WO2022064509A1

WO2022064509A1 - Delayed release non-aqueous suspension of posaconazole

Info

Publication number: WO2022064509A1
Application number: PCT/IN2020/050972
Authority: WO
Inventors: Vardhaman Chandrakant Bafna; Sagar Vitthalrao Punde; Mahesh Mohanrao Bhadgale
Original assignee: Kinedexe Uk Ltd
Current assignee: Kinedexe Uk Ltd
Priority date: 2020-09-28
Filing date: 2020-11-20
Publication date: 2022-03-31
Anticipated expiration: 2023-03-28

Abstract

The present invention provides a stable, delayed release non-aqueous suspension of Posaconazole, which is easy to administer and particularly beneficial for the pediatric and geriatric patients. Present invention also provides a process for preparing stable delayed release non-aqueous suspension of Posaconazole.

Description

DELAYED RELEASE NON-AQUEOUS SUSPENSION OF POSACONAZOLE

PRIORITY:

This application claims the benefit of Indian complete application number 202021042137 dated 28^th Sept. 2020 entitled, ‘Delayed release non-aqueous suspension of Posaconazole’, the contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION:

The present invention relates to a stable, delayed release non-aqueous suspension of Posaconazole, which is easy to administer and particularly beneficial for the paediatric and geriatric patients, having similar bioavailability as that of Noxafil (Posaconazole) delayed release tablets 100 mg. Present invention also relates to a process for preparing stable delayed release non-aqueous suspension of Posaconazole.

BACKGROUND OF THE INVENTION:

Posaconazole is chemically known as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro- 5-(lH-l,2,4-triazol-l-ylmethyl)-3-furanyl]methoxy]phenyl]-l piperazinyl]phenyl]-2-

[(lS,2S)-l-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one and is represented by compound of structural formula I. Posaconazole is having an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8.

Formula I

Posaconazole is an azole antifungal agent sold in USA market under trade name “NOXAFIL” and is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. U.S. Patent No. 5,661,151 discloses the Posaconazole of structural formula I and its potent antifungal activity against a broad range of fungi such as Aspergillus, Candida, Cryptococcus, Fusarium, and other opportunistic fungi.

Posaconazole is a potent broad-spectrum azole antifungal agent useful in the treatment of invasive fungal infections. Like other azole antifungal agents, Posaconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Compared to itraconazole, Posaconazole is a significantly more potent inhibitor of sterol C14 demethylation, particularly in Aspergillus. Posaconazole has a broad spectrum of activity against opportunistic fungal infections. Representative fungal agents that Posaconazole is generally potent against include Candida spp., Cryptococcus neoformans, Aspergillus spp., Rhizopus spp., Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, dermatophytes and dematiaceous fungi.

U.S. Publication No. 2007/0281011 discloses compositions comprising a nanoparticulate Posaconazole, or a salt or derivative thereof, having improved bioavailability. The said nanoparticulate composition comprises Posaconazole particles having an effective average particle size of less than about 2000 nm and can be utilized in solid or liquid dosage formulations, such as liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations which are useful in the prevention and treatment of fungal infection and related diseases.

U.S. Patent No. 8, 263,600 discloses stable, liquid suspensions containing effective amount of micronized Posaconazole, at least one thickening agent, a non-ionic surfactant, and a pharmaceutically acceptable liquid carrier, and methods of using the suspensions to treat or prevent fungal infections.

U.S. Publication No. 2015/0150990 discloses novel solid compositions comprising Posaconazole and a polymer wherein the composition has a glass transition temperature (Tg) of less than about 110° C. The application also describes solid compositions comprising Posaconazole and a polymer having a bulk density of greater than about 0.4 mg/mL, wherein polymer is selected from a hydroxypropylmethylcellulose-derivative polymer (HPMC- derivative polymer), preferably HPMC-derivative polymer to be hydroxypropylmethylcellulose acetate succinate polymer (HPMC-AS). The application also describes a novel process for preparing a solid composition comprising posaconazole dissolved or molecularly dispersed in a hydroxypropylmethylcellulose-derivative polymer by melting the admixture.

