WO2018153977A1 - Stable composition of tenofovir alafenamide - Google Patents

Abstract

The present invention relates to a composition comprising tenofovir alafenamide, a stabilizing agent, preferably an earth alkali salt and/or silicon dioxide, and a pharmaceutical excipient. Further, the invention relates to a method of preparing said composition. The pharmaceutical compositions of the present invention can be used for the treatment and/or prophylaxis of viral infections such as HIV infections.

Description

Stable composition of tenofovir alafenamide

The present invention relates to a composition comprising tenofovir alafenamide, a stabilizing agent, preferably an earth alkali salt and/or silicon dioxide, and a pharmaceutical excipient. Further, the invention relates to a method of preparing said composition. The pharmaceutical compositions of the present invention can be used for the treatment and/or prophylaxis of viral infections such as HIV infections.

Background of the Invention

Tenofovir alafenamide is a prodrug of tenofovir, wherein tenofovir is reported to be useful in the treatment of viral infections. The IUPAC name of tenofovir alafenamide is 9-[(R)- 2-[[(S)-[[(S)- 1 -(isopropoxycarbonyl)ethyl]amino]phenoxy- phosphinyl]methoxy]propyl] adenine and the compound is represented by the following chemical structure according to formula (I):

formula (I)

As mentioned above, tenofovir alafenamide is an antiviral compound useful for the treatment and/or prophylaxis of viral infections including infections caused by DNA viruses, RNA viruses, herpesviruses (e.g. CMV, HSV 1 , HSV 2, VZV), retroviruses, hepadnaviruses (e.g. HBV), papillomavirus, hantavirus, adenoviruses and HIV. The compound is also known under the lab code "GS-7340". Tenofovir alafenamide may be administered alone or in combination with other antiviral agents to patients in need.

Tablets containing tenofovir alafenamide are marketed under the tradename Vemlidy. According to the prescribing information, apart from the pharmaceutical active ingredient the tablets contain croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Further, the tablets are film-coated with a coating containing iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Furthermore, tenofovir alafenamide is also marketed under the tradenames Genvoya (a four-drug combination of elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide), Odefsey (a three-drug combination of emtricitabine, tenofovir alafenamide and rilpivirine) and Descovy (a two-drug combination of emtricitabine and tenofovir alafenamide). The chemical name, empirical formula, molecular weight, and structure of the active ingredient tenofovir alafenamide fumarate in the prescribing information show that the marketed products contain the hemifumarate form of tenofovir alafenamide. Tenofovir alafenamide may occur in free form as well as in the form of acid addition salts, cocrystals and/or crystalline forms.

For example, WO 02/008241 A2 discloses crystalline tenofovir alafenamide free base and a tenofovir alafenamide monofumarate (referred to herein as form I) as well as processes for their preparations. Another disclosure of tenofovir alafenamide monofumarate can be found in Example 6 and Figure 2 of WO 2015/040640 A2. According to the latter document, the process for the preparation is similar to the process described in Example 4 of WO 02/008241 A2. WO 2013/025788 Al describes a crystalline hemifumarate form of tenofovir alafenamide. Further, it is reported in paragraph [0071] of the document that the solid form of tenofovir alafenamide monofumarate obtained by the procedure described in WO 02/084241 A2 is thermodynamically unstable. In view of this a stress stability of tenofovir alafenamide hemifumarate (referred to hereinafter as TAF HF) and tenofovir alafenamide monofumarate (referred to hereinafter as TAF MF) was performed. The testing conditions for evaluation of the chemically stability were as follows:

- 7 days at 60°C / 75%RH, open dish; (60°C/75 OD -7days)

- 7 days at 60°C / 30%RH, open dish; (60°C/30 OD -7days)

- 7 days at 60°C closed vial (60°C - 7 days)

- 7 days at 40°C closed vial (40°C - 7 days)

Table 1 : stability test of TAF HF and TAF MF

Both TAF HF and TAF MF show significant degradation under stress conditions. Two major degradants were formed, which were identified as PMPA ((R)-9-[2- (phosphonomethoxy)propyl]adenine) and phenyl hydrogen((((i?)-l-(6-amino-0H-purin- 9-yl)propan-2-yl)oxy)methyl)phosphonate.

Thus, there is still a need for a pharmaceutical composition containing tenofovir alafenamide, wherein the stability of the active pharmaceutical ingredient can be ensured. In particular, a pharmaceutical composition in which the degradation of the active pharmaceutical ingredient is prevented or at least significantly reduced even under harsh conditions should be provided. Hence, it was an object of the present invention to overcome the drawbacks of the above-mentioned prior art.

In particular, it was an object of the present invention to provide a chemically stable pharmaceutical composition containing tenofovir alafenamide wherein the degradation is advantageously reduced. In addition, it was an object of the present invention to provide a physically stable pharmaceutical composition, i.e. a pharmaceutical composition in which the conversion of the active pharmaceutical ingredient into other polymorphic form(s) is advantageously reduced or prevented. Thus, it was an object to provide a pharmaceutical composition in which the tenofovir alafenamide is present in a stabilized form. It was another object to provide a stable pharmaceutical composition containing tenofovir alafenamide wherein the potential cracking of the film-coating is avoided or at least significantly reduced.

Summary of the invention

According to the present invention, the above objects are unexpectedly achieved by a pharmaceutical composition comprising tenofovir alafenamide, an earth alkali metal salt and/or silicon dioxide, and pharmaceutical excipient, wherein the pharmaceutical composition has a specific water activity. Alternatively, the above objects are unexpectedly achieved by a pharmaceutical composition comprising (A) tenofovir alafenamide, (B) silicon dioxide, magnesium chloride, calcium chloride and/or magnesium sulfate as well as (C) a pharmaceutical excipient, preferably having a water content of less than 3 wt%. Thus, a subject of the invention is a pharmaceutical composition comprising

(A) tenofovir alafenamide

(B) earth alkali metal salt and/or silicon dioxide

(C) pharmaceutical excipient, wherein the pharmaceutical composition has a water activity value being less than 0.15. An alternative subject of the invention is a pharmaceutical composition comprising

(A) tenofovir alafenamide

(B) silicon dioxide, magnesium chloride, calcium chloride and/or magnesium sulfate (C) pharmaceutical excipient, wherein the pharmaceutical excipient (C) preferably has a water content of less than 3 wt%.

Both subjects are alternative solutions to the above-mentioned problem.

