BE1024339A1 - MULTILAYER MICROPARTICLES RELEASING A PHARMACEUTICALLY ACTIVE COMPOUND IN A LIQUID PHARMACEUTICAL FORM - Google Patents

Abstract

The present invention relates to a controlled release multilayer microparticle containing a pharmaceutically active compound, said microparticle being for oral administration or direct administration in the stomach in the form of a liquid pharmaceutical composition. It also relates to the liquid pharmaceutical composition containing it, a kit for the preparation of said liquid pharmaceutical composition, a solid pharmaceutical composition intended to be reconstituted in the form of said liquid composition and a process for preparing said liquid composition.

Description

(30) Priority data:

(71) Applicant (s):

BE PHARBEL MANUFACTURING SA

6180, COURCELLES

Belgium (72) Inventor (s):

RONCHI Federica 20124 MILAN Italy

GOOLE Jonathan

1200 WOLUWE-SAINT-LAMBERT

Belgium

AMIGHI Karim

1150 WOLUWE-SAINT-PIERRE Belgium

GUILLAUME Georges 1421 OPHAIN Belgium

STEPHENNE Vincent 1470 BAISY-THY Belgium (54) MULTILAYER MICROPARTICLES RELEASING A COMPOUND

PHARMACEUTICALLY ACTIVE IN A LIQUID PHARMACEUTICAL FORM (57) The present invention relates to a multilayer controlled release microparticle containing a pharmaceutically active compound, said microparticle being intended for oral administration or direct administration in the stomach in the form of a liquid pharmaceutical composition. It further relates to the liquid pharmaceutical composition containing it, a kit for the preparation of said liquid pharmaceutical composition, a solid pharmaceutical composition intended to be reconstituted in the form of said liquid composition and a process for the preparation of said liquid composition.

Time (h) ~ 4-ULB12h2ül4 Lose c 40 mg (100

FIG 1

B E2016 / 5555

MULTILAYER MICROPARTICLES RELEASING A PHARMACEUTICALLY ACTIVE COMPOUND IN A PHARMACEUTICAL FORM

LIQUID

The invention relates to the technical field of a controlled release composition of a pharmaceutically active compound. In particular, it relates to a multilayer microparticle releasing a pharmaceutically active compound in a liquid pharmaceutical composition.

Oral administration of pharmaceutically active compounds improve the quality of life of patients, in particular by improving the ease of administration and by increasing patient compliance and cost-effectiveness. The flexibility of design of a wide variety of different pharmaceutical compositions further makes oral administration attractive for formulating a wide variety of active substances.

A large number of pharmaceutically active compounds can achieve maximum pharmacological effect or limit undesirable side effects when released from the pharmaceutical composition into the intestine (i.e., the proximal or distal region of the intestine ).

In particular, many “fragile” pharmaceutically active compounds have insufficient stability in the acidic environment of the stomach.

They are called acid-labile compounds. Examples of acid-labile compounds are antibiotics (such as erythromycin) or proton pump inhibitors (PPI) such as omeprazole, lansoprazole, tenatoprazole, esomeprazole, rabeprazole, pantoprazole etc. Acid-labile compounds administered in the acidic environment of the stomach (by oral administration or by infusion or direct injection into the stomach) are susceptible to degradation before reaching the enteric region where they can be absorbed into the systemic circulation. .

Other pharmaceutically active compounds administered orally may cause irritation of the gastric mucosa and should therefore preferably be protected against gastric environments until released into the intestine (e.g., intestinal release and

BE2016 / 5555 colic) where they can be absorbed into the systemic circulation. This is the case for pharmaceutically active compounds such as pharmaceutically active non-steroidal anti-inflammatory compounds (for example diclofenac, aceclofenac, ibuprofen, ketoprofen, oxaprozin, indomethacin, meloxicam, piroxicam, tenoxicam, celecoxib, etoricoxib, nabumetone aspirin).

Other pharmaceutically active compounds administered orally must specifically target a section of the gastrointestinal tract other than the stomach, such as the colon or the intestine. This is the case of chemotherapeutic agents for the treatment of (colon) cancer (for example, fluorinated pyrimidines such as hexcarbamoyl-5-fluorouracil (carmofur), uracil / tegafur, uracil / tegafur / leukovorin, capecitabine etc.) or for the treatment of intestinal diseases such as ulcerative colitis or Crohn's disease such as anti-inflammatory drugs (for example, mesalazine, sulfasalazine) or oral corticosteroids (for example budesonide, beclometasone).

Finally, other pharmaceutically active compounds administered orally have an improved or prolonged therapeutic efficacy by using a prolonged-release pharmaceutical composition, such as antibiotics (for example, amoxicillin, cefadroxil, cefazolin, cefuroxime, cefotaxime, meropenem, aztreonam, erythromycin, azithromycin, clarithromycin, roxithromycin, spiramycin, doxycycline, minocycline, clindamycin, lincomycin, ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, trimlifacin, sulfametropin, sulfametropin , amlodipine, barnidipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nimodipine, nisoldipine, nitrendipine, verapamil, diltiazem), antiarrhythmics (e.g. flecainide, amiodarone, cibenzoline, disopyramide , metoprolol, atenolol, biso prolol, carvedilol, celiprolol, esmolol, labetalol, nebivolol, propranolol), diuretics (for example, furosemide, torasemide, spironolactone), anti-inflammatory drugs (for example, ibuprofen, diclofenac) or pain relievers (for example, tramadol, oxycodone, morphine).

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Therefore, the advantages of the use of oral administration combined with the need to protect the pharmaceutically active compounds against the gastric environment, in order to target a release at a specific site or to prolong their action explains that the current oral pharmaceutical compositions often exhibit controlled release properties (e.g. delayed release, prolonged release, continuous release, etc.).

However, as is the case with pharmaceutically active compounds, pharmaceutical compositions administered orally are also exposed to the wide range of highly variable conditions during their transit through the gastrointestinal tract. The ingestion of food and the type of meal (caloric content, volume, viscosity, physical state) influence gastric physiology and, consequently, the release of the pharmaceutically active compound from the pharmaceutical composition. In fact, the gastric pH fluctuates around pH 1-3 on an empty stomach and in a pH range of 3 to 7 after a meal, while the intestinal pH is in a range between 6 and 8.

Oral pharmaceutical compositions can be liquid pharmaceutical compositions (suspensions, emulsions, dispersion of a solid in a liquid, solutions, pastes, gels) or solid pharmaceutical compositions (for example, tablets, microparticles (also called granules), capsules, powders).

Solid oral pharmaceutical compositions are generally preferred over liquid pharmaceutical compositions because they provide increased stability of the incorporated pharmaceutical compound during storage. Indeed, it is known that the presence of water or another solvent in liquid pharmaceutical compositions, and even, the presence of a substantial amount of residual moisture in solid pharmaceutical forms increases both biological contamination. and the physico-chemical degradation of the pharmaceutically active compounds. Solid oral pharmaceutical compositions include individual unit pharmaceutical compositions such as tablets, capsules or powders and multiple unit pharmaceutical compositions such

BE2016 / 5555 as microparticles (granules). Both individual unitary and multiple unitary pharmaceutical compositions can be coated in order to solve physiological problems encountered in the gastrointestinal tract such as pH modification or enzymatic and microbiological activity. Multiple unit controlled release (i.e., delayed or prolonged or continuous release) pharmaceutical compositions contained in a capsule or tablet (e.g. MUPS®), which can be opened or dispersed prior to administration, are particularly practical for the development of controlled release pharmaceutical compositions since they make it possible to reduce the inter-subject variability of the absorbed dose of the pharmaceutically active compound and the probability of rapid dose reduction ("dumping"), to have a more reproducible gastric residence time and present better dispersion throughout the gastrointestinal tract.

Multiple unit pharmaceutical compositions are particularly useful for the preparation of controlled delivery systems of acid-labile pharmaceutically active compounds such as, for example, PPIs. There are several approaches to improve the properties of the enteric coating of microparticles, leading to both protection of the acid-labile active pharmaceutical compounds and control of their release in the intestinal region optimized.

Although the use of solid oral pharmaceutical compositions has many advantages, large solid oral pharmaceutical compositions such as tablets or capsules can hardly be administered orally to young patients (pediatric patients) and others. patients who have difficulty swallowing or who cannot swallow (such as patients in critical condition). These include pediatric and geriatric patients who have difficulty swallowing or chewing solid pharmaceutical compositions; patients who refuse to take solid pharmaceutical compositions due to fear of strangulation; very elderly patients who cannot swallow a daily dose of a pharmaceutically active compound or schizophrenic patients in an institutional context who may try to conceal a tablet

BE2016 / 5555 conventional under their tongue to avoid taking their daily dose of therapeutic agents. Young children and elderly and sick patients often need controlled release pharmaceutical compositions in order to simplify the dosage.

For patients with difficulty swallowing or swallowing disorder, oral administration of multiple unit controlled release (i.e. delayed or prolonged release) pharmaceutical compositions contained in a capsule or tablet (e.g. example, MUPS®) also has problems. In these cases, before their administration, the microparticles contained in the capsule or tablet can sometimes be dispersed in a suitable liquid vehicle such as water, yogurt, fruit juice or applesauce. However, there is a risk that the microparticles will be chewed before being swallowed, which leads to the potential degradation of pharmaceutically active compounds (such as acid-labile pharmaceutically active compounds) in the acidic gastric environment once ingested and, therefore, in the absence of control of the doses administered. Other disadvantages of dispersing microparticles in a liquid vehicle before ingestion are a handling error (for example, inappropriate dispersion, loss of microparticle particles) due to repeated handling of the pharmaceutical form, possible unpleasant taste (in the cases where the microparticles are chewed) and unpleasant palatability due, in particular, to the size of the microparticles, which cause an inappropriate dosage or rejection by the patients, in particular by the young patients.

In some other cases, the multiple unit controlled release (i.e., delayed or sustained release) pharmaceutical compositions contained in a capsule or tablet (e.g. MUPS®) are mixed with an aqueous solution (such as sterile water for injection) and administered directly to the stomach using a gastric naso30 tube or gastrostomy tube. However, in this case, there are problems of microparticle aggregation and obstructions.

A dose taken from the mixture of controlled release microparticles with a liquid vehicle (reconstituted mixture) is generally administered

BE2016 / 5555 quickly to the patient because the coatings (e.g. enteric coatings) frequently dissolve at a pH above 6 (such as that observed in the intestinal tract), leading to degradation of the pharmaceutically active compound .

Other problems are associated with such a preparation such as the lack of convenience and, consequently, poor compliance, the absence of reproducible administered doses, the risks of chewing the microparticles, which causes the degradation of the pharmaceutically active compound. even before ingestion.

Consequently, there is a need to develop a liquid pharmaceutical composition containing controlled release multilayer microparticles which keeps the pharmaceutically active compounds unchanged (not degraded, pharmacologically active) for long periods of time at 4 ° C., advantageously at room temperature (c ' i.e. 20 to 25 ° C), for example several days (such as 7 days), in particular several weeks (for example, two weeks), more particularly 28 days and which guarantees that several uniform doses are taken ( for example, 1 to 2 doses per day for 28 days), each dose containing substantially the same concentration of the pharmaceutically active compound.

