Patent Application
20250099451
The present invention relates to a pharmaceutical composition for oral administration, particularly in the form of a tablet, or a powder suitable to be filled into a capsule shell, comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)-piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
The compound 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) and derivatives thereof have been disclosed in WO 2018/115591. Compound of formula (I) is a selective inhibitor of CYP11A1 enzyme and is useful in the treatment of hormonally regulated diseases such as cancer including prostate cancer and breast cancer.
Compound (I) and pharmaceutically acceptable salts thereof have been found to be suitable for oral administration. However, when formulated together with carriers and excipients for the development of solid oral compositions, such as tablets and capsules, the active ingredient was found to be prone to stability issues. The suitable amount of the active ingredient in the solid oral compositions for the treatment of human patients was also found to be exceptionally small, generally from about 0.5 mg to about 10 mg, typically from about 1 mg to about 8 mg. Therefore, the percentage of the active ingredient in a tablet composition remains low as the tablet should not be too small making it difficult to handle by the patient.
The present invention provides a pharmaceutical composition for oral administration, particularly in the form of a tablet, or a powder suitable to be filled into a capsule shell, comprising compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. It has been found that the use of wet granulation, high intragranular drug load, neutral or slightly acidic pharmaceutical ingredients and/or inclusion of oxygen scavengers provide improved stability of the active ingredient. Moreover, it was found that the amount of the active ingredient sufficient in the composition for the treatment of human patients is exceptionally small. The composition provides good dose content uniformity and efficient release of the active ingredient and constant dissolution properties producing effective and reproducible in vivo plasma concentrations. Therefore, the composition according to the invention is particularly suitable as a dosage form for the treatment of patients suffering from hormonally regulated diseases where CYP11A1 inhibition is desired, such as prostate cancer and breast cancer.
Thus, according to one embodiment, the present invention discloses a wet granulated pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof and at least one excipient.
According to another embodiment, the present invention provides a pharmaceutical composition comprising
According to still another embodiment, the present invention provides a package comprising a pharmaceutical composition comprising 2-(isoindolin-2-yl-methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof and at least one excipient, the package also comprising an oxygen scavenger.
The present invention relates to a pharmaceutical composition for oral administration, particularly in the form of a tablet, or a powder suitable to be filled into a capsule, comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)-piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Compound of formula (I) or a pharmaceutically acceptable salt thereof may be in amorphous or crystalline state. Suitable pharmaceutically acceptable salts of compound (I) are salts with organic or inorganic acids including salts with p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, hydrobromic acid, nitric acid, benzenesulfonic acid, hydrochloric acid, maleic acid, 1,2-ethanedisulfonic acid, oxalic acid, ethanesulfonic acid, sulfuric acid and methanesulfonic acid. One particular embodiment of the invention is salts with p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid and hydrobromic acid. Another particular embodiment of the invention is a salt with p-toluenesulfonic acid.
In accordance with one embodiment of the present invention, there is provided a wet granulated pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof and at least one excipient. Wet granulation has been found to protect compound (I) or a pharmaceutically acceptable salt thereof from degradation during manufacture and/or storage of the dosage form, such as tablets and powders, and tablets in particular.
According to another embodiment, the present invention provides a pharmaceutical composition comprising
According to another embodiment, the present invention provides a package comprising a pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof and at least one excipient, the package also comprising an oxygen scavenger. An oxygen scavenger has been found to improve the stability of the dosage form by preventing or inhibiting degradation of the active ingredient during the storage of the dosage form.
In a subclass of any of the above embodiments are compositions comprising an intragranular part which comprises at least about 5%, for example from about 5% to about 20%, from about 5% to about 15%, or from about 5% to about 12%, per weight of the intragranular part, of 2-(isoindolin-2-ylmethyl)-5-((1-(methyl-sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, and at least one excipient.
In a subclass of the above embodiment are pharmaceutical compositions which comprise
In a subclass of any of the above embodiments are pharmaceutical compositions comprising from about 0.5 mg to about 10 mg, for example from about 1 mg to about 8 mg, for example about 2.5 mg, about 3.5 mg, about 5 mg or about 7.1 mg, of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof.
High drug load in the intragranular part has been found to improve the stability of compound of formula (I) or a pharmaceutically acceptable salt thereof. Thus, even if the suitable amount of compound of formula (I) or a pharmaceutically acceptable salt thereof in the dosage form is small, it is preferred to maintain high drug load in the intragranular part in order to improve stability of the dosage form during manufacture and/or storage.
