WO2007038979A1

WO2007038979A1 - Effervescent metformin composition and tablets and granules made therefrom

Info

Publication number: WO2007038979A1
Application number: PCT/EP2005/054757
Authority: WO
Inventors: Franz HÄUSLER; Till RÖHRICH
Original assignee: Swissco Development Ag
Priority date: 2005-09-22
Filing date: 2005-09-22
Publication date: 2007-04-12
Also published as: EP1945190A1

Abstract

The invention relates to an effervescent composition of metformin, comprising: (a) at least one pharmaceutically acceptable salt of metformin, (b) an acid compound or an acid salt, c)an alkaline effervescing compound, and (d) one or more compressible binders, (e) one or more excipients, wherein the weight ratio of said acid compound or acid salt (b) to said alkaline effervescing compound (c) is greater than 2 : 1.The invention also relates to tablets and granules obtained therefrom. The invention also relates to a process for preparing said composition as well as to processes for making effervescent tablets and granules. The invention is particularly directed to metformin hydrochloride compositions and tablets and granules made therefrom.

Description

EFFERVESCENT METFORMIN COMPOSITION AND TABLETS AND GRANULES MADE THEREFROM

FIELD OF THE INVENTION

The present invention relates to a composition containing at least one pharmaceutically acceptable salt of metformin that effervesces when added to water, and to tablets and granules obtained therefrom. The invention also relates to a process for preparing said composition as well as to processes for making said tablets and granules. More specifically, the invention is directed to metformin hydrochloride compositions and tablets and granules made therefrom.

BACKGROUND OF THE INVENTION

A water-soluble tablet that includes a pharmaceutically acceptable acceptable salt of metformin and dissolves to form a clear aqueous solution is disclosed in WO 2004/082664. The conditions in which such a tablet dissolves are not indicated in that International patent application. The data concerning the hardness (see page 5, line 19) show that such a tablet is relatively soft, which makes it difficult to be packaged. As such a tablet is fragile, it can be easily broken upon extraction from the packaging. Further, the shell-life of that tablet is relatively short. Moreover, the dissolution in only 30 ml of water gives a high concentration of the active ingredient, which imparts a strong unpleasant taste to the solution, especially when the active ingredient is metformin hydrochloride.

Metformin hydrochloride is an orally-administered antihyperglycemic agent, used in the management of non-insulin-dependent (type 2) diabetes mellitus, generally sold in tablets containing 500 mg, 850 mg and 1000 mg and available from many sources. For instance, in the United States and elsewhere it is sold by Bristol-Myers Squibb as Glucophage®. Glucophage® tablets have a core made of metformin hydrochloride, povidone and magnesium stearate, which is film-coated. From Ranbaxy Pharmaceuticals, Inc. RIOMET®, an oral solution is available containing 500 mg of metformin hydrochloride per 5 ml.

A high percentage of patients suffering from type 2 diabetes are elderly people showing a relatively high incidence of dysphagia. This means that those patients are unable to swallow tablets or have at least difficulties in doing so. In the case of metformin, this problem becomes even more relevant since the medication has normally to be taken lifelong day by day and the tablets are quite big due to the high dose of 500-1000 mg. In oral metformin hydrochloride tablets, besides the active drug, further excipients are needed such as binders and lubricants for technical reasons. Furthermore functional excipients are needed to modify the disintegration of the tablets and the release of the drug from the dosage form. So, for metformin hydrochloride, a tablet comprising 1000 mg of metformin hydrochloride would need to have a size of 19 mm x 10.5 mm (Glucophage® 1000 mg tablets) or more and would be very difficult to swallow. For this reason, metformin hydrochloride tablets are not suitable for a significant number of patients.

The only available alternative for such patients is the above- mentioned oral solution RIOMET®. This composition is only available in the United States, and it has the well known disadvantages of all kinds of syrup compositions, which are:

- heavy to carry, because of the high water content;

- risk of microbiological contamination of the solution during storage at home, especially if people do not use up the bottle within a reasonable time or drink directly from the bottle; and

- difficult to measure out the dose, risk of dosing errors especially for people suffering from eye problems and from trembling.

Therefore it is the main object of the present invention to provide an effervescent tablet or granule composition of at least one metformin salt, particularly metformin hydrochloride, combining the advantages of a tablet or granule form, such as accurate dose, high stability, easy to carry, with the advantages of a liquid form, such as easy to swallow, and to avoid the disadvantages of both dosage forms.

A further object is to provide an effervescent tablet with a reasonable disintegration time in water of less than three minutes and with a palatable taste of the resulting solution.

A third object is to provide a sodium-free effervescent tablet, since a high daily sodium intake is contraindicated in some diseases which are frequently correlated to the diabetes type 2 disease. This feature is highly advantageous for the composition of a generic drug.

SUMMARY OF THE INVENTION

The invention may be summarized in the following items 1-23 :

1. An effervescent composition of metformin comprising:

(a) at least one pharmaceutically acceptable salt of metformin,

(b) an acid compound or an acid salt,

(c)an alkaline effervescing compound,

(d) one or more compressible binders,

(e) one or more excipients,

wherein the weight ratio of said acid compound or acid salt (b) to said alkaline effervescing compound (c) is greater than 2 : 1 , preferably greater than 3 : 1.