A further subject of the invention is the method for preparing a dosage form according to the present invention comprising the steps of providing component (A), component (B) and component (C), optionally dry granulating the mixture from step (i) and optionally one or more further pharmaceutical excipient(s) (D),

compressing the mixture from step (i) or the granules from step (ii) and optionally one or more further pharmaceutical excipient(s) (D) to a tablet or

filling the mixture from step (i) or the granules from step (ii) and optionally one or more further pharmaceutical excipient(s) (D) into a capsule.

Further, the invention relates to the pharmaceutical composition according to the present invention for use in the treatment and/or prophylaxes of HIV and HBV infections.

It was unexpectedly found that the pharmaceutical composition of the present invention allows the stabilisation of tenofovir alafenamide. Thus, an advantageous composition can be provided which shows, even under harsh conditions, an advantageously reduced amount of degradation product of the active pharmaceutical ingredient.

Definitions

Where the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. For the purpose of the present invention, the term "consisting of is considered to be the preferred embodiment of the term "comprising". If hereinafter a group is defined as comprising at least a certain number of embodiments, this is also to be understood as disclosing a group which optionally consists only of these embodiments.

Where an indefinite or definite article is used when referring to a singular noun e.g. "a", "an" or "the", this includes a plural of the noun unless something else is specifically stated.

Furthermore, the terms "(i)", "(ii)" and "the like" in the description and the claims are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. The term "oral dosage form" as used herein denotes preparations (e.g. tablets) for oral administration, each containing a single dose of one or more active pharmaceutical ingredient(s).

As described herein, the term "tenofovir alafenamide" refers to 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino]phenoxyphosphinyl]methoxy]propyl] adenine according to formula (I) disclosed herein above. A process for the preparation is disclosed in WO 02/008241 A2. Further, the term tenofovir alafenamide as used herein also refers to tenofovir alafenamide in the form of the free base as well as to its pharmaceutically acceptable salts, cocrystals, hydrates, solvates, polymorphs and mixtures thereof. Thus, for example the invention also refers to polymorphs of pharmaceutically acceptable salts or cocrystals of tenofovir alafenamide according to formula (I) or to solvates of salts or hydrates or polymorphs or the like.

A pharmaceutically acceptable acid addition salt of tenofovir alafenamide can for example be obtained by the reaction of tenofovir alafenamide with any acid which can form a pharmaceutically acceptable, non-toxic tenofovir alafenamide acid addition salt. Suitable acids can for example be sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, hydrobromic acid, acetic acid, fumaric acid, succinic acid, maleic acid, citric acid and tartaric acid.

In the context of the present invention, the term "chemical stability" means that the sum of all degradation products derived from tenofovir alafenamide is below 2.0%, preferably below 0.5% of the total amount of tenofovir alafenamide subjected to defined conditions. In a preferred embodiment, these conditions are selected from:

- 7 days at 60°C closed vial

- 7 days at 60°C, 10 μΐ, water, closed vial

Analysis and detection of degradation products is performed by HPLC.

As used herein, the term "measured at a temperature in the range of from 20 to 30°C" refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature. Standard conditions can mean a temperature of about 22°C. Standard conditions can also mean a temperature of about 25°C. Typically, standard conditions can additionally mean a measurement under 20-80% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% relative humidity. As used herein, the term "room temperature" refers to a temperature in the range of 20 to 30°C.

Further, an earth alkali metal salt is referred to as a salt wherein the cation is an earth alkali metal cation such as magnesium, calcium or barium. Preferably, the anion is an inorganic anion. An inorganic anion is for example referred to as an anion being substantially free of carbon atoms, wherein carbonate and bicarbonate are exceptions and thus considered as inorganic anions. Further examples of inorganic anions are halogens such as chloride, bromide and iodide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, nitrate, nitrite and the like. Alternatively preferred the anion can be an organic anion. Examples of organic anions include acetate and citrate, in particular citrate. Especially preferred is magnesium citrate as organic earth alkali salt. The term "anhydrous" as used herein, refers to a solid wherein no water is coordinated in or accommodated by the crystal structure. However, an anhydrate or a solid in anhydrous form may still comprise residual water due to surface adsorption, solvent inclusions and/or absorption in disordered regions. The term "solvate" as used herein refers to a solid wherein one or more organic solvent(s) is/are coordinated in or accommodated by the crystal structure. The term "hydrate" refers to a solid wherein water is coordinated in or accommodated by the crystal structure.

"Tenofovir alafenamide hemifumarate" as used herein refers to the hemifumarate form of tenofovir alafenamide, having a chemical structure wherein about two molecules of tenofovir alafenamide are associated with one molecule of fumaric acid. In one embodiment, the tenofovir alafenamide hemifumarate can be a crystalline salt, wherein protons have been transferred from at least some of the fumaric acid molecules to tenofovir alafenamide molecules. Since fumaric acid is a dicarboxylic acid, either one proton (i.e. hydrogen fumarate) or two protons (i.e. fumarate) can be transferred, dependent on the environment. In another embodiment, the tenofovir alafenamide hemifumarate can be a cocrystal, wherein substantially no protons have been transferred from fumaric acid molecules to tenofovir alafenamide molecules. Preferably, the term "tenofovir alafenamide hemifumarate" as used herein refers to a cocrystal.

Similarly, tenofovir alafenamide monofumarate as used herein refers to the monofumarate form of tenofovir alafenamide having a chemical structure comprising about one molecule of tenofovir alafenamide per molecule fumaric acid. In one embodiment, the tenofovir alafenamide monofumarate can be a crystalline salt, wherein protons have been transferred from at least some of the fumaric acid molecules to tenofovir alafenamide molecules. Since fumaric acid is a dicarboxylic acid, either one proton (i.e. hydrogen fumarate) or two protons (i.e. fumarate) can be transferred, dependent on the environment. In another embodiment, the tenofovir alafenamide monofumarate can be a cocrystal, wherein substantially no protons have been transferred from fumaric acid molecules to tenofovir alafenamide molecules. Preferably, the term "tenofovir alafenamide monofumarate" as used herein refers to a cocrystal. Tenofovir alafenamide monofumarate has a molar ratio of tenofovir alafenamide and fumaric acid typically and preferably in a range of from about 1.0 : 0.7 to 1.0 : 1.3, more preferably in a range of from about 1.0 : 0.8 to 1 : 1.2, most preferably in a range of from about 1.0 : 0.9 to 1 : 1.1, and in particular the molar ratio is about 1.0 : 1.0. The transfer of protons from one molecule to another in a crystal is dependent on the environment. Crystalline salts and cocrystals may be thought of as two ends of a proton transfer spectrum, where the salt has completed the proton transfer at one end and an absence of proton transfer exists for cocrystals at the other end. Detailed Description of the Invention

The present invention illustratively described in the following may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.