In a subclass of any of the above embodiments are pharmaceutical compositions comprising
As used herein, a “filler” refers to one or more pharmaceutically acceptable excipient(s) that adds bulkiness to a pharmaceutical composition. Examples of fillers include sugars (e.g., mannitol or sucrose), starch, pregelatinized starch, microcrystalline cellulose, lactose, calcium hydrogen phosphate and sorbitol. According to one embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, calcium hydrogen phosphate and a combination thereof. According to another embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, and a combinations thereof.
The term “calcium hydrogen phosphate” or “dicalcium phosphate”, as used herein, includes anhydrous calcium hydrogen phosphate and hydrates such as calcium hydrogen phosphate dihydrate.
As used herein, a “disintegrant” refers to one or more pharmaceutically acceptable excipient(s) which is added to the pharmaceutical composition to cause its disintegration to support the release of the active ingredient from the pharmaceutical composition. Examples of disintegrants include croscarmellose sodium, cross-linked polyvinylpyrrolidone and sodium starch glycolate. According to one embodiment, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate and a combination thereof. According to another embodiment, the disintegrant is croscarmellose sodium.
As used herein, a “binder” refers to one or more pharmaceutically acceptable excipient(s) that imparts enhanced cohesion by binding the active ingredient and the excipients together in a mixture. Examples of binders include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl acetate and polyvinyl alcohol. According to one embodiment, the binder is selected from hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and a combination thereof. According to another preferred embodiment, the binder is hydroxypropylmethyl cellulose (HPMC). According to still another embodiment, the binder is hydroxypropylmethyl cellulose (HPMC) and the disintegrant is croscarmellose sodium.
As used herein, a “lubricant” refers to one or more pharmaceutically acceptable excipient(s), which is added to the pharmaceutical composition to reduce friction, heat, and wear when introduced between solid surfaces. Examples of lubricants include sodium stearyl fumarate, magnesium stearate, stearic acid, talc, silica, calcium stearate and carnauba wax. According to one embodiment, the lubricant is sodium stearyl fumarate.
In a subclass of any of the above embodiments are pharmaceutical compositions comprising
In a subclass of any of the above embodiments are pharmaceutical compositions comprising
In a subclass of any of the above embodiments are pharmaceutical compositions, wherein the intragranular part comprises, from about 30% to about 95%, for example from about 50% to about 90% or from about 70% to about 85%, per weight of the composition.
It has been found that fine particles of the compound of formula (I) or a pharmaceutically acceptable salt thereof provide better dissolution rate and content uniformity than coarse particles.
Thus, for the manufacture of the pharmaceutical composition, compound of formula (I) or a pharmaceutically acceptable salt thereof, for example p-toluene-sulfonic acid salt, is suitably milled. In various embodiments, the milled compound has a particle size having the volume median diameter (Dv50) of not more than 50 μm, not more than 30 μm, or not more than 25 μm. For example, Dv50 may be in the range of 1-25 μm, between 2-20 μm, or between 5-15 μm. The particle size distribution can be analyzed by laser light diffraction, for example using Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with Tornado Dry Powder System using air as dispersion medium with measurement pressure 24″H2O±2″H2O, sample amount 10 ml, system controlled target 5% for obscuration and applying Fraunhofer optical model.
Milling of the active ingredient can be carried out using suitable feeder and milling equipment, for example, single or twin screw/auger feeders, hammer mills, pin mills, jet mills or sieve mills, using suitable rotor speeds such as, for example 3000-10000 rpm. The milling can be conducted in a suitable temperature, for example, in room temperature or lower.
Thus, in a further subclass of any of the above embodiments is a pharmaceutical composition wherein the composition provides a dissolution of at least 80% per weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof within 60 minutes, preferably within 45 minutes, in 0.05 M phosphate buffer pH 6.8 using paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37° C. and vessel volume of 500 ml. In one embodiment, the active ingredient is a p-toluene-sulfonic acid salt of compound (I) wherein the pharmaceutical composition provides dissolution of at least 80% per weight of p-toluenesulfonic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) within 60 minutes, or within 45 minutes, in 0.05 M phosphate buffer pH 6.8 using paddle apparatus (USP apparatus 2) with paddle speed of 75 rpm at 37° C. and vessel volume of 500 ml.
In a further subclass of any of the above embodiments is a pharmaceutical composition which is in the form of a coated or uncoated tablet. According to another subclass of any of the above embodiments, the pharmaceutical composition is in the form of a powder, including granules, which may be suitable to be filled into a capsule shell.
Thus, the term “powder”, as used herein, refers to powdery material such as milled powder or granules.
In a further subclass of any of the above embodiments is a pharmaceutical composition which is prepared by a method comprising wet granulation.
It is to be understood that when the composition is in the form of a powder, including granules, the component percentages above refer to the powder pharmaceutical composition without the capsule shell.
