Composition Comprising an Antacid and a H2-antagonists

The present invention relates to a stable solid composition comprising an antacid and a H2- antagonist without unpleasant or bitter taste, its process for preparation and its use for treating and preventing gastric disorders.

H2-antagonists, e.g. ranitidine, cimetidine or famotidine, act directly on the acid-secreting parietal cells located within the gastric gland of the stomach wall and therefore they can be used for the treatment or prevention of gastric disorders e.g. acid indigestion, heartburn and gastritis. However, their slow onset of action is unlikely to meet the consumer requirement for rapid relief.

Antacids, e.g. aluminium hydroxide, magnesium hydroxide or hydrotalcite, are described for providing rapid relief from the symptoms of excess of stomach acid by neutralizing the acid. They can be used for the treatment of heartburn, gastritis and other gastric disorders.

A combination of both ingredients is desirable in terms of rapid relief of heartburn affected by the antacid combined with a long lasting effect affected by the H2-antagonist.

EP 0 286 781 describes in example 2 a tablet comprising ranitidine as H2-antagonist, aluminium hydroxide and calciumcarbonat as antacid and in addition caramel flavour to domineer the unpleasant taste of ranitidine. The tablets are prepared by dry mixing of the ingredients and compressing to tablets. Data on stability are not disclosed.

WO 92/00102 and WO 93/12779 describe tablets comprising cimetidine, ranitidine or famotidine as H2-antagonists, aluminium hydroxide and magnesium hydroxide or sodium bicarbonate as antacids and in addition palatability aids such as flavours and icing sugar as coating for taste masking purposes. Data on stability are not disclosed.

EP 1 019 066 describes chewable tablets comprising coated famotidine granules and calcium carbonate and magnesium hydroxide as antacid. The coated famotidine granules are prepared by dry rotogranulation including a coating. The coating of the famotidine prohibits a unpleasant or bitter taste. Data on stability are not disclosed.

EP 0 600 725 describes tablets comprising coated famotidine granules and antacids wherein the famotidine granules and the antacid are in different layers separated by a impermeable barrier for stability reasons. The coated famotidine granules are prepared by dry rotogranulation including a coating. The coating of the famotidine prohibits a unpleasant or bitter taste and the barrier prohibits the interaction of both ingredients.

US 6,090,412 describes chewable tablets containing cimetidine, famotidine or ranitidine as H2 antagonists and magnesium hydroxide and aluminium hydroxide as antacids wherein at least parts of the antacids are used as coated granules. The coating effects that there is no over reaction between the antacid and the acid of the stomach administered, i.e. pH remains constant which is the contrary when as a comparative example an uncoated chewable tablet containing the same ingredients is administered (the pH value in the stomach increases). Data on stability or unpleasant taste are not disclosed.

US 6,663,892 describes bilayered tablets containing in a first layer a H2-antagonist (e.g. famotidine) and in a second layer an antacid without an intervening barrier between both layers. Separation of ingredients in two layers having even a common contact surface suffices for stability. Data on unpleasant taste are not disclosed. Specific examples are not given.

The problem to be solved was, providing an alternative stable solid dosage form containing a H2- antagonist and an antacid having no unpleasant taste.

Surprisingly the problem can be solved by a solid dosage form comprising a H2-antagonist and an antacid wherein the H2-antagonist is used in the form of granules obtainable by wet granulation wherein the wet granulation process comprises the steps of spraying of a suspension comprising the H2-antagonist and at least one or more first hydrophilic polymeric substances to at least one or more second polymeric substances in dry form and perform the granulation by mixing.

H2-antagonists are well known and include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine and mixtures thereof. Preference is given to famotidine.

Antacids are well-known and include, but are not limited to, magnesium hydroxide, magnesium carbonate, calcium carbonate, aluminium hydroxide, aluminium carbonate, aluminium phosphate, aluminium hydroxyl carbonate, dihydroxy aluminium sodium carbonate, aluminium magnesium glycinate, dihydroxy aluminium aminoacetate, dihydroxy aluminium aminoacetic acid, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, calcium phosphate, hydrated magnesium aluminate, magnesium aluminium silicates, magnesium glycinate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, hydrotalcite and mixtures thereof. Preference is given to hydtrotalcite , calcium carbonat, magnesium hydroxide and magnesium carbonate, hi particular hydrotalcite is used as antacid.

