EP4784101A1 - Lactose-free solid oral dosage form of itopride - Google Patents

Abstract

An orally swallowable, immediate release tablet, comprising itopride or a pharmaceutically acceptable salt thereof as an active ingredient, characterized in that the tablet comprises granules containing the active ingredient, mannitol and optionally at least one additional pharmaceutically acceptable excipient, wherein the tablet does not contain lactose. Said tablet for use in prevention or treatment of gastrointestinal motility disorders. A method for manufacturing the orally swallowable, immediate release tablet according to any of the preceding claims, comprising: a) granulating itopride or a pharmaceutically acceptable salt thereof with mannitol and optionally at least one additional pharmaceutically acceptable excipient, b) optionally blending the granules obtained in step a) with at least one extra-granular pharmaceutically acceptable excipient, and c) compressing the granules from step a) or the blend from step b) into tablets.

Description

Lactose-free solid oral dosage form of itopride

Field of the invention

The present invention relates to an immediate release pharmaceutical dosage form of itopride or a pharmaceutically acceptable salt thereof, wherein said dosage form is an orally swallowable tablet free of lactose.

Background art

Itopride hydrochloride is a benzamide derivative that stimulates gastrointestinal (GI) motor activity through synergistic effects of dopamine D2 receptor blockade and acetylcholine esterase inhibition. Higher acetylcholine concentration increases GI peristalsis, increases the lower oesophageal sphincter pressure, stimulates gastric motility, accelerates gastric emptying, and improves gastro-duodenal coordination. In addition to prokinetic effect, itopride exhibits an antiemetic effect based on its dopamine D2 receptor antagonistic activity. It is primarily used in the treatment of disorders associated with reduced gastrointestinal motility, such as functional dyspepsia, gastroparesis (delayed gastric emptying), or gastroesophageal reflux disease.

The drug is available in some EU countries in the form of immediate release tablets comprising 50 mg of itopride hydrochloride that are marketed under various brand names, such as Ganaton, Prokit, or Kinito. However, all these products contain lactose, which makes them unsuitable for patients suffering from lactose intolerance. These individuals are unable to fully digest lactose, a sugar primarily found in milk and dairy products. This occurs due to a deficiency in lactase, the enzyme responsible for breaking down lactose into glucose and galactose in the small intestine. As a result, consuming lactose can lead to symptoms like diarrhea, gas, bloating, and abdominal pain. The severity of these symptoms depends on the amount of lactose ingested and the individual's degree of lactase deficiency, but it is generally recommended to limit lactose intake.

Avoiding lactose is also beneficial in people suffering from other gastrointestinal disorders, such as functional dyspepsia or gastroparesis, who often experience exacerbated symptoms when consuming lactose due to their underlying digestive issues. In gastroparesis, delayed stomach emptying causes undigested lactose to remain in the stomach longer, leading to bacterial fermentation, which produces gas, bloating, and discomfort. This can intensify symptoms like nausea and abdominal pain, already common in gastroparesis. Similarly, for individuals with functional dyspepsia, lactose can exacerbate discomfort because the condition often involves heightened visceral sensitivity and poor digestion of certain foods, including dairy product. The gas and bloating from lactose fermentation can add to the discomfort these patients already experience, such as upper abdominal pain and fullness after meals.

Consequently, use of lactose in the drug products indicated for patients suffering from lactose intolerance, functional dyspepsia, gastroparesis or related gastrointestinal conditions is not desirable.

Lactose is one of the most widely used excipients in the pharmaceutical industry due to its versatile functions. It serves as a filler, adding bulk to tablets or capsules, and as a binder, providing the necessary strength to hold the ingredients together. Additionally, it enhances the flow properties of formulations, facilitating efficient production. Lactose is particularly valued for its chemical stability, which helps preserve the integrity and effectiveness of active ingredients over time. Its non-reactivity with most drugs ensures it won't interfere with the medication's efficacy or cause unwanted chemical reactions. Furthermore, its solubility allows for easy dissolution and absorption in the digestive system, ensuring the active drug is properly released. For all these reasons, its replacement in the formulation is problematic. Accordingly, there is a need in the art for immediate release itopride oral dosage forms that are lactose-free, but have the same bioavailability as lactose-containing forms.

Summary of the invention

The present invention provides a lactose-free solid oral dosage form comprising itopride or a pharmaceutically acceptable salt thereof as the active ingredient. The dosage form is an orally swallowable immediate release tablet that comprises the active ingredient in the form of granules containing itopride together with a non-lactose filler, which is mannitol. By excluding lactose from the formulation, the dosage form of the present invention improves patient compliance and comfort during and after administration.

Itopride, chemically identified as N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4- dimethoxybenzamide, is the active pharmaceutical ingredient responsible for the therapeutic effect of the dosage form. The term “itopride” as used herein, encompasses both the free base and its acid addition salts, with itopride hydrochloride salt being particularly preferred. In a preferred embodiment, itopride is the sole active ingredient present in the dosage form, meaning that no other ingredients with therapeutic action are present.

In some embodiments, the dosage form of the invention comprises from 25 mg to 150 mg, preferably from 50 mg to 100 mg, and most preferably about 50 mg of itopride hydrochloride or a molar equivalent amount of a free base or a different pharmaceutically acceptable salt thereof.

