AU2013347264B2 - Dispersible tablet - Google Patents

Abstract

The present invention relates to a tablet comprising Nimorazole. In particular, the invention concerns a pharmaceutical composition or a tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof, for dispersion in water and administration via a tube to a patient with swallowing difficulties.

Description

PCT/DK2013/050384 WO 2014/075692

Dispersible tablet

The present invention relates to a pharmaceutical composition comprising Nimorazole, which disintegrates in water. In particular, the invention concerns a pharmaceutical composition such as a tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof, for dispersion in water and administration via a tube to a patient with swallowing difficulties.

Technical Background

The patent US 4371540 describes the use of radiosensitizers for hypoxic cells. Administration is performed via an intravenous route or suggested to be done orally using a prodrug, wherein the prodrug is the acetate ester of the compound.

The patent US 4462992 suggests administration parenterally, subcutaneously, intravenously, intramuscularly or intraperitoneally, or alternatively oral administration.

The patent application US 2010/322939 describes oral administration of Nimorazole 90 minutes prior to radiotherapy treatment.

According to Bowman, Corinne ("Administration of drugs to patients with swallowing difficulties", Journal of the Malta College of Pharmacy Practice, Issue 12 Winter 2007, pp. 42-45) patients who are unable to swallow due to a debilitating condition become dependent on an enteral feeding tube both for nutritional needs and for administration of medicines. Information regarding this mode of administration is very scarce and also associated with increased risk of tube obstruction, increased toxicity and reduced efficacy due to an inadequate administration method. Bowmann notes that "Unfortunately, crushing tablets is mistakenly taken for granted by some healthcare professionals without considering that the properties of the medication may be affected", and finally "Crushed tablets are the most frequent cause of obstruction of feeding tubes which results in increased morbidity and trauma to the patient besides the cost of replacing the tube. This may require surgical intervention".

Summary of the invention

Nimorazole is inter alia used to improve the efficacy of irradiation treatment for cancer patients.

Patients such as cancer patients may suffer from swallowing difficulties. In particular cancer patients undergoing irradiation treatment in the head and neck region and concurrent Nimorazole treatment may have difficulties swallowing Nimorazole tablets, and thus have a need for having Nimorazole administered via an alternative route. The amount of Nimorazole necessary for an effective treatment, such as about 2 g for each treatment, aggravates this problem, as it implies the use of large tablets or a high number of tablets.

Nimorazole is slightly soluble in water (The Merck Index, 14th Edition). Experiments indicate that the solubility in water is about 5 mg/ml. Further, in order to achieve a reasonable dissolution rate, it is usually necessary to apply excessive amounts of liquid in order to obtain sink conditions. Preparing a bulky solution of Nimorazole for further distribution creates additional problems in terms of storage stability and difficulties distributing a large container comprising liquid. 1 PCT/DK2013/050384 WO 2014/075692

There is a need for providing a liquid medium comprising an amount of Nimorazole exceeding the solubility limit of Nimorazole in water, in order to be able to administer effective amounts of Nimorazole via a feeding tube while avoiding the intake of excessive amounts of liquid medium. There is a need for being able to provide a liquid medium comprising Nimorazole within a short time frame. In addition, there is a need to provide a liquid medium comprising Nimorazole which is able to pass via a feeding tube without causing obstruction.

Attempts were made to provide a granulate comprising Nimorazole, which was formulated with the intent to be dispersed in water, administered via a feeding tube, and quickly dissolve in the stomach at low pH. However, the granulate suffered from the drawback that the granulate was not sufficiently dispersed in water at neutral pH, and thus created obstructions in a feeding tube. The development of the granulate comprising Nimorazole was subsequently stopped.

Attempts were made to provide a powder comprising Nimorazole, which was formulated to be quickly dispensed in water at neutral pH. Up to five sachets of powder had to be opened and carefully emptied into water, making sure that all the powder of each sachet was emptied completely. While this powder did not obstruct the feeding tube, it was seen as a quite tedious procedure that could impact patient compliance to the treatment. The development of the powder comprising Nimorazole was subsequently stopped. Further, the powder was less suitable for oral administration unless it was dispersed in water.

According to aspects and embodiments of the invention, the abovementioned problems are addressed by the present invention.

Surprisingly, it has been possible to provide a liquid medium comprising an amount of Nimorazole exceeding the solubility limit of Nimorazole in water, making it possible to administer effective amounts of Nimorazole via a feeding tube while avoiding the intake of excessive amounts of liquid medium. Further, it has been possible to provide a liquid medium comprising Nimorazole within a short time frame. In addition, it has been possible to provide a liquid medium comprising Nimorazole which is able to pass via a feeding tube without causing obstruction.

According to an aspect, the invention concerns a pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, for disintegration in water or an aqueous medium and administration via a tube. A feeding tube may suitably be used. In particular, the invention concerns a pharmaceutical composition which allows administration using a feeding tube to a patient with swallowing difficulties.

The pharmaceutical formulation or tablet according to the invention preferably disintegrates upon contact with water, forming a dispersion. The forming of the dispersion may be aided by stirring in the water, or shaking a container comprising the tablet and water.

According to another aspect, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a 2 PCT/DK2013/050384 WO 2014/075692 disintegrant; optionally one or more additional excipients; and a coating; said pharmaceutical composition allowing administration via at least two different routes: i) oral administration, or ii) disintegration in water or an aqueous medium to provide a dispersion, and subsequent administration of said dispersion via a tube.

Surprisingly, it has been possible to device a pharmaceutical formulation or tablet, which may be used directly for oral administration, and which alternatively may be dispersed in water in a short time frame for administration via a feeding tube. The pharmaceutical formulation or tablet may be dispersed in a small volume of water. The dispersed particles are sufficiently small to provide a slow sedimentation rate, allowing administration of the particles in dispersed state from e.g. a bottle via a feeding tube. A pharmaceutical formulation in the form of a tablet is easy to handle and dosage may easily be measured and subsequently checked. Using a powder from individual sachets makes a dosing of several sachets cumbersome. Further, the use of a powder makes a dosage check after measurement of the intended dosage cumbersome, while a small number of tablets are easily counted for verification of dosage. Finally, a tablet provides a smaller surface area than a powder, thus potentially increasing the storage stability of the product.

According to an aspect, the invention concerns a kit of parts comprising a pharmaceutical composition according to the invention, and instructions for preparing a dispersion of said pharmaceutical composition for administration via a tube.

According to an aspect, the invention concerns a method for manufacturing a pharmaceutical formulation or tablet according to the invention, comprising wet granulation of Nimorazole.

Further information concerning wet granulation may be found in references such as: International Journal of Pharmaceutical Frontier Research, April-June 2011; 1(1):65-83, "Pharmaceutical Processing - A Review on Wet Granulation Technology", Rajesh Agrawal and Yadav Naveen; "Wet Granulation: End-Point Determination and Scale-Up", Michael Levin, Ph. D. Metropolitan Computing Corporation, East Flanover, New Jersey, USA; and Parikh D. "Flandbookof Pharmaceutical Granulation Technology", Marcel Dekker, Inc. New York, 1997.

