SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF MESALAZINE

Field of Invention

The present invention relates to pharmaceutical compositions comprising mesalazine or a pharmaceutically acceptable salt thereof wherein the composition is free of acrylic acid and methacrylic acid and their derivatives.

Background of Invention

Aminosalicylates are a group of medicines that can help to control the symptoms of some inflammatory bowel (gut) diseases. They are mainly used to help keep people with ulcerative colitis in remission and to treat flare-ups of ulcerative colitis. There is also some evidence that if you have ulcerative colitis then taking an aminosalicylate on a long-term basis can significantly reduce your risk of developing bowel cancer.

They include balsalazide, mesalazine, olsalazine and sulfasalazine, and come in a variety of different forms as tablets or liquid to be taken by mouth, liquid or foam enemas, suppositories to be inserted into the rectum.

All of the aminosalicylate medicines contain the active ingredient called 5-aminosalicylic acid (5-ASA). Mesalazine is an agent derived from sulfasalazine. Its chemical name is 5- amino-2-hydroxybenzoic acid and its chemical structure is shown in the Formula 1.

Formula 1. Mesalazine

Mesalazine is a molecule with antiinflammatory activity, widely used for the treatment of chronic inflammatory diseases of the intestinal tract. Chronic intestinal inflammatory diseases are a group of inflammatory diseases, with acute or subtle onset, which mainly but not exclusively involve the intestine; they have chronic course and fluctuating activities and progressions over time. In this disease group, the most important are ulcerative colitis and Crohn's disease, serious and disabling diseases, which negatively affect the quality of life of the patients in addition to their health.

Mesalazine is normally administered orally or rectally; in particular, most of the oral compositions currently present on the market are formulated in tablets or granules. The oral forms currently present on the market are mainly formulated in such a manner that the active principle goes beyond the stomach, and often also beyond the small intestine, so as to be essentially released in a site-specific manner at the site of the inflammation, where it acts in a topical manner in direct contact with the mucosa. In order to obtain such site-specificity and the relative topical effectiveness, it is known that the oral forms of mesalazine are coated by one or more layers which allow controlling its release.

Mesalazine comes in six different brand names: Asacol®, Ipocol®, Octasa®, Mezavant®, Pentasa®, Salofalk®. They are all different in terms of manufacturing process and mechanism of action. Tablet forms marketed under the name Asacol®, Ipocol®, Mesren® and Salofalk® have special coatings which dissolve to release the active ingredient (5- ASA) at a certain pH within the gut. On the other hand, each Pentasa® tablet is made up of tiny granules and the active ingredient is gradually released over the length of the gut. Mezavant® tablets have a hard core that contains 5-ASA and they have a special coating providing extended release of 5-ASA all along the large intestine.

In the state of the art, it is disclosed a controlled release tablet formulation of mesalazine by which a continuous and homogenous release of the active agent is intended to provide. In this context, the dosage form is constituted of 3 essential part one of which is the inert central core. In order to enhance content uniformity, the indispensable presence of this central core, which does not contain any active agent and which is covered by an intermediate layer comprising mesalazine and an enteric coating, causes an increase in the tablet size and accordingly decreases the patient compliance. This tablet structure shall also not permit a secondary coating layer due to dimensional issues. Therefore, it can be anticipated that the disintegration profile of this dosage form won’t meet the expectations. Stability problems based on the air humidity can also appear during the shelf life. The prior art also gives information about the tablet core hardness; specifically, the hardness is held between 80 N and 105 N. It is arguable whether it is compact enough to provide an easy-to-swallow tablet with a smooth surface and an acceptable size, especially when it is considered that at least one coating will be added on this core. This value shall not provide a desirably low friability which ensures a steady coating. In the prior art, the structural integrity and friability of mesalazine tablets have not been seen as a technical problem. Therefore, increasing the patient compliance by providing tablets with increased tablet core hardness has never been the main issue. The patient compliance is also dependent on the tablet size. However, mesalazine tablets having a weight of 1000 mg or even more are presented in patent documents up to now.

Another significant issue about mesalazine tablets is the release area of the active agent which is adjustable by the selection of the type, amount and layer number of the enteric coating. As the enteric coating plays a crucial role for the bioavailability and stability of the tablet, so does the physical and chemical compatibility between the core and the enteric coating.

The prior art represents a large number of delayed release mesalazine formulations with at least one layer of enteric coating comprising polymers selected from polymeth acrylic acid, polymethacrylates, polyacrylic acid, polyacrylates or copolymers thereof. However, it is a fact that polymethacrylates, which are known under the trade name Eudragit, are incompatible with magnesium stearate (Handbook of Pharmaceutical Excipients edited by Raymond C. Rowe, Paul J. Sheskey and Marian E. Quinn, sixth edition, page 531 ). This incompatibility has an undesirable limiting effect on the selection of the excipients in the formulation.