This is greatly necessary to meet the need for the administration of multilayer controlled release microparticles comprising pharmaceutically active compounds to patients with difficulty in swallowing, such as pediatric patients, elderly patients, critically ill patients and disabled subjects.

WO 2004/04718 describes a liquid formulation of acid-labile active substances consisting in dispersing enteric coated microgranules (size from 100 to 900 μm) in an acidic aqueous phase having a pH below 6.0 and, consequently, preventing the microgranule from to dissolve. The inventors claim improved stability, low volumes of liquid required and compliance for ad-hoc administration via nasogastric tubes or gastrostomy tubes. Any one of

BE2016 / 5555 known enteric coating materials are suitable for use in this invention. Other components such as flavoring agents, surfactants, sweeteners and other known excipients can be added. WO 2004/04718 further describes a kit comprising 2 containers, one for the liquid and the other for the microgranules, which makes it possible to prepare the liquid formulation before use.

However, WO 2004/04718 mainly describes the preparation of an extemporaneous aqueous suspension of microgranules, in particular for its injection by means of a nasogastric tube. Therefore, the preparation is used within a short time after mixing the microgranules with the liquid vehicle (maximum 60 minutes). Consequently, this document does not describe a liquid pharmaceutical composition which is stable for more than a few hours when it is stored at room temperature before its administration.

WO 2004/04719 describes a composition comprising an IPP (lansoprazole) and a liquid vehicle whose pH is greater than 6.5 and whose viscosity is at least 50 cP (Brookfield). It is claimed that the formulation comprising ΙΊΡΡ, a metal salt buffer and a thickening agent and having a viscosity of at least 50 cP maintains an appropriate and homogeneous concentration of IPP throughout the formulation for 15 minutes. It is claimed that the formulation is readily administered to patients having difficulty swallowing. Therefore, similarly to WO 2004/04718, this document relates to the preparation of liquid pharmaceutical compositions which are stable only for very short periods of time. Consequently, WO 2004/04719 does not provide a solution to the problem of preparing a liquid pharmaceutical composition which is stable for more than 15 minutes.

EP 1830816 relates to a solid fast gel oral pharmaceutical composition comprising an IPP compound as an active substance distributed in a multitude of enteric coated granules and a suspension modification granulate. EP1830816 describes the use of a dry suspension modification granulate and the enteric coated particles containing an IPP are dissolved / suspended in an aqueous vehicle for

BE2016 / 5555 obtain a viscous liquid formulation for oral administration. The suspension modification aggregate, when suspended in water, rapidly and reproducibly forms an aqueous vehicle having the desired pH, stable viscosity and viscoelasticity. Therefore, the objective of EP 1830816 is to ensure that the liquid pharmaceutical composition is stable for only short periods of time before its administration (i.e., via, for example, nasogastric tubes). The solution proposed by EP 1830816 is the use of the suspension modification granulate described therein and it is claimed that it is suitable for allowing the rapid and reproducible formation of a viscous liquid environment for the microparticles which guarantees the administration of the appropriate dose of pharmaceutically active compounds shortly after preparation of the viscous liquid. The microparticles, as such, are not modified. In particular, the outer layer of the microparticles is the enteric coating and this is not surrounded by an additional overlay as mentioned in paragraph [0045] of this document. EP 1830816 gives no indication that the enteric coating will be stable over time once the liquid pharmaceutical composition is prepared. In addition, no indication is given that the concentration of the pharmacologically active compound will remain essentially unchanged over time.

EP 1051174 describes a formulation of microgranules containing omeprazole, with enteric coating, said formulation containing at least one hydrophobic substance chosen to increase the stability of omeprazole, namely by protecting it against ambient humidity (40 to 75% humidity at 25 ° C) and to obtain the dissolution profile of the pharmaceutically active compound. The hydrophobic substance (Gelucire, silicone) can be located in the different layers of the multilayer assembly, including in the outer enteric coating. In the latter case, EP 1051174 describes the use of hydrophobic agents such as glycerides in combination with the components conventionally used to prepare the enteric coating. Therefore, such a coating, which is still an enteric coating, should not be stable in an aqueous environment of

BE2016 / 5555 liquid having a pH greater than 6. In addition, as such, EP 1051174 gives no indication that the microparticles of EP 1051174 are capable of resisting the hydrolytic action of the water contained in the liquid phase when dispersed therein.

EP 1728512 describes the use of waxes to improve the controlled release of active substances contained in pharmaceutical compositions. This document describes a controlled release pharmaceutical composition comprising: 1) a nucleus containing a physiologically active substance unstable in an acid medium and a disintegrant; and 2) a controlled release coating which covers the core and which contains a water insoluble polymer, an enteric polymer and a hydrophobic wax. Similarly to EP 1051174, the objective of the invention is to obtain suitable dissolution profiles for a pharmaceutically active compound and is not intended to increase the stability of multilayer microparticles with modified release in a liquid pharmaceutical composition. In addition, such a coating still has the function of an enteric coating layer and, therefore, should not be stable over time in a liquid preparation having a pH greater than

6.

Consequently, there is still a need to formulate controlled release microparticles in the form of a liquid pharmaceutical composition intended for oral administration which must be stable for a longer period of time than the prior art and, in particular, during more than a few hours at room temperature.

This is particularly necessary in the case of pharmaceutically active compounds which must not be released into the stomach, such as pharmaceutically active compounds which are acid-labile or aggressive for the gastric mucosa and which therefore require protection against the environment. gastric after ingestion. This is also necessary in the case of pharmaceutically active compounds administered orally which must specifically target a section of the gastrointestinal tract other than the stomach or in the case of pharmaceutically active compounds administered

BE2016 / 5555 by the oral route having improved or prolonged therapeutic efficacy by using a prolonged-release pharmaceutical composition.

The inventors have unexpectedly discovered that it is possible to formulate such a composition by coating the microparticles with an outer coating layer which protects the particles against the deleterious effect of the liquid medium and, consequently, prevents the release of the compounds. pharmaceutically active in the liquid pharmaceutical composition before its ingestion while maintaining the effectiveness of said pharmaceutically active compound, the outer coating layer being soluble in the gastric fluid so that the particles recover their controlled release characteristic which was protected by this layer, after administration in the stomach.

Consequently, the particles thus obtained simultaneously:

- are stable in the liquid pharmaceutical composition for at least several hours, preferably several days, and more preferably several weeks, when it is stored at 4 ° C. and

- have a controlled release characteristic after ingestion, in particular in order to avoid the release of the pharmaceutically active compound contained therein in the stomach or to start the release only in the stomach, the release being terminated outside stomach (extended release).

In order to have this function, the inventors have discovered that the outer coating layer must contain a mixture of

a) a hydrophilic gastro-soluble component which is insoluble in an aqueous medium at a pH of between 6.5 and 7.5, advantageously at a pH> 5, and

b) a hydrophobic and / or insoluble component.

Consequently, the present invention relates to a multilayer controlled release microparticle containing a pharmaceutically active compound, said microparticle being intended for oral administration or direct administration in the stomach in the form of a liquid pharmaceutical composition and said microparticle comprising :

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- a nucleus comprising the pharmaceutically active compound;

- an intermediate coating layer with controlled release;

- an outer external protective coating layer surrounding the controlled release intermediate coating layer and containing a mixture of

a) a hydrophilic gastro-soluble component which is insoluble in an aqueous medium at a pH of between 6.5 and 7.5, advantageously at a pH> 6.5, more advantageously at a pH> 6, in particular at a pH> 5.0 and

b) a hydrophobic and / or insoluble component.

In the context of the present invention, the term “controlled release microparticle” is intended to mean that the release of the pharmaceutically active compound contained in the microparticle is controlled and, in particular, that the release of the total amount of the pharmaceutically active compound contained in it should not occur in the stomach (for example, enteric-releasing, colon or sustained-release pharmaceutical forms). Therefore, it is not an immediate release microparticle. In some cases, the release of the pharmaceutically active compound could start in the stomach (e.g. prolonged-release pharmaceutical form) and then continue in another part of the gastrointestinal tract but, preferably, the release does not occur from the everything in the stomach.

Therefore, the "controlled release microparticle" can be a delayed or sustained release microparticle. In the case of delayed release, the release of the pharmaceutically active compound can occur in the intestine or even in the colon.

The term "pharmaceutically active compound" is intended to denote any compound having pharmaceutical activity in the organism of an animal, in particular in the organism of a human being.

In particular, the pharmaceutically active compound is:

- a pharmaceutically active acid-labile compound or a pharmaceutically active compound unstable under acidic conditions such as a proton pump inhibitor, in particular chosen from the group consisting of omeprazole, lansoprazole, tenatoprazole, esomeprazole, rabeprazole and

BE2016 / 5555 pantoprazole, or an antibiotic such as erythromycin or an antiretroviral agent (such as didanosine) or peptides and proteins (such as insulin, pancreatin);

- a pharmaceutically active compound which is aggressive for the gastric mucosa such as a non-steroidal anti-inflammatory pharmaceutically active compound (for example, diclofenac, aceclofenac, ibuprofen, ketoprofen, oxaprozin, indomethacin, meloxicam, piroxicam, tenoxicam, celecoxib, etoroxib) nabumetone, naproxen or aspirin).

- a pharmaceutically active compound whose therapeutic efficacy must be improved or prolonged with a prolonged-release layer, such as an antibiotic (for example amoxicillin, cefadroxil, cefazolin, cefuroxime, cefotaxime, meropenem, aztreonam, erythromycin, azithromycin, Clarithromycin, roxithromycin, spiramycin, doxycycline, minocycline, clindamycin, lincomycin, Ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, sulfamethazole and trimethroprim, isoniazid, rifampinin, rifampicin, amifoline, rifampicin, etifipine, etifiphine, rifampicin, etifipine, nifipine, rifampicin, amifipine, rifampicin, amifinine, rifampicin, amifipine, nifiphine, rifampicin, amifipine, rifampicin, amifinine, rifampicin, amifinine, rifampicin, amifinine, rifampicin, amifinine, rifampicin, amifinine, rifampicin, amethipine, rifampicin, etifipine] , lacidipine, lercanidipine, nicardipine, nimodipine, nisoldipine, nitrendipine, verapamil, diltiazem), an antiarrhythmic drug (for example, flecainide, amiodarone, cibenzoline, disopyramide, sotalol), beta-blocker, for example, metololololololedolololedol , celiprolol, esmolol, labetalol, nebivolol, proprano lol), a diuretic (for example, furosemide, torasemide, spironolactone), a cardiovascular medication (for example, doxazosin), an anti-inflammatory medication (for example, ibuprofen, diclofenac) or an analgesic (for example, tramadol, oxycodone , morphine)

- a pharmaceutically active compound which must target a section of the gastrointestinal tract other than the stomach such as a chemotherapeutic agent for the treatment of cancer (of the colon) (for example, fluorinated pyrimidines such as rhexycarbamoyl-5-fluorouracil ( carmofur), uracil / tegafur, uracil / tegafur / leucovorin, capecitabine etc.) or for the treatment of intestinal diseases such as ulcerative colitis or Crohn's disease such as an anti-inflammatory drug (for example, mesalazine,

BE2016 / 5555 sulfasalazine) or an oral corticosteroid (e.g. budesonide, beclometasone).