According to an aspect, the invention concerns a method of treatment of cancer, wherein irradiation treatment is combined with the administration of at least one pharmaceutical formulation or tablet according to the invention, wherein said at least one pharmaceutical formulation or tablet is allowed to disintegrate in water or an aqueous medium and administered via a tube. This is particularly relevant when the patient has or acquires problems with swallowing, such as for cancer in the head and neck region.

This method is particularly preferred for patients with swallowing difficulties undergoing treatment with Nimorazole. 3 PCT7DK2013/050384 WO 2014/075692

According to an aspect, the invention concerns a method of radiosensitizing hypoxic tumor cells comprising administering Nimorazole, wherein the administration comprises: providing a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof; dispersing said solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion; and administering said dispersion via a tube.

According to an aspect, the invention concerns a use of a tablet according to the invention, wherein said tablet is dispersed in water and administered via a tube.

According to an aspect, the invention concerns an aqueous pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, wherein at least part of said Nimorazole or pharmaceutically acceptable salt thereof is dispersed in an aqueous medium in form of solid particles.

Detailed Disclosure

According to an embodiment, the invention concerns a pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, for disintegration in water or an aqueous medium and administration via a tube. A feeding tube may suitably be used.

The expression "water or an aqueous medium" covers the possibility of using water or water comprising one or more salts, such as a saline solution, and/or any (other) components for the patient, such as at least one active ingredient. It also covers the possibility of water comprising one or more nutrients, optionally with one or more active ingredients.

The pharmaceutical composition or tablet according to the invention preferably disintegrates upon contact with water, forming a dispersion. The forming of the dispersion may be aided by stirring in the water, or shaking a container comprising at least one tablet and water.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for administration to a patient with swallowing difficulties. According to a preferred embodiment, the invention concerns a pharmaceutical composition or tablet for administration to a patient with little, insufficient or no saliva, such as a patient with non-normal salivary function.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a disintegrant; optionally one or more additional excipients, such as a binder; and a coating; said pharmaceutical composition allowing administration via at least two different routes: oral administration, or disintegration in water or an aqueous medium to provide a dispersion, and subsequent administration of said dispersion via a tube.

The solid pharmaceutical composition is preferably a tablet.

The pharmaceutical composition is preferably provided in a solid form which is stable over time. Preferably, the pharmaceutical composition is stable for 6 months, preferably 12 months, more preferred 18 months, preferably 24 months, more preferred 30 months, preferably 36 months, or even longer. Preferably, the pharmaceutical composition retains its dispersibility upon storage, i.e. 4 PCT/DK2013/050384 WO 2014/075692 during storage for 6 months, preferably 12 months, more preferred 18 months, preferably 24 months, more preferred 30 months, preferably 36 months, or even longer.

The disintegrant makes it possible to provide a dispersion in a short time interval. Preferably, the solid pharmaceutical composition allows the provision of a dispersion comprising an amount of Nimorazole or a pharmaceutically acceptable salt thereof, wherein the amount of Nimorazole or a pharmaceutically acceptable salt thereof exceeds the solubility limit of Nimorazole in the water or the aqueous medium. Preferably, the solid pharmaceutical composition allows the provision of a dispersion comprising an amount of Nimorazole or a pharmaceutically acceptable salt thereof, wherein the amount of Nimorazole or a pharmaceutically acceptable salt thereof exceeds the 5 mg / ml of water or the aqueous medium.

The coating may serve as taste-masking, as Nimorazole has an unpleasant taste. An unpleasant taste may lower patient compliance. Additionally, a coating may improve storage stability of the pharmaceutical formulation.

Having a pharmaceutical composition which allows two different routes of administration carries a number of advantages. Firstly, patient compliance is improved, as the patient is already used to the pharmaceutical composition if or when the patient needs to change route of administration. Secondly, the costs associated with production and obtaining marketing approval are lowered, as only one product needs to be produced and approved.

Preferably the dispersion of the solid pharmaceutical composition may be done by the patient. It is further preferred that administration of the dispersion may be performed by the patient. This allows out-patient or ambulatory use.

An excipient is generally a pharmacologically inactive substance. Examples include, but are not limited to, diluents, disintegrants, binders, glidants, lubricants, and coatings. Other examples of suitable excipients may be found in Handbook of Pharmaceutical Excipients, 7th Ed. by Rowe, Raymond C. et al.. Pharmaceutical Press, London.

Diluents are inactive ingredients that are added to tablets and capsules in addition to the active drug. Some very common diluents in tablets include starch, cellulose derivatives, and magnesium stearate (also a lubricant). Diluents fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, diluents make it possible for the final product to have the proper volume for patient handling. A good diluent must be inert, compatible with the other components of the formulation, non-hygroscopic, relatively cheap, compactible, and preferably tasteless or pleasant tasting. Plant cellulose (pure plant Diluent) is a popular diluent in tablets or hard gelatin capsules. Dibasic calcium phosphate is another popular tablet diluent. A range of vegetable fats and oils can be used in soft gelatin capsules. Other examples of diluents include: lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.

Disintegrants expand and dissolve when wet causing the tablet to break apart. They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution or dispersion. Examples of disintegrants include, but are not limited to: crosslinked 5 PCT/DK2013/050384 WO 2014/075692 polymers, such as crosslinked polyvinylpyrrolidone (crospovidone), and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium); and the modified starch sodium starch glycolate. Specific examples further include Indion 414, L-HPC, and pregelatinised starch.

Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to tablets. Examples of binders include: saccharides and their derivatives: disaccharides, sucrose, lactose; polysaccharides and their derivatives, such as starches, cellulose or modified cellulose, such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); sugar alcohols such as xylitol, sorbitol or maltitol; further Protein: gelatin; and Synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol. Other examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.

Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Examples include fumed silica, talc, and magnesium carbonate.

Lubricants are agents added to tablet and capsule formulations to improve certain processing characteristics. Lubricants inter alia prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are examples of lubricants used in tablets or hard gelatin capsules.

Coatings protect ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose ether hydroxypropyl methylcellulose (HPMC) film coating is used which is free of sugar and potential allergens. Occasionally, other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides. A specific example is Opadry. Capsules are coated with gelatin.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: diluent; disintegrant; binder; glidant; lubricant; and optionally one or more additional excipients; and a coating.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: diluent, 1 - 50 %; disintegrant, 0.5 -15%; binder, 0.5 -15 %; glidant, 0.5 - 3 %; lubricant, 0.5 - 3 %; and optionally one or more additional excipients; and a coating, 0.5 - 5 %.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: diluent, 2 - 25 %, preferably 4 -15%, more preferred 6 -10%, preferably 7-9%; disintegrant, 1 -12 %, preferably 3 - 10%, more preferred 5 - 9%, preferably 7-8%; binder, 1 -10 %, preferably 2 - 6 PCT/DK2013/050384 WO 2014/075692 8%, more preferred 3 - 6%, preferably 4 - 5%; glidant, 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; lubricant, 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; and optionally one or more additional excipients; and a coating, 0.7 - 4 %, preferably 1 - 3%, more preferred 1.5 - 2.5%, preferably 2-2.2%.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a) An intragranular part, comprising: diluent; disintegrant; and binder; and b) An extragranular part, comprising: diluent; disintegrant; glidant; and lubricant; and c) A coating.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a) An intragranular part, comprising: diluent, 1 - 50 %; disintegrant, 0.5 -15%; and binder, 0.5 -15 %; and b) An extragranular part, comprising: diluent, 0.5 - 50%; disintegrant, 0.5 -15%; glidant, 0.5 -3 %; and lubricant, 0.5 - 3 %; and c) A coating, 0.5 - 5 %.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a) An intragranular part, comprising: diluent, 2 - 25 %, preferably 4 -15%, more preferred 6 - 10%, preferably 7 - 8%; disintegrant, 0.7 -10 %, preferably 1 - 8%, more preferred 1.5 -5%, preferably 2-3%; and binder, 1 -10 %, preferably 2 - 8%, more preferred 3 - 6%, preferably 4-5%; and b) An extragranular part, comprising: diluent, 0.7 - 25 %, preferably 0.8 -10%, more preferred 0.9 - 5%, preferably 1 - 2%; disintegrant, 1 -10 %, preferably 2 - 8%, more preferred 4 - 7%, preferably 5-6%; glidant, 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; and lubricant, 0.6 - 2.5 %, preferably 0.8 - 2%, more preferred 0.9 - 1.8%, preferably 1 - 1.5%; and c) A coating, 0.7 - 4 %, preferably 1 - 3%, more preferred 1.5 - 2.5%, preferably 2 - 2.2%.

