WO2019106692A1

WO2019106692A1 - Oral suspension of nintedanib esylate

Info

Publication number: WO2019106692A1
Application number: PCT/IN2018/050793
Authority: WO
Inventors: Bhushan JADHAV; Harshal Jahagirdar; Amol Kulkarni; Shirish Kulkarni; Rajamannar Thennati
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2017-11-29
Filing date: 2018-11-28
Publication date: 2019-06-06
Anticipated expiration: 2020-05-29

Abstract

The present invention relates to an oral suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)- methylcarbonyl)-N-methyl-amino)-anilino)-1-pheny1-methylene]-6-methoxycarbonyl-2- indolinone-monoethanesulphonate adapted for encapsulation in soft gelatin capsules.

Description

ORAL SUSPENSION OF NINTEDANIB ESYLATE

FIELD OF THE INVENTION

The present invention relates to an oral suspension of 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)- methylcarbonyl)-N-methyl-amino)-anilino)-l-phenyl-methylene]-6-methoxycarbonyl-2- indolinone-monoethanesulphonate adapted for encapsulation in soft gelatin capsules.

BACKGROUND OF THE INVENTION

Nintedanib esylate, 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)-methyl-carbonyl)-N-methyl- amino)-anilino)-l -phenyl-methylene] -6-methoxycarbonyl-2-indolinone-monoethanesulphonate, has the following formula

It is available in the form of soft gelatin capsules marketed under the trade name Ofev ^® in US and Europe. Soft gelatin capsules containing nintedanib esylate equivalent to 100 mg and 150 mg nintedanib are indicated for the treatment of idiopathic pulmonary fibrosis (IPF). Ofev ^® is a suspension of nintedanib esylate with hard fat, triglycerides, lecithin as inactive ingredient filled into soft gelatin capsules. United States Patent Publication Number US20110301177 and US20110190318 describe different types of oral dosage forms such as coated tablets, syrups, elixirs, hard gelatin capsules, emulsion, pellets, powders and suspensions. The disclosure includes lipidic suspensions that comprise medium chain triglyceride, hard fat and lecithin. Medium chain triglyceride and hard fat are hydrophobic whereas the only surfactant is lecithin. The amount of the lecithin surfactant that may be used is from 0.1 to 10% by weight and most preferably it is 0.25% to 2.5%. The present inventors, during the development of an oral dosage form of nintedanib esylate, discovered a novel oral suspension adapted for encapsulation in soft gelatin capsules, the suspension consisting of nintedanib esylate, medium chain triglyceride, surfactant having hydrophilic-lipophilic balance value in the range from 8 to 10 and a melting point in the range of 33 °C to 38 °C and lecithin. The surfactants used in the composition are thus a mixture of a surfactant having hydrophilic-lipophilic balance value in the range from 8 to 10 and a melting point in the range of 33 °C to 38 °C with lecithin. The amount of the surfactant having hydrophilic-lipophilic balance value in the range from 8 to 10 and a melting point in the range of 33 °C to 38 °C is present in an amount in the range from about 4% to 25% by weight of the suspension and the amount of lecithin is present in an amount in the range from about 0.1 to 2% by weight of the suspension. The present inventors discovered that the suspension constituting a greater percent of surfactants is suitable for encapsulation in soft gelatin capsules and when ingested orally provides desired oral bioavailability.

DESCRIPTION OF THE FIGURES

Figure 1 illustrates a graph of mean plasma concentrations of nintedanib versus time achieved when the oral suspension encapsulated in soft gelatin capsule of the present invention containing nintedanib esylate equivalent to 150 mg of nintedanib, was administered in fed states in 26 healthy subjects.

Figure 2 illustrates the dissolution profile of Nintedanib Capsules 150 mg with particle size (D₅o) of nintedanib esylate, of 4.71 microns, 15.90 microns and 30.30 microns.

DESCRIPTION OF THE INVENTION

The present invention provides an oral pharmaceutical suspension adapted for encapsulation in soft gelatin capsules, the suspension consisting of

a) particles of nintedanib esylate in an amount ranging from about 25% to 50% by weight of the suspension,

b) medium chain triglycerides in an amount ranging from about 25% to 55% by weight of the suspension, c) a surfactant having hydrophilic-lipophilic balance value ranging from 8 to 10 and a melting point in the range of 33 °C to 38 °C wherein the surfactant is a trans-esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils in an amount ranging from about 4 % to 25 % by weight of the suspension, and

d) lecithin in an amount ranging from about 0.1 % to 2 % by weight of the suspension.