The present invention relates to a pharmaceutical composition comprising (A) tenofovir alafenamide, (B) earth alkali metal salt and/or silicon dioxide, and (C) pharmaceutical excipient, wherein the pharmaceutical composition has a water activity value of less than 0.15.

Preferably, the earth alkali metal salt is an inorganic earth alkali metal salt. In a preferred embodiment of the invention in the inorganic alkali earth metal salt the cation can be an alkali earth metal cation, can preferably a magnesium or calcium cation. Further, the inorganic anion can preferably be a halogen or a sulfate. In a particularly preferred embodiment the inorganic alkali earth metal salt can be magnesium chloride (MgCb), calcium chloride (CaCl₂), magnesium sulfate (MgS04) or mixtures thereof, especially magnesium chloride (MgCl₂). In a preferred embodiment component (B) can be silicon dioxide, in particular amorphous silica. The silicon dioxide can have a specific surface area of 600 to 1000 m²/g, preferably about 800 m²/g. The specific surface area is regarded as "BET"-surface area and determined according to Ph. Eur., 6^th edition, Chapter 2.9.26. Preferably the silicon dioxide has a density between 0.3 and 0.5 kg/dm³. An example of preferred silicon dioxide is available under the tradename Syloid^®, preferably Syloid^® AL-1.

It is further preferred that silicon dioxide (S1O2), magnesium chloride (MgCl₂), calcium chloride (CaCl₂) and/or magnesium sulfate (MgS0₄) can be present in an anhydrous form.

In an alternatively preferred embodiment magnesium chloride (MgCl₂), calcium chloride (CaCl₂) and/or magnesium sulfate (MgS04) can be present in hydrated form. For example magnesium chloride (MgCl₂) can be present as magnesium chloride hexahydrate (MgCl₂x6H₂0). Further, calcium chloride (CaCl₂) can be present as calcium chloride dihydrate (CaCl₂x2H₂0). Magnesium sulfate (MgS0₄) can for example be present as magnesium sulfate heptahydrate (MgS04x7H₂0).

In a further aspect of the invention component (B) can be an alkali metal salt, preferably selected from sodium sulfate (Na₂S04) and sodium acetate (NaOAc) or a zinc salt, preferably ZnS0₄.

The pharmaceutical composition of the present invention further comprises a pharmaceutical excipient (C). Suitbale pharmaceutical excipients are for example disclosed in "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", published by H.P. Fielder, 4^th Edition, and "Handbook of Pharmaceutical Excipients", 3^rd Edition, published by A.H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London. It is preferred that the pharmaceutical excipient (C) has a water content of less than 3 wt%. It is further preferred that the pharmaceutical excipient (C) has a water content of less than 2.5 wt%, more preferably less than 2.0 wt%. In a particularly preferred embodiment the pharmaceutical excipient (C) has a water content of less than 1.5 wt%. The lower limit of the water content could be e.g. 0.01 wt%, 0.1 wt%, 0.2 wt% or 0.5 wt%. The water content can be preferably determined as described below in the experimental section.

Further, the pharmaceutical composition of the present invention has a water activity value of less than 0.15, preferably less than 0.12, in particular less than 0.10. Contrary to the content of water of a substance or composition, the water activity value is a measure for the "active" or "available" water of the substance or composition. The water activity value (a_w) is defined as the ratio of the water vapor partial pressure of the substance (p) to the saturated vapor pressure of pure water (po) at a distinct temperature and thus can be calculated from the following equation: a_w= p / po

The water activity value of a substance or composition can be preferably determined as described below in the experimental section.

The present invention relates to an alternative pharmaceutical composition comprising (A) tenofovir alafenamide, (B) silicon dioxide, magnesium chloride, calcium chloride and/or magnesium sulfate and (C) pharmaceutical excipient.

In a preferred embodiment the above-described embodiments could be combined. As far as (A) tenofovir alafenamide is concerned, the same applies as described above.

Further, the earth alkali metal salt of component (B) can be one or more specific salt(s) selected from magnesium chloride, calcium chloride and/or magnesium sulfate. As far as these specific salts are concerned, the same applies as described above.

Component (C) can be a pharmaceutical excipient to which the same applies as described above. It is preferred that the (C) pharmaceutical excipient has a water content of less than 3.0 wt%, preferably of less than 2.5 wt%, more preferably less than 2.0 wt%, in particular of less than 1.5 wt%. The lower limit of the water content could be e.g. 0.01 wt%, 0.1 wt%, 0.2 wt% or 0.5 wt%.

As described above the term "tenofovir alafenamide" refers to 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino]phenoxyphosphinyl]methoxy]propyl] adenine according to above formula (1) as well as to tenofovir alafenamide in the form of the free base as well as to its pharmaceutically acceptable salts, cocrystals, hydrates, solvates, polymorphs and mixtures thereof. In a preferred embodiment component (A) is present in a crystalline form of tenofovir alafenamide fumarate, more preferably in form of tenofovir alafenamide hemifumarate or tenofovir alafenamide monofumarate.

In a particularly preferred embodiment component (A) can be tenofovir alafenamide hemifumarate .

In a preferred embodiment crystalline tenofovir alafenamide hemifumarate as used herein can be the crystalline form of tenofovir alafenamide hemifumarate disclosed in WO 2013/025788 Al . A polymorphic form can be represented by one or more, preferably at least three, specific diffraction peaks in X-ray powder diffraction (XRPD).