The compositions are suitably prepared by wet granulation as wet granulation has been found to protect compound of formula (I) or a pharmaceutically acceptable salt thereof from degradation during manufacture and/or storage of the dosage form.
Thus, in accordance with one embodiment of the invention the process for manufacturing a pharmaceutical composition according to any of the above embodiments is characterized by the steps of (a) mixing compound of formula (I) or a pharmaceutically acceptable salt thereof and other intragranular components in a suitable mixer; (b) granulating the mixture by spraying granulating liquid, for example water, into the mixture; (c) drying the wet granules; (d) mixing the extragranular components with the dried granules; and, in case the composition is a tablet, (e) compressing the obtained mixture into tablets. In case the composition is a powder, the mixture of step (d) can be filled directly into a capsule shell.
In accordance with another embodiment of the invention the process for manufacturing a pharmaceutical composition according to any of the above embodiment is characterized by the steps of (a) mixing compound of formula (I) or a pharmaceutically acceptable salt thereof and other intragranular components except at least part of the binder in a suitable mixer; (b) granulating the mixture by spraying combination of granulating liquid, for example water, and at least part of the binder into the mixture; (c) drying the wet granules; (d) mixing the extragranular components with the dried granules; and, in case the composition is a tablet, (e) compressing the obtained mixture into tablets. In case the composition is a powder, the mixture of step (d) can be filled directly into a capsule shell.
According to another embodiment, all components are blended together and filled into a capsule shell without granulation step.
According to one embodiment, the composition of the invention is suitably manufactured, for example, by first mixing compound of formula (I) or a pharmaceutically acceptable salt thereof, filler, binder and at least part of the disintegrant (typically from about 30% to about 70%, for example about 50%, per weight, of the total) in a suitable granulator vessel, for example wet high shear granulator. The mixture is then suitably granulated in the granulator using purified water as granulating liquid. Alternatively, the binder can be mixed with the granulation liquid instead of mixing the binder with other intragranular components in the first step. The wet granules can then be screened, for example, using a screening mill unit (rotating impeller) and subsequently dried, for example, in a fluid bed dryer.
The dried granules may then be screened with a screening apparatus, for example a screening mill. When the composition is a powder to be filled into a capsule shell, the extragranular filler and optional other ingredients are mixed with the granules. The obtained powder can then be filled into a capsule shell, for example a gelatin capsule shell or a HPMC capsule shell. When the composition is a tablet, the extragranular filler and the possible rest of the disintegrant may be added to the granules followed by blending the mixture in, for example, a diffusion mixer. The lubricant is added to the mass of the previous step followed by blending. The tablet mass is then compressed into tablet cores, for example, in a power assisted rotary tablet press.
The tablet cores can be provided with a water-soluble film coating, if desired, to facilitate tablet swallowing, to protect from direct contact with the drug substance and to improve aesthetics. A suitable film coating agent may be selected from the group consisting of plasticizers, film-forming agents, surfactants, colorants and flavouring agents. Optionally an anti-tacking agent, glidant or opacifier may be used. A plasticizer, such as polyethylene glycol (PEG) or glycerol, a film-forming agent such as hydroxypropylmethyl cellulose (HPMC), a colorant, such as ferric oxide or titanium dioxide, a glidant such as talc or magnesium stearate, and a flavouring agent such as polydextrose or sucrose, may be combined with a film-coating liquid, preferably water, to result in a homogeneous coating suspension which is brought up, preferably sprayed, on the tablets in a suitable coating device, such as for example a perforated drum coater. The film coating typically amounts to from about 2% to about 5%, for example from about 2.5% to about 4%, per weight of the tablet composition.
The unit dose tablet or unit dose powder to be filled into a capsule shell typically contains from about 0.5 mg to about 10 mg, for example from about 1 mg to about 8 mg, for example about 2.5 mg, about 3.5 mg, about 5.0 mg or about 7.1 mg, of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, for example, a salt of p-toluenesulfonic acid. The unit dose tablet or unit dose powder typically has the weight from about 50 mg to about 100 mg, for example from about 70 mg to about 90 mg. The tablet may have, for example, oval or round shape and have a diameter typically from about 4 mm to about 8 mm, for example from about 5 mm to about 7 mm, for example 6 mm.