Preferably, the present invention provides an oral suspension adapted for encapsulation in soft gelatin capsules, the suspension consisting of

a) particles of nintedanib esylate in an amount ranging from about 35 % to 45 % by weight of the suspension,

b) medium chain triglycerides in an amount ranging from about 30 % to 40 % by weight of the suspension,

c) a surfactant having hydrophilic-lipophilic balance value ranging from 8 to 10 and a melting point in the range of 33 °C to 38 °C wherein the surfactant is a trans-esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils in an amount ranging from about 15 % to 25% by weight of the suspension, and

d) lecithin in an amount ranging from about 0.1 % to 0.7 % by weight of the suspension.

The“term consisting of’ as used herein means that the oral suspension consists of only nintedanib esylate, medium chain triglyceride, surfactant of hydrophilic -lipophilic balance value ranging from 8 to 10 and a melting point in the range of 33 °C to 38 °C, wherein the surfactant is a trans-esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils and lecithin. In other words, the suspension is free of any other additional excipients for example hard fat or water.

The term“medium chain triglycerides” as used herein means a triglyceride of fatty acid having a carbon chain length of C₆ to Ci₂. The medium chain triglycerides preferably used in the oral suspension of the present invention are liquid at room temperature. The medium chain triglycerides used in the present invention include the triglycerides with at least one of caproic acid (C₆), caprylic acid (CH), capric acid (Cio), lauric acid (C12) or combination thereof. The medium chain triglycerides also include triglycerides with C₆ to C12 fatty acid and any other fatty acid for example long chain fatty acid like myristic acid (CM), palmitic acid (Ci₆), stearic acid (Ci₈), arachidic acid (C₂₀), oleic acid (Ci₈), linoleic acid (Ci₈) etc. Examples of the medium chain triglycerides used in the oral suspension of the present invention include but are not limited to, caprylic/capric triglycerides; caprylic/capric/linoleic triglycerides; and caprylic/capric/succinic triglycerides. Medium chain triglycerides are supplied by various manufacturers and one such manufacturer is“Peter Cremer”, who supplies various grades of medium chain triglyceride sold under the trade name, Miglyol^®. The preferred medium chain triglyceride used in the present invention is caprylic/capric triglycerides available under brand name Miglyol^® 812. Another preferred medium chain triglyceride used in the present invention is caprylic/capric triglycerides available under brand name Miglyol^® 810. Miglyol^® 810 differs from Miglyol^® 812 in the ratio of caprylic (C₈) to capric acid (Cio) ratio. The viscosity and cloud point of Miglyol^® 810 is lower than Miglyol^® 812 due to low content of capric acid (Cio). Another preferred medium chain triglyceride used in the present invention is caprylic/capric/linoleic triglycerides available under brand name Miglyol^® 818. Another preferred medium chain triglyceride used in the present invention is caprylic/capric/succinic triglycerides available under brand name Miglyol^® 829. The medium chain triglycerides used in the oral suspension of the present invention is present in an amount in the range from about 25 % to 50 % by weight of suspension, preferably 30 % to 40 % by weight of the suspension.

The oral pharmaceutical suspension of the present invention adapted for encapsulation in soft gelatin capsules consists of nintedanib esylate as the sole active ingredient. In a preferred embodiment, nintedanib esylate is 120 mg to about 180 mg per soft gelatin capsule, which corresponds to 100 mg to about 150 mg of nintedanib base. Particularly, the amount of nintedanib base in most preferred embodiment is 100 mg or 150 mg. Nintedanib esylate is present at a concentration in an amount in the range from about 25 % to 50 %, preferably 35 % to 45 % by weight of the oral suspension. Nintedanib esylate can be present as crystalline or amorphous substance, in micronized form or in unmicronized form. In one embodiment, the particle size distribution of the micronized particles of the nintedanib esylate is such that 90 % of the particles are below 80 microns, preferably below 50 microns. In another embodiment, the particle size distribution of the micronized particles of the nintedanib esylate is such that mean particle size (D₅o) ranges from about 4 microns to 100 microns, preferable from about 10 microns to 40 microns.

The surfactant used in the oral suspension of the present invention is trans-esterification products of reaction of polyalcohol with natural or hydrogenated oils have hydrophilic-lipophilic balance value in the range of about 8 to 10 and having the melting point in the range of 33 °C to 38 °C. Examples of surfactants in the oral suspension of the present invention having hydrophilic- lipophilic balance value in the range of about 8 to 10 and having the melting point in the range of 33 °C to 38 °C include, but are not limited to, oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, lauroyl polyoxyl-6 glycerides or combination thereof and is present is present in an amount in the range from about 10 % to 25 % by weight of the oral suspension. Lauroyl polyoxyl-6 glyceride is the preferred surfactant, available under brand name Labrafil^® M 2130 CS and it is present in an amount in the range from about 4 % to 25 %, preferably within 15 % to 25 % by weight of the oral suspension.

