WO2018095576A1

WO2018095576A1 - Topical pharmaceutical formulation comprising n-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide

Info

Publication number: WO2018095576A1
Application number: PCT/EP2017/001397
Authority: WO
Inventors: Yogeshwar BACHHAV; Wilfried Schwab; Alexander Birkmann; Tamara Pfaff
Original assignee: Aicuris Anti-Infective Cures Gmbh
Priority date: 2016-11-28
Filing date: 2017-11-28
Publication date: 2018-05-31
Also published as: UY37497A; AR110250A1; TW201825095A

Abstract

The present invention relates to pharmaceutical formulations of anti-viral active agents for the use in topical application, particularly for the use of these in the treatment of human herpes virus infections, wherein the anti-viral active agents may be selected from the group comprising the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate, the maleate salt of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, the mesylate salt of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, and the free base of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide. Specifically, the present invention provides said pharmaceutical formulations for the use in topical application, wherein said formulations comprise an anti-viral agent as described above in dissolved state or in solubilized form, butylated hydroxyl toluene (BHT) and Super Refined™ PEG 400 at an apparent pH of 4.0 to 5.0, preferably at an apparent pH of 4.0 to 4.5.

Description

Topical pharmaceutical formulation comprising N-[5-(aminosulfonyl)-4-methyl-l,3- thiazol-2-y 1] -N-methy 1-2- [4-(2-py ridiny l)-pheny 1] -acetamide

Field of the invention

The present invention relates to pharmaceutical formulations of anti- viral active agents for use in topical applications, particularly to the use thereof in the treatment of human herpes virus infections, wherein the anti-viral active agents may be selected from the group comprising the free base N- [5 -(aminosulfonyl)-4-methyl- 1 , 3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)- phenyl] -acetamide hemihydrate, the maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, the mesylate salt of N-[5-(amino- sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, and the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridiny l)pheny 1] acetamide . In the stated above and throughout the following text, the "free base N-[5-(aminosulfonyl)-4- methyl-1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate" means the free base hemihydrate of N- [5 -(aminosulfonyl)-4-methyl- 1,3 -thiazol-2-yl] -N-methyl-2- [4- (2-pyridinyl)-phenyl] -acetamide in accordance with the invention as further set out below. Specifically, the present invention provides said pharmaceutical formulations for the use in topical application, wherein said formulations comprise an anti-viral agent as described above in dissolved state or in solubilized form, butylated hydroxyl toluene (BHT) and Super Refined™ PEG 400 with a pH of 4.0 to 5.0, preferably with a pH of 4.0 to 4.5. Background

N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]- acetamide (hereinafter also referred to as "pritelivir") is a known anti-viral compound used in the treatment of infections of herpes simplex viruses (Herpes Simplex Virus 1 and 2, respectively) as disclosed in WO 2006/10301 1 Al. HSV-1 and/or -2 infections are the cause of diseases such as labial herpes (cold sores mainly due to infections with HSV-1), genital herpes (mainly due to HSV-2 infections), but may rarely also cause severe diseases, such as keratitis and encephalitis. The viruses are ubiquitously distributed throughout the world. A well-known drug used in the treatment of herpes simplex infections is acyclovir (2-Amino- l,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one), which is a specific inhibitor of the viral DNA polymerase.

WO 01/47904 Al describes thiazolyl amide derivatives, a method for producing them and their uses as medicaments, especially as antiviral medicaments.

WO 03/000259 Al describes the topical application of substituted thiazolyl amides in the treatment of herpes infections in humans, preparations suitable for the topical application and methods for the production thereof.

The aforementioned WO 2006/103011 Al describes pharmaceutical preparations for oral administration containing N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide or hydrates or solvates thereof, as well as an acid thereof. Said document also concerns a method of producing said preparations, as well as uses thereof for treating/preventing diseases mediated by herpesviruses, in particular diseases mediated by Herpesvirus simplex.

WO 2013/045491 Al describes crystalline mesylate monohydrate salts of N-[5- (aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in a definite particle size distribution and with a specific surface area range, which have increased long-term stability and release kinetics from pharmaceutical compositions thereof. Accordingly, also pharmaceutical compositions containing said crystalline mesylate monohydrate salts of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide are described therein.

WO 2013/045479 Al describes an improved and shortened synthesis process of N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide and the mesylate salt thereof by using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds. Moreover, also the crystalline mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]- acetamide with increased long-term stability and release kinetics from pharmaceutical compositions thereof is described therein. Antiviral drugs against herpes viruses can be administered to a patient in multiple ways, e.g., systemically, topically, and parenterally. As with all drugs, the stability upon storage and when used on or in the patients is of utmost importance. The development of formulations of an active pharmaceutical ingredient is one of the major obstacles in the manufacturing of a medicament. The formulation is fundamentally important since it determines, in practice, whether the dose can be successfully delivered to the patient.

A formulation should have the following characteristics: the active pharmaceutical ingredient must be stable and it must be acceptable to the patient. Moreover, it is important to consider the formulation excipients and the potential for any adverse effects. All of the ingredients must be compatible with each. Furthermore, it is important to check whether these factors will effect the bioavailability of the drug. In a specific aspect of the invention, a formulation should have the following characteristics: the active pharmaceutical ingredient must be stable in dissolved state or in solubilized form and it must be acceptable to the patient. Moreover, it is important to consider the formulation excipients and the potential for any adverse effects. All of the ingredients must be compatible with each. Furthermore, it is important to check whether these factors will effect the skin penetration properties of the active ingredient and its bioavailability to the respective skin layers.

A problem to be solved was the provision of different forms of topical pharmaceutical formulations against herpes virus infections, e.g. HSV, comprising the active pharmaceutical ingredient pritelivir, whereby the topical formulations should assure rapid and significant delivery of pritelivir. Furthermore, the pharmaceutical ingredient should be stable against oxidation at acidic pH (in the range of pH 4-5) in dissolved state over an extended period.

In a specific aspect of the invention, a further problem to be solved was the provision of different forms of topical pharmaceutical formulations against herpes virus infections, e.g. HSV, comprising the active pharmaceutical ingredient pritelivir, whereby the topical formulations should assure rapid and significant delivery of pritelivir to the respective skin compartments. Furthermore, the pharmaceutical ingredient should be stable against oxidation at acidic pH (in the range of pH 4.0 to 5.0, preferably in the range of 4.0 to 4.5) in dissolved state and when being present in solubilized form within the pharmaceutical matrix over an extended period of its use in the treatment.

The free base of N-[5-(Aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-py- ridinyl)phenyl]acetamide is further described in the US patent 7,105,553, the disclosure of which is incorporated herein by reference.

The mesylate salt is further described in the US patent 9,1 19,786, the disclosure of which is incorporated herein by reference.

Hemihydrate of the free base

The free base N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]-acetamide hemihydrate having the molecular formula C₁₈H₁₈N₄0₃S₂ x 0.5 H₂0 was identified by extensive polymorph hydrate screening starting from the free base of N-[5- (aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base mesylate in order to identify a suitable or the most stable form of said compound in formula I (the free base of the mesylate of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]- N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide):

Formula (I).

In addition, the free base N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide hemihydrate having the molecular formula Ci₈H₁₈N₄0₃S₂ x 0.5 H₂0 was identified by extensive polymorph, salt and solvate screening starting from the free base of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]-acetamide in order to identify a suitable or the most stable form of said compound in formula I (i.e. the free base of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)-phenyl] -acetamide) :

Formula (I).

Several polymorph/solvates were identified and characterized by single XRPD and DSC, Karl Fischer water content. Surprisingly, the free base hemihydrate was the only stable polymorph. The polymorphism screening was performed using an approach to find kinetically preferred polymorphs as well as thermodynamically preferred or in other words more stable polymorphs. The kinetically preferred polymorphs were examined using evaporation and cooling crystallisations, the thermodynamically preferred polymorphs were examined using slurry type experiments. The XRPD-spectrum of the free base hemihydrate is shown in Figure 1.

Furthermore and with the above context, several polymorphs/salts/solvates were identified and characterized by single XRPD and DSC, Karl Fischer water content. Surprisingly and unexpectedly, the free base hemihydrate was the only pharmaceutically stable polymorphic form of the identified hydrates. The polymorphism screening was performed using an approach to find kinetically preferred polymorphs as well as thermodynamically preferred or in other words more stable polymorphs suitable for pharmaceutical use.

A maleate salt of the free base of pritelivir

The term "maleate salt" or similar terms denote a maleate salt of the free base of the compound N-[5-(aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]-acetamide having the molecular formula II.

An Ortep Plot of the compound is shown in Figure 2. Said Figure 2 specifically depicts a single crystal X-ray analysis of the said compound (II).

In the context of the description the expression "maleate salt" or similar expressions denote the salt obtained from the free base of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide reacted with maleic acid. The maleate ion is the ionized form of maleic acid. Maleic acid or cis-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is H0₂CCHCHC0₂H. Maleic acid is the cis-isomer of butenedioic acid, whereas fumaric acid is the trans-isomer. Maleic acid is a less stable molecule than fumaric acid. Maleic acid is more soluble in water than fumaric acid. The melting point of maleic acid (135 °C) is also much lower than that of fumaric acid (287 °C). Both properties of maleic acid can be explained on account of the intramolecular hydrogen bonding that takes place in maleic acid at the expense of intermolecular interactions, and that are not possible in fumaric acid for geometric reasons. Specifically, maleic acid and the ionized form of maleic acid, i.e. the maleate ion, is further characterized by three double-bondings. The present invention relates to formulations for a topical application with a physio- chemically stable salt form of the free base N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]- N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide with maleic acids. The herein provided maleate salts of the free base of pritelivir exhibit unexpectedly higher intrinsic pH values without decreasing the solubility properties. Specifically, and very surprisingly, the maleate salts of the formulations of the present invention exhibit a significant photostability, which is advantageous particularly for the use in topical formulations thereof that are intended to be used in methods of treating/preventing infections with herpes virus infections. A pharmaceutical formulation of a photostable API at higher pH simultaneously reduces skin irritation effects and allows for stability thereof even under light exposure. Moreover, when said maleate salt as API is used in oral administration forms, due to the above-described properties, the bioavailability properties of the maleate salt are not affected. In addition, the present invention provides for formulations with stable forms of the maleate salt of the free base of pritelivir that per se have a high degree of purity when directly being obtained from the herein disclosed manufacturing process and due to the stability can be stored for prolonged periods of time. Furthermore, upon formulation as pharmaceuticals and storage the maleate salt as API is present at high concentrations essentially without or extremely low decomposition, which ensures that the therapeutically effective concentration per volume unit of a pharmaceutical provided by the invention remains high.

With the context of the above paragraph, the expression "upon formulation as pharmaceuticals" means upon the formulation as pharmaceutical product.

Before describing the invention in detail, it is deemed expedient to provide definitions for certain technical terms used throughout the description. Although the present invention will be described with respect to particular embodiments, this description is not to be construed in a limiting sense. Before describing in detail exemplary embodiments of the present invention, definitions important for understanding the present invention are given.

Abbreviations used

BHT = butylated hydroxyl toluene

SR = Super Refined™ PEG 400

HSV = Herpes simplex virus

XRPD = X-Ray Powder Diffractogram

DSC = Differential Scanning Calorimetry

API = active pharmaceutical ingredient(s)

IR spectroscopy = Infrared spectroscopy BHA = butylated hydroxyanisole RH = relative humidity

Ph. Eur. = European Pharmacopoeia USP = U.S. Pharmacopeia

DMSO = dimethylsulphoxide

Definitions

As used in this specification and in the appended embodiments, the singular forms of "a" and "an" also include the respective plurals unless the context clearly dictates otherwise.

In the context of the present invention, the terms "about" and "approximately" denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ± 20 %, preferably ± 15 %, more preferably ± 10 %, and even more preferably ± 5 %.

It is to be understood that the term "comprising" is not limiting. For the purposes of the present invention the term "consisting of is considered to be a preferred embodiment of the term "comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is meant to also encompass a group, which preferably consists of these embodiments only.

Furthermore, the terms "first", "second", "third" or "(a)", "(b)", "(c)", "(d)" etc. and the like in the description and in the embodiments, 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.

In case the terms "first", "second", "third" or "(a)", "(b)", "(c)", "(d)" etc. relate to steps of a method or use there is no time or time interval coherence between the steps, i.e. the steps may be carried out simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks, months or even years between such steps, unless otherwise indicated in the application as set forth herein above or below.

According to the present invention, the term "antiviral effective amount" means the total amount of each active component that is sufficient to show a meaningful patient benefit, i.e., healing of acute conditions characterized by inhibition of the herpes virus infection. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

With the above paragraph, the expression "ingredient" or "active ingredient" denotes the active pharmaceutical ingredient(s) (API). The terms "treat, treating, treatment" as used herein and in the embodiments means preventing or ameliorating diseases associated with herpes virus infection.

The terms "prophylaxis or prevention" as used herein and in the embodiments refers to the administration or use of the herein disclosed compounds or compositions in order to protect a non-infected organism or a non-infected cell of an organism from being infected, i.e., an organism may be infected by a virus, but the spread of the virus in the organism (from cell to cell) or within the organisms' social environment is prevented. The organism may be human or other mammal. In one aspect of the invention, the organism to whom the compound or pharmaceutical composition is administered is a human being that is infected by a herpes virus, e.g., HSV-1 and/or HSV-2, or a human being that is in danger of being infected by such viruses.

With the context of the present invention the anti-viral pritelivir agents may be present in the provided topical formulations in dissolved state or in solubilized form.

The expressions "solubilized" or "solubilized form" or similar expressions denote with the context of the invention that the anti-viral pritelivir agents of the invention are present in the herein provided topical formulations in a complete soluble form, that is, said pritelivir agents are completely dissolved when determined by light scattering methods, Raman spectroscopy and IR spectroscopy and by the respective absence of solid phases during XRPD.

With this context, the expression "dissolved" or "dissolved state" or similar expressions denote with reference to an anti-viral pritelivir agent of the invention as a solid to become completely incorporated into a liquid or semi-liquid matrix homogeneously distributed, so as to form a solution or semi-solid-phase solution for the topical formulations in accordance with the present invention. With the above context, basically, both terms„solubilized" and„dissolved" go hand in hand and refer to the same chemical scenario with two different standpoints in definition. „Solubility" is a characteristic property of the solute and„dissolution" is the process in which a solute dissolves in a solvent to result a solution. Therefore, by definition,„solubility" is a thermodynamic factor and dissolution" is a kinetic factor. The term "solubilities" refers to the homogenous distribution of the active pharmaceutical ingredient within the excipient matrix possessing the same phase (as liquid, semi-liquid or solid solution).

Hence, in the„dissolved state" with the context of the invention, the anti-viral pritelivir agents are present homogenously distributed - and in fully solubilized form throughout the topical formulations as provided herein.

Thereby, a„solute" is the anti-viral pritelivir agent, which is to be dissolved in the solvents of the herein provided topical formulations. „Solvent" is generally a liquid that is used to dissolve the solute.„Solution" is referred to as the mixture that results from dissolving the solute in solvent. Hence, the topical formulations as provided herein, basically, are liquid or semi-liquid solutions that are may be further processed and comprising the pritelivir anti-viral agents as a solute which was dissolved in the solvents of the formulations, so to be present in solubilized form in said topical formulations. With the above context, said solubility may be determined by light scattering methods, Raman spectroscopy and IR spectroscopy and the respective absence of solid phases during XRPD. With the above context, said dissolved state may be determined by light scattering methods, Raman spectroscopy and IR spectroscopy and the respective absence of solid phases during XRPD. The expressions "Super Refined™ PEG 400, SR PEG 400 or similar expressions" with the context of the invention denote the excipient Super Refined™ PEG 400 as a high purity grade of polyethylene glycol 400. It may be used in pharmaceutical applications as a solvent, suspending agent and viscosity modifier and is suitable for parenteral use. „Polyethylene glycol (PEG)" is a polyether compound with many applications from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular weight. The structure of PEG is commonly expressed as H-(0-CH₂-CH₂)_n-OH. PEG, PEO, and POE refer to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but historically PEG is preferred in the biomedical field, whereas PEO is more prevalent in the field of polymer chemistry. Because different applications require different polymer chain lengths, PEG has tended to refer to oligomers and polymers with a molecular mass below 20,000 g/mol, PEO to polymers with a molecular mass above 20,000 g/mol, and POE to a polymer of any molecular mass. PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g/mol to 10,000,000 g/mol.

PEG and PEO are liquids or low-melting solids, depending on their molecular weights. While PEG and PEO with different molecular weights find use in different applications, and have different physical properties (e.g. viscosity) due to chain length effects, their chemical properties are nearly identical. Different forms of PEG are also available, depending on the initiatorused for the polymerization process - the most common initiator is a monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated mPEG. Lower-molecular-weight PEGs are also available as purer oligomers, referred to as monodisperse, uniform, or discrete. Very high purity PEG has recently been shown to be crystalline, allowing determination of a crystal structure by x-ray diffraction. Since purification and separation of pure oligomers is difficult, the price for this type of quality is often 10-1000 fold that of polydisperse PEG.

PEGs are also available with different geometries. · Branched PEGs have three to ten PEG chains emanating from a central core group.

• Star PEGs have 10 to 100 PEG chains emanating from a central core group.

• Comb PEGs have multiple PEG chains normally grafted onto a polymer backbone.

The numbers that are often included in the names of PEGs indicate their average molecular weights (e.g. a PEG with n = 9 would have an average molecular weight of approximately 400 daltons, and would be labeled PEG 400.) Most PEGs include molecules with a distribution of molecular weights (i.e. they are polydisperse). The size distribution can be characterized statistically by its weight average molecular weight (Mw) and its number average molecular weight (Mn), the ratio of which is called the polydispersity index (Mw/Mn). MW and Mn can be measured by mass spectrometry.

Herein below, various embodiments of the invention are explained in more detail. Wherever, respective alternatives in terms of ingredients in compositions, types of pharmaceutical compositions, concentrations of ingredients, periods of time of administration, frequencies of administration, medical indications to be treated are mentioned, the person skilled in the would immediately understand that individual combinations can be made as long as these are technically possible or if not otherwise explicitly indicated.

Detailed description of the embodiments of the present invention

Subject matter of the present invention is a pharmaceutical formulation for use in topical application to a subject in need thereof, said formulation comprising: i) 1-10 % w/w of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)phenyl]acetamide,

ii) 0-90 % w/w of at least one solvent,

iii) 0-10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 2.0 to 8.0, preferably a pH of 4.0 to 5.0, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C/ 60 % RH, wherein said solvent is selected from the group comprising ethanol, dimethyl isosorbide, isopropanol, Transcutol P, propylene glycol, polyethylene glycol, PEG 400, PEG 4000 and Super Refined™ (SR) PEG 400.

With the context of the above paragraph, the said pharmaceutical formulation has a more preferred pH value of 4.0 to 4.5.

Also subject matter of the present invention is a pharmaceutical formulation for use in topical application to a subject in need thereof, said formulation comprising: i. 1 - 10 % w/w of N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl- 2- [4-(2-pyridinyl)phenyl]acetamide,

ii. > 0 - 90 % w/w of at least one solvent,

iii. > 0 - 10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 2.0 to 8.0, preferably a pH of 4.0 to 5.0, more preferably a pH value of 4.0 to 4.5, wherein the N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C / 60 % RH, wherein said solvent is selected from the group comprising ethanol, dimethyl isosorbide, isopropanol, Transcutol P, propylene glycol, polyethylene glycols, PEG 400, PEG 4000 and Super Refined™ PEG 400, and wherein said antioxidant agent is selected from a group comprising butylated hydroxyl toluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate salt.

In another aspect of the invention, said N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N- methyl -2- [4-(2-pyridinyl)phenyl]acetamide in the pharmaceutical formulations as described above is stable in dissolved state or in solubilized form for at least 24 months at 25 °C / 60 % RH.

