FIELD OF INVENTION

The present invention relates to high drug load oral pharmaceutical compositions comprising Favipiravir or its pharmaceutically acceptable salt thereof manufactured by using wet granulation method.

BACKGROUND OF THE INVENTION

Favipiravir, its chemical name is 6-Fluoro-3-hydroxy-2-pyrazinecarboxamide, is an anti-viral agent that selectively and potently inhibits RNA dependent RNA polymerase (RdRP), which are necessary for the transcription and replication of viral genomes.

The empirical formula of Favipiravir is C ₅ H ₄ FN ₃ O ₂ and molecular weight is 157.104 g/mole.

The chemical structure of Favipiravir is shown in the Formula I.

Favipiravir is a white to light yellow powder. It is not hygroscopic at 25°C/51% to 93%RH and is sparingly soluble in acetonitrile and in methanol and slightly soluble in water and in ethanol. It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.

Favipiravir and its pharmaceutically acceptable salts first have been declared in EPl 112743 by Toyama Chemical Co. Ltd who discovered through screening chemical library for anti-viral activity against the influenza virus.

Favipiravir was first commercially authorized in Japan to treat cases of influenza that were unresponsive to conventional treatment.

The innovative product of Favipiravir is currently in the form of tablet form under the name AVIGAN ^® in the strength of 200 mg in worldwide. Favipiravir is indicated for the treatment of novel or re-emerging influenza virus infections and also has shown anti-viral activity even against amantadine, oseltamivir and zanamivir resistant influenza viruses in vitro like COVID- 19. The recommended term of Favipiravir treatment is 5 -day at the beginning period of its use in COVID-19 treatment. Moreover, the new publications and clinical studies have shown that the term of Favipiravir treatment may be longer for a comprehensive recovery up to 14 days.

Moreover, the usual recommended dose of Favipiravir is 1600 mg orally twice daily in the first day of treatment and followed by 600 mg orally twice daily for four days. These doses are administered in two equal amounts daily.

The recommended total administration period should be at least five days. The daily administered dose is very high.

The number of AVIGAN ^® 200 mg Tablet to be administered daily, in the first day is 18 and this number is 6 on the following four days. AVIGAN ^® is in the form of film-coated tablet contains Favipiravir as active ingredient and povidone, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, crospovidone, sodium stearyl fumarate, hypromellose, titanium dioxide, talc and yellow ferric oxide as pharmaceutically acceptable excipients.

Favipiravir is well absorbed orally with bioavailability of approximately 97.6%, plasma protein binding of 54%. Favipiravir is not metabolized by cytochrome P-450 (CYP) enzyme. It is metabolized in liver mostly by aldehyde oxidase and partly to a hydroxylated form by xanthine oxidase. It is excreted in hydroxylated form by kidneys.

In the state of art there are many patents/patent applications which are summarized below.

EP2407166 relates to a pharmaceutical composition comprising Favipiravir or pharmaceutically acceptable salt thereof, a low substituted hydroxypropyl cellulose or croscarmellose sodium and a binder manufactured by a fluidized bed granulation method wherein Favipiravir contained is 50 to 95% of the mass of the tablet or the granulated powder.

EP2623493 relates to a pharmaceutical composition comprising Favipiravir or pharmaceutically acceptable thereof wherein Favipiravir is in the salt of meglumine salt for the development of an injectable preparation with superior solubility.

CN111450063 relates to a pharmaceutical composition comprising Favipiravir or pharmaceutically acceptable thereof wherein the prepared granulation contains Favipiravir, filler, suspending agent, sweetener, glidant, and pH regulator wherein Favipiravir has a particle size volume distribution with a D90 less than 40 microns. CN107737128 relates to a pharmaceutical composition comprising Favipiravir or pharmaceutically acceptable thereof wherein the prepared granulation contains 200 mg Favipiravir, 24 to 45 mg microcrystalline cellulose, 10 to 18 mg lactose, 8 to 16 mg polyethylene glycol, 0.8 to 1.3 mg sodium lauryl sulfate, 2 to 5 mg fumed silica, and 1 to 2.5 mg magnesium stearate wherein Favipiravir has a particle size volume distribution with a D90 less than 40 microns and D50 between 26 and 33 microns.

CN 106667926 relates to a pharmaceutical composition comprising Favipiravir or pharmaceutically acceptable thereof wherein the prepared granulation contains Favipiravir, silicified microcrystalline cellulose and a binder.

The present invention relates to oral pharmaceutical compositions comprising Favipiravir or its pharmaceutically acceptable salt in high drug load and at least one pharmaceutically acceptable excipient as the immediate release dosage form manufactured by using wet granulation method with improved mechanical characteristics which reduces the number of daily administrations.

Summary of the Invention

The object of this invention is to develop an immediate release composition comprising high and therapeutically effective amounts of Favipiravir or pharmaceutically acceptable salt thereof requiring high drug load in the composition used in the treatment of novel or re-emerging influenza virus infections like COVID-19.

