Patent Application
20170296570
The present invention relates to a high drug load tablet comprising a polymorphic form of sofosbuvir which is stable when exposed to moisture, and a process for the preparation of the tablet. Further, the present invention relates to the use of the tablet for the treatment of hepatitis C. Yet further, the present invention relates to the use of a polymorphic form of sofosbuvir which is stable when exposed to moisture for the preparation of a high drug load tablet.
Sofosbuvir according to formula (I)
with IUPAC name (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-amino)propanoate is a drug inhibiting the RNA polymerase used by the hepatitis C virus to replicate its RNA.
In WO 2010/135569 A, sofosbuvir is described as a moisture instable compound. In particular, it was found that under stress conditions at 40° C. and a relative humidity (RH) of 75%, sofosbuvir deliquesces after a few hours. WO 2013/082003 A describes compositions comprising sofosbuvir. Among other, capsules and tablets are disclosed.
Generally, a sufficiently fast and complete dissolution of such compositions is desired to allow for a sufficient bioavailability of the sofosbuvir. Tablets exhibiting such dissolution after 15 minutes are described in WO 2013/082003 A. These tablets contain polymorphic form 1 of sofosbuvir in an amount of 33.33 weight-%. According to the general description of WO 2013/082003 A, the maximum content of pharmaceutical compositions comprising sofosbuvir is disclosed to be 35 weight-%, and at least 65 weight-% of the tablets consist of pharmaceutically acceptable excipients.
Therefore, due to this high amount of excipients according to this teaching of the prior art, comparatively large tablets have to be prepared for administering the desired amount of sofosbuvir to a patient in need thereof, and swallowing such large tablets is uncomfortable for the patient.
Thus, an object of the present invention was the provision of tablets comprising sofosbuvir and exhibiting a sufficiently fast and complete dissolution, avoiding the disadvantages of the tablets disclosed in the prior art.
Surprisingly, although WO 2013/082003 A, on page 23, line 27, explicitly teaches that with regard to tablets, already a sofosbuvir content of 33 weight-% has to be considered as a relatively high content, it was found that tablets comprising sofosbuvir can be provided having a very high drug load when a specific polymorphic form of sofosbuvir is used. Specifically, it was found that contrary to the teaching of WO 2013/082003 A, tablets having a significantly higher sofosbuvir content can be prepared using a polymorphic form of sofosbuvir which has a specific moisture stability.
Further it has surprisingly been found that tablets comprising polymorphic form 7 of sofosbuvir of formula (I) in an amount of at least 25 weight-% have a good dissolution profile.
Therefore, the present invention relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure.
Preferably, the polymorphic form of sofosbuvir comprised in the tablet is substantially free of its corresponding phosphorous-5 based diastereomer (S)-isopropyl 2-(((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate. Preferably, the polymorphic form of sofosbuvir comprised in the tablet is at least 95% free from its corresponding phosphorous-based diastereomer. More preferably, the polymorphic form of sofosbuvir comprised in the tablet is at least 97% free from its corresponding phosphorous-based diastereomer. More preferably, the polymorphic form of sofosbuvir comprised in the tablet is at least 99% free from its corresponding phosphorous-based diastereomer. More preferably, the polymorphic form of sofosbuvir comprised in the tablet is at least 99.5% free from its corresponding phos-phorous-based diastereomer. More preferably, the polymorphic form of sofosbuvir comprised in the tablet is at least 99.9% free from its corresponding phosphorous-based diastereomer.
While tablets comprising the polymorphic form of sofosbuvir in an amount in the range of at least 36 weight-% or at least 37 weight-% or at least 38 weight-% or at least 39 weight-% are not excluded from the present invention, the preferred content is at least 40 weight-%. More preferably, the tablet comprises the polymorphic form in an amount in the range of from 40 to 95 weight-%, more preferably from 40 to 90 weight-%, more preferably from 45 to 90 weight-%, more preferably from 45 to 85 weight-%, more preferably from 45 to 80 weight-%, more preferably from 50 to 80 weight-%, based on the total weight of the tablet. More preferably, the tablet comprises the polymorphic form in an amount of from 50 to 75 weight-% based on the total weight of the tablet. Preferred ranges include, for example, a range of from 50 to 60 weight-% or a range of from 55 to 65 weight-% or a range of from 60 to 70 weight-% or a range of from 65 to 75 weight-%. More preferably, the tablet comprises the polymorphic form in an amount of ≧75 weight-% based on the total weight of the tablet. Preferred ranges include, for example, a range of from 75 to 90 weight-% or a range of from 75 to 85 weight-%, or a range of from 75 to 80 weight-% or a range of from 80 to 90 weight-% or a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferred content of the tablet comprising the polymorphic form 6 of sofosbuvir is of at least 40 weight-%. More preferably, the tablet comprises the polymorphic form 6 in an amount in the range of from 40 to 95 weight-%, more preferably from 40 to 90 weight-%, more preferably from 45 to 90 weight-%, more preferably from 45 to 85 weight-%, more preferably from 45 to 80 weight-%, more preferably from 50 to 80 weight-%, based on the total weight of the tablet. More preferably, the tablet comprises the polymorphic form 6 in an amount of from 50 to 75 weight-% based on the total weight of the tablet. Preferred ranges include, for example, a range of from 50 to 60 weight-% or a range of from 55 to 65 weight-% or a range of from 60 to 70 weight-% or a range of from 65 to 75 weight-%. More preferably, the tablet comprises the polymorphic form 6 in an amount of ≧75 weight-% based on the total weight of the tablet. Preferred ranges include, for example, a range of from 75 to 90 weight-% or a range of from 75 to 85 weight-%, or a range of from 75 to 80 weight-% or a range of from 80 to 90 weight-% or a range of from 85 to 90 weight-% based on the total weight of the tablet.
Tablets comprising the polymorphic form 7 of sofosbuvir as defined according to the present invention in an amount in the range of at least 25 weight-%, at least 30 weight-%, at least 35 weight-%, or at least 36 weight-% or at least 37 weight-% or at least 38 weight-% or at least 39 weight-% are embodiments of the present invention. Preferred content of the tablet comprising the polymorphic form 7 of sofosbuvir is at least 40 weight-%. More preferably, the tablet comprises the polymorphic form 7 in an amount in the range of from 40 to 95 weight-%, more preferably from 40 to 90 weight-%, more preferably from 45 to 90 weight-%, more preferably from 45 to 85 weight-%, more preferably from 45 to 80 weight-%, more preferably from 50 to 80 weight-%, based on the total weight of the tablet. More preferably, the tablet comprises the polymorphic form 7 in an amount of from 50 to 75 weight-% based on the total weight of the tablet. Preferred ranges include, for example, a range of from 50 to 60 weight-% or a range of from 55 to 65 weight-% or a range of from 60 to 70 weight-% or a range of from 65 to 75 weight-%. More preferably, the tablet comprises the polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet. Preferred ranges include, for example, a range of from 75 to 90 weight-% or a range of from 75 to 85 weight-%, or a range of from 75 to 80 weight-% or a range of from 80 to 90 weight-% or a range of from 85 to 90 weight-% based on the total weight of the tablet.
Even more precisely, the moisture stability of the polymorphic form is defined as the amount in mg of the polymorphic form which is present after an exposure of an amount of 30 mg of the polymorphic form to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours in a humidity chamber, relative to the amount of 30 mg of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm of the polymorphic form before the exposure and via said X-ray powder diffraction pattern analysis after the exposure.