Hereby, and likewise throughout the text, the term "> 0 - 90 %" or similar expressions means a value more than "0" and up to and including 90 %.

Hereby, and likewise throughout the text, the term "> 0 - 10 %" or similar expressions means a value more than "0" and up to and including 10 %. In one embodiment of the present invention, the active pharmaceutical ingredient N-[5- (amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in the pharmaceutical formulation of the aforementioned embodiment is stable in dissolved state or in solubilized form for 12 months at 25 °CI 60 % RH. In one embodiment of the present invention, the active pharmaceutical ingredient N-[5- (amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in the pharmaceutical formulation of the aforementioned embodiment is stable in dissolved state or in solubilized form for at least 24 months at 25 °C/ 60 % RH. In another embodiment of the present invention, the active pharmaceutical ingredient N-[5- (amino-sulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in the pharmaceutical formulation of the aforementioned embodiments is stable in dissolved state or in solubilized form for 12 months at 25 °C/ 60 % RH, when determined in accordance with compendial methods as per European Pharmacopoeia (Ph. Eur.) and/or the U.S. Pharmacopeia (USP).

In another embodiment of the present invention, the active pharmaceutical ingredient N-[5- (amino-sulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in the pharmaceutical formulation of the aforementioned embodiments is stable in dissolved state or in solubilized form for at least 24 months at 25 °C/ 60 % RH, when determined in accordance with compendial methods as per European Pharmacopoeia (Ph. Eur.) and/or the U.S. Pharmacopeia (USP). In the context of the present application, the term "formulation" relates to a mixture of excipients and active ingredients and may take the form of creams, gels or ointments, prepared according to a specific procedure (called a "formula"). Formulations are a very important aspect of creating medicines, since they are essential to ensure that the active part of the drug is delivered to the designated part of the body, in the right concentration, and with the right kinetics (not too fast and not too slowly). A good example is a drug delivery system that exploits supersaturation. They also need to have an acceptable consistency, a good storage stability, and be sufficiently stable both physically and chemically to be transported from where they are manufactured to the patient. With the context of the above paragraph, said "right kinetics" refer to the right penetration kinetics.

In the context of the present application, the term "topical formulation" is used herein to generally include a formulation that can be applied to skin or mucosa. Topical formulations may, for example, be used to confer therapeutic benefit to a patient or cosmetic benefits to a consumer. Topical formulations can be used for both topical and transdermal administration of substances. The term "topical administration" is used herein to generally include the delivery of a substance, such as a therapeutically active agent, to the skin or a localized region of the body.

The term "subject" as used herein refers to a living human or non-human organism, preferably a human subject, wherein the subject is healthy, apparently healthy, suffering from

herpes virus infections, especially due to Herpes simplex- Virus 1 (HSV-1) and Herpes simplex- Virus 2 (HSV-2).

In the context of the present application, "in dissolved state" means that the solid forms of pritelivir form a solution in a solvent.

With the context of the above paragraph, "in dissolved state" means that the solid forms of pritelivir may also form a liquid or semi-liquid solution in an excipient matrix.

In the context of the present application, a solvent is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a solution. A solvent is usually a liquid but can also be a solid or a gas. The quantity of solute that can dissolve in a specific volume of solvent varies with temperature. A solvent is the component of a solution that is present in the greatest amount. Moreover, with the context of the above paragraph a solvent is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a liquid or semi-liquid solution. A solvent is usually a liquid but can also be a semi-solid, solid or a gas.

In the present application, the embodimented formulations comprise at least one solvent, that means that further solvents (a second, third, fourth solvent etc.) may be present as auxiliary solvent to enhance the solvent power of the primary solvent.

In the context of the present application, "an antioxidant" is a molecule that inhibits the oxidation of other molecules, particularly antioxidants interrupt oxidation reactions and prevent the effects of oxygen radicals (e.g. peroxides) both processes known to damage the integrity and function of various natural substances. Antioxidants are useful in preventing the degradation of ingredients in the formulation product. Moreover, with the context of the above paragraph, "an antioxidant" is a molecule that inhibits the oxidation of other molecules, particularly antioxidants interrupt oxidation reactions and prevent the effects of oxygen radicals (e.g. peroxides) both processes known to damage the integrity and function of various oxidative sensitive substances like the pharmaceutical active ingredient or an excipient. Antioxidants are useful in preventing the degradation of these ingredients in the formulation product.

In another embodiment of the present invention, the at least one solvent is selected from the group comprising polyethylene glycols, preferably PEG 400, more preferably Super Refined™ (SR) PEG 400.

In one embodiment of the present invention, N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2- yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide of the pharmaceutical formulation of the present invention is selected from the group comprising:

• N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate,

• the maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide,

• the mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, and

• the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)phenyl]acetamide.

In another embodiment of the present invention, said antioxidant agent is selected from the group comprising butylated hydroxyl toluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate salt.

In a further embodiment of the present application, said antioxidant agent is BHT.

In another embodiment of the present application, said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, pastes, solutions, oils, lipogels. In another embodiment of the present application, said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, pastes, solutions, oils, lipogels, and patches.

Patches

With the context of the above paragraph, the pritelivir active pharmaceutical ingredients in accordance with the invention can also be administered using patches that are applied on parts of the body of an organism, e.g. of a human being, that is infected by a herpes virus, e.g. infected with HSV-1 and/or HSV-2. More particularly, such patches of the invention may exemplarily comprise a skin adhesive layer, a backing layer and a release liner; thereby, the adhesive layer may comprises a pritelivir active pharmaceutical ingredient in accordance with the invention, and/or other active compounds dissolved in a low volatile solvent and a polymeric adhesive soluble in highly volatile solvents. A pritelivir active pharmaceutical ingredient may be incorporated as antiviral agent in the adhesive layer in a therapeutically and/or prophylactically effective amount, e.g., from 0.1 to 10 % w/w, preferably around 5 % w/w of the dried adhesive layer, dissolved in a low volatile solvent. In one embodiment, the present invention relates to ointments; creams or gels for topical application, which comprise the active pharmaceutical ingredient in any of the above forms.

Topical preparations exist in many forms, such as ointments, gels, creams, lotions, solutions, suspensions, foams, and shampoos. The most commonly used topical preparations are semi- solid or semi-liquid dosage forms that include ointments, creams, emulsion, lotions, and gels. The common property of these pharmaceutical semisolid preparations is the ability to cling to the application surface for a reasonable period of time before they are washed off or worn off. They usually serve as vehicles for topically applied drugs, as emollients, or as protective. In the context of the present application, the term "ointments" comprise hydrocarbon gels, lipogels, absorption bases, W/O ointment bases, mixed emulsions or polyethylene glycols as base.

As used herein, creams comprise O/W bases. With the context of the above two paragraphs, the term "ointments" comprise hydrocarbon gels, lipogels, absorption bases, W/O ointment bases, mixed emulsions or polyethylene glycols as main carrier system. Accordingly, creams may comprise O/W bases as main carrier system.

In the context of the present application, the term pastes comprise large amounts of powdered ingredients such as, for example, zinc oxide, talc, starch or titanium dioxide, besides an ointment or cream base.

With the context of the above paragraph, the term pastes comprise large amounts of powdered ingredients such as, for example, zinc oxide, talc, starch or titanium dioxide, besides an ointment or cream base as main carrier system. As used herein, the term "gel" comprises solvents such as water, ethanol, isopropanol or propylene glycol and are produced using gel formers such as cellulose ethers, alginates, polyacrylates, bentonite, gelatin, tragacanth, polyvinylpyrrolidone or polyvinyl alcohol. Lipophilic gel bases or microemulsions can also be used. In the context of the present application, powders comprise powdered additives such as starch, stearates, silica, clay, magnesium carbonate, talc, cellulose, zinc oxide and, in particular, lactose.

It is possible to add stabilizers, antioxidants, preservatives, humectants, superfatting agents, solvents or excipients to improve penetration and efficacy to all the preparations.

With the context of the above paragraph, it is possible to add stabilizers, antioxidants, preservatives, humectants, superfatting agents, solvents or excipients as skin penetration enhancers, so to improve penetration and efficacy for all the herein disclosed topical formulations. Numerous compounds have been evaluated for such penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. In one embodiment of the present invention, the active pharmaceutical ingredient pritelivir in the pharmaceutical formulation is selected from the range of 1.1 to 10 % w/w, more preferably 1.1 to 5 % w/w. In another embodiment of the present invention, in the pharmaceutical formulation the concentration of the at least one solvent is 0.1-90 % w/w, for example 5-90 % w/w, 10-90 % w/w, 10-80 % w/w, 20-80 w/w, 25-80 % w/w, 15-50 % w/w or 30-45 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation the concentration of a second solvent is 0.1-60 % w/w, more preferred 10-50 % w/w, most preferred 10-40 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation the concentration of the antioxidant agent is 0.01-10 % w/w, more preferred 0.025-5 % w/w, most preferred 0.05-2 % w/w.

Surprisingly and unexpectedly, in specific aspects of the invention, the inventors found that by the formulation of the herein provided pritelivir anti-viral agents with BHT and Super Refined™ PEG 400, said pritelivir anti-viral agents are present in solubilized form in said formulations. Thereby, said solubilized form ensures for the topical formulations the delivery of its pritelivir anti-viral agents in pharmaceutically sufficient amounts to the respective target side, so to effectively address the HSV-1 and/or HSV-2 virus.

Along with the provision of the pritelivir anti-viral agents in solubilized form, stability challenges may arise, so to make and keep a solubilized drug stable. With this context, the inventors surprisingly found that the addition of BHT as radical forming agent significantly stabilizes the pritelivir anti-viral agents in the herein provided topical formulations. But, in the final topical formulations for medical uses, said BHT is significantly reduced to amounts, which lay below the detection threshold of BHT for medicinal products.

Moreover, by the addition of Super Refined PEG™ 400, the inventors unexpectedly found that the pritelivir anti-viral agents in solubilized form can be kept stable for 24 months at 25 °C / 60 % RH in the final formulation. Hereby, the generated peroxide impurities resultant from the usage of PEG 400 and Super Refined PEG™ 400 are neutralized by the admixed BHT, which also acts as radical scavenging agent for said peroxide impurities. This radical scavenging activity may be a cause for said significant decrease of BHT in the final topical formulations of the invention. Hence, the initial BHT amounts of the topical formulations of the invention is, somehow, consumed within the formulations and reduced in that they do not exceed the regulatory thresholds for BHT at release contents as documented in the respective release specification in medical topical formulations (see further below).

With the context of the above three paragraphs and with the context of the present invention, it shall be noted that the IIG limit set by the U.S. Food and Drug Administration (FDA) for BHT for the topical route in the commercially available topical formulations is up to 0.1 % w/w; and based on the data of the BHT in the current clinical formulation as disclosed herein, the fixed maximum of the final topical formulations for use in topical application to a subject in need thereof is 0.1 % w/w. Hereto, said IIG limit set by the FDA may be found via the weblink: https://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm.

With this context, it shall be noted that BHT may be added to the topical formulations of the inventions during the manufacturing processes in amounts exceeding said 0.1 % w/w limit set by the FDA. But as stated above, BHT is consumed in the course of formulation preparation towards the final product, and thus does not exceed said 0.1 % w/w limit in the final topical formulations of the invention.

Further specifications of an exemplary final product in accordance with the invention can be derived from the below table with an overview:

Hence, specifically, the present invention provides said pharmaceutical formulations for the use in topical application, wherein said formulations comprise an anti-viral agent as described above in solubilized form, butylated hydroxyl toluene (BHT) and Super Refined™ PEG 400.

With the above described context, the inventors also found that the pH value of the final topical formulations of the invention is decisive to maintain the stability of the pritelivir antiviral agents in solubilized form in the formulations as provided herein. In a specific aspect of the invention, a pH of 4.0 to 4.5 for the final topical formulations of the invention were found optimal in terms of stability and the avoidance of skin irritation of a subject in need of administration thereof.

Ointment formulations

Another embodiment of the present application relates to an ointment formulation of the pharmaceutical formulation of the present invention. In a specific embodiment the present invention provides a pharmaceutical formulation for use in topical application to a subject in need thereof, wherein said formulation is an ointment formulation comprising: (i) 15 - 20 % w/w PEG 4000,

(ii) 7.5 - 10 % w/w propylene glycol,

(iii) 1.1 - 5 % w/w active pharmaceutical ingredient pritelivir,

(iv) 0.05 - 2 % w/w butylated hydroxyl toluene (BHT),

(v) 25 - 80 % w/w Super Refined™ PEG 400, and

(vi) 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent, wherein the said pharmaceutical formulation has a pH value of 4.0 - 5.0, preferably a pH value of4.0 to 4.5. With the above paragraph it shall be noted that said pH value refers to the apparent pH. pH / apparent pH / topical formulations

With the context of the present invention, pH is an important parameter for topical formulations especially due to its impact on the patient compliance, drug stability and skin permeation of the active moiety. Most conventional topical formulations are based on aqueous systems such as gels, creams and lotions, however, non-aqueous systems such as oils, ointments are also used for hydrophobic drugs. Precise pH measurement of non-aqueous formulations is much more complex compared to aqueous formulations. In theory, while measuring pH of the aqueous solutions, a proportion of the water molecules are dissociated into H⁺ and OH^" ions, and therefore pH value can be precisely obtained on the scale of 0 to 14. However, the pH scale of 0 to 14 may not be applicable for non-aqueous systems. As the pH value is a measure of hydrogen ion activity, in a solution with aprotic solvents the concentration of hydrogen ions would be markedly reduced or almost negligible.

The pH electrodes used in normal lab setting are calibrated using aqueous buffers and very well suited to record H⁺ ion concentration of aqueous systems. The electrochemistry of these pH electrodes may not be suited to record H⁺ ion concentrations in the non-aqueous systems due to very less concentration.

Porras and Kenndler suggested that pH measurement of non-aqueous system is possible using an aqueous calibration, however, the pH value should be considered as an apparent pH. Apparent pH provides relative acidity/alkalinity of the system.

Several practical difficulties can be encountered while measuring apparent pH of the nonaqueous systems. Low H⁺ ion concentration can be responsible for imprecise detection of the electrochemical potential between the glass pH-indicating electrode and the test sample, which can result in fluctuating pH measurements, long response times and inaccurate readings.

There are other factors that can contribute to these effects:

• Majority of pH electrodes rely on a hydrated gel layer on the outside of the glass bulb to detect H⁺ activity. Dehydration of the gel layer due to the low water content in nonaqueous samples results in slow response times and imprecise measurements.

• Non-aqueous systems may have poor electrical conductance and therefore decrease the efficiency of the electrical components required for detecting changes in H⁺ activity.

• Aqueous buffers used for calibrating the pH meter may not be compatible with nonaqueous samples therefore the results cannot be directly translated.

The instant inventors surprisingly found that the anti-virally effective pritelivir agents in accordance with the invention as active substances are more stable at a pH of 4.0 to 5.0, more preferably at a pH of 4.0 to 4.5, most preferred at a pH around 4.0. Therefore, the instant invention also provides e.g. for specific ointment formulations for the use in topical application with a pH of 4.0 to 5.0, more preferably at a pH of 4.0 to 4.5, most preferred at a pH around 4.0, although it is well known that this is an apparent pH due to very low concentration of the aqueous component.

With this context it is important to note that stability analysis of the inventors revealed apparent pH values ranging from 4.0 to 5.0 without any impact on the purity of the pritelivir active pharmaceutical ingredients. Therefore, a measured shift in apparent pH has no impact on assay and purity of the pritelivir active pharmaceutical ingredients of the invention, e.g. in an ointment formulation thereof. In a further specific embodiment the present invention provides for a pharmaceutical formulation for use in topical application to a subject in need thereof, wherein said formulation is an ointment formulation comprising:

(i) 17.5 % w/w PEG 4000,

(ii) 9.78 % w/w propylene glycol,

(iii) 5 % w/w pritelivir free base hemihydrate,

(iv) 0.1 % w/w butylated hydroxyl toluene (BHT),

(v) 55 % to 67.62 % w/w Super Refined™ PEG 400, and

(vi) 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent, wherein the said pharmaceutical formulation has a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5.

With the above paragraph it shall be noted that said pH value refers to the apparent pH.

With the context of the above paragraph and throughout the text it shall be noted that the expression "55 % to 67.62 % w/w Super Refined™ PEG 400" means with the context of the invention that the current clinical ointment formulation comprises an initial addition of 55 % w/w Super Refined™ PEG 400 and this is filled up by a second addition of Super Refined™ PEG 400 to the final amount of 67.62 % w/w Super Refined™ PEG 400 in said clinical ointment formulation.

In a further specific embodiment the present invention provides for a pharmaceutical formulation for use in topical application to a subject in need thereof, wherein said formulation is an ointment formulation comprising:

(i) 17.5 % w/w PEG 4000,

(ii) 9.78 % w/w propylene glycol,

(iii) 5 % w/w pritelivir free base hemihydrate, (iv) 0.1 % w/w butylated hydroxyl toluene (BHT),

(v) 55 % w/w Super Refined™ PEG 400, and

(vi) a second addition of Super Refined™ PEG 400 quantum satis to make up a final concentration of Super Refined™ PEG 400 of 67.62 % w/w,

(vii) diluted HC1 or diluted NaOH solution as pH-adjustment agent quantum satis to reach a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5, wherein the said pharmaceutical formulation has a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5.

With the context of the above paragraph and throughout the text it shall be noted that the expression "55 % w/w Super Refined™ PEG" and ,,67.62 % w/w Super Refined™ PEG 400" means with the context of the invention that the current clinical ointment formulation comprises an initial addition of 55 % w/w Super Refined™ PEG 400 and this is filled up by a second addition of Super Refined™ PEG 400 to the final amount of 67.62 % w/w Super Refined™ PEG 400 in said clinical ointment formulation.

In one embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is an ointment further comprising 0.01-20 % w/w of at least one pH-adjustment agent.

In another embodiment of the present invention, in the pharmaceutical formulation for an ointment the concentration of the at least one solvent is 25-90 % w/w, more preferred 25-80 % w/w, most preferred 60-80 % w/w.

In one embodiment of the present invention, in the pharmaceutical formulation for an ointment the concentration of a second solvent is 0.1-40 % w/w, more preferred 5-20 % w/w, most preferred 7.5-10 % w/w.

In one further embodiment of the present invention, in the pharmaceutical formulation for an ointment the concentration of a third solvent is 0.1-30 % w/w, more preferred 5-30 % w/w, most preferred 15-20 % w/w. In another embodiment of the present invention, in the pharmaceutical formulation for an ointment the concentration of the antioxidant agent is 0.015-10 % w/w, more preferred 0.1-5 % w/w, most preferred 0.1-2 % w/w. In a further embodiment of the present invention, in the pharmaceutical formulation for an ointment the concentration of the pH-adjustment agent is 0.015-20 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation for an ointment the concentration of the pH-adjustment agent is 0.015-20 % w/w to obtain a pH value of 4.0-5.0.

In another embodiment of the present invention, in the pharmaceutical formulation for an ointment the solvent is selected from the group comprising polyethylene glycols, propylene glycol, petrolatum, liquid paraffin, lanolin, mineral oil, silicone oils, silicone derivatives, short chain fatty acids mono- di- and triesters of glycerol, medium chain fatty acids mono-, di- and triesters of glycerol, long chain saturated fatty acids mono-, di- and triesters of glycerol, long chain unsaturated fatty acids mono-, di- and triesters of glycerol, vegetable oils, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grapeseed oil, mustard seed oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid esters, short chain fatty acids mono- and diesters of propylene glycol, medium chain fatty acids mono- and diesters of propylene glycol, long chain saturated fatty acids mono- and diesters of propylene glycol, long chain unsaturated fatty acids mono- and diesters of propylene glycol, fatty alcohol, branched fatty alcohol, vitamin E, vitamin E acetate, tocopherol, tocopherol acetate, saturated fatty acids, unsaturated fatty acids. In another embodiment of the present invention, in the pharmaceutical formulation for an ointment the pH-adjustment agent is selected from the group comprising buffers, acidic and basic solutions, organic acids (e.g. citric acid, lactic acid), inorganic acids (hydrochloride acid, sulfuric acid, phosphoric acid), alkaline agents (sodium hydroxide, sodium bicarbonate), meglumine. Cream formulations

Another embodiment of the present application relates to a cream formulation of the pharmaceutical formulation of the present invention.