The oral suspension further consists of lecithin. Examples of the different types of lecithin used include, but are not limited to, egg lecithin, soyabean lecithin, non-genetically modified lecithin, rapeseed lecithin, sunflower lecithin, lyolecithin or combination thereof. The preferred lecithin used in the present invention is available under brand name Topcithin SB. In a preferred embodiment, the lecithin is present in an amount in the range from about 0.1 % to 2 %, preferably, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 % by weight of suspension.

The present invention provides an unexpected and significant improvement in oral bioavailability under fasted states, of nintedanib capsules 150 mg, when the mean particle size D₅O is increased. This unexpected result is contrary to the general knowledge, that when the particle size of the drug substance is reduced, it increases the oral bioavailability. The finding that when the particle size of nintedanib esylate is increased, it causes an improvement in the oral bioavailability when ingested in fasted state, is indeed very surprising. The oral suspension of the present invention, thus achieves plasma levels equivalent to the already FDA approved Ofev^® of Boehringer, both in fed as well as fasted state. The present invention also provides the effects of particle size of nintedanib esylate and concentraton of lauroyl polyoxyl-6 glycerides in the dissolution rate of suspension filled in soft gelatin capsules. The low concentration of lauroyl polyoxyl-6 glycerides has shown lower dissolution rate. The 15% to 25% concentration of lauroyl polyoxyl-6 glycerides in the composition has shown satisfactory results in dissolution, that is, at least 82% in-vitro dissolution within 10 minutes, when capsules are subjected to in-vitro dissolution test in 900 ml of 0.1N hydrochloric acid in USP-II Paddle at 100 RPM. The defined amount of lauroyl polyoxyl-6 glycerides in a composition with variable mean particle size (D₅o) of nintedanib esylate has also been studied. The mean particle size (D₅o) of nintedanib esylate less than 5 microns has shown lesser dissolution rate, while the composition with mean particle size (D₅o) of nintedanib esylate from about 10 microns to 40 microns has shown faster dissolution rate, that is, more than 80% drug release from soft gelatin capsules within 10 minutes, when subjected to in-vitro dissolution test in 900 ml of 0.1N hydrochloric acid in USP-II Paddle at 100 RPM.

The present invention also provides a process for preparing an oral suspension of nintedanib esylate adapted for encapsulation in soft gelatin capsules, the process comprising steps of:

a) mixing the surfactant having hydrophilic-lipophilic balance value in the range from 8 to 10 and a melting point in the range of 33 °C to 38 °C wherein the surfactant is a trans esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils with a part of the medium chain triglycerides to obtain a solution;

b) mixing specified amount of lecithin with another part of medium chain triglycerides and adding it to solution of step (a);

c) adding specified quantity of nintedanib esylate to solution of step (b) and homogenizing this mixture to yield a suspension;

d) mixing glycerine, gelatin, ferric oxide red, ferric oxide yellow, titanium dioxide and purified water to obtain gelatin mass for making soft gelatin capsule;

e) feeding the gelatin mass into rotary die soft gelatin capsules manufacturing machine, injecting the metered quantity of nintedanib esylate suspension of step (c) and sealing to obtain encapsulated soft gelatin capsules; and

f) optionally, lubricating the filled soft gelatin capsule with lubricant oil. The present invention also provides a process for preparing an oral suspension of nintedanib esylate adapted for encapsulation in soft gelatin capsules, the process further comprising additional steps of:

g) mixing the surfactant having hydrophilic-lipophilic balance value in the range from 8 to 10 and a melting point in the range of 33 °C to 38 °C wherein the surfactant is a trans esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils under continuous stirring until melted with a part of the medium chain triglycerides at temperature of about 40°C to 60°C;

h) mixing lecithin with another part of medium chain triglycerides under continuous stirring for 5 to 20 minutes;

i) mixing together the mass obtained in step (a) and step (b) under continuous stirring at temperature of about 35 °C to 45 °C;

j) adding nintedanib esylate to the mixture obtained in step (c) under continuous stirring for 5 to 25 minutes which is then homogenized to yield the suspension of nintedanib esylate; k) de-aerating and sieving the suspension through a suitable sieve to obtain the oral suspension ready for encapsulation into soft gelatin capsule;