The amount of H2-antagonist in the composition according to the invention is from 1 to 500 mg, preferably from 5 to 100 mg. Preferred amounts of famotidine in the composition is from 5 to 50 mg, preferably from 5 to 20 mg, more preferably 10 mg. A suitable amount of cimetidine in the

composition is from 1 to 50 mg, preferably 1 to 25 mg, more preferably 1 to 10 mg. Preferred amounts of ranitidine in the composition are from 1 to 50 mg, preferably 1 to 25, more preferably 1 to 25, most preferably 1 to 5 mg.

According to the present invention the amount of the antacid in the composition is in a dosage range of from about 5 to 160 ANC, preferably from 5 to 20 ANC (ANC = acid neutralizing capacity, determined according to the Current British Pharmacopoeia (method for hydrotalcite), and for Carbonates or to Rossett Rice test (method for calcium and magnesium carbonates). The amount of the antacid, preferably hydrotalcite, in the composition is from 100 to 2000 mg, preferably from 350 to 1500 mg, more preferably from 500 to 1100 mg.

The first hydrophilic polymeric substances include, but are not limited to, polyvinylic alcohol, hypromellose (hydroxypropylrnethylcellulose or HPMC), starch, starch derivatives, pregelatinized starch, cellulose derivatives, microcrystalline cellulose, croscarmellose (carboxymethylcellulose), sodium carboxymethylcellulose, polyvinylpyrrolidon (PVP) and crosslinked polyvinylpyrrolidon.

Preference is given to a first hydrophilic polymeric substance selected from the group consisting of hypromellose (hydroxypropylmethylcellulose or HPMC), pregelatinized starch, microcrystalline cellulose and croscarmellose (carboxymethylcellulose). Most preferably the first hydrophilic polymeric substance is hypromellose (hydroxypropylmethylcellulose or HPMC).

According to the present invention the amount of the first hydrophilic polymeric substance or substances is from 0.1 to 5 %, preferably from 0.3 to 2 %, more preferably from 0.5 to 1 % by weight of the total composition.

The second polymeric substances include, but are not limited to, hypromellose (hydroxypropylmethylcellulose or HPMC), starch, starch derivatives, pregelatinized starch, cellulose derivatives, microcrystalline cellulose, croscarmellose (carboxymethylcellulose), sodium carboxymethylcellulose, polyvinylpyrrolidon (PVP) and crosslinked polyvinylpyrrolidon.

Preference is given to a second polymeric substance selected from the group consisting of hypromellose (hydroxypropylmethylcellulose or HPMC), pregelatinized starch, microcrystalline cellulose and croscarmellose (carboxymethylcellulose). Most preferably the second polymeric substance is a mixture consisting of pregelatinized starch, microcrystalline cellulose and croscarmellose (carboxymethylcellulose) .

According to the present invention the amount of the second polymeric substance or substances is from 1 to 20 %, preferably from 7 to 15 %, more preferably from 8 to 12 % by weight of the total composition.

The composition according to the invention is administered orally one or more, preferably up to three, more preferably up to two times per day. With each administration the number of dosage forms taken in at the same time should not exceed two.

The composition according to the present invention can be used for treating or preventing gastric disorders e.g. acid indigestion, heartburn, hyperacidity and gastritis, preferably acute gastritis, in a patient. A patient, for the purpose of this invention, is a mammal, including a human.

Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, type and degree of the disorder, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases.

Subject of the present invention is a stable and solid oral composition comprising a H2-antagonist and an antacid having no unpleasant or bitter taste.

Normally several provisions have to be met to provide a stable composition comprising a H2- antagonist and an antacid having no bitter or unpleasant taste. Compounds which are H2- antagonists are normally characterized by their unpleasant and/or bitter taste, so that a complex and expensive taste masking technology is needed to mask the taste of the H2-antagonist. hi addition H2-antagonists and antacids comprised in one formulation can cause stability problems.

The prior art describes several solutions such as coating of granules (EP 1 019 066, US 6,090,412) or multilayered tablets (US 6,663,892, EP 0 600 725).

hi the present invention the problem is solved by a solid composition comprising a H2-antagonist and an antacid wherein the composition is made of a first granulate comprising the H2-antagonist produced by wet granulation and of a second granulate comprising the antacid wherein the wet granulation process of the first granulate comprises the steps of spraying of a suspension comprising the H2-antagonist and at least one or more first hydrophilic polymeric substance to at least one or more second polymeric substances in dry form and perform the granulation by mixing.