In one embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is a cream formulation further comprising:

(i) 0-5 % w/w preservatives

(ii) 0-20 % w/w of at least one surfactant

(iii) 1-40 % w/w oil phase/emollient

(iv) 0-40 % w/w Water.

With the above paragraph and with the context of the present invention the term "preservative(s)" denote antimicrobial substances / agents which are used to extend the shelf- life of medicines by respectively retarding the oxidation of active substances and excipients, and by reducing microbial proliferation. The properties of these substances are due to certain chemical groups which are usually aggressive towards living cells and which lead to certain risks when used in man.

With this context, "antioxidants" may act as preservative and are thus a subgroup of said preservatives in accordance with the invention.

In another embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is a cream formulation further comprising:

(i) > 0-5 % w/w preservatives

(ii) > 0-20 % w/w of at least one surfactant

(iii) > 1-40 % w/w oil phase/emollient

(iv) > 0-40 % w/w Water.

In the context of the present application, preservatives (antimicrobials) are incorporated to reduce the risk of microbial contamination of the formulation during manufacture, storage and use.

As used herein, surfactant is the short term for surface-active agent. Surfactants are any ingredients that lower tension between a surface and a liquid or between two or more immiscible substances. Surfactants are chemicals, which have parts that are both hydrophilic and lipophilic. This molecular composition means they have the ability to reduce the surface tension when placed into solutions of oil and water. Thus, they act as emulsifiers to create stable mixtures of oil and water. Some examples of surfactants are sodium or ammonium lauryl or laureth sulphate, sodium methyl cocoyl taurate, sodium lauroyl or cocoyl sarcosinate cocomidopropyl betaine, triethanolamine (TEA) compounds, dethanolamine (DEA) compounds, monethanolamine (MEA) compounds, polyethylene glycol (PEG) compounds, Quaterniurn-7, 15, 31, 60, et cetera, lauryl or cocoyl sarcosine disodium oleamide or dioctyl sulfosuccinate. In the context of the present application, emollient or moisturizer are complex mixtures of chemical agents specially designed to make the external layers of the skin (epidermis) softer and more pliable. They increase the skin's hydration by reducing evaporation. Naturally occurring skin lipids and sterols, as well as artificial or natural oils, humectants, emollients, lubricants, etc., may be part of the composition of commercial skin moisturizers.

In another embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of the at least one solvent is 0.1-60 % w/w, more preferred 15-50 % w/w, most preferred 30-45 % w/w. In another embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of a second solvent is 0.1-40 % w/w, more preferred 5-30 % w/w, most preferred 10-20 % w/w.

In one embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of a third solvent is 0.1-20 % w/w, more preferred 2-20 % w/w, most preferred 3-7 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of the preservative is 0.01-5 % w/w, more preferred 0.025-5 % w/w, most preferred 1-2 % w/w.

In one embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of the antioxidant agent is 0.01-5 % w/w, more preferred 0.025-1 % w/w, most preferred 0.05-0.15 % w/w. In another embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of the surfactant is 0.01-20 % w/w, more preferred 2-18 % w/w, most preferred 5-15 % w/w. In a further embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of the oil phase/emollient is 1-20 % w/w, more preferred 2-15 % w/w, most preferred 4-10 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of a second surfactant is 0.015-20 % w/w, more preferred 0.5-10 % w/w, most preferred 1 -4 % w/w.

In one further embodiment of the present invention, in the pharmaceutical formulation for a cream the concentration of water is 0.01-40 % w/w, more preferred 5-30 % w/w, most preferred 10-20 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation for a cream the preservative is selected from the group comprising Phenoxyethanol, benzyl alcohol, parabens (e.g. methyl paraben, butyl paraben) and salt thereof, benzoic acid and salt thereof, quaternary ammoniums (e.g. benzalkonium chloride, benzethonium chloride), boric acid, chlorhexidine, chlorobutanol, cresol and derivatives thereof, edetic acid and salt thereof, metabisulfite salt, thimerosal, sulfites, sorbic acid.

In another embodiment of the present invention, in the pharmaceutical formulation for a cream the penetration enhancer is selected from the group comprising propylene glycol, polyethylene glycol, dimethyl sulfoxide, decyl methyl sulfoxide, azone, N-methylpyrrolidone, diethyltoluamide, ethanol, isopropyl myristate, isopropyl palmitate, oleic acid and its esters, medium chain-length triglycerides, dimethylisosorbide, 2-octyldodecanol, branched-chain fatty acid esters, benzyl alcohol, urea, salicylates and surfactants.

In one embodiment of the present invention, in the pharmaceutical formulation for a cream the surfactant is selected from the group comprising alkyl polyglycol ether, an alkyl polyglycol ester, an ethoxylated alcohol, a polyoxyethylene sorbitan fatty acid ester, castor oil derivatives, polyoxyethylene fatty acid ester, polyoxyethylene glycol hydrogenated castor oil, polyoxyethylene glycol castor oil, a sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide such as for example, poloxamers, preferably poloxamer 188, poloxamer 407; tyloxapol; polysorbates; sucrose alkyl esters; sucrose alkyl ether; short chain fatty acids mono- and diesters of glycerol; medium chain fatty acids mono- and diesters of glycerol; long chain saturated fatty acids mono- and diesters of glycerol; long chain unsaturated fatty acids mono- and diesters of glycerol; short chain fatty acids monoesters of propylene glycol; medium chain fatty acids monoesters of propylene glycol; long chain saturated fatty acids monoesters of propylene glycol; long chain unsaturated fatty acids monoesters of propylene glycol; polyoxylglycerides; polyoxyethylene alkyl esters; polyoxylethylene ethers; vitamine E polyethylene glycol succinate, alkylpolyglycosides; quaternary ammonium based surfactant, fatty acid ester based anionic surfactant.

In one further embodiment of the present invention, in the pharmaceutical formulation for a cream the further emollient/oil phase is selected from the group comprising short chain fatty acids mono- di- and triesters of glycerol, medium chain fatty acids mono-, di- and triesters of glycerol, long chain saturated fatty acids mono-, di- and triesters of glycerol, long chain unsaturated fatty acids mono-, di- and triesters of glycerol, vegetable oils, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grapeseed oil, mustard seed oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid esters, short chain fatty acids mono- and diesters of propylene glycol, medium chain fatty acids mono- and diesters of propylene glycol, long chain saturated fatty acids mono- and diesters of propylene glycol, long chain unsaturated fatty acids mono- and diesters of propylene glycol, fatty alcohol, branched fatty alcohol, silicone oils, silicone derivatives, mineral oils, petrolatum, vitamin E, vitamin E acetate, tocopherol, tocopherol acetate, saturated fatty acids, unsaturated fatty acids, phospholipids.

Gel formulation

Another embodiment of the present application relates to a gel formulation of the pharmaceutical formulation of the present invention. In one embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is a gel formulation further comprising:

(i) 0-30 % w/w penetration enhancer

(ii) 0-20 % w/w gelling agent

(iii) 0-50 % w/w water

(iv) 0.01-20 % w/w of at least one pH-adjustment agent,

(v) optionally further comprising a preservative at an amount of about 0-5 % w/w.

With the context of the above paragraph, said "penetration enhancer" is a skin penetration enhancer.

In another embodiment of the present invention, the pharmaceutical formulation according to any one of the preceding embodiments is a gel formulation further comprising:

(i) > 0-30 % w/w penetration enhancer

(ii) > 0-20 % w/w gelling agent

(iii) > 0-50 % w/w water

(iv) 0.01-20 % w/w of at least one pH-adjustment agent,

The term "penetration enhancer" is used herein to generally include an agent that improves the transport of molecules such as an active agent into or through the skin. Various conditions may occur at different sites in the body either in the skin or below the skin creating a need to target delivery of compounds. A "penetration enhancer" may be used to assist in the delivery of an active agent directly to the skin or underlying tissue or indirectly to the site of the disease through systemic distribution. A penetration enhancer may be a pure substance or may comprise a mixture of different chemical entities.

With the context of the above paragraph, the stated also applies to a "skin penetration enhancer" in accordance with the invention. In the context of the present application, gels are semisolid, jelly-like formulations that range widely in viscosity. They are made from gelling agents that undergo a high degree of cross linking or association when dissolved or dispersed in the appropriate media. These gelling agents confer the variety of different viscosities and properties of the specific gel. Gelling agent are for example cellulose derivatives, Methylcellulose (MC), Carboxymethylcellulose (CMC), Hydroxypropylcellulose, Carbomers, Carbopol^® 910, Carbopol^® 941, Poloxamers, Pluronic^® or Tween.

In one further embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the at least one solvent is 1-90 % w/w, more preferred 10-80 % w/w, most preferred 30-70 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of a second solvent is 0.1-50 % w/w, more preferred 5-40 % w/w, most preferred 15-25 % w/w.

In one further embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the penetration enhancer is 0.1-30 % w/w, more preferred 5-25 % w/w, most preferred 10-20 % w/w.

In one further embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the preservative is 0.25-5 % w/w, more preferred 0.5-3 % w/w, most preferred 1-2 % w/w. In another embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the antioxidant agent is 0.01-5 % w/w, more preferred 0.025-3 % w/w, most preferred 0.05-2 % w/w.

In one further embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the gelling agent is 0.01-20 % w/w, more preferred 0.1-10 % w/w, most preferred 0.5-5 % w/w. In one embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the gelling agent carbomer is 0.25-5 % w/w, more preferred 0,5-3 % w/w, most preferred 1-2 % w/w. In one further embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of water is 0.1-50 % w/w.

In another embodiment of the present invention, in the pharmaceutical formulation for a gel the concentration of the pH-adjustment agent 0.015-20 % w/w.

In one further embodiment of the present invention, in the pharmaceutical formulation for a gel the solvent is PEG, preferably PEG 400, more preferably SR PEG 400.

In another embodiment of the present invention, in the pharmaceutical formulation for a gel the gelling agent is selected from the group comprising carbomers, poloxamer, polycarbophil, povidone, copovidone, PVA, vinyl ether polymers and copolymers, cellulose and cellulose derivatives, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, guar gum, chitosan, alginic acid and salts thereof, carrageenan, xanthan gum, polyethylene glycols, dextrans, silk proteins, gelatin, agar, preferably carbomer.

Specific ointment formulations

In one further embodiment of the present invention, the pharmaceutical formulation is an ointment comprising 0.1-90 % w/w SR PEG 400, 0.1-30 % w/w Propylene glycol, 0.1-40 % w/w PEG 4000, 0.01-10 % w/w Butylated hydroxy toluene and 0.01-20 % w/w diluted HCl or diluted NaOH solution as pH-adjustment agent, more preferred 10-80 % w/w SR PEG 400, 5- 20 % w/w Propylene glycol, 5-30 % w/w PEG 4000, 0.025-5 % w/w Butylated hydroxy toluene and 0.01-20 % w/w diluted HCl or diluted NaOH solution as pH-adjustment agent, most preferred 25-80 % w/w SR PEG 400, 7.5-10 % w/w Propylene glycol, 15-20 % w/w PEG 4000, 0.05-0.2 % w/w butylated hydroxy toluene and 0.01-20 % w/w diluted HCl or diluted NaOH solution as pH-adjustment agent.

In another embodiment of the present invention, the pharmaceutical formulation is an ointment comprising the following excipients in the disclosed ranges of Table 1 : Table 1. Ointment formulation

Specific cream formulations

In another embodiment of the present invention, the pharmaceutical formulation is a cream further comprising 0.1-20 % w/w ethanol, 0.1-60 % w/w PEG 400, 0.1-40 % w/w Transcutol HP, 0.01-5 % w/w Phenoxyethanol, 0.01-5 % w/w Butylated hydroxy toluene, 0.01-10 % w/w Brij-72, 0.01-20 % w/w Cetostearyl alcohol, 1-20 % w/w Crodamol GTCC, 0.01-20 % w/w Brij-721, 0-10 % w/w Dimethicone and 0.01-40 % w/w water, more preferred 2-20 % w/w ethanol, 15-50 % w/w PEG 400, 5-30 % w/w Transcutol HP, 0.025-5 % w/w Phenoxyethanol, 0.025-1 % w/w Butylated hydroxy toluene, 0.5-7 % w/w Brij-72, 3-15 % w/w Cetostearyl alcohol, 2-15 % w/w Crodamol GTCC, 0.5-10 % w/w Brij-721, 0.25-5 % w/w Dimethicone and 5-30 % w/w water; most preferred 3-7 % w/w ethanol, 30-45 % w/w PEG 400, 10-20 % w/w Transcutol HP, 1-2 % w/w Phenoxyethanol, 0.05-15 % w/w Butylated hydroxy toluene, 1-3 % w/w Brij-72, 5-10 % w/w Cetostearyl alcohol, 4-10 % w/w Crodamol GTCC, 1-4 % w/w Brij-721, 0.5-3 % w/w Dimethicone and 10-20 % w/w water.

In another embodiment of the present invention, the pharmaceutical formulation is a cream comprising the following excipients in the disclosed ranges of Table 2:

Table 2: Cream formulation

Specific gel formulations

In another embodiment of the present invention, the pharmaceutical formulation is a gel further comprising 1-90 % w/w SR PEG 400, 0.1-50 % w/w Propylene glycol, 0.1-30 % w/w Dimethyl isosorbide, 0.25-5 % w/w Phenoxyethanol, 0.01-5 % w/w Butylated hydroxy toluene, 0.25-5 % w/w carbomer, 0.1-50 % w/w water and 0.01-20 % w/w diluted HCl or diluted NaOH solution as pH-adjustment agent (please complement), more preferred 10-80 % w/w SR PEG 400, 5-40 % w/w Propylene glycol, 5-25 % w/w Dimethyl isosorbide, 0.5-3 % w/w Phenoxyethanol, 0.025-3 % w/w Butylated hydroxy toluene, 0.5-3 % w/w carbomer, 0.1- 50 % w/w water and 0.01-20 % w/w diluted HCl or diluted NaOH solution as pH-adjustment agent, most preferred 30-70 % w/w SR PEG 400, 15-25 % w/w Propylene glycol, 10-20 % w/w Dimethyl isosorbide, 1-2 % w/w Phenoxyethanol, 0.05-2 % w/w Butylated hydroxy toluene, 1-2 % w/w carbomer, 0.1-50 % w/w water and 0.01-20 % w/w diluted HCl or diluted NaOH solution as pH-adjustment agent. In another embodiment of the present invention, the pharmaceutical formulation is a gel comprising the following excipients in the disclosed ranges of Table 3:

In a further embodiment of the present invention, the pharmaceutical formulation is an ointment comprising 67.72 % w/w SR PEG 400, 9.78 % w/w Propylene glycol, 17.5 % w/w PEG 4000 and 5 % active pharmaceutical ingredient pritelivir, wherein the pH value is pH 4.0 - 5.0.

In a further embodiment of the present invention, the pharmaceutical formulation is an ointment comprising 67.62 % w/w SR PEG 400, 9.78 % w/w Propylene glycol, 17.5 % w/w PEG 4000, 0.1 % BHT and 5 % active pharmaceutical ingredient pritelivir, wherein the pH value is pH 4.0 to 4.5.

In another embodiment of the present invention, the pharmaceutical formulation is a gel further comprising 39.1 % w/w SR PEG 400, 9.59 % w/w Ethanol, 4.8 % w/w pH 4 buffer, 23.98 % w/w Transcutol HP, 14.39 % w/w dimethylisosorbide, 1.92 % w/w Benzyl alcohol, 1.25 % w/w hydroxypropylcellulose.

In one embodiment of the present invention, the embodimented pharmaceutical formulation is for use as medicament. In another embodiment of the present invention, the pharmaceutical formulation is for use in the treatment and/or prevention of herpes virus infections.

In one embodiment of the present invention, the pharmaceutical formulation is for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses. In another embodiment of the present invention, the pharmaceutical formulation is for use in the treatment and/or prevention of herpes virus infections, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2).

Another embodiment of the present invention relates to a method of treatment and/or prophylaxis of a herpes virus infection comprising administering the topical pharmaceutical formulation to a subject in need thereof. Free base hemihydrate

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of about 5.0 % w/w. With the context of the above paragraph and throughout the text, the expression "5 % w/w pritelivir anti-viral agent" or similar expressions for any of the herein disclosed pritelivir active pharmaceutical ingredients denote that the pritelivir drug is added to the topical formulations in amounts that ensure for the presence of finally 5 % w/w of pritelivir free base as active moiety. This means exemplarily for the pritelivir free base hemihydrate that this is added to the topical formulations with 5.11 % w/w due to the present crystal water, but will result finally in only 5 % w/w free base pritelivir as active moiety. The same applies to indications of e.g. 1.0 % to 10 % w/w pritelivir in topical formulations of the invention. Hence, basically, and throughout the text, the given amounts for the pritelivir ever refer to the final free base content as active moiety; in case of the hemihydrate e.g. without the consideration of the present crystal water in the pritelivir free base hemihydrate. Of note, this applies to the entire text as presented herein.

In one embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of 5.0 % w/w, wherein the pharmaceutical composition is an ointment.

In one further embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl]acetamide is present in an amount of about 1.0 to about 7.5 % w/w, particularly about 5.0 % w/w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day.

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of 1.0 to 7.5 % w/w, particularly 5.0 % w/w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day, and wherein the ointment is administered over a period of 2 to 14 days, 3 to 10 days, 3 to 7 days, 4 to 5 days, or over 5 days, or over 4 days.

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of 5.0% w/w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 5 times a day, and wherein the ointment is administered over a period of 4 days. In another embodiment of the present invention, in the pharmaceutical formulation

the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)phenyl]acetamide is present in an amount sufficient to reach a concentration of > 10 nM in the epidermis and dermis of an individual subjected to a treatment with said composition.

In another embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use as a medicament. In another embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment and/or prevention of herpes virus infections. In a further embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses.

In another embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment and/or prevention of said herpes virus infections, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2).

In another embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide or derivative thereof is for use in a topical pharmaceutical formulation in the treatment and/or prevention of a herpes virus infection in a subject in need thereof.

In a further embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide or derivative thereof is for use in a topical pharmaceutical formulation in the treatment of a subject in need thereof, wherein said subject has a herpes virus infection or is suspected to have a herpes virus infection.

In one embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in topical administration to a subject in need thereof, wherein said topical administration is for facial application, and/or application to the mouth, the genitals, and/or the eyes. In one embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in topical administration to a subject in need thereof, wherein said topical administration is for any other body compartments besides the explicitly given ones in the above paragraph. In another embodiment of the present invention, in the pharmaceutical formulation a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in systemic administration to a subject in need thereof, wherein said subject is suspected to have a herpes virus infection or is a subject having a herpes virus infection.

In a further embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of recurrent herpes labialis.

In a specific embodiment of the present invention, the pharmaceutical formulation of the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is preferably provided for the use in the treatment of recurrent herpes labialis.

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of recurrent herpes labialis selected from the group of patients showing signs of the prodromal stage of herpes labialis, patients having erythema, patients showing labial papules, patients having labial vesicles, patients with labial ulcers and/or soft crusts, patients having labial hard crusts, patients having residual labial erythema. In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of herpes genitalis.

In a further embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of herpes keratitis.

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of herpes meningitis and/or encephalitis.

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of herpes infections in the newborn.