In the present application, the XRPD is measured as described below in the experimental section. Tenofovir alafenamide hemifumarate as disclosed in WO 2013/025788 Al can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.9 ± 0.2)°, (8.6 ± 0.2)°, (10.0 ± 0.2)°, (1 1.0 ± 0.2)°, (12.2 ± 0.2)°, (15.9 ± 0.2)°, (16.3 ± 0.2)°, (20.2 ± 0.2)° and (20.8 ± 0.2)° when measured at a temperature in the range of from 20 to 30°C with Cu K-alpha₁₎₂ radiation having a wavelength of 0.15419 nm. The term "reflection" with regards to powder X-ray diffraction as used herein means peaks in an X-ray diffractogram which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to the literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see "Fundamentals of Powder Diffraction and Structural Characterization of Materials " by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

The term "essentially the same" with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-theta. Thus, a reflection that usually appears at 7.3° 2-Theta for example can appear between 7.1° and 7.5° 2-theta, preferably between 7.2° and 7.4° 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

As used herein, the term "substantially pure" with reference to a particular physical form means that the physical form includes at most 20%, preferably at most 10%, more preferably at most 5%, even more preferably at most 3% and most preferably at most 1 wt% of any other physical form of the compound.

In an alternatively particular preferred embodiment component (A) can be tenofovir alafenamide monofumarate. Tenofovir alafenamide monofumarate as component (A) can be preferably present in crystalline form.

In a preferred embodiment crystalline component (A) can be the crystalline form of tenofovir alafenamide monofumarate form I as described in example 4 of WO 02/08241 A2. This form can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (5.3 ± 0.1)°, (9.8 ± 0.1)°, (10.4 ± 0.1)°, (15.9 ± 0.1)°, (16.2 ± 0.1)° and (16.6 ± 0.1)° when measured at a temperature in the range of from 20 to 30°C with Cu K-alphai,₂ radiation having a wavelength of 0.15419 nm.

In an alternatively preferred embodiment crystalline component (A) can be the crystalline form of tenofovir alafenamide monofumarate in form II. Tenofovir alafenamide monofumarate in form II can be prepared by suspending tenofovir alafenamide monofumarate in form I in acetonitrile at room temperature, for example as described in Example 1 of PCT/EP2017/052121 filed on February 1, 2017. Tenofovir alafenamide monofumarate in form II can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of:

(7.3 ± 0.2)°, (9.4 ± 0.1)° and (10.1 ± 0.1)°; or

(7.3 ± 0.2)°, (9.4 ± 0.1)°, (10.1 ± 0.1)° and (13.0 ± 0.1)°; or

(5.6 ± 0.1)°, (7.3 ± 0.2)°, (9.4 ± 0.1)°, (10.1 ± 0.1)° and (13.0 ± 0.1)°; or

(5.6 ± 0.1)°, (7.3 ± 0.2)°, (9.4 ± 0.1)°, (10.1 ± 0.1)°, (13.0 ± 0.1)° and (28.4 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu K-alphai,₂ radiation having a wavelength of 0.15419 nm.

In an alternatively preferred embodiment crystalline component (A) can be the crystalline form of tenofovir alafenamide monofumarate in form III. Tenofovir alafenamide monofumarate in form III can be prepared as described in Examples 2 and 8 of PCT/EP2017/052121 filed on February 1, 2017. Tenofovir alafenamide monofumarate in form III can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of:

(5.6 ± 0.1)°, (7.3 ± 0.2)° and (10.5 ± 0.1)°; or (5.6 ± 0.1)°, (7.3 ± 0.2)°, (10.5 ± 0.1)° and (12.6 ± 0.1)°; or

(5.6 ± 0.1)°, (7.3 ± 0.2)°, (10.5 ± 0.1)°, (12.6 ± 0.1)° and (17.0 ± 0.1)°; or

(5.6 ± 0.1)°, (7.3 ± 0.2)°, (9.4 ± 0.1)°, (10.5 ± 0.1)°, (12.6 ± 0.1)° and (17.0 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu K-alphai, 2 radiation having a wavelength of 0.15419 nm.

The terms "physical form" and "solid form" are used interchangeably herein and refer to any crystalline and/or amorphous phase of a compound. As used herein, the term "about" means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1 % and most typically within 0.1 % of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.

In a preferred embodiment of the present invention component (A) is present from 5 to 40 wt% based on the total weight of the pharmaceutical composition. More preferably, component (A) can be present from 6.0 to 25 wt%, in particular from 7.0 to 12.0 wt%.

In a preferred embodiment the pharmaceutical composition of the present invention comprises tenofovir alafenamide as single active pharmaceutical ingredient.

In an alternatively preferred embodiment the pharmaceutical composition of the present invention comprises tenofovir alafenamide as active pharmaceutical ingredient in combination with one or more further active pharmaceutical ingredient(s). Examples for such further active pharmaceutical ingredients are emtricitabine, darunavir, cobicistat, elvitegravir, rilpivirine, efavirenz and dolutegravir.

In a preferred embodiment component (A), preferably tenofovir alafenamide monofumarate, can for example be used in the following combination, which includes, but is not limited to, single oral dosage form regimens: (a) emtricitabine / tenofovir alafenamide monofumarate;

(b) cobicistat / tenofovir alafenamide monofumarate;

(c) rilpivirine / emtricitabine / tenofovir alafenamide monofumarate;

(d) efavirenz / emtricitabine / tenofovir alafenamide monofumarate;

(e) emtricitabine / darunavir / cobicistat / tenofovir alafenamide monofumarate;

(f) emtricitabine / elvitegravir / cobicistat / tenofovir alafenamide monofumarate.

In a preferred embodiment of the present invention component (B) is present from 2 to 15 wt% based on the total weight of the pharmaceutical composition. More preferably, component (B) can be present from 2.5 to 12 wt%, even more preferably from 3.0 to 9.0 wt%, in particular from 4.0 to 8.0 wt%.

In a preferred embodiment of the present invention the weight ratio of component (A) to component (B) is from 8: 1 to 1 :3, preferably from 7: 1 to 1 :2, in particular from 6: 1 to 1 :1, especially from 5 : 1 to 2: 1.

It turned out that by using the above-mentioned amount of component and/or the above- mentioned weight ratio of component (A) to component (B) that the degradation of component (A), preferably tenofovir alafenamide monofumarate, can be significantly reduced.

As indicated above, the pharmaceutical composition of the present invention further comprises a pharmaceutical excipient (C). Generally, there are no specific restrictions concerning the chemical nature of these excipients provided that the excipient(s) comprised in the pharmaceutical composition is/are pharmaceutically acceptable. A pharmaceutically acceptable excipient is an excipient which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the tenofovir alafenamide, preferably alafenamide monofumarate, so that any side effects ascribable to the excipient do not vitiate the beneficial effects of the tenofovir alafenamide, preferably alafenamide monofumarate. Therefore, according to the present invention, excipients are for example disintegrants, binders, lubricants, fillers, plasticizers, surfactants and wetting agents, film-forming agents and coating materials, sweeteners, flavoring agents, and coloring agents such as for example pigments. Other excipients known in the field of pharmaceutical compositions may also be used. In a preferred embodiment of the invention the pharmaceutical excipient (C) is a filler.