It can be seen that there is no teaching, suggestion or motivation in the prior art about how to develop a mesalazine tablet with reduced size, reduced friability and increased patient compliance. Accordingly, there is still a need for compact and stable mesalazine tablet formulations with a steady enteric coating which is free of acrylate, methacrylate, acrylic acid, methacrylic acid and copolymers thereof and which provide the desired disintegration and the dissolution rates at the specified site of delivery. Objects and Brief Description of the Invention

The main object of the present invention is to obtain solid oral pharmaceutical compositions of mesalazine eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.

Another object of the present invention is to develop tablet compositions of mesalazine with at least one enteric coating ensuring the delivery of the active agent in the colon (large bowel).

Another object of the present invention is to obtain tablet compositions of mesalazine with reduced size and friability.

Another object of the present invention is to obtain tablet compositions of mesalazine with enhanced stability and patient compliance.

A further object of the present invention is to develop tablet compositions of mesalazine providing an improved level of dissolution rate and solubility at the specified site of delivery.

A further object of the present invention is to develop tablet compositions of mesalazine which is free of acrylate, methacrylate, acrylic acid, methacrylic acid and copolymers thereof.

Yet another object of the present invention is to improve a process for preparing the said mesalazine tablet compositions, comprising wet granulation method which makes round and compact granules having a high bulk density and a narrower range of particle sizes.

Detailed Description of the Invention

In accordance with the objects outlined above, detailed features of the present invention are given herein.

The present invention relates to a solid oral pharmaceutical composition comprising mesalazine or a pharmaceutically acceptable salt thereof wherein the composition comprises an enteric coating which is free of acrylic acid and derivatives, methacrylic acid and derivatives, and copolymers thereof.

In the most preferred embodiment, the composition comprises an enteric coating which is free of polymethacrylates and copolymers thereof.

According to the preferred embodiment, the composition is in the form of an enteric- coated tablet.

In one embodiment, the composition is composed of a tablet core comprising mesalazine and an enteric coating with at least one layer wherein the tablet core has a tablet hardness of not less than 130 N.

This value of tablet hardness is specified to ensure increased compactness and decreased friability for the tablet core. Moreover, it has a significantly positive effect on the adherence between the tablet core and the enteric coating. Thus, patient compliance and bioavailability are also enhanced.

According to the preferred embodiment, the tablet core comprises a film coating.

Suitable film coating ingredients are selected from the group comprising hypromellose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.

Preferably, the film coating comprises polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc. Most preferably, the film coating is Opadry® White.

According to the preferred embodiment, the enteric coating comprises two layers which are the inner layer and the outer layer.

Suitable inner layer ingredients are selected from the group comprising hypromellose, hypromellose acetate succinate, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), ethyl cellulose, polyethylene glycol (PEG), talc, triethyl citrate, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethyl cellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.

In the most preferred embodiment, the inner layer comprises hypromellose acetate succinate (HPMC AS), preferably HPMC AS-HG, triethyl citrate and talc.

HPMC AS-HG is a partially esterified derivative of hypromellose in which succinoyl and acetyl residues are bound to the cellulose backbone. It has a pH solubility greater than or equal to 6.5 and its mean particle size is ranging between 0,005-1 mm.

Suitable outer layer ingredients are selected from the group comprising hypromellose, hypromellose acetate succinate, sodium hydroxide, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), ethyl cellulose, polyethylene glycol (PEG), talc, triethyl citrate, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethyl cellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.

In the most preferred embodiment, the outer layer comprises hypromellose acetate succinate (HPMCAS), preferably HPMCAS-MG, sodium hydroxide, triethyl citrate and iron oxide.

HPMCAS-MG, which has a pH solubility greater than or equal to 6.0, is also a partially esterified derivative of hypromellose. Its mean particle size is ranging between 0,005-1 mm.

According to the preferred embodiment, the ratio of HPMC AS-HG to HPMC AS-MG is in the range of 0.2:1 - 10:1 , preferably 0.5:1 - 5:1 , more preferably 0.8:1 - 1 .2:1 by weight.

It has been seen that the presence of hypromellose acetate succinate in the inner and outer layers and this selected range of amount provides enhanced bioavailability, disintegration rate and a smooth surface on the tablet core. A compact and surprisingly stable enteric coating is also provided due to the synergistic effect of the inner layer and the outer layer. The desired site of delivery of mesalazine, which is the colon in the gastrointestinal tract, is maintained by the specific adjustment of these ratios. Moreover, the selection of hypromellose acetate succinate for both the inner and the outer layers ensures the compatibility between the tablet core and the enteric coating.

According to the preferred embodiment, the amount of mesalazine is between 10-90%, preferably 40-80%, more preferably 60-80% by weight of the tablet core.

According to the preferred embodiment, the tablet core further comprises at least one excipient selected from disintegrants, binders, buffering agents, lubricants, glidants or mixtures thereof.

According to one embodiment, the pharmaceutical composition comprises at least one binder which is selected from the group comprising polyvinylpyrrolidone (PVP), copovidone, copolyvidone, carnauba wax, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, starch, pregelatinized starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polaxomer, polyethylene glycol (PEG), sugars, glycose syrups, natural gums, tragacanth gum, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose or mixtures thereof.