In another embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of herpes infections in the immunocompetent and/or immunocompromised individuals.

In a further embodiment of the present invention, in the pharmaceutical formulation the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is for use in the treatment of herpes infections in immunocompromised individuals, wherein the immunocompromised individuals are selected from the group comprising recipients of an organ transplant, individuals having an infection by another virus or bacterium, particularly an infection with HIV and/or another herpes virus, and individuals infected with a herpes simplex virus that is resistant to at least one anti-viral active.

In another embodiment the present invention relates to a method of treatment and/or prophylaxis of a herpes virus infection comprising administering a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide to a subject in need thereof.

The term(s) "prophylaxis and/or prevention" or similar term(s) in the art pertinent to the instant invention clearly mean to one of ordinary skill in the art the suppression or reduction of the recurrence of infection or the suppression or reduction of transmission of infection with herpes simplex virus subtype 1 or 2. In the context of the invention, the term(s) "prophylaxis and/or prevention" does not mean with, even under the broadest reasonable interpretation, the complete and total absence of any infectious virus particles or infected cells from a patient. With the background of the instant invention, such a position is reasonable in the art pertinent to the disclosed subject matter. In support of these definitions of the term(s) "prophylaxis and/or prevention" the following publications are herein incorporated by reference:

Abdool Karim,S.S., et al. (2015). Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection. N Engl. J Med 373, 530-539.

Andrei,G. et al (201 1). Topical tenofovir, a microbicide effective against HIV, inhibits herpes simplex virus-2 replication. Cell Host. Microbe 10, 379-389. Corey, L., et al., (2004). Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N. Engl. J. Med. 350, 11-20. leymann, G., et al. (2002). New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat. Med. 8, 392-398.

Mertz, G.J., et al., (1985). Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm. Dis. 12, 33-39. Reitano, M., et al., (1998). Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J. Infect. Dis. 178, 603-610.

Schiffer, J.T., et al., (1997). Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J. Clin Invest 99, 1092-1097.

Wald, A., et al. (2014). Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl. J Med 370, 201-210. Wald, A., et al. (2000). Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 342, 844-850.

Zhu, J., et al. (2007). Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595-603. Gold, D., and Corey,L., MINIREVIEW Acyclovir Prophylaxis for Herpes Simplex Virus Infection. Antimicrobial Agents and Chemotherapy, Mar. 1987, p. 361-367.

Tyring, S., Baker,D., Snowden, W., Valacyclovir for Herpes Simplex Virus Infection: Long- Term Safety and Sustained Efficacy after 20 Years' Experience with Acyclovir. The Journal of Infectious Diseases 2002; 186(Suppl l):S40-6.

These documents support the correlation between helicase-primase inhibition and the prevention or prevention of transmission of herpes simplex virus infection as having been demonstrated in the art. Further, the above mentioned Kleymann, 2002, teaches on page 396, bottom of the left column, that recurrent disease and asymptomatic virus shedding are nearly completely suppressed by helicase-primase inhibitors, which should decrease person-to- person transmission, i.e., to effectively prevent the transmission of HSV. The above mentioned disclosure in Corey, 2004, teaches at the bottom of page 11 and on page 17, first column, that once daily suppressive therapy with valacyclovir significantly reduces the risk of transmission, i.e., prevented the transmission, of genital herpes among heterosexual, HSV-2 discordant couples. The study achieved these results by a drug that has been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces. See the top of page 11. Further, it has been found that the frequency and amount of HSV that is shed subclinically on genital mucosal surfaces is the principal source of transmitted infections. See citations 20- 22, dating back to 1997, 1998 and 1997 in the order recited. As such, an approach to reduce the frequency and amount of HSV that is shed subclinically on genital mucosal surfaces is a way to achieve prevention of transmission of herpes.

Karim, 2015, teaches at the bottom of page 530 that based on the study therein, it was shown that pericoital application of tenofovir gel reduced HSV-2 acquisition in women, i.e., prevented getting HSV. The effectiveness was a reduction of 51%. See page 534, second column. In an earlier study by the same group dating back to 2010 (see citation 6 in this reference), it was shown that pericoital application of a topical vaginal-gel formulation of tenofovir reduced HIV acquisition. While HIV is a different virus, it is not unbelievable by those of ordinary skill in the art in view of the above that a drug is able to prevent the acquisition of a viral infection. Moreover, such is explicitly confirmed to occur by Karim in the case of HSV. Gold and Corey from March 1987 support the well-known effective prophylaxis of acyclovir (i.e., viral DNA polymerase inhibitor). In addition, Tyring et al. from 2002 supports the efficacy of the prodrug valacyclovir (i.e., viral DNA polymerase inhibitor).

The person skilled in the art is aware that in case of HSV-1 and HSV-2 infection, although the viruses are present within the body due to infection, there is no symptomatic outbreak because N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate effectively suppresses viral shedding and outbreak, which is "prophylaxis" or "suppression" against the resultant symptoms of HSV-1 and HSV-2 infection. In further support of the prophylaxis = suppression aspect of the invention, the above mentioned citations for valacyclovir (i.e. Tyring et al. 2002) and acyclovir (i.e. Gold et al. 1987) are reiterated, which also prove that it is well established that HSV infections are in normal individuals asymptomatic, and what prophylactic/suppressive therapy means in this art. Moreover, effective HSV-prophylaxis has been clinically demonstrated in human trials, and as such. In this regard, a poster from ICAAC 2014 for the HSV-2 genital herpes indication is incorporated by reference (Wald et al., 2014, supra). Finally, one of ordinary skill in the art knows that by analogy to Tenofovir, N-[5-(amino- sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as helicase-primase inhibitor is known to have an even higher antiviral efficacy than Tenofovir in case of HIV, and thus, for the skilled person, N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide also would be expected to have a more pronounced prophylactic efficacy. In this regard, particularly relevant are the publications by Andrei et al. and Kleymann et al. as mentioned above. The IC₅o-values demonstrated therein for Tenofovir are significantly higher when compared to N- [5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate.

Method of the manufacture of the free base hemihydrate

Another embodiment of the present invention relates to a method of manufacturing N-[5- (amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate, wherein said method comprises the following steps: a) Mixing 4-pyridine-2yl-phenyl)-acetic acid and amionothiazole sulfonic acid amide in N-Methylpyrrolidone (NMP);

b) Cooling the mixture obtained in step a); c) Adding N-Ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HC1) to said mixture obtained in step b);

d) Stirring the solution obtained in step c) and addition to purified H₂0;

e) Filtering the solution obtained in step d);

f) Washing the product cake obtained in step e);

g) Drying the product obtained in step f);

h) Adding H₂0 to the solution obtained in step g);

i) Stirring the suspension obtained in step h);

j) Cooling the suspension obtained in step i);

k) Stirring the suspension obtained in step j);

1) Isolating the product by filtration of the suspension obtained in step k);

m) Washing the product obtained in step 1) with H₂0;

n) Drying the product obtained in step m). In another embodiment of the present invention, a pharmaceutical composition comprising a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl]acetamide is obtainable by a method as described in the preceding embodiment. In one embodiment of the present invention, a pharmaceutical composition is

obtainable by formulation of a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl- l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide as obtained by the method as described in the preceding embodiments with at least one pharmaceutical excipient. Another embodiment of the present invention relates to the use of free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide that is obtainable in a method as described in the preceding embodiments as a medicament. Maleate

Another embodiment of the present invention relates to a pharmaceutical composition comprising a free base maleate, wherein the free base maleate of N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is present in an amount of about 5.0 % w/w. With the context of the above paragraph and throughout the text, the expression "5 % w/w pritelivir anti-viral agent" or similar expressions for any of the herein disclosed pritelivir active pharmaceutical ingredients denote that the pritelivir drug is added to the topical formulations in amounts that ensure for the presence of finally 5 % w/w of pritelivir free base as active moiety. This means exemplarily for the pritelivir maleate salt that this is added to the topical formulations in amounts may exceeding said 5 % w/w, but will result finally in only 5 % w/w free base pritelivir as active moiety. The same applies to indications of e.g. 1.0 % to 10 % w/w pritelivir maleate salt in topical formulations of the invention. Hence, basically, and throughout the text, the given amounts for the pritelivir ever refer to the final free base content as active moiety.

Another preferred embodiment of the present invention relates to a pharmaceutical composition comprising a free base maleate, wherein the free base maleate of N-[5-(amino- sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is present in an amount of about 1.0 to about 7.5 % w/w, particularly about 5.0% w/w.

Another embodiment of the present invention relates to a maleate salt of the free base of N- [5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide, wherein said maleate salt is characterised by a photostability of at least 70 % residual free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide after light exposure with wavelengths ranging as of from 300 nm to 800 nm, and with a light exposure quantity of at least 1.2 million Lux hours, and with a light exposure energy of at least 200 watt hours/m² over at least 29 hours when said photostability is determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

A further embodiment of the present invention relates to the maleate salt according to the preceding embodiments, wherein said maleate salt is further characterised by having characteristic XRPD peaks at 6.6, 15.9, 16.2, 18.1, 20.5, 22.5, 26.1, and 28.6 2theta when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

Another embodiment of the present invention relates to the maleate salt according to the preceding embodiments, wherein said maleate salt is physico-chemical stable characterised by recoveries of said maleate salt of the start concentration of at least 85 % after two weeks storage at room temperature and at a pH as of from 3.5 - 7.0 in aqueous solution when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

Another embodiment of the present invention relates to the maleate salt according to the preceding embodiments, wherein said maleate salt is characterised by solubility in water of about 0.48 mg/mL when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

A further embodiment of the present invention relates to a pharmaceutical composition comprising a free base maleate, wherein the maleate salt is present in an amount sufficient to reach a concentration of > 10 nM in the epidermis and dermis of an individual subjected to a method of topical treatment with said composition when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

Another embodiment of the present invention relates to a pharmaceutical composition comprising a free base maleate for use in the treatment and/or prevention of herpes virus infections.

Another embodiment of the present invention relates to a process for the manufacture of the maleate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl- 2-[4-(2-pyridinyl)phenyl]acetamide as defined in the preceding embodiments, said process comprising the steps of: i) providing a mixing means, preferably a mixing means with overhead stirring, ii) filling said mixing means of step i) with 460 to 490 g free base of pritelivir, iii) suspending the free base of pritelivir of step ii) with 3 to 5 volumes of water, iv) heating the suspension of step iii) to 45 to 55 °C by suitable heating means, v) adding 225 to 240 g of maleic acid in solid form over a time period of 40 to 90 min. until resultant solution is obtained,

vi) cooling the solution obtained under step v) down towards 44 to 52 °C

vii) seeding an aliquot of the solution of step vi) with a maleate salt of the free base pritelivir,

viii) over a period as of from 1.5 to 2.5 hours the resultant suspension of step vii) is allowed to cool down towards 18 to 24 °C, ix) stirring the suspension of step viii) overnight follows,

x) the suspension of step ix) was filtered, so to obtain a resultant filter cake, xi) the solid filter cake obtained under step x) is transferred to a mixing means, preferably a flask,

xii) rotary evaporation of the mixing means of step xi) follows for 25 to 32 hours while applying the following conditions:

a. an ambient temperature of 30 to 40 °C,

b. a pressure of 15 to 25 mbar,

so to obtain a constant mass,

xiii) homogenisation follows, preferably homogenisation with mortar and pastle follows,

xiv) so to obtain a maleate salt of the free base of pritelivir in accordance with the invention.

Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following embodiments.

With the above context, the following consecutively numbered embodiments provide other specific aspects of the invention:

1. A pharmaceutical formulation for use in topical application to a subject in need thereof, said formulation comprising: i.) 1-10 % w/w of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide, ii. ) 0-90 % w/w of at least one solvent,

iii. ) 0-10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 2.0 to 8.0, preferably a pH of 4.0 to 5.0, , wherein the N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C/ 60 % RH, wherein said solvent is selected from the group comprising ethanol, dimethyl isosorbide, isopropanol, Transcutol P, propylene glycol, polyethylene glycols, PEG 400, PEG 4000 and Super Refined (SR) PEG 400. In an adjacent embodiment to embodiment 1, a pH value of 4.0 to 4.5 is preferred for the said pharmaceutical formulation.

In an adjacent embodiment to embodiment 1, the N-[5-(amino-sulfonyl)-4-methyl-l ,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for at least 24 months at 25 °C/ 60 % RH. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in embodiment 1 , wherein the at least one solvent is selected from the group comprising polyethylene glycols, preferably PEG 400, more preferably SR PEG 400. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in embodiments 1 and 2, wherein the said N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is selected from the group comprising:

• N-[5-(amino-sulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate, • maleate salt of N-[5-(amino-sulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)phenyl]acetamide,

• mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol- 2-yl] -N-methyl-2- [4-(2-pyridiny l)phenyl] acetamide, and

• free base of N- [5 -(amino-sulfonyl)-4-methy 1-1,3 -thiazol-2-yl] -N-methyl-2- [4- (2-pyridinyl)phenyl]acetamide. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of embodiments 1 to 3, wherein said antioxidant agent is selected from the group comprising butylated hydroxyl toluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate salt. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 4, wherein said antioxidant agent is BHT. The pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the embodiments 1 to 5, wherein said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, paste, solutions, oils, lipogels.

In an adjacent embodiment to embodiment 6, said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, paste, solutions, oils, lipogels, and patches. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 6, wherein the concentration of the active pharmaceutical ingredient pritelivir is selected from the range of 1.1 to 10 % w/w, more preferably 1.1 to 5 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 7, wherein the concentration of the at least one solvent is 0.1 - 90 % w/w, for example 5 - 90 % w/w, 10 - 90 % w/w, 10 - 80 % w/w, 20 - 80 % w/w, 25 - 80 % w/w, 15 - 50 % w/w or 30 - 45 % w/w.

9. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 8, wherein the concentration of a second solvent is 0.1 - 60 % w/w, more preferred 10 - 50 % w/w, most preferred 10 - 40 % w/w.

10. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 9, wherein the concentration of the antioxidant agent is 0.01 - 10 % w/w, more preferred 0.025 - 5 % w/w, most preferred 0.05 - 2 % w/w.

11. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 10, wherein said formulation is an ointment further comprising

(i) 0.01 - 20 % w/w of at least one pH-adjustment agent. 12. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in embodiment 11 , wherein for said ointment formulation the concentration of the at least one solvent is 25 - 90 % w/w, more preferred 25 - 80 % w/w, most preferred 60 - 80 % w/w. 13. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 1 to 12, wherein for an ointment formulation the concentration of a second solvent is 0.1 - 40 % w/w, more preferred 5 - 20 % w/w, most preferred 7.5 - 10 % w/w. 14. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 11 to 13, wherein for an ointment formulation the concentration of a third solvent is 0.1 - 30 % w/w, more preferred 5 - 30 % w/w, most preferred 15 - 20 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 11 to 14, wherein for an ointment formulation said concentration of the antioxidant agent is 0.015 - 10 % w/w, more preferred 0.1 - 5 % w/w, most preferred 0.1 - 2 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of embodiments 11 to 15, wherein for an ointment formulation the concentration of the pH-adjustment agent is 0.015 - 20 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 11 to 16, wherein for an ointment formulation said solvent is selected from the group comprising polyethylene glycol, propylene glycol, petrolatum, liquid paraffin, lanolin, mineral oil, silicone oils, silicone derivatives, short chain fatty acids mono- di- and triesters of glycerol, medium chain fatty acids mono-, di- and triesters of glycerol, long chain saturated fatty acids mono-, di- and triesters of glycerol, long chain unsaturated fatty acids mono-, di- and triesters of glycerol, vegetable oils, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grapeseed oil, mustard seed oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid esters, short chain fatty acids mono- and diesters of propylene glycol, medium chain fatty acids mono- and diesters of propylene glycol, long chain saturated fatty acids mono- and diesters of propylene glycol, long chain unsaturated fatty acids mono- and diesters of propylene glycol, fatty alcohol, branched fatty alcohol, vitamin E, vitamin E acetate, tocopherol, tocopherol acetate, saturated fatty acids, unsaturated fatty acids. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 17, wherein said pH-adjustment agent is selected from the group comprising buffers, acidic and basic solutions, organic acids (e.g. citric acid, lactic acid), inorganic acids (hydrochloride acid, sulfuric acid, phosphoric acid), alkaline agents (sodium hydroxide, sodium bicarbonate), meglumine.

With the context of embodiment 18 and with the context of the present invention, it shall be noted that a pH adjustment agent is used in the sense of an "apparent pH adjustment agent". All given pH values for the present topical formulations of the invention refer to the apparent pH. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 10, wherein said formulation is a cream further comprising:

i. 0 - 5 % w/w of a preservative

ii. 0 - 20 % w/w of at least one surfactant iii. 1 - 40 % w/w oil phase/emollient

iv. 0 - 40 % w/w water. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in embodiment 19, wherein for a cream formulation the concentration of the at least one solvent is 0.1 - 60 % w/w, more preferred 15 - 50 % w/w, most preferred 30 - 45 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of embodiments 19 to 20, wherein for a cream formulation the concentration of a second solvent is 0.1 - 40 % w/w, more preferred 5 - 30 % w/w, most preferred 10 - 20 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 21, wherein for a cream formulation the concentration of a third solvent is 0.1 - 20 % w/w, more preferred 2 - 20 % w/w, most preferred 3 - 7 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 22, wherein for a cream formulation the concentration of the preservative is 0.01 - 5 % w/w, more preferred 0.025 - 5 % w/w, most preferred 1 - 2 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 23, wherein for a cream formulation the concentration of the antioxidant agent is 0.01 - 5 % w/w, more preferred 0.025 - 1 % w/w, most preferred 0.05 - 0.15 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 24, wherein for a cream formulation the concentration of the surfactant is 0.01 - 20 % w/w, more preferred 2 to 18 % w/w, most preferred 5 to 15 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 25, wherein for a cream formulation the concentration of the oil phase/emollient is 1 - 20 % w/w, more preferred 2 - 15 % w/w, most preferred 4 - 10 % w/w.

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 26, wherein for a cream formulation the concentration of a second surfactant is 0.015 - 20 % w/w, more preferred 0.5 - 10 % w/w, most preferred 1 - 4 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 19 to 27, wherein for a cream formulation the concentration of water is 0.01 - 40 % w/w, more preferred 5 - 30 % w/w, most preferred 10 - 20 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 28, wherein said preservative is selected from the group comprising phenoxyethanol, benzyl alcohol, parabens (e.g. methyl paraben, butyl paraben) and a salt thereof, benzoic acid and salts thereof, quaternary ammoniums (e.g. benzalkonium chloride, benzethonium chloride), boric acid, chlorhexidine, chlorobutanol, cresol and derivatives thereof, edetic acid and a salt thereof, metabisulfite salt, thimerosal, sulfites, sorbic acid. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 29, wherein said penetration enhancer is selected from the group comprising propylene glycol, polyethylene glycol, dimethyl sulfoxide, decyl methyl sulfoxide, azone, N-methylpyrrolidone, diethyltoluamide, ethanol, isopropyl myristate, isopropyl palmitate, oleic acid and its esters, medium chain-length triglycerides, dimethylisosorbide, 2-octyldodecanol, branched-chain fatty acid esters,benzyl alcohol, urea, salicylates and surfactants.

With the context of embodiment 30 and throughout the text, "penetration enhancer" means "skin penetration enhancer".

