HK1115308B - Solid dosage form comprising proton pump inhibitor and suspension made thereof - Google Patents

Description

Solid dosage forms comprising proton pump inhibitors and suspensions made therefrom

Technical Field

The present invention relates to a solid, rapidly gelling, oral pharmaceutical dosage form, as well as aqueous suspensions prepared therefrom, comprising an acid susceptible proton pump inhibitor as active ingredient distributed in a plurality of enteric coating coated pellets and suspension modified granules. Furthermore, the present invention relates to an improved method for its production and the use of the formulation in medical treatment including the prevention of gastrointestinal (gastrointestinal) diseases in humans.

Background of the invention and Prior Art

Having H⁺K⁺Proton pump inhibitor (hereinafter also referred to as "PPI") compounds acting as ATPase inhibitors are known, with the generic names omeprazole, lansoprazole, pantoprazolePrazole, rabeprazole, tenatoprazole, and esomeprazole.

These active substances are useful for inhibiting gastric acid secretion in mammals and man. In a more general sense, they may be used for the prevention and treatment of gastric acid related diseases in mammals and man, including, for example, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, they may also be used for the treatment of other gastrointestinal disorders where gastric acid inhibitory effect is required, such as patients with NSAID therapy, patients with non-ulcer dyspepsia, patients with symptoms of gastroesophageal reflux disease and patients with gastrinomas. They may also be used in patients in intensive care conditions, patients with acute upper gastrointestinal bleeding, prevention of acid aspiration (acid aspiration) of gastric acid before and after surgery, and prevention and treatment of stress ulcers. Furthermore, they can be used for the prevention and treatment of Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, asthma, laryngitis, Barret's syndrome, sleep apnea, sleep disorders, psoriasis and for the prevention and treatment of infections with the genus helicobacter and the diseases associated with the above.

However, these active compounds are susceptible to degradation/conversion in acidic and neutral media. The degradation is catalyzed by acidic compounds and is stabilized when mixed with basic compounds. The stability of the active substance is also affected by moisture, heat, the amount of organic solvent and to some extent by light.

Oral dosage forms are particularly problematic for many patients, as many patients are unable or unwilling to swallow solid dosage forms. This problem occurs mainly in children and the elderly. It affects patient compliance and is therefore a problem in therapy.

For many years, it has been recognized that there is a need for an oral dosage form that avoids the dysphagia associated with conventional tablets. Syrups, elixirs, microcapsules containing a slurry and other novel tablets or capsules have been developed. An alternative form of oral pharmaceutically active substance is, among others, the use of solutions or suspensions of the active ingredient in an aqueous medium.

In addition to the disadvantages of ready to take (ready to control) suspensions (or solutions) having large storage volumes, often limited shelf-life or the need for refrigerated storage, a particular problem sometimes occurs with aqueous suspensions is the strong tendency of some solid particles to sink to the bottom of the container (vessel) used for administration. This may result in a portion of the dose remaining in the container, and not allowing the entire dose to enter the oral route. Another problem that is sometimes experienced is that when using suspensions of particles in a liquid medium for administration through nasogastric tubes (nasogastric tubes), the particles may aggregate or clump, thus possibly making them unable to pass through the tube used. Another problem is that when the liquid medium has too high a viscosity/viscoelasticity, administration through a nasogastric tube under practical pressure becomes impossible.

There is a strong need, particularly when administering acid labile compounds such as proton pump inhibitors, e.g. omeprazole, esomeprazole, pantoprazole and lansoprazole, to obtain an easily and rapidly prepared, easily swallowable homogeneous suspension comprising the proton pump inhibitor in a form that protects it from an acidic environment (e.g. acidic gastric juice). Furthermore, the suspension needs to be viscoelastic and viscous to be suitable for allowing it to be administered via a gastric tube or swallow. While liquid suspension formulations require a certain viscosity to remain stable over a longer period of time.

Additional challenges/problems arise when storing pharmaceutical formulations as dry powders comprising water-insoluble components, and intended as homogeneous suspensions for immediate preparation.

With some prior art compositions, the problem is that the maximum viscosity level is obtained only after a long time, i.e. the viscosity is not constant over a short time period from the preparation of the suspension to its usual administration to the patient. There is also a problem of batch-to-batch variation in the time required to obtain a stable maximum viscosity level in the suspension from the dry powder mixture.

Intolerance to lactose-containing foods is a common problem, and therefore lactose-containing drugs can be a problem for these people.

There have been suggestions in the art for compositions comprising proton pump inhibitors, and other methods for rapidly dispersing and/or dissolving the formulation.

US 5,731,002 describes a stable, oral pharmaceutical composition comprising a proton pump inhibitor in a paste-like gel for the treatment of gastric acid related diseases in mammals.

US 5,840,737 describes a method of treating gastric acid disorders (gastrotic acid disorders) with a composition comprising omeprazole or lansoprazole and a bicarbonate salt. Problems associated with administering bicarbonate, such as sodium or potassium bicarbonate, to, for example, humans include the potential for eructation when the carbonate is neutralized in the stomach. Patients with gastroesophageal reflux may aggravate or worsen their disease because belching causes upward movement of stomach acid (Brunton, Agents for The controlled gastric acidity and treatment of gastric acidity. in: Goodman A G, et al, The pharmacological basis of therapeutics, p.907.(New York, 1990.)). In addition, intake of sodium bicarbonate may lead to metabolic alkalosis.