Fillers can be used to increase the bulk volume and weight of a low-dose drug to a limit at which a pharmaceutical dosage form can be formed. Fillers may fulfil several requirements, such as being chemically inert, non-hygroscopic and pharmaceutically acceptable. Examples of fillers according to the present invention include, but are not limited to, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, lactose such as anhydrous lactose or lactose monohydrate form, sugars, such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols, such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, carrageenan, polyethylene glycol and starch.

The filler (C) can preferably be present from 40-90 wt%, more preferably from 42-75 wt%, in particular from 45-65wt%, based on the total weight of the composition. The filler can preferably have a water content of less than 3 wt%, preferably of less than 2.5 wt%, more preferably of less than 2.0 wt%, in particular of less than 1.5 wt%. The lower limit of the water content could be e.g. 0.01 wt%, 0.1 wt%, 0.2 wt% or 0.5 wt%.

It is further preferred that the filler (C) has a water activity value of from 0.001 to 0.1, preferably from 0.005 to 0.08, more preferably from 0.01 to 0.06. Further, the water activity value of filler (C) can preferably be from 0.005 to 0.07, more preferably from 0.01 to 0.06.

In a further preferred embodiment of the invention component (C) is a filler, more preferably component (C) is microcrystalline cellulose. It is particularly preferred that component (C) is microcrystalline cellulose having the before -mentioned water content. In an alternatively preferred embodiment of the invention component (C) is a filler, more preferably component (C) is lactose. It is particularly preferred that component (C) is anhydrous lactose. It turned out that the use of a filler, preferably microcrystalline cellulose, preferably having the before -mentioned water content, and/or anhydrous lactose, reduces the degradation of tenofovir alafenamide, in particular of tenofovir alafenamide monofumarate. In a preferred embodiment the pharmaceutical composition of the present invention comprises

5-40 wt%, more preferably 6-25 wt%, in particular 7-12 wt% of component (A), 2-15 wt%, more preferably 3.0-9.0 wt%, in particular 4.0-8.0 wt% of component (B),

40-90 wt%, more preferably 42-75 wt%, in particular 45-65 wt% of component (C).

It is further preferred that the pharmaceutical composition of the present invention can comprise one or more further pharmaceutical excipient(s) (D). For one or more further pharmaceutical excipient(s) (D) the same applies as to pharmaceutical excipient (C), with the proviso that pharmaceutical excipient (C) and one or more further pharmaceutical excipient(s) (D) are different. In case that pharmaceutical excipient (C) is a filler, the one or more further pharmaceutical excipient(s) (D) can for example be disintegrants, lubricants, surfactants, glidants, binders, film-forming agents and coating materials, plasticizers and/or coloring agents. Disintegrants are compounds which enhance the ability of the dosage form, preferably the ability of the tablet, to break into smaller fragments when in contact with a liquid, preferably water. Disintegrants can be present for example in an amount of 0 to 10 wt%, preferably in an amount of 0.5 to 5 wt% based on the total weight of the composition. Suitable disintegrants according to the present invention include, but are not limited to, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose (crosslinked carboxymethyl cellulose) sodium, cross-linked polyvinylpyrrolidone, crospovidone (cross-linked povidone, a synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidone), alginic acid, micro crystalline cellulose (such as refined wood pulp derived from alpha cellulose), hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch.

Lubricants generally can be regarded as substances which are suitable to reduce friction, such as static friction, sliding friction and rolling friction. In particular, lubricants reduce the shearing forces occurring on the borderline between tablet and mould, especially the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall on the one hand and between the edge of the tablet and the die wall on the other hand. Lubricants can be present for example in an amount of 0 to 5 wt%, preferably in an amount of 0.5 to 2.5 wt% based on the total weight of the composition. Suitable lubricants according to the present invention include, but are not limited to, glyceryl monostearate, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol, in particular magnesium stearate.

Surfactants have the tendency of adsorbing at surfaces and interfaces and thereby reducing the surface tension between the phases. Suitable surfactants according to the present invention include, but are not limited to, heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxy- ethylene stearate, polyoxyethylen sorbitan monolaurate, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbates, for example polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, sorbitan monopalmitate, sodium salts of fatty alcohol sulfates, such as sodium lauryl sulfate, sodium dodecylsulfate, sodium salts of sulfosuccinates, such as sodium dioctylsulfosuccinate, partial esters of fatty acids with alcohols, such as glycerine monostearate, partial esters of fatty acids with sorbitans, such as sorbitan monolaurate, partial esters of fatty acids with polyhydroxyethylene sorbitans, such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, ethers of fatty alcohols with polyhydroxyethylene, esters of fatty acids with polyhydroxy ethylene, copolymers of ethylenoxide and propylenoxide (Pluronic®) and ethoxylated triglycerides.

Glidants can be used to improve the flowability. Suitable glidants are for example colloidal silicon dioxide, talcum or mixtures thereof. Glidants can be present in an amount of 0 to 8 wt%, preferably in an amount of 0.1 to 3 wt% based on the total weight of the composition.

Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders can be present in an amount of 0 to 15 wt%, preferably in an amount of 3 to 10 wt% based on the total weight of the composition. Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxy- propyl methylcellulose, HPMC), acacia, alginic acid, carboxymethyl cellulose, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, polyvinyl alcohol, polyacrylates, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch.

Suitable film-forming agents and coating materials according to the present invention include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose, HPMC), methylcellulose, ethyl cellulose, cellulose acetate phthalate, shellac, polyvinylpyrrolidone, copolymers of vinyl pyrrolidone and vinyl acetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethyl- ammonium methyl acrylate, copolymers of dimethylamino-methacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester and copolymers of acrylic acid and acrylic acid methylester.

Suitable plasticizers according to the present invention include, but are not limited to, polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol.

Suitable coloring agents according to the present invention include, but are not limited to, pigments, inorganic pigments, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, ferric oxide red, ferric oxide yellow and titanium dioxide.