PCT Publication No. 2009/129301 discloses a solid molecularly dispersed composition comprising a poorly water soluble and weakly basic azole antifungal compound, such as Posaconazole and a pH sensitive polymer, such as hypermellose acetate succinate wherein said composition is prepared by spray-drying technique or hot-melt extrusion technique. The said composition may thus be utilized in preparation of solid dosage forms, for example, capsules, tablets, granules, powders, and unit dose packets.

PCT Publication No. 2017/025292 discloses a gastro-resistant pharmaceutical composition comprising a solid solution prepared by hot-melt extrusion, wherein the solid solution contains posaconazole, an enteric polymer and a non-enteric polymer. The composition is preferably a granulate material that can be filled into a capsule or compressed into a tablet.

Posaconazole is a white powder with a low aqueous solubility and the bioavailability of posaconazole is significantly enhanced when co-administered with food.

Posaconazole is commercially available in the USA under the trade name NOXAFIL® as a Solution; IV (Infusion) - 300 mg/16.7 ml (18 mg/ml), Suspension; Oral - 40 mg/ml and Tablet, Delayed Release; Oral - 100 mg.

Dosage information for NOXAFIL®, Solution; IV (Infusion) - 300 mg/16.7 ml (18 mg/ml) is as shown below:

Dosage information for NOXAFIL®, Suspension; Oral - 40 mg/ml is as shown below:

Dosage information for NOXAFIL®, Tablet, Delayed Release; Oral - 100 mg

As per above dosage information patient needs to take three delayed release tablets having 100 mg Posaconazole at a time to achieve required single dose of 300 mg Posaconazole, which is boredom for patients. Also in commercially available Posaconazole oral formulations, patient need to take required dose of Posaconazole during or immediately within 20 minutes after the meals, as the bioavailability of Posaconazole is significantly enhanced when co-administered with food.

Administration of existing Noxafil® (posaconazole) oral suspension 40 mg/mL results into variable & poor plasma exposure of drug especially under fasted state. Noxafil® (posaconazole) oral suspension 40 mg/mL is having significantly lower bioavailability under fasting and fed conditions & cannot be interchanged with Noxafil tablets. Thus, there is no liquid formulation available in the market which is having similar bioavailability as that of Noxafil® (posaconazole) delayed-release tablets 100 mg.

Therefore the inventors of present application developed a stable, delayed release non-aqueous suspension of Posaconazole which is having similar bioavailability with Noxafil® (posaconazole) delayed-release tablets 100 mg and can obviate prior art problems and increases patient compliance.

OBJECT OF THE INVENTION:

The object of the invention is to develop a stable, delayed release non-aqueous suspension of Posaconazole which is having similar bioavailability with Noxafil® (posaconazole) delayed- release tablets 100 mg with improved patient compliance.

SUMMARY OF THE INVENTION:

A first aspect of the present invention is to provide a stable delayed release non-aqueous suspension of Posaconazole having similar bioavailability with Noxafil® (posaconazole) delayed-release tablets 100 mg

Another aspect of the present invention is to provide a stable delayed release non-aqueous suspension of Posaconazole, wherein the composition comprises: a) an extrude or granules comprising: i. Posaconazole; and ii. release controlling polymer; b) non-aqueous vehicle; and c) Other pharmaceutically acceptable excipients.

In another aspect of the embodiment, the suspension exhibits (a) T/R ratio for AUCo-t between 80% and 125%, and (b) T/R ratio for AUCo-/, which is between 80% and 125%. b) T/R ratio for Cmax, which is between 80% and 125%.

Another aspect of the present invention is to provide a stable delayed release non-aqueous suspension of Posaconazole, wherein the composition comprises: a) an extrude or granules comprising: i. Posaconazole; and ii. release controlling polymer; b) non-aqueous vehicle; and c) Other pharmaceutically acceptable excipients selected from thickening agent, sweetening agent, opacifier, surfactant, preservatives or flavouring agent.

Another aspect of the present invention is to provide a process for the preparation of stable delayed release non-aqueous suspension of Posaconazole comprising: a) preparing an extrude or granules comprising Posaconazole and release controlling polymer by hot-melt extrusion technique; b) preparing dispersing medium with non-aqueous vehicle and other pharmaceutical acceptable excipients selected from thickening agent, sweetening agent, surfactants, opacifier, preservatives or flavouring agent; c) adding extrude or granules obtain in step-a to the dispersing medium prepared in the step-b to obtain mixture; and d) Homogenizing mixture obtain in step-c to obtain the delayed release non-aqueous suspension of Posaconazole.