According to the preferred embodiment, the composition comprises one binder which is polyvinylpyrrolidone.

The amount of polyvinylpyrrolidone is between 1 -15%, preferably 3-8% by weight of the total composition.

According to one embodiment, the pharmaceutical composition comprises at least one disintegrant which is selected from the group comprising croscarmellose sodium, microcrystalline cellulose, sodium carbonate, hydroxylpropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidon), copovidon, polycarbophil, low-substitue poloxamer, sodium starch glycolate, starch, pregelatinized starch, alginic acid and alginates, ion- exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, docusate sodium, guar gum, polyacrylin potasium, sodium alginate, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.

According to the preferred embodiment, the pharmaceutical composition comprises two disintegrants which are microcrystalline cellulose and croscarmellose sodium.

The amount of microcrystalline cellulose is between 1 -20%, preferably 2-10% by weight of the total composition.

The amount of croscarmellose sodium is between 0.5-15%, preferably 1 -7% by weight of the total composition.

According to one embodiment, the pharmaceutical composition comprises at least one buffer agent which is selected from the group comprising glycine, sodium carbonate, alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof, and preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate, glycine , glutamic acid or mixtures thereof.

According to the preferred embodiment, the pharmaceutical composition comprises two buffer agents which are glycine and sodium carbonate.

The amount of glycine is between 0.1 -10%, preferably 0.5-4% by weight of the total composition.

The amount of sodium carbonate is between 1 -30%, preferably 10-20% by weight of the total composition.

According to one embodiment, the pharmaceutical composition comprises at least one lubricant and one glidant which are selected from the group comprising calcium stearate, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.

According to the preferred embodiment, the composition comprises calcium stearate as the lubricant.

The amount of calcium stearate is between 0.1 -5%, preferably 0.5-4% by weight of the total composition.

According to one embodiment, the composition comprises magnesium stearate as the lubricant.

The amount of magnesium stearate is between 0.1 -5%, preferably 0.5-4% by weight of the total composition.

According to the preferred embodiment, the composition comprises colloidal silicon dioxide as the glidant.

The amount of colloidal silicon dioxide is between 0.1 -5%, preferably 0.5-4% by weight of the total composition.

According to one embodiment, the tablet core comprises;

— 10-90% by weight of mesalazine,

— 1 -15% by weight of polyvinylpyrrolidone,

— 1 -20% by weight of microcrystalline cellulose,

— 0.5-15% by weight of croscarmellose sodium,

— 0.1 -10% by weight of glycine,

— 1 -30% by weight of sodium carbonate,

— 0.1 -5% by weight of calcium stearate,

— 0.1 -5% by weight of colloidal silicon dioxide,

— 1 -10% by weight of film coating. According to one embodiment, the inner layer solution comprises;

— 1 -20% by weight of hypromellose acetate succinate (HPMC AS-HG),

— 0.1 -5% by weight of triethyl citrate,

— 0.1 -5% by weight of talc,

— 30-60% by weight of ethanol,

— 30-60% by weight of distilled water.

According to one embodiment, the outer layer solution comprises;

— 1 -20% by weight of hypromellose acetate succinate (HPMC AS-MG), — 0.01 -1% by weight of sodium hydroxide,

— 0.1 -5% by weight of triethyl citrate,

— 0.01 -1% by weight of iron oxide hydrate,

— 30-60% by weight of ethanol,

— 30-60% by weight of distilled water.

These analytically selected ratios ensure the required effective doses for the treatment and enhance stability, disintegration and dissolution profiles of the enteric-coated tablet subjected to the invention. According to all these embodiments, the below given formulation can be used in the tablet composition subjected to the invention.

Example 1 : Enteric-coated tablet

The inner layer solution mentioned above is prepared by following these steps:

— Mixing ethanol and distilled water to obtain an ethanol solution — Adding HPMC AS-HG into the ethanol solution and mixing until it is completely dissolved

— Adding triethyl citrate and mixing about 15 minutes

— Adding talc and mixing until a homogeneous solution is obtained

The outer layer solution mentioned above is prepared by following these steps:

— Mixing ethanol and distilled water to obtain an ethanol solution

— Adding HPMC AS-MG into the ethanol solution and mixing until it is completely dissolved

— Adding sodium hydroxide solution and mixing about 15 minutes — Adding triethyl citrate and mixing about 15 minutes

— Adding iron oxide hydrate and mixing until a homogeneous solution is obtained The enteric-coated tablets mentioned above are prepared by following these steps:

— Mixing mesalazine and polyvinylpyrrolidone

— Granulating this binary mixture with distilled water

— Adding microcrystalline cellulose, croscarmellose sodium, glycine and sodium carbonate into the granulation medium while continuing granulating

— Sieving the granules through a 2mm mesh sieve

— Drying the sieved granules in a fluid bed

— Sieving the dried granules through a 0.85mm to 1 mm mesh sieve — Adding colloidal silicon dioxide and calcium stearate into the granules — Compressing the final granule mixture into tablets

— Coating these tablets with a film coating

— Coating these film-coated core tablets with the inner layer solution and the outer layer solution respectively