“Immediate release dosage form” refers to a tablet that is formulated to quickly release the API upon contact with gastrointestinal fluid without any intentional delay or extended release mechanism, ensuring prompt absorption of the API into the bloodstream, thus allowing for quick onset of action. Therefore, all formulations allowing the drug to dissolve in the GI contents, with no intention of delaying or prolonging the dissolution or absorption of the drug, qualify as immediate release.

The immediate release products may also be defined by their dissolution characteristics. Thus, the European Medicines Agency (EMA) defines immediate release as a product where at least 75% of the active substance is dissolved within 45 minutes. Preferably, for itopride-containing immediate release dosage forms of the invention, the product demonstrates rapid dissolution, when 85% or more of the drug substance is dissolved within 15 minutes. The appropriate dissolution medium, testing apparatus (e.g., paddle or basket apparatus), and dissolution test conditions are known to those skilled in the art and can be selected according to the European Pharmacopoeia (Ph. Eur). Preferably, the dissolution test is carried out using a 1000 mL medium at pH 1.2 (0.1M HC1), with the apparatus set to paddle rotation at 100 revolutions per minute (rpm).

“Orally swallowable tablet”, also called conventional tablet or pill, refers to a solid dosage form of medication that is intended to be swallowed whole with the aid of water or another suitable liquid. It is designed to pass through the digestive tract where it dissolves or disintegrates, releasing the active pharmaceutical ingredient (API) for absorption into the bloodstream. Unlike orodispersible tablets, swallowable tablets do not disintegrate in the mouth and are formulated to maintain their integrity until they reach the stomach or intestines. They differ also from the chewable tablets that are designed to be chewed and then swallowed by the patient rather than swallowed whole.

The tablets of the present invention comprise itopride and at least mannitol as a non-lactose filler, but they may also contain other excipients, except lactose. “Excipients” are therapeutically inactive, pharmaceutically acceptable ingredients that are added to the pharmaceutical composition for a specific purpose, e.g., to enable and/or facilitate the production, preparation, storage, and administration of the composition and/or the final dosage form. At the same time, their properties may favourably influence the disintegration of the tablet in the body, the release characteristics of the active ingredient substance, etc.

On the basis of their functions, excipients can be categorized as fillers, diluents, binders, disintegrants, glidants, lubricants, anti -adherents, surfactants, antioxidants, antimicrobials, preservatives, colourants, flavours, sweeteners, coating agents, etc. Excipients falling into these and other categories of excipients are well known in the art of pharmaceutical formulation and manufacture.

Fillers or diluents are substances that help add volume, in order to ensure consistent tablet size, facilitate uniform mixing of active ingredients, and aid in the manufacturing process. However, some fillers can have multiple functions and be suitable for use as other classes of excipients, e.g., microcrystalline cellulose can also be used as a binder and/or disintegrant.

In prior art itopride-containing compositions, lactose is commonly employed as the filler of choice. The present invention aims at replacing lactose in the composition, ensuring that the bioavailability of the final dosage form remains within the bioequivalence criteria and that all other parameters, such as assay, content uniformity, dissolution, and degradation products, meet compendial standards. In particular, the assay of the active ingredient should fall within the acceptable range of 95% to 105%, and the dissolution profile should demonstrate substantial similarity to the reference medicinal product. Additionally, the composition should be optimized for industrial-scale manufacturing, especially with regard to its flow properties.

The inventors have first tested various alternative fillers for which it was hoped that they might fulfil all conditions set. Those alternative fillers were microcrystalline cellulose, pregelatinized starch, dicalcium phosphate anhydrous, and fructose. However, it turned out that these fillers did not allow to achieve both the required dissolution rate corresponding to the reference product and flowability of their mixture with itopride. A combination of microcrystalline cellulose and pregelatinized starch led to the required dissolution rate, but API assay and flowability were not satisfactory, in particular the API assay value did not comply with the pharmacopoeia requirement.

Mannitol was considered as an alternative filler only after the hopeful alternatives all failed. This excipient is often used as a taste masking agent in orodispersible tablets and is also a suitable filler for sustained release dosage forms. However, its use is not recommended in immediate release conventional tablets comprising active ingredients lacking excellent permeability. Sugar alcohols, such as mannitol and sorbitol, are known to reduce drug absorption by increasing gastrointestinal fluid volume, which in turn dilutes intraluminal drug concentration and reduces small intestinal transit time. This effect is even more pronounced in substances with lower permeability, i.e. those from classes III and IV of the biopharmaceutical classification system (BCS). As itopride hydrochloride is a borderline for BCS I and III drug due to its moderate permeability, there was a serious concern that the use of mannitol would alter itopride bioavailability and pharmacokinetic to an extent that the tablet would not be bioequivalent to the reference drug product. Unfortunately, such effect cannot be sufficiently verified in dissolution tests. This is also the reason, why regulatory authorities typically require in vivo testing for mannitol-containing immediate release solid oral dosage forms even if the active ingredient exhibits high solubility and is classified into BCS class I or III.

Surprisingly, using mannitol as a non-lactose filler in the oral dosage form of the present invention provided tablets showing dissolution profiles comparable to the reference drug product and having similar bioavailability. Moreover, the API assay values are satisfactory, and even the desired flowability parameters, essential for industrial-scale manufacturing, are achieved.