Preferably, the polymorphic form has a moisture stability of at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%. For example, the polymorphic form has a moisture stability of 100%. For example, a moisture stability of 100% relates to a polymorphic form which, after having been exposed to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours as described above, is not present in another polymorphic form and/or is not present in amorphous form and/or has not deliquesced.
Generally, no specific restrictions exists how a polymorphic form exhibiting the moisture stability as defined above is provided or prepared. Preferably, the polymorphic form is obtainable or obtained by a process comprising crystallization of the polymorphic form in the presence of at least one organic solvent and preferably at least one organic anti-solvent. Generally, the polymorphic form, after having been crystallized and when being used as starting material for the preparation of the tablet, may or may not contain at least traces of the at least one organic solvent. Therefore, the tablet of the present invention may comprise the at least one organic solvent which is contained in the polymorphic form due to its crystallization in this at least one organic solvent. Further, it is also possible that the polymorphic form, after having been crystallized and when being used as starting material for the preparation of the tablet, does not contain any more the at least one organic solvent in which the polymorphic form has been crystallized. In such a case, it is possible that the tablet of the present invention contains the at least one organic solvent in which the polymorphic form has been crystallized, or at least one other suitable organic solvent, wherein this organic solvent is used as starting material for the preparation tablet in addition to the polymorphic form.
Generally, the tablet of the invention comprises the at least one organic solvent in small amounts, preferably in amount of at most 1 weight-%, more preferably at most 0.9 weight-%, more preferably at most 0.8 weight-%, more preferably at most 0.7 weight-%, more preferably at most 0.6 weight-%, more preferably at most 0.5 weight-%, more preferably at most 0.4 weight-%, based on the total weight of the tablet. More preferably, the tablet comprises the at least one organic solvent in an amount in the range of from 0.002 to 0.3 weight-%, more preferably of from 0.005 to 0.2 weight-%, more preferably from 0.01 to 0.1 weight-%, based on the total weight of the tablet. If the at least one organic solvent consists of two or more organic solvents, the amounts mentioned above are to be understood as referring the total amount of all organic solvents.
Preferably, the at least one organic solvent comprises an aliphatic alcohol, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, n-butanol, or a mixture of two or more thereof. More preferably, the at least one organic solvent comprises ethanol or n-butanol. More preferably, the at least one organic solvent is ethanol or n-butanol.
Generally, the polymorphic form exhibiting the moisture stability as defined above can be obtainable or obtained by a process comprising crystallization of the polymorphic form in the presence of at least one organic anti-solvent, in addition to the at least one organic solvent. Generally, the polymorphic form, after having been crystallized and when being used as starting material for the preparation of the tablet, may or may not contain at least traces of the at least one organic anti-solvent. Therefore, the tablet of the present invention may comprise the at least one organic anti-solvent which is contained in the polymorphic form due to its crystallization in this at least one organic anti-solvent. Further, it is also possible that the polymorphic form, after having been crystallized and when being used as starting material for the preparation of the tablet, does not contain any more the at least one organic anti-solvent in which the polymorphic form has been crystallized. In such a case, it is possible that the tablet of the present invention contains the at least one organic anti-solvent in which the polymorphic form has been crystallized, or at least one other suitable organic anti-solvent, wherein this organic anti-solvent is used as starting material for the preparation tablet in addition to the polymorphic form.
Generally, the tablet of the invention comprises the at least one organic anti-solvent in small amounts, preferably in amount of at most 0.5 weight-%, more preferably at most 0.4 weight-%, more preferably at most 0.3 weight-%, more preferably at most 0.2 weight-%, more preferably at most 0.1 weight-%, more preferably at most 0.09 weight-%, more preferably at most 0.08 weight-%, more preferably at most 0.07 weight-%, more preferably at most 0.06 weight-%, based on the total weight of the tablet. More preferably, the tablet comprises the at least one organic anti-solvent in an amount in the range of from 0.0002 to 0.05 weight-%, more preferably of from 0.0005 to 0.03 weight-%, more preferably of from 0.001 to 0.01 weight-%, based on the total weight of the tablet. If the at least one organic anti-solvent consists of two or more organic anti-solvents, the amounts mentioned above are to be understood as referring the total amount of all organic anti-solvents.
Preferably, the at least one organic anti-solvent comprises an alkane, preferably a C5 alkane, a C6 alkane, a C7 alkane, a C8 alkane, or a mixture of two or more thereof, more preferably a C7 alkane. More preferably, the at least one organic anti-solvent comprises n-heptane. More preferably, the at least one organic anti-solvent is n-heptane.
According to a conceivable embodiment, the present invention relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, preferably from 40 to 90 weight-%, more preferably from 45 to 80 weight-%, more preferably from 50 to 75 weight-% or in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet, wherein the polymorphic form is obtainable or obtained by a process comprising crystallization of the polymorphic form in the presence of at least one organic solvent and optionally at least one organic anti-solvent, wherein the tablet may further comprise at least one organic solvent, preferably the at least one organic solvent as described above, preferably in the amounts as described above, wherein the tablet optionally further comprises at least one organic anti-solvent as described above, preferably in the amounts as described above.
According to a conceivable embodiment, the present invention relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, preferably from 40 to 90 weight-%, more preferably from 45 to 80 weight-%, more preferably from 50 to 75 weight-% or in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-%, based on the total weight of the tablet, wherein the tablet further comprises at least one organic solvent, preferably the at least one organic solvent as described above, preferably in the amounts as described above, wherein the tablet optionally further comprises at least one organic anti-solvent as described above, preferably in the amounts as described above.
Preferably, the polymorphic form comprised in the tablet is polymorphic form 6 of sofosbuvir having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1±0.2)°, (8.2±0.2)°, (10.4±0.2)°, (12.7±0.2)°, (17.2±0.2)°, (17.7±0.2)°, (18.0±0.2)°, (18.8±0.2)°, (19.4±0.2)°, (19.8±0.2)°, (20.1±0.2)°, (20.8±0.2)°, (21.8±0.2)°, (23.3±0.2)°, when measured at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm. Polymorphic form 6 of sofosbuvir and a process for its preparation are described, for example, in WO 2011/123645 A.
The term “agitation” as used in some of these embodiments and in the respective context of the present invention relates to any motion of a macroscopic constituent of the solution comprising sofosbuvir which is induced from outside, relative to another macroscopic constituent of the solution. The term “mechanical agitation” as used in some of these embodiments and in the respective context of the present invention relates to any motion of a macroscopic constituent of the solution comprising sofosbuvir which is induced from outside via a device, such as shaking or stirring or sonication, relative to another macroscopic constituent of the solution. The term “stirring” as used in some of these embodiments and in the respective context of the present invention to any motion of a macroscopic constituent of the solution comprising sofosbuvir which is induced from outside via a stirring device, relative to another macroscopic constituent of the solution.
Preferably, according to the present invention, the polymorphic form 6 of sofosbuvir and a process for its preparation are characterized by the following embodiments and combinations of embodiments as indicated by the respective dependencies and references:
Also preferably, the polymorphic form comprised in the tablet is polymorphic form 7 of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8°, preferably comprising reflections at 2-theta values of (8.1±0.2)°, (10.4±0.2)°, (12.4±0.2)°, (17.3±0.2)°, (19.4±0.2)°, when measured at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm. The polymorphic form 7 of sofosbuvir and a process for its preparation are characterized by the following embodiments and combinations of embodiments as indicated by the respective dependencies and references:
According to the present invention, it is also possible that the tablet comprises a mixture of polymorphic form 6 and polymorphic form 7 of sofosbuvir. According to a preferred embodiment of the present invention, the tablet comprises polymorphic form 7 of sofosbuvir, wherein more preferably, the polymorphic form of sofosbuvir which is comprised in the tablet is polymorphic form 7 of sofosbuvir. Preferably, the polymorphic form of sofosbuvir comprised in the tablet of the present invention is not polymorphic form 1 and is not polymorphic form 2 and is not polymorphic form 3 and is not polymorphic form 4 and is not polymorphic form 5.
