WO2016156330A1

WO2016156330A1 - Solid pharmaceutical composition comprising amorphous sofosbuvir and a phospholipid

Info

Publication number: WO2016156330A1
Application number: PCT/EP2016/056820
Authority: WO
Inventors: Ralph Stefan; Dirk Schenk; Hans-Juergen Mika
Original assignee: Ratiopharm Gmbh
Priority date: 2015-03-30
Filing date: 2016-03-29
Publication date: 2016-10-06

Abstract

The present invention relates to a solid pharmaceutical composition comprising amorphous sofosbuvir and at least one phospholipid, preferably in the form of a tablet. The patent also relates to a process for preparing such compositions and to the use of the solid pharmaceutical composition for the treatment of hepatitis C virus infections.

Description

Solid pharmaceutical composition comprising amorphous sofosbuvir and a phospholipid

The present invention relates to a solid pharmaceutical composition comprising amorphous sofosbuvir and at least one phospholipid, preferably in the form of a tablet. The patent also relates to a process for preparing such compositions and to the use of the solid pharmaceutical composition for the treatment of hepatitis C virus (HCV) infections.

Sofosbuvir is an active ingredient which is known to be useful for treating hepatitis C virus infections. In this connection, it can be referred to WO 2013/082003 where sofosbuvir is designated as GS-7977. A sofosbuvir containing medicament is also on the market under the tradename Sovaldi^®.

The recommended dose of sofosbuvir is 400 mg administered orally once daily. Thus, it is advantageous if a pharmaceutical composition containing sofosbuvir contains 400 mg of the active ingredient so that it only needs to be administered once per day. Accordingly, the commercial product Sovaldi* is in the form of a tablet which contains 400 mg of crystalline sofosbuvir. However, sofosbuvir is difficult to handle and to formulate. The tablet Sovaldi^® has a total weight of 1200 mg, thus providing a drug load of only 33.33 %. Tablets with a total weight of 1200 mg containing 400 mg of crystalline sofosbuvir are also described in WO 2013/082003. Pharmaceutical compositions with a weight of more than about 1000 mg are difficult to swallow and, therefore, there are often problems with patient compliance. The fact that the Sovaldi* tablet has a high weight and large size which renders it difficult to swallow the tablet is a clear indication of the problems which occur in formulating sofosbuvir.

WO 2014/120981 describes combination tablets which comprise crystalline sofosbuvir and amorphous ledispavir. The crystalline sofosbuvir drug content is described to be up to 50 % in these tablets. The tablets contain no surfactant and a solid dispersion of ledispavir in copovidone. With crystalline drugs the problem of conversion between polymorphs exists. There exists a need for a pharmaceutical composition which allows for high sofosbuvir drug loading, wherein the pharmaceutical composition has a small size and a low weight. The pharmaceutical composition should also dissolve fast in order to provide a suitable bioavailability. In this respect, it is also advantageous if dissolution is pH independent and dissolution profiles are highly reproducible. The pharmaceutical composition should have further suitable properties such as e.g. being easy to manufacture and to handle.

In order to solve these problems, the present inventors have carried out significant studies concerning suitable excipients for preparing sofosbuvir containing solid pharmaceutical compositions. The present invention therefore provides a solid pharmaceutical composition comprising amorphous sofosbuvir and at least one phospholipid. The solid pharmaceutical composition is for oral use. Preferably, the solid pharmaceutical composition of the present invention is in form of a tablet. The tablet is optionally coated. The solid pharmaceutical composition usually does not contain liposomes.

The term amorphous denotes a physical state which is not crystalline and may be verified by x-ray diffraction and/or other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry.

Examples of preparing crystalline and amorphous forms of sofosbuvir (GS-7977) are disclosed in US patent applications No, 2010/0298257 and 201 1/0251 152. With respect to sofosbuvir and methods for its production it can also be referred to e.g. US patent 7,964,580 and patent application US 2010/0016251.

To obtain the solid pharmaceutical composition of the present invention, amorphous sofosbuvir can be used directly as starting compound for preparation of the solid pharmaceutical composition of the present invention. Alternatively, it is also possible to work with crystalline sofosbuvir as a starting compound and convert it into amorphous sofosbuvir during preparation of the solid pharmaceutical composition. In this respect, it was e.g. found that amorphous sofosbuvir can be obtained when melt extruding a phospholipid together with crystalline sofosbuvir.

In a preferred embodiment, the solid pharmaceutical composition of the present invention comprising amorphous sofosbuvir and at least one phospholipid comprises no or essentially (less than 20%, preferably less than 10%, more preferably less than 5% or less than 2%) no crystalline sofosbuvir.

As the at least one phospholipid preferably a phosphoglyceride (glycerophospholipid) or sphingophosphatide (sphingophospholipid) can be used in the present invention. Phospholipids can e.g. be obtained from animal or plant material, such as soybean. The phospholipids are preferably surfactants.

Phosphoglycerides to be used in the present invention are e.g. those of formula I below:

R -CO-0-CH₂

RT-CO-O— CH O

N O— P-O -R ,

OR,

(I) wherein R1 and R2 are independently selected from H and C1 -C24 optionally substituted straight or branched alkyl, alkenyl, or alkynyl chains,

R3 is H, -CH2-CHNH2-COOH, CH2-CHOH-CH20H, or -CH2-CH2-N⁺(CH3)~H₃., wherein n is 0, 1 , 2 or 3, and

R4 is a negative charge, H or a C1 -C24 optionally substituted straight or branched alkyl, alkenyl, or alkynyl chain.