Advantageously the pharmaceutically active compound is a pharmaceutically active acid-labile compound or a pharmaceutically active compound unstable under acidic conditions such as a proton pump inhibitor, in particular chosen from the group consisting of omeprazole, lansoprazole, tenatoprazole, esomeprazole, rabeprazole and pantoprazole, or an antibiotic such as erythromycin. More advantageously, it is a proton pump inhibitor, in particular chosen from the group consisting of omeprazole, lansoprazole, tenatoprazole, esomeprazole, rabeprazole and pantoprazole. Even more advantageously, it is omeprazole.

In another particular embodiment, the pharmaceutically active compound is chosen from the group consisting of diclofenac, furosemide and tramadol.

In the context of the present invention, the term “multilayer microparticle” is intended to designate a particle containing at least two layers, in particular more than two layers, surrounding its core.

In fact, the microparticle according to the present invention comprises:

- a nucleus comprising the pharmaceutically active compound;

- an intermediate coating layer with controlled release;

- an outer external protective coating layer surrounding the controlled release intermediate coating layer and containing a mixture of

a) a hydrophilic gastro-soluble component which is insoluble in an aqueous medium at a pH of between 6.5 and 7.5, advantageously at a pH> 5.0 and

b) a hydrophobic and / or insoluble component.

Consequently, the multilayer microparticle has an “onion-type” structure, and, in particular, is prepared according to batch or continuous coating steps using one or more coating techniques known to those skilled in the art such as extrusion-spheronization, lamination techniques such as powder lamination, solution lamination, suspension lamination, spheronization, coagulation techniques or spray coagulation techniques. Adapted equipment such

BE2016 / 5555 that a coating turbine, a coating granulator or a fluidized bed coating apparatus using water and / or organic solvents can be used.

The core of the microparticle according to the present invention comprises the pharmaceutically active compound.

The pharmaceutically active compound can therefore be, for example, incorporated into the neutral granule which is the core of the microparticle (internal part) and / or into one or more layers of the multilayer microparticle which are, for example, sprayed onto the granule . In the latter case, the core consists of a multilayer core.

The core of the microparticle which is to be film-coated may consist of granules used as a support for successive coatings. Lactose and sugars are preferably avoided to allow administration of the stable liquid pharmaceutical composition to diabetic patients.

The granules can be, for example, microcrystalline cellulose and cellulose derivatives, mannitol (such as Μ-Cell®), starch, silica or different oxide, organic polymers, inorganic salts alone or in mixtures, non-similar, a lipid or carnauba wax (for example C-Wax Pellets®) or calcium hydrogen phosphate, advantageously, the granules are made of microcrystalline cellulose, in particular sold under the trade name Cellets®, such as Cellets® 1000, 700,

500, 350, 200, 100.

They can be manufactured by a process known in the art such as extrusion-spheronization, film-coating techniques or spray coagulation techniques.

Alternatively, the nucleus may already contain the pharmaceutically active compound (for example, if it is produced by an extrusion / spheronization process). The core can include the pharmaceutically active compounds in the form of agglomerates, compacted forms, etc.

Advantageously, the core of the microparticle is a film-coated core consisting of a neutral granule on which a layer containing the pharmaceutically active compound is applied by a technique known in the art,

BE2016 / 5555 for example by spraying. The layer containing the pharmaceutically active compound may also contain a binder and other suitable excipients. Binders are, for example, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), polyethylene glycols, polyvinyl alcohols, sugars (preferably, not lactose), starches, etc. It can also comprise a lubricant or an antiadhesive agent such as talc or an antioxidant such as ascorbyl palmitate.

In the case where the pharmaceutically active compound is omeprazole, the layer containing omeprazole which surrounds the nucleus may also contain polyvinylpyrrolidone (PVP), ascorbyl palmitate and talc.

The core according to the present invention can comprise another material such as surfactants, fillers, disintegrants, alkaline additives, alone or in mixtures.

The surfactants are, for example, selected from the group of a nonionic surfactant such as, for example, Polysorbate 80 or ionic surfactants such as, for example, sodium lauryl sulfate.

Fillers can be used in the nucleus of the microparticle. Examples of fillers include, for example, mannitol and dicalcium phosphate.

A disintegrating agent can be used in the nucleus of the microparticle. Examples of disintegrants which can be used are, for example, crosslinked polyvinylpyrrolidone (i.e., Crospovidone), pregelatinized starch, microcrystalline cellulose and crosslinked carboxymethylcellulose (i.e. , Croscarmellose sodium).

According to one embodiment of the invention, the pharmaceutically active compound can also be mixed with a pharmaceutically acceptable alkaline substance (or substances). Such substances may, after excluding bicarbonate salts or carbonate salts, be selected from, but are not limited to, substances such as the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, d citric acid or other suitable inorganic or organic weak acids; substances normally used in antacid preparations such as

BE2016 / 5555 as hydroxides of aluminum, calcium and magnesium; magnesium oxide; organic pH buffers such as trihydroxymethylaminomethane, basic amines or amino acids and their salts, or other similar pharmaceutically acceptable pH buffers.

In another particular embodiment, another layer may be included between the core and the layer containing the pharmaceutically active compound. Such a layer may comprise a film-forming agent such as ethylcellulose (in particular ethocel EP), fillers such as talc and / or titanium dioxide, a plasticizer such as triethyl citrate (TEC) or triethyl citrate of acetyl (ATEC), a binder and / or a lubricant as described above.

Such a layer is intended to protect the nucleus against the osmotic effect.

In the case where the pharmaceutically active compound is omeprazole, such a layer may comprise ethylcellulose (such as ethocel EP), triethyl citrate (TEC), talc and titanium dioxide.

The microparticle according to the present invention comprises an intermediate coating layer with controlled release. This layer confers the controlled release profile (delayed, prolonged or continuous release by means of enteric, colic or insoluble layers) depending on the pharmaceutical compound to be administered. It includes a film-forming polymer to obtain controlled release properties, such as an enteric polymer (for example, for a PPI such as omeprazole, esomeprazole, pantoprazole, lansoprazole, tenatoprazole, rabeprazole) (for example, for mesalazine), insoluble (for example, for pain relievers such as tramadol).

Enteric film-forming polymers are pharmaceutically acceptable polymers such as polymers of stearic acid, palmitic acid or behenic acid, polymers such as hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate , methacrylic acid copolymers (for example, poly (methacrylic acid-ethyl co-acrylate) 1: 1 such as Eudragit® L30D-55,

BE2016 / 5555 poly (methacrylic acid-methyl co-methacrylate) 1: 1 and 1: 2 such as Eudragit® L-100 and S-100), cellulose acetate trimellitate, carboxymethylcellulose, shellac or d other suitable enteric polymers.

Colonic film-forming polymers are pharmaceutically acceptable polymers such as copolymers derived from acrylic acid (for example, poly (methacrylic acid-methyl co-methacrylate) 1: 1 and 1: 2, Eudragit® L100 and S-100, poly (methyl acrylate-methyl co-methacrylate-co-methacrylic acid) 7: 3: 1, Eudragit® FS30D) or polymers which may be degraded by the enzymatic activity of the proximal intestinal microflora (e.g. azopolymers or polysaccharides such as guar gum, pectin, chondroitin sulfate, dextran, chitosan).

The insoluble film-forming polymers are pharmaceutically acceptable polymers such as neutral insoluble polymethacrylate ester derivatives (poly (ethyl acrylate-methyl co-methacrylate) 2: 1, Eudragit® NE30D) or slightly cationic (poly (acrylate d (ethyl-methyl co-methacrylate-trimethylammonioethyl methacrylate cochloride), 1: 2: 0.1 and 1: 2: 0.2, Eudragit® RS and RL) or insoluble cellulose derivatives such as ethylcellulose.

Advantageously, therefore, the intermediate controlled release coating layer is a delayed release coating layer such as an enteric coating layer, a colonic coating layer or an insoluble coating layer or a coating layer. continuous release coating, in particular it is an enteric coating layer.

Such a controlled release layer may also comprise a lubricant such as talc, a filler such as titanium dioxide, a surfactant, for example, chosen from the group of a nonionic surfactant such as, for example, polysorbate 80 and / or an anti-foaming agent such as a silicone oil.

It can also contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as the flexibility and the hardness of the enteric coating layer. Such plasticizers are, for example, but not limited to, triacetin, esters of citric acid such as

BE2016 / 5555 triethyl citrate (TEC) or acetyl triethyl citrate (ATEC), phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

The controlled release intermediate coating layer can be applied to the core material by suitable coating or lamination procedures in suitable equipment such as a coating turbine, a coating granulator or a coating apparatus. fluidized bed coating using water and / or organic solvents for the coating process. Alternatively, the controlled release intermediate coating layer can be applied to the core material using a powder coating technique.

In the case where the pharmaceutically active compound is omeprazole, the enteric coating layer may comprise an anionic copolymer based on methacrylic acid and ethyl acrylate (Eudragit® L30D55, for example), talc, polysorbate 80, silicone oil and acetyl triethyl citrate (ATEC).

The controlled release layer can be directly coated on the core (which can be a film-coated core as previously described) or another intermediate layer can be included between the core and the controlled release intermediate coating layer.

Consequently, in a particular embodiment, the microparticle according to the present invention contains at least one other intermediate layer between the core and the intermediate coating layer with controlled release, in particular an intermediate protective coating layer.

Consequently, in the latter case, optionally, one or more protective layers can be added, which can be composed of one or more neutral hydrophilic polymer (s) capable of protecting the medicament incorporated in the core (or in the layer surrounding the core in the case of a film-coated core) against potential early degradation due to the components contained in the other layers (for example, the adjacent layers). By way of illustration, this is the case for acid-labile drugs such as, for example, omeprazole, the contact of which with the enteric polymers included in the next layer containing groups

BE2016 / 5555 acids in their chemical structure is enough to inactivate the drug.

One or more separation layers can also be used to avoid potential undesirable interactions / incompatibilities between the polymer (such as film-forming polymers) and the constituents of the adjacent layers. By way of illustration, this is the case of an enteric polymer containing acid groups of a first layer which can interact with gastro-soluble polymers containing alkaline groups of the next layer.

The materials for the protective or separation layer (s) are known to those skilled in the art and are, for example, sugars, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (HPMC) and the like, used alone or as a mixture.

Additives such as plasticizers, dyes, pigments, fillers, antiadhesive and antistatic agents, such as, for example, magnesium stearate, titanium dioxide, fumed silica, talc and other additives can also be included in the separating or protective layer (s).