In addition to the polymorphic form of sofosbuvir, and optionally in addition to the at least one organic solvent as described above and further optionally in addition to the at least one organic anti-solvent as described above, the tablet preferably comprises at least one pharmaceutically acceptable excipient.
The term “pharmaceutically acceptable excipient” as used in this context of the present invention relates to a compound that is used to prepare the tablet, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for human pharmaceutical use.
With regard to the at least one excipient, no specific restrictions exist provided that the tablet of the invention having the desired dissolution properties are obtained. Conceivable excipients include diluents, disintegrants, glidants, lubricants, coloring agents, taste-masking agents, coating agents, and the like,
Preferably, the at least one pharmaceutically acceptable excipient comprises at least one diluent, or at least one disintegrant, or at least one glidant, or at least one lubricant, or a combination of at least one diluent and at least one disintegrant, or a combination of at least one diluent and at least one glidant, or a combination of at least one disintegrant and at least one lubricant, or a combination of at least one diluent and at least one disintegrant and at least one glidant, or a combination of at least one diluent and at least one disintegrant and at least one lubricant, or a combination of at least one disintegrant and at least one glidant and at least one lubricant, or a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant. More preferably, the at least one pharmaceutically acceptable excipient comprises a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant.
More preferably, the at least one pharmaceutically acceptable excipient is a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant. More preferably, the at least one pharmaceutically acceptable excipient is a combination of at least one diluent and one disintegrant and one glidant and one lubricant.
With regard to the at least one diluent, no specific restrictions exist provided that the tablet of the invention having the desired dissolution properties are obtained.
Preferably, the at least one diluent comprises, preferably is, at least one of calcium carbonate, dicalcium phosphate, dry starch, calcium sulfate, cellulose, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil type I, inositol, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, powdered sugar, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, more preferably at least one of dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, mannitol, microcrystalline cellulose, starch, tribasic calcium phosphate, more preferably at least one of mannitol, microcrystalline cellulose.
More preferably, the at least one diluent comprises a combination of mannitol and microcrystalline cellulose. More preferably, the at least one diluent is a combination of mannitol and microcrystalline cellulose.
With regard to the at least one disintegrant, no specific restrictions exist provided that the tablet of the invention having the desired dissolution properties are obtained.
Preferably, the at least disintegrant comprises, preferably is, at least one of agar, alginic acid, bentonite, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, cellulose, a cation exchange resin, cellulose, gums, citrus pulp, colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, guar gum, hydrous aluminum silicate, an ion exchange resin (e.g., polyacrin potassium), magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, modified cellulose gum, modified corn starch, montmorillonite clay, natural sponge, polyacrilin potassium, potato starch, powdered cellulose, povidone, pregelatinized starch, sodium alginate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid, sodium starch glycolate, starch, silicates, more preferably at least one of croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, povidone, pregelatinized starch, sodium starch glycolate.
More preferably, the at least one disintegrant comprises croscarmellose sodium. More preferably, the at least one disintegrant is croscarmellose sodium.
With regard to the at least one glidant, no specific restrictions exist provided that the tablet of the invention having the desired dissolution properties are obtained.
Preferably, the at least one glidant comprises, preferably is, is at least one of colloidal silicon dioxide, talc, starch, starch derivatives.
More preferably, the at least one glidant comprises colloidal silicon dioxide. More preferably, the at least one glidant is colloidal silicon dioxide.
With regard to the at least one lubricant, no specific restrictions exist provided that the tablet of the invention having the desired dissolution properties are obtained.
Preferably, the at least one lubricant comprises, preferably is, at least one of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, more preferably at least one of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc.
More preferably, the at least one lubricant comprises magnesium stearate. More preferably, the at least one lubricant is magnesium stearate.
The tablet may further comprise a coating agent. The coating agent can be formed from an aqueous film coat composition, wherein the aqueous film coat composition may comprise a film-forming polymer, water and/or an alcohol as a vehicle and optionally one or more adjuvants such as are known in the film-coating art. The coating agent may be selected from among hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate, carboxymethyl cellulose, polyvinylpyrrolidone, zein, and an acrylic polymer such as methacrylic acid or methacrylic acid ester copolymers such as methacrylic acid or methylmethacrylate copolymers, and the like, and a polyvinyl alcohol. In particular, the coating agent may comprise a polyvinyl alcohol.
The coating agent may further comprise a taste-masking agent. In this case, the coating agent may be formed from an aqueous film coat composition, wherein the aqueous film coat composition may comprise a film-forming polymer, water and/or an alcohol as a vehicle, and optionally one or more adjuvants such as are known in the film-coating art. The coating agent may be selected from among hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate, carboxymethyl cellulose, polyvinylpyrolidone, zein, and an acrylic polymer such as methacrylic acid or methacrylic acid ester copolymers such as methacrylic acid or methylmethacrylate copolymers, and the like, and a polyvinyl alcohol. In particular, the coating agent may comprise a polyvinyl alcohol.
With respect to the coating agent, film-forming polymers are typically provided in either aqueous or organic solvent-based solutions or aqueous dispersions. However, the polymers may be provided in dry form, alone or in a powdery mixture with other components such as a plasticizer and/or a colorant, which is made into a solution or dispersion by the user by admixing with the aqueous vehicle. It will be appreciated that the aqueous film coat composition may further comprise water as a vehicle for the other components, to facilitate their delivery to the surface of the tablet. The vehicle may optionally further comprise one or more water soluble solvents such as an alcohol and/or a ketone. Examples of an alcohol include but are not limited to methanol, isopropanol, propanol, etc. A non-limiting example for the ketone is acetone. The skilled person can select appropriate vehicle components to provide good interaction between the film-forming polymer and the vehicle to ensure good film properties. In general, polymer-vehicle interaction is designed to yield maximum polymer chain extension to produce films having the greatest cohesive strength and thus mechanical properties. The components are also selected to provide good deposition of the film-forming polymer onto the surface of the tablet, such that a coherent and adherent film is achieved. Suitable aqueous film coating compositions include those commercially available from Colorcon, Inc. of West Point, Pa., under the trade name Opadry® and Opadry® II. Non-limiting examples include Opadry® II Purple and Opadry II® Yellow.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) which is a combination of form 6 and form 7 and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) which is a combination of form 6 and form 7 and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) which is a combination of form 6 and form 7 and the at least one pharmaceutically acceptable excipient.