The skilled person will appreciate that depending on formulation context and concentration a particular excipient can fulfill various and sometimes even different functions. For example, microcrystalline cellulose is a particular hydrolyzed cellulose, which can be used as a filler, binder and/or disintegrating material in tablet production, dependent on formulation context and concentration. The skilled person will therefore appreciate that terms like "disintegrant", "binder", "lubricant", "filler", "plasticizer", "surfactant", "wetting agent", "film-forming agent", "coating material", "sweetener", "flavoring agent" and "coloring agent" are primarily functional definitions and that the structural characterizations provided above are given so as to more easily allow identification of suitable excipients.

It is preferred that the pharmaceutical composition of the invention be preferably present in an oral doasage form. The oral solid dosage form of the present invention is preferably a compressed or a non-compressed dosage form. Preferably, the oral solid dosage form of the present invention is a granule, a capsule, for example a capsule filled with granules, a sachet, a pellet, a dragee, a lozenge, a troche, a pastille, or a tablet, such as an uncoated tablet, a coated tablet, an effervescent tablet, a soluble tablet, a dispersible tablet, an orodispersible tablet, a tablet for use in the mouth, a chewable tablet or an extrudate. In a preferred embodiment the oral dosage form is a capsule or tablet, preferably a tablet. In other words, another subject of the present invention is an oral dosage form, preferably a tablet, comprising the composition of the present invention as described above and below.

In case that the oral dosage form is a tablet, the tablet can preferably be coated, more preferably film-coated.

Generally, film coatings that do not affect the release of the active agent(s) and film coatings affecting the release of the active agent(s) can be employed with tablets according to invention. The film coatings that do not affect the release of the active agent(s) are preferred.

Preferred examples of film coatings which do not affect the release of the active ingredient can be those including poly(meth)acrylate, methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA) and mixtures thereof. More preferred is hydroxypropyl methylcellulose (HPMC). These polymers can have a weight-average molecular weight of 10,000 to 150,000 g/mol. In a preferred embodiment the film can have a thickness of 2 μιη to 150 μιη, preferably 10 to 100 μιη, more preferably 20 to 60 μιη.

The preferred coating may comprise a film-forming agent and one or more of the following: lubricant, surfactant, glidant, pigment and water.

In a preferred embodiment of the present invention the dosage form of the present invention is packed by a suitable packaging material. The packaging material preferably reduces or prevents water exchange between the pharmaceutical composition of the present invention and the environment. For example, if the dosage forms are tablets or capsules, suitable blister pack materials can be used. The blister pack may comprise a cavity or pocket, preferably containing a thermoformed plastic. This usually has as a backing a lidding seal containing an aluminum and/or plastic foil. Further, if the composition is in form of a granulate, suitable sachets can be used.

In a particularly preferred embodiment the pharmaceutical composition or the dosage form of the present invention is packed by a material having a water vapor permeability of 0.001 to 0.15 g/m day at 38°C/5%/90% RH, preferably of 0.01 to 0.12 g/m day at 38°C/5%/90% RH, in particular 0.05 to 0.10 g/m7day at 38°C/5%/90% RH, wherein said water vapor permeability is determined according to ASTM F1249-13. Preferably, a Permatran-W Model 3/33 device is used. The measurement is preferably carried out at 38°C. Further, preferably the humidity in the dry chamber is 5% relative humidity (=RH), whereas the humidity in the wet chamber is 90% RH.

In a preferred embodiment the packaging material can preferably be selected from polyvinylchloride (PVC), polyvinylidene chloride (PVDC), polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET) polystyrol (PS), polyamide and alumina or combinations thereof.

In a preferred embodiment the packing material comprises layered sheets, which can be thermoformed, containing one or more layers. In a preferred embodiment the packing material can be a composite material, e.g. co-extruded composite material, e.g. a polyamide-alumina-polyvinyl chloride composite material, which is also referred to as Nylon^®- Alu-PVC. In a preferred embodiment the packaging material has a thickness of 1 μιη to 1 mm. In case of a blister pack the thermoformed plastic pocket preferably has a thickness of 100 to 1000 μιη, more preferably of 150 to 800 μιη. Further, the backing foil usually has a thickness of 10 to 150 μιη, more preferably of 15 to 100 μιη. In a preferred embodiment the packed dosage form of the present invention also contains a desiccant, such as silica gel bags and/or molecular sieves. A further subject of the present invention is a method for preparing a dosage form according to the invention comprising the steps of

(i) providing component (A), component (B) and component (C),

(ii) optionally dry granulating the mixture from step (i) and optionally one or more further pharmaceutical excipient(s) (D),

(iii) compressing the mixture from step (i) or the granules from step (ii) and optionally one or more further pharmaceutical excipient(s) (D) to a tablet or filling the mixture from step (i) or the granules from step (ii) and optionally one or more further pharmaceutical excipient(s) (D) into a capsule.

As far as components (A), (B) and (C) are concerned, for the present method the same applies as to the before-mentioned pharmaceutical composition.

In step (i) components (A), (B) and (C) are provided. In a preferred embodiment components (A), (B) and (C) and optionally one or more further excipient(s) (D), preferably a disintegrant, can be blended. In an alternative embodiment a premix containing components (A) and (B) can be formed by blending and sieving these components. To the sieved premix a second, preferably sieved, premix comprising component (C) and preferably one or more further excipient(s) (D), preferably a disintegrant, can be added. Sieving can be preferably carried out with a sieve having a mesh size of 25 to 1000 μιη, preferably 50 to 800 μιη, especially 100 to 600 μιη. The resulting mixture of components (A) to (C) and optionally one or more further excipient(s) (D), preferably a disintegrant, can preferably be blended in order to provide a composition having a homogenous distribution of the corresponding mixture.

Blending can be carried out with conventional mixing devices, e.g. in a free-fall mixer. Blending can be carried out e.g. for 1 minute to 30 minutes, preferably for 2 minutes to less than 10 minutes. In optional step (ii) the mixture from step (i) and optionally one or more further excipient(s) (D) can be dry-granulated.

"Dry" is usually understood to mean that the step is carried out in the absence of a liquid, in particular in the absence of water. "Granulating" is generally understood to mean the formation of relatively coarse or granular aggregate material as a powder by assembling and/or aggregating finer powder particles (agglomerate formation or build-up granulation) and/or the formation of finer granules by breaking up coarser aggregates (disintegration or break-down granulation). Dry granulation can preferably be carried out by using pressure or temperature. In a preferred embodiment of the invention, granulating the mixture from step (i) can be performed for example by "slugging", using a large heavy-duty rotary press and breaking up the slugs into granulates with a hammer mill or by roller compaction, using for example roller compactors by Powtec or Alexanderwerk. The granuls are then optionally screened.

