JP2015537013A - Fast-disintegrating tablets - Google Patents

Abstract

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

Description

  The present invention relates to a pharmaceutical composition comprising nimorazole and disintegrating in water. In particular, the present invention relates to a pharmaceutical composition, such as a tablet, comprising nimorazole or a pharmaceutically acceptable salt thereof, dispersed in water and administered via a tube to a patient with dysphagia.

  Patent US 4371540 describes the use of radiosensitizers for hypoxic cells. Administration is suggested to be carried out via the intravenous route or orally using a prodrug, which is the acetate ester of the compound.

  Patent US4462992 suggests parenteral, subcutaneous, intravenous, intramuscular or intraperitoneal or oral administration.

  Patent application US2010 / 322939 describes the oral administration of Nimorazole which precedes radiotherapy for 90 minutes.

  Bowman, Corinne ("Administration of drugs to patents with swallowing difficities", Journal of the Malta Collision, Ref. Rely on enteral feeding tubes for both nutritional requirements and drug administration. Information on this mode of administration is very limited and is also associated with increased risk of tube obstruction, increased toxicity, and decreased efficacy due to inappropriate methods of administration. Bowmann says, “Unfortunately, tablet grinding has been mistakenly taken for granted by some medical professionals without considering that it can affect the properties of drug therapy.” “The crushed tablets are the most frequent cause of blockage of the supply tube, and blockage of the supply tube results in increased morbidity and trauma to the patient in addition to the cost of tube replacement. May require manual intervention. "

U.S. Pat. No. 4,371,540 U.S. Pat. No. 4,426,992 US Patent Application Publication No. 2010/322939

Bowman, Corinne "Administration of drugs to patients with swallowing differences", Journal of the Malta Collage of Pharmacology, 42-45 Winter 2007.

(Summary of the Invention)
Nimorazole is particularly used to improve the effectiveness of radiation therapy for cancer patients.

  Patients such as cancer patients may suffer from dysphagia. In particular, cancer patients who received radiation therapy and simultaneous nimorazole treatment in the head and neck areas may have dysphagia with nimorazole tablets and therefore need to be administered via another route There is. The amount of nimorazole required for effective treatment, for example about 2 g for each treatment, exacerbates this problem as it means the use of large tablets or multiple tablets.

  Nimorazole is sparingly soluble in water (The Merck Index, 14th edition). Experiments have shown that the solubility in water is about 5 mg / ml. Furthermore, in order to achieve a reasonable dissolution rate, it is usually necessary to apply an excess amount of liquid to obtain sink conditions. Preparing a bulk solution of Nimorazole for further distribution creates additional problems in terms of storage stability and difficulties in distributing large containers containing liquids.

  There is a need to provide a liquid medium containing an amount of Nimorazole that exceeds the solubility limit of Nimorazole in water in order to allow administration of an effective amount of Nimorazole through a supply tube while avoiding ingestion of an excessive amount of liquid medium. Exists. There is a need to be 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 that can pass through the supply tube without causing occlusion.

  Attempts were made to provide granules containing nimorazole, which granules were dispersed in water, administered via a feeding tube and formulated with the intention to dissolve quickly at low pH in the stomach. However, this granule suffered from the disadvantage that the granule was not well dispersed in water at neutral pH and therefore caused blockage in the supply tube. The development of granules containing nimorazole was subsequently discontinued.

  Attempts were made to provide a powder containing nimorazole, which was formulated to disperse quickly in water at neutral pH. Up to 5 bags of powder had to be opened and carefully emptied into water to ensure that all powder in each sachet was completely empty. This powder did not occlude the supply tube, but was regarded as a very cumbersome procedure that could affect patient compliance with treatment. The development of powders containing Nimorazole was subsequently discontinued. Furthermore, this powder was not well suited for oral administration unless it was dispersed in water.

  In accordance with aspects and embodiments of the present invention, the above problems are addressed by the present invention.

  Surprisingly, it is possible to provide a liquid medium containing an amount of Nimorazole that exceeds the solubility limit of Nimorazole in water, which allows the administration of an effective amount of Nimorazole via a supply tube to an excess amount of the liquid medium. Made possible while avoiding ingestion. Furthermore, it was possible to provide a liquid medium comprising nimorazole within a short time frame. In addition, it was possible to provide a liquid medium comprising nimorazole that could pass through the supply tube without causing occlusion.