Sphingophosphatides are e.g. those of formula II below:

(II) wherein R5 is defined as R1 in formula (I) above, and

R6 is defined as R4 in formula (I) above.

In one embodiment of the present invention, the at least one phospholipid comprised in the composition is thus a phosphoglyceride as defined above or a sphingophosphatide as defined above.

In a preferred embodiment of the present invention, the at least one phospholipid is a phosphoglyceride of formula I, wherein R1 and R2 are independently selected from C4- C24 aikyl or alkenyl chains, R3 is CH2-CH2-N⁺(CH3)₃ and R4 is a negative charge or H.

Preferably, the at least one phospholipid in the present invention is selected from one member of the group consisting of phosphatidylcholine, phosphatidic acid, phosphatidy!ethanolamine, phosphatidylglycerol and phosphatidylserine.

The at least one phospholipid can e.g. be selected from table 1 below.

Table 1. Phospholipids

Abbreviation CAS Type

1 ,2-Dierucoyl-sn-glycero- Phosphatidylethanola

DEPE 988-07-2

3-phosphoethanolamine mine

1 ,2-Dierucoyl-sn-glycero-

DEPG-NA 3[Phospho-rac-(1 - Phosphatidylglycerol

glyceroL .) (Sodium Salt)

1 ,2-Dilauroyl-6Y7-giycero-3- Phosphatidylethanola

DLPE

phosphoethanolamine mine

DLPG-NA 1 ,2-Dilauroyl-sn-glycero- Phosphatidylglycerol Abbreviation CAS Name Type

3[Phospho-rac-(1 - glycerol...) (Sodium Salt)

1 ,2-Dilauroyl-sn-glycero- 3[Phospho-rac-(1 -

DLPG-NH4 Phosphatidylglycerol glycerol...) (Ammonium

Salt)

1 ,2-Dilauroyl-sn-glycero-3-

DLPS-NA phosphoserine (Sodium Phosphatidylserine

Salt)

1 ,2-Dimyristoyl-sn-glycero-

DMPA-NA 80724-3 Phosphatidic acid

3-phosphate (Sodium Salt)

1 ,2-Dimyristoyl-sn-g'ycero-

DMPC 18194-24-6 Phosphatidylcholine

3-phosphocholine

1 ,2-Dimyristoyl-sn-glycero- Phosphatidyiethanola

DMPE 988-07-2

3-phosphoethanolamine mine

1 ,2-Dimyristoyl-sn-glycero-

DMPG-NA 67232-80-8 3[Phospho-rac-(1 - Phosphatidylglycerol glycerol...) (Sodium Salt)

1 ,2-Dimyristoyl-sn-glycero- 3(Phospho-rac-(1 -

DMPG-NH4 Phosphatidylgiyceroi glycerol...) (Ammonium

Salt)

1 ,2-Dimyristoyl-sn-glycero-

DMPG- 3[Phospho-rac-(1-

Phosphatidylglycerol NH4/NA glycerol...)

(Sodium/Ammonium Salt)

1 ,2-Dimyristoyl-sn-glycero-

DMPS-NA 3-phosphoserine (Sodium Phosphatidylserine

Salt)

1 ,2-Dioleoyl-sn-glycero-3-

DOPA-NA Phosphatidic acid phosphate (Sodium Salt)

1 ,2-Dioleoyl-sn-glycero-3-

DOPC 4235-95-4 Phosphatidylcholine phosphocholine

1 ,2-Dioleoyl-sn-glycero-3- Phosphatidyiethanola

DOPE 4004-5-1

phosphoethanolamine mine

1 ,2-Dioleoyl-sn-glycero-

DOPG-NA 62700-69-0 3[Phospho-rac-(1 - Phosphatidylglycerol glycerol,.,) (Sodium Salt)

1 ,2-Dioleoyl-sn-gjycero-3-

DOPS-NA 70614-14-1 phosphoserine (Sodium Phosphatidylserine

Salt)

1 ,2-Dipalmitoyl-sn-glycero-

DPPA-NA 71065-87-7 Phosphatidic acid

3-phosphate (Sodium Salt)

1 ,2-Dipalmitoyl-sn-glycero-

63-89-8 Phosphatidylcholine

3-phosphocholine

1 ,2-Dipalmitoyl-sn-glycero- Phosphatidyiethanola

DPPE 923-61 -5

3-phosphoethanolamine mine Abbreviation CAS Name Type

1 ,2-Dipalmitoyl-sn-glycero-

DPPG-NA 67232-81 -9 3[Phospho-rac-(1 - Phosphatidyiglycerol glyceroi... ) (Sodium Salt)

1 ,2-DipaImitoyI-sn-gIycero- 3[Phospho-rac-(1 -

DPPG-NH4 73548-70-6 Phosphatidylglycerol glycerol...) (Ammonium

Salt)

1 ,2-Dipalmitoy!-sn-glycero-

DPPS-NA 3-phosphoserine (Sodium Phosphatidylserine

Salt)

108321 -18- 1 ,2-Distearoyl-sn-glycero-

DSPA-NA Phosphatidic acid

2 3-phosphate (Sodium Salt)