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 30, wherein said surfactant is selected from the group comprising alkyl polyglycol ether, an alkyl polyglycol ester, an ethoxylated alcohol, a polyoxyethylene sorbitan fatty acid ester, castor oil derivatives, polyoxyethylene fatty acid ester, polyoxyethylene glycol hydrogenated castor oil, polyoxyethylene glycol castor oil, a sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide such as for example, poloxamers, preferably poloxamer 188, poloxamer 407; tyloxapol; polysorbates; sucrose alkyl esters; sucrose alkyl ether; short chain fatty acids mono- and diesters of glycerol; medium chain fatty acids mono- and diesters of glycerol; long chain saturated fatty acids mono- and diesters of glycerol; long chain unsaturated fatty acids mono- and diesters of glycerol; short chain fatty acids monoesters of propylene glycol; medium chain fatty acids monoesters of propylene glycol; long chain saturated fatty acids monoesters of propylene glycol; long chain unsaturated fatty acids monoesters of propylene glycol; polyoxylglycerides; polyoxyethylene alkyl esters; polyoxylethylene ethers; vitamine E polyethylene glycol succinate, alkylpolyglycosides; quaternary ammonium based surfactant, fatty acid ester based anionic surfactant. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 31 , wherein said emollient/oil phase is selected from the group comprising short chain fatty acids mono- di- and triesters of glycerol, medium chain fatty acids mono-, di- and triesters of glycerol, long chain saturated fatty acids mono-, di- and triesters of glycerol, long chain unsaturated fatty acids mono-, di- and triesters of glycerol, vegetable oils, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grapeseed oil, mustard seed oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid esters, short chain fatty acids mono- and diesters of propylene glycol, medium chain fatty acids mono- and diesters of propylene glycol, long chain saturated fatty acids mono- and diesters of propylene glycol, long chain unsaturated fatty acids mono- and diesters of propylene glycol, fatty alcohol, branched fatty alcohol, silicone oils, silicone derivatives, mineral oils, petrolatum, vitamin E, vitamin E acetate, tocopherol, tocopherol acetate, saturated fatty acids, unsaturated fatty acids, phospholipids. 33. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 10, wherein said formulation is a gel further comprising:

(i) 0 - 30 % w/w penetration enhancer

(ii) 0 - 20 % w/w of at least one gelling agent

(iii) 0 - 50 % w/w water

(iv) 0.01 - 20 % w/w of at least one pH-adjustment agent,

(v) optionally further comprising a preservative at an amount of about 0 - 5 %w/w. 34. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in embodiment 33, wherein for a gel formulation the concentration of the at least one solvent is 1 - 90 % w/w, more preferred 10 - 80 % w/w, most preferred 30 - 70 % w/w. 35. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 34, wherein for a gel formulation the concentration of a second solvent is 0.1 - 50 % w/w, more preferred 5 - 40 % w/w, most preferred 15 - 25 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 35, wherein for a gel formulation the concentration of the penetration enhancer is 0.1 - 30 % w/w, more preferred 5 - 25 % w/w, most preferred 10 - 20 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of embodiments the 33 to 36, wherein for a gel formulation the concentration of the preservative is 0.25 - 5 % w/w, more preferred 0.5 - 3 % w/w, most preferred 1 - 2 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 37, wherein for a gel formulation the concentration of the antioxidant agent is 0.01 - 5 % w/w, more preferred 0.025 - 3 % w/w, most preferred 0.05 - 2 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 38, wherein for a gel formulation the concentration of the gelling agent is 0.01 - 20 % w/w, more preferred 0.1 - 10 % w/w, most preferred 0.5 - 5 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 39, wherein for a gel formulation the concentration of the gelling agent carbomer is 0.25 - 5 % w/w, more preferred 0.5 - 3 % w/w, most preferred 1 - 2 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 40, wherein for a gel formulation the concentration of water is 0.1 - 50 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 41, wherein for a gel formulation the concentration of the pH-adjustment agent is 0.015 - 20 % w/w. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 33 to 42, wherein for a gel formulation the solvent is PEG, preferably PEG 400, more preferably SR PEG 400. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 43, wherein said gelling agent is selected from the group comprising carbomers, poloxamer, polycarbophil, povidone, copovidone, PVA, vinyl ether polymers and copolymers, cellulose and cellulose derivatives, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, guar gum, chitosan, alginic acid and salts thereof, carrageenan, xanthan gum, polyethylene glycols, dextrans, silk proteins, gelatin, agar, preferably carbomer. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 18, wherein said formulation is an ointment comprising 0.1 - 90 % w/w SR PEG 400, 0.1 - 30 % w/w propylene glycol, 0.1 - 40 % w/w PEG 4000, 0.01 - 10 % w/w butylated hydroxy toluene and 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent, more preferred 10 - 80 % w/w SR PEG 400, 5 - 20 % w/w propylene glycol, 5 - 30 % w/w PEG 4000, 0.025 - 5 % w/w butylated hydroxy toluene and 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent, most preferred 25 - 80 % w/w SR PEG 400, 7.5 - 10 % w/w propylene glycol, 15 - 20 % w/w PEG 4000, 0.05 - 0.2 % w/w butylated hydroxy toluene and 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 10 and 19 to 32, wherein said formulation is a cream comprising 0.1 - 20 % w/w ethanol, 0.1 - 60 % w/w PEG 400,

0.1 - 40 % w/w Transcutol HP, 0.01 - 5 % w/w phenoxyethanol, 0.01 - 5 % w/w butylated hydroxy toluene, 0.01 - 10 % w/w Brij-72, 0.01 - 20 % w/w cetostearyl alcohol, 1 - 20 % w/w crodamol GTCC, 0.01 - 20 % w/w Brij-721, 0-10 % w/w dimethicone and 0.01 - 40 % w/w water, more preferred 2 - 20 % w/w ethanol, 15 - 50

% w/w PEG 400, 5 - 30 % w/w Transcutol HP, 0.025 - 5 % w/w phenoxyethanol,

0.025 - 1 % w/w butylated hydroxy toluene, 0.5 - 7 % w/w Brij-72, 3-15 % w/w cetostearyl alcohol, 2 - 15 % w/w Crodamol GTCC, 0.5 - 10 % w/w Brij-721, 0.25 - 5

% w/w dimethicone and 5 - 30 % w/w water; most preferred 3 - 7 % w/w ethanol, 30 - 45 % w/w PEG 400, 10 - 20 % w/w Transcutol HP, 1 - 2 % w/w phenoxyethanol, 0.05 - 15 % w/w butylated hydroxy toluene, 1 - 3 % w/w Brij-72, 5 - 10 % w/w Cetostearyl alcohol, 4 - 10 % w/w Crodamol GTCC, 1 - 4 % w/w Brij-721, 0.5 - 3 % w/w Dimethicone and 10 - 20 % w/w water. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 10 and 33 to 44, wherein said formulation is a gel comprising 1 to 90 % w/w SR PEG 400, 0.1 to 50 % w/w propylene glycol, 0.1 - 30 % w/w dimethyl isosorbide, 0.25 - 5 % w/w Phenoxyethanol, 0.01 - 5 % w/w butylated hydroxy toluene, 0.25 - 5 % w/w carbomer,

0.1 - 50 % w/w water and 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent, more preferred 10 - 80 % w/w SR PEG 400, 5 - 40 % w/w Propylene glycol, 5 - 25 % w/w dimethyl isosorbide, 0.5 - 3 % w/w phenoxyethanol, 0.025 - 3 % w/w butylated hydroxy toluene, 0.5 - 3 % w/w carbomer, 0.1 - 50 % w/w water and 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent, most preferred 30 - 70 % w/w SR PEG 400, 15 - 25 % w/w propylene glycol, 10 - 20 % w/w dimethyl isosorbide, 1 - 2 % w/w phenoxyethanol, 0.05 - 2 % w/w butylated hydroxy toluene, 1 - 2 % w/w carbomer, 0.1 - 50 % w/w water and 0.01 - 20 % w/w diluted HC1 or diluted NaOH solution as pH-adjustment agent. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 47, wherein said formulation is an ointment comprising 67.72 % w/w SR PEG 400, 9.78 % w/w propylene glycol, 17.5 % w/w PEG 4000 and 5 % active pharmaceutical ingredient pritelivir, wherein the pH value is pH 4.0 - 5.0. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 48, wherein said formulation is a gel comprising 39.1 % w/w SR PEG 400, 9.59 % w/w ethanol, 4.8 % w/w pH 4 buffer, 23.98 % w/w Transcutol HP, 14.39 % w/w dimethylisosorbide, 1.92 % w/w benzyl alcohol, 1.25 % w/w hydroxypropylcellulose. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 49 for use as medicament. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 50 for use in the treatment and/or prevention of herpes virus infections. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 51 for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 52 for use in the treatment and/or prevention of herpes virus infections according to the embodiments 51 to 52, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2). A method of treatment and/or prophylaxis of a herpes virus infection comprising administering the topical pharmaceutical formulation as defined in any one of the embodiments 1 to 53 to a subject in need thereof. The topical pharmaceutical formulation as defined in any one of the embodiments 1 to 54, wherein the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is present in an amount of about 5.0 % w/w. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 54, wherein the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of 5.0 % w/w, wherein the pharmaceutical composition is an ointment. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 56, wherein the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of about 1.0 to about 7.5 % w/w, particularly about 5.0 % w/w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 57, wherein the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of 1.0 to 7.5 % w/w, particularly 5.0 % w/w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day, and wherein the ointment is administered over a period of 2 to 14 day, 3 to 10 days, 3 to 7 days, 4 to 5 days, or over 5 days, or over 4 days.

The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 58, wherein the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of 5.0 % w/w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 5 times a day, and wherein the ointment is administered over a period of 4 days. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 59, wherein the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount sufficient to reach a concentration of >10 nM in the epidermis and dermis of an individual subjected to a treatment with said composition. A free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment and/or prevention of herpes virus infections. A free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses. A free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment and/or prevention of herpes virus infections according to embodiment 62, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2). A free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide or derivative thereof for use in a topical pharmaceutical formulation in the treatment and/or prevention of a herpes virus infection in a subject in need thereof. A free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide or derivative thereof for use in a topical pharmaceutical formulation in the treatment of a subject in need thereof, wherein said subject has a herpes virus infection or is suspected to have a herpes virus infection The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in topical administration to a subject in need thereof, wherein said topical administration is for facial application, and/or application to the mouth, the genitals, and/or the eyes. A free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in systemic administration to a subject in need thereof, wherein said subject is suspected to have a herpes virus infection or is a subject having a herpes virus infection. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of recurrent herpes labialis. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of recurrent herpes labialis selected from the group of patients showing signs of the prodromal stage of herpes labialis, patients having erythema, patients showing labial papules, patients having labial vesicles, patients with labial ulcers and/or soft crusts, patients having labial hard crusts, patients having residual labial erythema. 70. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- < methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of herpes genitalis. 71. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of herpes keratitis.

72. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- : methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of herpes meningitis and/or encephalitis.

73. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of herpes infections in the newborn.

74. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of herpes infections in the immunocompetent and/or immunocompromised individuals. 75. The free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment of herpes infections in immunocompromised individuals, wherein the immunocompromised individuals are selected from the group comprising recipients of an organ transplant, individuals having an infection by another virus or bacterium, particularly an infection with HIV and/or another herpes virus, and individuals infected with a herpes simplex virus that is resistant to at least one anti-viral active.

76. A method of treatment and/or prophylaxis of a herpes virus infection comprising administering a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide to a subject in need thereof.

77. A method of manufacturing N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate, wherein said method comprises the following steps: a) Mixing 4-pyridine-2yl-phenyl)-acetic acid and amionothiazole sulfonic acid amide in N-Methylpyrrolidone (NMP);

b) Cooling the mixture obtained in step a);

c) Adding N-Ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HC1) to said mixture obtained in step b);

d) Stirring the solution obtained in step c) and addition to purified H₂0;

e) Filtering the solution obtained in step d);

f) Washing the product cake obtained in step e);

g) Drying the product obtained in step f);

h) Adding H₂0 to the solution obtained in step g);

i) Stirring the suspension obtained in step h);

j) Cooling the suspension obtained in step i);

k) Stirring the suspension obtained in step j);

1) Isolating the product by filtration of the suspension obtained in step k);

m) Washing the product obtained in step 1) with H₂0;

n) Drying the product obtained in step m).

78. A pharmaceutical composition comprising a free base hemihydrate of N-[5-(amino- sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide obtainable in a method according to embodiment 77.

79. A pharmaceutical composition obtainable by formulation of a free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide obtainable in a method according to embodiment 77 with at least one pharmaceutical excipient.

80. Use of free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]- N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide obtainable in a method according to embodiment 77 as medicament.

81. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 80, wherein the free base maleate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide is present in an amount of about 5.0 % w/w. 82. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the embodiments 1 to 81, wherein the free base maleate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is present in an amount of about 1.0 to about 7.5 % w/w, particularly about 5.0 % w/w.

83. The maleate salt according to the embodiments 81 to 82, wherein said maleate salt is characterised by a photostability of at least 70 % residual free base of N-[5-(amino- sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide after light exposure with wavelengths ranging as of from 300 nm to 800 nm, and with a light exposure quantity of at least 1.2 million Lux hours, and with a light exposure energy of at least 200 watt hours/m² over at least 29 hours when said photostability is determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

84. The maleate salt according to any one of the preceding embodiments, wherein said maleate salt is further characterised by having characteristic XRPD peaks at 6.6, 15.9, 16.2, 18.1, 20.5, 22.5, 26.1, and 28.6 2theta when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

85. The maleate salt according to any one of the preceding embodiments, wherein said maleate salt is physico-chemical stable characterised by recoveries of said maleate salt of the start concentration of at least 85 % after two weeks storage at room temperature and at a pH as of from 3.5 - 7.0 in aqueous solution when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

86. The maleate salt according to any one of the preceding embodiments, wherein said maleate salt is characterised by solubility in water of about 0.48 mg/niL when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

87. The topical pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any one of the preceding embodiments,

wherein the maleate salt is present in an amount sufficient to reach a concentration of > 10 nM in the epidermis and dermis of an individual subjected to a method of topical treatment with said composition when determined by using a compendial method as per "Ph. Eur" and/or "USP" methods.

88. A free base maleate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl- 2-[4-(2-pyridinyl)phenyl]acetamide for use in the treatment and/or prevention of herpes virus infections.

89. A process for the manufacture of the maleate salt of the free base of N-[5-(amino- sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide as defined in the embodiments 81 to 88, said process comprising the steps of: i) providing a mixing means, preferably a mixing means with overhead stirring, ii) filling said mixing means of step i) with 460 to 490 g free base of pritelivir, iii) suspending the free base of pritelivir of step ii) with 3 to 5 volumes of water, iv) heating the suspension of step iii) to 45 to 55 °C by suitable heating means, v) adding 225 to 240 g of maleic acid in solid form over a time period of 40 to 90 min. until resultant solution is obtained,

vi) cooling the solution obtained under step v) down towards 44 to 52 °C

viii) over a period as of from 1.5 to 2.5 hours the resultant suspension of step vii) is allowed to cool down towards 18 to 24 °C,

ix) stirring the suspension of step viii) overnight follows,

xii) rotary evaporation of the mixing means of step xi) follows for 25 to 32 hours while applying the following conditions: a. an ambient temperature of 30 to 40 °C,

b. a pressure of 15 to 25 mbar, so to obtain a constant mass, xiii) homogenisation follows, preferably homogenisation with mortar and pastle follows, xiv) so to obtain a maleate salt of the free base of pritelivir in accordance with the invention.

With the above context of the invention, further specific aspects of the invention are provided by the below consecutively listed embodiments: a. A pharmaceutical formulation for use in topical application to a subject in need thereof, said formulation comprising: 1-10 % w/w of N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl- 2-

[4-(2-pyridinyl)phenyl]acetamide,

0-90 % w/w of at least one solvent,

0-10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 2.0 to 8.0, preferably a pH of

4.0 to 5.0, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 month at 25-60 °C, wherein said solvent is selected from the group comprising ethanol, dimethyl isosorbide, isopropanol, Transcutol P, polyethylene glycol, PEG 400, PEG 4000 and Super Refined™ (SR) PEG 400.

In an adjacent embodiment to embodiment a, a pH value of 4.0 to 4.5 is preferred for the said pharmaceutical formulation.

In an adjacent embodiment to embodiment a, the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol- 2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for at least 24 months at 25 °C/ 60 % RH. b. The pharmaceutical formulation as defined in embodiment a, wherein the at least one solvent is selected from the group comprising polyethylene glycols, preferably PEG 400, more preferably SR PEG 400. c. The pharmaceutical formulation as defined in embodiments a - b, wherein the N-[5- (amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, is selected from the group comprising N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate,

maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl] acetamide,

mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2- yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, and

free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide. d. The pharmaceutical formulation as defined in any one of embodiments a - c, wherein said antioxidant agent is selected from the group comprising butylated hydroxyl toluene

(BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate salt. e. The pharmaceutical formulation according to embodiments a - d, wherein said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, paste, solutions, oils, lipogels. f. The pharmaceutical formulation as defined in any one of embodiments a - e, wherein the concentration of the N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide is selected from the range of 1.1 to 10 % w/w, more preferably 1.1 to 5 % w/w. g. The pharmaceutical formulation as defined in any one of embodiments a - f, wherein the concentration of the at least one solvent is 0.1-90 % w/w, for example 5-90 % w/w, 10-90

% w/w, 10-80 % w/w, 20-80 w/w, 25-80 % w/w, 15-50 % w/w or 30-45 % w/w. h. The pharmaceutical formulation as defined in any one of embodiments a - g, wherein said formulation is an ointment further comprising: 0.01 - 20 % w/w of at least one pH-adjustment agent. i. The pharmaceutical formulation as defined in any one of embodiments a - h, wherein said formulation is a cream further comprising:

0-5 % w/w preservatives

0- 20 % w/w of at least one surfactant

1- 40 % w/w oil phase/emollient

0-40 % w/w Water. j. The pharmaceutical formulation as defined in any one of embodiments a - i, wherein said formulation is a gel further comprising: 0-30 % w/w penetration enhancer

0-20 % w/w of at least one gelling agent

0-50 % w/w water

0.01-20 % w/w of at least one pH-adjustment agent. k. The pharmaceutical formulation as defined in any one of embodiments a - j for use as medicament.

1. The pharmaceutical formulation as defined in any one of claims a - k for use in the treatment and/or prevention of herpes virus infections. m. The pharmaceutical formulation as defined in any one of claims a - 1 for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses. n. The pharmaceutical formulation as defined in any one of embodiments a - m for use in the treatment and/or prevention of herpes virus infections, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2).

With the above context of the invention, further specific aspects of the invention are provided by the below consecutively numbered embodiments:

I. A pharmaceutical formulation for use in topical application to a subject in need thereof, said formulation comprising: i. 1 - 10 % w/w of N-[5-(amino-sulfonyl)-4- methyl- 1 ,3 -thiazol-2-yl] -N-methyl-

2-[4-(2-pyridinyl)phenyl]acetamide,

ii. > 0 - 90 % w/w of at least one solvent,

iii. > 0 - 10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 2.0 to 8.0, preferably a pH of 4.0 to 5.0, wherein the N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C / 60 % RH, wherein said solvent is selected from the group comprising ethanol, dimethyl isosorbide, isopropanol, Transcutol P, propylene glycol, polyethylene glycols, PEG 400, PEG 4000 and Super Refined™ PEG 400, and wherein said antioxidant agent is selected from a group comprising butylated hydroxyl toluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, dodecyl gallate, octyl gallate, thiosulfate salt.

In an adjacent embodiment to embodiment I, a pH value of 4.0 to 4.5 is preferred for the said pharmaceutical formulation.

In an adjacent embodiment to embodiment I, the N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol- 2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for at least 24 months at 25 °CI 60 % RH.

A pharmaceutical formulation for use in topical application to a subject in need thereof according to embodiment I, wherein said formulation comprises: i. 1 - 10 % w/w of N-[5-(amino-sulfonyl)-4- methyl-l ,3-thiazol-2-yl]-N- methyl- 2-[4-(2-pyridinyl)phenyl]acetamide,

ii. 0.1 - 90 % w/w of at least one solvent,

iii. 0.01 - 10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C / 60 % RH, wherein said solvent is selected from the group comprising polyethylene glycols, PEG 400, PEG 4000 and Super Refined™ PEG 400, and wherein said antioxidant agent is butylated hydroxyl toluene (BHT).