The separation layer (s) can serve as a diffusion barrier and can act as a pH buffer zone. The pH buffer properties of the separation layer (s) can be further enhanced by the introduction into the layer (s) of substances modifying or buffering the pH, after exclusion of the bicarbonate or carbonate salts. , selected from a group of compounds commonly used in antacid formulations such as, for example, magnesium oxide or hydroxide, aluminum or calcium hydroxide or silicates; aluminum / magnesium composite compounds such as, for example MgO.AI ₂ O ₃ , 2SiO ₂ .nH ₂ O, or other pharmaceutically acceptable pH buffer compounds such as, for example sodium, potassium salts, calcium, magnesium and aluminum of phosphoric, citric acid or other suitable inorganic or organic weak acids; or suitable organic bases, comprising basic amino acids or amines

BE2016 / 5555 and salts thereof. Talc or other compounds can be added to increase the thickness of the layer (s) and thus strengthen the diffusion barrier.

The separation or protective layer (s) can be applied to the core material by suitable coating or coating procedures in suitable equipment such as a coating turbine, a coating granulator or a fluidized bed coating apparatus using water and / or organic solvents for the coating process. Alternatively, the separating or protective layer (s) can be applied to the core material using a powder coating technique.

In the case where the pharmaceutically active compound is omeprazole, the microparticle according to the invention can contain at least one intermediate separation layer. Said protective layer may contain titanium dioxide, talc and PVP.

The microparticle according to the present invention further comprises an outer external protective coating layer surrounding the intermediate release coating layer.

This external external protective coating layer may be placed just above the intermediate controlled release coating layer without an intermediate layer between the intermediate controlled release coating layer and the external external protective layer.

Advantageously and in particular in the case where the pharmaceutically active compound is a proton pump inhibitor, there is at least one intermediate layer between the external external protective coating layer and the controlled release intermediate coating layer. .

The intermediate coating layer is an intermediate protective layer as described above. In the case where the pharmaceutically active compound is omeprazole, the microparticle according to the invention can contain at least one intermediate protective layer. Said protective layer may contain talc and PVP.

BE2016 / 5555

In all cases, this external external protective coating layer will be the only layer of the microparticle in direct contact with the liquid medium having a pH> 6 when the microparticles are dispersed therein in order to form the liquid pharmaceutical composition.

Said external external protective layer has barrier properties, that is to say it protects the incorporated pharmaceutically active compound against degradation caused by water, a solvent or other components in the liquid phase of the liquid medium. having a pH> 6 of the liquid pharmaceutical composition in which the microparticles are dispersed and avoids the early diffusion / release of the pharmaceutically active compound from the microparticles in the liquid medium during its storage and therefore, before its administration.

This external external protective layer also protects the controlled release layer against the liquid medium having a pH> 6 of the liquid pharmaceutical composition in which the microparticles are dispersed. Consequently, it prevents the dissolution and / or the degradation of this layer in said liquid.

This external external protective layer is also susceptible to degradation in the acidic environment of the gastroenteric region and, consequently, will disappear (will be degraded or dissolved) quickly in the stomach, advantageously in less than 3 hours, more advantageously in 2 hours, even more advantageously immediately (i.e., <45 min), after contact with the gastric environment. Consequently, the microparticles, soon after reaching the gastric environment, will be in a state as if the external external protective layer had never been present and will recover their controlled release properties.

Consequently, the microparticles according to the present invention will have the same characteristics (comprising, for example, the release profiles of pharmaceutically active compound) as those obtained when the multilayer microparticles without the external external protective coating layer are administered orally. in the form of a solid oral pharmaceutical composition (ingestion of a tablet or capsule containing microparticles, such as MUPS).

BE2016 / 5555

Finally, the external external protective layer will also help the particles to remain in suspension in the liquid medium having a pH> 6 in which they are dispersed. Consequently, it will avoid their aggregation and decantation.

To obtain these characteristics, the outer protective layer must contain a mixture of two components:

a) a hydrophilic gastro-soluble component which is insoluble in an aqueous medium at a pH of between 6.5 and 7.5, advantageously at a pH> 5.0 and

b) a hydrophobic and / or insoluble component.

Compound a) is responsible for the degradation of microparticles in the stomach and helps the microparticles to remain in suspension in the liquid medium having a pH> 6 in which they are dispersed.

Compound b) is responsible for the liquid barrier effect from the liquid medium to the nucleus of the particle.

In the context of the present invention the term "hydrophilic component" is intended to denote any component which is attracted and tends to be dissolved by water.

In the context of the present invention the term "insoluble" is intended to mean that no more than 10,000 parts of solvent (volume) is necessary to dissolve part of the component (weight).

In the context of the present invention, the term “hydrophobic component” is intended to denote a component which has no affinity for water.

The hydrophilic and hydrophobic behavior of a molecule can be characterized by its value of the hydrophilic-lipophilic balance (HLB). Currently measured by the Griffin method, an HLB value of 0 corresponds to a fully lipophilic / hydrophobic molecule, and a value of 20 corresponds to a fully hydrophilic / lipophobic molecule.

The hydrophilic gastro-soluble component (a) is, therefore, insoluble in an aqueous medium at a pH between 6.5 and 7.5, advantageously at a pH> 6, in particular at a pH> 5. On the other on the other hand, it is a gastrosoluble component, which means that it is at least soluble in a gastric environment, that is to say, at a pH <6, more advantageously at a pH <5.5, in particular at pH <5.

BE2016 / 5555

In the context of the present invention the term "soluble in a gastric environment" means that 10 to 30 parts of the gastric fluid (by volume) will dissolve one part of a component (by weight).

In an advantageous embodiment, the hydrophilic gastro-soluble component is a synthetic or natural cationic polymer, in particular chosen from the group consisting of a cationic polymer, such as a polymer based on dimethylaminomethyl methacrylate, butyl methacrylate and methyl methacrylate, chitosan and chitin. In particular, it is a cationic polymer based on dimethylaminomethyl methacrylate, butyl methacrylate and methyl methacrylate, more particularly with a ratio of dimethylaminomethyl methacrylate / butyl methacrylate / methyl methacrylate of 2/1/1 such that, for example example, Eudragit E® (e.g. Eudragit® E100, Eudragit® E12.5 and Eudragit® E PO). Such a polymer has the following formula:

and a weight average molecular weight (Mw) based on the SEC process of about 47,000 g / mol. Eudragit E® is soluble in aqueous fluids up to pH 5.0. However, it is also swellable and permeable above pH 5.0 which makes it unsuitable to act as a barrier in a liquid for an extended period of time when used alone in the outer outer coating layer as exemplified in example 1.

In an advantageous embodiment, the hydrophobic and / or insoluble component (b) is chosen from the group consisting of glycerides such as glyceryl monostearate or glyceryl dibehenate (for example, Compritol® 888 ATO), a wax, magnesium stearate, a fatty alcohol, ethylcellulose, a copolymer based on ethyl acrylate and methyl methacrylate, in particular a copolymer of ethyl acrylate, methacrylate of

BE2016 / 5555 methyl and a low content of methacrylic acid ester with quaternary ammonium groups (the molar ratio of ethyl acrylate / methyl methacrylate / trimethylammonioethyl methacrylate being, for example, about 1: 2: 0.1, more preferably with a weight average molecular weight Mw based on the SEC process of 32,000 g / mol) such as Eudragit® RS 100, a silicone, stearic acid and, in particular, in the group consisting of glycerides, stearic acid and magnesium stearate, more advantageously in the group consisting of magnesium stearate and glyceryl monostearate, even more advantageously, it is glyceryl monostearate.

In an advantageous embodiment, the weight ratio of hydrophilic gastro-soluble component / hydrophobic and / or insoluble component in the outer external protective coating layer is between 200/1 and 1/1, in particular 50/1 to 5/1, more advantageously between 10/1 and 30/1, even more advantageously of approximately 20/1.

In another advantageous embodiment, the external external protective coating layer represents 8 to 20%, in particular 8 to 10% by weight of the total weight of the microparticle.

In yet another advantageous embodiment, the% by weight of the hydrophobic and / or insoluble component based on the total weight of the mixture of gastro-soluble component + hydrophobic and / or insoluble component is between 1 and 20%.

In another advantageous embodiment, the external external protective coating layer of the microparticle according to the invention contains another excipient, in particular a lubricant such as talc.

Advantageously, the microparticle according to the present invention has an average diameter D ₅₀ in volume measured by the laser granulometer Malvern Mastersizer 3000, with the dry dispersion unit Aero S (Malvern Instruments, United Kingdom) between 80 pm and 2000 pm, advantageously included between 100 pm and 1000 pm, more advantageously between 200 pm and 500 pm. These

BE2016 / 5555 last dimensions make it possible to avoid discomfort of palatability and the risks of involuntary chewing of the external protective coating or of the microparticles before swallowing them.

The present invention further relates to a liquid pharmaceutical composition intended for oral administration or direct administration into the stomach comprising the microparticles according to the present invention homogeneously dispersed in a liquid medium having a pH> 6, advantageously having a pH > 6.5, in particular a pH between 6.5 and 7.5. The liquid medium can be an organic or aqueous liquid medium. Advantageously, it is an aqueous liquid medium.

In the context of the present invention, the term “homogeneously distributed” (or uniform distribution) means that the distribution of the multilayer controlled release microparticles according to the present invention in the first dose taken of the liquid pharmaceutical composition according to the present invention and the following doses up to the last dose taken from said liquid pharmaceutical composition according to the present invention is similar (that is to say, between 85% and 115% of the nominal dose, advantageously between 90 and 110 % of the nominal dose).

The liquid medium can include water as the liquid phase. It can also comprise other components apart from the microparticles and the liquid, as is known to those skilled in the art, such as viscosifying agents, osmotic agents and / or buffering agents, in particular, it comprises agents viscosifiers, osmotic agents and buffering agents. It can also comprise other excipients known to those skilled in the art such as sweeteners, gums, cellulose or acrylic derivatives, thixotropic or pseudoplastic agents, stabilizers, preserving agents, etc.

Advantageously, the viscosifying agent is chosen from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP) and a mixture of these. More advantageously, it is polyvinylpyrrolidone (PVP) or a mixture of microcrystalline cellulose and sodium carboxymethylcellulose which can be easily dispersed in a

BE2016 / 5555 aqueous medium, preferably at room temperature and under gentle dispersion, in particular in the form of a spray-dried mixture such as, for example, Avicel® RC-951 or Avicel® CL-611. Even more advantageously, it is PVP, in particular in an amount of 16% w / w based on the total weight of the composition.

Advantageously, the osmotic agent is a polyol, such as mannitol, sorbitol or xylitol, more advantageously it is sorbitol, even more advantageously in an amount of 30% by weight, based on the total weight of the mixture.

Advantageously, the buffering agent is chosen from the group consisting of glycine or a borate buffer, in particular borate. Advantageously, the concentration of borate buffer is 0.01 M. Advantageously, the concentration of glycine buffer is between 0.1 M and 0.2 M, more advantageously it is 0.1 M.