,2-Distearoy!-sn-glycero-

DSPC 816-94-4 Phosphatidylcholine

3-phosphocholine

1 ,2-Distearoyl-sn-glycero- Phosphatidylethanoia

DSPE 1069-79-0

3-phosphoethanolamine mine

1.2-Distearoyl-sn-g!ycero- DSPG-NA 67232-82-0 3[Phospho-rac-(1 - Phosphatidyiglycerol glycerol...) (Sodium Salt)

1 ,2-Distearoyl-sn-glycero- 108347-80- 3[Phospho-rac-(1-

DSPG-NH4 Phosphatidylglycerol

4 glycerol...) (Ammonium

Salt)

1 ,2-Distearoyl-sn-glycero-

DSPS-NA 3-phosphoserine (Sodium Phosphatidylserine

Salt)

EPC Egg-PC Phosphatidylcholine

HEPC Hydrogenated Egg PC Phosphatidylcholine

HSPC Hydrogenated Soy PC Phosphatidylcholine

LYSOPC 1 -Myristoyl-sn-glycero-3- Lysophosphatidylcholi

18194-24-6

MYRISTIC phosphocholine ne

LYSOPC 1 -Palmitoyl-sn-glycero-3- Lysophosphatidylcholi

17364-16-8

PALMITIC phosphocholine ne

LYSOPC 1 -Stearoyl-sn-glycero-3- Lysophosphatidylcholi

19420-57-6

STEARIC phosphocholine ne

Milk

1 -Myristoyl-2-palmitoyl-sn-

Sphingomyeli Phosphatidylcholine glycero 3-phosphocholine

n MPPC

1 -Myristoyl-2-stearoyl-sn-

MSPC Phosphatidylcholine glycero-3-phosphocholine

1 -Palmitoyl-2-myristoyl-sn-

PMPC Phosphatidylcholine glycero-3-phosphocholine

1 -Palmitoyl-2-oleoyl-sn-

POPC 26853-31 -6 Phosphatidylcholine glycero-3-phosphocholine

1 -Palmitoyl-2-oieoyl-sn- Phosphatidylethanoia

POPE

giycero-3- mine Abbreviation CAS Name Type

phosphoethanolamine

1 -Palmitoyl-2-oleoyl-sn-

POPG-NA 81490-05 -3 glycero-3[Phospho-rac-( 1 - Phosphatidylglycerol

glycerol)...] (Sodium Salt)

1 -Palmitoyl-2-stearoyl-sn-

PSPC Phosphatidylcholine

glycero-3-phosphocholine

1 -Stearoyl-2-myristoyl-sn- SMPC Phosphatidylcholine

glycero-3-phosphocholine

1 -Stearoyl-2-oleoyl-sn-

SOPC Phosphatidylcholine

glycero-3-phosphocholine

1 -Stearoyl-2-palmitoyl-sn- SPPC Phosphatidylcholine

glycero-3-phosphocholine

In a more preferred embodiment of the present invention, the at least one phospholipid is a phosphatidylcholine. Of course, the solid pharmaceutical composition of the present invention can also comprise two or more different phospholipids.

In one more preferred embodiment, the solid pharmaceutical composition of the present invention comprises a lecithin which comprises phosphatidylcholine, such as Lipoid S 75.

While the inventors of the present invention found that dissolution of unformulated amorphous sofosbuvir was slow and variable, and dissolution became even worse in a dissolution medium comprising Tween 80 (see figure 4), surprisingly, the solid pharmaceutical composition comprising amorphous sofosbuvir and a phospholipid shows fast dissolution with little variation between individual tablets and independently of the pH of the dissolution medium. This has been demonstrated in examples 1 and 2 of the specification where figures 1 and 2 show the dissolution behavior of tablets according to the present invention containing 40 or even 45 wt.-% sofosbuvir and a phospholipid. It can be seen that the dissolution is very fast with little inter tablet variability. Figure 3 shows the dissolution of tablets containing 40 wt.-% sofosbuvir and poloxamer instead of a phospholipid. Dissolution is clearly not as fast as with the composition of the present invention and some variability is observed dependent on the pH of the dissolution medium and between individual tablets. Also, dissolution of Sovaldi tablets containing 33 wt-% crystalline sofosbuvir is slower than for the pharmaceutical composition of the present invention and the Sovaldi tablets show a higher dependency on the pH of the dissolution medium. The solid pharmaceutical composition of the present invention can e.g. comprise 10-70 %, preferably 20-60 %, more preferabIy30-50 % or 35-55 %, and even more preferably 40 to 50 % sofosbuvir. The use of a phospholipid in a sofosbuvir composition has been shown to be particularly favorable when the composition comprises a high drug load.

All percentages in the present specification are on a weight basis and refer to the total weight of the solid pharmaceutical composition, if nothing else is especially indicated or obvious under the circumstances. It is to be understood that a value of e.g. 40 % includes all values from 39.50 % to 40.49 %. The same applies to all other percentages disclosed herein (if nothing else is explicitly mentioned or obvious under the circumstances).

In one embodiment the solid pharmaceutical composition according to the present invention contains about 400 mg of sofosbuvir. In an alternative embodiment the solid pharmaceutical formulation according to the present invention contains less than 400mg of sofosbuvir, such as about 300, about 250 or about 200 mg of sofosbuvir. The term "about" means ± 10 % in this connection.

