WO2020048641A1 - Pharmaceutical composition comprising a magnesium oxide salt complex of febuxostat and method for the preparation thereof - Google Patents

Abstract

The present invention relates to a stable pharmaceutical formulation of solid dosage forms for oral administration comprising a therapeutically effective amount of Febuxostat MgO complex to enhance API solubility. It also relates to a process for the preparation thereof

Description

PHARMACEUTICAL COMPOSITION COMPRISING A MAGNESIUM OXIDE SALT COMPLEX OF FEBUXOSTAT AND METHOD FOR THE PREPARATION THEREOF TECHNICAL FIELD OF INVENTION

The present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of a non-purine selective inhibitor of xanthine oxidase such as Febuxostat in complex with magnesium oxide (MgO) and a method for the preparation thereof.

BACKGROUND OF THE INVENTION

Uric acid is formed from the breakdown of certain chemicals (purines) in the body. Hyperuricemia occurs when the body produces more uric acid than it can eliminate. The uric acid forms crystals in joints (gouty arthritis) and tissues, causing inflammation and pain. Elevated blood uric acid levels also can cause kidney disease and kidney stones. Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine to xanthine to uric acid. Both steps in the above transformations are catalyzed by xanthine oxidase (XO). Febuxostat is a 2- arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat has been shown to inhibit both the oxidised and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism.

For many years allopurinol has been the most widely used urate-lowering agent. Febuxostat which is structurally different from allopurinol by lacking the purine ring is a more selective and potent inhibitor of XO and has no effect on other enzymes involved in purine or pyrimidine metabolism.

The chemical name of Febuxostat is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-l,3- thiazole-5 -carboxylic acid. The molecular formula is C16H16N2O3S corresponding to a molecular weight of 316.374. It is a white crystalline powder. Febuxostat is practically insoluble in water, sparingly soluble in ethanol, soluble in dimethylsulfoxide and freely soluble in dimethylformamide. Febuxostat exhibits polymorphism. The crystal forms of Febuxostat disclosed in EP 1020454, namely anhydrate A, anhydrate B, anhydrate C, hydrate G, a solvate with methanol (Form D) and anhydrated form K are the most known crystalline forms. Crystalline form A is the thermodynamically most stable form. Even though the present invention does not make use of such most stable form, it achieves enhanced stability profile through an innovative technology.

WO-A-2012/153313 discloses an immediate-release Febuxostat composition comprising an inert carrier covered with at least one layer containing Febuxostat in a micronized form, a hydrophilic polymer and, optionally, a surfactant.

WO-A-2014/125504 discloses an immediate release tablet comprising Febuxostat and an acid component in an amount of from 0.05% to 2% by weight of the tablet.

Although each of the patents above represents an attempt to provide stable Febuxostat compositions for oral administration, there still remains the need in the art for alternative formulations with enhanced dissolution and adequate chemical and physical characteristics.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide a thermodynamically stable and efficient product comprising a salt complex of a non-purine selective inhibitor of xanthine oxidase such as Febuxostat suitable for oral administration. The present invention aims at developing a formulation that not only matches the physical and chemical attributes of the reference product but also overcomes the disadvantages associated with the prior art compositions through the application of an innovative technology. A major object of the present invention is to provide a film-coated tablet comprising Febuxostat MgO complex, which is bioavailable and with sufficient self-life.

Further 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 Febuxostat MgO complex which is manufactured through a fast, simple and cost-effective process. According to another embodiment of the present invention, a process for the preparation of a solid dosage form for oral administration, containing Febuxostat as an active ingredient and an effective amount of a specific alkalizing agent in order to be formed a complex ensuring enhanced API solubility is provided, which comprises the following steps:

-Sifting and mixing the internal phase excipients;

-Kneading with water;

-Drying;

-Sizing the granules;

-Mixing with external phase excipients;

-Adding at least one lubricant and mixing;

-Compressing the resulted mixture into a tablet dosage form;

-Optionally applying a film-coating on the core.

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 Febuxostat for oral administration that is simple to manufacture, bioavailable, cost effective and possesses good pharmacotechnical properties.

Febuxostat exhibits polymorphism. Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD spectrum and IR-spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up; however, they may have distinct advantageous physical properties which can have a direct effect on the ability to process and/or manufacture the drug substance as well as on drug product stability, dissolution, and bioavailability. These distinct physical properties of different polymorphs of the same compound can render different polymorphs more or less useful for a particular purpose, such as for pharmaceutical formulation.

Febuxostat crystalline forms generally exhibit problems related to polymorphic conversion during preparation and/or typical formulation conditions and storage.