The liquid composition can, for example, be a suspension, an emulsion, such as a microemulsion, a dispersion, a gel or a paste, even more advantageously, it is a suspension, for example, a suspension in a medium aqueous such as a buffered solution, a syrup or an oily medium. In particular, the liquid composition exhibits a thixotropic or pseudoplastic behavior.

In an advantageous embodiment, the pharmaceutically active compound contained in the microparticles of the liquid pharmaceutical composition according to the present invention is chemically stable for at least 1 day when it is stored at 4 ° C., advantageously at room temperature (approximately 20 to 25 ° C), advantageously at least a week, more advantageously at least 1 month.

In the context of the present invention, the term “chemically stable pharmaceutically active compound” is intended to mean that the physico-chemical stability of the pharmaceutically active compound remains unchanged in the liquid pharmaceutical composition according to the present invention during its storage (for example, structure chemical profile

BE2016 / 5555 dissolution, crystal / amorphous structure, pharmacological activity). Consequently, the level of non-degraded pharmaceutically active compound incorporated in the microparticles does not decrease below 70% by weight, preferably not below 80%, even more preferably, not below 85% relative to at the level of the pharmaceutically active compound contained in the corresponding microparticle, before they are mixed with the liquid medium.

In another advantageous embodiment, less than 20% by weight, advantageously less than 10%, more advantageously less than 5% of the pharmaceutically active compound contained in the microparticles is released into the liquid medium of the liquid composition according to the present invention when the composition is stored for at least 1 day at 4 ° C., advantageously at room temperature, advantageously at least one week, more advantageously at least 1 month.

In an advantageous embodiment, the pharmaceutically active compound contained in the microparticles of the liquid pharmaceutical composition according to the present invention is physically stable for at least 10 seconds, preferably 20 seconds, even more preferably 30 seconds after homogenization by gentle mixing before d be taken by the patient. In the context of the present invention, the term “physically stable” means that the microparticles remain distributed in a uniform or homogeneous manner throughout the total volume of the liquid medium at least 10 seconds, preferably 20 seconds, even more preferably 30 seconds after homogenization by gentle mixing and that sedimentation, phase separation, aggregation, the formation of layered structures of aggregated microparticles and the like are avoided.

The present invention further relates to a kit for the preparation of a liquid pharmaceutical composition for oral administration or direct administration in the stomach according to the present invention comprising:

the microparticles according to the present invention and

BE2016 / 5555

- A liquid medium having a pH> 6, advantageously a pH> 6.5, more advantageously between 6.5 and 7.5, in particular as described above.

The microparticles and the liquid medium can be contained in separate containers and must be mixed together before use. Therefore, the kit can be provided with appropriate instructions for mixing the particles with the liquid medium.

In another advantageous embodiment, other excipients known to those skilled in the art such as sweeteners, gums, cellulose or acrylic derivatives, thixotropic agents, pseudoplastic agents, stabilizers, preservatives , etc., and, in particular, a buffering agent, an osmotic agent and / or a viscosifying agent, advantageously as described above, can be added to the microparticles and, therefore, the kit contains a mixture of the microparticles with these excipients and / or viscosifying agents and / or buffers and / or an osmotic agent and a liquid medium, which must be mixed by the patient or by a competent person (for example the pharmacist, a nurse, ...) before administration or before the start of treatment with the pharmaceutically active compound.

The present invention further relates to a solid pharmaceutical composition intended to be reconstituted in the form of a liquid pharmaceutical composition for oral administration or direct administration in the stomach, said solid composition comprising the microparticles according to the present invention, optionally in admixture with a viscosifying agent and / or a buffering agent and / or an osmotic agent. Advantageously, the viscosifying agent is as described above. More advantageously, the buffering agent is as described above. Even more advantageously, the osmotic agent is as described above.

The solid pharmaceutical composition according to the invention may be in the form of a dry syrup, a powder or of aggregates or even a tablet with rapid dispersion.

BE2016 / 5555

If it is in the form of a powder or granules, it can be packaged in sachets.

In order to prepare the liquid pharmaceutical composition according to the invention, it is simply necessary to add a liquid medium having a pH> 6, advantageously a pH> 6.5, in particular a pH between 6.5 and 7.5, to the solid pharmaceutical composition according to the invention and to mix them together, in particular with gentle stirring. The liquid medium can be as described above or it can simply be purified, mineral or tap water.

Consequently, the present invention also relates to a process for the preparation of a liquid composition for oral administration or direct administration in the stomach according to the present invention comprising the addition of a liquid having a pH> 6, advantageously a pH> 6.5, in particular a pH between 6.5 and 7.5, in the solid pharmaceutical composition according to the present invention. Then, the resulting composition is mixed, advantageously with gentle stirring, in particular by the patient or by a competent person (for example, the pharmacist, a nurse, ...) before administration or before the start of treatment with the pharmaceutically active compound. .

The reconstituted liquid pharmaceutical composition thus obtained can be administered in the form of a single dose (single administration) or in the form of multiple doses (chronic administration).

The liquid pharmaceutical composition according to the present invention can be administered to a patient in need thereof orally or directly into the stomach by means of any suitable infusion device such as a nasogastric tube or a gastrostomy tube or any other suitable device known to those skilled in the art.

The liquid pharmaceutical composition according to the present invention is particularly suitable for pediatric and geriatric patients who have difficulty swallowing or chewing pharmaceutical compositions

BE2016 / 5555 solids; patients who refuse to take solid pharmaceutical compositions due to fear of strangulation; very elderly patients who cannot swallow a daily dose of a pharmaceutically active compound or mentally ill patients in an institutional context who may try to hide a conventional tablet under their tongue in order to avoid taking their daily dose of agents therapeutic.

If the pharmaceutically active compound is omeprazole, the liquid pharmaceutical composition according to the present invention is intended to be used as a medicament for the prevention and / or treatment of gastrointestinal disorders, in particular for inhibiting acid secretion gastric in mammals and humans. In a more general sense, it can be used for the prevention and treatment of diseases associated with gastric acid in mammals and in humans, including, for example, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. In addition, it can be used for the treatment of other gastrointestinal disorders when an inhibitory effect on gastric acid is desirable, for example, in patients receiving NSAID therapy, in patients with non-ulcerative dyspepsia, in patients with symptomatic gastroesophageal reflux disease, and in patients with gastrinomas. It can also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acidic aspiration of stomach acid and to prevent and treat ulceration related to stress. In addition, it can be useful for the prevention and treatment of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, laryngitis, Barrett's syndrome, sleep apnea, a sleep disorder, and psoriasis is also useful for the prevention and treatment of Helicobacter infections and diseases related to the conditions described above.

BE2016 / 5555

The invention will appear more clearly on reading the description of the figures and examples which are presented without implied limitation.

FIG. 1 represents the change in the amount of omeprazole (in% by weight), released during a dissolution test in an aqueous medium (11.37 ° C., paddle process, 100 rpm), from the microparticles 12H2014 as described in Example 1 and reference microparticles containing omeprazole (Losec 40 mg from AstraZeneca) depending on the pH conditions.

The microparticles are placed in phosphate buffer (pH 7.0) for 2 hours, then in an acid medium (pH 1.2) for 2 hours and finally in phosphate buffer pH 6.8 (Example 1).

FIG. 2 represents the dissolution profile of lot 1612014 of the microparticles according to the present invention (Example 1) using the recommendation of the European Pharmacopoeia VUIth edition for an enteric pharmaceutical form: 2 hours in acid medium followed by 45 min in phosphate buffer pH 6.8 (11, 37 ° C, pallet process, 100 rpm) (example 1).

FIG. 3 represents the comparison between 3 microparticles containing omeprazole suspended in water (2 microparticles according to the present invention: lot n ° 02B2015 and 16C2015 and a microparticle with commercial enteric coating: Omeprazole-Sandoz 40 mg) of the omeprazole retained (in the microparticles: pellet) and the omeprazole released (in the aqueous medium:

supernatant) after 7 days of storage in a refrigerator (4 to 8 ° C) (Example 3).

FIG. 4 represents the change in the amount of omeprazole (in% by weight) released into the aqueous medium surrounding the 02B2015 microparticles according to the present invention and the reference commercial microparticles containing omeprazole (Omeprazole-Sandoz) according to l dissolution test at 3 stages, that is to say, stage 1 (from 0 to 4 h; pH 7.0 - syrup type storage state), stage 2 (from 4 hours to 6 hours in acidic environment pH 1.2 (conditions

BE2016 / 5555 gastric)) and step 3 (45 min in phosphate buffer pH 6.8 (intestinal conditions) (example 4).

FIG. 5 represents the rheological profile (viscosity (cp) vs. shear stress (rpm) of an aqueous solution containing PVP 16% w / w + sorbitol 30% w / w + 0.01 M borate buffer pH 7.4 at room temperature, 12-2.5-5-10-30-40-50-75-100 rpm (Brookfield, United States).

Materials and processes

The microparticles used as an inert core for the coated formulations developed according to the examples below consist of microcrystalline cellulose microspheres called Cellets® which are characterized by different particle sizes (d (0.5) measured by laser diffraction):

Cellets® 1000: 1000-1400 pm

Cellets® 700: 700-1000 pm

Cellets® 500: 500-710 pm

Cellets® 350: 350-500 pm

Cellets® 200: 200-355 pm

Cellets® 100: 100-200 pm

Bulk omeprazole was purchased from Aurobindo Pharma (India), polymers derived from film-forming acrylic acid Eudragit® were purchased from Evonik (UK), all other excipients are pharmaceutical grade.

The marketed products used as references are Losec 40 mg from Astrazeneca and Omeprazole-Sandoz 40 mg.

Coating parameters

The coatings are carried out in a fluidized bed dryer: fluidized bed coating apparatus of the Aeromatic laboratory, GEA (Switzerland) and a fluidized bed apparatus SLFLL-5, LLeal (Spain).

Briefly, depending on the nature of the substances used, solutions / suspensions are dissolved or dispersed in the solvents. The solutions / suspensions are

BE2016 / 5555 prepared with an Ultra-Turrax® high shear homogenizer. The solutions / dispersions are continuously stirred magnetically to avoid sedimentation of insoluble particles during the process. Between 500 and 1500 g of Cellets® (type specified in the examples) are introduced inside the fluidized bed apparatus. The drying air pressure is set at 40-45 ° C and 50-55 ° C for organic and aqueous solutions / dispersions, respectively. The air pressure is in the range of 0.5 to 3.0 bar. The drying air flow is adjusted in order to obtain an optimal movement of the microparticles and the flow is in the range between 5 and 10 g / min. when an acrylic polymer is present in the coating, a hardening step is carried out for 12 hours at 30 ° C.