2. The effervescent composition according to item 1 , wherein the component (b) is an acid compound selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides and their mixtures.

3. The effervescent composition according to item 2, wherein the acid is citric acid or tartaric acid.

4. The effervescent composition according to item 3, wherein the acid salt is a salt of citric acid or tartaric acid.

5. The effervescent composition according to any one of the items 1- 4, wherein the component (c) is selected from the group consisting of carbonate salts, bicarbonate salts and mixtures thereof.

6. The effervescent composition according to item 5, wherein the component (c) is sodium bicarbonate, sodium carbonate anhydrous, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, calcium carbonate, L-lysine carbonate, arginine carbonate and mixtures thereof.

7. The effervescent composition according to item 6, wherein the alkaline effervescing compound is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or mixtures thereof.

8. The effervescent composition according to item 7, wherein the alkaline effervescing compound is potassium carbonate.

9. The effervescent composition according to any one of the items 1-

8, wherein the component (d) is a polymer binder, a sugar, a soluble starch derivative, an alcohol sugar or a mixture thereof.

10. The effervescent composition according to item 9, wherein the component (d) is an aqueous solution of a polymer binder. 11. The effervescent composition according to item 10, wherein the polymer binder is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone and their mixtures.

12. The effervescent composition according to any one of the items 1-10, wherein the component (d) is an aqueous solution of sorbitol, mannitol or their mixtures.

13. The effervescent composition according to any one of the items 1-12, wherein the component (a) is a pharmaceutically acceptable salt of metformin selected in the group consisting of phosphate, sulfate, hydrochloride, salicylate, maleate, benzoate, ethanedisulfonate, fumarate, glycolate, salts of dibasic acids, fumarate, succinate and combinations of two or more of these salts.

14. The effervescent composition according to item 13, wherein the component (a) is metformin hydrochloride.

15. The effervescent composition according to any one of the items

1-14, wherein the component (a) is present in an amount of from 10% to 30% by weight of the composition.

16. The effervescent composition according to any one of the items 1-15, wherein the component (b) is present in an amount of from 40% to 60% by weight of the composition.

17. The effervescent composition according to any one of the items 1-16, wherein the component (c) is present in an amount of from 5% to 25% by weight of the composition.

18. The effervescent composition according to any one of the items 1 -17, wherein the component (d) is present in an amount of from 5% to 20% by weight of the composition. 19. Process for preparing an effervescent composition according to any one of the items 1-18, wherein the components (a) - (e) are blended in their respective amounts.

20. Tablets or granules comprising the effervescent composition according to any one of the items 1 -18.

21. A process for making effervescent tablets, comprising the direct compression of an effervescent composition according to any one of the items 1-18 to form said effervescent tablets.

22. A process for making effervescent granules, comprising the granulation of an effervescent composition according to any one of the items 1- 18 to form said effervescent granules.

23. A process for making effervescent tablets from the effervescent composition according to any one of the items 1-18, comprising

- the granulation of the component (b) with a part of component (d), followed by

- the blending of the obtained granules with the components (a), (b), (c), (e) and the rest of component (d), and

- the compression of the obtained blend to form the effervescents tablets.

The composition of the invention may be in the form of a powder.

The tablets and granules obtained from the effervescent composition of the invention guarantee a rapid dissolution and satisfactory taste properties and which are stable under pharmaceutical test conditions both in tubes with desiccants and in aluminium strip packs. DETAILED DESCRIPTION OF THE INVENTION

The component (a) of the composition, tablet or granules of the invention is a pharmaceutically acceptable salt of metformin or a combination of pharmaceutically acceptable salts of metformin.

Pharmaceutically acceptable salts of metformin that can be used in the composition, tablet or granules of the invention may include phosphate, sulfate, hydrochloride, salicylate, maleate, benzoate, ethanedisulfonate, fumarate, glycolate, salts of dibasic acids, fumarate, succinate and combinations of two or more of these salts. Metformin hydrochloride is preferred and that is why the invention will now be described with reference to metformin hydrochloride, although it must not be considered to be limited to the use of metformin hydrochloride.

Metformin hydrochloride is used as oral antihyperglycemic drug for the management of type 2 diabetes. Metformin hydrochloride (N₁N- dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4H11N₅ • HCI and a molecular weight of 165.63 g.

Metformin hydrochloride is freely soluble in water and practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4; the pH of a 1% aqueous solution of meformin hydrochloride is 6.68. The metformin hydrochloride compositions of the invention are characterized by a surprisingly high amount of an acid compound and by a surprisingly small amount of an alkaline effervescing compound.

Several standard compositions for effervescent tablets containing an acid compound and an alkaline effervescing compound in a ratio of about 2 : 1 have been tested.

Several methods for making effervescent metformin hydrochloride tablets were investigated, including granulation with water and/or alcohol, roller compaction and melt granulation.

Surprisingly, only tablets or granules containing an acid compound and an alkaline effervescing compound in a ratio greater than 2 : 1 , made by direct compression or made by special granulation techniques were able to give excellent tablets or granules with the required dissolution properties and with the required stability profile.