Another aspect of the present invention is to provide a method for the treatment of invasive fungal infections, particularly in Aspergillus, Candida spp., Cryptococcus neoformans, Aspergillus spp., Rhizopus spp., Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, dermatophytes and dematiaceous fungi by using a stable delayed release nonaqueous suspension of Posaconazole.

DETAILED DESCRIPTION OF THE INVENTION:

The term “Delayed release” as used herein, means that the composition releases the active pharmaceutical ingredient(s) after passing through the stomach. In particular, the delayed release compositions of the present invention release the active pharmaceutical ingredient(s) in the upper tract of the intestine. Preferably, no dissolution of the composition occurs in the stomach.

The term "stable," in the context of the present invention, refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least six months to the extent necessary for the sale and use of the composition.

In one embodiment, the present invention relates to a stable delayed release non-aqueous suspension of Posaconazole.

Accordingly present invention provides a stable delayed release non-aqueous suspension of Posaconazole, wherein the composition comprises: a) an extrude or granules comprising: i. Posaconazole; and ii. release controlling polymer; b) non-aqueous vehicle; and c) other pharmaceutically acceptable excipients selected from thickening agent, sweetening agent, opacifier, surfactant, preservatives or flavouring agent.

The Posaconazole used in the present invention may be obtained by method described in U.S. Patent No. 5,661,151, which is incorporated herein by reference only.

The Posaconazole used in the present invention may have average particle size more than 2000 nm.

The concentration of Posaconazole in delayed release non-aqueous suspension composition may ranges between 5 mg/ml to 100 mg/ml.

The examples of release controlling polymer may be selected from the group consisting of enteric polymer and/or non-enteric polymer.

The examples of enteric polymer may include but not limited to hydroxypropylmethylcellulose-derivative.

The examples of hydroxypropylmethylcellulose-derivative may include but not limited to hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate or HPMCAS) and hydroxypropylmethylcellulose phthalate (HPMCP). The examples of non-enteric polymer may include but not limited to polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose and hydroxypropyl cellulose.

The enteric polymer may be present in an amount ranges between 0.5% - 40.00% w/v.

The non-enteric polymer may be present in an amount ranges between 0.001% - 10.00% w/w.

The examples of non-aqueous vehicle may include but not limited to short/medium/long chain triglycerides such as Miglyol 810/812.

The short/medium/long chain triglycerides may be present in an amount ranges between 0.05% - 60.00% w/v.

The examples of thickening agent may include but not limited to colloidal silicon dioxide, xanthan gum, sodium carboxymethyl cellulose, soya lecithin, yellow beeswax, magnesium aluminum, gaur gum, hard vegetable fats or mixture(S) thereof.

The thickening agent may be present in an amount ranges between 2% - 10.00% w/v.

The examples of sweetening agent may include but not limited to saccharine, sorbitol liquid, maltitol liquid, corn syrup, sucrose, acesulfame potassium, aspartame, sucralose, neotame or mixture(S) thereof.

The sweetening agent may be present in an amount ranges between 0.001% - 10.00% w/v or w/w.

The examples of opacifier may include but not limited to metal oxides, especially titanium dioxide.

The opacifier may be present in an amount ranges between 0.001% - 10.00% w/v.

The examples of surfactant may include but not limited to Polysorbate 80, sodium lauryl sulphate, Polyethoxylated alcohols, Polyoxyethylene sorbitan The surfactant may be present in an amount ranging between 0.5% - 3% w/v.

The examples of preservatives may include but not limited to methyl paraben, propyl paraben, sodium benzoate, sodium methyl paraben, sodium propyl paraben, sorbic acid, potassium sorbate, butylated hydroxyanisole, sodium metabisulfite or mixture(S) thereof.

The preservative may be present in an amount ranges between 0.001% - 5.00% w/v.

The examples of flavouring agent may include but not limited to peppermint oil, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, lingon berries, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia, aloe vera balsam, spearmint, eucalyptus, ethyl vanillin or combinations thereof.

The flavouring agent may be present in an amount ranges between 0.001% - 10.00% w/v.