According to an embodiment, the invention concerns a pharmaceutical composition which is an immediate release tablet. An immediate release tablet disintegrates in water within 30 minutes.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for disintegration in water within 15 minutes, preferably 10 minutes, more preferred 5 minutes, preferably within 3 minutes to produce a dispersion for administration to a patient via a tube.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet, wherein said dispersion passes through a sieve screen with a nominal mesh aperture of 710 pm. 7 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet, which disintegrates within 10 min., preferably within 5 min., using water at 25°C, preferably 20°C, more preferred at 15°C.

According to an embodiment, the invention concerns a pharmaceutical composition which is a dispersible tablet. The expression "dispersible tablet" refers to a tablet, which may be dispersed in water before administration, providing a homogeneous dispersion. Dispersible tablets disintegrate within 3 minutes using water at 15 - 25°C. The fineness of dispersion should comply with a test comprising placing 2 tablets in 100 ml water and stirring until completely dispersed. A smooth dispersion is produced, which passes through a sieve screen with a nominal mesh aperture of 710 pm.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet, which allows complete dispersion of one or more pharmaceutical compositions or tablets comprising a total of at least 1000 mg Nimorazole in 100 ml water at 25°C upon stirring, thereby providing a dispersion; said dispersion passing through a sieve screen with a nominal mesh aperture of 710 pm. According to embodiments, the term "complete dispersion" covers the case wherein at least 90%, more preferred at least 95%, preferably at least 98%, more preferred 99%, preferably 100% Nimorazole is dispersed or dissolved.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for administration via a feeding tube.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for administration via a feeding tube selected among the group consisting of a percutaneous endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric feeding tube, and a jejunostomy feeding tube.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for administration via a percutaneous endoscopic gastrostomy ("PEG") tube or a nasogastric ("NG") feeding tube.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of bedridden or geriatric patients. These patient groups often suffer from difficulties swallowing tablets.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of patients undergoing irradiation treatment, particularly irradiation treatment of the head and/or neck region.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of intubated patients, such as patients having inserted a tube into the gastrointestinal tract. Individual differences may influence if and at what point during a treatment regime patients are intubated. 8 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of patients having received at least a number selected among 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 irradiation treatments for cancer of the head and/or neck region.

While Nimorazole is usually administered from the first irradiation treatment, using a tube becomes particularly relevant when the patient begins to experience problems swallowing, usually from the 5th or 6th irradiation treatment.

Thus, the need for administration of Nimorazole via a feeding tube does usually not occur before after the 4th or 5th irradiation treatment, as the swallowing difficulties is usually not present early. During the first about four fractions of irradiation treatment direct oral administration is preferred, i.e. in the form of a tablet taken orally, while the need for administration via a feeding tube usually occurs later, i.e. from the 5th or 6th irradiation treatment.

Hence, for a Nimorazole tablet to be used with concurrent radiotherapy, it is convenient to have a tablet which may both be administered directly orally, and which may be used for making a dispersion or solution for administration via a feeding tube. However, due to the unpleasant taste of Nimorazole, it is preferable that the tablet comprises a coating, masking the taste.

Conventional coatings suffers from the drawback that they make it difficult to make a dispersion, and parts of the coating may get stuck in a feeding tube.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for swallowing or for disintegration in water or an aqueous medium and administration via a tube.

This tablet is specifically adapted to allow swallowing or allow disintegration in water or an aqueous medium at the discretion of a person administering the tablet.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet further comprising a coating facilitating swallowing and masking the taste of Nimorazole.

The taste of Nimorazole is unpleasant to most patients. Thus, without a coating, many patients will feel the swallowing of Nimorazole tablets objectionable. However, a coating tends to impede the disintegration of the tablet in water. Surprisingly, it has been possible to device a coating, which facilitates swallowing, and masks the taste of Nimorazole, and still allows producing a dispersion in water quickly.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for curative treatment or reirradiation of cancer.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for 1st line irradiation treatment of cancer with curative intent or 2nd line reirradiation treatment of cancer with curative and/or palliation intent.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for curative or palliative treatment of cancer in patients undergoing radiotherapy, particularly for patients with cancer in the head and/or neck region. 9 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of patients with hypoxic cancer. Methods for testing whether cancers are hypoxic are known in the art.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of an indication selected among breast cancer, head/neck cancer, esophagus cancer, lymphoma, cervical cancer, colorectal cancer, brain cancer, lung cancer, bladder cancer, and prostate cancer. The invention is particularly relevant for patients with a swallowing problem, which may or may not be caused by irradiation treatment. The cancer treatment may be with or without concurrent chemotherapy.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of head/neck cancer.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of cervical cancer or inoperable lung cancer.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment of non-smokers. Nimorazole may appear to have reduced or little influence on the efficacy of irradiation treatment of cancer among patients who have not stopped smoking during treatment. According to an embodiment, cessation of smoking during therapy is warranted.

According to an embodiment, the invention concerns a pharmaceutical composition, comprising at least 250 mg Nimorazole or a pharmaceutically acceptable salt thereof.

According to an embodiment, the invention concerns a pharmaceutical composition, comprising 10 - 2500 mg, more preferred 100 - 2000 mg, preferably 300 -1500 mg, more preferred 400 -1000 mg, preferably 500 mg Nimorazole or a pharmaceutically acceptable salt thereof.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet, subject to the proviso that 3 - 5 of said pharmaceutical compositions or tablets may be dispersed in 2 dl water at 25°C, preferably 20°C, more preferred 15°C within 15, preferably 10, more preferred 5, preferably within 3 minutes.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet allowing dispersion of 1500 - 2500 mg, preferably 2000 mg, Nimorazole in 2 dl water at 25°C, preferably 20°C, more preferred 15°C within 15, preferably 10, more preferred 5, preferably within 3 minutes.