Preference is given to a solid composition comprising a H2-antagonist and an antacid wherein the composition is made of a first granulate comprising the H2-antagonist but no antacid produced by wet granulation and of a second granulate comprising the antacid but no H2-antagonist wherein the wet granulation process of the first granulate comprises the steps of spraying of a suspension comprising the H2-antagonist and at least one or more first hydrophilic polymeric substance to at least one or more second polymeric substances in dry form and perform the granulation by mixing.

In the wet granulation step the solvent can be water or alcohol such as ethanol or a mixture thereof.

Preference is given to a solid tablet wherein the first granulate comprising the H2-antagonist and the second granulate comprising the antacid are compressed together to a single matrix.

Advantage of the composition of the present invention is that for the preparation of the composition a complex and expensive taste masking technology known in the prior art such as coating of tablets or coating of granules or putting one or more of the ingredients into a capsule is not needed. The composition of the present invention can be prepared by simple and well-known standard procedures. Another well-known taste masking method is the addition of flavours in order to cover and mask the unpleasant taste. This kind of taste masking is normally restricted to only a few applicable flavours which have to be selected in each case. However, flavouring ingredients are not needed for taste masking in the composition of the present invention.

Advantage of the composition of the present invention is also that a particular technology in order to guarantee a high stability, such as coating technologies, multilayer tablets, tablets containing barriers, are not needed.

Subject of the present invention is a stable and solid oral composition comprising a H2-antagonist and an antacid which has no unpleasant or bitter taste and which is not a coated tablet, coated granule, multilayered tablet or capsule but consists of a single matrix. In addition the composition according to the invention is characterized by a high stability.

The composition according to the invention comprises suitable administration forms which deliver the compounds of the invention and which include, but are not limited to, solid formulations such as tablets, tablets which disintegrate rapidly in the oral cavity (orodispersible tablets), powders, sachets, granules, pellets, chewable tablets, and dispersible tablets.

Preference is given to tablets, granules, orodispersible tablets, chewable tablets, chewing gums, dispersible tablets. More preferably the application forms are tablets, chewable tablets, orodispersible tablets and dispersible tablets.

Further ingredients of the oral dosage forms are those which are accepted for pharmaceuticals and nutritional supplements and physiologically unobjectionable, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders (e.g. polyvinylpyrrolidone, gelatin, starch derivatives and cellulose derivatives), and all other excipients required to produce formulations of pharmaceuticals and nutritional supplements of the desired properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g. crosslinked polyvinylpyrrolidone, sodium

carboxymethylcellulose), e.g. wetting agents (e.g. sodium lauryl sulphate), e.g. release-slowing agents (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. stabilizers, e.g. antioxidants, e.g. preservatives, e.g. coloured pigments.

Excipients for pharmaceuticals familiar to the skilled person are also described for example in the following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, PJ. , American Pharmaceutical Association, Washington, 4rth edition 2003.

The composition according to the present invention involves three steps: i) wet granulation of the H2-antagonist, ii) granulation of the antacid, iii) mixing of the granulates of i) and ii) to the final blend and optionally compression into tablets.

Step i): At least one or more first hydrophilic polymeric substance is suspended by mixing in a portion of solvent, preferably water and/or ethanol, more preferably water, optionally pre-heated to a temperature from 50 to 95 ⁰ C, more preferably from 80 to 9O ⁰ C. Solvent, preferably water, more preferably water having a temperature of 5 to 10 ⁰ C, is added to the suspension until a clear solutions is formed. The solution is brought to room temperature and the H2-antagonist, preferably famotidine, is added to form a suspension. In a second mixer at least one or more second polymeric substances in dry form are blended. Wet granulation is performed by spraying the H2- antagonist containing suspension into the blend while mixing. After granulation the wet granulate is optionally screened through a screen with a pore size from 5 to 15 mesh, preferably 10 to 15 mesh. The wet granulate is dried by e.g. a fluid bed dryer and optionally screened through a screen with a pore size of 25 to 35 mesh, preferably 20 to 30 mesh (i.e. 600 to 800 μm) to give the final H2-antagonist granulate.

Preference is given to a wet granulation step wherein no antacid is added during the preparation of the H2-antagonist granulate.

The amount of the first hydrophilic polymeric substance or substances in the granulate containing the H2-antagonist is from 1 to 20 %, preferably from 5 to 15 %, more preferably from 10 to 13 % by weight of the total famotidine granulate.

The amount of the second polymeric substance or substances in the granulate containing the H2- antagonist is from 50 to 90 %, preferably from 65 to 85 %, more preferably from 70 to 82 % by weight of the total famotidine granulate.