The physico-chemical properties of metformin hydrochloride indicate that the drug should be quite suitable for effervescent compositions, especially effervescent tablet compositions. The substance characteristics which are relevant for the suitability for effervescent compositions are similar to those of paracetamol or look even a little better for metformin hydrochloride. Since paracetamol is a substance widely used in effervescent tablets, also metformin hydrochloride was not expected to cause major composition problems. The following table A presents a comparison of both drug substances:

Any effervescent composition in any dosage form essentially consists of an alkaline component which is able to provide gaseous CO₂ when it gets in contact with an acid component which is able set free the CO2 gas from the alkaline component.

The acid component of the composition can be any suitable acid for effervescent compositions. Typically, the acid is an organic or mineral acid that is safe for consumption and which provides effective and rapid effervescent disintegration upon contact with water and the alkaline effervescent compound. The acid may be selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides, related organic acids and their mixtures. Preferably, the acid is citric acid, especially anhydrous citric acid, or tartaric acid.

The acid salt of the composition can be any suitable acid salt or any mixture of suitable salts. Examples of such a suitable acid salt include disodium dihydrogen pyrophosphate, acid citrate salts including mono sodium citrate, and other salts of related organic acids. Combinations thereof are possible. Preferably, the acid salt is a salt of citric acid or tartaric acid, especially monosodium citrate or monosodium tartarate.

The alkaline component can be any suitable alkaline effervescent compound, and typically it is an inorganic base (e.g., an alkali metal carbonate) that is safe for human consumption and provides an effective and rapid effervescent disintegration upon contact with water and the acid compound. The alkaline effervescing compound may be selected from the group consisting of carbonate salts, bicarbonate salts, and mixtures thereof. Preferably, the alkaline compound is sodium bicarbonate, sodium carbonate anhydrous, potassium carbonate, and potassium bicarbonate, sodium glycine carbonate, calcium carbonate, L-lysine carbonate, arginine carbonate, and combinations thereof. In preferred embodiments, the alkaline effervescing compound is sodium bicarbonate, potassium bicarbonate, sodium carbonate or mixtures thereof.

Based on these drug characteristics presented in table A, it should be possible to make metformin hydrochloride effervescent tablets by using a standard paracetamol effervescent tablet composition replacing only the paracetamol by metformin hydrochloride. The following table B presenting a comparison of both tablet compositions shows that both drug substances show indeed a very similar behaviour:

(1 ) : measured according to the "European Pharmacopeia 2.9.8. Resistance to crushing of tablets"

(2) : measured in 200 ml of 15-25⁰C water, according to the "European Pharmacopeia, monograph", Tablets Taste tests with effervescent ready-to-drink solutions of different pH levels show that the bitter taste of paracetamol is reduced to its minimum at a pH between 5.0 and 6.0. Due to the different taste profile of the metformin hydrochloride the taste of effervescent solutions containing metformin is at these pH levels very stale and unpleasant. Optimization trials showed that the best taste is achieved at a pH level between 3.5 and 4.0.

Therefore attempts have been made to formulate effervescent tablets providing 1000 mg of metformin hydrochloride and a ready-to-drink solution with a pH of about 3.7. This pH value of 3.7 is an absolutely common pH value for effervescent tablets, and overall most effervescent tablets in the market have a pH between 3.0 and 4.0.

Very surprisingly the concept of a metformin hydrochloride tablet providing a ready-to-drink solution with a pH of 3.7 did not work at all. To reach this pH value it was necessary to use per tablet an amount of 1740 mg of citric acid and 195 mg of carbonate ion (ratio citric acid : carbonate of 8.9 : 1). This absolute amount of carbonate was much too low to create a sufficient effervescent reaction and to form enough CO2gas to guarantee the dissolving of the tablet within a reasonable time. The dissolution time in 200 ml of 15-25⁰C water was therefore above 4 minutes which is not acceptable for the patients and which is close to the upper limit of the European Pharmacopoeia which is 5 minutes.

For normal active drug substances which are neither acids nor bases (pH of 1% metformin hydrochloride solution = 6.8) the pH of the effervescent solution depends only on the ratio of citric acid and carbonate. In the case of metformin hydrochloride surprisingly the drug itself has a dramatic influence on the pH of the effervescent solution. This is also proved by the following table C showing the influence of the metformin hydrochloride dose on the citric acid : carbonate ratio of an effervescent tablet with a pH of 3.7:

Further investigations showed that there exist only a small pH window between about 4.1 and 4.7, which can be used to formulate effervescent tablets having a palatable and fresh taste, on the one hand, and an acceptable dissolution time of less than 3 minutes, on the other hand.

A comparison of paracetamol and metformin hydrochloride effervescent tablets with the same pH of 4.4 shows again the very specific influence of the drug substance:

At a pH of 4.4, more than 50 % of the citric acid is used to neutralize the metformin hydrochloride drug substance and is not available to react with the carbonate and to set free CO2 gas from the carbonate.

The characteristic reaction of any effervescent composition is the reaction between an acidic compound and a carbonate salt forming CO₂ gas:

2 H⁺ + CO₃ ^2" * H₂O + CO₂ 1

The CO₂ gas is responsible for the creation of the characteristic effervescent bubbles and for the disintegration and the subsequent dissolution of the effervescent tablet. Therefore any effervescent tablet needs to contain a sufficient absolute amount of carbonate to be able to dissolve within a reasonable time showing the typical effervescent reaction.