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Febuxostat belongs to class II according to the Biopharmaceutical Classification System. It is permeable but relatively insoluble, and is considered not such good clinical candidate without the use of enhanced formulation techniques aimed at increasing solubility or rate of dissolution. 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 of poorly soluble drugs 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.

Febuxostat solubility is pH dependent; in alkalic media the solubility is higher. Therefore, an alkalizing agent may enhance dissolution rate. The alkalizer is used to create a microenvironment in the formulation to optimize drug release after the formulation is in a hydrated media. The alkalizers used in the present invention are capable of raising the pH of the micro-environment of the hydrated formulation to a pH greater of the starting pH of the media. Alkalizing agents used in the present invention include, for example, magnesium oxide, dibasic calcium phosphate, tricalcium phosphate, calcium carbonate and are used in an amount 3-10% (w/w). Preferably, magnesium oxide is used in the present invention. The innovative technology as elaborated in the present invention overcomes problems associated with poor solubility of Febuxostat and instability of its crystalline forms. The formation of Febuxostat MgO complex results in the loss of the initial crystalline form that was responsible for poor API solubility. Such complex provides enhanced API solubility without compromising the stability profile of the preferred composition of the present invention.

A ratio by weight of Febuxostat base to alkalizing agent of about 3:1 gave the best results in terms of enhanced solubility. The ratio by weight of Febuxostat base to alkalizing agent can be from 4:1 to 2:1. However, only in combination with MgO was formed a stable complex according to the purposes of the present invention.

Additionally, the particle size of the API is a critical parameter that can affect the solubility of low solubility API’s such as Febuxostat. 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 of poorly soluble drugs such as Febuxostat is to increase the surface available for dissolution by reducing particle size. It has been surprisingly found that the objects of the present invention are achieved when the formulation is prepared using Febuxostat with specific particle size, in particular wherein D90<30pm.

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

EXAMPLES Febuxostat solubility is pH dependent; in alkalic media the solubility is higher. Therefore, it was decided to add an alkalizing agent into the internal phase excipients in order to enhance dissolution rate.

Table 1 : Compositions 1-4

The manufacturing process of Compositions 1-4 includes a wet granulation of internal phase ingredients. The preparation steps followed are presented below:

• Raw materials dispensing;

• Sifting the raw materials;

• Blending API with internal phase excipients and water;

• Drying the wet mass at 40°C;

• Addition of rest amount of croscarmellose sodium and aerosil;

• Lubrication with Magnesium stearate. Compositions 1-4 were tested for their dissolution rate.

Table 2: Dissolution profile of Compositions 1-4

Composition 1 with magnesium oxide as alkalizing agent gave the best dissolution profile.

Further studies revealed that the higher amount of alkalizing agent offers a faster dissolution rate at the early stages but does not improve solubility significant at the final dissolution points. Thus, the effective amount of alkalizing agent is set to be in the range of 5-10%.

In order to investigate the effect of particle size to Febuxostat solubility further evaluation was designed based on Composition 1 with API of particle size by volume of D (0, 9) = 30 mm, (Composition 1.1) D (0, 9) = 20 mm (Composition 1.2) and D (0, 9) = 5 mm (Composition 1.3). The dissolution results at buffer pH=6.0, paddles, 75rpm are shown in table 3 below:

Table 3: Dissolution profile of Compositions 1, 1.1, 1.2, 1.3

Comparing dissolution profiles of Compositions 1, 1.1, 1.2 and 1.3 it can be concluded that particle size of the active ingredient has an effect on dissolution properties and most particular on the early stages of the dissolution rate. At 30 minutes the PSD reduction enhances the dissolution rate above the target of 85% release for this time interval. Thus, the effective particle size is set to be in the range of D90: 5-30 mm.

Tablets of Composition 1 were placed in chambers under normal (25°C / 60% RH), and accelerated conditions (40°C/ 75% RH) and were examined in appropriate time points in order to control their stability.

Table 4: Stability results

X-ray powder diffraction (XRD) analysis is a rapid analytical technique primarily used for phase identification of a crystalline material and can provide information on unit cell dimensions. The X-ray diffraction pattern of the following samples was recorded to evaluate the physical form stability of Febuxostat drug substance in the preferred composition of the present invention, i.e. Composition 1.

Composition 1, Zero Time

Composition 1, 6 months under Long-term storage conditions (25°C/60% RH) Composition 1, 6 months under Accelerated storage conditions (40°C/75%

RH)

Febuxostat Crystalline Form

Febuxostat tabs, PLACEBO

Adenuric® f.c. tabs (Menarini)

Febuxostat MgO complex

The XRD pattern of aforementioned samples was recorded up to 50° diffraction angle with a scanning diffraction rate 0.05°.

The characteristic peaks on XRD graph on Febuxostat samples are summarized in Table 5 & 6.