Quantification method

Approximately 1 g of cured microparticles is ground and an exact amount of approximately 55 mg is placed in a flask with 200 ml of 0.2 M phosphate buffer, pH 6.8. After 20 minutes of sonication, the volume is brought to 200 ml. 10 ml of each sample are taken and placed in a Falcon tube containing 2 ml of 0.25 N NaOH. After mixing, the final suspensions are filtered using 0.45 μm Millipore filters. A small volume of each filtered solution is placed in vials and loaded into the HPLC system. The tests are conducted in quintuple.

Release of omeprazole in water

In general, 5 to 20 g of omeprazole microparticles are dispersed in a 100 ml flask containing purified water and stored at 5 ° C. However, in Example 2, only 100 mg is dispersed in the 100 ml vial containing purified water. After the necessary duration specified in the examples, the amount of omeprazole is quantified by HPLC in the solution (evaluation of its release) and inside the microparticles (evaluation of its capacity to be retained in the pharmaceutical form).

Dissolution test

BE2016 / 5555

The indicated volume of the dissolution medium (± 11) is placed in each tank of the device 2, 100 rpm, n = 3 (Distek 2100C dissolution system,

Malvern Instrument, UK). The dissolution medium is equilibrated at ° C and the correct amount of microparticles is placed in each tank.

The cells are protected from light during the whole test. At the times specified, 10 ml of each sample are taken, diluted with 2 ml of 0.25 N NaOH. The final solutions are filtered using 0.45 μm Millipore filters. A small volume of each filtered solution is placed in vials and loaded into the HPLC system to assess the release of omeprazole. The samples are immediately filtered after collection with a 0.45 µm filter. The medium used for the dissolution test is a prepared buffer

with: Acetic acid: 3.0g - K2HPO4: 8.7 g - Polysorbate 20: 1.0 g 15 - Water: 1.0 1

for the acid step, the buffer described above is brought to pH 1.2 by the addition of 1N HCl. The samples of microparticles remain in this medium for 2 hours. For the buffer step, the same buffer is brought to pH 6.8 by adding 8N NaOH. The samples of microparticles remain in this medium for 45 minutes. At the end of the dissolution test, the quantity of omeprazole not released is quantified. If necessary, the microparticles are previously dispersed in phosphate buffer pH 7.0 for 2 hours before being placed in an acid medium.

Thermogravimetric analysis

ATG analysis is carried out in order to evaluate the residual solvent in the final batch of microparticles. ATG Q500 Hig equipment. Res. (TA Instruments, United States) is used for this purpose. The tests (~ 10 mg of sample) are carried out with platinum trays from 25 ° C to 200 ° C at a heating rate of

10 ° C / min at high resolution. The humidity is determined by the weight loss obtained between 25 ° C and 160 ° C.

High performance liquid chromatography (HPLC)

BE2016 / 5555

The HPLC system consists of a high performance liquid chromatography system (Agilent Technologies), equipped with a single pump, an automatic injector and a UV detector with diode array. The column is Nucleosil C8 125 mm x 4.6 mm (5 pm) Lot no: 21007023 (MachereyNagel). The mobile phase is a 0.05 M ammonium acetate buffer pH 7.6 and the dilution phase is a 0.2 M phosphate buffer pH 6.8. The wavelength is set to 305 nm; the flow rate at 1 ml / min; the temperature at 25 ° C; the volume injected is 20 μl and the duration of the test is 20 min.

Example 1: Development of a 5-layer coated microparticle according to the invention

500 g of Cellets® 1000 are poured into the fluidized bed device.

The first layer contains omeprazole as a model drug (the pharmaceutically active compound according to the invention), ascorbyl palmitate as an antioxidant, PVP as a binder, talc as an agent diluent. The materials are dispersed in ethanol. Consequently, the Cellets® coated with the first layer corresponds to the nucleus comprising the pharmaceutically active compound according to the invention.

The purpose of the second layer is to isolate the drug from the film-forming polymer Eudragit® type L. It contains PVP both as an insulating and binding polymer, titanium dioxide as an opacifying agent and talc as a diluent. The materials are dispersed in ethanol. This second layer corresponds to the protective intermediate coating layer according to the invention.

The third layer is the effective layer which gives the final release characteristics to the product: it is the intermediate coating layer with controlled release according to the invention. The aqueous dispersion contains Eudragit® L30D55 as an enteric film-forming polymer, acetyl triethyl citrate (ATEC) as a plasticizer, polysorbate 80 as a surfactant, silicone as an anti-foaming agent and talc as a diluent. The function of the fourth layer is to isolate the two acrylic acid derivatives, Eudragit® type L and type E, from each other. The ethanolic solution contains PVP as an insulating agent and talc as

BE2016 / 5555 as a diluting agent. The fourth layer corresponds to another protective intermediate coating layer according to the present invention. The outer outer layer contains Eudragit® E100 as a gastro-soluble film-forming polymer, silicone as an anti-foaming agent and talc as a diluting agent.

The composition of the layers of the microparticle (lot 12H2014) is indicated in table 1.1 below.

Table 1.1. Composition of the lot 12H2014

Layer 1 (g) Layer 2 (g) Layer 3 (g) Omeprazole 50 PVP 10 Eudragit® L30D55 100 Palmitate ascorbyle 0.025 TiO ₂ 5 ATEC 15 PVP 20 Talc 5 Polysorbate 80 1 Talc 20 Silicone 1 Ethanol 400 Ethanol 150 Talc 20 Water 500 Dry residue 90.025 Dry residue 20 Dry residue 120 Layer 4 (g) Layer 5 (g) PVP 15 Eudragit® E 100 120 Talc 10 Silicone 1 Ethanol 150 Talc 30 Ethanol 1200 Dry residue 25 Dry residue 150

The preparation process (coating the core and the following layers) is as described above in the coating parameters part of the Materials and processes section.

Dissolution studies using the dissolution test method indicated above in the Materials and Processes section show that the outer coating

BE2016 / 5555 outside seems to resist for 2 hours in phosphate buffer pH 7.0 (Figure 1). In fact, the new developed coating system has been shown to be able to prevent the early release of omeprazole for 2 hours in pH 7.0 buffer. This means that the outer outer layer acts as a barrier. Then, omeprazole is not released for 2 hours at all in an acid medium. The enteric coating withstands a pH below 6.0. Finally, the drug is effectively released into pH 6.8 buffer since the enteric coating is dissolved. On the other hand, the marketed product of omeprazole (Losec 40 mg) releases the omeprazole which is already partially degraded under acidic conditions. However, the microparticles are not stable during storage at 4 ° C. Thus, 5 g of batch 12H2014 are dispersed in 100 ml of water for 1 day. The release of omeprazole is quantified by HPLC using the process indicated above in the Materials and Processes section. It is observed that the coated microparticles are not stable when they are placed in the refrigerator (4 ° C) and at room temperature. The outer outer layer of Eudragit® E swells strongly, making the microparticles porous. Consequently, more than 60% of omeprazole is released into the external environment.

Consequently, the use only of a hydrophilic gastro-soluble component in the external external layer is not sufficient to obtain the required characteristics: indeed, even if the dissolution profile seems satisfactory, the microparticles are not stable for storage at 4 ° C in aqueous media.

To resolve this problem, magnesium stearate is added to the outer outer coating layer in lot 1612014 (Table 1.2).

Table 1.2. Composition of lot 1612014

Layer 1 (g) Layer 2 (g) Layer 3 (g) Omeprazole 50 PVP 12 Eudragit® L30D55 125 Palmitate ascorbyle 0.025 TiO ₂ 5 ATEC 19 PVP 20 Talc 5 Polysorbate 80 1

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Talc 20 Silicone 1 Ethanol 400 Ethanol 150 Talc 20 Water 500 Dry residue 90.025 Dry residue 22 Dry residue 145 Layer 4 (g) Layer 5 (g) PVP 15 Eudragit E 100 240 Talc 10 Mg stearate 15 Ethanol 200 Isopropanol 1152 Acetone 768 Dry residue 25 Dry residue 255

Unexpectedly, when 5 g of lot 1612014 are dispersed in 100 ml of water for 3 days according to the process indicated above in the omeprazole-to-water release part of the Materials and processes section, it is observed that the coated microspheres appear stable when placed both in the refrigerator (4 ° C) and at room temperature. Indeed, the swelling of Eudragit® E seems to be avoided. More unexpectedly, the addition of magnesium stearate does not change the dissolution profile of the microparticles (Figure 2) when using the dissolution test described above in the Materials and Methods section. Indeed, as described in this figure, the coated 5-layer microparticle is capable of preventing the release of omeprazole in an acid medium. The total amount of the drug is then released in 45 min in pH phosphate buffer

6.8.

Therefore, it was decided to optimize the fifth coating by combining the gastro-soluble polymer Eudragit® E with a hydrophobic agent such as magnesium stearate in order to increase the stability of the coating microspheres during storage.

Example 2: compositions suitable for preparing the external outer layer according to the invention

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In order to assess the barrier properties of outer outer layer compositions, microparticles containing omeprazole are prepared on which different compositions comprising gastro-soluble polymers and hydrophobic agents have been deposited.

The microparticles are prepared as follows: in a first step, 500 g of Cellets® 1000 (microcrystalline cellulose granules) are poured inside a fluidized bed coating apparatus (Aeromatic, STREA-l ™; scale of laboratory) and a solution / suspension containing omeprazole, PVP, ascorbyl palmitate in ethanol is sprayed with a peristaltic pump at a flow rate of 8 g / min. Then, the outer outer layer is deposited by spraying solutions comprising compositions of Eudragit® E (the polycationic gastro-soluble polymer (a) according to the invention) with ethylcellulose, Eudragit® RS, l stearic acid, Compritol® 888 ATO, magnesium stearate or GMS (glyceryl monostearate) as hydrophobic and / or insoluble component (b) according to the invention.

Table 2.1 shows the composition of the microparticles containing omeprazole before coating with the outer outer layer.

Table 2.1

First layer deposited on Cellets® Omeprazole 50g PVP 20g Talc 20g Ascorbyle palmitate (Palm. 0.025 g Asc) Ethanol 400 g Dry residue 90.025 g

Table 2.2 shows the composition of the outer outer layer 20 deposited on the microparticles containing omeprazole.

Table 2.2

(g) Lot no. # 1 # 2 # 3 # 4 N ° 5 N ° 6 # 7 # 8 N ° 9 N ° 1O Eudragit® E 31.25 31.25 31.25 31.25 31.25 31.25 31.25 62.5 62.5 62.5 Talc 2.6 2.6 2.6 2.6 2.6 2.6 2.6 5.2 5.2 13.5 Ethylcellulose 0.15

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Eudragit® RS Acid stearic 3.12 6.24 0.15 1.5 3.125 Compritol® 888 ATO Stearate Mg 0.31 1.5 5.2 GMS * 13.5 Isopropanol 300.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0 Acetone 195.3 195.3 195.3 195.3 195.3 195.3 195.3 195.3 Dry residue (g) 34.00 36.97 40.09 34.00 35.35 34.16 35.35 39.57 72.9 79.12 Report in weight of compounds (a) / (b) 1/20 10/1 5/1 200/1 1/20 100/1 1/20 1/20 12/1 4.6 / 1 % of 5.0 5.0 4.95 5.0 5.0 5.0 5.0 10.0 9.4 9.3

polymer

GMS *: glyceryl monostearate

The microparticles were characterized as follows:

v Omeprazole released and not released after 3 days of storage at 5 ° C 5 The quantity of omeprazole not released / released is measured for each of the batches:

In order to measure the quantity of omeprazole released by the multilayer microparticles in the aqueous solution, 100 mg of batches 1 to 10 are dispersed in 100 ml of purified water and stored at 5 ° C. At 24 hour intervals, 10 ml of a filtered sample are taken and placed in a Falcon tube containing ml of 0.25 N NaOH. After mixing, the solutions are filtered (filters

Millipore 0.45 pm) and subjected to quantification of omeprazole by HPLC. The quantities of omeprazole released after 3 days of storage are presented in Table 2.3.