In another embodiment, present invention provides a process for the preparation of stable delayed release non-aqueous suspension of Posaconazole comprising: a) preparing an extrude or granules comprising Posaconazole and release controlling polymer by hot-melt extrusion technique; b) preparing dispersing medium with non-aqueous vehicle and other pharmaceutical acceptable excipients selected from thickening agent, sweetening agent, surfactant opacifier, preservatives or flavouring agent; c) adding extrude or granules obtain in step-a to the dispersing medium prepared in the step-b to obtain mixture; and d) Homogenizing mixture obtain in step-c to obtain the delayed release non-aqueous suspension of Posaconazole.

The preparation of extrude or granules may involve following steps: a) sifting Posaconazole and release controlling polymer through suitable sieve, b) blending sifted Posaconazole and release controlling polymer, c) preparing solid dispersion of blend obtain in step-b using twin screw extruder, d) collecting extrude or granules from die and pass through chill rollers, e) Milling extrude or granules to obtain uniform extrude or granules with suitable particle size.

The advantages of delayed release non-aqueous suspension of Posaconazole:

1) Beneficial for the pediatric and geriatric patients.

2) Patient can take recommended Posaconazole dose any time after meal.

3) Recommended Posaconazole dose (2.5 mL i.e. 100 mg) can be interchangeable with Noxafil® (posaconazole) delayed-release tablets 100 mg

In another embodiment, the present invention provides a method for the treatment of invasive fungal infections, particularly in Aspergillus, Candida spp., Cryptococcus neoformans, Aspergillus spp., Rhizopus spp., Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, dermatophytes and dematiaceous fungi by using a stable delayed release nonaqueous suspension of Posaconazole.

The delayed release non-aqueous suspension of Posaconazole according the present invention may be orally administered to a patient having invasive fungal infections, particularly in Aspergillus, Candida spp., Cryptococcus neoformans, Aspergillus spp., Rhizopus spp., Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, dermatophytes and dematiaceous fungi.

EXAMPLES:

In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1 : Preparation of delayed release non-aqueous suspension of Posaconazole.

Table 1: The composition of delayed release non-aqueous suspension of Posaconazole 40 mg/ ml

General Manufacturing Procedure:

The manufacturing process of delayed release non-aqueous suspension mainly divided into two steps i.e. Step a) Preparation of extrude and Step b) Preparation of suspension.

Step a): Preparation of extrude:

1. Sifting: Sift dispensed quantity of Posaconazole and Hypromellose acetate Succinate and/or Hydroxypropyl Cellulose through suitable sieve.

2. Blending: Blend above sifted material.

3. Hot Melt Extrusion Process: Prepare Solid dispersion of Blend of step 2 by using twin screw extruder.

4. Collect the-extrudes from die and pass through the chill rollers.

5. Milling:

5.1 Mill the extrudes to get suitable particle size.

5.2 Blend the milled extrudes in order to achieve uniform extrudes. Weigh theoretical quantity of extrudes required for the batch.

Step b): Preparation of suspension: Mixing/Homogenization:

(i) Required quantity of Miglyol dispensed in to S.S Vessel and stirred it in order to form vortex by using Mechanical Stirrer/Mechanical Homogenizer.

(ii) Accurately weighed quantity of Colloidal Silicon Dioxide is added in to step no. (i) under stirring/Homogenizing and continued stirring/homogenization to form viscous, clear solution.

(iii) Accurately weighed quantity of Titanium Dioxide is added to step no. (ii) under stirring/Homogenizing and continued stirring/homogenization to form uniform dispersion.

(iv) Accurately weighed quantities of Peppermint oil and Butylated Hydroxyanisole are added in to step no. (iii) Under stirring/Homogenizing and continued stirring/homogenization to form uniform dispersion.

(v) Required quantity of Posaconazole: Hypromellose acetate Succinate: and/or Hydroxypropyl Cellulose extrudes were added slowly to above step no. (iv) under stirring/Homogenizing and continued stirring/homogenization to form uniform dispersion.

(vi) Final Volume made up by adding remaining quantity of Miglyol.

(vii) The above step no. (vi) is homogenized to obtain desired suspension.