Further patent applications are further published in the same patent family, e.g. US2002/0045646 a1, disclosing a solid non-enteric coating dosage form composition comprising a proton pump inhibitor and a buffer. Other applications in this family, US2003/118669, US2003/144306, US2003/191159, US2003/215527, US2004/048896 and US2004/171646, disclose, for example, liquid oral pharmaceutical compositions comprising a proton pump inhibitor and a buffering agent, and methods of increasing the absorption of the proton pump inhibitor.

US 2004/0005362 a1(Taneja) and US 2004/0082618 a1(Taneja) describe a pharmaceutical formulation comprising an acid labile drug coated with an enteric coating and a liquid carrier having a pH of less than 6.0. Other published applications by the same inventors describe, for example, liquid carriers viscous enough to suspend microparticles comprising PPIs predominantly identically arranged (US 2004/0081700 a1) or (US 2004/0006109 a1 and US 2004/0081671 a1), wherein the pH of the liquid carrier is greater than 6.5.

WO 2004/004690 a1(Taneja) describes a liquid dosage form with enteric coated microparticles comprising an acid labile drug and a liquid suspension having a pH of less than 6.0 and being sufficiently viscous to suspend the microparticles. Carbonates or bicarbonates may be used in the dosage form.

US 2004/0022854 a1 describes an oral form of an acid-labile active compound in which the excipients are not suitable for forming an enteric layer (enteric coating). The prepared units of active compound can be formulated, for example, as sachets (sachets) with lactose, or as effervescent compositions with a carbonate salt containing an excipient.

EP 1,232,746 describes an easily suspendable dry powder mix composition comprising a gelling or thickening agent, comprising at least one xanthan gum having a specific particle size distribution, a filler, a humectant or a surfactant, and a pharmaceutically active substance.

US 4,886,669 describes a water-dispensable tablet comprising a pharmaceutically active agent, at least one disintegrant and a swellable material. It is described therein that tablets disintegrate rapidly in water to form a homogeneous highly viscous suspension which can be easily swallowed.

US 5008117 relates to a method of preparing a formulation for rapid partitioning and dissolution of thickening or suspending agents and other excipients, in which drug microcapsules can be easily partitioned. But no proton pump inhibitors are mentioned.

EP 0491910B 1 describes a solid pharmaceutical composition for addition to water to produce a suspension of the drug. The composition comprises a thickening or suspending agent, an acid and a carbonate or bicarbonate salt.

US 6,261,602 describes a particulate composition which can be used as a pharmaceutical carrier, which can be used to prepare pharmaceutical compositions capable of rapidly suspending ions in water or an aqueous medium. The composition may be prepared by a process comprising wet granulation or dry granulation of a mixture of the thickening agent and the disintegrant with an aqueous medium as a humectant to produce a granulated product.

Brief description of the invention

The present invention avoids the above discussed disadvantages of the prior art compositions and proposes a solution to the above problems. Further provided is a method for preparing a pharmaceutical carrier, which is suitable for transgastric tube (gastrotic tube) administration due to the good viscosity and viscoelasticity of the resulting carrier (suspension). For example, in a sense, such as being sufficiently robust (robust), the amount of water used may provide approximately the same viscosity, even though it varies from 50% to 150% of the prescribed amount.

The present invention relates to a solid fast gelling oral pharmaceutical dosage form comprising as active ingredient an acid susceptible proton pump inhibitor distributed in a plurality of enteric coating coated pellets, and suspension modifying granules.

Furthermore, it has surprisingly been found that it is advantageous to use a granulate of a specific composition in admixture with a plurality of enteric coated pellets comprising a proton pump inhibitor, wherein the granulate, when suspended in water, will rapidly and reproducibly form an aqueous carrier having the desired pH, the desired level of stable viscosity and satisfactory viscoelasticity. The particles are also referred to hereinafter as "suspension modifying particles". Furthermore, the particles should be free of bicarbonate and carbonate. According to one embodiment of the invention, the particles may be made lactose-free, i.e. suitable for people intolerant to lactose.

The dosage forms of the present invention make it possible to rapidly form viscous, stable suspensions. Prior to administration, the solid dry suspension-modifying particles and the enteric-coated pellets are dissolved/suspended in an aqueous liquid, such as tap water, to give a viscous liquid formulation for oral administration. When the formulation of the present invention is administered to a patient, it is important that the formulation should dissolve or suspend as quickly as possible while providing a suspension that is homogeneous with respect to the distribution of the solid particles comprising the pharmaceutically active ingredient. Thus, the final liquid formulation should ensure that virtually all doses, even if contained in suspended, particulate form, are delivered into the oral cavity, i.e. enter the oral route in a safe, reliable and reproducible manner.

When the active ingredient is contained in the enteric coating coated pellets, the pH of the suspension medium must not cause premature dissolution of the enteric coating layer of the pellets containing the active ingredient. At the same time, the requirements for the final liquid formulation for administration via nasogastric tube are that it should have suitable and stable viscosity, viscoelasticity, and not have a tendency for the suspended particles to agglomerate.

It is further characterized in that the suspension is suitable for administration through a tubule for pediatric use. The term gastric tube includes nasogastric tubes and other tubes or syringes used to pass suspensions or dispersions into the stomach of a patient.

Viscoelasticity and viscosity become particularly important because the tubes used in pediatric treatments may have a narrow inner diameter and, therefore, are sensitive to liquids that have unsuitable properties that result in high back pressure when administered. An example of a tube with a narrow inner diameter is the "pediatric feeding tube (Infant feeding tube), FT 1606/105(CH/FG6-2.0mm outer diameter, 1.4mm inner diameter), PennineHealthcare".