The daily recommended administration dose of Favipiravir is very high although the present marketed available composition comprises 200 mg Favipiravir per tablet. Thus, it is advantages if two doses of pharmaceutical compositions containing 800 mg and 600 mg active substance per dosage form are available, so that a patient has to take only four dosages - of 800 mg/dosage form on the first day of the treatment. This administration is also recommended to be scheduled in twice daily which means 2 dosage forms of 800 mg could be administered in the morning and 2 dosage forms of 800 mg could be administered in the evening.

Also, the patients continue to the treatment with only two administrations of 600 mg/dosage form daily for the following remaining duration of the treatment. One dosage form of 600 mg can be administered in the morning and one dosage form of 600 mg can be administered in the evening.

The present invention relates to high drug load pharmaceutical composition comprising Favipiravir and its pharmaceutically acceptable salt in dose of 600 mg. The present invention relates to high drug load pharmaceutical composition comprising Favipiravir and its pharmaceutically acceptable salt in dose of 800 mg.

The administrations of 600 mg and 800 mg Favipiravir or pharmaceutically acceptable salt thereof in a small size immediate release oral pharmaceutical compositions are possible for a given dose of Favipiravir which means between 70-80% by weight of the total composition.

The present invention relates to an immediate release composition comprising Favipiravir and at least one pharmaceutically acceptable excipient manufactured by using wet granulation process.

The present invention relates to an immediate release composition manufactured by using wet granulation method in which there are two phases named as intra-granular and extra-granular phases.

Another object of the present invention is to provide a preparation method of a pharmaceutical composition of Favipiravir wherein the pharmaceutical compositions herein disclosed can be manufactured into dosage forms, such as powder, granule, pellet, capsule, tablet, oral solution, oral suspension having desired dissolution profiles.

Another object of the present invention is to provide pharmaceutical compositions containing Favipiravir by using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, binder, diluent, disintegrants, glidant and lubricant wherein at least one excipient is present in both phases during manufacturing.

Detailed Description of the Invention

The present invention provides a pharmaceutical composition comprising high amounts of Favipiravir and at least one pharmaceutically acceptable excipient is developed in the immediate release dosage form with improved pharmaceutical characteristics.

The present invention is a pharmaceutical formulation contains a "high-load" of drug substance due to the relative large amount of drug substance needed for administration to patients. Thus, in the present description, the term "high drug load" means that the solid pharmaceutical formulation contains at least 50% by weight, calculated on the basis of the total weight of the formulation, of the active substance.

The most important advantage of high drug load pharmaceutical composition is about patient compliance, because of the route of administration is oral swallowing a product with high total weight of the formulation is very difficult. However, high drug load compositions have the highest therapeutically amount of active substance with design of low total weight of the formulation which makes the composition very dense.

The inventors surprisingly found that, administrations of 600 mg and 800 mg Favipiravir or salt thereof in a small size immediate release oral pharmaceutical compositions are possible for a given dose of Favipiravir which means between 70-80% by weight of the active substance calculated on the basis of the total weight of the formulation.

Moreover, the present invention is in immediate release form which means it should dissolve or disintegrate in the stomach within a short period of time and present rapid dissolution and absorption to produce rapid onset of action.

It is known that the granulation may be manufactured by the methods like direct compression, dry granulation or wet-granulation before tableting. The selection of the manufacture process procedure depends on the physical and mechanical properties of the active ingredient and the excipients.

The mechanical properties of high drug load finished drug product are dominantly very similar to active ingredient as being the highest amount of ingredient in the total composition. Based on this information, the characterization of active ingredient should be performed intensively. For example, the flowability of powder blend behaves like a powder active ingredient alone. If the flowability of active ingredient is poor the compression and compaction processes couldn’t be performed successively which means characterization of active ingredient affects the quantitative and qualitative composition and the manufacturing method of finished drug product.

The characterization studies were performed with the investigation of active substance solubility at die beginning. The identification of solubility will be used to define components and the manufacturing method of finished drug product. In addition, it will give opportunity to predict in vitro - in vivo correlation.

Table-1: Solubility results in simulated gastric or intestinal fluids

The lowest solubility was observed in pH 1.2 medium and the highest solubility value was observed in pH 6.8 medium.

The results were evaluated with the table given in the international guidelines. The solubility test was carried out by dissolving the maximum amount of active substance in 250 ml simulated gastric or intestinal fluids. It is to be assumed that this could also influence the permeability criterion as defined by the Biopharmaceutics Classification System (BCS).

In the various guidance documents, different definitions of the dose strength to be used for establishing the Dose/Solubility (D/S) ratio can be found. The highest dosage strength of a marketed immediate release drug product to be used, the World Health Organization (WHO) and European Medicine Agency (EMA) guidance define that the D/S ratio should be established with the highest single dose (which could consist of administering multiple dosage forms to achieve a required dose).