The solid pharmaceutical composition according to the present invention preferably has a weight of not more than 1020 mg, preferably 700 to 1020 mg, such as 700 to 950 mg, more preferably 750 to 900 mg (900 - 1050mg).

The volume of the solid pharmaceutical composition, in particular when the composition is in form of a tablet, is preferably 400 - 700 mm³, preferably 450 to 700 mm³, such as 500 to 700 mm³. The dimensions of the pharmaceutical composition, in particular when the composition is in form of a tablet, are preferably less than 20 x 9 mm, more preferably less than 19 x 9 mm, such as less than 18 x 9 mm, for example equal or less than 18 x 8.7 mm. The tablet according to the present invention may for example be oval, oblong or baguette- shaped.

The solid pharmaceutical composition according to the present invention contains preferably at least 3 % phospholipids in total, more preferably at least 5 % in total, such as at least 7 % in total based on the total weight of the pharmaceutical composition. The use of phospholipids in solid pharmaceutical compositions, such as tablets is unusual, particularly in the amounts indicated. In one embodiment, the solid pharmaceutical composition comprises at least 5 % phosphatidylcholine based on the total weight of the pharmaceutical composition.

The solid pharmaceutical composition according to the present invention preferably contains one or more glidants, Glidants are well known in the art and include e.g. colloidal silicon dioxide or talc and the preferred glidant is colloidal silicon dioxide such as the commercial product Syloid 244FP.

The glidant can be comprised in the solid pharmaceutical composition of the present invention in a relative high amount. A solid pharmaceutical composition comprising one or more glidants is preferred wherein the total amount of glidants is at least 10 % based on the total weight of the composition, preferably at least 15 % or even at least 20 wt.-%.

Lubricants can also be comprised in the solid pharmaceutical composition of the present invention. Examples of lubricants are magnesium stearate, stearic acid, silica, sodium steary! fumarate etc., preferred is sodium steary! fumarate, e.g. the brandname Pruv.

The solid pharmaceutical composition according to the present invention preferably comprises one more binders and one or more disintegrants. In one embodiment the solid pharmaceutical composition comprises one or more binders, one or more disintegrants and optionally one or more lubricants.

Examples of typical binders that can be comprised in the solid pharmaceutical composition include microcrystalline cellulose ( CC), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone and copovidone. The most preferred binder according to the present invention is microcrystalline cellulose and here it is particularly preferred to use Avicel PH 200. As disintegrants preferably one or more so-called "superdisintegrants" are used in the present invention. Preferred superdisintegrants are modified cellulose (croscarmellose sodium), sodium carboxymethyl starch (sodium starch gylcolate), cross-linked polyvinyl pyrrolidone (crospovidone), cross-linked alginic acid and Xanthan gum. More preferred is the modified cellulose, such as croscarmellose sodium, e.g. the commercial product Ac-Di- Soi.

The solid pharmaceutical dosage form can contain one or more surfactants (ionic surfactant or a non-ionic surfactant) other than phospholipids. Ionic surfactants can be anionic surfactants such as sodium lauryl sulfate or cationic surfactants such as cetyl pyridinium chloride and cetyltriethylammonium bromide. Non-ionic surfactants are e.g. polysorbates (such as polysorbate 20, 21 , 40, 80, 61 , 65, 80, 81 , 85 and 120) which are sold under the tradenames span and tween and poloxamer (e.g, Lutrol F127). In one embodiment of the present invention, the solid pharmaceutical composition comprises less than 5 % by weight based on the total weight of the composition, preferably less than 2.5 % and more preferably less than 1.0 % or no surfactant other than phospholipids.

Very often, pharmaceutical compositions also contain diluents and fillers and it is not excluded that the solid pharmaceutical composition of the present invention also contains diluents or fillers. However, in view of a high relative amount of sofosbuvir in the composition of the present invention it is preferred that the solid pharmaceutical composition contains no diluents and no fillers.

In one embodiment, the solid pharmaceutical composition of the present invention contains one or more glidants. one or more binders and one or more disintegrants (preferably superdisintegrants), and optionally at least one or more lubricants in addition to sofosbuvir and the phospholipid.

The solid pharmaceutical composition of the present invention e.g. comprises an amount of disintegrants (preferably superdisintegrants) of less than 20 %, preferably less than 15 % based on the total weight of the composition. However, the disintegrants (preferably superdisintegrants) in the solid pharmaceutical composition of the present invention can also be present in an amount of at least 10 %, or at least 12 %, or at least 14 % by weight based on the total weight of the composition. The amount of binder is preferably in the range of 4 to 20 %. The amount of binder can, e.g., be in the range of 10 to 18 %, or in the range of 12 to 17 %.

A process for preparing solid pharmaceutical compositions in the form of tablets according to the present invention, e.g., comprises the following process steps: i) preparing granules comprising amorphous sofosbuvir, phospholipid and optionally one or more glidants,

ii) compressing the granules together with at least one or more binders and one or more disintegrants and optionally one or more lubricants to form tablets, iii) iii) optionally coating the tablets.

In the following table, preferred solid pharmaceutical compositions of pharmaceutical compositions of the present invention are summarized. The compositions preferably contain the corresponding ingredient in the indicated amounts. Preferably, the compositions consist of the indicated ingredients in the indicated amounts, which means that no other ingredients are present.

The above total amounts are in percent and the total amount of all components add up to 100 % if no other ingredients are present

In the above table in a preferred embodiment the solid pharmaceutical composition comprises phosphatidylcholine.