Binders are used to improve the cohesion of powders, granules and other ingredients that are contained within the pharmaceutical composition. Some excipients can be used as both a filler and a binder. Suitable binders for use in the present invention are polysaccharides, such as starch or starch derivatives; polymers, such as povidone (polyvinylpyrrolidone, PVP) and copovidone, cellulose and its derivatives, such as hydroxypropyl methylcellulose (HPMC), or hydroxypropyl cellulose (HPC). Preferred binder is povidone or pregelatinized starch, with povidone being particularly preferred.

Disintegrants are agents added in the pharmaceutical compositions to facilitate the breakup or disintegration of the dosage form into smaller particles that dissolve more rapidly in the gastrointestinal fluids. In one embodiment, the dosage form of the invention comprises at least one disintegrant. Preferably, the disintegrant content in the tablet is between 3 wt. % and 8 wt. %. Suitable disintegrants for use in the present invention are preferably selected from the group consisting of sodium starch glycolate, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), and crosslinked polyvinylpyrrolidone (crospovidone). Preferred disintegrant is croscarmellose sodium or crospovidone, with crospovidone being particularly preferred.

Glidants are substances that improve the flowability of a pharmaceutical composition by reducing the interparticle friction, surface charge, and cohesion. In one embodiment, the dosage form comprises at least one glidant. Suitable glidants for use in the present invention are preferably selected from the group consisting of anhydrous colloidal silicon dioxide (fumed silica), talc, magnesium stearate, and glycerol monostearate. Preferred glidant is anhydrous colloidal silicon dioxide.

Lubricants are substances added to the pharmaceutical composition to decrease friction between a tablet’s surface and the die wall cavity, in which the tablet is formed, thereby preventing the adhesion of the material to the surface of the die and punches during compression. Use of these excipients allows for smoother tablet production and reduces possible defects on the produced tablets. In one embodiment, the dosage form of the invention comprises at least one lubricant. Suitable lubricants for use in the present invention are preferably selected from the group consisting of magnesium and calcium stearate, glycerol distearate (type I), stearic acid, talc, colloidal silicon dioxide, sodium stearyl fumarate, and sodium lauryl sulphate. Preferred lubricant is magnesium stearate.

The tablets of the present invention may be formulated with or without a coating. The coating is a polymer-based film covering the tablet surface that typically contains at least one polymer, at least one plasticizer and potentially other desired ingredients, such as pigments and opacifiers. Within the framework of the present invention, coated tablets are preferred.

The solid oral dosage form of the present invention comprises granules containing itopride or a pharmaceutically acceptable salt thereof, mannitol, and optionally at least one additional pharmaceutically acceptable excipient. This improves the flowability of the blend for tableting and facilitates industrial-scale manufacturing. The granules preferably comprise the active ingredient and mannitol in a weight ratio from about 1 : 1 to about 1 : 1.75, more preferably in a weight ratio from about 1 : 1.25 to about 1 : 1.5.

The granules contain substantially all the active ingredient which is contained in the tablet.

The granulation method is not particularly limited, and the granules can be produced by any of the granulation techniques known in the art, e.g., by a dry granulation or a wet granulation method. Granules obtained by wet granulation are preferred. The dry granulation method will typically comprise a step of strongly compressing the blend of itopride, mannitol and optionally at least one additional pharmaceutically acceptable excipient into large compacts, by using roller compaction or slugging. The large ribbons or slugs are then crushed into smaller particles, known as granules. This is typically done through milling and/or screening to achieve the desired granule size.

The wet granulation method will typically comprise a steps of adding a liquid to the blend of itopride, mannitol, a binder and optionally at least one additional pharmaceutically acceptable excipient, to facilitate particle agglomeration. The liquid can be water or an organic solvent. Once dried, the granules are milled and sieved to achieve uniform granule size. High-shear granulation is a particularly preferred wet granulation method.

In one embodiment, the at least one additional pharmaceutically acceptable excipient incorporated into the granules is at least one binder, that may be selected from any of those disclosed herein. The binder helps glue the powder particles together into larger agglomerates or granules and is essential in wet granulation.

In one embodiment, the at least one additional pharmaceutically acceptable excipient incorporated into the granules is at least one disintegrant, that may be selected from any of those disclosed herein. Preferably the tablet comprises at least one disintegrant in both the intra- granular and extra-granular phases. The disintegrant(s) used in both phases may be the same or different, but use of the same disintegrant(s) in both phases is preferred. The weight ratio of the intra-granular to extra-granular disintegrant is preferably from about 1 : 2 to about 2 : 1, and most preferably the weight ratio is about 1 : 1. The (partial) incorporation of a disintegrant into the granules enables better control of the dissolution rate.

In one embodiment, the granules contain both at least one binder and at least one disintegrant as additional pharmaceutically acceptable excipients. Thus, the tablet preferably comprises granules containing:

30 to 45 wt. % of itopride or its pharmaceutically acceptable salt,

45 to 65 wt. % of mannitol,

2 to 6 wt. % of at least one binder, preferably povidone and/or pregelatinized starch,

0.5 to 10 wt. % of at least one disintegrant, preferably crospovidone and/or croscarmellose sodium.