According to an embodiment, the invention concerns a pharmaceutical composition or a tablet for treatment alone or combined with chemotherapy. According to an embodiment, the invention concerns a tablet for treatment alone or combined with chemotherapy for patients undergoing irradiation of a total of > 40 Grey during a course of treatment. 10 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns a kit of parts comprising a pharmaceutical composition according to the invention, and instructions for preparing a dispersion of said pharmaceutical composition for administration via a tube.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising wet granulation of Nimorazole.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising a wet granulation step performed using a Rapid Mixer Granulator, or alternatively using a device selected among the group consisting of a Super Mixer Granulator, Oscillating Granulator, Inline homegenizer, Caleva Mini Mixer, and High Shear Mixers.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising a wet granulation step preceded by dry mixing in a granulator or alternatively, said dry mixing may be performed using a device selected among the group consisting of a Conta blender, Octagonal blender, Double cone blender, Conical blender, and a Multi Mill.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising drying the wet granular mass resulting from a wet granulation until a pre-determined loss on drying (%LOD) is obtained.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising drying the wet granular mass resulting from a wet granulation until said %LOD is in the range of 0 to 10%, preferably 0.5 to 5.0%, more preferred within 1.5 to 3.0%.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising sifting all granules through a no. 20 (20#) sieve or finer prior to compression.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, comprising sifting all extragranular ingredients through a 20#, preferably 25#, more preferred 30# sieve or finer prior to compression.

According to an embodiment, the invention concerns a method of treatment of cancer, wherein irradiation treatment is combined with the administration of at least one tablet according to the invention, wherein said at least one tablet is allowed to disintegrate in water or an aqueous medium and administered via a tube. This method is particularly preferred for patients with swallowing difficulties undergoing treatment with Nimorazole.

According to an embodiment, the invention concerns a method of radiosensitizing hypoxic tumor cells comprising administering Nimorazole, wherein the administration comprises: Providing a solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof; Dispersing said solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion; and Administering said dispersion via a tube. 11 PCT/DK2013/050384 WO 2014/075692

Patients receiving Nimorazole in form of tablets may have difficulties swallowing. A new route or way of administration of Nimorazole particularly suitable for these patients is suggested. There is a need for a pharmaceutical composition, which may be administered via a tube without the need of crushing tablets. The dispersion to be administered may easily be prepared by the patient, in particular without the need to crush tablets. Thus, this is particularly suitable for out-patient administration, i.e. patients receiving Nimorazole as part of ambulatory treatment, e.g. patients who are requested to take the treatment in the home or on the way to the hospital before irradiation treatment at a treatment facility such as a hospital. Further, there is a need of taste-masking pharmaceutical compositions or tablets comprising Nimorazole.

According to an embodiment, the invention concerns a use of a tablet according to the invention, wherein said tablet is dispersed in water and administered via a tube.

According to an embodiment, the invention concerns an aqueous pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, wherein at least part of said Nimorazole or pharmaceutically acceptable salt thereof is dispersed in water or an aqueous medium in form of solid particles.

According to an embodiment, the invention concerns an aqueous pharmaceutical composition obtainable by dispersing a pharmaceutical composition in water or an aqueous medium.

According to an embodiment, the invention concerns an aqueous pharmaceutical composition, wherein said Nimorazole or pharmaceutically acceptable salt is present in a concentration exceeding 5 mg / ml water or an aqueous medium.

The term "concentration" refers to the abundance of a constituent divided by the total volume of a mixture. The term can be applied to any kind of mixture, and is not confined to solutes and solvents in solutions.

According to an embodiment, the invention concerns a solid pharmaceutical composition comprising: i) Nimorazole or a pharmaceutically acceptable salt thereof; ii) a disintegrant; iii) optionally one or more additional excipients; and iv) a coating; said pharmaceutical composition allowing oral administration, preferably as a tablet, and further allowing, as an alternative, administration via a feeding tube, wherein prior to administration via a feeding tube the pharmaceutical composition is disintegrated in water or an aqueous medium to provide a dispersion which is administered via the feeding tube.

According to an embodiment, the invention concerns the pharmaceutical composition wherein the additional excipients comprise a diluent, a binder, a glidant, and a lubricant. 12 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns the pharmaceutical composition comprising: diluent, 1-50 wt%; disintegrant, 0.5 -15 wt%; binder, 0.5 -15 wt%; glidant, 0.5 - 3 wt%; lubricant, 0.5 - 3 wt%; optionally one or more additional excipients; and a coating, 0.5 - 5 wt%.

According to an embodiment, the invention concerns the pharmaceutical composition comprising: diluent, 7 - 9 wt%; disintegrant, 7-8 wt%; binder, 4 - 5 wt%; glidant, 1 - 1.5 wt%; lubricant, 1 - 1.5 wt%; optionally one or more additional excipients; and a coating, 2 - 2.2 wt%.

According to an embodiment, the invention concerns the pharmaceutical composition comprising: an intragranular part, comprising a diluent, a disintegrant, and a binder; an extragranular part, comprising a diluent, a disintegrant, a glidant, and a lubricant; and a coating.

According to an embodiment, the invention concerns the pharmaceutical composition that is formulated as a tablet, an immediate release tablet or a dispersible tablet.

According to an embodiment, the invention concerns the pharmaceutical composition that disintegrates in water at 20°C within 5 minutes. 13 PCT7DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns the pharmaceutical composition that after disintegration in water or an aqueous medium passes through a sieve screen with a nominal mesh aperture of 710 pm.

According to an embodiment, the invention concerns the pharmaceutical that can be dispersed to provide at least 1000 mg Nimorazole in 100 ml water at 25°C within 5 minutes upon stirring, wherein said dispersion passes through a sieve screen with a nominal mesh aperture of 710 pm.

According to an embodiment, the invention concerns the pharmaceutical composition, wherein the feeding tube is selected from the group consisting of a percutaneous endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric feeding tube, and a jejunostomy feeding tube.

According to an embodiment, the invention concerns the pharmaceutical composition, wherein the coating facilitates swallowing and masks the taste of Nimorazole.

According to an embodiment, the invention concerns the pharmaceutical composition, wherein the composition comprises at least 250 mg Nimorazole or a pharmaceutically acceptable salt thereof per dosing unit.

According to an embodiment, the invention concerns the pharmaceutical composition that can be dispersed to provide at least 2000 mg of Nimorazole or a pharmaceutically acceptable salt thereof in 2 dl of water at 25°C within 3 minutes.

According to an embodiment, the invention concerns a kit of parts comprising the pharmaceutical composition and instructions for preparing a dispersion of the pharmaceutical composition for administration to a patient via a feeding tube.

According to an embodiment, the invention concerns a kit of parts comprising: a) a solid pharmaceutical composition comprising: i) Nimorazole or a pharmaceutically acceptable salt thereof; ii) a disintegrant; iii) optionally one or more additional excipients; and iv) a coating; said pharmaceutical composition allowing administration to a patient via a feeding tube by disintegrating the solid pharmaceutical composition in water or an aqueous medium to provide a dispersion which is administered via the feeding tube; and b) instructions for disintegrating the solid pharmaceutical composition in water or an aqueous medium to form a dispersion and administering the dispersion via a feeding tube. 14 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns the pharmaceutical composition, made by a method comprising performing wet granulation of a composition comprising Nimorazole or a pharmaceutically acceptable salt thereof.

According to an embodiment, the invention concerns a method for manufacturing a pharmaceutical composition, the method comprising performing wet granulation of Nimorazole or a pharmaceutically acceptable salt thereof.