In a further preferred embodiment silicium dioxide is contained as glidant.

It is further preferred embodiment croscarmellose sodium is contained as disintegrant.

In a further preferred embodiment MCC is contained as binder.

An embodiment which comprises the relative amounts indicated in the above table and wherein the phospholipids, glidants disintegrants and binders all comprise the preferred embodiments as indicated above is also preferred.

In addition to the active ingredient sofosbuvir, the solid pharmaceutical composition of the present invention can comprise one or more other active ingredients. A skilled person is well aware of the distinction between pharmaceutically active ingredients and pharmaceutical excipients.

Of course, the solid pharmaceutical composition according to the present invention can also be administered with one or more other active ingredients than sofosbuvir in a combination therapy wherein the one or more other active ingredient is/are comprised in (a) separate pharmaceutical composition(s) from the sofosbuvir composition. In particular, the solid pharmaceutical composition of the present invention can be used in known combination therapies, e.g. in the same way as the known commercial product Sovaldi^®.

For example, the one or more other therapeutic agents can be for treating HCV and/or other conditions such as HIV infections. In one embodiment, non-iimiting examples of suitable other therapeutic agents include interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-giucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs or therapeutic agents for treating HCV.

The one or more other therapeutic agents agent may further be those which treat other conditions, such as HIV infections. Accordingly, the one or more other therapeutic agents may be compounds useful in treating H!V, for example HIV protease inhibiting compounds, non-nucleoside inhibitors of HIV reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucieoside inhibitors of HCV, and other drugs for treating HCV.

Suitable one or more other therapeutic agents are particularly listed WO 2014/120981 to which it is explicitly referred.

In one embodiment, the solid pharmaceutical composition of the present invention comprises ledispavir. Ledispavir is in this case preferably comprised in the composition of the present invention in an amount of 10 to 25 % based on the total weight of the pharmaceutical composition. The present invention, e.g., relates to a solid pharmaceutical composition comprising ledispavir and wherein the total amount of sofosbuvir is 100-400 mg, preferably 300-400 mg and more preferably 400 mg. Such pharmaceutical compositions are, e.g., administered to a patient once a day. In one embodiment the pharmaceutical composition of the present invention comprises about 400 mg sofosbuvir and about 90 mg ledispavir. In another embodiment, the solid pharmaceutical composition does not contain ledispavir. The solid pharmaceutical composition of the present invention may then also be administered in combination with a separate pharmaceutical composition comprising ledispavir.

In one embodiment, the solid pharmaceutical composition of the present invention comprises velpatasvir. Velpatasvir is in this case preferably comprised in the pharmaceutical composition of the present invention in an amount of 1 to 15 % based on the total weight of the pharmaceutical composition. The present invention, e.g., relates to a solid pharmaceutical composition comprising velpatasvir and wherein the total amount of sofosbuvir is 100-400 mg, preferably 300-400 mg and more preferably 400 mg. In another preferred embodiment the present invention, e.g., relates to a solid pharmaceutical composition comprising velpatasvir and wherein the total amount of sofosbuvir is below 350 mg or below 300 mg, preferably 200-350 mg or 250-350 mg. Such pharmaceutical compositions are, e.g., administered to a patient once a day. In one embodiment, the pharmaceutical composition of the present invention comprises sofosbuvir in one of the afore described amounts and 10-150 mg velpatasvir. In another embodiment, the solid pharmaceutical composition does not contain velpatasvir. The solid pharmaceutical composition of the present invention may then also be administered in combination with a separate pharmaceutical composition comprising velpatasvir.

The solid pharmaceutical compositions according to the present invention are preferably for use in treating hepatitis C virus infections. As indicated above, the compositions according to the present invention can be used alone or in the form of a combination therapy as is known in the art.

In one embodiment, the present invention relates to a solid pharmaceutical composition wherein the composition comprises a melt extrudate comprising amorphous sofosbuvir, phospholipid and optionally further constituents, and wherein the extrudate is obtainable by melt extruding the phospholipid together with crystalline sofosbuvir and optionally further constituents. The present invention further also relates to a process for preparing solid pharmaceutical compositions according to the present invention comprising the step of melt extruding the phospholipid together with crystalline sofosbuvir and optionally further constituents to obtain an extrudate comprising amorphous sofosbuvir, phospholipid and optionally further constituents.

The solid pharmaceutical composition according to the present invention is preferably one wherein the composition comprises granules comprising amorphous sofosbuvir, phospholipid and optionally further constituents, and wherein the granules are obtainable by melt extruding the phospholipid together with crystalline sofosbuvir and optionally further constituents and shaping the extrudate into granules. The shaping can e.g. be performed by cutting, breaking, spheronizing or sieving the extrudate to form granules,

The present invention further also relates to a process for preparing solid pharmaceutical compositions according to the present invention comprising the following process step: a) melt extruding the phospholipid together with crystalline sofosbuvir and optionally further constituents and shaping the extrudate into granules comprising amorphous sofosbuvir, phospholipid and optionally further constituents.

In one embodiment at least a glidant, e.g. colloidal silicon dioxide, is used as further constituent.

In one embodiment, step a) in the process comprises steps a1 ) granulating the phospholipid onto one or more glidants and drying the obtained glidant/phospholipid granules

a2) blending the dried glidant/phospholipid granules with crystalline sofosbuvir and optionally sieving the blend

a3)melt extruding the blend and shaping the extrudate into granules comprising amorphous sofosbuvir, phospholipid and glidant(s).