l) preparing the gelatin mixture by mixing the measured quantity of glycerin (-27% by weight) and purified water in the reactor jacketed with hot water; adding gelatin (-72% by weight) into the reactor when the inlet temperature is about 50 to 75 °C, preferably at 65 °C; and mixing them until it is melted; and applying the vacuum at -550 to -700 mmHg for 90 minutes to remove the air bubbles;

m) preparing the colloidal dispersion of ferric oxide red, ferric oxide yellow and titanium dioxide with required quantity of glycerin and purified water and milling the dispersion in the colloid mill;

n) mixing the colloidal dispersion of step (g) with the gelatin mixture of step (f) in the reactor and applying the vacuum of -550 to -700 mmHg to remove the air bubbles to obtain the gelatin mass, which is then maintained at a temperature of about 50 to 75 °C, preferably at 65 °C before and during the encapsulation;

o) transferring the oral suspension of nintedanib of step (e) in the hopper of the encapsulation machine and set the fill weight; p) feeding the gelatin mass directly to the two metering box of a rotary die soft gelatin capsules manufacturing machine, which controls the flow of gelatin onto two air-cooled rotating drums, where two gelatin ribbons casts of required thickness (0.85 mm ± 5 mm); injecting the metered nintedanib esylate suspension through the leads and wedge and into the gelatin ribbons between the die rolls into die pockets where it is encapsulated, shaped, hermetically sealed and cut from the gelatin ribbon to obtain the encapsulated soft gelatin capsules;

q) checking and recording the ribbon thickness (0.85 mm ± 5 mm), fill weight, wet shell weight, seam edge thickness etc. at regular intervals;

r) passing the capsules through tumble-dryer till the capsules are substantially free from lubricant oil; and drying the soft gelatin capsules in tray dryer at temperature not more than 25 °C and relative humidity not more than 25 % till the loss on drying of gelatin shell is between 4.0 % to 9.0 % w/w, preferably 7.0 % w/w; and

s) finally subjecting the encapsulated soft gelatin capsules to inspection and quality control steps.

Hereinafter, the invention will be more specifically described with reference to examples. The examples are not intended to limit the scope of the invention and are merely used as illustrations. EXAMPLES:

Comparative Example 1 and Example 1 :

Table 1. Composition of Comparative Example 1 and Example 1

Procedure: a) A part of the triglyceride of capric acid and caprylic acid was transferred in stainless steel container and heated on water bath to a temperature of about 42°C. In case of Example 1, lauroyl polyoxyl-6 glyceride was added under stirring until it melted.

b) Lecithin was mixed with another part of triglyceride of capric acid and caprylic acid under continuous stirring for 10 minutes.

c) The mass obtained in step (a) and step (b) was mixed together under continuous stirring at temperature of 40 °C. The remaining part triglyceride of capric acid and caprylic acid was added to the mixture.

d) Nintedanib esylate 180 mg (equivalent to 150 mg nintedanib base, mean particle size D₅o of about 4.71 microns) was added to the mixture obtained in step (c) under continuous stirring which was then homogenized to yield the oral suspension.

e) The oral suspension obtained in step (d) was transferred into the hopper of an encapsulation machine (Make: Arbes tools, Model: CAP-X-8). The fill weight of 420 mg (control range ± 7.5%) and wet shell weight was checked and recorded while beginning encapsulation and then after every hour. Gelatin ribbon thickness was maintained at 0.85 mm ± 5 mm; the metering box temperature was maintained at 55 °C ± 5 °C; chilled air temperature was about 11 °C; and die roll size used was of 8 minims and of oblong shape. The seam edge thickness was checked initially and then after every 2 hours of interval. The soft gelatin capsules were passed through tumble-dryer till the capsules were substantially free from lubricant oil. f) Lastly, the soft gelatin capsules was dried in tray dryer at temperature not more than 25 °C and relative humidity not more than 25 % till the loss on drying of gelatin shell was between 4.0 % to 9.0 % w/w.

Table 2: In vitro dissolution study of capsule compositions

The filled soft gelatin capsules were subjected to in vitro dissolution in 900 ml of 0.1 N HCL for 60 minutes in USP-II Paddle (Sinker) at 100 RPM. The results are provided in Table 2 as above.

The oral suspension of the present invention showed an improved rate of dissolution compared to the suspension without any surfactant having hydrophilic -lipophilic balance value in the range from 8 to 10 and a melting point in the range of 33 °C to 38 °C wherein the surfactant is a trans esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils. The soft gelatin capsules of Example 1 were subjected to oral bioavailability determination in a fed state in human subjects. The soft gelatin capsules provided good bioavailability as illustrated by figure 1.