  According to one aspect, the present invention relates to a pharmaceutical composition for disintegration in water or an aqueous medium and administration via a tube comprising nimorazole or a pharmaceutically acceptable salt thereof.

  The supply tube can be used appropriately. In particular, the present invention relates to a pharmaceutical composition that can be administered to a patient with dysphagia using a delivery tube.

  The pharmaceutical formulation or tablet according to the present invention preferably disintegrates upon contact with water to form a dispersion. The formation of the dispersion can be aided by stirring in water or shaking the container containing the tablets and water.

According to another aspect, the present invention relates to a 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 comprising , At least two different pathways:
i) oral administration, or ii) administration through a tube of said dispersion after it has been formed by disintegration in water or an aqueous medium,
It can be administered via.

  Surprisingly, it was possible to devise pharmaceutical formulations or tablets that could be used directly for oral administration or dispersible in water in a short time frame for administration via a supply tube. The pharmaceutical formulation or tablet can be dispersed in a small amount of water. The dispersed particles are small enough to provide a slow settling rate and can be administered in a dispersed state, for example, from a bottle via a supply tube.

  Pharmaceutical formulations in the form of tablets are easy to handle and the dosage can be easily measured and then checked. Using powder from individual sachets complicates the administration of several sachets. Furthermore, the use of powders complicates the dosage check after the intended dosage measurement, while a small number of tablets are easily counted for dosage verification. Finally, tablets have a smaller surface area than powders and may therefore increase the storage stability of the product.

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

  According to one aspect, the present invention relates to a method for producing a pharmaceutical formulation or tablet according to the present invention comprising wet granulation of nimorazole.

  For further information on wet granulation, see, for example, International Journal of Pharmaceutical Frontier Research, April-June 2011; 1 (1): 65-83, “Pharmaceutical Processing-A Review on Wet Tran G “Wet Granulation: End-Point Determination and Scale-Up”, Michael Levin, Ph .; D. Metropolitan Computing Corporation, East Hanover, New Jersey, USA; and Parikh D. et al. “Handbook of Pharmaceutical Granulation Technology”, Marcel Dekker, Inc. New York, 1997, and other references can be found.

  According to one aspect, the present invention combines radiation therapy and administration of at least one pharmaceutical formulation or tablet according to the present invention, said at least one pharmaceutical formulation or tablet being disintegrated in water or an aqueous medium and The present invention relates to a method for treating cancer that can be administered via a tube. This is particularly relevant when the patient has problems or results in swallowing, for example due to cancer in the head and neck regions.

  This method is particularly preferred for patients with dysphagia who have been treated with Nimorazole.

  According to one aspect, the present invention includes the step of administering nimorazole, wherein the administration provides a solid pharmaceutical composition comprising nimorazole or a pharmaceutically acceptable salt thereof, said solid pharmaceutical composition in water or an aqueous medium. Dispersing to obtain a dispersion and administering the dispersion via a tube to a method of making hypoxic tumor cells radiosensitive.

  According to one aspect, the invention relates to the use of a tablet according to the invention, said tablet being dispersed in water and administered via a tube.

  In accordance with one aspect, the present invention includes nimorazole or a pharmaceutically acceptable salt thereof, wherein at least a portion of said nimorazole or pharmaceutically acceptable salt thereof is dispersed in an aqueous medium in the form of solid particles. Related to things.

After stirring, a uniform dispersion without precipitation was formed from tablet A1 (right), while in the dispersion formed from tablet F4, phase separation was evident and a clear solvent phase was evident at the bottom of the beaker Present on the visible precipitate (left). When the beaker is emptied, a negligible amount of residue remains in the beaker used for tablet A1 (right), while the beaker used for tablet F4 still contains debris from precipitation. (left). Mixture I produced a stable, uniform dispersion with a milky appearance (right). The dispersion of mixture I showed long-term stability. Both Mixture II (left) and Mixture III provided a non-homogenous mixture with a clear phase separation between the solvent and the precipitate. The mixture was poured into sieve screens # 20, # 30 and # 40 having openings of 900 μm, 600 μm and 400 μm, respectively. Mixture I passed through all three sieve screens, leaving no traces of precipitate on any of the sieve screens (screens # 20, # 30, # 40 from left to right). When Mixtures II and III were poured into the three sieve screens, in both cases, the particles remained on all three sieve screens (screens # 20, # 30, # 40, respectively, from left to right). When Mixtures II and III were poured into the three sieve screens, in both cases, the particles remained on all three sieve screens (screens # 20, # 30, # 40, respectively, from left to right).