Due to the special chemical properties of the metformin hydrochloride and due to the special requirements of the diabetes type 2 disease treatment, there are three issues limiting and reducing the absolute amount of carbonate in the metformin hydrochloride effervescent to a very critical level.

1. Due to the high dose of metformin hydrochloride being 500 mg to 1000 mg per tablet, the space within the tablet for necessary excipients such as binders, flavours, sweeteners, lubricants and the effervescent couple is quite limited.

2. Due to the high acid neutralization capacity of the drug at lower pH values, a very high amount of acid is needed, and the ratio between acid and carbonate has to be very high . In other words, the effervescent couple which is anyway small because of the high drug load, contains an extraordinarily small part of carbonate.

3. For physiological and medical reasons the present invention may advantageously provide a sodium-free effervescent composition. The sodium carbonate and sodium hydrogen carbonate salts most commonly used for effervescent compositions may not be used in the inventive composition. The reactivities of calcium carbonate and magnesium carbonate are for this kind of composition too low; potassium hydrogen carbonate can cause stability problems, especially if the tablets are packed into aluminium strips. Therefore the preferred carbonate source in the inventive sodium-free composition is potassium carbonate. The following table E shows the carbonate content of the different carbonate salts which are commonly used for the composition of effervescent tablets.

As the table shows, the preferred carbonate source (K₂CO₃) for the metformin hydrochloride effervescent tablet is the one with the lowest carbonate content of all commonly used carbonate sources. This fact reduces again the absolute amount of carbonate which is present in the composition.

The three above-mentioned issues together mean that metfomin hydrochloride effervescent tablets must have a composition with an extremely small amount of carbonate. The following table F compares a standard effervescent tablet with the requirements of a metformin hydrochloride effervescent tablet in terms of absolute carbonate content:

It is surprising that it is possible to develop effervescent compositions with such a strange weight ratio of acid and carbonate ions and with such a small absolute amount of carbonate ions. To make such compositions possible, special manufacturing methods have to be applied, since as expected standard manufacturing procedures are not suitable to produce tablets meeting all tablet requirements as they are defined by the pharmacopoeias and by marketing needs.

A special and additional problem with this composition is that metformin hydrochloride is a substance with very poor tabletting and mixing properties. The substance is very sticky and forms hard and big lumps in the shipping containers. After sieving the material there is a strong tendency of re- agglomeration during the manufacturing process, especially during the mixing process. As a result of this property, an inhomogeneous distribution of the drug in the tablets has been observed even at the high dosed 1000 mg tablets. Some of the produced batches did not meet the requirements of the European Pharmacopoeia in terms of uniformity of drug content.

Such kinds of tabletting and mixing problems are normally solved by performing a granulation of the drug substance together with parts of the citric acid and the carbonate. The granulation process can be done with an aqueous binder solution in a fluid bed granulator or with an alcoholic binder solution in single-pot equipment. Polymers like polyethyleneglycol or polyvinylpyrrolidone are used as binder substances. Due to the agglomeration during the granulation process, the granules normally show improved properties in terms of flowability, stickiness and tabletting properties.

Unfortunately granulation of metformin hydrochloride with citric acid and carbonate does not provide the expected improvement of the tableting properties. Tablet hardness and mechanical stability of the tablets cannot be improved by granulation, and surprisingly granulation increases the dissolution time significantly, which is anyway crucial for these compositions.

Unfortunately it is not possible to overcome these granulation-related problems by modifying the granulation process according to the state of the art methods. Granulation of the active drug only with the carbonate compound causes a significant increase of the dissolution time to values above five minutes. On the other hand, granulation of the active drug only with the acidic compound causes severe stability problems especially when the tablets are packed into aluminium strips.

Granulation is a costly production step within the manufacturing process of a tablet, and therefore, if it is not necessary, granulation is avoided if possible and the manufacturing of the ready-to-press mixture is performed by a direct mixing process. On the other hand, if any kind of problems occur with the ready-to-press mixture, granulation is the generally accepted and preferred method to overcome those tabletting problems.

Surprisingly for metformin hydrochloride effervescent tablets it is not possible to overcome drug-related tabletting problems by granulating the drug substance, but direct mixing without any additional steps except sieving and direct compression is the only way to obtain tablets meeting all specification limits.

A solution which has been found to improve tabletting properties and tablet hardness without increasing dissolution time is to perform a granulation only of the citric acid anhydrous with one or more compressible binders. Preferably the binder is an aqueous solution of a polymer binder such as polyethylene glycol, polyvinlypyrrolidone and their mixtures or an aqueous solution of sorbitol, mannitol and their mixtures. This type of granulation does not modify the critical mixing and tabletting properties of the drug substance but it helps tabletting the whole ready-to-press mixture by improving the tabletting behaviour of the most important excipient which is in the tablet with a percentage of up to nearly 50 %.

The above-mentioned composition principles can, according to this invention, also be used to prepare powder compositions, or granules containing metformin hydrochloride. Such powders or granules can be packed into single dose sachets or sticks made from aluminium foil. They can be dissolved in water prior to administration, or they can be taken directly into the mouth. For powder or granules composition, the amount of effervescent couple (acid and carbonate) can be significantly reduced compared to tablet compositions. The use of anti-caking agents such as colloidal silicon dioxide, surface modified silicon dioxide, di-calcium phosphate and so on, in a concentration from about 0.5 % to about 5.0 % is mandatory.