The granules can of course also comprise further constituents than sofosbuvir, phospholipid and glidant(s). During melt extrusion a temperature above the melting temperature of the employed crystalline sofosbuvir should be used. In the melt extrusion process crystalline sofosbuvir should be converted into amorphous sofosbuvir. In one embodiment, the phospholipid and crystalline sofosbuvir and optionally further constituents are melt-extruded using an extrusion temperature above 100 °C, preferably above 1 10 °C, 120 or 125 °C.

For example, granules comprising amorphous sofosbuvir can e.g. be prepared by melt extruding the blend of the dried glidant/phospholipid granules with crystalline sofosbuvir on a twin screw extruder, preferably using a temperature of at least 100 °C, preferably above 1 10 °C, 120 or 125 "C, and sieving the extrudate to obtain the granules.

The granules can be further processed; for example, tablets can be compressed using the granules or capsules can be filled with the granules. In the present invention, the tablets e.g. have a hardness between 100 and 200 N.

Preferably, the process according to the present invention and by which the solid pharmaceutical compositions of the present invention are obtainable comprises the following process steps after step a): b) compressing the granules together at least with one or more binders and one or more disintegrants and optionally one or more lubricants to form tablets

c) optionally coating the tablets.

In one embodiment, the solid pharmaceutical compositions according to the present invention are prepared by a method as shown in the example of this application.

Instead of solid pharmaceutical compositions comprising amorphous sofosbuvir and at least one phospholipid, also solid pharmaceutical compositions comprising crystalline sofosbuvir and at least one phospholipid can be prepared for obtaining compositions with favorable properties.

The crystalline sofosbuvir can have any of the crystalline forms as described in US patent applications Nos, 2010/0298257, 201 1/0251 152, 2010/0016251 and US patent 7,964,580. Other crystalline forms can also be used. Preferably, in the solid pharmaceutical compositions comprising crystalline sofosbuvir and at least one phospholipid the crystalline sofosbuvir is a crystal form of sofosbuvir as described in CN 104130302 A to which it is explicitly referred. Preferably, crystalline sofosbuvir as described in any of claims 1 -10 of CN 104130302 A is used. In one embodiment of the solid pharmaceutical compositions comprising crystalline sofosbuvir and at least one phospholipid, a crystal form A of sofosbuvir having an X-ray powder diffraction pattern comprising peaks expressed in degrees 2Θ at 8.19, 12.47 and 19.47 ± 0.2, wherein the X-ray powder diffraction pattern is obtained using copper K-alpha radiation, is thus comprised in the solid pharmaceutical composition.

In the following, some embodiments of solid pharmaceutical compositions comprising crystalline sofosbuvir and at least one phospholipid and a preparation process thereof are described:

Embodiment 1 : Solid pharmaceutical composition comprising crystalline sofosbuvir and at least one phospholipid.

Embodiment 2: Solid pharmaceutical composition according to embodiment 1 , wherein the composition is in the form of a tablet.

Embodiment 3: Solid pharmaceutical composition according to embodiment 1 or 2, wherein the at least one phospholipid is a phosphoglyceride of formula I

R-C

R—C

wherein R1 and R2 are independently selected from H and C1 -C24 optionally substituted straight or branched alkyl, alkenyl, or alkynyl chains,

R3 is H, -CH2-CHNH2-COOH, CH2-CHOH-CH20H, or -CH2-CH2-N'{CH3). H₃.,, wherein n is 0, 1 , 2 or 3, and R4 is a negative charge, H or a C1 -C24 optionally substituted straight or branched alkyl, alkenyl, or alkynyi chain, or a sphingophosphatide of formula II

(II)

wherein R5 is defined as R1 in formula (I) above, and

R6 is defined as R4 in formuia (I) above.

Embodiment 4: Solid pharmaceutical composition according to any of embodiments 1 -3, wherein the at least one phospholipid is a phosphoglyceride of formula I, wherein R1 and R2 are independently selected from C4-C24 alkyi or alkenyl chains, R3 is CH2-CH2- N+(CH3)3 and R4 is a negative charge or H.

Embodiment 5: Solid pharmaceutical composition according to any of embodiments 1 -4, wherein the at least one phospholipid is a phosphatidylcholine.

Embodiment 6: Solid pharmaceutical composition according to any of embodiments 1 -5, wherein the composition comprises sofosbuvir in an amount of 35 to 55 %, more preferably 40 to 50, based on the total weight of the composition.

Embodiment 7: Solid pharmaceutical composition according to any of embodiments 1 -6, wherein the composition comprises about 400 mg sofosbuvir.

Embodiment 8: Solid pharmaceutical composition according to any of embodiments 1 -7, wherein the composition comprises at least 5 % phospholipids in total based on the total weight of the composition. Embodiment 9: Solid pharmaceutical composition according to any of embodiments 1-8, wherein the composition comprises one or more glidants in a total amount of at least 10 % based on the total weight of the composition.

Embodiment 10: Solid pharmaceutical composition according to any of claims 1 -9, wherein the composition comprises one or more other active ingredients in addition to sofosbuvir.

Embodiment 1 1 : Solid pharmaceutical composition according to any of embodiments 1-10, wherein the composition comprises ledispavir.