Even more preferably, the tablet comprises granules containing: 35 to 40 wt. % of itopride or its pharmaceutically acceptable salt,

50 to 60 wt. % of mannitol,

2 to 6 wt. % of povidone and/or pregelatinized starch, and

0.5 to 5 wt. % of crospovidone and/or croscarmellose sodium.

In one embodiment, the tablet comprises granules as defined above, at least one extra-granular disintegrant, at least one extra-granular glidant, and/or at least one extra-granular lubricant. Thus, the tablet preferably comprises:

80-98 wt. % of the granules as defined above,

0.5 to 10 wt. % of at least one extra-granular disintegrant, preferably crospovidone and/or croscarmellose sodium,

0.5 to 2 wt. % of at least one glidant, preferably colloidal silicon dioxide,

0.5 to 3 wt. % of at least one lubricant, preferably magnesium stearate and/or talc, and optionally at least one other extra-granular pharmaceutically acceptable excipient.

The at least one other extra-granular pharmaceutically acceptable excipient may be selected from any of the excipients described above, e.g. additional binder or filler. However, there is preferably no other extra-granular excipient besides at least one extra-granular disintegrant, at least one glidant, and at least one lubricant.

Even more preferably, the tablet comprises:

95 to 97 wt. % of the granules as defined above,

1 to 3 wt. % of crospovidone and/or croscarmellose sodium,

0.5 to 1 wt. % of colloidal silicon dioxide, and

0.5 to 2.0 wt. % of magnesium stearate and/or talc.

In one embodiment, the tablet comprises 50 mg of itopride hydrochloride, 65 mg to 75 mg of mannitol, 1.5 mg to 8 mg of crospovidone and/or croscarmellose sodium, 3 mg to 6 mg of povidone and/or pregelatinized starch, 0.5 mg to 2 mg of colloidal silicon dioxide, and 1 mg to 3 mg of magnesium stearate and/or talc.

The tablet of the present invention can be used for prevention or treatment of conditions that benefit from stimulation of gastrointestinal motor activity. These include gastrointestinal motility disorders, such as functional dyspepsia, gastroparesis (delayed gastric emptying), gastroesophageal reflux disease, and their symptoms, including indigestion, bloating, nausea, heartburn, upper abdominal discomfort, feeling of fullness, vomiting, and decreased appetite. The invention further provides a method for manufacturing the orally swallowable, immediate release tablet as defined above, comprising the steps of: a) granulating itopride or a pharmaceutically acceptable salt thereof with mannitol and optionally at least one additional pharmaceutically acceptable excipient, b) optionally blending the granules obtained in step a) with at least one extra-granular pharmaceutically acceptable excipient, and c) compressing the granules from step a) or the blend from step b) into tablets.

The weight ratio of itopride and mannitol in step a) is preferably from about 1 : 1 to about 1 : 1.75, more preferably from about 1 : 1.25 to about 1 : 1.5.

The granulation method is not particularly limited, and the granules can be produced by any of the granulation techniques disclosed above. However, wet granulation using water as a granulation medium is preferred. Therefore, in one embodiment the manufacturing method comprises the following steps: a) wet granulating itopride or a pharmaceutically acceptable salt thereof with mannitol, at least one binder, and optionally at least one additional pharmaceutical excipient. b) drying the granules from step a), c) optionally blending the dry granules with at least one extra-granular pharmaceutically acceptable excipient, and d) compressing the granules from step a) or the blend from step b) into tablets.

The wet granulation may be carried out using any method known in the art. However, high- shear granulation is particularly preferred.

The at least one binder may be selected from any of those disclosed herein. Preferably, the binder is selected from povidone, pregelatinized starch, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

In one embodiment, the at least one additional pharmaceutical excipient in step a) is at least one disintegrant. Preferably, at least one disintegrant is also added as the at least one extra-granular pharmaceutically acceptable excipient in step c). Thus, the tablet obtained by the method has at least one disintegrant both in the intra- and extra-granular phase. The disintegrant(s) used in both phases may be the same or different, but use of the same disintegrant(s) in both phases is preferred. The weight ratio of the disintegrant(s) in the intra- and extra-granular phase is preferably from about 1 : 2 to about 2 : 1, but most preferably the weight ratio is about 1 : 1. The at least one disintegrant may be selected from any of those disclosed herein. Preferably, the disintegrant is selected from crospovidone, croscarmellose sodium, and sodium starch glycolate.

In a preferred embodiment, the manufacturing method comprises the following steps: a) wet granulating itopride or a pharmaceutically acceptable salt thereof with mannitol, at least one binder, preferably povidone or pregelatinized starch, and with a first portion of at least one disintegrant, preferably crospovidone or croscarmellose sodium. b) drying the granules from step a), c) blending the dry granules with a second portion of the at least one disintegrant, preferably povidone or pregelatinized starch, at least one glidant, preferably colloidal silicon dioxide, and/or at least one lubricant, preferably magnesium stearate or talc, and d) compressing the blend into tablets.

The blending of the dry granules and the second portion of at least one disintegrant with the glidant and/or the lubricant in step c) may be simultaneous or sequential, with the latter being preferred.

