixtures thereof.

4. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 3, wherein the substituted acrylic acid copolymer soluble at pH above 5.5 is chosen from anionic copolymers of acrylic acids such as Methacrylic Acid - methacrylate Copolymer (1 :1), Methacrylic Acid - methyl methacrylate Copolymer (1 :1), Methacrylic Acid Methyl - Methacrylate Copolymer (1 :2), Methacrylic Acid - Ethyl acrylate Copolymer (1 :1) and mixtures thereof.

5. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 4, wherein the cellulose derivative is chosen from a list consisting of ethylcellulose, methylcellulose, microcrystalline cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloe, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium caroboxymethylcellulose, and mixtures thereof.

6. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 5 , wherein the at least one active ingredient is chosen from all active ingredients exhibiting a low or irregular bioavailability, due for example to slow dissolution, or exhibiting a small absorption window, preferably at gastric level, or exerting a medicinal action at the gastric level.

7. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 6, wherein the at least one active ingredient is chosen from the list consisting of antibiotics, antiviral agents, gastric antisecretory, proton pump inhibitors, histamine type 2- receptor antagonists, selective 5-HT2 serotonin receptor antagonists, anticonvulsants, calcium inhibitors, diuretics, antiarrhythmic, mineral supplements, antidiabetic agents, antidiarrheal agents, anti-inflammatory drugs, hormones, antihormones, antiparkinsonians, antihypertensives, alpha-blockers, beta-blockers, prostaglandins analogues and neuroleptics.

8. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 7, wherein the at least one active ingredient is chosen from the list consisting of cephalosporin such as cefaclor and its salts or ciprofloxacin, acyclovir or inosine or pranobex or tribavirine or vidarabine or zidovudine, metoclopramide, omeprazole or esomeprazole or lansoprazole or rabeprazole or pantoprazole or mixtures thereof, ranitidine or cimetidine and salts thereof, ketanserin, valproic acid and its derivates or carbamazepine, verapamil or nifedipine or nicardipine or amlodipine or nitrendipine, furosemide, dihydroquinidine, potassium, metformin and its derivatives, loperamide, etodolac or ketoprofen or ibuprofen, estrogens such as oestradiol and progestins such as progesterone, flutamide, levodopa or levodopa/carbidopa, methyldopa and its salts, alfusozine and its salts, acebutolol, misoprostol, butyrophenones such as penfluridol, phenothiazines, preferably omeprazole or esomeprazole or lansoprazole or rabeprazole or pantoprazole or mixtures thereof or metformin and its derivatives.

9. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 8, wherein the quantity of the at least one active ingredient is at least 2% w/w, preferably from 3% to 80% w/w, and more preferably from 5% w/w to 70% w/w of the active phase.

10. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 9, wherein the non-active phase comprises: a substituted acrylic acid copolymer soluble at pH above 5.5 alone, or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients, and/or a cellulose derivative, and optionally pharmaceutically acceptable excipients, and/or - a diluent and optionally pharmaceutically acceptable excipients.

11. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 10, which is a tablet, preferably a twice weekly release tablet, and more preferably a once weekly release tablet.

12. The gastro-retentive swellable sustained release composition according to claim 11 , wherein the tablet is a double core tablet, a bi-layer tablet or a tri-layer tablet.

13. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 12, wherein the active phase is deprived of any gas generating components.

14. The gastro-retentive swellable sustained release composition according to anyone of claims 1 to 12, wherein the total composition is deprived of any gas generating components.

15. A method of manufacturing the gastro-retentive swellable sustained release composition as defined in anyone of claims 1 to 12, wherein it comprises the steps of: a) Providing at least one active ingredient; a’) Optionally dry and/or wet granulating manufacturing process at least one active substance and optionally pharmaceutically acceptable excipients to obtain at least one active ingredient; b) Providing a substituted acrylic acid copolymer soluble at pH above 5.5, alone and/or in combination with a cellulose derivative, and optionally pharmaceutically acceptable excipients; c) Optionally film coating the at least one active ingredient with at least one delayed and/or insoluble pH independent film coating phase; d) Blending the optionally film coated active ingredient with the ingredients of step b), e) Tableting the blend obtained in step d), f) Optionally, film coating the obtained tableted blend obtained at step e) with at least one delayed and/or insoluble pH independent film coating phase; at least one of steps c) or f) being present.

16. The gastro-retentive swellable sustained release composition as defined in anyone of claims 1 to 12 or as prepared according to claim 15, for use in the treatment of chronic diseases in humans or animals for example asthma, lung or liver diseases, hypertension, cancer or metabolic diseases such as for example obesity and/or diabetes.

17. Use of a substituted acrylic acid copolymer soluble at pH above 5.5 alone as a swellable matrix in a gastro-retentive sustained released pharmaceutical composition for increasing its gastric residence time to at least 12h, at least 24h, at least 48h, at least 72h, at least 3 days, at least 4 days, at least 7 days.

18. The gastro-retentive swellable sustained release composition according to any one of the claims 1 to 14 and 16, which presents a volume increase at least of 30% to 70%, preferably 40% to 60% after immersion in a gastric medium.

19. The gastro-retentive swellable sustained release composition according to any one of the claims 1 to 14, 16 and 18 which presents a swelled stable form when immersed in a gastric medium during at least 12h, at least 24h, at least 48h, at least 72h, at least 3 days, at least 4 days, at least 7 days.