According to an embodiment, the invention concerns a method of treating cancer by radiosensitizing hypoxic tumor cells, the method comprising performing radiation treatment combined with the administration of at least one solid pharmaceutical composition comprising: i) Nimorazole or a pharmaceutically acceptable salt thereof; ii) a disintegrant; iii) optionally one or more additional excipients; and iv) a coating; wherein said at least one solid pharmaceutical composition is allowed to disintegrate or is dispersed in water or an aqueous medium and administered to a patient via a feeding tube.

According to an embodiment, the invention concerns a method of treating cancer by radiosensitizing hypoxic tumor cells, the method comprising performing radiation treatment combined with the administration of at least one solid pharmaceutical composition, wherein said at least one solid pharmaceutical composition is allowed to disintegrate or is dispersed in water or an aqueous medium and administered to a patient via a tube.

According to an embodiment, the invention concerns the method, wherein the radiation treatment comprises: providing said solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof; dispersing the solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion; administering the dispersion to a patient via a feeding tube; and administering radiation to the patient.

According to an embodiment, the invention concerns the method, wherein the dispersion contains said Nimorazole or pharmaceutically acceptable salt thereof at a concentration exceeding 5 mg / ml of water or the aqueous medium.

According to an embodiment, the invention concerns the method, further comprising administering chemotherapy to the patient. 15 PCT/DK2013/050384 WO 2014/075692

According to an embodiment, the invention concerns the method, wherein the cancer is selected from the group consisting of breast cancer, head/neck cancer, esophagus cancer, lymphoma, cervical cancer, colorectal cancer, brain cancer, lung cancer, bladder cancer, and prostate cancer.

According to an embodiment, the invention concerns a dispersion containing dispersed 5 particulate Nimorazole or a pharmaceutically acceptable salt thereof in water or an aqueous medium, wherein the concentration of Nimorazole or its pharmaceutically acceptable salt exceeds the solubility limit in water or the aqueous medium, and wherein the dispersion is formulated for administration to a patient via a feeding tube.

According to an embodiment, the invention concerns the aqueous dispersion, wherein the 10 particulate Nimorazole or its pharmaceutically acceptable salt has an average diameter of less than 710 pm.

All cited references are incorporated by reference.

The accompanying Figures and Examples are provided to explain rather than limit the present 15 invention. It will be clear to the person skilled in the art that aspects, embodiments and claims of the present invention may be combined.

Unless otherwise mentioned, all percentages are in w/w.

Examples

Examples Al, A2, A3, and A4 20 Tablet ingredients and manufacture

Name of ingredient Specification Tablet A1 Tablet A2 Tablet A3 Tablet A4 mg/tablet mg/tablet mg/tablet mg/tablet Intragranular Nimorazole INH. 500 500 500 500 Cellulose microcrystalline (Avicel PH 101) Ph. Eur. 50 50 50 34 Sodium Starch Glycolate 14 Crospovidone (Kollidon CL) Ph. Eur. 14 14 19.5 Povidone K30 [Binder] Ph. Eur. 28 28 28 28 16 PCT/DK2013/050384

Purified water BP as. as. as. as. Extragranular Cellulose microcrystalline (Avicel 102) Ph. Eur. 9 9 9 9 Crospovidone (Kollidon CL) Ph. Eur. 35 35 35 45.5 Silica Colloidal anhydrous (Cab-o-sil) Ph. Eur. 7 7 7 7 Magnesium Stearate (VG) Ph. Eur. 7 7 7 7 Total weight of core tablet 650 650 650 650 Film Coating Opadry 03B57695 Grey INH. 6.5 6.5 13 16.25 Purified water BP 58.5 58.5 117 as. Total weight of coated tablet 656.5 656.5 663 666.25 Purified water evaporates during process and does not appear in finishec product. WO 2014/075692

Unless otherwise mentioned, the environmental conditions are about 22°C. Crospovidone was replaced with Sodium Starch Glycolate for Tablet Al. Tablets were manufactured using the following steps. 5 10 15 20 i. Sifting with vibratory sifter: Crospovidone was mixed with cellulose microcrystalline PH 101 and finally mixed with Nimorazole. The material was sifted through a 30# sieve using vibratory sifter. ii. Binder preparation and binder addition: Povidone K30 was dispersed into weighed quantity of purified water to prepare a 20% w/w dispersion under stirring. iii. Dry mixing in rapid mixer granulator: The sifted material from step i. was loaded into Rapid Mixer Granulator, and the material dry mixed for 10 min at slow speed of impeller, keeping Chopper off. iv. Wet mixing: The binder of step ii. was added into step iii. within 2 minutes with slow speed of impeller, keeping Chopper off. If required, additional sufficient quantity of purified water was added within one min. v. The wet mass of step iv. was mixed up to 1 minute with slow speed of impeller and slow speed chopper to get uniform consistency of the wet mass. The wet mass was discharged from Rapid Mixer Granulator with impeller at slow speed. vi. Wet milling in co-mill: The wet mass of step v. was passed through a 8.00 mm screen using co-mill at 700 RPM. 17 PCT7DK2013/050384 WO 2014/075692 vii. Drying in fluidized bed processor / dryer of the wet granular mass was performed with an inlet temperature of 60±10°C, ensuring uniform drying, until loss on drying (%LOD) was obtained. The percent loss on drying (%LOD) of the granules was determined at 105°C in auto mode in moisture analyzer, and drying was continued until %LOD reached within the limit, in the range of 1.5 to 3.0%. viii. Sizing: The dried granules obtained in step vii. were sifted through a 20# sieve using Vibratory sifter to get uniform sized granules. ix. 20# retained granules of step viii. were sifted through 14#. 14# retained and 14# passed granules were collected separately. x. The 14# retained granules obtained in step ix. were milled through 2.0mm SS screen using co-mill at 700 RPM. The milled granules were passed through 20# sieve using vibro sifter. xi. Both the oversized granules obtained in step x. and 14# passed 20# retained fraction of step ix. were milled through 1.0mm SS screen using co-mill at 700 RPM. The milled granules were passed through 20# sieve using vibro sifter. xii. All the granules were finally sifted through 20# SS sieve using vibratory sifter. xiii. Blending & Lubrication in pillar type bin blender: Extragranular cellulose microcrystalline and crospovidone was sifted through 40# sieve using vibratory sifter. Subsequently, this was blended with the sifted granules for 10 minutes. Separately, silica colloidal anhydrous and magnesium stearate was sifted through 30# sieve using vibratory sifter. The mixture was added, and lubrication performed for 3 minutes. xiv. Compression in rotary press tablet compression machine. Tablets with average weight of 650 mg were produced, having a disintegration time of not more than 15 minutes. xv. Coating dispersion preparation in stirrer: Opadry 03B57695 Grey was dispersed in to weighed quantity of purified water to prepare a 10% w/w dispersion under stirring. xvi. Coating in autocoater: The compressed core tablets were sprayed with the film coating dispersion. The curing was at 45°C inlet temperature. xvii. Packaging in blister packing machine.

Tablets Al, A2, A3 and A4 are all suitable for oral administration as well as dispersion in water before being administered via a feeding tube. The tablets differed in terms of time necessary for dispersion and storage stability. Preliminary experiments indicate the amount of coating provides a trade-off between storage stability and dispersion time. More coating tend to provide improved storage time but also increased time for disintegration or dispersion.