For direct compression to be successful one must find a dry binder excipient or a combination of dry binding excipients that gives suitable hardness to the tablet but also give sufficient flowability of the blended materials during the mixing and compression processes. In standard direct compressible compositions for effervescent tablets such excipients are used in a concentration of about 15 %. In the case of metformin hydrochloride, it is necessary for the above mentioned reasons to use only minimum amounts of such dry binding excipients. Excellent results are obtained from sorbitol or an excipient mixture containing sorbitol and mannitol in concentrations of 10-12 %. Specific embodiments of this technique are described in Example 1.

Sorbitol has better compression characteristics (more hardness) than mannitol, but is hygroscopic, and can cause sticking on the rotary press. Mannitol is less hygroscopic, but the tablets are not as hard as with sorbitol. The use of mannitol can reduce the negative aspects of sorbitol. It is therefore interesting to use a combination of sorbitol and mannitol, wherein the weight ratio of sorbitol to mannitol is 1 : 1.

Particle size is critical for controlling the flowability and compression characteristics of the ingredients. The mean particle size of the sorbitol to be used is 200 - 400 μm (microns), preferably about 250 to 300 μm. In the examples the mean particle size was about 280 μm. The mean particle size of the mannitol used is about 150 - 300 μm. In the examples the mean particle size is about 200 μm.

The acid component of the composition can be any suitable acid for effervescent compositions. Typically, the acid is an organic or mineral acid that is safe for consumption and which provides effective and rapid effervescent disintegration upon contact with water and the alkaline effervescent compound. The acid may be selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides and related organic acids. Preferably, the acid is citric acid, especially anhydrous citric acid, or tartaric acid.

When an acid salt is used in the composition in place of an acid, it can be any suitable acid salt or any mixture of suitable salts. Examples of such a suitable acid salt include disodium dihydrogen pyrophosphate, acid citrate salts including mono sodium citrate, and other salts of related organic acids. Preferably, the acid salt is a salt of citric acid or tartaric acid, especially monosodium citrate or monosodium tartarate. If an acid salt is used in the composition, it is preferably used in combination with an acid.

The alkaline component can be any suitable alkaline effervescent compound, and typically it is an inorganic base (e.g., an alkali metal carbonate) that is safe for human consumption and provides and effective and rapid effervescent disintegration upon contact with water and the acid compound. The alkaline effervescing compound may be selected from the group consisting of carbonate salts, bicarbonate salts, and mixtures thereof. Preferably, the alkaline compound is sodium bicarbonate, sodium carbonate anhydrous, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, calcium carbonate, L-lysine carbonate, arginine carbonate, and combinations thereof.

The technically preferred alkaline effervescing compounds are sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or mixtures thereof.

The use of non-sodium alkaline effervescing compounds may be desirable for patients requiring electrolyte maintenance, such as hypertensive and other cardiac patients receiving ACE inhibitors (angiotensin converting enzyme inhibitor). Therefore the preferred alkaline compounds for the inventive compositions are potassium carbonate and potassium bicarbonate; especially preferred for stability reasons is potassium carbonate. In compositions of the prior art, the acid is typically present in an amount of from about 15 % to about 60 % (e.g., about 25% to about 50%) based on the total weight of the composition. For example, about 800 mg to about 2000 mg of acidic compound is present in the effervescent composition.

In the compositions of the prior art, the alkaline effervescent compound is typically present in such an amount that the ratio between acid and carbonate ions is from about 1.5 : 1 to about 3.0 : 1 , preferably 2.0 : 1 to 2.5 :1 based on the total weight of the composition. For the specific metformin hydrochloride effervescent composition presented in this invention the weight ratio between the acid and the carbonate ions is greater than 3.0 :1. For the 1000 mg meformin hydrochloride composition of the invention, the preferred weight ratio is about 5.0 :1.

When the effervescent composition is completely dissolved in water a buffer is produced which preferably has a pH of about 2.5 to about 6.5, more preferably about 3.0 to about 5.5. To achieve at the same time a dissolution time below 3 minutes and a fresh, palatable taste, the pH of the specific metformin hydrochloride effervescent composition presented in this invention is within quite narrow limits between about 4.0 and 4.8. An especially preferred pH value is 4.4. The buffer produced upon dissolution of the effervescent composition in water is sufficient to alter the pH of a patient's stomach. The pH of the gastric juice in the stomach of the patient is raised to about 3 or greater, preferably to about 4. The buffer solution typically is capable of mediating the pH of a patient's stomach from 15 to 30 minutes up to about 1 hour.

According to a preferred embodiment of the invention, the formulation of the effervescent composition is as follows, in weight % based on the total weight of the composition :

- from 10% to 30% of component (a);

- from 40% to 60% of component (b);

- from 5% to 25% of component (c); - from 5% to 20% of component (d);

- the remainder (to achieve 100%), component (e), being one or more excipient, such as a sweetener, flavorant, colorant, fragrance, anti-caking agent, glidant, etc.

The effervescent compositions described above optionally further comprise a sweetener and/or a flavorant. In some embodiments, the effervescent composition contains both a sweetener and a flavorant. Typically, the sweetener or flavorant is present in an amount of from about 0.1% to about 5% by weight of the total composition.