The amount of omeprazole not released after 3 days of storage at 5 ° C is presented in Table 2.3.

v Evolution of the pH of the surrounding aqueous medium during storage

The pH is regularly measured during storage at 5 ° C as an easy means to assess the possible solubilization of the outer outer layer due to a change in the pH. The pH values of the aqueous medium surrounding the microparticles of the 10 batches after 3 days of storage at 5 ° C. are presented in Table 2.3.

Table 2.3: rate of omeprazole released and not released after 3 days of storage of the microparticles according to the invention obtained by coating the microparticles of table 2.1 with the external external layers (lots 1 to 10) of table 2.2. and pH values of the aqueous solution after 3 days of storage at 5 ° C.

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Lot no. 1 2 3 4 5 6 7 8 9 10 Quantity omeprazole in the granule (% in weight) > 93 82 90 83 > 98 95 70 > 98 95 > 93 Quantity omeprazole in water (% in weight) 7 18 10 3 2.5 3 13.5 1.5 1.5 <0.5 PH 6.02 5.84 5.92 6.04 6.4 5.78 5.94 6.06 6.07 6.1

Conclusion:

All the tested mixtures of Eudragit® E (cationic polymer) with a hydrophobic compound (such as ethylcellulose, stearic acid, Compritol® 888 ATO, Mg stearate and glyceryl monostearate) confer the barrier properties against water to microparticles according to the present invention. The best results are obtained with stearic acid, glyceryl monostearate and Mg stearate (the lowest amount of the drug in the aqueous medium and the highest amount of the drug inside the Cellets®). Since stearic acid is not easy to handle, glyceryl monostearate and Mg stearate are the best choices as the hydrophobic component (b) of the outer outer protective layer. In particular, glyceryl monostearate (GMS) is the preferred choice being

BE2016 / 5555 given that the results indicate a release of omeprazole in water of less than 0.5% by weight.

Example 3: Multilayer microparticles containing omeprazole with the outer outer layer comprising GMS and Eudragit® E (02B2015 and 16C2015 ^

Two batches of multilayer microparticles containing omeprazole coated with an external outer layer comprising both Eudragit® E and GMS according to the present invention are prepared (sample 02B2015 and sample 16C2015). The samples differ in the presence, in sample 16C2015, of an additional layer of ethylcellulose deposited directly on the surface of the microcrystalline cellulose granules (Cellets®) in order to further contribute to limiting the diffusion of water from the medium. surrounding aqueous to the nucleus of the microparticles.

Preparation:

The preparation of the core and layer No. 1 of sample 02B2015 is identical to the preparation of the core and the first layer according to Example 2 and as described in the coating parameters of the Materials and processes section. Thus, 500 g of Cellets® 1000 are placed inside the fluidized bed device (Aeromatic, Switzerland). The coating parameters are described in the Materials and processes section.

The composition of sample 02B2015 is presented in Table 3.1.

Table 3.1:

Layer 1 Layer 2 Layer 3 Layer 4 Layer 5 Omeprazole 50g no ₂ 5g Eudragit® 100g Talc 10g Eudragit® 62.5g L30D55 ΞΡΟ Talc 20g Talc 5g Talc 20g PVP 10g lay 13.5g PVP 20g ³ VP 10g ATEC * 15g SMS 3.125 g Palm. Asc. 0.025 g Polysorbate i g 80 Oil of i g silicone

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Ethanol 400 g Ethanol 150 g water 500 g Ethanol 150 g Isopropanol 300 g Acetone 195.3 g Dry residue 90.025 g 20g 120g 20g 79.125 g Total dry residue including 500 g of Cellets® 1000 = 829.15 g % 6.0 omeprazole related to total dry residue of microparticles % 12.0 Eudragit®L compared dry residue total microparticle s % 7.5 Eudragit® E by contribution to '' total dry residue your Tiicroparticles

* ATEC =: acetyl triethyl citrate

The composition of the 16C2015 sample is presented in Table 3.2.

Table 3.2:

Layer 1 Layer 2 Layer 3 Layer 4 Layer 5 Layer 6

Ethocel 35g Dmeprazole 50 g TiO ₂ 5g Eudragit® 200g Talc 10g Eudragit® 62.5g FP L30D55 E prem. TEC * 7g Talc 20g Talc 5g Talc 48 g PVP 10g Talc 26g Talc 20g PVP 20g PVP 10g ATEC * 15g GMS 3.125 g TiO ₂ 5g Like Asc. 0.025 ’VP 23g g no ₂ 10g Polysorbate ig 30 Oil of i g silicone Ethanol 600 g Ethanol 400 g Ethanol 150g Water 400 g Ethanol 150 Isopropanol 300g g Acetone 195.3 g Residue 60g 90.025 20g 281g 20g 91.625 g dry g Total dry residue including 500 g of Cellets® 1000 = 1062.65 g % 4.7 % 18.8 % 5.9 ameprazole Eudragit® L Eudragit® E aar compared to aar report aar report '' dry residue dry residue dry residue : all : all rotai des • microparticle microparticle • microparticle 3 3 3

BE2016 / 5555 * ATEC =: acetyl triethyl citrate * TEC =: triethyl citrate

The retention of undegraded omeprazole inside the microparticles according to the present invention of lots 02B2015 and 16C2015 after 8 days of storage in purified water at 5 ° C. is compared with the retention of omeprazole, under the same conditions. , within enteric coated omeprazole units (i.e., microparticles of omeprazole microspheres marketed Omeprazole-Sandoz 40 mg). These latter microparticles are designed to dissolve at the high pH of the small intestine to release omeprazole for absorption but to remain unchanged in the acidic pH environment of the stomach. The enteric outer layer of these marketed microparticles is therefore incapable of imparting a barrier capacity against water if said marketed microparticles are stored in water, even for short periods.

The release of omeprazole into water was quantified by HPLC using the method described above in the omeprazole release into water section of the Materials and Methods section.

Thus, 5 g of each of the 3 samples are dispersed in a volume of 100 ml of purified water and stored at 5 ° C. After 8 days of storage, the omeprazole is measured by HPLC (i) in the aqueous medium and (ii) inside the microparticles.

The results are shown in Figure 3.

Compared to the microparticles sold (without the outer outer layer of the invention comprising Eudragit® E and GMS), the level of omeprazole not released in the two samples of 02B2015 and 16C2015 according to the present invention after a storage period of 8 days in water (5 ° C) increases from approximately 35% (commercial sample) to 73% and 85%, respectively. Therefore, the highest amount of omeprazole which is already released into the aqueous medium is obtained with Omeprazole-Sandoz®, which is not able to prevent the early release of the drug during storage. On the other hand, the two lots 02B2015 and 16C2015 are capable of reducing the release of omeprazole during the

BE2016 / 5555 storage. Consequently, the quantity of omeprazole that remains inside the pharmaceutical forms is higher in the microparticles according to the present invention than in the commercial microparticles containing omeprazole.

The increase from 73% (02B2015) to 85% (16C2015) shows the effect of the optional additional ethylcellulose layer deposited on the Cellets® which reinforces the role of the external outer layer to increase the level of undegraded omeprazole in microparticles.

The 02B2015 dissolution test according to the present invention and marketed microparticles containing omeprazole (OmeprazoleSandoz 40 mg) is carried out to compare the amount of omeprazole released after 3 successive stages:

- step 1 - 4 hours of storage at 37 ° C in purified water (50 rpm; 750 ml containing 650 mg of microparticles). Step 1 mimics the storage conditions of the microparticles under conditions of syrup type at neutral pH. Compared to Example 3, the storage is carried out for a shorter duration (4 hours) but at a higher temperature (37 ° C.) to simulate accelerated storage conditions;

- step 2 - 2 hours of storage at 37 ° C in an acidic aqueous solution (pH 1.2, 0.1 N HCl; 100 rpm; 1000 ml containing the 650 mg of microparticles from step 1. The step 2 mimics the gastric environment;

- step 3 - 45 minutes of storage at 37 ° C in a neutral aqueous solution (pH 6.8; 0.05 M phosphate buffer; 100 rpm; 1000 ml containing the same 650 mg of microparticles from step 2) . Stage 3 mimics the conditions of the intestinal release phase of the drug (conventional recommendations state that not less than 75% of omeprazole must be released under these conditions).

At the end of each of steps 1, 2 and 3, a volume of 10 ml of the aqueous solution is taken, diluted with 2 ml of 0.25 N NaOH. The amount of omeprazole is measured by HPLC. Each assay is performed in triplicate.

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Figure 4 shows that the omeprazole is already partially released after 4 hours in pH 7.0 buffer since the enteric coating of Omeprazole-Sandoz® is dissolved. Under gastric conditions, the drug is degraded. Consequently, under enteric conditions (phosphate buffer 6.8), the amount of omeprazole, which remains in the aqueous medium, reaches only 31%. On the other hand, omeprazole is not released during the two stages 1 and 2 with the 02B2015 microparticles according to the present invention. Therefore, in intestinal conditions, the total amount of the drug is properly released.

Consequently, compared with the marketed microparticles containing omeprazole, the 02B2015 multilayer microparticles coated with the external external layer comprising Eudragit E and GMS according to the present invention make it possible to suppress the release of omeprazole from the internal part of the microparticle. aqueous medium during storage at 37 ° C for 4 hours. These conditions mimic long periods of storage of said microparticles under syrup type conditions stored at room temperature or at 4-5 ° C. The behavior of the same microparticles (after their 4 hours of storage in water at 37 ° C), when they are placed under acidic conditions for 2 hours (gastric environment) is ie same as that of the marketed microparticles containing omeprazole, which means that the microparticles of the invention resist acid conditions by restoring the gastro-resistance of state-of-the-art gastro-resistant granules. When the same microparticles meet intestinal conditions at neutral pH, the quantity of omeprazole expected (not less than 75%) is released in 45 minutes.