Example B

Nimorazole Coated Tablets Comprising Crospovidone - General Recipe

Dry mix containing Nimorazole, cellulose microcrystalline, crospovidone, granulated using granulating fluid, dried and sized. Granules further blended and lubricated with extragranular material and compressed in to tablets. Core tablets further film coated. Tablets deliver 500 mg of Nimorazole. 18 PCT/DK2013/050384

Sr. No. Name of Ingredient Category Qty. Per Tablet [range] Qty. Per Tablet (mg) [Actual] Intragranu ar 01. Nimorazole Active ingredient 500.000 mg 500.000 02. Cellulose microcrystalline (Avicel PH 101) Diluent 1-50% 50.000 (7.69%) 03. Crospovidone (Kollidon CL) Disintegrant 0.5 -15% 14.000 (2.154%) 04 Povidone K30 Binder 0.5 -15 % 28.00 (4.30 %) 05 Purified Water Q.S. Q.S. Extragranular 06. Cellulose microcrystalline (Avicel 102) Diluent 0.5 - 50% 9.000 (1.385%) 07. Crospovidone (Kollidon CL) Disintegrant 0.5 -15% 35.000 (5.385 %) 08 Silica Colloidal anhydrous ( Cab- o -Sil) Glidant 0.5 - 3 % 7.000 (1.07%) 09 Magnesium Stearate (VG) Lubricant 0.5 - 3 % 7.000 (1.07%) Coating 10. Opadry 03B57695 Grey Coating 0.5 - 5 % 13.00 (2.0%) WO 2014/075692

Example C

Nimorazole Tablets Comprising Sodium Starch Glycolate - General Recipe

Dry mix containing Nimorazole, cellulose microcrystalline, Sodium starch glycolate, granulated 5 using granulating fluid, dried and sized. Granules further blended and lubricated with extragranular material and compressed in to tablets. Tablets deliver 500 mg of Nimorazole.

These tablets have no coating. The absence of a coating means that in general patients dislike swallowing the tablets due to the unpleasant taste of the active ingredient.

Sr. No. Name of Ingredient Qty. Per Tablet [range] Qty. Per Tablet (mg) [Actual] Intragranu ar 01. Nimorazole 500.000 mg 500.000 02. Cellulose microcrystalline (Avicel PH 101) 1 - 50 % 50.000 (7.69%) 03. Sodium starch glycolate 0.5 -15% 14.000(2.154%) 19 PCT/DK2013/050384 04 Povidone K30 0.5-15 % 28.00 (4.30 %) 05 Purified Water as. as. Extragranular 06. Cellulose microcrystalline (Avicel 102) 0.5 - 50% 9.000 (1.385%) 07. Sodium starch glycolate 0.5 -15% 35.000 (5.385 %) 08 Silica Colloidal anhydrous ( Cab- o -Sil) 0.5 - 3 % 7.000 (1.07%) 09 Magnesium Stearate (VG) 0.5 - 3 % 7.000 (1.07%) WO 2014/075692

Example D

Nimorazole Oral Powder

Dry mix of Nimorazole, Citric acid Anhydrous, Aspartame, Mannitol and Sucrose granulated using 5 granulating fluid to prepare granules. Granules dried and sized and blended with flavor. Blend packed in single unit dosage form i.e. sachet. When one sachet is dispersed in 250 ml water yields a dispersion which delivers 500 mg of Nimorazole.

This oral powder is less suited for direct oral administration without being dispersed in water.

Sr. No. Name of Ingredient Qty. Per Sachet {range) Qty. Per Sachet(mg) (Actual) Intragranu ar 01. Nimorazole 500.00 mg 500.00 02. Citric acid Anhydrous 0.5 -15 % 40.00 (3.13%) 03. Aspartame 0.5-25% 250.00 (19.6 %) 04 Mannitol 0.5 - 50% 185.00(14.51%) 05 Sucrose 0.5-50 % 100.00 (7.84%) 06. Purified Water as. Q.S. Extragranular 07. Flavor 0.5 - 50% 40 (3.17%) 08 NAT FL Modulator (Sweet) FMTTM P 0.5 - 50% 160 (12.5%)

10 Example E

Nimorazole oral granules

Nimorazole, Cellulose Microcrystalline, Silica Colloidal Anhydrous, Maize Starch, Hydroxypropylcellulose, Povidone granulated by spraying granulating fluid by using Top spray 20 PCT/DK2013/050384 WO 2014/075692 assembly. Granules further coated with basic butylated methacrylate copolymer hydro-alcoholic solution. Quantity equivalent to unit dose packed in sachet dispersed in 250 ml of water delivers 500 mg.

These granules have a tendency to clog a feeding tube, when the granules are allowed to 5 disintegrate or disperse in water.

Sr. No. Name of Ingredient Qty. Per Dose (range) Qty. Per Dose (mg) (Actual) Core granules 01. Nimorazole 500 mg 500 mg 02. Cellulose Microcrystalline (Avicel 101) 0.5 - 50% 140* (19.8%) 03. Silica Colloidal Anhydrous 0.5 - 3% 5.00* (0.7%) 04 Maize Starch 0.5 -15% 22.00*(3.11) 05 Hydroxypropylcellulose (HPC-L) 0.5 -15% 7.50*(1.06%) 06. Povidone (Dry Mixing) 0.5 -15% 5.00*(0.7%) 07. Povidone (Binding) 0.5 -15% 20.00*(2.82%) 08. Purified Water q.s. q.s. Extragranular 09. Talc 0.25 - 3% 5.25 (0.74%) 10. Silica Colloidal Anhydrous 0.15-3% 1.75 (0.25%) Coated Granules Coating Dispersion Ingredient 11. Basic Butylated Methacrylate Copolymer 0.5 -10% 26.25(3.71%) 12. Macrogol 6000 2 - 30% 2.625 ®(10.0%) 13. Talc 5 - 50% 13.125® (50%) 14. Silica Colloidal Anhydrous 0.5 - 3% 0.058® (0.22%) 15. Isopropyl Alcohol q.s q.s 16. Purified Water q.s q.s Total weight Lubrication of coated Granules 17. Talc 0.05 - 3% 0.800 18. Silica Colloidal Anhydrous 0.02 - 3% 0.354 * Quantity expressed as % w/w of core granules ® Quantity expressed as % w/w of Polymer weight

Disintegration and Solubility 10 Experiments indicate the solubility of Nimorazole in water is 4.91 mg/ml. 21 PCT/DK2013/050384 WO 2014/075692

Tablet Al

Tablets Al had a thickness of 5.61 to 5.65 mm. The disintegration time was measured to 2 - 3 min. Tablet A2

Tablets A2 had a thickness of 5.65 to 5.68 mm. The disintegration time was measured to 18 5 seconds.

Dissolution

The % Cumulative Drug Release was measured in 900 ml 0.1 N HCI in a USP type II apparatus at 50 RPM for 30 minutes, with measurements performed at 5,10, 20, and 30 minutes. 500 mg Nimorazole tablets % Cumulative Drug Release 5 min. 10 min. 20 min. 30 min. Tablet Al 74 94 96 100 Tablet A2 86 94 96 98 The use of Crospovidone as a disintegrant instead of Sodium Starch Glycolate c ecreased the 10 disintegration time, and provided a significant increase in dissolution rate, wherein more than 85% of the drug was released within 5 minutes.