In an adjacent embodiment to embodiment II, a pH value of 4.0 to 4.5 is preferred for the said pharmaceutical formulation.

In an adjacent embodiment to embodiment II, the N-[5-(amino-sulfonyl)-4-methyl- l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for at least 24 months at 25 °C/ 60 % RH.

A pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the embodiments I to II, said formulation comprising: i. 1.1 - 5 % w/w of N-[5-(amino-sulfonyl)-4- methyl-l,3-thiazol-2-yl]-N- methyl- 2-[4-(2-pyridinyl)phenyl]acetamide,

ii. 0.1 - 90 % w/w of at least one solvent,

iii. 0.01 - 10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C / 60 % RH, wherein said solvent is Super Refined™ PEG 400, and wherein said antioxidant agent is butylated hydroxyl toluene (BHT). In an adjacent embodiment to embodiment III, a pH value of 4.0 to 4.5 is preferred for the said pharmaceutical formulation.

In an adjacent embodiment to embodiment III, the N-[5-(amino-sulfonyl)-4-methyl- l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for at least 24 months at 25 °C/ 60 % RH.

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the preceding embodiments I to III, wherein the said N-[5- (amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is selected from the group comprising:

• the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate,

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the embodiments I to IV, wherein the said N-[5-(amino- sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, or the said

• N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate,

• maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)phenyl]acetamide,

• mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol- 2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, and • free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl]acetamide. is present in dissolved state or in solubilized form when determined by light scattering methods, Raman spectroscopy and IR spectroscopy and by the respective absence of solid phases during XRPD.

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the preceding embodiments I to V, said formulation comprising: i. 5 % w/w of N-[5-(amino-sulfonyl)-4- methyl- 1,3 -thiazol-2-yl] -N-methyl - 2-[4-(2-pyridinyl)phenyl]acetamide, or of the said

N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate,

• maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide,

• mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide,

• free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide, ii. 25 - 80 % w/w of at least one solvent,

iii. 0.05 - 2 % w/w of at least one antioxidant agent, wherein the said pharmaceutical formulation has a pH value of 4.0, and wherein said solvent is SR PEG 400, and wherein said antioxidant agent is butylated hydroxyl toluene (BHT).

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the embodiments I to VI, wherein the said N-[5-(amino- sulfonyl)-4-methyl- 1 ,3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)phenyl] acetamide is selected from the group comprising: • the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate in dissolved state,

• the maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide in dissolved state,

The pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the preceding embodiments I to VII, wherein said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, paste, solutions, oils, lipogels.

In an adjacent embodiment to embodiment VIII, said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, paste, solutions, oils, lipogels, and patches.

The pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the embodiments I to VIII, wherein said formulation is an ointment further comprising:

(i) 0.01 - 20 % w/w of at least one pH-adjustment agent.

In an adjacent embodiment to embodiment IX, said pH-adjustment agent is an apparent pH-adjustment agent.

The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in embodiment IX, wherein said formulation is an ointment comprising:

17.5 % w/w PEG 4000,

9.78 % w/w propylene glycol, 5 % w/w active pharmaceutical ingredient pritelivir,

0.1 % w/w butylated hydroxyl toluene (BHT),

67.62 % w/w Super Refined™ PEG 400, and wherein the said pharmaceutical formulation has a pH value of 4.0 to 5.0, preferably a pH value of 4.0 to 4.5.

The pharmaceutical formulation for use in topical application to a subject in need thereof according to embodiment XIII, wherein said formulation is a cream formulation further comprising: i. 0 - 5 % w/w preservatives

ii. 0 - 20 % w/w of at least one surfactant agent

iii. 1 - 40 % w/w oil phase/emollient

iv. 0 - 40 % w/w water.

The pharmaceutical formulation for use in topical application to a subject in need thereof according to embodiment XIII, wherein said formulation is a gel further comprising: i. 0 - 30 % w/w penetration enhancer

ii. 0 - 20 % w/w gelling agent

iii. 0 - 50 % w/w water

iv. 0.01 - 20 % w/w of at least one pH-adjustment agent,

v. optionally further comprising a preservative at an amount of about > 0 - 5 % w/w.

vi.

In an adjacent embodiment to embodiment XII, said formulation comprises under item (i) 0 - 30 % skin penetration enhancer.

The pharmaceutical formulation as defined in any one of the preceding embodiments I to XVII for use as medicament.

The pharmaceutical formulation as defined in any one of the preceding embodiments I to XIII for use in the treatment and/or prevention of herpes virus infections. XV. The pharmaceutical formulation as defined in any one of preceding embodiments I to XIV for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses.

XVI. The pharmaceutical formulation as defined in any one of the preceding embodiments I to XV for use in the treatment and/or prevention of herpes virus infections, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2). 0 Short description of the Figures

Fig. 1 : X-Ray powder diffraction (XRPD) analysis of N-[5-(aminosulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate. 5 Fig. 2: Cumulative amount ^g/cm²) of pritelivir (free base (FB) and mesylate salt (MS)) and acyclovir released per unit area following application of the developed formulations and Zovirax^® using a nylon membrane. Each time point represents mean ± SEM (n = 6).

Fig. 3: Enhanced: Cumulative amount ^g/cm²) of pritelivir (free base (FB) and mesylate0 salt (MS)) released per unit area following application of the developed formulations and Zovirax^® using a nylon membrane. Each time point represents mean ± SEM (n = 6).

Fig. 4: Cumulative amount ^g/cm²) of pritelivir (free base (FB) and mesylate salt (MS)) and acyclovir released per unit area at t = 1 h following application of the developed formulations5 and Zovirax^® using a nylon membrane. Each time point represents mean ± SEM (n = 6).

Fig. 5: Schematic representation of Franz diffusion cell.

Fig. 6: Cumulative amount of pritelivir released per unit area ^g/cm²) following application0 of the formulations using a nylon membrane. Each time point represents mean ± SEM (n = 6).

Fig. 7: Recovery or pritelivir (ng) from skin strata (Stratum corneum (SC), epidermis, dermis) and receiver fluid (RF) at 1 h and 8 h (experiments 1 and 2, respectively) following application of the formulation. Fig. 8: Process flow diagram for pritelivir 5% w/w ointment.

Fig. 9: Representative characteristic properties of a maleate salt of the free base of pritelivir of the invention.

Fig. 10: An Ortep plot of a maleate salt of the free base of pritelivir.

Fig. 11 : TGA of a maleate salt of the free base of pritelivir in accordance with the invention with a weight loss of 0.74% w/w up to 150 °C. The next steps indicate decomposition of maleic acid in the melt.

Fig 12: XRPD of a maleate salt of the free base of pritelivir in accordance with the invention, which shows a crystalline form.

Fig. 13: The table of Fig. 13 shows a peak list of the PXRD pattern of the maleate salt of the free base of pritelivir as further depicted in the Figs. XY. The characteristic peaks for the said maleate salt have been highlighted therein. Fig. 14: Characteristic peaks in the Powder X-ray Diffraction Pattern of the maleate salt of the free base of pritelivir (code: P071-02-PXRD-01). Said characteristic peaks of each phase have been marked with an arrow.

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples, which follow, represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Examples

Example 1 : Formulation development

A topical ointment formulation was developed based on the extensive preformulation studies using both N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate and N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2- yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mesylate salt (hereinafter also referred to as "Pritelivir free base" and "Pritelivir mesylate"), respectively. The development included determination of the solubility and stability of both forms of N-[5-(aminosulfonyl)-4-methyl- l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in different excipients. Further, formulations were subjected to in vitro skin permeation and skin irritation studies. Based on the short-term stability studies, a lead formulation was selected for further scale up studies. Composition of the formulation

The 5% w/w N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate ointment is a white to slightly coloured opaque ointment for topical administration. Each gram of active ingredient N-[5-(aminosulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate 5% w/w ointment contains 51.1 mg of N-[5-(aminosulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] -acetamide free base hemihydrate dissolved in a Super Refined™ polyethylene glycol 400 (SR PEG 400) base. The qualitative and quantitative composition in % (w/w) is provided in the Table 4 below.

Table 4

a Corresponding to 5.0% of pritelivir (active moiety)

The above table 4 describes the basic composition of the clinical ointment formulation in accordance with the invention.

The excipients used in the manufacture of the finished product and their functions are listed in the Table 5 below. All excipients are well-known and widely used in the manufacture of ointments.

Table 5

The above table 5 describes the functions and grades of the components used in the clinical ointment formulation.

Identification, assay and related substances of N-[5-(aminosulfonyl^')-4-methyl-l,3-thiazol-2- yll-N-methyl-2-[4-(2-pyridinylVphenyl]-acetamide by HPLC

For identification, the retention time of the pritelivir peak in the sample chromatogram is compared to the retention time of the pritelivir peak in the reference chromatogram and the UV spectrum extracted from the pritelivir peak in the sample chromatogram is compared to that extracted from the reference standard chromatogram. Assay is determined using external standard quantification. The reporting level is set with 0.05% area/area.

The following HPLC parameters are used:

HPLC system: HPLC with DAD detector and data processing software

Column: Phenomenex Luna CI 8, 5 μπι, 250 x 3.0 mm; or equivalent

Guard column: CI 8 guard cartridge

Sample temperature: 5 ± 2 °C

Column temperature: 45 ± 2 °C

Injection volume: 2

Flow rate: 0.5 mL/min

Run time: 75.0 min

Detection wavelength: 282 nm

Mobile phase A: 10 mM ammonium acetate buffer pH 5.0

Mobile phase B: Acetonitrile

Gradient: see Table 6 below.

Table 6

Standard and sample diluent: 0.1% v/v formic acid in 50:50 v/v watenacetonitrile

Injection blanks: 0.1% v/v formic acid in 50:50 v/v water :acetonitrile

Needle wash: 60:40 v/v methanol: water

Known impurities: PP acetic acid: RRT approx. 0.33 Aminothiazole sulfonamide: RRT approx. 0.19

The above table 6 describes the gradient used for chromatography as described above by way of the given HPLC parameter.

Formulation Development

The formulation development aimed at a topical formulation comprising 5% of N-[5- (aminosulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide that rapidly penetrates skin (epidermis) with a target level of N-[5-(aminosulfonyl)-4-methyl- l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate in the epidermis and dermis of not less than 10 nM to 20 nM and only little systemic exposure, that is easy to spread, absorbs quickly, and that is moisturizing, non-greasy and aesthetically pleasing to use. The herein described formulations were chosen based on results of solubility and compatibility experiments, short-term (photo)stability studies, in vitro drug release experiments, in vitro skin permeation and penetration experiments as well as a dose range- finding study in mini-pig and an in vitro skin irritancy study. Solubility studies

Table 7 below shows the saturation solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol- 2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate compared to mesylate salt. The N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate shows significantly higher solubility compared to mesylate salt.

Table 7: Saturation solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl- 2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate compared to mesylate salt.

Solvent systems

Solvent systems were designed based on the solubility data. Compositions are shown in Table 8 below

Table 8 - Solvent systems

Table 21. Solvent systems used to determine the saturated solubility of Pritelivir (free base and mesylate salt), lidocaine and hydrocortisone.

(-): not included.

Solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate was determined in the solvent systems. As evident, N-[5-(aminosulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate showed significantly higher solubility compared to mesylate salt as shown be in Table 9:

The above table 8 describes the solvent systems tested for the clinical ointment formulation.

Table 9

Table 22. Pritelivir free base, mesylate salt, hydrocortisone and lidocaine solubility in solvent systems. Values represent the average with the range in brackets, n=3.

The above table 9 describes the solubility of the pritelivir free base and mesylate salt in the solvent systems used.

Short-term stability:

Short term stability testing of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate was carried out in the individual excipients and solvent systems. Good free base hemihydrate recovery (between 90 - 110 %) in comparison to the t=0 value was observed when the compound was placed on short-term stability alone at 40° and 50 °C for both two and four weeks in benzyl alcohol, propylene glycol, Arlasolve DMI, 10 % w/v Kleptose solution and SS5 (propylene glycol: buffer pH 3.5) (Table 10). Low recovery (< 50 % in comparison to t=0) of N-[5-(aminosulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate free base was observed in PEG alone and binary and solvent systems containing a high percentage of PEG 400. The peak purity data was observed to correspond well to the percentage recovery of N- [5 -(aminosulfonyl)-4-methyl- 1 ,3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)-phenyl] - acetamide free base hemihydrate.

Table 10: Percentage recovery and peak purity or pritelivir free base determined in solvents at t = 0 and after storage at the stated time point and temperature. Recovery in comparison to t = 0 value, n = 2 with range illustrated in brackets (assay method). Peak purity values, n= 1 (impurity method).

Mesylate salt was also subjected to short-term stability studies in the selected excipients and solvent systems. Good pritelivir mesylate salt recovery (between 90 - 110% in comparison to t=0) was observed when pritelivir mesylate salt was placed on short-term stability alone at 40 and 50 °C for both 2 and 4 weeks in benzyl alcohol, phenoxyethanol, propylene glycol, 10% w/v Kleptose solution, water SS5, SS6 and SS7 with corresponding peak purity data (Table 8). Poor stability of pritelivir mesylate salt (peak purity < 90% at t=4 weeks, 50 °C) was observed in benzyl alcohol, PEG 400, Transcutol P, glycerol, 50:50 pH 4: PEG 400 and SS1- 4; however, when compared to pritelivir free base, the mesylate salt appeared to have improved stability in both individual excipients and solvent systems.

Table 11: Percentage recovery and peak purity or pritelivir mesylate salt determined in solvents at t = 0 and after storage at the stated time point and temperature. Recovery in comparison to t = 0 value, n = 2 with range illustrated in brackets (assay method). Peak purity values, n= 1 (impurity method).

Further short-term stability studies were carried out in additional excipients such as SR PEG 400 for both free base and mesylate salt. Results indicated that N-[5-(ammosulfonyl)-4-methyl-l,3-thiazol-2- yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate showed superior stability in SR PEG 400 compared to mesylate salt (see Table 12 below).

Table 12 a (see the table above) - Percentage recovery and peak purity of pritelivir free base in solvents at TO and after storage at the stated time point and temperature. Recovery in comparison to TO value, n=2 with range illustrated in brackets (assay method), peak purity values n=l (impurity method).

Table 12 b (see the table below) - Percentage recovery and peak purity of pritelivir mesylate salt determined in solvents at t=0 and after storage at the stated time point and temperature. Recovery in comparison to t=0 value, n=2 with range illustrated in brackets (assay method). Peak purity values, n=l (impurity method).

Saturation solubility in these solvent systems is shown as below in Table 14 for the basis of developing creams.

Table 13 describes the percentage recovery and peak purity of pritelivir mesylate salt determined in solvents at t=0 and after storage at the stated time point and temperature. Recovery in comparison to t=0 value, n=2 with range illustrated in brackets (assay method). Peak purity values, n=T (impurity method).

Table 14 describes the solubility of pritelivir base and salts in the different solvent systems used to develop a topical gel.

The below Table 15 shows that solubility of free base and mesylate salt of N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in the solvent systems for ointment formulation. It should be noted that N-[5-(aminosulfonyl)-4- methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate has very high solubility compared to the mesylate salt which is a prerequisite to achieve a drug loading of 5 %.

Table 15

Table 43. Saturated solubility of pritelivir free base and mesylate salt in solvent systems used for the basis of developing ointments.

'extraction value above ULOQ, ^*n=2

Table 15 describes the solubility of pritelivir base and salts in the different solvent systems used to develop a topical ointment. SSOl and SS03 were selected as compositions for the development of ointment formulations containing pritelivir free base and pritelivir mesylate salt at 5 % w/w and 1% w/w, respectively.

The section below shows formulations selected in the development of creams, gels and ointments.

Cream formulations

Table 18 - Composition of cream formulations containing pritelivir free base hemihydrate.

Table 46: Composition of cream formulations containing pritelivir base.

Table 19 - Composition of cream formulations containing pritelivir mesylate salt.

Table 20: Concentration (μΜ) of pritelivir or acyclovir observed in the epidermis and partial dermis after t = 1 and 8 h. Each value represents the mean ± SEM (n= 4-6).

Ointment based formulations

Table 21 - Composition of ointment formulations containing pritelivir free base hemihydrate.

Table 48: Composition of ointment formulations containing pritelivir base.

{-): not included Table 22 - Composition of ointment formulations containing pritelivir mesylate salt.

Table 49: Composition of ointment formulations containing pritelivir mesylate salt.

(-): not included

In vitro skin permeation studies

In vitro skin permeation studies were carried out using representative formulations:

The concentration range of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)-phenyl]-acetamide free base (μΜ) in the epidermis and dermis at t=15 min, 1 and 8 h (based on average amounts and a range of skin thickness) following application of the formulations has been presented in Table 23, where the levels observed were substantially higher (1,000 - 1,000,000 fold) than the target levels for Pritelivir (10 - 20 nM) and higher than the IC50 for Acyclovir (2 μΜ). It should additionally be noted that the speed of onset was also important.

Table 23 - Concentration range of Pritelivir hemihydrate free base (μm) and mesylate salt in the epidermis and dermis at t=15 min, 1 and 8 hrs (based on average amounts and a range of skin thickness) following application of the formulation. Values represent a range based on skin thickness and average amount recovered, n=5-6.

Table 56: Concentration range of priteiivir (μΜ) in the epidermis and dermis at t=15 min, 1 and 8 h (based on average amounts and a range of skin thickness) following application of the formulations. Values represent a range based on skin thickness and average amount recovered, n=5-6.

DRF studies in mini pigs

The following formulations Table 24 were used in the dose range finding studies in mini pigs.

Table 24 - Composition of excipients to prepare formulations for the DRF mini-pig study

The amount of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate deposited in the skin layers was determined on day 1 and day 5 and Table 26 below shows the results. Table 26 (amount of Pritelivir recovered (ng))

Table 26 shows the amount of pritelivir recovered in [ng] from the skin layers. Recovery of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate from the Stratum corneum, epidermis and dermis from biopsy samples was performed as follows. At day 1, the following rank order in the recovery of free base hemihydrate from the epidermis was observed, where no statistical difference (p > 0.05) was evident: G7V3 > 03v4 > C3v3. At day 5 and after necropsy, the same rank order in the recovery of free base hemihydrate from the epidermis as at day 1 was observed, however the recovery of free base hemihydrate following application of G7v3 was statistically greater (p < 0.05) than that from the remaining formulations. When considering the recovery of free base hemihydrate from the partial dermis, the following rank order was observed where the recovery of free base following application of G7v3 was statistically greater (p < 0.05) than that from the remaining formulations at day 1 ; greater than C3 v3 at day 5 and no statistical difference at necropsy (p > 0.05): Day 1 : G7V3 > 03v4 > C3v3.

Day 5: G7V3 > 03v4 > C3v3

Necropsy: G7V3 > C3v3 > 03v4.

In general, the level of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl] -acetamide free base hemihydrate observed in the Stratum corneum, epidermis and dermis was observed to decrease with increasing time, suggesting that the N- [5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]- acetamide free base hemihydrate was absorbed into the blood with time.

Further formulation development

Following the in vitro skin permeation and penetration experiments it was decided to continue formulation development with the aim of achieving a target concentration of 5 % and 1.5 % N- [5-(aminosulfonyl)-4-methyl- 1 ,3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)-phenyl] - acetamide free base hemihydrate and the mesylate salt, respectively, with an apparent pH of about 4. It was also decided to assess UV blockers in order to develop a photostable formulation. There are a large number of sunscreen active ingredients summarised in the list below:

• UVA filters: Benzophenones (oxybenzone, sulisobenzone, dioxybenzone), Dibenzoylmethanes (avobenzone), Anthralates (meradimate), Camphors (ecamsule)

• UVB filters: Aminobenzoates (p-aminobenzoic acid, padimate-O), Cinnamates (cinoxate, octinoxate), Salicylates (octisalate, homosalate, trolamine salicylate), Octocrylene, Ensulizole

• Inorganic filters: Titanium dioxide, Zinc oxide.