In step (iii) the mixture of step (i) or the granules of step (ii) and optionally further excipients (D), preferably a lubricant, can preferably be compressed into a tablet. Compressing the mixture of step (i) or the granules from step (ii) into a tablet can preferably be carried out by compressing said formulation on a rotary press. The main compression force can range from 1 to 50 kN, preferably from 3 to 40 kN, more preferably from 4 to 20 kN. The resulting tablets can have a hardness of 50 to 220 N, more preferably of 60 to 190 N, particularly preferably of 70 to 180 N, more preferably of 80 to 170 N, wherein the hardness can be measured according to Ph. Eur. 6.0, Chapter 2.9.8. Alternatively preferred, in step (iii) the mixture of step (i) or the granules of step (ii) and optionally further excipients (D) can be filled into a capsule.

The method of the present invention can preferably comprise a step (iv), in which the tablets from step (iii) can preferably be film coated, wherein film coatings such as Opadry II can be used. The method of the present invention can preferably comprise a step (iv), in which the tablets from step (iii) or step (iv) can be packaged. Preferably, the materials as described above are used. In a preferred embodiment steps (i), (ii) and (iii) can be performed under non-humid conditions. In particular, these steps can be performed at a temperature of from 0°C to 30°C, preferably 10°C to 25°C. Further, said process is preferably performed at 0 to 40% RH or less, preferably at 5 to 30% RH. The same conditions can be chosen for optional steps (iv) and (v).

Further, the dosage form, preferably the tablet, of the invention preferably has a content uniformity, i.e. a content of active agent(s) which lies within the concentration of 90 to 1 10%), preferably 95 to 105%, especially preferred of 98 to 102% of the average content of the active agent(s). The "content uniformity" is determined with a test in accordance with Ph. Eur., 6.0, Chapter 2.9.6. According to that test, the content of the active agent of each individual tablet out of 20 tablets must lie between 90 and 1 10%>, preferably between 95 and 105%, especially between 98 and 102% of the average content of the active agent(s). Therefore, the content of the active agent in each tablet of the invention differs from the average content of the active agent by at most 10%, preferably at most 5% and especially at most 2%.

In addition, the resulting tablet preferably has a friability of less than 5%, particularly preferably less than 2%, especially less than 1 %. The friability is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.7. The friability of tablets generally refers to tablets without coating.

Alternatively, the present invention relates to a method for treating and/or preventing HIV and HBV infections, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the invention, in particular a compound according to formula (I) where the residues are defined as above, or the pharmaceutical composition of the invention. To this compound and this pharmaceutical composition the same explanations (e.g. regarding combination of possible embodiments) apply as to the compound and the pharmaceutical composition as described above. In an embodiment the treatment of HIV infections is especially preferred. The invention shall be illustrated by the following examples.

1. Analytical Methods

1.1 XPRD

PXRD was performed with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphal ,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-theta at ambient conditions. A typical precision of the 2-theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-theta. Thus, the diffraction peak of crystalline tenofovir alafenamide monofumarate form II that appears for example at 7.3° 2-Theta can appear in the range of from 7.1 to 7.5° 2-theta, preferably in the range of from 7.2 to 7.4° 2-Theta on most X-ray diffractometers under standard conditions. The terms XRPD and PXRD are used interchangeably herein.

1.2 Water content according to Karl Fisher The water content was determined according to Ph.Eur 6.0, 2.5.12 Method A, wherein an Excellence Titrator T70 (Mettler Toledo) can be used.

Preferably, the following measurement parameters can be used:

Weight sample: 200mg

Density: l .Og/mL

Temperature: 25°C

Titration agent: KFl-comp 5 Nominal concentration

Weight

Temperature:

Duration for mixing:

Sensor type:

Sensor

Unit:

Indication

Ipol

Stirring:

Regulation:

Endpoint:

Control band:

Dosing rate (max) :

Dosing rate (min):

Stop

Type:

Drift

at Vmax:

Time (min,)

Time (max.) Calculation

Result: Content

Result (unit) %

Formula: Rl =(VEQ · CONC-TIME · DRIFT/1000) · C/m Constant C= 0.1 The sample is prepared and weighted in a glove box with less than 5%RH. For determination of the water content 5 samples were measured and the average from the corresponding values was calculated. 1.3 Water activity

Determination of the relative humidity (in %) in the air above a specimen after establishment of the humidity equilibrium in a closed system at constant temperature with the following equipment:

Hygrometer: chamber Rotronic AW-VC and hygrometer BT-RS 1

Temperature: 25±1°C

Glove box: flushed with dry air or nitrogen, equipped with hygrometer, 5% RH Procedure:

The sample dish was filled with the specimen and the sample dish was placed in the measuring chamber which had been thermostated to 25 ±1°C. Then, the measuring chamber was sealed. When equilibrium of the relative humidity was established (trend indication disappears), the corresponding value was determined.

1.4 Evaluation of stability of tenofovir alafenamide fumarates

In order to compare the chemical stability of tenofovir alafenamide monofumarate with that of tenofovir alafenamide hemifumarate and to evaluate stabilizing effect of mentioned excipients, a gradient UPLC determination with external standard was performed according to the following method:

Solutions: 1. Solvent: buffer, pH = 3.0 : methanol = 400 : 600 (V/V)

2. buffer, pH = 3.0: Weight 0.6 g NaH₂P0₄ into 1000ml of water and adjust pH with phosphoric(V) acid to pH= 3.0 + 0.2.

3. buffer, pH = 3.80: Weight 1.5 g CH₃COONH₄ into 1000ml of water and adjust pH with acetic acid to pH= 3.80 ± 0.05. Chromatographic conditions:

1. Mobile phase A: buffer, pH = 3.8

Mobile phase B: acetonitrile: water = 9: 1 (V/V)

2. Column: UPLC HSS T3, 1.8 μπι, 100 x

3. Temperature: 40 °C

4. Flow rate: 0.5 ml/min

5. Detector: 260 nm

6. Injection volume: 1 μΐ

7. Gradient:

Time for column equilibration: 2 min

2. Stability studies of binary mixtures

2.1 A compatibility study of tenofovir alafenamide monofumarate with a series of excipients was performed.

Compatibility mixtures:

Mixtures of tenofovir alafenamide monofumarate with several excipients were prepared, each in a weight ratio of 1 : 1. To obtain homogenous mixtures, the API and the corresponding excipient were thoroughly mixed in a mortar and the mixture was sieved trough 0.5 mesh sieve and blended. 400 mg of the resulting compatibility mixtures were exposed to the following conditions:

60°C in a closed vial for 7 days ( referred hereinafter as "dry conditions") 60°C with addition of 10 μΐ, of water in a closed vial for 7 days (referred hereinafter as "wet conditions")

The results are shown in the following Table 2 .

