Field

The present invention relates to pharmaceutical tablet formulations of the angiotensin Il receptor antagonist telmisartan.

Background

Telmisartan is an angiotensin Il receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP 0 502 314. It is chemically described as 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)- benzimidiazol-1-ylmethyl]-biphenyl-2-carboxylic acid. Telmisartan's empirical formula is C ₃₃ H ₃₀ N ₄ O ₂ and its structural formula is:

Telmisartan is commonly manufactured and supplied in the free acid form. Crystalline telmisartan exists in two polymorphic forms having different melting points, as disclosed in WO 00/43370. The lower melting polymorph B transforms irreversibly into the higher melting polymorph A under the influence of heat and humidity. Both forms are characterized by a very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7. Pharmaceutical formulations of telmisartan are often alkaline and commonly include a basic solubilisation agent such as meglumine. In addition, dissolution rates are enhanced by the inclusion of surfactants or emulsifiers to the solid dosage forms. Telmisartan-only tablets are known especially from EP 1 545 467 but require relatively complex manufacture and inclusion of surfactant, solubiliser and other components to achieve satisfactory formulation. Furthermore, the addition of surfactant to the formulation can soften the tablet product, increasing the risk of damage during handling. Patient compliance can be reduced by any formulation that is overtly damaged.

An aim of the present invention is to provide tablet formulations that ameliorate or overcome one or more of the above identified issues.

Invention

Accordingly, the invention provides a telmisartan formulation comprising

(a) telmisartan;

(b) in excess of 60% by weight of the formulation of water soluble diluent; and (c) optionally, one or more of a lubricant, a binder, a pH adjuster and a surfactant.

Preferred formulations of the invention comprise 3-40% by weight of telmisartan, more preferably 5-30% by weight telmisartan, even more preferably 10-20% by weight telmisartan. In addition, preferred telmisartan formulations are substantially free of an active agent other than telmisartan. The preferred dosage form takes the form of a tablet, especially one with fast dissolution properties (meaning at least 70% of the drug, preferably at least 90% of the drug is dissolved within 30 minutes).

Suitable water soluble diluents include monosaccharides such as glucose; oligosaccharides like sucrose, anhydrous lactose and lactose monohydrate; and sugar alcohols such as mannitol, sorbitol, erythritol, dulcitol, ribitol and xylitol. In specific examples below, we have used mannitol.

Formulations of the invention are characterised by high levels of water soluble diluents, and preferred formulations of the invention comprise in excess of 65% by weight water soluble diluents, more preferably in excess of 70% by weight water soluble diluents, even more preferably in excess of 72% by weight water soluble diluents. The diluents may be one or a mixture of diluents, and generally, the amount of diluents should not exceed an upper limit of about 90% by weight, or 80% by weight.

When included in the formulation, suitable surfactants may be ionic or non-ionic, the latter being preferred. Specific examples include poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulphate, and polyethoxylated and hydrogenated castor oil.

In particularly preferred embodiments of the invention, however, it has surprisingly been found that the use of high amounts of the diluents can reduce or avoid the need to include a surfactant in the formulation, the formulation having nevertheless acceptable dissolution properties. In specific embodiments of the invention set out in detail below, telmisartan formulations have been prepared which are free of surfactant but were nevertheless found to fulfil the fast dissolution requirements for this active agent. Therefore, in use of the invention it is possible to dispense with the requirement of adding surfactant to the formulation. Preferred formulations of the invention can comprise 2% or less by weight surfactant, more preferably 1% or less by weight surfactant, but even more preferably the formulation can be substantially free of surfactant or completely free of surfactant.

The pH adjuster in the form of a basic agent can act as a solubiliser. Specific examples of suitable basic agents are alkali metal salts, e.g. alkali metal hydroxides such as NaOH and KOH. Further examples include NaHCO ₃ , KHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Na ₂ HPO ₄ , K ₂ HPO ₄ . In addition basic amino acids such as arginine, lysine and meglumine (N-methyl-D-glucamine) can act as solubilizing agents. - A -

Known telmisartan formulations include both an alkali metal salt and a basic amino acid, e.g. meglumine. In specific embodiments of the invention set out in detail below, telmisartan formulations have been prepared which contain only an alkali metal salt, and are free of a basic amino acid but were nevertheless found to fulfil the fast dissolution requirements. Hence the invention also provides the possibility to dispense with the requirement of adding a basic amino acid such as meglumine to the formulation. This is advantageous since this enables a further simplification and, as a result, cost reduction in manufacture of the formulations. Preferred formulations of the invention may be substantially or completely free of a basic amino acid as solubilizing agent, e.g. are free of meglumine. As an example, we have used sodium hydroxide as the basic agent. Preferred formulations of telmisartan comprise 0-5% by weight basic agent, more preferably 0-3% by weight basic agent.