Preferably, the tablet contains the at least one pharmaceutically acceptable excipient in an amount of at most 75 weight-% or at most 60 weight-%, more preferably in the range of from 55 to 10 weight-%, more preferably from 55 to 15 weight-%, more preferably from 55 to 20 weight-%. More preferably, the tablet contains the at least one pharmaceutically acceptable excipient in an amount in the range of from 50 to 25 weight-%, based on the total weight of the tablet. Preferred ranges include a range of from 50 to 40 weight-% or a range of from 45 to 35 weight-% or a range of from 40 to 30 weight-% or a range of from 35 to 25 weight-% based on the total weight of the tablet. Preferably, the tablet contains the at least one pharmaceutically acceptable excipient in an amount of <25 weight-% based on the total weight of the tablet or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-% based on the total weight of the tablet.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-%, more preferably at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I), mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I), mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Also preferably, the tablet contains mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate in an amount of at most 75 weight-% or at most 60 weight-%, more preferably in an amount in in the range of from 55 to 10 weight-%, more preferably from 55 to 15 weight-%, more preferably from 55 to 20 weight-%, more preferably from 50 to 20 weight-%, based on the total weight of the tablet. More preferably, the tablet contains mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate in an amount in the range of from 50 to 25 weight-% or in an amount of <25 weight-% based on the total weight of the tablet or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-% based on the total weight of the tablet. More preferably, the tablet contains mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate in an amount in the range of from 50 to 30 weight-%-% or in an amount of <25 weight-% based on the total weight of the tablet or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-%, based on the total weight of the tablet. Preferred ranges include a range of from 50 to 40 weight-% or a range of from 45 to 35 weight-% or a range of from 40 to 30 weight-%-% or a range of from 25 to 10 weight-% or a range of from 25 to 15 weight-%, or a range of from 25 to 20 weight-% or a range of from 20 to 10 weight-% or a range of from 15 to 10 weight-% based on the total weight of the tablet.
As mentioned above, it is preferred that the at least one excipient comprises, preferably is, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant. In this case, it is preferred that the weight ratio of the at least one disintegrant relative to the at least diluent is in the range of from 0.005:1 to 0.75:1, preferably from 0.01:1 to 0.5:1, more preferably from 0.02:1 to 0.2:1, more preferably from 0.05:1 to 0.1:1. It is further preferred that the weight ratio of the at least one glidant relative to the at least diluent is in the range of from 0.0005:1 to 0.2:1, preferably from 0.001:1 to 0.1:1, more preferably from 0.005:1 to 0.05:1, more preferably from 0.01:1 to 0.02:1. It is further preferred that the weight ratio of the at least one lubricant relative to the at least diluent is in the range of from 0.001:1 to 0.5:1, preferably from 0.005:1 to 0.2:1, more preferably from 0.01:1 to 0.1:1, more preferably from 0.02:1 to 0.05:1.
As mentioned above, it is further preferred that the at least one diluent comprises, preferably is, a combination of mannitol and microcrystalline cellulose, the at least one disintegrant comprises, preferably is, croscarmellose sodium, the at least one glidant comprises, preferably is, colloidal silicon dioxide, and the at least one lubricant comprises, preferably is, magnesium stearate. In this case, it is preferred that the weight ratio of croscarmellose sodium relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.005:1 to 0.75:1, preferably from 0.01:1 to 0.5:1, more preferably from 0.02:1 to 0.2:1, more preferably from 0.05:1 to 0.1:1. It is further preferred that the weight ratio of colloidal silicon dioxide relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.0005:1 to 0.2:1, preferably from 0.001:1 to 0.1:1, more preferably from 0.005:1 to 0.05:1, more preferably from 0.01:1 to 0.02:1. It is further preferred that the weight ratio of magnesium stearate relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.001:1 to 0.5:1, preferably from 0.005:1 to 0.2:1, more preferably from 0.01:1 to 0.1:1, more preferably from 0.02:1 to 0.05:1.
Therefore, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7, wherein the tablet further comprises at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate
Therefore, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6 wherein the tablet further comprises at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Therefore, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 25 weight-%, preferably at least 40 weight-%, more preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 7 wherein the tablet further comprises at most 75 weight-% or at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Therefore, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 25 weight-%, preferably at least 40 weight-%, more preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is a combination of the polymorphic form 6 and 7 wherein the tablet further comprises at most 75 weight-% or at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Preferably, the tablet comprises the polymorphic form 6 or the polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 in an amount of ≧75 weight-% or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the polymorphic form 6 in an amount of ≧75 weight-% or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
The tablet comprises the polymorphic form 7 in an amount of at least 25 weight-%, or at least 30 weight-%, or at least 35 weight % or at least 40 weight % or at least 45 weight-% or in an amount of ≧75 weight-% or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises a combination of polymorphic form 6 and polymorphic form 7 in an amount of ≧75 weight-% or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the at least one pharmaceutically acceptable excipient in an amount of <25 weight-% or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-%, based on the total weight of the tablet, wherein the at least one pharmaceutically acceptable excipient comprises preferably is, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprises, preferably is a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Thus, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7, wherein the tablet further comprises at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of the at least one disintegrant, preferably croscarmellose sodium, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.01:1 to 0.5:1, preferably from 0.02:1 to 0.2:1, more preferably from 0.05:1 to 0.1:1, the weight ratio of the at least one glidant, preferably colloidal silica, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.001:1 to 0.1:1, preferably from 0.005:1 to 0.05:1, more preferably from 0.01:1 to 0.02:1, and the weight ratio of the at least one lubricant, preferably magnesium stearate, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.005:1 to 0.2:1, preferably from 0.01:1 to 0.1:1, more preferably from 0.02:1 to 0.05:1.
Thus, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 40 weight-%, preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6, wherein the tablet further comprises at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of the at least one disintegrant, preferably croscarmellose sodium, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.01:1 to 0.5:1, preferably from 0.02:1 to 0.2:1, more preferably from 0.05:1 to 0.1:1, the weight ratio of the at least one glidant, preferably colloidal silica, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.001:1 to 0.1:1, preferably from 0.005:1 to 0.05:1, more preferably from 0.01:1 to 0.02:1, and the weight ratio of the at least one lubricant, preferably magnesium stearate, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.005:1 to 0.2:1, preferably from 0.01:1 to 0.1:1, more preferably from 0.02:1 to 0.05:1.
Thus, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 25 weight-%, of at least 40 weight-%, preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 7, wherein the tablet further comprises at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of the at least one disintegrant, preferably croscarmellose sodium, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.01:1 to 0.5:1, preferably from 0.02:1 to 0.2:1, more preferably from 0.05:1 to 0.1:1, the weight ratio of the at least one glidant, preferably colloidal silica, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.001:1 to 0.1:1, preferably from 0.005:1 to 0.05:1, more preferably from 0.01:1 to 0.02:1, and the weight ratio of the at least one lubricant, preferably magnesium stearate, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.005:1 to 0.2:1, preferably from 0.01:1 to 0.1:1, more preferably from 0.02:1 to 0.05:1.
Thus, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount of at least 25 weight-%, of at least 40 weight-%, preferably ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 95%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is a combination of polymorphic form 6 and polymorphic form 7, wherein the tablet further comprises at most 60 weight-%, preferably <25 weight-% of at least one pharmaceutically acceptable excipient comprising, preferably being, a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of the at least one disintegrant, preferably croscarmellose sodium, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.01:1 to 0.5:1, preferably from 0.02:1 to 0.2:1, more preferably from 0.05:1 to 0.1:1, the weight ratio of the at least one glidant, preferably colloidal silica, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.001:1 to 0.1:1, preferably from 0.005:1 to 0.05:1, more preferably from 0.01:1 to 0.02:1, and the weight ratio of the at least one lubricant, preferably magnesium stearate, relative to the at least diluent, preferably the combination of mannitol and microcrystalline cellulose, is in the range of from 0.005:1 to 0.2:1, preferably from 0.01:1 to 0.1:1, more preferably from 0.02:1 to 0.05:1.