Formulations with and without octisalate were developed (n=2 per formulation type). As such, solvent systems incorporating octisalate were developed to ascertain the saturated solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl] -acetamide free base hemihydrate or mesylate salt and to determine whether the target concentration of 5 % and 1.5 % w/w N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]- N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate and mesylate salt, respectively, was possible.

I l l Table 27 shows the saturated solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]- N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate and mesylate salt, respectively, in octisalate. Values represent the average with the range in brackets, n=3.

Further solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate and mesylate salt in solvent systems:

Based upon the initial solubility data of N-[5-(aminosulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate and mesylate salt, respectively, at target concentrations of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate base and mesylate salt (5 % and 1.5 % w/w, respectively), further solvent systems were developed in an attempt to maximise the solubility of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)-phenyl]-acetamide free base hemihydrate and mesylate salt, respectively, at an apparent pH of 4 whilst maintaining drug thermodynamic activity and physical stability of the resulting formulation.

Short-term stress stability of gel, cream and ointment based formulations:

The percentage recovery and purity of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate and mesylate salt, respectively, in formulations following storage for t=2 and 4 weeks at 25°C and 40°C is summarised in the Tables below. When considering the formulations containing N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate, a good recovery (97 - 105%) was observed in all gel formulations up to t=4 weeks at 40 °C. This was supported by good percentage purity of N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate (> 99%) in G8, G8v3, G24 and G24v3. Variable recoveries were observed within some of the cream formulations, which may be attributed to phase separation observed upon storage at 40 °C in addition to inefficiencies with the drug extraction procedure, which was a generic method. Nonetheless, good percentage purity of N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base (> 99%) was observed in all formulations with the exception of Cr03v5 (98.62%). A good recovery of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate was observed in all ointment formulations with the exception of 04v4 OCT (ca. 87% following storage for t=4 weeks at 40 °C), however the percentage purity of N-[5-(aminosulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate in all ointment formulations was observed to be > 99%. In general, formulations containing N-[5- (aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mesylate salt were observed to be more unstable than formulations containing the free base hemihydrate. Nonetheless, a good recovery of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2- yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mesylate salt was observed in the gel formulations with the exception of G15 (81%). This was supported by the percentage peak purity of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]-acetamide mesylate salt in this formulation (86%), although a reduction in the percentage peak purity of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide mesylate salt from t=0 was observed in the remaining formulations. In summary, the N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate was surprisingly more stable than the mesylate salt.

Forced degradation studies

Forced degradation data of the formulation show that N-[5-(aminosulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide may be susceptible to degradation via oxidation. Further, degradation of the drug substance in standard PEG 400 quality was observed during formulation development, see below in Table 41. As such, a special PEG 400 grade is used (Super Refined™ PEG 400 and inclusion of antioxidants has been assessed. Based on the data obtained, butylated hydroxytoluene (BHT) as an antioxidant is included in the formulation at a concentration of 0.1 % w/w. The concentration used complies with concentrations of BHT used as antioxidant in comparable products (see FDA's Inactive Ingredients Database). Oxidative degradation of Pritelivir was restricted by using combination of Super Refined™ PEG 400, antioxidant (BHT) and acidic pH 4.0-5.0. Propylene glycol is used as additional solvent in the solvent system (ointment base). Data obtained during formulation development suggest that low pH values may improve the stability of pritelivir and therefore the use of acidified excipients has been assessed. The target pH value during manufacture of the product is set between 4.0 and 5.0. Hydrochloric acid and sodium hydroxide, if necessary, are used for pH adjustment. Excipients used for manufacture of the drug product have good compatibility with the drug substance and short-term formulation stability data showed acceptable results (see below Table 42).

Photo stability assessment

Formulations with and without the UV blocker, octisalate, were exposed to UV light under ICH conditions (1.2 million Lux hours and over 200 Watt hours per square meter), and the percentage recovery and purity of pritelivir (free base and mesylate salt) was determined, as summarised in the tables below, respectively. Formulations containing pritelivir free base were observed to have good percentage purities (> 99%) and there appeared to be no major advantage of incorporating octisalate. Formulations containing pritelivir mesylate salt, however, appeared to be unstable to UV light (percentage purity of pritelivir mesylate salt ranged from 74 to 99 %), and a huge increase in the percentage purity of Pritelivir mesylate salt was observed when octisalate was incorporated (for example, ca. 74 % to 98 % in Crl2 and Crl2v2, respectively). Caution should however be taken when interpreting such results, however, as these formulations were observed to behave similarly when incubated at 25 °C for t=2 and 4 weeks, not under UV light. The pritelivir free base was found to be more stable to photostress conditions compared to mesylate salt Table 43.

Table 43 - Percentage recovery (as a percentage of the theoretical concentration) and peak purity of pritelivir free base in formulations at t=0 and exposure to UV light under ICH conditions.

Table 96: Percentage recovery (as a percentage ot the theoretical concentration) and peak purity of Pritelivir free base in formulations at t=0 and exposure to UV light under ICH conditions

Table 44 - Percentage recovery (as a percentage of the theoretical concentration) and peak purity of pritelivir mesylate salt in formulations at t=0 and exposure to UV light under ICH conditions.

Table 97: Percentage recovery (as a percentage of the theoretical concentration) and peak purity of Pritelivir mesylate salt in formulations at t=0 and exposure to UV light under ICH conditions

In vitro skin permeation of the formulation in order to select lead formulation:

The experimental parameters to assess the in vitro skin permeation and penetration of the developed formulations were established during a previous study as such, no further feasibility experiments were performed as part of this study. The level of pritelivir (and acyclovir) in the various skin matrices after t=l and 8 h of application was determined. A total of 7 formulations were selected for the in vitro skin permeation and penetration experiments, which were performed and therefore selected based on the most promising candidates from short-term chemical stability experiments. When considering the amount of drug recovered from the epidermis at t=l h, the following rank order was observed, however there was no significant differences (p > 0.05) between any of the formulations:

01v3 > G8v3 > Zovirax (acyclovir) > G15vl > G8 > 02 > G7v3.

An objective of the present invention was to have target levels of pritelivir of 10 - 20 nM within the epidermis and partial dermis. Surprisingly, Table 47 demonstrates that the level of pritelivir within these skin layers exceeded the target by ca. 3,500 - 257,500 fold. Table 47

Table 47 shows the amount of pritelivir and acyclovir recovered from epidermis and partial dermis after 1 h and 8 h. Based upon the data generated during the in vitro skin permeation and penetration tests and supported by the in vitro drug release data, short-term chemical stability data and in vitro skin irritancy study 01v3 and G8v3 were selected as the lead and back-up formulation candidates (scale up, GLP supplies and ICH stability). In vitro drug release experiment

The in vitro release of pritelivir from a total of 9 formulations was determined and compared against the in vitro release of acyclovir from the marketed comparator, Zovirax^® (Acyclovir). Figure 2 summarises the entire data set, whilst Figure 3 focuses on the developed formulations only (Zovirax^® removed for clarity). As linear steady state drug release appeared to be between 0 and 2 h, a further graph depicting the amount of drug released per unit area at t=l h is shown in Figure 4. At t=l h, the following rank order in drug release from formulations was observed, where the release of pritelivir from formulation 02 was statistically higher (p < 0.05) than that from all formulations with the exception of 01v3, G7v3 and Zovirax^® (acyclovir): 02 > 01v3 > G7v3 > Zovirax > G8v3 > O3v4 > G15vl > G8 > G24 > CR12

Each of the formulations were optimised for drug thermodynamic activity (pritelivir was present in the formulation at ca. 70-85% of the saturation limit). Taken as such the data suggest the amount of drug released is driven by the concentration of pritelivir within the formulations. In general, a higher level of pritelivir present results in higher level of drug release. The raw data values for the mean cumulative amount of drug released at t=l h has also been presented in Table 48, in addition to the percentage of the applied dose, and the following rank order was observed: G15vl > 02 > 01v3 > Zovirax^® > G7v3 > G8 > G8v3 > 03v4 > G24 > CR12. This ranking normalises the data and shows that whilst G15vl released a low amount of pritelivir compared to a selection of the other formulations, it displayed a higher efficiency in the drug release at t=l h when compared to all other formulations. Whilst the in vitro skin permeation and penetration experiment was performed in parallel to the in vitro drug release, the data generated herein would appear to support the selection of G15vl , 02, 01v3, G7v3, G8 and G8v3 for assessment. Table 48

Table 48 shows the IVRT profile of the topical formulations of the pritelivir free base compared to Zovirax^®.

In vitro skin irritancy of the topical formulations

This study assessed the in vitro irritation potential of a series of gel, ointment and cream formulations with pritelivir free base (PFB) and pritelivir mesylate salt (PMS) (9 active and 9 placebo formulations) in addition to comparator (Zovirax^® Cold Sore Cream 5 % w/w Acyclovir). The overall aim of the study was to generate in vitro irritation data to aid in the selection of lead candidate formulations for pritelivir in combination with the ongoing formulation stability, in vitro skin permeation/penetration and drug release studies (252-1402- 01 and 252-1402-02). The reconstructed human epidermis (RHE) culture, EpiDerm™, used in this study is a normal, human cell-derived, 3-dimensional organotypic in vitro skin model. The method used in this study is based on MatTek's well-documented ET-50 (exposure time required for a chemical to reduce viability to 50 % of the control) assay, allowing to quantitatively measure the irritancy of the test material. During this study, the irritancy potential of the 19 formulations in a full scale in vitro skin irritancy study was assessed successfully. Feasibility experiments showed that all of the developed formulations (active and placebo formulations) were observed to interact with MTT (Standard MTT test used for phototoxicity studies). Additional investigation showed that BHA and BHT were the excipients responsible for the MTT interaction, as these were common to all of the formulations tested. Zovirax^® Cold Sore Cream 5 % w/w Acyclovir was also investigated and showed no interaction with MTT. The small scale in vitro irritancy experiment was then performed using 010 (PFB) active and placebo as the selected formulations, which were shown to be non-irritating (ET-50 > 24 h). Frozen (non-viable) RHE tissue controls were included in the small scale experiment and showed some interaction with MTT (all < 6 %). The results of the feasibility experiments led to the optimisation of the protocol used in the full scale in vitro skin irritancy experiment. Frozen (non-viable) control RHE tissues were therefore incorporated into the t=6 h time point only. This enabled a background subtraction to be performed in order to account for any MTT reduction from any residual formulation present in the RHE tissues. The full scale in vitro skin irritancy experiment showed that the formulations tested ranged from moderate/mild to non-irritating, where the active formulations behaved similarly to the respective placebo formulations. A summary of the ET- 50 values for each of the formulations investigated is listed in Table 49. The cell viability of RHE tissue following application of the developed formulations and comparator demonstrated that three of the formulations (G8 (PFB), 02 (PFB) and Crl2 (PFB)) had no significant impact on the viability of RHE tissues over the duration of the experiment (t=2, 6 and 24 h). Therefore it was not possible to calculate an exact ET-50 value and thus the formulations were deemed non-irritating. In contrast, G24 (PFB) displayed the greatest irritancy potential (ET-50 < 6 h). Formulations (G8 (PFB), 02 (PFB) and Crl2 (PFB)), which exhibited the least irritancy potential, behaved similarly to the marketed comparator, Zovirax^® Cold Sore Cream 5 % w/w Acyclovir. Therefore, the feasibility investigation showed that all of the formulations investigated (both actives and placebos) exhibited mild to strong interactions with MTT. This warranted further investigation, where the interaction of BHA and BHT with MTT was assessed due to all formulations containing either BHA or BHT. A mild interaction was observed for BHA and a strong interaction was observed for BHT, suggesting BHA and BHT were responsible for the interactions observed. As a result of these findings frozen (nonviable) RHE tissue controls were added to the small scale in vitro irritancy investigation, in order to account for the interaction between any residual formulation remaining on the RHE tissue surface and MTT. Zovirax^® Cold Sore Cream 5 % w/w Acyclovir, Reference Item 1, was not found to interact with MTT.

The small scale in vitro irritancy investigation suggested that the 010 (PFB) active and placebo formulations were non-irritating (ET-50 > 24 h) and showed that the time points and MTT assay method used were adequate for use in the full scale experiment. Furthermore, the residual formulation present in the treated RHE tissues showed some interaction with MTT, as evidenced by the frozen (non-viable) control RHE tissue viabilities (all < 6 %).

The full scale in vitro irritancy investigation showed that the formulations tested ranged from moderate/mild to non-irritating. The active formulations behaved similarly to the respective placebo formulations investigated. The formulations which exhibited the least irritant potential were G8 (PFB), 02 (PFB) and Crl2 (PFB), as these formulations behaved similarly to the marketed comparator, Zovirax^® Cold Sore Cream 5 % w/w Acyclovir (Reference Item 1). The most irritating formulation was G24 (PFB) (ET-50 < 6 h).

1 -month toxicity study in minipigs with recovery period and toxicokinetics

The study assessed the toxicity and toxicokinetic profile of pritelivir free base when administered topically twice daily to minipigs for 4 consecutive weeks and to assess the reversibility of test item adverse effects over a 2 weeks recovery period. A total of 38 Gottingen minipigs (19 males and 19 females; EUegaard Gottingen Minipigs A/S) were used in the study. The application areas of approximately 1 %, 5 % or 10 % of the total skin surface area were marked on the back of the animals by tattooing. The animals were dosed according to the schedule below (Table 50).

Table 50

The above table 50 shows the study plan for 1 -month toxicity study in minipigs. The following criteria were evaluated: mortality, clinical signs, body weight, food consumption, electrocardiography, ophthalmoscopy, clinical pathology including haematology, blood chemistry and urinalysis, full necropsy including macroscopic observations of treated and untreated skin, organ weights and histopathology. Blood samples for toxicokinetic evaluation were collected on day 1 and day 28 at 6 different time points. Furthermore, dosing sites were examined for reaction to treatment and scored for erythema, oedema and other dermal reactions. No test item related changes were seen. There, the topical administration of 5 % pritelivir 01v3 free base twice daily for 4 weeks was well tolerated. No test item related skin reactions or systemic toxicity were observed. Further studies on Q1V3 formulation (clinical formulation) - Photostability testing

Photostability testing of the formulation showed pritelivir to be stable following direct exposure to UV light according to ICH guideline QIB (providing an overall illumination of not less than 1.2 million lux hours and not less than 200 watt hours/square meter). The recovery and impurity levels of pritelivir are summarized in table 51 below:

Table 51 Results of the photo stability testing

Table 14. Results of photostability testing

In the above table 51, "t = 0" represents samples prior to photostress exposure. Standard ICH conditions were used for photostress studies.

Pritelivir mesylate salt is photosensitive, however a photostable topical formulation can be developed using a free base without use of photoblockers.

Forced Degradation Testing

Forced degradation testing of the pritelivir free base was performed (to further assess specificity and ensure the HPLC method is stability indicating) exposing it to heat, light, oxidation, acid and base (Table 52).

Table 52 - Results of forced degradation testing of the pritelivir free base

Table 13. Results of forced degradation testing

a pH adjusted to pH 8 for base hydrolysis

In vitro drug release testing

The in vitro drug release of pritelivir from the formulation (was tested using a Franz diffusion cell (Figure 5). During the development studies 2% w/v Brij 98 in phosphate buffer solution (PBS) was identified as a suitable receiver fluid for the analysis of samples from in vitro skin permeation experiments by HPLC1. For the purpose of in vitro release testing, the same receiver fluid was used. Data on stability of pritelivir in 2% w/v Brij 98 in PBS are provided in Table 53.

Table 53 - Stability of the free base hemihydrate in receiver fluid, quantified by HPLC. Each value represents the average recovery in comparison to the value obtained at t=0 with the range in brackets, n=3.

A saturated solubility of pritelivir in 2% w/v Brij 98 in PBS was observed to be 0.02% w/w. To avoid exceeding sink conditions during in vitro drug release testing, the entire contents of the receiver fluid were removed at each time point. Samples were analysed by HPLC.

The In Vitro Release Test (IVRT) profile of the formulation is shown in the figure 6 below'

In vitro skin permeation and penetration testing

In vitro skin permeation and penetration testing was performed to estimate the permeation of pritelivir across and into the human skin following application of the herein described formulation. Figure 7 depicts the recovery of pritelivir at t = 1 h and at t = 8 h from the Stratum corneum, the epidermis and the dermis.

Manufacturing Process:

Figure 8 below shows the process flow chart for Pritelivir 5% ointment.

The manufacturing process is exemplarily described for a batch size of 6 kg:

Preparation of 0.1 M hydrochloric acid in Super Refined™ PEG 400 Mix 1.75 g of hydrochloric acid, 37% and 198.25 g of Super Refined™ PEG 400 and stir until a visually homogenous solution is obtained.

Preparation of 0.1 M sodium hydroxide in Super Refined™ PEG 400 Mix 0.40 g of sodium hydroxide and 112.55 g of Super Refined™ PEG 400 and stir until a visually homogenous solution is obtained.

Preparation of PEG 4000 phase Weigh 1050.00 g of PEG 4000 into a stainless steel vessel labeled PEG 4000 PHASE and place the vessel into a water bath of approx. 65 °C. Heat (target temperature: approx. 65 °C) and stir until a clear melt is observed. Final formulation preparation:

Weigh 3948.60 g of Super Refined™ PEG 400 and 6.00 g of butylated hydroxytoluene into a stainless steel vessel labeled FINAL FORMULATION. Place the vessel into a water bath of approx, 40 °C and stir until BHT has dissolved completely. Then remove the vessel from the water bath. Add 586.80 g of propylene glycol and 306.60 g of pritelivir hemihydrate to the solution obtained. After transferring the vessel to the water bath of approx. 65 °C, heat the contents of the vessel until pritelivir hemihydrate has dissolved whilst continually stirring the solution. Then add 102.00 g of 0.1 M hydrochloric acid solution in Super Refined™ PEG 400. Heat the contents of the vessel until a temperature of approx. 65 °C is achieved, whilst continually stirring the solution. Once the contents of both vessels reach the target temperatures, transfer the contents of the vessel labelled as PEG 4000 PHASE to the vessel labelled as FINAL FORMULATION. Remove the vessel labelled as FINAL FORMULATION from the water bath of approx. 65 °C, place it into a water bath of approx. 40 °C and stir until the contents of the vessel reach approx. 40 °C. Then transfer the vessel to a water bath of approx. 25 °C and continue to stir the formulation until an off-white viscous ointment is observed. Measure the pH value of the formulation. If the pH is outside the limits 4.0 to 5.0 adjust the pH by the drop- wise addition of 0.1 M hydrochloric acid in Super Refined™ PEG 400 (to lower the pH) or of 0.1 M sodium hydroxide in Super Refined™ PEG 400 (to increase the pH). Stir the formulation during pH adjustment. Record the final pH value and the weight of the solution added. Calculate the amount of Super Refined™ PEG 400 required to obtain 100% in total.

Add the amount Super Refined™ PEG 400 as calculated, whilst continually stirring. Record the weight of Super Refined™ PEG 400 added. When the formulation has reached ambient temperature (15 °C to 25 °C), stop the stirring and remove the vessel from the water bath. [IPC bulk formulation - top+middle+bottom]. Place a lid on the vessel and seal it with laboratory film if to be left overnight. The bulk material is held at controlled ambient temperature until filling. Filling is ideally completed the day after manufacture completion. For phase 1 trials 100 ml amber color glass vials were used while for phase 2 trials ointment was filled aluminum tubes. Table 54 - In-process controls

Table 1. In-process controls

The above table 54 shows the in-process controls used during manufacturing of the topical ointment formulation.