The dosage forms of the present invention gel faster in water at room temperature, resulting in a uniform, stable dispersion, as compared to prior art formulations. They therefore give stable viscosities in a shorter time than the prior art and, in addition, they are robust with respect to the viscosities obtained.

In brief, the dosage form of the present invention comprises two main components: a suspension modifying granule and a plurality of enteric coated pellets containing the active ingredient.

Suspension modifying particles comprise:

fast dissolving diluents

-gelling agents

-acidic pH adjusting agents

-a binder and

-optionally a disintegrating agent,

furthermore, the particles do not comprise bicarbonate and/or carbonate.

According to one feature, the suspension modifying particles described above do not comprise lactose. This further advantage makes it suitable for patients with lactose intolerance, who may be treated with embodiments of the present invention.

It is a feature of the present invention that the fast dissolving diluent is brought into intimate/intimate contact with the gelling agent. This not only results in a fast gel time compared to the gelling agent itself, but also a fast and stable gel. One embodiment of the invention is to select the right diluent, which can also function as a sweetener.

According to a feature of the present invention, the rapid disintegration and rapid gelling of suspension modifying particles when suspended in water to a stable and reproducible viscosity level is achieved by a specific manufacturing process. According to this feature, the process comprises mixing the gelling agent and the diluent/sweetener, granulating them together and then drying them to obtain a low moisture content and/or a low solvent content. The preparation of enteric coated pellets will be described in the "detailed description of the invention" section, but they may generally be prepared according to WO 9601624 a1, given their particularly desired size. Furthermore, the pellets coated in the enteric coating do not require any "overcoat".

The present invention provides a safe and reliable dosage form for administration of enteric coating coated pellets comprising an acid labile proton pump inhibitor, such as omeprazole, esomeprazole, pantoprazole and lansoprazole, dispersed in an aqueous liquid medium. This is particularly suitable and advantageous for the treatment of geriatrics and paediatrics.

The compositions of the present invention also allow for the addition of a wide range of dosage levels and other agents such as taste/flavor masking and tonicity agents.

Drawings

Figure 1 shows the viscosity versus time for an embodiment of the invention (5 samples).

FIG. 2 shows an embodiment of the prior art (Lanzo)^TM4 samples) viscosity versus time.

Detailed Description

One aspect of the invention is a dosage form which is a mixture of component (I) a plurality of enteric coated pellets and another component (II) a suspension modifying granule, the mixture being dispensed in a container, such as a sachet (sachet). When suspended in an aqueous medium such as tap water, the mixture rapidly disintegrates and gels, forming a uniform, stable and robust suspension with reproducible and stable viscosity that can be easily swallowed by a patient or administered through, for example, a nasogastric tube. A further aspect of the invention is a ready-to-use (ready to use) liquid formulation, i.e. comprising three components: the two components (I) and (II) mentioned above, in addition to the liquid medium (III).

The fast gelling, i.e. short gelling time, obtained in the present invention can be seen as an effect on the time it takes for substantially all of the enteric coated pellets in the prepared suspension to remain suspended in the liquid medium and not sink to the bottom of the container (glass, beaker) from which they were prepared. Embodiments of the present invention require a gel time of generally less than 3 minutes, preferably less than 2 minutes, when measured as described in example 5.

The dosage form is free of bicarbonate and/or carbonate. Further, one embodiment of the present invention is also free of lactose. By "free" is meant that the compound is not added to the formulation. The presence of trace amounts in the composition and the accompanying presence in other materials is not considered within the scope of this phrase.

Enteric coated pellets

Enteric coated pellets containing the active ingredient are prepared with the outermost layer being an enteric coating layer. These pellets may be prepared according to methods known in the art, for example as described in WO 9601624 a1, taking into account the specific requirements for pellet size. Furthermore, no "outer coating" is required on the prepared enteric coated pellets.

According to one aspect of the invention, the mean diameter of the enteric coated pellets is 0.2-1.8mm, preferably 0.4-1.0mm, more preferably 0.5-0.8 mm.

In another aspect of the invention, the size range of the enteric coated pellets is 1.0 to 1.4mm in diameter.

The enteric coating coated pellets consist of the following structural components;

● contain a core material of the active ingredient,

● optionally isolating or bottom cladding, and

● the enteric-coated layer is coated on the surface of the film,

but no other coating layer is present over the enteric coating layer.

Core material

The core material is prepared by methods known in the art, such as extrusion-spheronization, coating techniques such as powder or solution/suspension coating, spray drying, balling (balling), condensation techniques (gelling techniques) or spray condensation techniques.

The core material comprises active ingredients and may also comprise one or a mixture of seeds (seeds), binders, surfactants, fillers, disintegrants, alkaline additives or other pharmaceutically acceptable ingredients.

Active ingredient

The pharmaceutical preparation of the present invention comprises an acid susceptible proton pump inhibitor or its basic salt (alkaline salt) or its single enantiomer or its basic salt of enantiomer as an active ingredient. Single enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two enantiomers are all suitable for the pharmaceutical formulations of the present invention.

The active ingredient is contained in small enteric coated pellets/beads, optionally together with excipients.