Description of the drawings

Figure 1 shows a comparison of dissolution profiles of the reference drug product and tablets formulated with different excipients (i.e. pregelatinized starch, microcrystalline cellulose, fructose, and mannitol), using direct compression.

Figure 2 shows a comparison of dissolution profiles of the reference drug product and tablets formulated with microcrystalline cellulose and pregelatinized starch in a weight ratio of 1 : 1, using either direct compression (DC) or high shear granulation (HSG).

Figure 3 shows a comparison of dissolution profiles of the reference drug product and tablets formulated with different ratios of microcrystalline cellulose and pregelatinized starch (1 : 1; 2 : 1; 1 : 2), using high shear granulation.

Figure 4 shows a comparison of dissolution profiles of the reference drug product and tablets formulated with microcrystalline cellulose and pregelatinized starch in a weight ratio of 1 : 1 that differ in the amount of a disintegrant. Figure 5 shows a comparison of dissolution profiles of the reference drug product and tablets formulated either with a mixture of microcrystalline cellulose and pregelatinized starch in a weight ratio of 1 : 1 and high amount of a disintegrant or with mannitol and medium amount of a disintegrant, using high shear granulation.

Examples

The invention is further illustrated by the following examples. Examples 1 to 9 are comparative examples showing that the use of the fillers that could be considered by skilled person as a relevant replacement of lactose did not solve the technical problem. On the contrary, mannitol which would not be considered by skilled person as a suitable replacement for lactose surprisingly allows to achieve the desired properties.

Itopride hydrochloride purchased from commercial supplier was used for the preparation of the exemplified formulations.

The dissolution curves were measured by Sotax USP 2 apparatus using paddle method at 900 ml acid buffer (pH 1.2), 50 RPM.

Example 1 : Analysis of the reference drug product

The reference drug product Ganaton, film-coated tablets manufactured by Mylan and packed in a PVC/PVDC blister, was analyzed by dissolution testing to assess its release characteristics. The dissolution curve is shown in Figures 1 to 5. The tablets contain 50 mg of itopride hydrochloride and 75 mg of pharmaceutical excipients. Table 1 summarizes the composition of Ganaton cores.

Table 1

As can be seen, Ganaton tablets comprise a substantial amount of lactose, and the same applies to other medicinal products that are available on the European market. One of those products that is known to be bioequivalent to Ganaton was chosen as a starting point for the lactose-free tablet development. Composition of its cores, recalculated per one tablet, is summarized in Table 2.

Table 2

Example 2: Compatibility study

Since lactose is problematic for many people due to a widespread reduction in ability to digest this sugar after infancy, it is desirable to substitute it with another excipient(s) having similar properties. An excipient-itopride compatibility study was carried out to find a suitable replacement for lactose in the formulation.

The compatibility was assessed through HPLC analysis of binary mixtures of excipient and drug substance at a 1 : 1 ratio in the solid state. Samples were stored at 25°C/60% RH and 40°C/75% RH in both open and closed containers for 1 month. Pregelatinized starch (Starch 1500®), microcrystalline cellulose (MCC102), and dicalcium phosphate anhydrous (DCP), were evaluated in the excipient compatibility study. Each binary mixture was prepared in quadruplicate. 100 mg of itopride hydrochloride was weighed into a 20 mL screw-sealed vessel. 100 mg of each tested excipient was added, and the solid mixture was well mixed by hand shaking in combination with vortex-mixing (10 min at 2500 RPM). Table 3 shows the results of the study. Table 3

All results obtained were evaluated in order to assess the compatibility of excipients and the active ingredient. Where an assay was within 95-105 % with good agreement between parallel preparations, the given excipient was evaluated as compatible. This was the case of pregelatinized starch and microcrystalline cellulose. However, dicalcium phosphate anhydrous showed results suggesting an incompatibility.

Example 3 : Itopride tablets containing pregelatinized starch - direct compression Pregelatinized starch was chosen to replace lactose as it was an excipient already present in the starting formulation from Example 1, but instead of corn starch, a special grade with spherical particles (StarTab) was chosen to facilitate direct compression. Pregelatinized starch (PGS) dissolves better than corn starch and is suitable for use as a filler-binder and therefore represents a good candidate for lactose replacement.

Itopride hydrochloride was blended with pregelatinized starch, croscarmellose sodium, and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press. The composition of the tablet cores is disclosed in Table 4.

Table 4 The final blend exhibited Hausner ratio of 1.48, indicating very poor flow properties that are unsuitable for an industrial scale processing. In addition, the dissolution measurement revealed a significantly slower dissolution rate compared to the reference drug product, as shown in Figure 1. Such slower dissolution kinetic was not expected for a product prepared by direct compression that should not significantly alter the dissolution behaviour. Therefore, while the poor flow properties may hopefully be addressed by employing a granulation step, this will inevitably slow down the dissolution even more. Consequently, the product will not be bioequivalent to the reference medicinal product.

Example 4: Itopride tablets containing microcrystalline cellulose - direct compression

In a further attempt to replace lactose in the composition, microcrystalline cellulose (MCC) was used. MCC is another widely used excipient and even though it is not soluble in water, it shows some disintegrating properties that may help improve dissolution kinetic.