  According to one embodiment, the present invention relates to a pharmaceutical composition for disintegration in water or an aqueous medium and administration via a tube comprising nimorazole or a pharmaceutically acceptable salt thereof. The supply tube can be used appropriately.

  The expression “water or aqueous medium” means water or water containing one or more salts, eg saline and / or any (other) ingredient for the patient, eg water containing at least one active ingredient. Includes the possibility of using. This expression also encompasses the possibility of water containing one or more nutrients, optionally one or more active ingredients.

  The pharmaceutical composition or tablet according to the present invention preferably disintegrates upon contact with water to form a dispersion. The formation of the dispersion can be aided by stirring in water or shaking a container containing at least one tablet and water.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for administration to a patient with dysphagia. According to a preferred embodiment, the present invention relates to a pharmaceutical composition or tablet for administration to a patient with little, insufficient or no saliva, for example a patient with abnormal salivary function.

  According to one embodiment, the present invention relates to 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, The pharmaceutical composition can be administered via at least two different routes: oral administration, or administration through a tube of the dispersion followed by formation of the dispersion with water or an aqueous medium.

  The solid pharmaceutical composition is preferably a tablet.

  The pharmaceutical composition is preferably provided in a solid form that is stable over time. Preferably, the pharmaceutical composition is stable for 6 months, preferably 12 months, more preferably 18 months, preferably 24 months, more preferably 30 months, preferably 36 months, or even longer. Preferably, the pharmaceutical composition retains its dispersibility during storage, ie 6 months, preferably 12 months, more preferably 18 months, preferably 24 months, more preferably 30 months, preferably 36 months or even longer. Hold for the preservation of.

  The disintegrant makes it possible to produce a dispersion at short time intervals. Preferably, the solid pharmaceutical composition makes it possible to provide a dispersion comprising an amount of nimorazole or a pharmaceutically acceptable salt thereof that exceeds the solubility limit of nimorazole in water or an aqueous medium. Preferably, the solid pharmaceutical composition makes it possible to provide a dispersion comprising nimorazole or a pharmaceutically acceptable salt thereof in an amount of more than 5 mg / water or 1 ml of aqueous medium.

  The coating serves as a flavor masking because nimorazole has an unpleasant flavor. Unpleasant flavors can reduce patient compliance. Furthermore, the coating can improve the storage stability of the pharmaceutical formulation.

  Having a pharmaceutical composition capable of two different routes of administration carries many advantages. First, patient compliance is improved if the patient has a need to change the route of administration, since the patient already uses the pharmaceutical composition. Secondly, the cost associated with obtaining production and marketing approvals is low because only the single product needs production and approval.

  Preferably, the dispersion of the solid pharmaceutical composition can be performed by the patient. More preferably, the administration of the dispersion can be performed by the patient. This allows for outpatient use or morphological use.

  Excipients are generally pharmacologically inert substances. Examples include, but are not limited to, diluents, disintegrants, binders, lubricants, lubricants, and coatings. Other examples of suitable excipients can be found in Handbook of Pharmaceutical Excipients, 7th Edition, Rowe, Raymond C, et al., Pharmaceutical Press, London.

  Diluents are inert ingredients that are added to tablets and capsules in addition to the active agent. Some very common diluents for tablets include starch, cellulose derivatives and magnesium stearate (which is also a lubricant). Diluents increase the size of tablets or capsules, making production practical and convenient for consumer use. By increasing the bulk volume, the diluent can be brought to a volume that the patient can properly handle the final product. A good diluent must be inert, compatible with the other ingredients of the formulation, non-hygroscopic, relatively inexpensive, compressible, and preferably tasteless or pleasant. Vegetable cellulose (pure vegetable diluent) is a common diluent for tablets or hard gelatin capsules. Dicalcium phosphate is another common tablet diluent. A variety of vegetable oils can be used in soft gelatin capsules. Other examples of diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate.