Table 5: XRD characteristic peaks of Adenuric®, Febuxostat Crystalline Form, Placebo & Febuxostat MgO complex

Table 6: XRD characteristic peaks of Febuxostat Composition 1 Zero Time, 6 months at 25°C & 40°C.

As per XRD pattern of Composition 1, the following peaks identification may be performed:

- Peaks 3, 4A-B, 5, 6, 9 & 10 may be attributed to the XRD pattern of Placebo

- Peaks 1, 2, 7 may be attributed to the XRD pattern of Febuxostat MgO complex Furthermore, it is obvious that RLD product, Adenuric® (Menarini), exhibits a different pattern than the preferred composition of the present invention (Composition 1). Thus, the XRD patterns of Composition 1 confirm the absence of crystalline Polymorph A, which is applied in RLD product. Based on the above data, the current pharmaceutical development focused further on Febuxostat MgO complex. Thus, the same series of samples were further analyzed with an additional analytical method indicated for samples characterization, vibrational method (ATR spectroscopy & NIR spectroscopy). The enhanced in-vitro drug release profile recorded on Composition 1 with Magnesium Oxide as alkalizing agent is the result of the innovative technology presented in the present invention. More particularly, the following formulation Trials were prepared and analysed to investigate the impact of Magnesium Oxide on drug release profile of Febuxostat API. Intentionally, the requested API amount was dispensed either within the Wet granulation step or on the external phase to alter the API-Mg Oxide ratio included in the Wet granulation step along the manufacturing process of finished product. The Formulation Trials are listed in the table below along with the critical differences among the relevant formulas. Table 7: Formulation Trials of Febuxostat f.c. tabs prepared for Dissolution discriminative study.

The drug release results recorded for Formulation Trial 1C & 1B are listed below in comparison to the Formulation Trial 1.3.

Table 8: In-vitro dissolution results of Compositions 1.3, 1B, 1C.

Based on the dissolution results, it is indicated that the presence of whole API stated amount within the product granule along with magnesium oxide and water for granulation significantly impacts the in-vitro dissolution performance of Febuxostat API. More particularly, the intentional preparation of a 90% API-Magnesium salt in the Formulation Trial 1C suppressed the dissolution profile of the API. The OOS result obtained at the specification limit (Q=75% at 15 min) for both Formulation Trials 1B & 1C demonstrate the alkalizing effect of magnesium oxide. It is noticed that in the presence of water, along the granulation step, magnesium oxide adequately modifies the API poor solubility at alkali environment.

The Febuxostat complexation with Magnesium oxide in the presence of water could justify the enhanced API solubility. The vibrational spectroscopic analysis was applied as following to Febuxostat samples to figure out the API-salt formation along the manufacturing process and the stability profile of the preferred product of the present invention.

Attenuated total reflection (ATR) is a sampling technique used in conjunction with infrared spectroscopy which enables samples to be examined directly in the solid state without further preparation. ATR uses a property of total internal reflection resulting in an evanescent wave. A beam of infrared light is passed through the ATR crystal in such a way that it reflects at least once off the internal surface in contact with the sample.

The following series of samples as previously were analyzed:

Composition 1, Zero Time

Composition 1, 6 months under Long-term storage conditions (25°C/60% RH) Composition 1, 6 months under Accelerated storage conditions (40°C/75% RH)

Febuxostat Crystalline Form

Febuxostat tabs, PLACEBO

Adenuric® f.c. tabs (Menarini)

Febuxostat MgO complex

ATR spectroscopy employs a single reflection diamond element. The samples spectra were measured at 4 cm ¹ resolution as averages of 100 scans in triplicate. The 2^nd derivative of ATR spectra of samples are stated in comparative mode in Table 9. Table 9: 2^nd Derivative ATR Characteristic peaks (in cm ¹) of Febuxostat samples.

As per ATR spectra of Composition 1 & Placebo, the Febuxostat samples do not display the vibrational signature of the Febuxostat Crystalline Form neither at Zero 5 time nor at the stability phase (Long-term & accelerated storage conditions) since a few characteristic peaks have been either shifted or nearly disappeared. The same notification can be recorded for Febuxostat MgO complex. A remarkable feature of these samples is the decrease of the relative intensity (or near disappearance) of the characteristic peak at -1700 cm ¹. ATR band which is attributed definitely to the 10 carboxylic acid group (-COOH) on the thiazole ring of API molecule. The disappearance of the -1700 cm ¹ band is accompanied by the growth of ATR features at - 1580cm ¹ , and - 1410cm ¹ (Table 9). A self-consistent assignment of these spectral changes could indicate the neutralization of the carboxylic acid group of Febuxostat API and its conversion to a carboxylate salt. The neutralization of -COOH group in 15 API molecule is being performed by Mg(OH)₂ which indicates the hydrolysis of MgO upon the presence of water in the surroundings, as per Reaction 1.