The compounds/active ingredients of interest for the novel pharmaceutical compositions of the present invention are compounds of the general formula I, their basic salts, one of their individual enantiomers or the basic salt of one of the enantiomers,

wherein, Het₁Is that

Or

Het₂Is that

Or

X＝

Or

Wherein

The benzimidazole moiety N is wherein one is R₆-R₉The substituted ring carbon atom is optionally replaced with a nitrogen atom without any substituent;

R₁、R₂and R₃Identical or different, selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;

R₄and R₅Identical or different, selected from hydrogen, alkyl and aralkyl;

R₆' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;

R₆-R₉identical or different from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl,Oxazolinyl, pyrrolyl and trifluoroalkyl, or adjacent R₆-R₉Forming a ring structure which may be further substituted;

R₁₀is hydrogen or with R₃Together form an alkylene chain and

R₁₁and R₁₂Identical or different, selected from hydrogen, halogen and alkyl.

In the above definitions, alkyl, alkoxy and portions thereof may be branched or straight chain C₁-C₉Chains or contain cycloalkyl groups, such as cycloalkylalkyl.

Examples of compounds of particular interest of the general formula I are:

including tautomeric forms thereof.

Preferred compounds of the oral pharmaceutical formulation of the present invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of the (-) -enantiomer of omeprazole. The latter has the common name: esomeprazole (esomeprazole). According to one embodiment, the active ingredient is esomeprazole magnesium trihydrate. In another embodiment of the invention, the active agent is tenatoprazole, or a pharmaceutically acceptable salt thereof, or an individual enantiomer thereof.

According to another aspect of the invention, the compound/active ingredient is a hydrated form of any of the above compounds/active ingredients.

In one aspect of the invention, the amount of active ingredient in the formulation ranges from 1mg to 100mg, from 2mg to 80mg, or from 5mg to 50 mg.

Seed of corn

The seeds to be layered with the active substance may be water-insoluble seeds comprising different oxides, celluloses, organic polymers and other substances, or one or a mixture thereof; or water-soluble seeds comprising various inorganic salts, sugars (other than lactose), non-pareils and others, either alone or in combination. Furthermore, these seeds may contain active substances in the form of aggregates (aggrerates), compacts (compacts) and the like.

Adhesive agent

Binders are, for example, celluloses, such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, sugars (except lactose), starch and other pharmaceutically acceptable substances with adhesive properties.

Surface active agent

Surfactants may be used in the dosage form. Suitable surfactants may be pharmaceutically acceptable non-ionic surfactants, such as polysorbate 80; or an ionic surfactant such as sodium lauryl sulfate.

Filler

Fillers may be used in the dosage form. Examples of the filler include, for example, mannitol and dicalcium phosphate.

Disintegrating agent

Disintegrants may be used in the dosage form. Examples of disintegrants that can be used are, for example: crospovidone, pregelatinized starch, microcrystalline cellulose, and croscarmellose sodium.

Alkaline additive

According to one embodiment of the invention, the active substance may be mixed with one or more basic pharmaceutically acceptable substances. After excluding bicarbonate or carbonate, these may be selected from, but not limited to, the following: such as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, citric acid or other suitable weak inorganic or organic acids; substances frequently used in antacid preparations, such as aluminum, calcium and magnesium hydroxides; a magnesium oxide; organic pH buffering substances such as tris, basic amines or amino acids and their salts or other similar pharmaceutically acceptable pH buffering substances.

Insulating or undercoating layers

The barrier or subcoating layer may be applied to the core material by a coating or enrobing process using water and/or organic solvents for the coating process in a suitable apparatus such as a coating pan, a coating granulator or in a fluid bed apparatus. Alternatively, the separating layer may be applied to the core material by using a powder coating technique. The substance used for the separation layer is a pharmaceutically acceptable compound such as one or a mixture of saccharides, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and others. Additives such as plasticizers, colorants, pigments, fillers, antistatics and antistatics, for example magnesium stearate, titanium dioxide, fumed silica, talc and other additives may also be included in the barrier layer.

The isolation layer may serve as a diffusion barrier (diffusion barrier) and may serve as a pH buffer. The pH buffering properties of the isolation layer may be further enhanced by the incorporation of a layer material selected from the following compounds often used in acid-resistant formulations, such as magnesium oxide, hydroxide or silicate of aluminum or calcium, after the exclusion of bicarbonate or carbonate; composite aluminium/magnesium compounds, e.g. MgO. Al₂O₃·2SiO₂·nH₂O, or other pharmaceutically acceptable pH buffering compounds such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, citric acid or other suitable weak inorganic or organic acids; or suitable organic bases including basic amino acids or amines and salts thereof. Talc or other compounds may be added to increase the thickness of the layer and thereby strengthen the diffusion membrane.

Enteric coating layer

One or more enteric coating layers may be applied to the core material or to the core material coated with a separating layer using suitable coating techniques. The enteric coating layer material may be dispersed or dissolved in water or a suitable organic solvent. One or more of the following, alone or in combination, may be used as the enteric coating layer polymer; for example, solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, 1,2, 4-trimellitic acid cellulose acetate, carboxymethyl ethyl cellulose, shellac, or other suitable enteric coating polymers.

The enteric coating layer comprises a pharmaceutically acceptable plasticizer to obtain the desired mechanical properties, such as elasticity and hardness of the enteric coating layer. Such plasticizers are, for example, but not limited to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbates, or other plasticizers.

Suspension modifying particles

Suspension modifying particles comprise:

fast dissolving diluents

-gelling agents

-acidic pH adjusting agents

-a binder and

-optionally a disintegrating agent,

furthermore, it does not contain bicarbonate or carbonate, in particular components which can cause effervescence.

According to one embodiment, the suspension modifying particles are prepared by the following method: the fast dissolving diluent is mixed with the gelling agent, granulated together and then dried.

The final moisture content in the suspension-modified particles as determined by loss on drying is < 3% (w/w), preferably < 1% (w/w). The final content of ethanol is < 0.2% (w/w), preferably less than 0.12% (w/w).