Tablets of the invention commonly contain lubricants to aid compressibility. Suitably examples of the lubricant can be magnesium stearate, stearic acid, sodium stearyl fumarate and glycerol tribehenate. In specific examples below, we have used magnesium stearate. Preferred formulations of the invention comprise 0-5% by weight lubricant, more preferably 1-4% by weight lubricant.

A binder may be selected depending on the manufacturing process chosen for the pharmaceutical composition. Suitable dry binders include cellulose powder, crystalline cellulose and silicified microcrystalline cellulose. Examples of wet granulation binders are corn starch, polyvinyl pyrrolidone (Povidone), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose. In the examples for formulations of telmisartan we have used Povidone. Preferred formulations of telmisartan comprise 0-15% by weight binder, more preferably 2-10% by weight binder.

Specific solid pharmaceutical compositions in the form of tablets are shown in the examples below. The formulations presented here are advantageous with respect to the prior art since they provide a simpler formulation that can avoid the requirement for both a surfactant and an amino acid-based solubilizing agent. This was achieved in the examples by using relatively high levels of water-soluble diluents, resulting in a simpler formulation that is cheaper and easier to manufacture.

Colouring agents can be used for identification and/or aesthetic purposes. Suitable colouring agents include dyes and pigments such as iron oxide red or yellow, titanium dioxide and talc.

Preferably, the telmisartan-containing formulation is a dissolving formulation.

The invention is now illustrated in the following examples.

Examples

Example 1 : Telmisartan formulation

Table 1 shows a pharmaceutical composition containing telmisartan according to the invention, which was compressed to form a tablet.

Table 1 :

Ingredient % w/w

Telmisartan 15.38

Sodium hydroxide 1.29

Povidone K-30 4.62

Mannitol 77.17

Magnesium stearate 1.54 In this formulation, sodium hydroxide acts as a basifying agent, Povidone K-30 acts as a binder, purified water acts as a granulation aid, mannitol acts as a water- soluble filler and magnesium stearate acts as a lubricant.

The above formulation was used to make a tablet containing: 80 mg telmisartan; 6.72 mg sodium hydroxide; 24 mg Povidone K-30; 401.28 mg mannitol; and 8 mg magnesium stearate. This provided a 520 mg tablet.

Manufacturing Process:

1. A granulation liquid or spray solution was prepared by dissolving 2.4 kg Povidone K-30, 672 g sodium hydroxide and 8 kg telmisartan in purified water (q.s.).

2. 40.128 kg mannitol was sifted and loaded in the bowl of a standard top spray fluid bed granulator and heated to the desired temperature.

3. The granulation liquid was sprayed on the mannitol.

4. The granules were dried and screened to achieve size uniformity.

5. The screened granules were blended with 800 g magnesium stearate using a suitable blender.

6. The final blend was compressed into tablets.

Example 2: Telmisartan formulation

Table 2 shows a further pharmaceutical composition according to the invention, which was compressed into tablets. Table 2:

Ingredient % w/w

Telmisartan 15.38

Sodium hydroxide 1.29

Povidone K-30 4.62

Meglumine 4.62

Mannitol 72.55

Magnesium stearate 1.54

In this formulation, sodium hydroxide acts as a basifying agent, Povidone K-30 acts as a binder, meglumine acts as a basic solubilisation agent, purified water acts as a granulation aid, mannitol acts as a water-soluble filler and magnesium stearate acts as a lubricant.

The above formulation was used to make a tablet containing: 80 mg telmisartan; 6.72 mg sodium hydroxide; 24 mg Povidone K-30; 24 mg meglumine; 377.28 mg mannitol; and 8 mg magnesium stearate. This provided a 520 mg tablet.

Manufacturing Process:

1. A granulation liquid or spray solution was prepared by dissolving 2.4 kg Povidone K-30, 672 g sodium hydroxide, 2.4 kg meglumine and 8 kg telmisartan in purified water (q.s.).

2. 37.728 kg of mannitol was sifted and loaded in the bowl of top spray fluid bed granulator and heated to the desired temperature.

3. The granulation liquid was sprayed on the mannitol. 4. The granules were dried and screened to achieve size uniformity.

5. The screened granules were blended with 800 g magnesium stearate using a suitable blender.

6. The final blend was compressed into tablets.

The invention thus provides telmisartan tablet formulations.