Itopride hydrochloride was blended with microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press. The composition of the tablet cores is disclosed in Table 5.

Table 5

The final blend before compression exhibited Hausner ratio of 1.48, indicating very poor flow properties that are unsuitable for an industrial-scale process. Moreover, the dissolution characteristics did not improve in comparison to the pregelatinized starch-based formulation, as shown in Figure 1. Consequently, the product will not be bioequivalent to the reference medicinal product. Example 5: Itopride tablets containing microcrystalline cellulose and pregelatinized starch - direct compression

Since neither pregelatinized starch, nor MCC alone did work well in the formulation, the next formulation experiment focused on their combination.

Itopride hydrochloride was blended with microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press. The composition of the tablet cores is disclosed in Table 6.

Table 6

During dissolution testing of the formulation, the inventors surprisingly found that there is a synergistic effect between disintegrating properties of water-insoluble MCC and water-soluble pregelatinized starch. The mixture of these excipients showed significantly faster dissolution compared to their single excipient counterparts. Finally, a dissolution similarity with the reference medicinal product Ganaton was achieved, as shown in Figure 2. Unfortunately, the tablet blend flow properties were still poor, exhibiting Hausner ratio of 1.46.

Example 6: Itopride tablets containing microcrystalline cellulose and pregelatinized starch - high-shear granulation

Example 5 disclosed that a formulation having fast in-vitro dissolution profile can be obtained by using the combination of pregelatinized starch (Starch 1500®) and microcrystalline cellulose (MCC102). However, the direct compression process is not applicable in production scale due to limited flow properties of the tableting mixture. In order to address the issue, a granulation step was included in the manufacturing process.

Three prototypes differing in the excipient ratio were manufactured. However, a different grade of microcrystalline cellulose (MCC101) intended for high-shear granulation process was used. The composition of the tablet cores is disclosed in Table 7.

Table 7

Itopride hydrochloride was granulated with microcrystalline cellulose (MCC101), pregelatinized starch (PGS) and the first half of the amount of croscarmellose sodium using water as a granulation medium. Wet granulation of the blend was carried out using a high-shear granulator. Wet granules were milled and dried in a fluid bed dryer. Dry granules were milled and blended with the second half of the amount of croscarmellose sodium and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press.

As can be seen in Table 8, the final blend for tableting had much better flow properties. A composition with the best flow properties was obtained when the mass ratio of Starch 1500® : MCC101 was 1 : 2.

Table 8

However, all prototypes had slow dissolution rates compared to the reference medicinal product. It was also observed that higher amount of microcrystalline cellulose led to a slower dissolution rate, as shown in Figure 3.

Example 7: Itopride tablets containing microcrystalline cellulose extra-granularly and pregelatinized starch intra-granularly - high-shear granulation

Prototypes containing Starch 1500 and MCC101, both added intra-granularly, showed slower dissolution rate compared to the reference product. Moreover, all tablet cores achieved lower values of tablet hardness. Since the increasing amount of MCC within the granules resulted in decreasing dissolution rate, further prototype was designed to have MCC extra-granularly. The product was based on Starch 1500 : MCC ratio 1 : 1, as this prototype dissolved faster in the previous example than the one having ratio 1 : 2. As MCC was added extra-granularly, a grade for direct compression (102) was used. Otherwise, the composition remained the same as in Example 6.

Itopride hydrochloride was granulated with pregelatinized starch and the first half of the amount of croscarmellose sodium using water as a granulation medium. Wet granulation of the blend was carried out using a high-shear granulator. Wet granules were milled and dried in a fluid bed dryer. Dry granules were milled and blended with microcrystalline cellulose (MCC 102), the second half of the amount of croscarmellose sodium, and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press.

The process produced granules of lower particle sizes compared to the prototype where microcrystalline cellulose was added intra-granularly. Although the tableting blend showed slightly worse flow properties, adding MCC extra-granularly resulted in tablet cores of significantly higher hardness, lower friability and slightly decreased disintegration time. Unfortunately, the dissolution rate was also significantly decreased. This is probably due to higher tablet hardness and, thus, more compact tablet formulation. Therefore, it was inapplicable for further development because of its slow dissolution rate.

Example 8: Itopride tablets containing microcrystalline cellulose, pregelatinized starch and higher amount of a disintegrant - high-shear granulation

None of the prototypes disclosed in Examples 6 and 7 had satisfactory dissolution rate. Therefore, the inventors investigated the influence of the disintegrant level. For this study, ratio of Starch 1500 : MCC was selected to be 1 : 1. In all cases, the disintegrant was added intra- (50% w/w) and extra- (50% w/w) granularly. Four disintegrant levels were prepared, as shown in Table 9.

Table 9

Itopride hydrochloride was granulated with microcrystalline cellulose (MCC 101), pregelatinized starch (PGS) and the first half of the amount of croscarmellose sodium using water as a granulation medium. Wet granulation of the blend was carried out using a high-shear granulator. Wet granules were milled and dried in a fluid bed dryer. Dry granules were milled and blended with the second half of the amount of croscarmellose sodium and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press.

The influence of the disintegrant level on tablet dissolution is shown in Figure 4. Increasing disintegrant level significantly increased the dissolution rate. It was found that prototypes containing 10% or 15% of a disintegrant showed similar dissolution rate as the reference product. The prototype containing 15% of a disintegrant was selected for further analysis.