Step ii): The granulate comprising the antacid can be prepared by standard granulation technology. In a preferred granulation the antacid, preferably hydrotalcite, more preferably very fine

hydrotalcite and free flowing hydrotalcite, pregelatinized starch, microcrystalline cellulose, croscarmellose and silicon dioxide are blended for e.g. 15 minutes wherein optionally the antacid, preferably hydrotalicte, more preferably very fine hydrotalcite and free flowing hydrotalcite, pregelatinized starch, microcrystalline cellulose, croscarmellose are screened through a screen with a pore size of 10 to 20 mesh, preferably 16 mesh, and the silicon dioxide is screened through a screen with a pore size of 25 to 35 mesh, preferably 30 mesh. Magnesium stearate is added and the blend is mixed for e.g. 3 minutes. The blend is roller compacted to form the final antacid granulate.

Preference is given to a granulation step wherein no H2-antagonist is added during the preparation of the antacid granulate.

Step iii): The H2-antagonist granulate of step i) and the antacid granulate of step ii) are mixed together with optionally further antacid, preferably hydrotalcite, more preferably free flowing hydrotalcite, and croscarmellose sodium. Optionally further ingredients/excipients are added. Magnesium stearate is added which is optionally previously screened through a screen with a pore size of 25 to 35 mesh, preferably 30 mesh. After mixing for e.g. 3 minutes the final blend is formed. Optionally the final blend can be compressed into tablets.

In the case of chewable tablets additional free flowing hydrotalicte and xylitol, which are optionally screened previously by a screen with a pore size of e.g. 18 mesh, are mixed together with the granulates of step i) and ii) for about 10 minutes. Magnesium stearate is added and mixed for further 3 minutes. Finally the blend is compressed into chewable tablets.

Examples:

Example 1 :

Formulations 1 to 3 are examples for swallowable tablets:

Example 2: Manufacturing process for swallowable tablets of example 1

Step i): Famotidine granules

Hypromellose is suspended by mixing in a portion of water pre-heated to a temperature from 80 to 90 ⁰ C. Cold water having a temperature of 5 to 10 ⁰ C is added to the suspension until a clear solutions is formed. The solution is brought to room temperature and famotidine is added to form a suspension. In a second mixer pregelatinized starch, microcrystalline cellulose and croscarmellose is blended. The H2-antagonist containing suspension is sprayed into the blend while mixing and the wet granulation is performed. The wet granulate is screened through a screen with a pore size of 10 mesh. The wet granulate is dried by a fluid bed dryer and screened through a screen with a pore size of 30 mesh to give the final famotidine granulate.

Step ii): Antacid granulate

Very fine hydrotalcite and free flowing hydrotalcite, pregelatinized starch, microcrystalline cellulose, croscarmellose and silicon dioxide are blended for 15 minutes wherein the very fine hydrotalcite, the free flowing hydrotalcite, pregelatinized starch, microcrystalline cellulose, croscarmellose are screened through a screen with a pore size of 16 mesh, and the silicon dioxide is screened through a screen with a pore size of 30 mesh. Magnesium stearate screened through a screen with a pore size of 30 mesh is added and the blend is mix for 3 minutes. The blend is roller compacted to form the final antacid granulate.

Step iii):

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The famotidine granulate of step i) and the antacid granulate of step ii) are mixed together with free flowing hydrotalcite and croscarmellose sodium. Magnesium stearate is added which is optionally previously screened through a screen with a pore size of 30 mesh. After mixing for 3 minutes the final blend is formed and can be compressed into swallowable tablets.

Example 3:

The 3 month accelerated stability data at 40°C and 75% room humidity determines the degradation of famotidine and shows for the formulations 1 and 2 of example 1 a high stability (remaining famotidine content in both formulations is 9.3 mg) in contrary to a regular formulation where the ingredients are only mixed together and then compressed (the amount of total impurities is 27.9% by weight of the total composition).

Example 4:

Formulations 4 to 6 are examples for chewable tablets:

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Example 5: Manufacturing process for chewable tablets of example 4

Step i) and ii) are identical to those described in example 2.

Step iii):

Free flowing hydrotalicte and xylitol are screened previously by a screen with screen of a pore size of 18 mesh and are mixed together with the granulates of step i) and ii) for about 10 minutes. Magnesium stearate screend with a screen havin a pore size of 30 mesh is added and mixed for further 3 minutes. Finally the blend is compress into chewable tablets.