TECHNICAL FIELD OF THE INVENTION

This present invention belongs to the technical field of pharmaceutical formulation. In particular, this invention relates to an immediate release formulation of Prasugrel besylate for oral administration and a process for preparing such formulation. BACKGROUND OF THE INVENTION

Prasugrel is a member of the thienopyridine class of antiplatelet agents. Prasugrel has a distinct chemical structure that permits efficient conversion to its active metabolite, R- 138727, that irreversibly inhibits platelet activation and aggregation mediated by the P ₂ i2 active adenosine diphosphate (ADP) receptor.

The chemical name of prasugrel is 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2- oxoethyl]-4, 5, 6, 7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. Prasugrel

®

hydrochloride is marketed under the trademark Effient in 5 or 10 mg strengths. The tablets are commercially supplied in blister packaging.

Formulation development of pharmaceutical composition containing prasugrel or salts thereof is challenging due to the poor chemical stability and the poor water solubility of the active pharmaceutical ingredient (API).

Poor chemical stability leads to degradation of the active ingredient and results in reduced effectiveness or treatment failure. Thus, careful selection of excipients is one of a key factor in developing finished dosage forms with good safety.

Prasugrel is a poor water soluble compound. The solubility of prasugrel in a wide range of pH buffer solutions shows that its solubility is high in acidic media and decreases with the increase in pH from neutral to alkali. Selection of the API crystalline form and proper physical properties is another important factor in developing finished dosage forms with desired dissolution behavior. Pharmaceutical compositions comprising prasugrel free base or salts thereof as the single drug substance have been disclosed, for example, in WO 2006/135605, WO 2008/073759, WO 2011/092720, WO 2013/150322, and WO 2015/103230. However, the prior art has encountered substantial difficulty in the production of the solid oral formulations with appropriate physical characteristics and stability, especially when Prasugrel is in the dosage form as salt other than hydrochloride.

Therefore, although each of the above patents represents an attempt to overcome the poor stability and poor water solubility problems associated with pharmaceutical compositions comprising prasugrel or pharmaceutically acceptable salts thereof, there still exists a need for improving the stability and therapeutic efficacy of such pharmaceutical compositions.

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide a pharmaceutical composition for oral administration of prasugrel besylate, which overcomes the deficiencies of the prior art and provides an effective and stable dosage form.

The present invention aims at developing a formulation that not only matches the physical and chemical attributes of the reference product but also is bioavailable and with sufficient self-life.

A major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients, the effective drug substance particle size distribution and the method of preparation of final product in order to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient. A further approach of the present invention is to provide a tablet composition for oral administration comprising Prasugrel besylate which is manufactured through a fast, simple and cost-effective process.

A major aspect of the present invention is to provide a pharmaceutical formulation that can enhance the solubility of Prasugrel besylate

Accordingly, the present invention provides a pharmaceutical composition comprising prasugrel besylate having particle size distribution of D90 below 60μιη and a surfactant in amount 3-8 wt , in which said surfactant is selected from sodium lauryl

®

sulfate (SLS) and soluplus .

The pharmaceutical composition according to the present invention further comprises mannitol as a diluent, microcrystalline cellulose as a filler, croscarmellose sodium as a disintegrant, hypromellose as a binder, colloidal silicon dioxide as glidant and magnesium stearate as a lubricant.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient is considered to be "stable" if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.

As already mentioned the main object of the present invention is to provide a stable pharmaceutical composition of Prasugrel besylate for oral administration that is simple to manufacture, bioavailable, cost effective and possesses good pharmacotechnical properties.

An important parameter to achieve desired concentration of drug in systemic circulation for the anticipated pharmacological response (bioavailability) is solubility. Solubility is the phenomenon of dissolution of solute in solvent to give a homogenous system. Prasugrel besylate, as already explained, possess variable solubility depending on pH value. Solubility enhancement is a major challenge for formulation development. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and addition of alkalizing or acidifying agents. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

It has been surprisingly found that the object of the present invention can be achieved

® ®

by employing SLS or Soluplus , in the composition. SLS and Soluplus are effective in enhancing the stability and the solubility of prasugrel besylate.

Sodium lauryl sulfate is an anionic surfactant freely soluble in water. It is widely used in oral and topical pharmaceutical formulations as a detergent and wetting agent effective in both alkaline and acidic conditions.

®

Soluplus is a graft copolymer comprised of polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam. Even though Soluplus ^® was developed as a matrix polymer for solid solutions, it is also capable of solubilizing poorly soluble drugs in aqueous media. It has also been found that the amount of the surfactant has an impact on the dissolution rate. The use of 3 wt% up to 8 wt% resulted in increased solubility. The target of higher than 85% dissolution at 30 minutes was achieved.