Example 4: Use of a mixture of AVICEL® RC-591 + SORBITOL as viscosifying agent in the liquid pharmaceutical composition according to the present invention

A liquid pharmaceutical composition according to the present invention is prepared using the microparticles of lot 02B2015 according to the invention as described in Example 3 which have been suspended in water using different viscosifying agents approved by the FDA for use

BE2016 / 5555 oral. These include; PVP from 1 to 20% w / w; Avicel® RC-951 from 1 to% w / w; used in combination with sorbitol 30% w / w as an osmotic agent. The objective is to select the best viscosifying agent, in combination with an osmotic agent, easy to disperse, in order to obtain a final aqueous system having a suitable viscosity.

g of neutral Cellets® 350 is placed in a 100 ml test tube filled with a viscous aqueous solution containing the viscosifying agents in combination with sorbitol. After dispersion by manual stirring, the sedimentation time is evaluated. The following two mixes maintain stability for more than 30 seconds:

- PVP 16% w / w + sorbitol 30% w / w

- Avicel® RC-951 2% w / w + sorbitol 30% w / w

Next, 5 g of 02B2015 microparticles are dispersed in a 100 ml flask containing the preselected viscous aqueous system and placed at 4 ° C. After one week, the two aqueous systems composed of PVP 16% w / w + sorbitol 30% w / w and Avicel® RC-951 + 30% w / w sorbitol allows stabilization of the coated microparticles. Indeed, no intense purple color appears, which corresponds to the degradation of omeprazole.

Example 5: Use of Buffering Agent in the Liquid Pharmaceutical Composition According to the Present Invention g of omeprazole 02B2015 microparticles according to the present invention as described in Example 3 are dispersed in a 100 ml flask containing a buffer and stored at 4 ° C. The selected buffers are not prepared with a phosphate salt due to its interaction with Eudragit® E.

The buffers selected have a pH range between 6.5 and 7.5.

After one week, the quantity of omeprazole is quantified in the solution (evaluation of its release) and inside the coated microparticles (evaluation of its capacity to be retained in the pharmaceutical form).

The buffers tested are:

Borate (0.1 M, 0.05 M, 0.01 M)

Glycine (0.2 M, 0.1 M).

In addition, a sample in water is analyzed as a reference.

Table 5.1 below presents the results obtained in terms of quantities of omeprazole in percentage by weight released in the flask and remaining inside the microparticles 02B2015 after 7 days at 4 ° C in buffers or in water tap.

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Table 5.1:

BUFFER MEDIUM + GAP TYPE% OF OMEPRAZOLE RELEASED (BY WEIGHT) AVERAGE + Standard Deviation% INDOOR OMEPRAZOLE MICROPARTICLES (IN WEIGHT) 0.1 M Borate 2.18 ± 0.00 61.29 ± 0.27 0.05 M Borate 1.68 ± 0.01 72.22 ± 0.71 0.01 M Borate 0.53 ± 0.00 89.22 ± 0.14 0.2 M glycine 0.55 ± 0.00 78.91 ± 0.18 0.1 M glycine 0.48 ± 0.01 83.78 ± 0.55 Water tap 0.37 ± 0.01 52.62 ± 0.54

During the test, the pH values are determined. In fact, the compounds present inside the different formulations can modify the pH of the medium in the vial, which can influence the resistance of Eudragit® E as a barrier and, consequently, the release of omeprazole .

Table 5.2 below presents the pH values of different liquid pharmaceutical compositions according to the invention containing different buffers or only water before storage and after 7 days of storage at 5 ° C.

Table 5.2:

BUFFER pH pH AFTER 7 DAYS 0.1 M Borate 7.4 7.34 0.05 M Borate 7.4 7.34 0.01 M Borate 7.4 6.99

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0.2 M glycine 7.4 6.83 0.1 M glycine 7.4 6.74 water 6.8 6.47

The test shows that the buffers can maintain the pH of the liquid pharmaceutical composition according to the present invention stable.

The most suitable buffer, depending on the amount of omeprazole which still remains inside the microparticles after a week at 4 ° C., seems to be the 0.01 M borate buffer.

Then, 5 g of 02B2015 microparticles are dispersed in a 100 ml flask containing an aqueous solution containing PVP 16% w / w or Avicel® RC-951 + sorbitol 30% w / w + 0.01 M borate buffer pH 7.4 in order to evaluate the quantity of omeprazole which still remains inside the coated microparticles.

After one week, 86% w / w and 72% w / w of omeprazole remains in the microparticles 02B2015 when they are dispersed in an aqueous medium containing respectively PVP and Avicel® RC-951 as viscosifying agents ,. After two weeks, 80% w / w and only 34% w / w of omeprazole remains in the 02B2015 microparticles when dispersed in an aqueous medium containing PVP and Avicel® RC-951 respectively. viscosifying agents.

Consequently, the rheological evaluation (FIG. 5) of an aqueous solution containing PVP 16% w / w + sorbitol 30% w / w + 0.01 M borate buffer pH 7.4 is carried out at room temperature with a Brookfield rheometer . It is observed that the system is characterized by pseudoplastic behavior. In fact, the viscosity decreases rapidly at the lowest values of shear stresses (1-2.5 rpm). This means that the syrup has rheological properties suitable for administration since it seems to flow properly after a low shear stress (for example, manual agitation before administration).

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In all of these examples, the omeprazole proton pump inhibitor is mainly used as the worst case model due to its high temperature sensitivity and photo-oxidation. The proof of concept carried out with such a labile drug allows a similar development for other more stable compounds such as, for example, diclofenac, furosemide and tramadol.

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Claims (18)

1. Multilayer controlled release microparticle containing a pharmaceutically active compound, said microparticle being intended for oral administration or direct administration in the stomach in the form of a liquid pharmaceutical composition and said microparticle comprising: - a nucleus comprising the pharmaceutically active compound; - an intermediate coating layer with controlled release; - an outer external protective coating layer surrounding the controlled release intermediate coating layer and containing a mixture of a) a hydrophilic gastro-soluble component which is insoluble in an aqueous medium at a pH of between 6.5 and 7.5, advantageously at a pH> 5 and b) a hydrophobic and / or insoluble component. 2. Microparticle according to claim 1, in which the pharmaceutically active compound is a pharmaceutically active acid-labile compound or a pharmaceutically active compound unstable under acidic conditions such as a proton pump inhibitor, an antiretroviral agent, a peptide, a protein or an antibiotic, a pharmaceutically active compound which is aggressive for the gastric mucosa such as a pharmaceutically active non-steroidal anti-inflammatory compound, a pharmaceutically active compound whose therapeutic efficacy must be improved or prolonged with an extended-release layer, such as an antibiotic, an antihypertensive, an antiarrhythmic, a beta-blocker, a diuretic, a cardiovascular drug, an anti-inflammatory drug or an analgesic or a pharmaceutically active compound which must target a section of the gastrointestinal tract other than the stomach such as a chemotherapeutic agent for tr Colon cancer treatment or for the treatment of intestinal diseases such as an anti-inflammatory drug or an oral corticosteroid, advantageously the pharmaceutically active compound is omeprazole. BE2016 / 5555 3. Microparticle according to any one of claims 1 and 2, in which the intermediate coating layer with controlled release is a coating layer with delayed release such as an enteric coating layer, a colonic coating layer or an insoluble coating layer or an extended-release coating layer, in particular it is an enteric coating layer. 4. Microparticle according to any one of claims 1 to 3, in which the hydrophilic gastro-soluble component is a synthetic or natural cationic polymer, in particular chosen from the group consisting of a cationic polymer based on dimethylaminomethyl methacrylate, methacrylate butyl and methyl methacrylate, chitosan and chitin. 5. Microparticle according to any one of claims 1 to 4, in which the hydrophobic and / or insoluble component is chosen from the group consisting of glycerides, wax, magnesium stearate, fatty alcohol, ethylcellulose, d '' a copolymer based on ethyl acrylate and methyl methacrylate, silicone, stearic acid, in particular in the group consisting of magnesium stearate and glyceryl monostearate, more advantageously it is monostearate glyceryl. 6. Microparticle according to any one of claims 1 to 5, in which the weight ratio hydrophilic gastro-soluble component / hydrophobic and / or insoluble component is between 200/1 and 1/1, in particular from 50/1 to 5/1. 7. Microparticle according to any one of claims 1 to 6, containing at least one other intermediate layer between the core layer and the intermediate coating layer with controlled release and / or between the intermediate coating layer with controlled release and the external external protective layer, in particular an intermediate protective coating layer. BE2016 / 5555 8. Microparticle according to any one of claims 1 to 7, characterized in that it is a microparticle with delayed or prolonged release. 9. Microparticle according to any one of claims 1 to 8, in which its volume average diameter measured by the Malvern Mastersizer laser granulometer is between 80 pm and 2000 pm, advantageously between 100 pm and 1000 pm, more advantageously between 200 pm and 500 pm. 10. A liquid pharmaceutical composition intended for oral administration or direct administration in the stomach comprising the microparticles according to any one of claims 1 to 9 dispersed homogeneously in a liquid medium having a pH> 6, advantageously a medium aqueous liquid. 11. Liquid composition according to claim 10, characterized in that it is a suspension, an emulsion, a dispersion, a gel or a paste, advantageously a suspension. 12. Liquid composition according to any one of claims 10 and 11, in which the pharmaceutically active compound contained in the microparticles is chemically stable for at least 1 day when it is stored at 4 ° C, advantageously at room temperature, advantageously at less a week, more preferably at least 1 month. 13. Liquid composition according to any one of claims 10 to 12, in which less than 20% by weight, advantageously less than 10%, more advantageously less than 5% of the pharmaceutically active compound contained in the microparticles is released into the liquid medium when it is stored for at least 1 day at 4 ° C., advantageously at room temperature, advantageously at least one week, more advantageously at least 1 month. BE2016 / 5555 14. Liquid composition according to any one of claims 10 to 13, in which the liquid medium contains a viscosifying agent, a buffering agent, and / or an osmotic agent, advantageously the viscosifying agent is chosen from the group consisting of polyvinylpyrrolidone , microcrystalline cellulose, 5 of sodium carboxymethylcellulose and a mixture thereof, the osmotic agent is sorbitol and the buffering agent is selected from the group consisting of glycine or a borate buffer. 15. Kit for the preparation of a liquid pharmaceutical composition for oral administration or direct administration in the stomach comprising: - the microparticles according to any one of claims 1 to 9 and - a liquid medium having a pH> 6, in particular as described in claim 14. 15 16. A solid pharmaceutical composition intended to be reconstituted in the form of a liquid composition for oral administration or direct administration in the stomach, said solid composition comprising the microparticles according to any one of claims 1 to 9, optionally in admixture with a viscosifying agent, an osmotic agent 20 and / or a buffering agent, advantageously the viscosifying agent, the osmotic agent and the buffering agent are as described in claim 14. 17. Solid pharmaceutical composition according to claim 16, characterized in that it is a dry syrup, a powder or an aggregate. 18. A method of preparing a liquid composition for oral administration or direct administration in the stomach according to any one of claims 10 to 14 comprising the addition of a liquid having a pH> 6 in the solid pharmaceutical composition according to l any of 30 claims 16 or 17 and the mixture, preferably with gentle stirring. BE2016 / 5555 Percentage dissolved (%) Percentage dissolved |%)