Finally, dissolution similarity with the reference medicinal product was achieved. However, the assay of granules, cores and final film-coated tablets revealed a significant loss of the active ingredient, as demonstrated in Table 10. Surprisingly, in terms of purity, there was not detected any increase of impurities within the production pathway.

Table 10

Since the assay of the product was less than 95%, it was not conforming to the acceptance limits for an assay of the active substance in a pharmaceutical product as set by the European Pharmacopoeia (Ph. Eur). These are generally set within the range of 95.0% to 105.0% of the declared content. It can be concluded that replacement of lactose by microcrystalline cellulose and pregelatinized starch in the itopride tablets failed to deliver a compliant product.

Example 9: Itopride tablets containing fructose - direct compression

Since the assay of MCC/PGS prototypes was not satisfactory, the inventors were looking for a different substitute for lactose. Fructose was selected, as it is a different water soluble sugar that has some characteristics similar to lactose.

Itopride hydrochloride was blended with fructose, pregelatinized starch, croscarmellose sodium, and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press. The composition of the tablets is disclosed in Table 11.

Table 11

From a technological point of view, fructose was not satisfactory in terms of flowability of the system, exhibiting Hausner ratio of 1.46. Moreover, the resulting tablets showed low hardness, making the subsequent film-coating process impossible. The dissolution behaviour was also negatively influenced by the tablet hardness as shown in Figure 1. Consequently, the product was not suitable for industrial-scale manufacturing process.

Example 10: Itopride tablets containing mannitol - direct compression

Itopride hydrochloride was blended with mannitol, pregelatinized starch, croscarmellose sodium, and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press. The composition of tablets is disclosed in Table 12.

Table 12 Once again, the tablet blend flow properties were poor, exhibiting Hausner ratio of 1.46, while the dissolution rate was too high compared to the reference medicinal product, as shown in Figure 1.

Example 11 : Itopride tablets containing mannitol - wet granulation

Considering all the above-mentioned formulation experiments, further development of the mannitol-containing composition was continued. The goal was to obtain tablets having dissolution rate similar to the reference drug product. At the same time, the assay of the product had to meet the Ph.Eur requirements.

The composition of the final prototype is disclosed in Table 13. Mannitol was selected as a filler for its fast dissolution kinetics. High shear granulation was employed to facilitate manufacturing as well as to slow down the dissolution. In addition, povidone was selected to replace pregelatinized starch as a binder, and crospovidone was selected for croscarmellose sodium replacement. The disintegrant amount was increased as it was added both intra- and extra-granularly (50% w/w).

Itopride hydrochloride was granulated with mannitol, povidone and the first half of the amount of crospovidone using water as a granulation medium. Wet granulation of the blend was carried out using a high-shear granulator. Wet granules were milled and dried in a fluid bed dryer. Dry granules were milled and blended with the second half of the amount of crospovidone and colloidal silicon dioxide. The resulting mixture was subsequently blended with magnesium stearate. The final blend was compressed on a rotary tablet press and the resulting cores were film-coated by a commercially available coating (Opadry II white 85F 18422) in a drum coating machine - 3 mg of the coating system per tablet. The composition of the drug product is listed in Table 13.

Table 13

Dissolution similarity with the reference medicinal product was achieved, as shown in Figure 5. Assay measurement confirmed that granules, tablet blend, tablets and film-coated tablets met Ph.Eur requirements in terms of assay.

Example 12: Bioequivalence study

The film-coated tablets from Example 11 were tested on healthy human subjects against the reference product Ganaton in a bioequivalence study, measuring the pivotal pharmacokinetic parameters AUC (area under the concentration time curve) and Cmax (maximum concentration), to assess the rate and extent of drug absorption.

The statistical results of this study indicate that the Test/Reference ratios of geometric LSmeans, and the 90% confidence intervals of Cmax and AUCO-T were all within the predefined acceptance range of 80.00 % to 125.00 % for itopride. Hence, based on the results, the tablets from Example 11 are considered to be equivalent to the reference medicinal product following a single 50 mg oral dose administration under fasting conditions in healthy adult subjects.

Claims

C L AI M S

1. An orally swallowable, immediate release tablet, comprising itopride or a pharmaceutically acceptable salt thereof as an active ingredient, characterized in that the tablet comprises granules containing the active ingredient, mannitol and optionally at least one additional pharmaceutically acceptable excipient, wherein the tablet does not contain lactose.

2. The tablet according to claim 1, wherein the amount of itopride or a pharmaceutically acceptable salt thereof in the tablet is from 25 mg to 150 mg of itopride hydrochloride or a molar equivalent amount of a free base or a different pharmaceutically acceptable salt thereof.

3. The tablet according to claim 1 or 2, wherein the amount of itopride or a pharmaceutically acceptable salt thereof in the tablet is from 50 mg to 100 mg.

4. The tablet according to any of the preceding claims, wherein the active ingredient is itopride hydrochloride.

5. The tablet according to any of the preceding claims, wherein the granules comprise the active ingredient and mannitol in a weight ratio from 1 : 1 to 1 : 1.75.