When the suspension modifying particles are suspended in tap water, a stable and near maximum viscosity is obtained in a short time. Furthermore, the resulting suspension is lump-free and robust in the sense that its viscosity is essentially the same even if too little or too much water is added by the patient when preparing the suspension from particles. Thus, a prescribed amount of water of 50% to 150% can be added to a dose of active ingredient and suspension modifying particles, and still a formulation with the desired properties can be obtained.

When the suspension modifying particles are added to an aqueous medium such as water, the gel formed has a viscosity of 3.0 to 6.0log (mpas) 10³～10⁶mPas, preferably 3.6-4.7 log (mPas) ═ 10^3.6～10^4.7mPas。

The viscosity at 20 ℃ was evaluated as the intercept on the viscosity axis when plotted as log (viscosity) versus log (rotational speed (rpm)). The line was made by linear fitting using least squares linear regression, and the intercept of the fitted line was determined. The viscosity is determined using a suitable apparatus, for example a physicaDV-I P viscometer, with a measurement geometry (measuring geometry) of No.2 spindle (spindle), diameter 18.7mm, length 6.9mm, operating at rotational speeds of 3.0, 6.0, 30 and 100rpm, until a stable value (about 1 minute) is obtained.

According to one aspect of the invention, when the suspension modifying granule is prepared using a particular manufacturing process, a fast disintegration and a fast gelling to a stable and reproducible viscosity level are achieved when the suspension modifying granule is suspended in water.

The preparation method comprises the following steps in the following order, including the alternative of interchanging steps I and II;

I) mixing the gelling agent with a pH adjusting agent, a fast dissolving diluent and optionally a disintegrant

II) dissolving the binder in ethanol

III) wetting the mixture obtained in step I (alternatively, if the order is interchanged, step II) with the solution obtained in step II (alternatively, if the order is interchanged, step I)

IV) agitating the wet mixture obtained in step III so that almost every gelling agent particle is brought into intimate/intimate contact with the above fast dissolving diluent,

v) drying the stirred wet mixture of step IV until the final moisture content in the suspension modified particles as determined by loss on drying is < 3% (w/w), preferably < 1% (w/w)

VI) grinding or milling the dried granules obtained in step V until more than 95% (w/w) of the granules pass through a sieve having a mesh opening of 1.0 mm.

It is a feature of the present invention that the fast dissolving diluent is brought into intimate/intimate contact with the gelling agent, thus not only obtaining a very fast gelling time compared to the gelling agent itself, but also a stable gel very quickly. One embodiment of the present invention is to select an appropriate rapidly disintegrating diluent that can also function as a sweetener.

When added to water, such as tap water, rapid gelling of the dry suspension modified particles is typically visible because the gelling is typically sufficient, i.e., 75% of the maximum obtainable level is reached in about 10 minutes. Typically 90% or more of the maximum viscosity is reached within 15 minutes. See the table of example 2 for a comparison.

In particular, when one suspension modifying particle of the invention is suspended in water and gently stirred, a suspension with a viscosity of more than 75% of the maximum achievable viscosity is obtained within 13 minutes, preferably a suspension with a viscosity of more than 75% of the maximum achievable viscosity is obtained within 10 minutes, as measured by adding 1g of the suspension modifying particle to 5ml of water. More than 90% of the maximum obtainable viscosity, preferably more than 90% in 25 minutes, is reached within 30 minutes, determined by adding 1g of suspension modifying particles to 5ml of water.

According to one embodiment of the invention, the suspension modified particles (and the enteric coated PPI containing pellets) do not comprise lactose.

Gelling agent

The gelling agent is used to form a gel suitable for administration through a gastric probe (gastic find)/nasogastric tube, i.e. a gel having suitable viscoelasticity and suitable viscosity when dispersed in an aqueous medium such as water. This is the route of administration required in geriatric or pediatric treatment.

Dissolution time also affects the choice of gelling agent.

Suitable gelling agents for the present invention are xanthan gums of various nature.

Other gelling agents are also contemplated, but in some cases, such as certain starch products, the appropriate range of concentrations is quite limited, such as Thick-It containing modified corn starch and maltodextrin^TMregular. The product can only be used in a narrow range of about 6-8% of the final suspension, corresponding to an amount of gelling agent in the suspension modifying particles of 34 to 38%, which is an inappropriately high proportion in the composition.

Another example is corn starch, which can swell many times rapidly, but has undesirable viscoelastic properties.

Gelling agents such as sodium carboxymethylcellulose (CMC) and carrageenan cannot be used in the present invention because they lack the proper viscoelastic properties or because they have unsuitable properties for the suspension obtained by administration through a gastric probe.

Thus, the gelling agent of the present invention is selected from xanthan gum.

The concentration of the gelling agent is 0.6-12% w/w of the suspension modified particles. In a preferred embodiment, the concentration of the gelling agent is 1.8 to 4.8% w/w. For practical reasons for the patient, a wide range of concentrations of gelling agent is advantageous and still has the appropriate properties of a viscoelastic gel.

In one embodiment of the invention, the preparation is carried out with a gelling agent having an average particle size of greater than 150 microns.

Fast dissolving diluent

The diluent has the function of diluting, but also of a sweetener.

The diluent is selected from monosaccharides, disaccharides and hydrates of any of them. According to one aspect of the invention, the preferred diluent is glucose, sucrose or a hydrate of any of them. According to the invention, fast dissolution means that the dissolution time of the diluent is less than 2 minutes when 2g of the diluent is dissolved in 10ml of water at 14 ℃ under slow continuous stirring. One diluent that specifically does not meet this requirement is mannitol.