Preferably, the tablet comprises the polymorphic form 6 or the polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the polymorphic form 6 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
The tablet according to the invention comprises the polymorphic form 7 in an amount of at least 25 weight-%, or at least 30 weight-%, at least 35 weight-%, preferably at least 40% more preferably ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the combination of polymorphic form 6 and polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the at least one pharmaceutically acceptable excipient in an amount of <25 weight-% based on the total weight of the tablet or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-%, based on the total weight of the tablet, wherein the at least one pharmaceutically acceptable excipient comprises, preferably is a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprises, preferably is, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the poly-morphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Hence, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount in the range of from 50 to 75 weight-%, preferably in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7, preferably polymorphic form 7, wherein the tablet further comprises at least one pharmaceutically acceptable excipient being a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of croscarmellose sodium relative to the combination of mannitol and microcrystalline cellulose, is in the range of from 0.05:1 to 0.1:1, the weight ratio of colloidal silica, relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.01:1 to 0.02:1, and the weight ratio of magnesium stearate relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.02:1 to 0.05:1.
Hence, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount in the range of from 50 to 75 weight-%, preferably in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6, wherein the tablet further comprises at least one pharmaceutically acceptable excipient being a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of croscarmellose sodium relative to the combination of mannitol and microcrystalline cellulose, is in the range of from 0.05:1 to 0.1:1, the weight ratio of colloidal silica, relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.01:1 to 0.02:1, and the weight ratio of magnesium stearate relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.02:1 to 0.05:1.
Hence, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount in the range of from 50 to 75 weight-%, preferably in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 7 wherein the tablet further comprises at least one pharmaceutically acceptable excipient being a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of croscarmellose sodium relative to the combination of mannitol and microcrystalline cellulose, is in the range of from 0.05:1 to 0.1:1, the weight ratio of colloidal silica, relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.01:1 to 0.02:1, and the weight ratio of magnesium stearate relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.02:1 to 0.05:1.
Hence, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount in the range of from 50 to 75 weight-%, preferably in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is a combination of polymorphic form 6 and polymorphic form 7, wherein the tablet further comprises at least one pharmaceutically acceptable excipient being a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of croscarmellose sodium relative to the combination of mannitol and microcrystalline cellulose, is in the range of from 0.05:1 to 0.1:1, the weight ratio of colloidal silica, relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.01:1 to 0.02:1, and the weight ratio of magnesium stearate relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.02:1 to 0.05:1.
Preferably, the tablet comprises the polymorphic form 6 or the polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the polymorphic form 6 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises a combination of polymorphic form 6 and polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet comprises the at least one pharmaceutically acceptable excipient in an amount of <25 weight-% based on the total weight of the tablet or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-%, based on the total weight of the tablet, wherein the at least one pharmaceutically acceptable excipient comprises, preferably is a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprising, preferably being, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Hence, preferably the tablet of the invention is a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7, preferably polymorphic form 7, wherein the tablet further comprises at least one pharmaceutically acceptable excipient and wherein at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir, and the at least one pharmaceutically acceptable excipient.
Preferably, the tablet comprises the at least one pharmaceutically acceptable excipient in an amount of <25 weight-% based on the total weight of the tablet or in a range of from 25 to 10 weight-% or in a range of from 25 to 15 weight-%, or in a range of from 25 to 20 weight-% or in a range of from 20 to 10 weight-% or in a range of from 15 to 10 weight-%, based on the total weight of the tablet, wherein the at least one pharmaceutically acceptable excipient comprises, preferably is a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably comprises, preferably is, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Hence, preferably the tablet of the invention is a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6, wherein the tablet further comprises at least one pharmaceutically acceptable excipient and wherein at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir, and the at least one pharmaceutically acceptable excipient.
Hence, preferably the tablet of the invention is a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 7 wherein the tablet further comprises at least one pharmaceutically acceptable excipient and wherein at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir, and the at least one pharmaceutically acceptable excipient.
Hence, preferably the tablet of the invention is a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is a combination of polymorphic form 6 and polymorphic form 7, preferably polymorphic form 7, wherein the tablet further comprises at least one pharmaceutically acceptable excipient and wherein at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir, and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
The tablet of the present invention may have a mass in the range of from 0.3 to 2.0 g, preferably from 0.4 to 1.5 g. More preferably, the tablet has a mass in the range of from 0.45 to 1.00 g, more preferably from 0.455 to 0.70 g, more preferably from 0.50 to 0.80 g.
Further, the tablet of the invention is preferably a round or an oval tablet, having a longest dimension of at most 20 mm, preferably at most 19, more preferably at most 18 mm. Longest dimensions of at most 17 or of at most 16 mm or of at most 15 mm are also conceivable.
The tablet of the present invention has advantageous dissolution characteristics.
preferably, the tablet exhibits a dissolution of at least 40%, preferably at least 45%, more preferably at least 50%, more preferably at least 55%, more preferably at least 60%, after 5 minutes in the mean dissolution profile as determined with a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml, described in Reference Example 8 hereinbelow.
Preferably, the tablet exhibits a dissolution of at least 60%, preferably at least 65%, more preferably at least 70%, more preferably at least 75%, more preferably at least 80%, after 10 minutes in the mean dissolution profile as determined with a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml, described in Reference Example 8 hereinbelow.
Preferably, the tablet exhibits a dissolution of at least 80%, preferably at least 85%, more preferably at least 90%, more preferably at least 95%, after 15 minutes in the mean dissolution profile as determined with a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml, described in Reference Example 8 hereinbelow.
More preferably, the tablet exhibits a dissolution of at least 60% after 5 minute, of at least 80% after 10 minutes, and of at least 90% after 15 minutes in the mean dissolution profile as determined with a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml, described in Reference Example 8 hereinbelow.
More preferably, the tablet of at least 60% after 5 minute, of at least 80% after 10 minutes, and of at least 95% after 15 minutes in the mean dissolution profile as determined with a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml, described in Reference Example 8 hereinbelow.
Therefore, the present invention also relates to a tablet comprising a polymorphic form of crystalline sofosbuvir according to formula (I)
in an amount in the range of from 50 to 75 weight-%, preferably in an amount ≧75 weight-% based on the total weight of the tablet, wherein the polymorphic form has a moisture stability of at least 99%, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7, preferably polymorphic form 7, wherein the tablet further comprises at least one pharmaceutically acceptable excipient being a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the weight ratio of croscarmellose sodium relative to the combination of mannitol and microcrystalline cellulose, is in the range of from 0.05:1 to 0.1:1, the weight ratio of colloidal silica, relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.01:1 to 0.02:1, and the weight ratio of magnesium stearate relative to the combination of mannitol and microcrystalline cellulose is in the range of from 0.02:1 to 0.05:1, wherein the tablet exhibits a dissolution of at least 60% after 5 minute, of at least 80% after 10 minutes, and of at least 90% after 15 minutes in the mean dissolution profile as determined with a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml, described in Reference Example 8 hereinbelow, and wherein the tablet has a mass in the range of from 0.50 to 0.80 g.