The tablets or capsules can be packaged in conventional pharmaceutical containers such as bottles or blisters, for example HDPE bottles or aluminium foiled PET blister packs. An oxygen scavenger has been found to improve the stability of the dosage form by preventing or inhibiting degradation of the active ingredient during storage of the dosage form. Therefore, the container may contain an oxygen scavenger. The term “oxygen scavenger” refers to material which consume, deplete or reduce the amount of oxygen from a given environment. Examples of oxygen scavenger materials comprise transition metals or salts thereof including, but not limited to, manganese II or III, iron II or III, cobalt II or III, nickel II or III, copper I or II, rhodium II, III or IV, and ruthenium, and non-metallic materials such as ascorbic acid and salts thereof, ethylene glycol, propylene glycol, glyceric acid, gallic acid, catechol, unsaturated hydrocarbons and hydrogenated rubbers. Small canisters containing oxygen scavenger material are commercially available, for example PharmaKeep® CD Canisters from Airnov Healthcare Packaging and StabilOx® Canisters from Multisorb Filtration Group. Such canister can be included in the pharmaceutical container such as plastic bottle together with tablets or capsules.
Compound of formula (I) or a pharmaceutically acceptable salt thereof is suitably administered, for example for the treatment of hormone dependent cancers, for example prostate cancer, in an amount ranging from about 0.5 mg to about 30 mg, or from about 1 mg to about 25 mg, for example from about 2 mg to about 15 mg, such as about 5 mg or about 7 mg per day to the patient. The dose can be administered once daily or divided to several times a day, for example twice daily.
The invention is further illustrated by the following examples.
a) Contains HPMC, TiO2, talc, polydextrose and PEG 3350
a) Contains HPMC, TiO2, talc, polydextrose and PEG 3350
a) Contains HPMC, TiO2, sucrose, magnesium stearate, polysorbate 80 and glycerol
The tablet compositions of Examples 1 to 3 are prepared by mixing the intragranular components in a high-shear mixer. The mixture is granulated by spraying water into the mixture. The granules are dried in a fluid-bed dryer and screened with a conical mill. Extragranular components are added, and the blend is compressed into tablets with a tablet press. Finally, the tablets are coated by spraying the coating suspension on the tablet cores in a heated pan coater until the theoretical weight gain in tablets is reached.
The tablet compositions of Examples 4 to 12 are prepared by mixing the intragranular components in a high-shear mixer. The mixture is granulated by spraying water into the mixture. The granules are dried in a fluid-bed dryer and screened with a conical mill. Extragranular components are added, and the blend is compressed into tablets with a tablet press.
The powder compositions of Examples 13 and 14 are prepared by mixing the intragranular components in a high-shear mixer. The mixture is granulated by spraying water into the mixture. The granules are dried in a fluid-bed dryer and screened with a conical mill. Extragranular components are added followed by blending. The blend is filled into capsule shells.
Various wet granulated (WG) tablet compositions WG1 to WG9 were prepared using the method as described for Examples 4-12. The stability of the compositions was tested by storing the tablets in 60° C./75% RH conditions for 4 weeks. The formulation descriptions and total amount of formed impurities after 4 weeks are given in the Table 1. The quantitative compositions of the formulations are presented in Table 2. The formulations WG6 to WG8 did not contain any extragranular components and suffered from poor tablet quality. It can be seen that croscarmellose sodium appears to improve stability in HPMC containing compositions.
The stability of a wet granulated (WG) tablet according to Example 3 (without film coating) and a corresponding direct compressed (DC) tablet having an equivalent quantitative composition was studied. Other direct compressed tablets were also prepared for the study. The stability of the compositions was tested by storing the tablets in 60° C./75% RH conditions for 4 weeks. The formulation descriptions and total amount of formed impurities after 4 weeks are given in the Table 3. The actual compositions of direct compressed formulations DC1 to DC4 are presented in Table 4. It can be seen that wet granulated composition has better stability than corresponding direct compressed composition.
The direct compressed tablets were prepared by blending the components together and compressing the mixture into tablets with a tablet press.
The stability of wet granulated (WG) tablets WG11 to WG15 was studied. The tablets were prepared using the method as described for Examples 4-12. The stability of the tablets was tested by storing 65 tablets in closed 60 ml or 100 ml HDPE bottle with 2 g of silica desiccant in 40° C./75% RH conditions for 6 months. The formulation descriptions are given in Table 5 and total amounts of formed impurities after 6 months and the intragranular drug load are given in Table 6. The results show that high intragranular drug load improves stability in wet granulated compositions.
The effect of oxygen scavenger on the stability of the tablets WG 14 and WG 15 (see Example 17) was studied. The stability of the tablets was tested by storing 65 tablets in closed 60 ml HDPE bottle with 2 g of silica desiccant in 40° C./75% RH conditions for 6 months. The stability was tested with or without oxygen scavenger canisters (PharmaKeep® Capsule CD-2.15G, Airnov Healthcare Packaging for WG14 and StabilOx®, Multisorb Filtration Group for WG 15) inside the bottle. The results are shown in Table 7. The results show that inclusion of an oxygen scavenger improved stability of the composition.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20225044 | Jan 2022 | FI | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FI2023/050043 | 1/19/2023 | WO |