As a result of the manufacturing process, the suspension modifying particles of the present invention have a fast dissolving diluent randomly distributed in and on the resulting individual particles.

Acidic pH regulator

When suspended in water, the suspension modifying particles form a suspension having a pH of 3.0 to 6.0, preferably 3.0 to 5.0, more preferably 3.5 to 4.5.

This can be achieved by adding a suitable acidic pH adjusting agent. The reagent may comprise a single acidic compound or a mixture of compounds selected from acidic and basic compounds other than any carbonate. Any mixture of such pH affecting compounds may be selected according to the following method, which when dissolved/suspended in water will result in a pH in the above desired (acidic) range.

Non-limiting examples of suitable acidic compounds are: citric acid, tartaric acid and malic acid. Non-limiting examples of mixtures of compounds selected from the group consisting of acidic and basic compounds are monosodium phosphate and disodium phosphate (in appropriate proportions to achieve a pH within the desired range)

Disintegrating agent

The optional disintegrant used in the dried suspension modifying granule may be a single disintegrant or a mixture thereof.

Non-limiting examples of suitable disintegrants include: crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose (Ac-Di-Sol)) And pregelatinized starch (Sta-Rx)1500)。

Adhesive agent

Suitable binders for use in the present invention are polymers soluble in water and ethanol. Suitable polymers are selected from hydroxypropyl cellulose of various nature. When hydroxypropyl cellulose is selected as the binder (hereinafter also referred to as HPC), the hydroxypropyl content ranges from 50-90%, or more preferably 60-81%, and the viscosity is below 450mpas (cps) measured at 5% concentration. These polymers are, for example, Klucel from AqualonJF and KlucelLF。

The hydroxypropyl cellulose used in this aspect of the invention, as a binder, excludes low substituted hydroxypropyl cellulose, also known as L-HPC.

The ratio of the binder to the gelling agent in the suspension modifying particles of the present invention is preferably 1: 2 to 1: 3, w/w.

Strength of dosage form

Different product strengths can be obtained by filling a unit size sachet with a specific amount of the enteric coated proton pump inhibitor pellets of the present invention and suspension modifying granules. According to one embodiment of the invention, enteric coated pellets comprising esomeprazole magnesium trihydrate are filled into unit size sachets together with suspension modifying granules.

The w/w ratio of the two components of the mixture, i.e. on the one hand the enteric coated pellets comprising the proton pump inhibitor and on the other hand the (dry) suspension modifying particles, may be in the range of 1: 1000 to 100: 1000, preferably in the range of 4: 1000 to 80: 1000, most preferably in the range of 8: 1000 to 60: 1000.

The amount of enteric coated pellets in one sachet

The drug content of the enteric coated pellets comprising PPI is 5% w/w to 40% w/w of the enteric coated pellets. That is, the highest theoretical amount of single dose pellets can be calculated considering the following situation, which results from the lowest drug concentration of the pellets and the highest dose of the drug (100 mg in the present invention), to a total amount of (100/0.05 ═ 2000mg of the pellets.

The lowest energy capacity of the pellets can be similarly obtained in the opposite case, from the highest concentration and the lowest dose (1 mg according to the invention) the smallest amount of pellets is obtained, i.e. (1/0.4 ═ 2.5mg of pellets.

In a preferred embodiment of the invention the drug content of the enteric coated pellets is 8-30% w/w.

The amount of enteric coated pellets in one sachet of the invention is in the range of 2.5 to 2000mg, in a preferred embodiment of the invention the amount of enteric coated pellets in one sachet is in the range of 3 to 1250 mg.

In an alternative embodiment of the invention, the drug amount of the enteric coated pellets is adapted to the predetermined drug dose in one sachet according to the following table;

TABLE 1

Predetermined dosage in a sachet	Drug content in adapted enteric coated pellets	Amount of pellets in one sachet
			1mg-40mg	8-12％w/w	8-500mg
＞40mg-70mg	15-25％w/w	160-467mg
			＞70mg-100mg	25-40％w/w	280-400mg

Thus, in one embodiment of the invention, the dose in one sachet is 1-40mg and the drug content in the enteric coated pellets is 8-12% (w/w).

In another embodiment of the invention the dose in one sachet is > 40mg-70mg and the drug content in the enteric coated pellets is 15-25% (w/w).

In a further embodiment of the invention the dose in one sachet is > 70mg-100mg and the drug content in the enteric coated pellets is 25-40% (w/w).

Ready-to-use liquid preparation

Prior to use, the contents of the sachet are emptied into a predetermined volume of aqueous liquid. Upon stirring, a viscous suspension formed. The liquid formulation is another aspect of the invention, comprising three main components: enteric coated pellets comprising a proton pump inhibitor, a (dry) suspension modified granulate and an aqueous liquid.

The amount of aqueous liquid is 5 times the amount of suspension modifying particles, but the patient is allowed to vary the amount of liquid from a predetermined amount ranging from 50% to 150%. That is, the amount of aqueous liquid of the ready-to-use liquid formulation may be 2.5 times to 7.5 times the amount of suspension-modifying particles.

In one aspect of the invention, the aqueous liquid is water.

The concentration of the gelling agent should be 0.1-2% w/w (the concentration difference is in the range of 20 times), preferably 0.3-0.8% w/w of the suspension. For practical reasons for the patient, a wide range of concentrations of gelling agent is advantageous and still maintains the relevant properties of a viscoelastic gel.