Generally, the tablet of the present invention can be prepared by all conceivable processes. Preferably, as mentioned above, the tablet of the present invention comprises at least one pharmaceutically acceptable excipient. The choice of particular types and amounts of excipients, and tableting technique employed generally depends on the properties of the polymorphic form of sofosbuvir and the excipients such as compressibility, flowability, particle size, compatibility, and density. In this regard, reference is made Remington: The Science and Practice of Pharmacy 2006, 21st edition, Lippincott Williams & Wilkins. Reference is also made to the Handbook of Pharmaceutical Excipients 1994, edited by A. Wade and P. J. Weller, The Pharmaceutical Press, 2nd Edition, London. The tablets may be prepared according to methods known in the art, including dry granulation, such as via roller compaction, wet granulation, such as via fluid bed granulation and high shear granulation, or direct compression, and the type of excipients used will vary accordingly. Therefore, the present invention relates to a process for preparing the tablet of the invention, comprising
Dry granulation is preferred for preparing the tablets of the invention. A preferred dry granu-lated tablet comprises granules comprising the polymorphic form of sofosbuvir and at least one diluent and/or at least one disintegrant and/or at least one glidant and/or at least one lubricant, preferably a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, wherein the granules are mixed with at least one diluent and/or at least one disintegrant and/or at least one glidant and/or at least one lubricant, preferably with a combination of at least one diluent and at least one disintegrant and at least one glidant and at least one lubricant, more preferably with a combination of microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Therefore, the present invention also relates to the process as described above, wherein (b) comprises
Preferably, the total weight contained in the first portion in (b.1) relative to the total weight of the at least one pharmaceutically acceptable excipient contained in the first portion in (b.1) and the second portion in (b.4) is in the range of from 30 to 99%, more preferably from 35 to 98%, more preferably from 40 to 97%, more preferably from 45 to 96%. More preferably, the total weight of the at least one pharmaceutically acceptable excipient contained in the first portion in (b.1) relative to the total weight of the at least one pharmaceutically acceptable excipient contained in the first portion in (b.1) and the second portion in (b.4) is in the range of from 50 to 95%, more preferably from 55 to 94%, more preferably from 60 to 93%, more preferably from 65 to 92%, more preferably from 70 to 90%. Preferred ranges include a range of from 70 to 80% or from 75 to 85% or from 80 to 90%.
Preferably, the first portion in (b.1) comprises, preferably is, a combination of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, and the second portion in (b.2) comprises, preferably is, a combination of microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Preferably, the compressing in (b.2) is carried out under a pressure in the range of from 50 to 250 bar, more preferably from 75 to 200 bar, more preferably from 100 to 150 bar. Preferred ranges include a range of from 100 to 120 bar or a range of from 110 to 130 bar or a range of from 120 to 140 bar or a range of from 130 to 150 bar.
Preferably, in (b.3), the sieve has mesh size in the range of from 0.5 to 1.5 mm, more preferably from 0.7 to 1.2 mm, more preferably from 0.75 to 1.25 mm. Preferred ranges include a range of from 0.75 to 0.95 mm or a range of from 0.85 to 1.05 mm or a range of from 0.95 to 1.15 mm or a range of from 1.05 to 1.25 mm.
Preferably, the compressing in (c) is carried out under a pressure in the range of from 50 to 300 bar, more preferably from 75 to 275 bar, preferably from 100 to 250 bar. Preferred ranges include a range of from 100 to 150 bar or a range of from 125 to 175 bar or a range of from 150 to 200 bar or a range of from 175 to 225 bar or a range of from 200 to 250 bar.
Preferably, the tablet of (c) comprises the polymorphic form in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet of (c) comprises the polymorphic form in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). Preferably, the tablet of (c) comprises the polymorphic form 6 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
Preferably, the tablet of (c) comprises the polymorphic form 7 in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet.
It is conceivable, that the tablet of (c) comprises the polymorphic form 7 in an amount of weight-at least 25 weight-%, of at least 30 weight-% of at least 35-weight-% of at least 40 weight-% based on the total weight of the tablet.
Preferably, the tablet of (c) comprises the polymorphic form in an amount of ≧75 weight-% based on the total weight of the tablet or in a range of from 75 to 90 weight-% or in a range of from 75 to 85 weight-%, or in a range of from 75 to 80 weight-% or in a range of from 80 to 90 weight-% or in a range of from 85 to 90 weight-% based on the total weight of the tablet wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet of (c) consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is polymorphic form 6 or polymorphic form 7 or a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I).
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet of (c) consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 6 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet of (c) consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient. More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form 7 of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient.
Preferably, at least 95 weight-%, preferably at least 97 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-% of the tablet of (c) consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.6 weight-%, more preferably at least 99.7 weight-%, more preferably at least 99.8 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). More preferably, at least 99.9 weight-% of the tablet consist of the polymorphic form of crystalline sofosbuvir according to formula (I) and the at least one pharmaceutically acceptable excipient, wherein the polymorphic form is a combination of polymorphic form 6 and polymorphic form 7 of crystalline sofosbuvir of formula (I). As mentioned above, generally no specific restrictions exists how a polymorphic form exhibiting the moisture stability as defined above is provided or prepared. Preferably, the polymorphic form is obtainable or obtained by a process comprising crystallization of the polymorphic form in the presence of at least one organic solvent and preferably at least one organic anti-solvent.
Therefore, the present invention relates to the process as defined above, wherein providing the polymorphic form of crystalline sofosbuvir according to formula (I) in (a) comprises crystallizing the polymorphic form in the presence of at least one organic solvent and preferably at least one organic anti-solvent.
Further, the present invention relates to the process as defined above, wherein the polymorphic form of crystalline sofosbuvir according to formula (I) provided in (a) is obtainable or obtained by a process comprising crystallizing the polymorphic form in the presence of at least one organic solvent and preferably at least one organic anti-solvent.
With regard to conceivable and preferred solvent and anti-solvents, reference is made to the respective disclosure hereinabove and to the respective embodiments 83 and 84 in the embodiment section hereinbelow.
Therefore, in case the polymorphic form comprised in the tablet is polymorphic form 6 of sofosbuvir, providing the polymorphic form in (a) preferably comprises
Therefore, in case the polymorphic form comprised in the tablet is polymorphic form 7 of sofosbuvir, providing the polymorphic form in (a) preferably comprises
Optionally, the process of the present invention further comprises a step (d) of coating the tablet obtained in (c) with at least one coating agent, preferably comprising a polyvinylalcohol and optionally comprising at least one taste-masking agent. Regarding step (d), reference is also made to the section “Coating agent” hereinabove.
The present invention also relates to a tablet which is obtainable or obtained by the process as described above.
The tablet of the present invention is preferably used for the treatment of hepatitis C in a human. Due to the high drug load of the tablet compared to the tablet described in the prior art, and thus, the provision of smaller tablets having the same drug load compared to the tablet of the prior art, the tablet of the invention allows, for example, for an easier swallowing and thus significantly contributes to heighten the patient's convenience.
Further, the present invention also relates to the use of a polymorphic form of crystalline sofosbuvir according to formula (I)
having a moisture stability of at least 95% for the preparation of tablet comprising the polymorphic form in an amount of at least 40 weight-%, based on the total weight of the tablet, wherein the moisture stability of the polymorphic form is defined as the amount of the polymorphic form which is present after an exposure to a relative humidity of (75±1) % at a temperature of (40±1)° C. for an exposure time of (18±1) hours, relative to the amount of the polymorphic form before said exposure, as determined via X-ray powder diffraction pattern analysis at a temperature in the range of from 15 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm before the exposure and after the exposure.
The present invention is further illustrated by the following embodiments and combinations of embodiments as indicated by the dependencies and references.
The present invention is further illustrated by the following reference examples, examples, and comparative examples.