Table 2. Impurities in binary mixtures under stress conditions

Polyvinylpyrrolidon (PVPK30) 15.86 29.15

Lactose anhydrous 0.43 1.67

Lactose monohydrate 0.63 16.95

Sodiu stearyl fumarate (PRUV) 16.02 73.35

Hydroxypropylmethylcellulose 0.45 1.95

(Pharmacoat 600)

Hydroxypropylcellulose (Klucel EF) 0.51 1.38

Tiethylcitrate 6.41 80.3

Polyethylene glycol (PEG 6000) 2.94 29.62

Calcium acetate 0.32 77.82

Magnesium chloride < 0.05 < 0.05

Ascorbic acid 0.43 38.93

Sodium lauryl sulfate 0.3 18.87

Cation exchange resin (Polacrilin 0.89 1

Potassium)

Silicon dioxide (Aerosil200) 2.24 28.3

Sodium chloride 0.28 32.57

Calcium chloride dihydrate 0.32 8.56

Glyceryl behenate 55.92 67.95

Calcium stearate 57.6 72.07

Magnesium chloride hexahydrate 0.23 4.99

Magnesium sulfate 1.32 1.31

The above results show that several excipients worsen the stability of tenofovir alafenamide monofumarate compared with the stability of the API alone. The destabilization often is significant under "wet conditions", but additionally or alternatively the stabilization also occurs under "dry conditions".

Further, these results demonstrate that the inorganic earth alkali metal salts improve the stability of tenofovir alafenamide monofumarate in binary mixtures compared to tenofovir alafenamide monofumarate both under "dry" and "wet" conditions. Surprisingly it turned out that the highest stabilizing effect was obtained in the binary mixture with magnesium chloride.

2.2 A study with tenofovir alafenamide monofumarate and magnesium chloride in different weight ratios was performed. The conditions correspond to the conditions as described under above item 2.1 wherein tenofovir alafenamide monofumarate (TAF MF) and magnesium chloride in different weight ratios were used. The results are shown in the following Table 3. Table 3: Impurities in mixtures of TAF MF and magnesium chloride in different weight ratio

These results show that in dry and wet conditions tenofovir alafenamide monofumarate is unexpectedly stabilized by MgCb in weight ratios of from 1 :5 to 20: 1. 3. Stability studies of tablets

3.1 General procedure for the preparation of the tablets Tenofovir alafenamide monofumarate was premixed with stabilizing agent (corresponding to present component (B)), if contained, and sieved. Microcrystalline cellulose having a water content of not more than 1.5 wt.% or of 3 to 5 wt.% and anhydrous lactose, if contained, and croscarmellose sodium, all previously sieved, were added to the mixture and the resulting mixture was blended to obtain a homogenous blend. Magnesium stearate, previously sieved, was added to the mixture and the resulting mixture was blended. The final blend was compressed on a press to a tablet. The contents of the components (in mg) in the tablet are shown in Table 4, wherein 31.09 mg tenofovir alafenamide monofumarate correspond to 25 mg tenofovir alafenamide.

Table 4: Contents and physical properties of the tablets

Ex =Ex ample

3.2 Comparison of the tablets

The tablets were subjected to the "dry" and "wet" conditions described above and the total amount of impurities was determined. The results are shown in the below 5.

Table 5 : Comparison of the tablets with regard to impurities

As can be seen from the above table, tablets containing present component (B) show significantly less impurities than tablets without said component.

Claims

Claims

1. Pharmaceutical composition comprising:

(A) tenofovir alafenamide

(B) earth alkali metal salt and/or silicon dioxide,

(C) pharmaceutical excipient,

wherein the pharmaceutical composition has a water activity value being less than 0.15.

2. Pharmaceutical composition according to claim 1 , wherein the earth alkali metal salt (B) is magnesium chloride, magnesium sulfate and or calcium chloride.

3. Pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical excipient (C) has a water content of less than 3 wt.%.

4. Pharmaceutical composition comprising:

(A) tenovofir alafenamide

(B) silicon dioxide, magnesium chloride, calcium chloride and/or magnesium sulfate

(C) pharmaceutical excipient having water content of less than 3 wt.%.

5. Pharmaceutical composition according to any one of claims 1 to 4, wherein component (A) is present as tenovofir alafenamide monofumarate or tenovofir alafenamide hemifumarate.

6. Pharmaceutical composition according to any one of claims 1 to 5, wherein component (B) is present from 2.0 to 15 wt.%, based on the total weight of the pharmaceutical composition.

7. Pharmaceutical composition according to any one of claims 1 to 5, wherein the weight ratio of component (A) to component (B) is from 8: 1 to 1 :3.

8. Pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical excipient (C) is a filler.

9. Pharmaceutical composition according to claim 8, wherein the filler is microcrystalline cellulose.

10. Pharmaceutical composition according to any one of claims 1 to 9, comprising: 5-40 wt.% component (A)

2-15 wt. % component (B)

40-90 wt.% component (C)

based on the total weight of the pharmaceutical composition.

11. Pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is present in form of an oral dosage form, preferably in form of a tablet.

12. Method for preparing a dosage form according to claim 11 comprising the steps of

(i) providing component (A), component (B) and component (C),

(ii) optionally dry granulating the mixture from step (i) and optionally one or more further pharmaceutical excipient(s) (D),

(iii) compressing the mixture from step (i) or the granules from step (ii) and optionally one or more further pharmaceutical excipient(s) (D) to a tablet or

filling the mixture from step (i) or the granules from step (ii) and optionally one or more further pharmaceutical excipient(s) (D) into a capsule.

13. Method according to claim 12, wherein step (ii) comprises compacting the mixture of step (i) to a slug and further granulating the slug.

14. Pharmaceutical composition according to any one of claims 1 to 11 for use in the treatment and/or prophylaxes of HIV and HBV -infections.