The sweetener can be any suitable natural or artificial sweetener or a combination of natural and artificial sweeteners. Acceptable natural sweeteners include members selected from the group of glucose, dextrose, invert sugar, fructose, glycyrrhizic acid, and mixtures thereof. Acceptable artificial sweeteners include members selected from the group consisting of saccharin; aspartame; chloro derivatives of sucrose such as sucralose, cyclamate, acesulfame-K; sugar alcohols such as sorbitol, mannitol, and xylitol; and mixtures thereof. Since metformin is an antidiabetic drug, glucose or glucose- containing sweeteners such as dextrose or invert sugar are not suitable for the inventive composition. The sweetness of sugar alcohols is not intensive enough to provide a sufficient sweetness to the ready-to-drink solution. Therefore, preferably, the sweetener is an artificial sweetener selected from the group consisting of aspartame, saccharin, acesulfame-K, cyclamate, Splenda®, and combinations thereof. The effective concentration of a sweetener is determined by the strength of its sweetness, solubility, and masking ability for a specific active ingredient(s). For example, when the sweetener is aspartame, about 10 mg to about 50 mg aspartame is present in the effervescent composition. When the sweetener is saccharin, about 10 mg to about 30 mg saccharin is present in the effervescent composition. When the sweetener is acesulfame-K, about 10 mg to about 50 mg saccharin is present in the effervescent composition. When the sweetener is cyclamate, about 10 mg to about 150 mg cyclamate is present in the effervescent composition. When the sweetener is Splenda®, about 10 mg to about 80 mg Splenda® is present in the effervescent composition.

The flavorants and sweeteners are not critical for the compression process, but can significantly influence the dissolution time of the effervescent tablets and are important for the taste and odor of the resulting solution once the tables are dissolved. The type and amount chosen should not influence the dissolution time and should mask the bitter taste of metformin hydrochloride.

The flavorant can be a natural, a natural-identical or synthetic compound. Acceptable flavorings include members selected from the group consisting of volatile oils, synthetic flavor oils, oleoresins, plant extracts, and combinations thereof. Desirable flavorings include a member selected from the group consisting of citrus oils such as lemon, orange, grape, lime and grapefruit; fruit essences such as apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot; and other fruit flavors. Other useful flavorants include aldehydes and esters such as benzaldehyde (cherry, almond), citral (lemon, lime), neral (lemon, lime), decanal (orange, lemon), C8- aldehyde (citrus fruits), Cg-aldehyde (citrus fruits), Ci₂-aldehyde (citrus fruits), tolylaldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), and 2- dodecenal (citrus, mandarin), and mixtures thereof. Preferably, the flavorant is lemon, orange or cherry. The flavorant typically is present in the effervescent composition in an amount of about 10 mg to about 150 mg.

Preferably, the effervescent tablet composition comprises 500 to 1000 mg metformin hydrochloride, about 1400 mg to about 2000 mg acid compound in the form of citric acid, about 500 mg to about 1000 mg alkaline effervescing compound in the form of potassium carbonate, about 250 mg to 550 mg binder in the form of sorbitol or mannitol or a mixture thereof, about 0.5% to about 2% sweetener and about 1% to about 5% flavorant. The percent amounts recited above are based on the total weight of the composition.

The effervescent compositions described above optionally further comprise a colorant. The colorant can be any suitable colorant including natural colorants, food, drug and cosmetics (FD&C) colorants, and drug and cosmetic (D&C) colorants. Suitable natural colorants include red beet powder and beta- carotene powder.

The effervescent compositions described above optionally comprise other ingredients to aid in the composition of the composition and/or for aesthetic purposes. Such other ingredients include fragrances, dyes, fillers such lactose, starch, anti-caking agents such as colloidal silicon dioxide, and natural or synthetic polymer binders. Desirable binders assist in tablet compression, and can include starches, pregelatinized starches, gelatin, methylcellulose, sodium carboxymethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, polyethylene glycols (e.g. macrogol 6000) and polyvinylpyrrolidone.

Effervescent metformin hydrochloride should be administered to the patient following a continuous schedule, generally once, twice or three times daily; generally with tablets containing 500 mg, 850 mg or 1000 mg.

Typically the effervescent compositions of the invention have a total weight of 1000 mg or more (e.g., 1500 - 5000 mg). Preferably, the effervescent tablet compositions have a total weight of about 3500 mg to about 4000 mg.

The following examples further illustrate the invention but should not be construed as limiting its scope.

EXAMPLE 1

This example illustrates a general process for preparing the effervescent tablets of the invention using sodium hydrogen carbonate as the alkaline compound, using a direct compression process and resulting in a pH of about 3.6. Metformin effervescent tablets (500 mg, 850 mg and 1000 mg) were formed from the ingredients listed in Tables 1a et 1 b. Table 1a

Table 1b

To de-lump and de-agglomerate the metformin hydrochloride, this compound is sieved through a sieve (e.g. type frewitt) or through a sieve mill (e.g. type co-mill). Directly after sieving/milling metformin hydrochloride is mixed with sodium hydrogen carbonate and with the other compounds except anhydrous citric acid in a container mixer or in another suitable mixer (e.g planetary mixer). This pre-mixture is again sieved and the anhydrous citric acid is added. By mixing both compounds (e.g. in a container mixer) the final ready- 0 to-press mixture is obtained. The ready-to-press mixture is compressed on a suitable tablet press (preferred rotary tablet press) into tablets of 3900 mg weight and with a hardness of about 50 - 90 N. The tablets are packed into tubes with desiccant or into aluminium strips. All production steps are carried out under low humidity conditions, preferably at a relative humidity below 30 %.