RE1.1 Amorphous sofosbuvir was prepared according to the following recipe: To 400 mg of sofosbuvir crystalline Form 1 prepared according to WO 2011/123645 A, Example 10, 3.5 mL ethanol were added, followed by 12 mL DI water. The mixture was subjected to sonication (2 to 5 minutes at room temperature in a VWR Ultrasonic Cleaner apparatus) to accelerate the dissolution of the solid material. The homogeneous solution was frozen in a bath of liquid nitrogen and lyophilized at −36° C. at a pressure of from 0 to 2 mbar, yielding amorphous sofosbuvir. It was characterized via XRPD analysis according to Reference Example 6. The respectively obtained XRPD pattern is shown in
In a vial equipped with a magnetic stirring bar were added 1.00 g of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) and 2.5 mL of n-butanol (≧99.5%, Merck KGaA). The solution was heated to a temperature of from 50 to 60° C. to allow solid dissolution. 5.0 mL of n-heptane (≧99%, Sigma-Aldrich) were added under stirring conditions (500 r.p.m.) at a temperature of from 50 to 60° C. The solution was further stirred at a velocity of from 300 to 400 r.p.m. and a temperature of from 25 to 28° C. for 6 h to allow crystallization to take place. The obtained suspension was filtered on a medium-porosity glass fitted funnel and the solid residue was washed with n-heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40° C. for 3 h whereafter heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25° C. at a pressure of from 20 to 30 mbar for 12 h, yielding 0.96 g (96% yield) of crystalline form 6 of sofosbuvir. It was characterized via XRPD analysis according to Reference Example 6. The respectively obtained XRPD pattern is shown in
30 mg of a given polymorphic form of sofosbuvir or of amorphous sofosbuvir prepared according to Reference Examples 1 to 4 were analyzed via XRPD as described in Reference Example 6. Then, these polymorphic forms of sofosbuvir or of amorphous sofosbuvir were exposed to an atmosphere having a relative humidity (RH) of 75% and a temperature of 40° C. for 18 hours in a humidity chamber and analyzed via XRPD as described in Reference Example 6. The results obtained are shown in Table 1 below:
XRPD patterns were obtained with an X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, pro-grammable XYZ stage with well plate holder, Cu-Kalpha1,2 radiation source (wavelength 0.15419 nm) with a focusing mirror, a 0.5° divergence slit, a 0.02° soller slit collimator and a 0.5° anti-scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° soller slit collimator, a Ni-filter and a solid state PIXcel detector on the diffracted beam side. The diffractogram was recorded at room temperature at a tube voltage of 40 kV, tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40 sec per step in the angular range of 2° to 40° 2-theta. A typical precision of the 2-theta values is in the range of ±0.2° 2-theta. Thus, a diffraction peak that appears for example at 9.4° 2-theta can appear between 9.2 and 9.6° 2-theta on most X-ray diffractometers under standard conditions.
Fourier transform infrared (FTIR) spectra were recorded with a Bruker IFS 25 spectrometer (Bruker Analytische Messtechnik GmbH, Karlsruhe, D) connected to a Bruker IR microscope I (15×-Cassegrain-objective). The samples were prepared on ZnSe-disks and measured at room temperature in transmission mode (spectral range (4000-600) cm−1, resolution 4 cm−1, 64 interferograms per spectrum). To record a spectrum a spatula tip of a sample was applied to the surface of the ZnSe in powder form. Then the sample was pressed onto the ZnSe and the spectrum was recorded. A spectrum of the clean ZnSe was used as background spectrum. A typical precision of the wavenumber values is in the range of about ±2 cm−1. Thus, an infrared peak that appears for example at 1668 cm−1 can appear between 1666 and 1670 cm−1 on most infrared spectrometers under standard conditions.
Differential scanning calorimetry (DSC) was performed with a DSC 7 (Perkin-Elmer, Norwalk, Ct., USA) using a Pyris 2.0 software and with a DSC 204F1 (Netzsch GmbH & Co. Holding AG, Selb, Germany). Approximately (1 to 5±0.005) mg sample (using a UM3 ultramicrobalance, Mettler, Greifensee, CH) was weighed into an Al-pan (30 microL), sealed with a cover, which was perforated by a needle and heated from 25 to 150° C. at a rate of 10 K/min. Dry nitrogen was used as the purge gas (purge: 20 mL/min).
Thermogravimetric analysis (TGA) was performed using the following equipment/conditions: Thermogravimetric-system TGA-7, Pyris-Software for Windows NT, (Perkin-Elmer, Norwalk, Ct., USA), Platinum-sample holder (50 microL), nitrogen as the purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min). Heating rate: 10 K/min; heating range: 25-145° C.
The moisture sorption desorption isotherms were acquired using a SPS-11 moisture sorption analyzer (MD Messtechnik, Ulm, D). The samples were weighed into Aluminium sample holders. The measurement cycles for the novel crystalline form according to the present invention were started at 43% RH, decreased to 40% RH (relative humidity), further decreased in 10% steps to 10% RH, decreased in 5% steps to 0% RH, increased in 5% steps to 10% RH, further increased in 10% steps to 90% RH and subsequently increased to 95% RH, decreased again to 90% RH, decreased in 10% steps to 10% RH, further decreased in 5% steps to 0% RH, again increased in 5% steps to 10%, subsequently increased in 10% steps to 40% RH and finally increased to 43% RH. The measurement cycles for form 1 were started at 43% RH, decreased to 40% RH, further decreased in 10% steps to 10% RH, decreased in 5% steps to 0% RH, increased in 5% steps to 10% RH, further increased in 10% steps to 90% RH and subsequently increased to 91% RH, decreased again to 90% RH, decreased in 10% steps to 10% RH, further decreased in 5% steps to 0% RH, again increased in 5% steps to 10%, subsequently increased in 10% steps to 40% RH and finally increased to 43% RH. The equilibrium condition for each step was set to a mass constancy of ±0.005% over 60 min. The temperature was (25±0.1)° C. The water content of the samples was determined after the moisture sorption/desorption experiments with a TGA 7 system (Perkin Elmer, Norwalk, Conn., USA) using the Pyris 2.0 software. The samples were weighed into Aluminium pans (50 microL). Dry nitrogen was used as purge gas (purge rate: 20 mL/min). The samples were heated from 25 to 200° C. using a heating rate of 10 K/min.
Intensity data for the crystal structure were recorded at 120 K on a Rigaku AFC12 goniometer driven by the CrystalClear-SM Expert 3.1 b27 software (Rigaku, 2012) and equipped with an enhanced sensitivity (HG) Saturn724+ detector mounted at the window of an FR-E+ Super Bright Mo rotating anode generator (lambda=0.71075 Angstrom) with HFVarimax optics. The structure was solved using the direct methods procedure in SHELXS97 and refined by full-matrix least squares on F2 using SHELXL97. All non-hydrogen atoms were refined anisotropically.
The dissolution properties of the tablets prepared according to the present invention were determined using a USP dissolution paddle apparatus 2 at 37° C., 75 r.p.m., using a phosphate buffer having a pH of 6.8 and a vessel having a volume of 900 ml. A given obtained dissolution profiles was obtained based on the analysis of one tablet.