20 The formation of magnesium salt has already been reported in the literature upon extended exposure of carboxylic acid group to moisture (Chow et al.20l0). All these ATR bands indicate the neutralization of the -COOH groups and the subsequent formation of Febuxostat-Magnesium salt after the wet granulation process along the manufacturing process of drug product. The bands are recorded in Febuxostat MgO complex as well and they are absent on Febuxostat Crystalline Form & Adenuric® ATR spectra.

Additionally to ATR spectroscopy, the vibrational signature of samples was recorded 5 with Near-infrared spectroscopy (NIR). NIR is a spectroscopic method that uses the near-infrared region of the electromagnetic spectrum. Similarly to ATR spectroscopy, NIR enables samples to be examined directly in the solid state without further preparation.

10 The same series of samples was analyzed for comparative reasons as well as the Febuxostat MgO complex. NIR spectra were collected by a diffuse reflectance optical fiber bundle (8cm ¹ resolution, 100 scans) in triplicate.

The samples spectra were measured at 4 cm ¹ resolution as averages of 100 scans in 15 triplicate. The 2^nd derivative of NIR spectra of samples are stated in comparative mode in Table 10 below.

Table 10: 2^nd Derivative NIR Characteristic peaks (in cm ¹) of Febuxostat samples.

20 As per NIR spectra of samples, it is noticed that the Composition 1 does not display the characteristic vibrational signature of the API Crystalline Form (eg. at 6058cm ¹, 5437cm ¹, 5033cm ¹ etc) neither at Zero time nor at the stability phase (Long-term & accelerated storage conditions). The same notice can be stated for Febuxostat MgO complex. Additionally, the reference product Adenuric® (Menarini) with Febuxostat API Form A exhibits a different vibrational signature which is primarily attributed to the API polymorph A (eg. characteristic peak at 6038cm-l).

Both vibrational spectroscopy methods of analysis (ATR & NIR) proved that Composition 1 exhibits a different vibrational signature from API Crystalline Form & Adenuric®. On the contrary, similar characteristic bands have been found in Febuxostat MgO complex on both Zero Time & stability samples. Thus, it can be stated that the API/MgO complexation takes place upon the wet granulation process on drug product manufacturing process and does not compromise the stability profile of drug product.

As per“EMA/CHMP/CVMP/QWP/284008/2015 Reflection paper on the use of cocrystals of active substances in medicinal products”, the different salt of an active substance shall be considered to be the same active substance if they contribute to improved stability, solubility profiles and/or bulk physical properties, unless they differ significantly in properties with regard to safety and/or efficacy. The bioequivalence among the preferred composition of the present invention and Adenuric® (Menarini) was proved through an open label, randomized, two-treatment, two-sequence, two-period, crossover, single-dose, oral bioequivalence study of in healthy, adult, human subjects under fasting conditions.

Overall, it can be stated that the poor solubility of Febuxostat Crystalline Form at alkali environment was successfully overcome with an alternative technology as elaborated in the present invention -API Salt formation with alkalizing agent performed along the manufacturing process of finished product- ensuring so far the in-vivo performance of Febuxostat API. Thus the pH-dependent solubility of API Crystalline Form did not impact the in-vitro & in-vivo performance of finished product. While the invention has been described with reference to various specific and preferred embodiments and examples, it should be however understood that variations and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A pharmaceutical composition for oral administration comprising a salt complex of Febuxostat with magnesium oxide.

2. The pharmaceutical composition according to claim 1, wherein the ratio by weight of Febuxostat base to magnesium oxide of said composition is about 3:1.

3. The pharmaceutical composition according to any of claims 1 or 2, wherein the salt complex is formed by wet granulating Febuxostat base and magnesium oxide.

4. The pharmaceutical composition according to any preceding claim, wherein magnesium oxide is present in an amount of 3-10% by weight.

5. The pharmaceutical composition according to any preceding claim comprising

Febuxostat base with particle size distribution by volume of D90<30mm.

6. The pharmaceutical composition according to any preceding claim, wherein it further comprises lactose, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate.

7. A process for the preparation of a pharmaceutical composition comprising a salt complex of Febuxostat with magnesium oxide, said process comprising the following steps:

-Mixing Febuxostat with magnesium oxide and any other excipient of the internal phase;

-Kneading with water;

-Drying the wet mass at 40°C;

-Sizing the granules;

-Mixing with external phase excipients;

-Adding at least one lubricant and mixing;

-Compressing the resulted mixture into a tablet dosage form;

-Optionally applying a film-coating on the core.

8. The process according to claim 7 comprising Febuxostat base with particle size distribution by volume of D90<30mm.