The solubility values should be minimum 800 mg/250 ml, 3.2 mg/ml to decide the active substance Favipiravir is in highly soluble class.

Table-2: Solubility results of Favipiravir active substance

Favipiravir is assigned as highly soluble based on the Table-2, since all solubility values in various media are higher than the value of 3.2 mg/ml.

Another physicochemical property flowability of Favipiravir active substance was identified by performing bulk density and tapped density properties. This analysis was performed according to the details declared in international guidelines.

Table-3: Results of flowability Table-4: Scale of flowability

The results were also evaluated based on the reference table, Table-4, given in the international guidelines and the flowability of Favipiravir was assigned as poor.

An equilibrium should be obtained between the relationship of the composition and manufacturing method. The first property to be improved to manage the manufacturing processes successfully was flowability. This could be possible with the selection of proper excipients.

The flowability is also effective in defining the proper manufacturing method. High favipiravir load powder blend will have the flowability of favipiravir.

The term “wet granulation” refers to converting a powder blend into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulation solution under shear to the mixed powders to complete the granulation process and get a granule to be mixed with other excipients required and to obtain a proper final blend for the compression process. This granulation and many mixing steps involved in wet granulation method will maintain to get a homogenous powder blend.

In one of the preferred embodiment of the present invention is to provide a pharmaceutical composition comprising favipiravir by using wet granulation method wherein the ingredients of the high drug load immediate release pharmaceutical composition include the active ingredient, release modifying agents, binders, disintegrant, plasticizer, lubricant, glidant, and granulation solvent selected as to be the most suitable excipients with respect to the intended form of administration. In some embodiments of the present invention are in the group comprising powder, granule, pellet, capsule, tablet, oral solution, oral suspension dosage forms.

In a preferred embodiment, suitable fillers may comprise but not limited to dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, the diluent is microcrystalline cellulose.

In a preferred embodiment, the pharmaceutical composition comprises at least a binder which can be selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is povidone.

In a preferred embodiment, the pharmaceutical composition comprises at least a disintegrant which can be selected from croscarmellose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrants are crospovidone and pregelatinized starch.

In silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate. Preferably, the glidant is silicon dioxide.

In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is sodium stearyl fumarate.

Wet granulation process relates to wet massing of the powder blend with a granulation fluid. The composition of granulation fluid could be at least one excipient used as binder and a solvent to dissolve it or solely a solvent.

The granulating fluid contains a solvent which can be volatized easily, so that it can be removed by drying by not requiring high values of temperature. The use of binder is used to ensure particle adhesion once the granule is dried. If the drying and subsequent handling is done in a proper conditions of manufacturing and the aggregates will maintain its integrity, the characterization of granule is both denser and more free flowing. The overall process of wet granulation consists the manufacturing steps of weighing, powder blending, wet granulating, drying, milling/sieving, lubrication of the blend and compression. In a preferred embodiment, the pharmaceutical composition comprises at least one granulation fluid which can be selected from deionized water, ethanol and isopropanol, either alone or in combination. Preferably, the granulation solvent is deionized water.

In one of the embodiments of the present invention is formulated in tablet dosage form.

Example 1: Unit Formula of Example 1

The detailed manufacturing steps were presented below: i. Favipiravir, Microcrystalline Cellulose and half amounts of Crospovidone and Pregelatinized Starch were screened through a proper sieve and transferred into high- shear mixer to stir, ii. Povidone was dissolved in a sufficient amount of deionized water till to dissolve completely, iii. The solution in Step (ii) was added into the powder blend prepared in Step (i) to perform granulation process, iv. The granules prepared in Step (iii) were dried in fluid bed dryer, v. The dried prepared granules in Step (iv) were screened through a proper sieve and stirred, vi. Silicon dioxide and the rest amount of the Crospovidone and Pregelatinized Starch were screened through a proper sieve and added into the powder blend prepared in Step (v), vii. Sodium Stearyl Fumarate was screened through a proper sieve and added into the powder blend prepared in Step (vi) and stirred to obtain a uniform final blend, viii. Tablet compression was performed with the final blend in Step (vii).

It was observed that the flowability of the high drug load pharmaceutical composition manufactured by using wet granulation method of the final blend was improved.

Another important analytical test to evaluate the characterization of Example-1 was in-vitro dissolution study and the dissolution conditions were designated considering the gastrointestinal pathway of orally applied dosage forms.

The dissolution study was performed under the conditions presented below:

Medium: pH 6.8 phosphate buffer

Volume of dissolution medium: 900 ml

Temperature: 37°C±0.5°C Rotation speed: 100 rpm Apparatus: Paddle Run time: 60-minute Table 5: The results of dissolution study of Example 1

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.