Tablet A4

Preliminary experiments indicate Tablet A4 disintegrates in less than 3 minutes. About 85% of the active ingredient, Nimorazole, dissolves before 10 minutes, and the active ingredient is almost 15 completely dissolved before 30 minutes.

Comparison with prior art tablets

Dispersibility

The tablet A1 (500 mg) of the present invention was compared with the tablet F4 (200 mg) of the prior art (this tablet is described in the article "Formulation and In-Vitro Characterization of 20 Nimorazole Mouth Dissolving Tablets", Ratnaparkhi, Mukesh R et al., Research Journal of Pharmaceutical, Biological and Chemical Sciences (2012), Vol. 3, Issue 3, pp. 303-308.

Dispersibility tests were performed using water at room temperature. In order to compare mixtures comprising the same concentration of the active ingredient Nimorazole, a tablet Al (500 mg) was dispersed in 50 ml water in a glass beaker, while a tablet F4 (200 mg) was dispersed in 20 25 ml water glass beaker. Stirring was continued for 3 min.

After stirring, a homogenous dispersion was formed from the tablet Al without precipitate (Fig. 1, right), while a phase separation was apparent in the dispersion formed from the tablet F4, having a clear solvent phase above a precipitate clearly visible at the bottom of the beaker (Fig. 1, left). 22 PCT/DK2013/050384 WO 2014/075692

Upon emptying the beakers, the beaker used for the tablet A1 was left with negligible amounts of residue (Fig. 2, right), while the beaker used for the tablet F4 still comprised remains from the precipitate (Fig. 2, left).

It was thus shown that the tablet A1 of the present invention upon stirring in water provided a 5 dispersion, while the prior art tablet F4 did not provide a dispersion upon stirring in water.

Sieve Testing

Tablets of the invention, A1 (500 mg), were compared with prior art tablets, F4 (200 mg, Ibid.). Mixtures of water at room temperature and tablets were prepared as noted in the tablet below.

Mixture Tablet Number of tablets Total amount of Nimorazole / mg Amount of water / ml 1 A1 2 1000 100 II F4 5 1000 100 III F4 2 400 100

Mixture I provided a stable, homogenous dispersion, having a milky appearance (Fig. 3, right). The 10 dispersion of Mixture I showed long term stability. Mixture II (Fig. 3, left) and Mixture III both provided non-homogenous mixtures, with a clear phase separation between solvent and precipitate.

The mixtures were poured through sieve screens #20, #30, and #40, having apertures of 900 pm, 600 pm and 400 pm, respectively. Mixture I passed through all 3 sieve screens without leaving 15 any trace of precipitate in any of the sieve screens (Fig. 4, from left to right: sieve #20, #30, #40). Upon pouring Mixture II and III through the 3 sieve screens, in both cases particles remained in all 3 sieve screens (Fig. 5 and 6, respectively; from left to right: sieve #20, #30, #40).

It was thus confirmed that Mixture I was a smooth dispersion, while Mixture II and Mixture III were not. 20 Further, it was noted that for Mixture I negligible amounts of material was left behind in the bottle used for mixing, while for Mixture II and III clearly visible lumps of the tablets were left behind. This indicates that for Mixture II and Mixture III not all of the active ingredient would be present in the mixture poured from the bottle. Further, that the use of Mixture II and III would increase the risk of blocking a feeding tube, and that the release of active ingredient from the 25 Mixtures II and III would be slower than for Mixture I, due to the larger particle sizes resulting from making mixtures of the prior art tablet.

In vitro Dissolution

The prior art tablet F4 (Ibid.) exhibits slower dissolution rate expressed in percentage at all measured points in time than the tablets A1 and A2 (see above) of the present invention. It is 23 PCT/DK2013/050384 WO 2014/075692 additionally surprisingly, since the prior art tablets F4 comprise 200 mg active ingredient, while the present tablets, A1 and A2, comprise 500 mg active ingredient. This should favor the % cumulative drug release of the tablets F4 as the actual concentration of the active ingredient Nimorazole is lower in the USP apparatus for the 200 mg tablets. 5 Thus, it is an advantage of the present tablet that higher dissolution rates are achieved in vitro, making it easier to achieve peak serum level of the active ingredient at a specific time, coinciding with irradiation treatment, and further increasing the serum peak level of the active ingredient.

Patient Compliance - Test of taste masking properties of Coating

The tablet A1 (500 mg) of the present invention was compared with the tablet F4 (200 mg) of the 10 prior art (described in the article "Formulation and In-Vitro Characterization of Nimorazole Mouth Dissolving Tablets", Ratnaparkhi, Mukesh R et al., Research Journal of Pharmaceutical, Biological and Chemical Sciences (2012), Vol. 3, Issue 3, pp. 303-308.

Two informed test persons (healthy volunteers) were requested to place individual tablets on the forefront of the tongue for 30 seconds by pressing the tongue with the tablet up against the 15 palate. After 30 seconds, the taste sensation is graduated on a scale from one to ten in terms of bitterness / taste sensation.

The following scale was used:

No 1 2 3 4 5 6 7 8 9 10 Taste Neutral taste Slightly unpleasant taste Very unpleasant taste Extremely unpleasant taste

In addition, a subjective description is given to whether the taste is deemed to have an adverse 20 effect in terms of compliance to treatment considering that the treatment will involve 3 -4 tablets a day over an average of 30 days.

The results are provided in the table below.

Reported taste and sensations Results tablet Al Results tablet F4 Test Person 1 1: No taste 8-9: Very or extremely unpleasant taste Very unpleasant, metallic taste after spitting the tablet out. This sensation remained a very long time after spitting the tablet out. 24 PCT/DK2013/050384 WO 2014/075692 25

Test Person 2 1: No taste during the 30 seconds. 7: Very unpleasant taste 2: Slight taste upon spitting out the Would not be able to keep this tablet in tablet. the mouth until dissolved due to very unpleasant metallic taste.

It was noted that the mouth dissolving tablet F4 would be unsuitable for patients having no saliva. Further, due to the very unpleasant taste, this tablet would not be suitable for combination with irradiation treatment, due to the large amounts of active ingredient and thus tablets required.

The suggested mode of administration of F4 (i.e. mouth dissolving) is hence not suitable for 5 treatments of patients.

Claims (46)

1. Solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: A disintegrant; Optionally one or more additional excipients; and A coating; Said pharmaceutical composition allowing administration via at least two different routes: i) oral administration, or ii) disintegration in water or an aqueous medium to provide a dispersion, and subsequent administration of said dispersion via a tube.

2. Solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: Diluent; Disintegrant; Binder; Glidant; Lubricant; and Optionally one or more additional excipients; and a Coating.

3. Solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: Diluent, 1 - 50 %; Disintegrant, 0.5 -15%; Binder, 0.5 -15 %; Glidant, 0.5 - 3 %; Lubricant, 0.5 - 3 %; and Optionally one or more additional excipients; and a Coating, 0.5 - 5 %.

4. Solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a. An Intragranular part, comprising: Diluent; Disintegrant; and Binder; and b. An Extragranular part, comprising: Diluent; Disintegrant; Glidant; and Lubricant; and c. A Coating.

5. Solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, and further comprising: a. An Intragranular part, comprising: Diluent, 1 - 50 %; Disintegrant, 0.5 -15%; and Binder, 0.5 -15 %; and b. An Extragranular part, comprising: Diluent, 0.5 - 50%; Disintegrant, 0.5 -15%; Glidant, 0.5 - 3 %; and Lubricant, 0.5 - 3 %; and c. A Coating, 0.5 - 5 %.

6. A solid pharmaceutical composition comprising Nimorazole or a pharmaceutically acceptable salt thereof, when used as a treatment comprising disintegration of said pharmaceutical composition in water or an aqueous medium and administration via a tube.

7. The pharmaceutical composition according to any one of the preceding claims, when administered to a patient with swallowing difficulties.

8. The pharmaceutical composition according to any one of the preceding claims, when administered to a patient with insufficient or no saliva.

9. The pharmaceutical composition according to any one of the preceding claims, which is a tablet.

10. The pharmaceutical composition according to any one of the preceding claims, which is an immediate release tablet.

11. The pharmaceutical composition according to any one of the preceding claims, for disintegration in water within 15 minutes to produce a dispersion, for administration to a patient via a tube.

12. The pharmaceutical composition according to claim 11, wherein said dispersion passes through a sieve screen with a nominal mesh aperture of 710 pm.

13. The pharmaceutical composition according to any one of the preceding claims, which disintegrate within 10 minutes in water at 20°C.

14. The pharmaceutical composition according to any one of the preceding claims which is a dispersible tablet.

15. The pharmaceutical composition according to any one of the preceding claims, which allows dispersion of one or more of said pharmaceutical compositions comprising a total of at least 1000 mg Nimorazole in 100 ml water at 25°C within 5 minutes upon stirring, thereby providing a dispersion; said dispersion passing through a sieve screen with a nominal mesh aperture of 710 pm.

16. The pharmaceutical composition according to any one of the preceding claims, when administered via a feeding tube.

17. The pharmaceutical composition according to any one of the preceding claims, when administered via a feeding tube selected among the group consisting of a percutaneous endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric feeding tube, and a jejunostomy feeding tube.

18. The pharmaceutical composition according to any one of the preceding claims, when used for the treatment of patients undergoing irradiation treatment.

19. The pharmaceutical composition according to any one of the preceding claims, when used for the treatment of intubated patients.

20. The pharmaceutical composition according to any one of the preceding claims, when used for swallowing or for disintegration in water or an aqueous medium and administration via a tube.

21. The pharmaceutical composition according to any one of the preceding claims, further comprising a coating facilitating swallowing and masking the taste of Nimorazole.

22. The pharmaceutical composition according to any one of the preceding claims, when used for the curative treatment or reirradiation of cancer.

23. The pharmaceutical composition according to any one of the preceding claims, when used for 1st line irradiation treatment of cancer with curative intent or 2nd line reirradiation treatment of cancer with curative and/or palliation intent.

24. The pharmaceutical composition according to any one of the preceding claims, when used for the treatment of patients with hypoxic cancer.

25. The pharmaceutical composition according to any one of the preceding claims, when used for the treatment of an indication selected among breast cancer, head/neck cancer, esophagus cancer, lymphoma, cervical cancer, colorectal cancer, brain cancer, lung cancer, bladder cancer, and prostate cancer.

26. The pharmaceutical composition according to any one of the preceding claims, when used for the treatment of cancer selected from the group comprising head/neck cancer, cervical cancer and inoperable lung cancer.

27. The pharmaceutical composition according to any one of the preceding claims, comprising at least 250 mg Nimorazole or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition according to any one of the preceding claims, comprising 100 - 2000 mg, Nimorazole or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to any one of the preceding claims, subject to the proviso that at least 4 of said pharmaceutical compositions may be dispersed in 2 dl water at 25°C within 5 minutes.

30. The pharmaceutical composition according to any one of the preceding claims, allowing dispersion of 2000 mg Nimorazole or a pharmaceutically acceptable salt thereof in 2 dl water at 25°C within 5 minutes.

31. The pharmaceutical composition according to any one of the preceding claims, allowing dispersion of 2000 mg Nimorazole in 2 dl water at 25°C within 3 minutes.

32. The pharmaceutical composition according to any one of the preceding claims, when used for treatment combined with chemotherapy.

33. Dispersible tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof, said tablet comprising a taste masking coating.

34. Dispersible tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof, said tablet allowing administration via a feeding tube after dispersion, and said tablet comprising a coating allowing oral administration.

35. Tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof, said tablet disintegrating within 3 min in 50 ml water upon stirring, using water at 15 - 25°C, producing a homogeneous dispersion, which passes through a sieve screen with a nominal mesh aperture of 710 pm, said tablet further comprising a taste masking coating.

36. A method of manufacturing a pharmaceutical composition or tablet according to any of claims 1 - 35, comprising wet granulation of a composition comprising Nimorazole.

37. The method of manufacturing a pharmaceutical composition or tablet according to claim 36, wherein said wet granulation step is performed using a Rapid Mixer Granulator, or alternatively using a device selected among the group consisting of a Super Mixer Granulator, Oscillating Granulator, Inline homegenizer, Caleva Mini Mixer, and High Shear Mixers.

38. The method of manufacturing a pharmaceutical composition or tablet according to claim 36 or claim 37, wherein said wet granulation step is preceded by dry mixing in a granulator or alternatively, said dry mixing may be performed using a device selected among the group consisting of a Conta blender, Octagonal blender, Double cone blender, Conical blender, and a Multi Mill.

39. The method of manufacturing a pharmaceutical composition or tablet according to any one of claims 36 - 38, wherein the wet granular mass resulting from said wet granulation is dried until a pre-determined loss on drying (%LOD) is obtained.

40. The method of manufacturing a pharmaceutical composition or tablet according to any one of claims 36 - 39, wherein the wet granular mass resulting from said wet granulation is dried until said %LOD is in the range of 0 to 10%.

41. The method of manufacturing a pharmaceutical composition or tablet according to any one of claims 36 - 40, wherein all granules are sifted through a no. 20 (20#) sieve or finer prior to compression.

42. The method of manufacturing a pharmaceutical composition or tablet according to any one of claims 36 - 41, wherein all extragranular ingredients are sifted through a 20# sieve or finer prior to compression.

43. A method of treatment of cancer, wherein irradiation treatment is combined with the administration of at least one pharmaceutical composition or tablet according to any one of claims 1 - 35, wherein said at least one pharmaceutical composition or tablet is allowed to disintegrate or is dispersed in water or an aqueous medium and administered via a tube.

44. A method of radiosensitizing hypoxic tumor cells comprising administering Nimorazole, wherein the administration comprises: Providing a solid pharmaceutical composition or tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof; Dispersing said solid pharmaceutical composition or tablet in water or an aqueous medium to obtain a dispersion; and Administering said dispersion via a tube.

45. A method according to claim 43 or claim 44, comprising administering said pharmaceutical composition or tablet 30 - 60 minutes before irradiation treatment.

46. Use of a pharmaceutical composition or tablet according to any one of claims 1 - 35, wherein said pharmaceutical composition or tablet is dispersed in water or another aqueous medium and administered via a tube.