EXAMPLE 2

This example illustrates a more specific process for preparing the sodium-free effervescent tablets of the invention using potassium carbonate as the alkaline compound, using only sorbitol as a dry binder, using a direct compression process and resulting in the preferred pH of about 4.4. Metformin effervescent tablets (500 mg, 850 mg and 1000 mg) were formed from the ingredients listed in Tables 2a and 2b.

Table 2a

Table 2b

The manufacturing process of the ready-to-press mixture, the tabletting process and the packaging process are the same as for example 1.

EXAMPLE 3

This example illustrates a specific embodiment of example 2 in which the anhydrous citric acid is granulated with a part of the sorbitol to increase o tablet hardness. Then the tablets are made from the obtained granules and the other ingredients. Additionally this example contains colloidal silicon dioxide as an anti- caking agent. Metformin effervescent tablets (500 mg, 850 mg and 1000 mg) were formed from the ingredients listed in Tables 3a and 3b.

Table 3a

Table 3b

Anhydrous citric acid is granulated in a suitable granulator (preferably in a fluid-bed granulator) with an aqueous solution of sorbitol. Per tablet about 200 mg of sorbitol are used to prepare the sorbitol solution. To de-lump and de- agglomerate the metformin hydrochloride this compound is sieved through a sieve (e.g. type frewitt) or through a sieve mill (e.g. type co-mill). Directly after 0 sieving/milling, metformin hydrochloride is mixed with sodium hydrogen carbonate, with the rest of the sorbitol and with the other compounds except the citric acid granules in a container mixer or in another suitable mixer (e.g planetary mixer). This pre-mixture is again sieved, and the citric acid granules are added. By mixing both compounds (e.g. in a container mixer) the final ready-to-press mixture is obtained.

The tabletting process and the packaging process are the same as for example 1.

EXAMPLE 4

This example illustrates a specific embodiment of the inventive composition in the form of effervescent granules which can be packed into aluminium sachets or into aluminium sticks. The granules can be taken directly in the mouth, or they can be dissolved prior in water to administration. Metformin effervescent granules (500 mg, 850 mg and 1000 mg) were formed from the ingredients listed in Tables 4a and 4b.

Table 4a

To de-lump and de-agglomerate the metformin hydrochloride, this compound is sieved through a sieve (e.g. type frewitt) or through a sieve mill (e.g. type co-mill). The sieved metformin hydrochloride, the anhydrous citric acid, the sorbitol, the sweetener and a part of the colloidal silicon dioxide are granulated in a suitable granulator (preferably in a fluid-bed granulator) with an aqueous solution of sorbitol. About 200 mg of sorbitol per dose unit are used to prepare the sorbitol solution. The granules are mixed with potassium carbonate and with the remaining excipients in a container mixer or in another suitable mixer (e.g planetary mixer).

This ready-to-use mixture is filled into aluminium sacchets or aluminium sticks on a suitable packaging machine.

The selection of the excipients is very important for the present direct compression process. The particle size of the components must be adapted to each other to avoid segregation of the components. The blend must display sufficient flow characteristics and sufficient compression characterizes to achieve constant weight and acceptable capacity of the tableting machine. The influence of the excipients correlates directly with the concentration and the physical characteristics of the active ingredient. Metformin hydrochloride is very fine, and has good water solubility; however, it forms very hard and big lumps and its flowability and compression characteristics are insufficient. Therefore the selection of excipients is very important.

Because the compressibility of is not ideal one must add an inert filler to the composition to obtain excellent compression characteristics. Usually one uses sugar or a sugar alcohol for this purpose because they are soluble in water and give a sweet taste. In the case of metformin sugar alcohols are preferred because ordinary sugar has an adverse effect on the therapy. Sorbitol in coarse form gives tablets with very good hardness. However, sorbitol is hygroscopic and tends to stick on the tablet press during tableting, therefore the amount is limited.

The compression characteristics of coarse mannitol is not as good as sorbitol, but it is less hygroscopic and has a positive effect on the dissolution and handling of the tableting blend. We found that a mixture of both these sugar alcohols can be superior during compression than the use of sorbitol alone.

For the compression of effervescent tablets without any glidant one should granulate most of the excipients, especially the acidic compound. Another possibility is to add a glidant, but the selection of a suitable glidant for effervescent tablets is very difficult. One needs the glidant effect of the lubricant, but it has adverse effects on disintegration of the tablet and increases the disintegration time with increasing concentration. Typical glidants used for normal tablets cannot be used for effervescent tablets because they are not water soluble and give the resulting solution an ugly appearance (film).

Lubrication in the present metformin hydrochloride composition can be achieved by the addition of Macrogol 6000 as internal glidant. This material dissolves clearly in water and has excellent glidant effect. In general the amount of glidant should be 10 mg to 100 mg per tablet. In the examples, 30 - 59 mg per tablet was suitable for glidant efficiency without adversely effecting disintegration time. Concerning the internal lubricants, the following substances beside Macrogol 6000 are also suitable: sodium-benzoate, Leucin (micronised), sodiumstearylfumarat (PRUV®).