Examples

Example 1a.

Preparation of suspension modified particles of the invention

Excipient Content (%)

Xanthan gum 11K 2.5

Cross-linked polyvinylpyrrolidone 2.5

Glucose, no water 93.8

Hydroxypropyl cellulose JF 1.0

Anhydrous citric acid 0.164

Yellow iron dioxide pigment 0.06

(Colour iron dioxide yellow)

Hydroxypropyl cellulose was dissolved in ethanol. This solution was added to the dry mixture of the remaining excipients to give a wet mass, which was granulated during the addition of the solution. The wet mass was dried and ground (maximum 5% particles > 1 mm).

3g of the suspension modified particles were dissolved in 15ml of water and the liquid formulation was stirred for 60 seconds. The pH was measured with a calibrated pH meter using a glass electrode and found to be 4.0.

(comparative) example 1b.

Suspension modifying particles of the prior art

As a comparison, commercial product "Lanzo" from Wyeth Lederle was used^TM30mg, granule "(batch 3ET032, expiration date 7 months 2006; and 3ET010, expiration date 3 months 2006).

The suspension particle composition (except for the enteric coated pellets) used in this product according to sweds were:

excipient Content (%)

Mannitol 45.8

Sucrose 45.8

Xanthan gum 3.5

Cross-linked polyvinylpyrrolidone 3.5

Dioctyl sulfosuccinate 0.015

Magnesium stearate 0.5

Silica 0.1

Citric acid anhydrous 0.4

Pigment (color) 0.05

Flavoring agent (Flarouring) 0.4

Ex2 viscosity measurement

Experimental conditions

Embodiments of the invention: 3g of suspension modified particles obtained according to example 1a were dissolved in 15ml of water and the liquid formulation was stirred for 60 seconds.

Prior art sample (Lanzo)^TM30mg, granules): pellets containing lansoprazole were removed from the total solids (5.7g) of the product described in example 1b, 30ml of water was added to the remaining powder/granulate (5.4g), and the liquid formulation was then stirred for 60 seconds.

For both samples, the viscosity measurement started after 1 more minute.

Equipment: relogica stress tech

The determination principle is as follows: oscillating disk/disk P302 mm slit (slit)

Measurement parameters are as follows: frequency 0.1 Hz; stress 0.07146 Pa.

Discussion of the related Art

In the case of lansoprazole (example 1b), despite the addition of a fast dissolving diluent (sucrose) to the suspension particle formulation, the formulation did not form a stable gel for the desired short period of time, see fig. 2, which was compared to that obtained in the present invention (example 1a), see fig. 1, and the results are shown in the table above.

The result of using a slow dissolving diluent will be a composition that slowly gels and increases in viscosity in a reasonable and reasonable amount of time. The present invention thus solves several problems to obtain lactose-free and bicarbonate/carbonate-free compositions with a fast gel time and a viscosity/viscoelasticity suitable for swallowing or for administration through tubes, e.g. the viscosity remains constant over time, there is no cake in the final suspension administered.

EXAMPLE 3 preparation of enteric coated pellets containing esomeprazole magnesium trihydrate

Core material

Esomeprazole magnesium trihydrate 445g

Sugar ball seed 300g

Hydroxypropyl methylcellulose 67g

Polysorbate 809 g

2100g of purified water

Bottom cladding

Hydroxypropyl cellulose 90g

Slide 340g

Magnesium stearate 22g

Purified water 3100g

Enteric coating layer

Methacrylic acid copolymer type C, 30% Dispersion 1270g

Triethyl citrate 38g

Monoglyceride and diester 19g

Polysorbate 802 g

Purified Water 500g

Suspension coating was performed in a fluidized bed apparatus using the bottom spray (bottom spray) technique. Esomeprazole is sprayed onto sugar sphere seeds from an aqueous suspension containing a binder and a surfactant. The size of the sugar pellet seeds is in the range of 0.25 to 0.35 mm.

The prepared core material was subcoated with a hydroxypropyl cellulose solution containing talc and magnesium stearate in a fluidized bed apparatus. The enteric coating layer is then sprayed as an aqueous dispersion onto the pellets coated with the separating layer in a fluidized bed apparatus.

Example 4 example of preparation of ratios of the Components of the final liquid formulation of different dosage strengths

^*Preparation according to example 3

^**Preparation according to example 1a

Example 5 description of the fast gel time of the invention

The contents of the sachet containing the final formulation, according to the 40mg dose strength of example 4, were emptied into a beaker containing a nominal 15ml amount of water.

The sample was then stirred for 15 seconds and then held still until 55 seconds from the start. Thereafter, it was stirred for another 5 seconds to uniformly disperse the active drug particles in the suspension.

The suspension was then examined for 30 seconds to determine whether substantially all of the enteric coated pellets were dispersed into the suspension or whether they accumulated on the bottom of the beaker.

If the pellets are not dispersed in the aqueous medium but accumulate at the bottom of the beaker, the process is repeated, waiting a further 25 seconds, stirring for 5 seconds, i.e. up to 2 minutes, and then checking for 30 seconds until substantially all of the pellets remaining are dispersed in the liquid medium. The time required for the pellet to remain in the liquid medium was recorded.