6. The tablet according to any of the preceding claims, wherein the granules comprise the active ingredient and mannitol in a weight ratio from 1 : 1.25 to 1 : 1.5.

7. The tablet according to any of the preceding claims, wherein the at least one additional pharmaceutically acceptable excipient contained in the granules is at least one binder.

8. The tablet according to claim 7, wherein the at least one binder is selected from povidone, pregelatinized starch, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

9. The tablet according to any of the preceding claims, wherein the at least one additional pharmaceutically acceptable excipient contained in the granules is at least one disintegrant.

10. The tablet according to claim 9, wherein the at least one disintegrant is selected from crospovidone, croscarmellose sodium, and sodium starch glycolate.

11. The tablet according to claim 9 or 10, wherein the at least one disintegrant is present both intra- and extra-granularly in a weight ratio from about 1 : 2 to about 2 : 1.

12. The tablet according to any of claims 9 to 11, wherein the at least one disintegrant is present both intra- and extra-granularly in a weight ratio of about 1 : 1.

13. The tablet according to any of the preceding claims, wherein the granules contain:

30 to 45 wt. % of itopride or its pharmaceutically acceptable salt,

45 to 65 wt. % of mannitol,

2 to 6 wt. % of at least one binder,

0.5 to 10 wt. % of at least one disintegrant.

14. The tablet according to any of the preceding claims, wherein the granules contain:

35 to 40 wt. % of itopride or its pharmaceutically acceptable salt,

50 to 60 wt. % of mannitol,

2 to 6 wt. % of povidone and/or pregelatinized starch, and

0.5 to 5 wt. % of crospovidone and/or croscarmellose sodium.

15. The tablet according to any of the preceding claims comprising:

80-98 wt. % of the granules,

0.5 to 10 wt. % of at least one extra-granular disintegrant

0.5 to 2 wt. % of at least one glidant,

0.5 to 3 wt. % of at least one lubricant, and optionally at least one other extra-granular pharmaceutically acceptable excipient.

16. The tablet according to any of the preceding claims comprising:

95 to 97 wt. % of the granules,

1 to 3 wt. % of crospovidone and/or croscarmellose sodium,

0.5 to 1 wt. % of colloidal silicon dioxide, and

0.5 to 2.0 wt. % of magnesium stearate and/or talc.

17. The tablet according to any of the preceding claims comprising: 50 mg of itopride hydrochloride, 65 mg to 75 mg of mannitol, 1.5 mg to 8 mg of crospovidone and/or croscarmellose sodium, 3 mg to 6 mg of povidone and/or pregelatinized starch, 0.5 mg to 2 mg of colloidal silicon dioxide, and 1 mg to 3 mg of magnesium stearate and/or talc.

18. The tablet according to any of the preceding claims for use in prevention or treatment of gastrointestinal motility disorders.

19. The tablet according to claim 18 for use in prevention or treatment of functional dyspepsia, gastroparesis, or gastroesophageal reflux disease.

20. The tablet according to claim 18 for use in prevention or treatment of indigestion, bloating, nausea, heartbum, upper abdominal discomfort, feeling of fullness, vomiting, and decreased appetite.

21. A method for manufacturing the orally swallowable, immediate release tablet according to any of the preceding claims, comprising: a) granulating itopride or a pharmaceutically acceptable salt thereof with mannitol and optionally at least one additional pharmaceutically acceptable excipient, b) optionally blending the granules obtained in step a) with at least one extra-granular pharmaceutically acceptable excipient, and c) compressing the granules from step a) or the blend from step b) into tablets.

22. The method for manufacturing according to claim 21, comprising: a) wet granulating itopride or a pharmaceutically acceptable salt thereof with mannitol, at least one binder, and optionally at least one additional pharmaceutically acceptable excipient, b) drying the granules from step a), c) optionally blending the dry granules with at least one extra-granular pharmaceutically acceptable excipient, and d) compressing the granules from step a) or the blend from step b) into tablets.

23. The method for manufacturing according to claim 22, wherein the at least one binder is selected from povidone, pregelatinized starch, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

24. The method for manufacturing according to any of claims 21 to 23, wherein the at least one additional pharmaceutically acceptable excipient in step a) is at least one disintegrant.

25. The method for manufacturing according to any of claims 21 to 24, wherein the at least one extra-granular pharmaceutically acceptable excipient is at least one disintegrant.

26. The method for manufacturing according to claim 25, wherein the weight ratio between the disintegrant(s) present intra- and extra-granularly is from about 1 : 2 to about 2 : 1.

27. The method for manufacturing according to claim 26, wherein the weight ratio is about 1 : 1.

28. The method for manufacturing according to any of the claims 24 to 26, wherein the at least one disintegrant is selected from crospovidone, croscarmellose sodium, and sodium starch glycolate.

29. The method for manufacturing according to any of the claims 22 to 28, comprising: a) wet granulating itopride or a pharmaceutically acceptable salt thereof with mannitol, at least one binder, and a first portion of at least one disintegrant, b) drying the granules from step a), c) blending the dry granules with a second portion of at least one disintegrant, at least one glidant, and/or at least one lubricant, and d) compressing the blend into tablets.

30. An orally swallowable, immediate release tablet, obtainable by the manufacturing method according to any of the claims 21 to 29.