Effect of particle size of nintedanib esylate and concentration of lauroyl polyoxyl-6 glycerides on the in-vitro dissolution from the suspension in soft gelatin capsule:

The particle size of drug substance was controlled by high speed homogenizer. The drug substance mean particle size (D₅o) was determined for different batches. All batches

(Comparative composition 2 and 3, working example composition 2 and 3) were prepared as per the procedure of Example 1 and evaluated for effect of mean particle size (D₅o) and in-vitro dissolution percentage of the drug product. The detailed compositions and summary of response is given in Table 3 as follows.

The comparative dissolution study of different batches of nintedanib capsules 150 mg having composition as per Table 3 were undertaken as per a USFDA recommended dissolution method (that is the suspension filled soft gelatin capsules were subjected to in-vitro dissolution test in 900 ml of 0.1N hydrochloric acid in USP-II Paddle at 100 RPM). From Table 3, we observe that the concentration of lauroyl polyoxy-6 glycerides has impact on drug product properties like dissolution and content uniformity. At low concentration of lauroyl polyoxyl-6 glycerides for example 4.76% and 11.9%, the capsules exhibited a lower dissolution rate, while at 18.2% and 23.2% concentration of lauroyl polyoxyl-6 glycerides, satisfactory results were achieved for capsule dissolution. Higher concentration above 28% may pose processing issues due to high viscosity. Table 3: In vitro dissolution study of different capsule compositions

The comparative dissolution study of different batches of nintedanib capsules 150 mg having composition similar to“working example composition 2” of Table 3, with different drug substance mean particle size (D₅o of 4.71 microns, 15.90 microns and 30.30 microns) was also studied. It was observed that product composition with particle size (Dso) of 4.71 microns exhibited a lower dissolution rate and also illustrated unit to unit dosage form variation in dissolution. However, drug product composition with particle size (D₅o) of 15.9 microns to 30.30 microns exhibited a faster dissolution rate (Figure 2). Effect of particle size of nintedanib esylate on the oral bioavailabilitv when ingested in fasted state:

The comparative in-vivo bioavailability study of Comparative composition 4 and working example composition 2 of nintedanib capsules 150 mg (Test product) versus nintedanib capsule 150 mg of reference product (Ofev^® of Boehringer) following oral administration of 150 mg dose under Fed and fasted states is shown in Table 4 as follows:

Table 4: Oral bioavailability study of capsule compositions

It is observed from Table 4, there is significant improvement in bioavailability of nintedanib capsules 150 mg when the mean particle size D₅o is increased from 4.94 microns to 26.20 microns following oral administration of 150 mg dose under fasted states.

Claims

Claims:

1. An oral pharmaceutical suspension adapted for encapsulation in soft gelatin capsules, the suspension consisting of :

b) medium chain triglycerides in an amount ranging from about 25% to 55% by weight of the suspension,

c) a surfactant having hydrophilic-lipophilic balance value ranging from 8 to 10 and a melting point in the range of 33 °C to 38 °C, wherein the surfactant is a trans-esterification product of a reaction of a polyalcohol with a natural or hydrogenated oils in an amount in the range from about 4 % to 25 % by weight of the suspension, and

2. The oral suspension according to claim 1, wherein the surfactant is present in an amount ranging from about 15% to 25% by the weight of the suspension.

3. The oral suspension according to claim 1, wherein the particles of nintedanib esylate having a mean particle size (D₅o) from about 4 microns to 100 microns.

4. The oral suspension according to claim 4, wherein the particles of nintedanib esylate having mean particle size (D₅o) from about 10 microns to 40 microns.

5. The oral suspension according to claims 1 to 4, wherein the soft gelatin capsule exhibits at least 82% in-vitro dissolution within 10 minutes, when said suspension filled soft gelatin capsule was subjected to in-vitro dissolution test in 900 ml of 0.1N hydrochloric acid in USP-II Paddle at 100 RPM.

6. The oral suspension according to claim 1, wherein medium chain triglycerides are present in an amount ranging from 30% to 40% by weight of the suspension.

7. The oral suspension according to claim 1, wherein medium chain triglycerides are triglycerides of fatty acid having a carbon chain length of C₆ to C12.

8. The oral suspension according to claim 1, wherein medium chain triglycerides are selected from caproic acid, caprylic acid, capric acid, lauric acid and combinations thereof.

9. The oral suspension according to claim 1, wherein the surfactant are selected from oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, lauroyl polyoxyl-6 glycerides and combinations thereof.

10. The oral suspension according to claim 1, wherein the 150 mg nintedanib dose upon oral administration in fasted state, provides Test/Reference Ln Cmax ratio of more than 103% and Test/Reference Ln AUCo-i ratio of more than 98%.