Embodiment 12: Solid pharmaceutical composition according to any of embodiments 1-1 1 , wherein the composition comprises velpatasvir.

Embodiment 13: Solid pharmaceutical composition according to any of embodiments 1-12, wherein the composition is for use in the treatment of hepatitis C virus infections.

Embodiment 14: Process for preparing solid pharmaceutical compositions in the form of tablets according to any of embodiments 2-13 comprising the following process steps: a) preparing granules comprising sofosbuvir, phospholipid and optionally one or more glidants

b) compressing the granules together with at least one or more binders and one or more disintegrants and optionally one or more lubricants to form tablets c) optionally coating the tablets.

Furthermore, features and embodiments that have been described above for the solid pharmaceutical composition of the present invention comprising amorphous sofosbuvir also apply for the solid pharmaceutical composition comprising crystalline sofosbuvir and at least one phospholipid and the preparation process thereof (if nothing else is obvious to the skilled person). For example, when it is described above that in one more preferred embodiment, the solid pharmaceutical composition of the present invention comprises a lecithin which comprises phosphatidylcholine, such as Lipoid S75, this means - applied to the solid pharmaceutical composition comprising crystalline sofosbuvir and at least one phospholipid - that in one more preferred embodiment of such pharmaceutical composition comprising crystalline sofosbuvir and at least one phospholipid the composition comprises a lecithin which comprises phosphatidylcholine, such as Lipoid S75,

The following example and comparative examples are illustrative without restricting the scope of protection. If in the examples and comparative examples a process detail is not explicitly described, a skilled person can easily find such detail according to the general practice in the art.

Example 1 ; Pharmaceutical composition with Phospholipid

'adjusted to potency of the active

"amount of Lipoid S 75 (according to the manufacturer Lipoid S 75 contains approximately 70 wt.-% phosphatidylcholine

Manufacturing;

Lipoid was dissolved in Ethanoi and granulated on the Syloid 244 FP and dried in a cabinet dryer at 40°C. Syloid 244FP/Lipoid granules were mixed together with crystalline Sofosbuvir (Form I) for 5 min in a tumble blender. The mixture was sieved through a 1000pm sieve and blended in a tumble blender for 5 minutes. The mixture was extruded on a 9mm twin screw extruder with 30 RpM and temperatures Zone 1 : 80°C, Zone 2: 100°C. Zone 3: 1 10 °C without die. The extrudate was sieved step wise through a 500 μητι, 250pm and 125pm sieve. 1/3 of sieved (mesh size SOOpm) PRUV was added and mixed for 5 min in a tumble blender. Avicel and Ac-Di-Sol were sieved (mesh size 500pm) added and mixed together for 5 min in a tumble blender. Residual PRUV was added through a sieve (mesh size SOOpm) and the final blend was mixed for further 3min in a tumble blender. The final blend was compressed into oblong tablets on an eccentric press with a hardness of about 120 N, The tablets contained amorphous sofosbuvir due to a conversion of crystalline sofosbuvir to amorphous sofosbuvir during the melt extrusion process. The tablets were subjected to dissolution tests. The conditions were the usual conditions of the US Pharmacopeia with paddle apparatus II in 900 ml of an aqueous solvent with a pH of 1.2 (0.1 M HCI) (n=3), 4.5 (50 mM acetate buffer) (n=3) or 8.8 (50 mM phosphate buffer) (n=2) at 37X and 75 rpm.

Figure 1 shows the dissolution of the tablets of example 1

Example 2: Pharmaceutical composition with Phospholipid

^*adjusted to potency of the active

Manufacturing and dissolution tests (at pH = 6.8) were performed as described in example

1. The tablets contained amorphous sofosbuvir due to a conversion of the employed crystalline sofosbuvir Form I to amorphous sofosbuvir during the melt extrusion process. The tablet size was 18 x 8.7 mm.

Figure 2 shows the dissolution of 3 tablets of example 2,

Comparative Exampie 1 : Pharmaceutical composition with Poloxamer

'adjusted to potency of the active

Manufacturing:

Lutrol was dissolved in Ethanol/Water 1 :1 and granulated on the Syioid 244 FP and dried in a cabinet dryer at 40°C. Syloid 244FP/Lutrol granules were mixed together with crystalline Sofosbuvir for 5 min in a tumble blender. The mixture was sieved through a 100pm sieve and blended in a tumble blender for 5 minutes. The mixture was extruded on a 9mm twin screw extruder with 30 RpM and temperatures Zone 1 : 80 X, Zone 2: 100°C, Zone 3: 1 10°C without die. The extrudate was sieved step wise through a 500pm, 250pm and 125pm sieve. 1/3 of sieved (mesh size 500pm) PRUV was added and mixed for 5 min in a tumble blender. Avicel and Ac-Di-Sol were sieved (mesh size 500pm) added and mixed together for 5 min in a tumble blender. Residual PRUV was added through a sieve (mesh size 500pm) and the final blend was mixed for further 3min in a tumble blender. The final blend was compressed into oblong tablets 21 x 10 mm on an eccentric press with a hardness of about 120 N. The tablets contained amorphous sofosbuvir due to a conversion of crystalline sofosbuvir to amorphous sofosbuvir during the melt extrusion process.

The tablets were subjected to dissolution tests as described in the exampie above (pH 1 ,2 (n=3), 4.5 (n=3) or 6.8 (n=2)).