The samples in the following table were evaluated in the manner described and the results were as follows:

sample (I)	The time required for the pellets to remain suspended
		1) Sachet content, 40mg dose strength according to example 4	2 minutes
2) Sachet content, 40mg dose strength according to example 4	2 minutes
		2) Sachet content, 10mg dose strength according to example 4	2 minutes
		I) Sachet "LanzoTM30mg”	5 minutes
II) sachets "LanzoTM30mg”	5 minutes

Claims (19)

1. An oral pharmaceutical dosage form which is a solid rapidly gelling granular mixture suitable for the preparation of a suspension comprising:

I) an acid labile proton pump inhibitor as active ingredient distributed in a plurality of enteric coated pellets, wherein the proton pump inhibitor is selected from esomeprazole, an alkaline salt thereof or a hydrated form of any of them, the enteric coated pellets having an average diameter of 0.2-1.8 mm; and

II) particles, characterized in that the particles are suspension modifying particles comprising:

-a fast dissolving diluent selected from glucose, sucrose and hydrates of any of them,

-a gelling agent selected from xanthan gum in an amount of 1.8% to 4.8% w/w of the particles,

-acidic pH adjusting agents

A binder which is hydroxypropyl cellulose having a hydroxypropyl content of 50 to 90%, and

-optionally a disintegrant;

wherein a fast dissolving diluent is mixed with a gelling agent and granulated together, and the granules do not comprise bicarbonate and carbonate, and wherein the ratio of binder and gelling agent in the suspension modifying granules is from 1: 2 to 1: 3 w/w.

2. The dosage form of claim 1, which does not comprise lactose.

3. The dosage form of any one of claims 1-2, wherein the suspension modifying particles form a suspension having a pH in the range of 3.0 to 6.0 when suspended in water.

4. The dosage form of any one of claims 1-2, wherein the suspension modifying particles form a suspension having a pH in the range of 3.0 to 5.0 when suspended in water.

5. The dosage form according to any of claims 1-2, wherein the enteric coating coated pellets consist of the following structural components: a core material comprising the active ingredient, a subcoating layer, an enteric coating layer, and no other coating layer over the enteric coating.

6. The dosage form according to any of claims 1-2, wherein the mean diameter of the enteric coated pellets is 0.4-1.0 mm.

7. A sachet comprising a dosage form according to any one of claims 1 to 6.

8. The sachet of claim 7, wherein the amount of active ingredient is 1mg to 100 mg.

9. The sachet of claim 7, wherein the amount of active ingredient is 1mg to 40 mg.

10. A ready-to-use liquid formulation comprising an aqueous liquid and a dosage form according to any one of claims 1 to 6 or a sachet according to any one of claims 7 to 9.

11. The liquid formulation of claim 10, wherein the amount of aqueous liquid is 2.5 to 7.5 times the amount of suspension modifying particles.

12. The liquid formulation of claim 10, wherein when the suspension modifying particles are suspended and stirred in an aqueous liquid, a suspension is obtained that reaches a maximum achievable viscosity of more than 75% within 13 minutes.

13. The liquid formulation of claim 10, wherein when the suspension modifying particles are suspended and stirred in an aqueous liquid, a suspension is obtained that reaches a maximum attainable viscosity of more than 75% within 10 minutes.

14. The liquid formulation of claim 10, wherein when the suspension modifying particles are suspended and stirred in an aqueous liquid, a suspension is obtained that reaches over 90% of the maximum attainable viscosity within 30 minutes.

15. The liquid formulation of claim 10, wherein when the suspension modifying particles are suspended and stirred in an aqueous liquid, a suspension is obtained that reaches over 90% of the maximum attainable viscosity in 25 minutes.

16. The liquid preparation according to any one of claims 10 to 15, wherein the aqueous liquid is water.

17. A method of making suspension modifying particles for use in a dosage form according to any one of claims 1 to 6, said suspension modifying particles comprising:

-a fast dissolving diluent selected from glucose, sucrose and hydrates of any of them,

a gelling agent selected from xanthan gum in an amount of 1.8% to 4.8% w/w of the particles,

-acidic pH adjusting agents

A binder which is hydroxypropyl cellulose having a hydroxypropyl content of 50 to 90%, and

-optionally a disintegrant;

wherein the fast dissolving diluent is mixed with the gelling agent and granulated together; and the particles do not comprise bicarbonate and carbonate, and wherein the ratio of binder to gelling agent in the suspension modifying particles is from 1: 2 to 1: 3 w/w.

18. The method of claim 17, wherein the method comprises the following steps in the following order:

I) mixing the gelling agent with a pH adjusting agent, a fast dissolving diluent and optionally a disintegrant,

II) dissolving the adhesive in ethanol,

III) wetting the mixture obtained in step I with the solution obtained in step II,

IV) agitating the wet mixture obtained in step III so that almost every particle of the gelling agent is brought into intimate/intimate contact with the fast dissolving diluent described above,

v) drying the stirred wet mixture of step IV until the final moisture content in the suspension modified particles as determined by loss on drying is < 3% (w/w),

VI) milling or grinding the dried granules obtained in step V until more than 95% (w/w) of the granules pass through a sieve having 1.0mm openings.

19. The method of claim 17, wherein the method comprises the following steps in the following order:

I) the adhesive is dissolved in the ethanol and then dissolved in the ethanol,

II) mixing the gelling agent with a pH adjusting agent, a fast dissolving diluent and optionally a disintegrant,

III) wetting the mixture obtained in step II with the solution obtained in step I,

IV) agitating the wet mixture obtained in step III so that almost every particle of the gelling agent is brought into intimate/intimate contact with the fast dissolving diluent described above,

v) drying the stirred wet mixture of step IV until the final moisture content in the suspension modified particles as determined by loss on drying is < 3% (w/w),

VI) milling or grinding the dried granules obtained in step V until more than 95% (w/w) of the granules pass through a sieve having 1.0mm openings.