Sofosbuvir of polymorphic form 6 was prepared according to Reference Example 3 above. 2.5 g of polymorphic form 6 were blended with 1.117 g mannitol, 0.919 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.017 g colloidal silica, and 0.028 g magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 140 bar to obtain flat tablets having a diameter of 15 mm. These tablets were crushed over a sieve having a mesh size of 1 mm. The obtained granulate was admixed with 0.186 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.019 g colloidal silica, and 0.028 g magnesium stearate. For admixing the granulate with the excipients, am overhead reax mixture was used. The obtained mixture was compressed under a pressure of 200 bar to obtain 800 mg oblong tablets of dimensions 18×8 mm. A respectfully prepared tablet had the following composition: 0.400 g polymorphic form 6 of sofosbuvir, 0.179 g mannitol, 0.177 g microcrystalline cellulose, 0.030 g crosscarmellose sodium, 0.006 g colloidal silica, 0.008 g magnesium stearate. In particular, the tablet had the following composition shown in Table 2.1, divided in intragranular and extragranular portion:
These tablets were subjected to dissolution properties testing according to Reference Example 8 above. The results are described in section “Results of the Examples and the Comparative Examples” below and shown in
Sofosbuvir of polymorphic form 6 was prepared according to Reference Example 3 above. 3.750 g of polymorphic form 6 were blended with 0.559 g mannitol, 0.459 g microcrystalline cellulose, 0.047 g crosscarmellose sodium, 0.008 g colloidal silica, and 0.014 g magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 140 bar to obtain flat tablets having a diameter of 15 mm. These tablets were crushed over a sieve having a mesh size of 1 mm. The obtained granulate was admixed with 0.093 g microcrystalline cellulose, 0.047 g crosscarmellose sodium, 0.009 g colloidal silica, and 0.014 g magnesium stearate. For admixing the granulate with the excipients, am overhead reax mixture was used. The obtained mixture was compressed under a pressure of 200 bar to obtain 533 mg oblong tablets of dimensions 18×8 mm. A respectfully prepared tablet had the following composition: 0.4000 g polymorphic form 6 of sofosbuvir, 0.0596 g mannitol, 0.0590 g microcrystalline cellulose, 0.0100 g crosscarmellose sodium, 0.0019 g colloidal silica, 0.0030 g magnesium stearate. In particular, the tablet had the following composition shown in Table 2.2, divided in intragranular and extragranular portion:
These tablets were subjected to dissolution properties testing according to Reference Example 8 above. The results are described in section “Results of the Examples and the Comparative Examples” below and shown in
The tablet of example E1.3 has been prepared with the same procedure of example E1.2.
Sofosbuvir of polymorphic form 7 was prepared according to Reference Example RE4.2 above. 2.5 g of polymorphic form 6 were blended with 1.117 g mannitol, 0.919 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.017 g colloidal silica, and 0.028 g magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 140 bar to obtain flat tablets having a diameter of 15 mm. These tablets were crushed over a sieve having a mesh size of 1 mm. The obtained granulate was admixed with 0.186 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.019 g colloidal silica, and 0.028 g magnesium stearate. For admixing the granulate with the excipients, am overhead reax mixture was used. The obtained mixture was compressed under a pressure of 200 bar to obtain 800 mg oblong tablets of dimensions 18×8 mm. A respectfully prepared tablet had the following composition: 0.400 g polymorphic form 7 of sofosbuvir, 0.179 g mannitol 0.177 g microcrystalline cellulose, 0.030 g crosscarmellose sodium, 0.006 g colloidal silica, 0.008 g magnesium stearate. In particular, the tablet had the following composition shown in Table 3.1, divided in intragranular and extragranular portion:
These tablets were subjected to dissolution properties testing according to Reference Example 8 above. The results are described in section “Results of the Examples and the Comparative Examples” below and shown in
Sofosbuvir of polymorphic form 1 was prepared according to Reference Example 2.1 above. 0.995 g of polymorphic form 1 were blended with 0.896 g mannitol, 0.737 g microcrystalline cellulose, 0.075 g crosscarmellose sodium, 0.013 g colloidal silica, and 0.022 g magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 140 bar to obtain flat tablets having a diameter of 15 mm. These tablets were crushed over a sieve having a mesh size of 1 mm. The obtained granulate was admixed with 0.149 g microcrystalline cellulose, 0.075 g crosscarmellose sodium, 0.015 g colloidal silica, and 0.022 g magnesium stearate. For admixing the granulate with the excipients, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 200 bar to obtain 800 mg oblong tablets of dimensions 20×9 mm. A respectfully prepared tablet had the following composition: 0.4000 g polymorphic form 1 of sofosbuvir, 0.3600 g mannitol, 0.3561 g microcrystalline cellulose, 0.0600 g crosscarmellose sodium, 0.0114 g colloidal silica, 0.0180 g magnesium stearate. In particular, the tablet had the following composition shown in Table 4.1, divided in intragranular and extragranular portion:
These tablets were subjected to dissolution properties testing according to Reference Example 8 above. The results are described in section “Results of the Examples and the Comparative Examples” below and shown in
Sofosbuvir of polymorphic form 1 was prepared according to Reference Example 2.2 above. 2.5 g of polymorphic form 1 were blended with 1.117 g mannitol, 0.919 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.017 g colloidal silica, and 0.028 g magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 140 bar to obtain flat tablets having a diameter of 15 mm. These tablets were crushed over a sieve having a mesh size of 1 mm. The obtained granulate was admixed with 0.186 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.019 g colloidal silica, and 0.028 g magnesium stearate. For admixing the granulate with the excipients, am overhead reax mixture was used. The obtained mixture was compressed under a pressure of 200 bar to obtain 800 mg oblong tablets of dimensions 18×8 mm. A respectfully prepared tablet had the following composition: 0.400 g polymorphic form 1 of sofosbuvir, 0.179 g mannitol, 0.177 g microcrystalline cellulose, 0.030 g crosscarmellose sodium, 0.006 g colloidal silica, 0.008 g magnesium stearate. In particular, the tablet had the following composition shown in Table 4.2, divided in intragranular and extragranular portion:
These tablets were subjected to dissolution properties testing according to Reference Example 8 above. The results are described in section “Results of the Examples and the Comparative Examples” below and shown in
Amorphous sofosbuvir was prepared according to Reference Example RE1.2 above. 2.5 g of amorphous sofosbuvir were blended with 1.117 g mannitol, 0.919 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.017 g colloidal silica, and 0.028 g magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 140 bar to obtain flat tablets having a diameter of 15 mm. These tablets were crushed over a sieve having a mesh size of 1 mm. The obtained granulate was admixed with 0.186 g microcrystalline cellulose, 0.093 g crosscarmellose sodium, 0.019 g colloidal silica, and 0.028 g magnesium stearate. For admixing the granulate with the excipients, am overhead reax mixture was used. The obtained mixture was compressed under a pressure of 200 bar to obtain 800 mg oblong tablets of dimensions 18×8 mm. A respectfully prepared tablet had the following composition: 0.400 g amorphous sofosbuvir, 0.179 g mannitol, 0.177 g microcrystalline cellulose, 0.030 g crosscarmellose sodium, 0.006 g colloidal silica, 0.008 g magnesium stearate. In particular, the tablet had the following composition shown in Table 5.1, divided in intragranular and extragranular portion:
These tablets were subjected to dissolution properties testing according to Reference Example 8 above. The results are described in section “Results of the Examples and the Comparative Examples” below and shown in
As shown in
A respective high drug load tablet comprising said polymorphic form 1 of sofosbuvir having a drug content of 50 weight-%, however, shows a very disadvantageous dissolution profile, as also depicted in
Surprisingly, high drug load tablets with a drug content of 50 weight-% were obtained when a polymorphic form of sofosbuvir was used as drug, which polymorphic form has a moisture stability of at least 95%. This general concept is shown for polymorphic form 6 and polymorphic form 7 of sofosbuvir; reference is made to
Also for high drug load tablets with a drug content of 60 or 75 weight-%, the advantageous properties described above were obtained. For example,
| Number | Date | Country | Kind |
|---|---|---|---|
| 14188205.0 | Oct 2014 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2015/073276 | 10/8/2015 | WO | 00 |