Figure 3 shows the dissolution of the tablets of comparative example 1 .

Comparative Example 2: Amorphous active ingredient

Method 1 : Amorphous sofosbuvir from Ethanol Form 1 of Sofosbuvir (8 g) was dissolved in ethanol (20 ml_). The solvent was removed on a rotary evaporator (bath temperature 50°C). The resulting solid was further dried in a vacuum oven at 40°C / 10 mbar for two days.

Method 2: Amorphous sofosbuvir by grinding

Form 1 of Sofosbuvir (8 g) was milled in a planetary ball mill (Fritsch Pulverisette 6) with 8 Zirkonium oxide grinding balls (25 mm diameter) for 1 h at 300 rpm.

400 mg of the samples as obtained above were subjected to dissolution tests. Dissolution tests at pH = 6.8 (50 mM phosphate buffer) were performed as described in example 1 above (n= 2)). Additionally, a dissolution test was performed with amorphous sofosbuvir (as obtained according to method 1 ) wherein a dissolution medium containing Tween was used (pH = 6.0, 1.5 % Tween 80, 10 mM phosphate buffer).

Figure 4 shows the dissolution of amorphous sofosbuvir samples of comparative example 2 (amorph (from EtOH) in pH 6.0 1 .5 % Tween 80 (n = 2), amorph (from grinding) in pH 6.8 (n = 2), amorph (from EtOH) in pH 6.8 (n = 2)).

Comparative Example 3: Sovaldi tablets

Sovaldi tablets (Batch MXHVD) were subjected to dissolution tests as described in the example above (pH 1 .2 (n=3), 4.5 (n=3) or 6.8 (n=6)).

Figure 5 shows the dissolution of the Sovaldi tablets of comparative example 3.

Claims

1. Solid pharmaceutical composition comprising amorphous sofosbuvir and at least one phospholipid.

2. Solid pharmaceutical composition according to claim 1 , wherein the composition is in the form of a tablet.

3. Solid pharmaceutical composition according to claim 1 or 2, wherein the at least one phospholipid is a phosphoglyceride of formula I

R CO-O— CH₂

R^CO-O— CH O

! ll

H₂C— O— P-O-R ,

OR₄

(I)

wherein R1 and R2 are independently selected from H and C1 -C24 optionally substituted straight or branched alkyi, alkenyl, or a!kynyl chains,

R3 is H, -CH2-CHNH2-COOH, CH2-CHOH-CH20H, or -CH2-CH2-N^*(CH3)_nH₃.n wherein n is 0, 1 , 2 or 3, and

R4 is a negative charge, H or a C1 -C24 optionally substituted straight or branched alkyl, alkenyl, or alkynyl chain. or a sphingophosphatide of formula II

CH_r(CH_?)_l ~CH=CH-CHCH

R— CO— NH-CH O

CH.T-0— P O— CH₂—-CH— (CH₃)₃

OR₆

(II)

wherein R5 is defined as R1 in formula (I) above, and

R6 is defined as R4 in formula (I) above.

4. Solid pharmaceutical composition according to any of claims 1 -3, wherein the at least one phospholipid is a phosphoglyceride of formula I,

wherein R1 and R2 are independently selected from C4-C24 alkyl or alkenyl chains, R3 is CH2-CH2-N+(CH3)3 and R4 is a negative charge or H.

5. Solid pharmaceutical composition according to any of claims 1-4, wherein the at least one phospholipid is a phosphatidylcholine.

6. Solid pharmaceutical composition according to any of claims 1 -5, wherein the composition comprises sofosbuvir in an amount of 35 to 55 % based on the total weight of the composition.

7. Solid pharmaceutical composition according to any of claims 1-6, wherein the composition comprises about 400 mg sofosbuvir.

8. Solid pharmaceutical composition according to any of claims 1 -7, wherein the composition comprises at least 5 % phospholipids in total based on the total weight of the composition.

9. Solid pharmaceutical composition according to any of claims 1 -8, wherein the composition comprises one or more glidants in a total amount of at least 10 % based on the total weight of the composition.

10. Solid pharmaceutical composition according to any of claims 1 -9, wherein the composition comprises one or more other active ingredients in addition to sofosbuvir.

1 1 . Solid pharmaceutical composition according to any of claims 1 -10, wherein the composition comprises ledispavir.

12. Solid pharmaceutical composition according to any of claims 1 -1 1 , wherein the composition comprises velpatasvir.

13. Solid pharmaceutical composition according to any of claims 1 -12, wherein the composition comprises granules comprising amorphous sofosbuvir, phospholipid and optionally further constituents, and wherein the granules are obtainable by melt-extruding the phospholipid together with crystalline sofosbuvir and optionally further constituents and shaping the extrudate into granules,

14. Solid pharmaceutical composition according to any of claims 1 -13, wherein the composition is for use in the treatment of hepatitis C virus infections.

15. Process for preparing solid pharmaceutical compositions according to any of claims 1-14 comprising the following process step: a) melt extruding the phospholipid together with crystalline sofosbuvir and optionally further constituents and shaping the extudate into granules comprising amorphous sofosbuvir, phospholipid and optionally further constituents.

16. Process according to claim 15 further comprising the following process steps: b) compressing the granules together with at least one or more binders and one or more disintegrants and optionally one or more lubricants to form tablets

c) optionally coating the tablets.