Lubricants for the table press may include hydrophobic compounds such as magnesium stearate, calcium stearate, zinc stearate, polyoxyethylene monostearate, talc, paraffin oil of different viscosity grades, silicon oil of different viscosity grades, light mineral oil of different viscosity grades, and combinations thereof. However, these lubricants do not dissolve in water and can only be used in extremely small quantities. Therefore they are not mixed into the tableting mixture, but are used in the form of external lubricants on the tablet press. The preferred external lubricants are paraffin oil and magnesium stearate, which imparts desirable dissolution characteristics to the tablets and facilitates the highspeed production of the tablets.

The tablet mixture is compressed on a suitable commercially available rotary tablet press. If no external lubrication with magnesium stearate is used, the use of polymer layered punches together with an external lubrication of the lower punch with paraffin oil is preferred for tabletting of the mass. The tablets are filled on-line into tubes with desiccant or into aluminium strips.

It appears that effervescent compositions of metformin hydrochloride

(through the action of CO₂ bubbles) increase paracellular absorption in the gastrointestinal tract leading to greater absorption. This effect is achieved without apparent damage to the physiology or integrity of the gut wall. Greater absorption for metformin hydrochloride results in a greater pharmacologic effect, and thus enhanced clinical effect. Administration of an effervescent solution allows more consistent and complete delivery of the drug to the site(s) of drug absorption in the upper gastrointestinal tract.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of the invention will become apparent to those of ordinary skill in the art upon reading the foregoing description. Skilled artisans are expected to employ such variations as appropriate so that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated or otherwise clearly contradicted by context.

Claims

1. An effervescent metformin composition, comprising:

(a) at least one pharmaceutically acceptable salt of metformin,

(b) an acid compound or an acid salt,

(c)an alkaline effervescing compound, and

(d) one or more compressible binders,

(e) one or more excipients,

wherein the weight ratio of said acid compound or acid salt (b) to said alkaline effervescing compound (c) is greater than 2 : 1.

2. The effervescent composition according to claim 1 , wherein the component (b) is an acid compound selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides and their mixtures.

3. The effervescent composition according to claim 2, wherein the acid is citric acid or tartaric acid.

4. The effervescent composition according to claim 3, wherein the acid salt is a salt of citric acid or tartaric acid.

5. The effervescent composition according to any one of the claims 1-4, wherein the component (c) is selected from the group consisting of carbonate salts, bicarbonate salts and mixtures thereof.

6. The effervescent composition according to claim 5, wherein the component (c) is sodium bicarbonate, sodium carbonate anhydrous, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, calcium carbonate, L-lysine carbonate, arginine carbonate and mixtures thereof.

7. The effervescent composition according to claim 6, wherein the alkaline effervescing compound is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or mixtures thereof.

8. The effervescent composition according to claim 7, wherein the alkaline effervescing compound is potassium carbonate.

9. The effervescent composition according to any one of the claims 1-8, wherein the component (d) is a polymer binder, a sugar, a soluble starch derivative, an alcohol sugar or a mixture thereof.

10. The effervescent composition according to claim 9, wherein the component (d) is an aqueous solution of a polymer binder.

11. The effervescent composition according to claim 10, wherein the polymer binder is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone and their mixtures.

12. The effervescent composition according to any one of the claims 1-10, wherein the component (d) is an aqueous solution of sorbitol, mannitol or their mixtures.

13. The effervescent composition according to any one of the claims 1-12, wherein the component (a) is a pharmaceutically acceptable salt of metformin selected in the group consisting of phosphate, sulfate, hydrochloride, salicylate, maleate, benzoate, ethanedisulfonate, fumarate, glycolate, salts of dibasic acids, fumarate, succinate and combinations of two or more of these salts.

14. The effervescent composition according to claim 13, wherein the component (a) is metformin hydrochloride.

15. The effervescent composition according to any one of the claims 1-14, wherein the component (a) is present in an amount of from 10% to 30% by weight of the composition.

16. The effervescent composition according to any one of the claims 1-15, wherein the component (b) is present in an amount of from 40% to 60% by weight of the composition.

17. The effervescent composition according to any one of the claims 1-16, wherein the component (c) is present in an amount of from 5% to 25% by weight of the composition.

18. The effervescent composition according to any one of the claims

1-17, wherein the component (d) is present in an amount of from 5% to 20% by weight of the composition.

19. Process for preparing an effervescent composition according to any one of the claims 1-18, wherein the components (a) - (e) are blended in their respective amounts.

20. Tablets or granules comprising the effervescent composition according to any one of the claims 1-18.

21. Process for making effervescent tablets, comprising the direct compression of an effervescent composition according to any one of the claims 1-18 to form said effervescent tablets.

22. Process for making effervescent granules, comprising the granulation of an effervescent composition according to any one of the claims 1- 18 to form said effervescent granules.

23. Process for making effervescent tablets from the effervescent composition according to any one of the claims 1 -18, comprising - the granulation of the component (b) with a part of component (d), followed by

- the compression of the obtained blend to form the effervescents tablets.