The particle size of the API is another parameter that can affect its solubility. The specific surface area is increased with decreasing particle size of the drug, resulting in an increase in dissolution rate. In most circumstances the dissolution rate of poorly soluble drugs is strongly related to the particle size distribution and thus the dissolution profile of the final product. In order for a drug to have its effect after oral administration it must go into solution and then diffuse through the gut wall into the body. The first step in that process is the disintegration of the dosage form followed by dissolution of the active ingredient. One way to increase dissolution rate is to increase the surface available for dissolution by reducing particle size. For prasugrel besylate crystalline API, we found that a particle size distribution of D90 below 60μιη is suitable to ensure good dissolution rate.

The pharmaceutical compositions of the present invention may also contain one or more additional formulation excipients such as diluents, disintegrants, binders, lubricants, provided that they are compatible with the active ingredient of the composition, so that they do not interfere with it in the composition and in order to increase the stability of the drug and the self-life of the pharmaceutical product. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (MCC), dextrose, fructose, mannitol, maltodextrin, maltitol, lactose. The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include sodium starch glycolate, alginic acid, carboxymethylcellulose sodium, croscarmelose sodium, colloidal silicon dioxide (aerosil). Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose function include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include hydroxyethyl cellulose, methylcellulose, hydroxypropyl cellulose (HPC), polydextrose, polyethylene oxide, povidone.

When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause surface irregularities to the product. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include talc, magnesium stearate, calcium stearate, glyceryl behenate. Two polymorphic forms of prasugrel besylate are described in the literature, namely form P and form M. Crystalline Form M of Prasugrel besylate is characterized by the Powder X-ray diffraction having characteristic peaks at 9.34, 17.41, 20.01, 24.03, 25.15 (+) 0.2° degree 2-theta. Crystalline Form P of Prasugrel besylate is characterized by the Powder X-ray diffraction having characteristic peaks at 7.1, 8.15, 9.2, 10.24, 11.03, 13.25, 14.68, 16.05, 19.27, 21.51, 23.21 (+) 0.2° degree 2-theta. The selected crystalline form in the present invention was form P but similar results are to be expected with crystalline form M.

Manufacturing processes such as dry granulation, wet granulation with ETOH and Acetone can be used to produce the solid oral dosage form of the composition of the present invention.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

EXAMPLES Example 1: The performance of four different surfactants was evaluated in compositions prepared by dry granulation. The manufacturing process followed for the four formulations comprised the following steps:

• Sifting the raw materials

· Blending API with, internal phase excipients

• Lubrication with Magnesium stearate

• Compression Table 1 : Formulations 1 to 4

The release of the active ingredient from formulations 1 to 4 was evaluated by performing dissolution testing USP app. II at 75 r.p.m. using a citrate-Phosphate buffer with pH value of 4.

Table 2: Dissolution profile of formulations 1 to 4

The results present a higher release rate for formulations 2 and 4 but not as high as the required for an immediate release dosage form.

Example 2:

SLS was tested, as one of the two surfactants having better results, in various amounts and using a wet granulation process. Table 3: Formulations 5 to 8

The manufacturing process of formulations 5 to 8 includes wet granulation of internal phase ingredients. The preparation steps followed are presented below:

• Sifting the raw materials

• Blending API with SLS in an amount of acetone

• Addition of internal phase excipients and the rest amount of acetone and blending.

· Drying the wet mass at 40°C

• Lubrication with Magnesium stearate and

• Compression

Table 4: Dissolution profile of formulations 5 to 8

Formulations 6 to 8 having an amount of surfactant from 4% to 8% achieve the required release profile. Comparable results were obtained with the use of Soluplus ^® as the surfactant. Example 3:

Various modifications of formulation were also investigated in order to see how they affect the dissolution profile. In formulation trial 7 of example 2, Aerosil ^® was added in the external phase for better granule flow and the amount of disintegrant was increased to 8% by weight and split equally between internal and external phase. The amounts of other excipients were modified accordingly. Table 5: Formulation 9

The manufacturing process of Formulation Trial 9 above was a wet granulation similar as in example 2.

Table 6: Dissolution profile of formulation 9

% Dissolved

Time interval (min)

9

5 73,53

10 83,56

15 87,60

20 90,32

30 92,61

45 92,78 The release profile of formulation 9 is acceptable and comparable to that of formulations 6 to 8 of example 2. The only improvement observed was related to the disintegration time of the tablets that was reduced to below than 2 minutes.

Example 4:

The formulation of example 3 was further evaluated with respect to change in manufacturing process and reduction of particle size of Prasugrel besylate. Three new formulation trials were prepared with the same qualitative and quantitative composition as that in table 5 (example 3). All were prepared by direct compression manufacturing process: sifting and blending all ingredients of external phase; mixing with Aerosil ^® ; mixing with magnesium stearate and tableting

Table 7: Formulation 10 to 12

The dissolution profiles of formulations 10 to 12 are presented below. Table 8: Dissolution profile of formulations 10 to 12

No significant difference was observed with particle size reduction and manufacturing process change.

Tablets resulted from the present invention were placed in chambers under normal, intermediate and accelerated conditions and were examined in appropriate time points in order to control their stability. The results were within limits proving a stable formulation during storage time.