Specifications used for analysis of the drug product

The quality control specifications for pritelivir 5 % w/w ointment are provided in Table 55. The specifications are preliminary specifications and will be reviewed as more batch data are generated.

Table 55 - Quality control specifications

Table 1. Quality control specifications

a: Reporting level: 0.05%

TAMC: Total Aerobic Microbial Count; TYMC: Total Yeasts and Molds Count; CFU: Colony-fonning Unit

The above table 55 shows the quality control specifications for the topical ointment formulation.

Appearance: Appearance is determined visually.

Microscopic appearance: The microscopic appearance of the formulation is assessed using light microscopy with a 400x magnification. Both polarized and non-polarized light is used for examination for the presence of crystalline material. Identification, assay and related substances of pritelivir (HPLC): For identification the retention time of the pritelivir peak in the sample chromatogram is compared to the retention time of the pritelivir peak in the reference chromatogram and the UV spectrum extracted from the pritelivir peak in the sample chromatogram is compared to that extracted from the reference standard chromatogram. Assay is determined using external standard quantification. The reporting level is set with 0.05 % area/area.

Identification and quantitation of BHT (HPLC)

Assay of BHT is determined using external standard quantification. HPLC method was used to estimate BHT content.

Apparent pH: Measurement of apparent pH is performed according to USP <791>.

Apparent viscosity: Apparent viscosity is determined using a Brookfield viscometer (Spindle

E, helipath, 0.6 rpm, 25 °C, readings to be taken after 2 minutes).

Microbiological quality

Testing of microbiological quality is performed according to USP <61> and <62> and Ph. Eur. 2.6.12 and 2.6.13, respectively.

Antimicrobial effectiveness testing

Antimicrobial effectiveness testing is performed according to USP <51>. Batch analysis.

Results of the different batch analysis are shown below in Table 56

The above table 57 shows the batch analysis for pritelivir 5 % w/w free base hemihydrate ointment used in clinical trial.

The above table 58 shows the batch analysis for the 5 % w/w pritelivir free base hemihydrate ointment.

ICH Stability data: Stability in aluminum tubes

A stability study is conducted on one technical batch pritelivir 5 % w/w ointment, packaged in 2 g collapsible aluminum tubes with screw cap (type: flowerpot piercer cap) at 25 °C / 60 % RH and at 40 °C / 75 % RH.

Stability in glass bottles (previous packaging)

The stability results obtained for one technical batch and for one GMP batch are detailed below. Both batches contain 4.89 % pritelivir (free base) instead of 5 % due to the drug substance's hemihydrate form. This was rectified in the Phase II clinical manufacture where the API concentration was adjusted in order for the final product to contain 5 % pritelivir (free base). The batches are packaged in 100 mL amber glass bottles with screw cap. Specifications of the technical batch slightly differ from specifications of the GMP batch. The test methods are those listed above, except for testing identification, assay and related substances of pritelivir (HPLC), when indicated, and except for testing apparent viscosity (Brookfield viscometer, Spindle E, helipath, 50 rpm, 25 °C). In-use stability results obtained are also provided.

Example 2

Solubility of maleate salt

Table 76 - Solubilit of maleate salt in water and relevant formulation vehicles

Table 77 - Solubility of maleate salt in topical formulation base

*SS01 represents formulation based used for current clinical formulation Stability of maleate salt

Maleate salt shows better stability in SR PEG 400 compared to PEG 400 as shown below in Tab t= me

Photostability testing of current clinical formulation 01v3

Photostability testing of the lead formulation (01v3) in 252-1402-01 showed pritelivir free base (batch BXR2KVE, Test Item 1) to be stable to light exposure. Additional photostability testing Was performed on 01v3 containing pritelivir hemihydrate (M023862-CA15-033, Test Item 2) to confirm the formulation prepared using this form of pritelivir was stable following exposure to light. Samples of filled borosilicate vials containing 01v3 were exposed to light according to ICH Guidelines Q1B and the pritelivir recovery and purity levels have been summarised in Tables 80 and 81, respectively. The data illustrates that after exposure to UV light the pritelivir in formulation (01v3) appeared stable due to little change in percentage recovery and purity of pritelivir from t=0, supporting observations previously made in 252- 1402-01. Slight discrepancies in the mean purity levels can be attributed to related substances close to the LOQ of the analytical method.

Table 80: Mean percentage recovery of pritelivir hemihydrate (%) at t = 0 and following exposure to UV light according to ICH Guidelines Q1B mean (range n= 3).

Short term stability of free base and mesylate salt in the individual excipients and solvent systems

Both free base and mesylate salt dissolved in individual excipients and solvent systems were subjected to 2 and 4 weeks at 40 °C and 50 °C.

Stability of the free base in the different solvent systems for 2 and 4 weeks at 40 °C and 50 °C.

Table 84 - Percentage recovery and peak purity of pritelivir free base determined in solvents at t = 0 and after storage at the stated time point and temperature. Recovery in comparison to t= 0 value, n= 2 with range illustrated in brackets (assay method). Peak purity values, n= 1 (impurity method).

Significant difference in the solubility of free base and mesylate salt was seen under the similar conditions in the different vehicle systems.

Solubility of the free base versus mesylate salt in photoblockers

As seen in the table XX above, free base shows higher solubility in the octisalate

(photoblocker) compared to mesylate salt.

Table 86- Saturated solubility of pritelivir (free base and mesylate salt) in octisalate. Values represent the average with the range in brackets, n= 3.

Solubility differences for free base and mesylate salt in different solvent systems

Solubility was evaluated for free base versus mesylate salt in the solvent systems used to develop ointment formulations. As evident in the table 87 below free base showed significantly higher solubility compared to the mesylate salt. Hence it was only possible to develop 5 % ointment formulations with the free base of pritelivir and not with the mesylate salt thereof.

Maintaining the drug in the solubilized form has significant impact on the rate of permeation of drug across the skin and ultimately for efficacy upon topical application.

Short-term stability data for pritelivir free base and mesylate salt containing formulations of the invention

Pritelivir free base and mesylate salt containing formulations were subjected to 40 °C and 50 °C for 4 weeks.

Free base was found to be relatively stable when compared to the mesylate salt.

Table 88 - Percentage purity pritelivir free base in formulations at t=0 and following storage for t=2 and 4 weeks at 25 °C and 40 °C, n=l .

Long-term stability data of the current clinical formulation

24 months stability data has been generated for a topical formulation 01 V3 containing the free base hemihydrate where drug is in dissolved form (5 % drug loading) and formulation is stable with respect to assay, purity, pH, viscosity.

Below table shows 90 months stability of said topical formulation 01 V3.

Table 90 - 01v3, 5% stability testing results at 25 °C / 60 % RH and 40 °C / 75 % RH packaged in Borosilicate vials

Stability of free base and mesylate salt formulations in presence and absence of photoblockers under photostress conditions

Topical formulations of free base and mesylate salt of pritelivir with and without photoblockers were subjected to UV-stress conditions in accordance with the ICH guidelines. Thereby, the free base was found to be stable to photostress conditiosn in both presence and absence of photoblockers. However, the pritelivir mesylate salt was only stable in the presence of photoblockers in most of the cases.

Table 91 - Percentage recovery (as a percentage of the theoretical concentration) and peak purity of pritelivir free base determined in formulations at t = 0 and exposure to UV light under ICH conditions.

Table 92 - Percentage recovery (as a percentage of the theoretical concentration) and peak purity of pritelvir mesylate salt determined in formulations at t = 0 and exposure to UV light under ICH conditions.

Comparative solubility of free base and free base hemihydrate in individual excipients

The free base hemihydrate showed higher solubility than two batches of the free base. Hence, all the data obtained for free base can be extrapolated to the free base hemihydrate regarding solubility.

Saturated solubility (% w/w) of two forms of pritelivir (batches BXR2KVE for the free base and M023862-CA15-033 for pritelivir free base hemihydrate) in PEG 400 and propylene glycol, mean (range, n=3) are shown in Table 93 below.

Table 93

^* determined during 252-1402-01 .

Photostability testing of the current clinical formulation

The current clinical formulation comprises the following excipients and active ingredients (in % w/w):

Super Refined PEG 400 55.00

0.5 M NaOH/HCI to make up pH 4-5

Super Refined™ PEG 400 (second addition) q.s. 100 %

Propylene glycol 9.78

BHT 0.10

PEG 4000 17.50

Pritelivir free base hemihydrate 5.0 Photostability testing of the above clinical formulation containing pritelivir free base hemihydrate to confirm the formulation prepared using this form of pritelivir was stable following exposure to light. Samples of filled borosilicate vials containing said clinical formulation were exposed to light according to ICH Guidelines QIB and the pritelivir free base hemihydrate recovery and purity levels have been summarised in the Tables 94 and 95, respectively. The data illustrates that after exposure to UV light the pritelivir free base hemihydrate in said clinical formulation appeared stable due to little change in percentage recovery and purity of pritelivir free base hemihydrate from t = 0, supporting observations previously made in 252-1402-01. Slight discrepancies in the mean purity levels can be attributed to related substances close to the LOQ of the analytical method.

Long-term stability data of the current clinical formulation are presented for 24 months at 25 °C / 60 % RH:

24 months stability data has been generated for the current clinical formulation containing the free base hemihydrate of pritelivir as active pharmaceutical ingredient which is present in solubilized form with a 5 % w/w drug loading equivalent for the pritelivir free base as active moiety, and the respective topical formulation has been found stable with respect to assay, purity, pH, and viscosity. This formulation is composed of Super Refined™ PEG 400 at an apparent pH of 4.0 to 4.5 (adjusted during manufacturing process). The below table 96 shows respective 24 months stability data of the current clinical formulation.

Tables 96 a) - c): Long-term stability data of the current clinical formulation with 5 % w/w pritelivir free base hemihydrate are presented for 24 months at 25 °C / 60 % RH.

Table 96 a): Clinical formulation with 5 % w/w pritelivir free base hemihydrate - stability testing results at 25 °C / 60 % RH and 40 °C / 75 % RH (batch no.: BMR7264/001) packaged in Borosilicate vials.

Impact of grade of PEG 400:

Pritelivir in solubilized form was subjected to stress conditions for 4 weeks at 40 °C and 50 °C using PEG 400 versus Super Refined™ PEG 400. shown in the table 97 below, extent of degradation was significantly higher when the pritelivir drug was dissolved in PEG 400 compared to Sup Refined™ PEG 400.

Table 97: Percentage recovery and peak purity of pritelivir free base when formulated with PEG 400 versus Super Refined PEG 400

Impact of pH of the vehicle:

Pritelivir in solubilized form was subjected to stress conditions for 4 weeks at 40 °C and 50 °C using PEG 400 with and without pH adjustment 4.0. As shown in the table 98 below, extent of degradation was significantly higher when said pritelivir drug was dissolved in PEG 400 without a pH adjustment compared to pH 4.0. Hence it can be said that said pritelivir drug in solubilized form shows higher stability when pH is on the acid range (i.e. 4.0 to 4.5). And from physiological acceptability point of view, pH 4.0 appears to be the lowest possible pH accepted.

Table 98 - Percentage recovery and peak purity of pritelivir free base when tested for different apparent pH

Based on this data obtained it can be said that the presence of oxidising impurities (e.g. by PEG 400) and a neutral pH appears to disadvantageous for the stability of the pritelivir drug in solubilised form. Hence, the topical formulations of the invention with Super Refined PEG 400 using a combination with BHT (as an antioxidant) at pH 4.0 to 4.5 when subjected to long-term stability studies (6 months at 40 °C / RH and 24 months at 25 °C / 60 %) proved to be sufficiently stable.

Photostability of the current clinical formulation:

Pritelivir in solubilised form is sensitive to photostress conditions, however, surprisingly and unexpectedly, the current clinical formulation is stab to photostress conditions. These findings also explain the role of Super Refined™ PEG 400, BHT and pH 4.0 to 4.5 to stabilize pritelivir again photostress conditions.

Table 99 - Photostability of the current clinical formulation

Impact of use of PEG 400 versus Super Refined PEG 400 in an ointment formulation of the invention

The current clinical formulation as ointment formulation was prepared using standard PEG 400 and Super Refined™ PEG 400 while using t identical process and composition. These test formulations were subjected to the storage for 2 months at 40 °C / 75 % RH. Table 100 - Stability data of the current clinical formulation using Super Refined™ PEG 400, and BHT at a pH 4.0

Table 101 - Stability data of the current clinical formulation using standard PEG 400, BHT and pH 4.0

As seen above in the tables 100 and 101, the replacement of Super Refined PEG 400 with standard PEG 400 led to increase in impurities j after storage of 2 months (although formulation contained BHT at pH 4.0). So, the role of Super Refined™ PEG 400 in combination with BHT a at a pH 4.0 is significantly important to stabilize the drug and prevent it from any oxidative degradation (when it is present in solubilized form).

Impact of no pH adjustment:

The current clinical formulation as ointment formulation was prepared using Super Refined PEG™ 400 and without any pH adjustment agent usi the identical process and composition. It is subjected to the storage for 2 months at 40 °C / 75 %.

Table 102 - Stability data of the current clinical formulation using Super Refined PEG 400, BHT and no pH adjustment

0.45%

RRT

0.92:

0.74%

RRT

0.93:

0.85%

RRT

0.96:

0.83%

RRT

0.98:

0.66%

RRT

1.03:

0.09%

RRT

1.09:

0.06%

Total <5.0%

Total <5.0% a/a ND 24.4%

a/a

As seen above in table 102, absence of pH adjustment led to significant degradation of pritelivir (around 24 % of degradation in 2 months at 40 ° 75 RH). Hence, pH-adjustment towards 4.0 to 4.5 is very critical for the stabilization of the pritelivir drug in dissolved state or solubilized form as accordance with the present invention.

Impact of grade of PEG 400 and no pH adjustment

The current clinical formulation as ointment formulation was prepared using standard PEG 400 and without any pH adjustment using the identic process and composition. It is subjected to the storage for 2 months at 40 °C / 75 % RH.

Table 103 - Stability data of the current clinical formulation using standard PEG 400, BHT and no pH adjustment

As seen above, absence of pH adjustment and use of standard PEG 400 lead to significant degradation of pritelivir (around 88.6 % of degradation 2 months at 40 °C / 75 %). Hence, pH-adjustment to 4.0 to 4.5 in combination with Super Refined PEG™ 400 is very critical for the stabilization pritelivir is dissolved state or solubilized form.

Claims

1. A pharmaceutical formulation for use in topical application to a subject in need thereof, said formulation comprising: i. 1 - 10 % w/w of N-[5-(amino-sulfonyl)-4- methyl- l,3-thiazol-2-yl]-N- methyl- 2-[4-(2-pyridinyl)phenyl]acetamide,

ii. > 0 - 90 % w/w of at least one solvent,

2. A pharmaceutical formulation for use in topical application to a subject in need thereof according to claim 1 , wherein said formulation comprises: i. 1 - 10 % w/w of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl- 2-[4-(2-pyridinyl)phenyl]acetamide,

ii. 0.1 - 90 % w/w of at least one solvent,

iii. 0.01 - 10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, wherein the N- [5-(amino-sulfonyl)-4-methyl- 1 ,3 -thiazol-2-y 1] -N-methyl-2- [4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C / 60 % RH, wherein said solvent is selected from the group comprising polyethylene glycols, PEG 400, PEG 4000 and Super Refined™ PEG 400, and wherein said antioxidant agent is butylated hydroxyl toluene (BHT).

3. A pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the claims 1 to 2, said formulation comprising: i. 1.1 - 5 % w/w of N-[5-(amino-sulfonyl)-4- methyl- 1,3 -thiazol-2-yl]-N- methyl- 2-[4-(2-pyridinyl)phenyl]acetamide,

ii. 0.1 - 90 % w/w of at least one solvent,

iii. 0.01 - 10 % w/w of at least one antioxidant agent, wherein the pharmaceutical formulation has a pH value of 4.0 to 5.0, wherein the N-[5-(amino-sulfonyl)-4-methyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide is stable in dissolved state or in solubilized form for 12 months at 25 °C / 60 % RH, wherein said solvent is Super Refined™ PEG 400, and wherein said antioxidant agent is butylated hydroxyl toluene (BHT).

4. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the preceding claims, wherein the said N-[5-(amino- sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is selected from the group comprising:

• the N-[5-(amino-sulfonyl)-4-methyl-l ,3 -thiazol-2-yl] -N-methyl-2- [4-(2- pyridinyl)phenyl]acetamide free base hemihydrate, • the maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide,

• the mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l ,3- thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)phenyl] acetamide, and

5. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the preceding claims, wherein the said N-[5-(amino- sulfonyl)-4-mefhyl-l ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, or the said

• N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide free base hemihydrate,

• mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol- 2-yl] -N-methyl-2- [4-(2-pyridinyl)phenyl] acetamide, and

• free base of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl]acetamide. is present in dissolved state or in solubilized form when determined by light scattering methods, Raman spectroscopy and IR spectroscopy and by the respective absence of solid phases during XRPD.

6. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the preceding claims, said formulation comprising: i. 5 % w/w of N-[5-(amino-sulfonyl)-4- methyl- 1,3 -thiazol-2-yl] -N-methyl- 2- [4-(2-pyridinyl)phenyl] acetamide, or of the said

N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide free base hemihydrate, • maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl]acetamide,

• mesylate salt of the free base of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)phenyl] acetamide,

7. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in any of the preceding claims, wherein the said N-[5-(amino- sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is selected from the group comprising:

• the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide free base hemihydrate in dissolved state,

• the maleate salt of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)phenyl] acetamide in dissolved state,

8. The pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the preceding claims, wherein said formulation is selected from the group comprising formulations for creams, ointments, gels, salves, skin lotions, wax formulations, lipsticks, tonics, mousses, foam, films, emulsions, paste, solutions, oils, lipogels.

. The pharmaceutical formulation for use in topical application to a subject in need thereof according to any of the preceding claims* wherein said formulation is an ointment further comprising:

(i) 0.01 - 20 % w/w of at least one pH-adjustment agent.

10. The pharmaceutical formulation for use in topical application to a subject in need thereof as defined in claim 9, wherein said formulation is an ointment comprising:

17.5 % w/w PEG 4000,

9.78 % w/w propylene glycol,

5 % w/w active pharmaceutical ingredient pritelivir,

0.1 % w/w butylated hydroxyl toluene (BHT),

67.62 % w/w Super Refined™ PEG 400, and wherein the said pharmaceutical formulation has a pH value of 4.0 to 4.5.

11. The pharmaceutical formulation for use in topical application to a subject in need thereof according to claim 8, wherein said formulation is a cream formulation further comprising: i. 0 - 5 % w/w preservatives

ii. 0 - 20 % w/w of at least one surfactant agent

iii. 1 - 40 % w/w oil phase/emollient

iv. 0 - 40 % w/w water.

12. The pharmaceutical formulation for use in topical application to a subject in need thereof according to claim 8, wherein said formulation is a gel further comprising: i. 0 - 30 % w/w penetration enhancer

ii. 0 - 20 % w/w gelling agent

iii. 0 - 50 % w/w water

iv. 0.01 - 20 % w/w of at least one pH-adjustment agent, v. optionally further comprising a preservative at an amount of about > 0 - 5 % w/w.

13. The pharmaceutical formulation as defined in any one of the preceding claims for use as medicament.

14. The pharmaceutical formulation as defined in any one of the preceding claims for use in the treatment and/or prevention of herpes virus infections.

15. The pharmaceutical formulation as defined in any one of preceding claims for use in the treatment and/or prevention of herpes virus infections, wherein said herpes viruses are selected from the order of simplex viruses.

16. The pharmaceutical formulation as defined in any one of the preceding claims for use in the treatment and/or prevention of herpes virus infections, wherein said simplex virus is selected from Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2).