Dissolution Study:

Table 2: Dissolution profile of delayed release non-aqueous suspension of Posaconazole

40 mg/ml

Example 2: The formulation from Example 1 (C) has been subjected to bioequivalent study under Fed condition and results tabulated below.

An open-label, balanced, randomized, single-dose, crossover, oral comparative bioavailability of Posaconazole Delayed Release Oral Suspension 40 mg / mL (Dose : 100 mg) (Test Product) with Noxafil® (posaconazole) delayed release tablets 100 mg (Reference Product: Merck & Co. Inc., White House Station, NJ 08889, USA) conducted in healthy, adult, human subjects under fed condition.

Table 3: T/R ratio of test product versus Noxafil Tablets under Fed Conditions

From the bioequivalence results, it is observed that the Posaconazole delayed release suspension 40mg/ml is found to be having similar bioavailability ( i.e. Cmax AUCo-t& AUCo- inf ) to that of reference product i.e. Noxafil tablets under fed state as T/R ratio for Cmax, AUCo- t& AUCo-inf lies within 80-125%.

Example 3: The formulation from Example 1 (C) has been subjected to bioequivalent study under Fasting condition and results tabulated below.

An open-label, balanced, randomized, single-dose, crossover, oral comparative bioavailability of Posaconazole Delayed Release Oral Suspension 40 mg / mL (Dose : 100 mg) (Test Product) with Noxafil® (posaconazole) delayed release tablets 100 mg (Reference Product: Merck & Co. Inc., White House Station, NJ 08889, USA) conducted in healthy, adult, human subjects under fasting condition.

Table 4: T/R ratio of test product versus Noxafil Tablets under Fasting Conditions From the bioequivalence results, it is observed that the Posaconazole delayed release suspension 40mg/ml is found to be having similar bioavailability ( i.e. Cmax, AUCo-t& AUCo- inf ) to that of reference product i.e. Noxafil tablets under fasting state as T/R ratio for Cmax, AUCO-t & AUCO-inf. Lies within 80-125%.

Example 4: Accelerated and long term stability data of the composition from Example 1 (C)

able 5: Accelerated and long term stability data of the composition from Example 1

(C)

Claims

WE CLAIM:

1. A stable delayed release non-aqueous suspension composition of Posaconazole for oral administration, wherein the composition comprises: a) an extrude or granules comprising: i. Posaconazole; and ii. release controlling polymer; b) non-aqueous vehicle; and c) other pharmaceutically acceptable excipients selected from thickening agent, sweetening agent, opacifier, preservatives or flavouring agent, wherein the suspension exhibits (a) T/R ratio for AUCo-t which is between 80% and 125%, and (b) T/R ratio for AUCo-/, which is between 80% and 125%. b) T/R ratio for Cmax, which is between 80% and 125% upon administration to a human subject in a fasting and fed state.

2. The composition as claimed in claim 1, wherein the composition is bioequivalent to that of Posaconazole delayed release tablets 100 mg.

3. The composition as claimed in claim 1, wherein Posaconazole is having average particle size more than 2000 nm.

4. The composition as claimed in claim 1, wherein Posaconazole is present in a concentration from the range between 5 mg/ml to 100 mg/ml.

5. The composition as claimed in claim 1, wherein the release controlling polymer is enteric polymer or non-enteric polymer or a mixture thereof.

6. The composition as claimed in claim 4, wherein the enteric polymer is hydroxypropylmethylcellulose-derivative selected from hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate or HPMCAS) and hydroxypropylmethylcellulose phthalate (HPMCP) in an amount ranges between 0.5% - 40.00% w/v. The composition as claimed in claim 4, wherein the non-enteric polymer such as polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose and hydroxypropyl cellulose in an amount ranges between 0.001% - 10.00% w/w. The composition as claimed in claim 1, wherein the non-aqueous vehicle is selected from short/medium/long chain triglycerides such as Miglyol 810/812 in an amount ranges between 0.05% - 60.00% w/v; or mixture thereof. The composition as claimed in claim 1, wherein the thickening agent is selected from the group consisting of colloidal silicon dioxide, xanthan gum, sodium carboxymethyl cellulose, soya lecithin, yellow beeswax, magnesium aluminum, gaur gum, hard vegetable fats or mixture(S) thereof in an amount ranges between 2% - 10.00% w/v.