  The disintegrant expands and dissolves when wet, and the tablet collapses and falls apart. The disintegrant ensures that when the tablet comes into contact with water, it quickly breaks into fine pieces and facilitates dissolution or dispersion. Examples of disintegrants include, but are not limited to, crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone) and crosslinked sodium carboxymethylcellulose (croscarmellose sodium) and modified starch sodium starch glycolate. Specific examples further include Indion 414, L-HPC and pregelatinized starch.

  The binder holds the raw materials together in the tablet. The binder can form tablets and granules with the required mechanical strength to ensure that the tablet has a volume. Examples of binders include saccharides and their derivatives: disaccharides, sucrose, lactose; polysaccharides and their derivatives, eg processed cellulose such as starch, cellulose and microcrystalline cellulose and cellulose such as hydroxypropylcellulose (HPC) Ethers; sugar alcohols such as xylitol, sorbitol or maltitol; further proteins: gelatin; and synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). Examples include gelatin, cellulose, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose and polyethylene glycol. Other examples include cellulose, methylcellulose, polyvinyl pyrrolidone and polyethylene glycol.

  Lubricants are used to promote powder flow by reducing friction and agglomeration between particles. These are used in combination with lubricants because they do not have the ability to reduce mold wall friction. Examples include fumed silica, talc and magnesium carbonate.

  Lubricants are drugs that are added to tablet and capsule formulations to improve certain processing characteristics. Lubricants prevent, inter alia, raw materials from agglomerating and sticking to tablet punches and capsule filling machines. Lubricants can also ensure tablet formation and release with low friction between the solid and the mold wall. Common minerals such as talc or silica and lipids such as vegetable stearin, magnesium stearate or stearic acid are examples of lubricants used in tablets or hard gelatin capsules.

  The coating protects the raw material from degradation due to moisture in the air and makes it easier to swallow large or unpleasant flavored tablets. For most coated tablets, a film coating of the cellulose ether hydroxypropylmethylcellulose (HPMC), which does not contain the potential of sugars and allergens, is used. Sometimes other coating materials are used, such as synthetic polymers, shellac, corn protein zein or other polysaccharides. A specific example is Opadry. Capsules are coated with gelatin.

  According to one embodiment, the present invention comprises nimorazole or a pharmaceutically acceptable salt thereof, further comprising a diluent, disintegrant, binder, lubricant, lubricant and optionally one or more additional excipients and coatings. It relates to a solid pharmaceutical composition comprising.

  According to one embodiment, the present invention comprises nimorazole or a pharmaceutically acceptable salt thereof, 1-50% diluent, 0.5-15% disintegrant, 0.5-15% binder, lubricant A solid pharmaceutical composition comprising 0.5-3% of a lubricant, 0.5-3% of a lubricant and optionally further 0.5-5% of one or more additional excipients and a coating.

  According to one embodiment, the present invention comprises nimorazole or a pharmaceutically acceptable salt thereof with 2-25% diluent, preferably 4-15%, more preferably 6-10%, preferably 7-9%. 1-12%, preferably 3-10%, more preferably 5-9%, preferably 7-8%, disintegrant 1-10%, preferably 2-8%, more preferably 3 −6%, preferably 4-5%, lubricants 0.6-2.5%, preferably 0.8-2%, more preferably 0.9-1.8%, preferably 1-1.5 %, 0.6-2.5% lubricant, preferably 0.8-2%, more preferably 0.9-1.8%, preferably 1-1.5%, and optionally one These additional excipients, as well as the coating, are 0.7-4%, preferably 1-3%, more preferably 1 5-2.5%, preferably relates to a solid pharmaceutical composition comprising further 2-2.2%.

According to one embodiment, the present invention includes nimorazole or a pharmaceutically acceptable salt thereof,
a) an intragranular part comprising a diluent, a disintegrant and a binder, and b) an extragranular part comprising a diluent, a disintegrant, a lubricant and a lubricant, and c) a coating,
A solid pharmaceutical composition further comprising:

According to one embodiment, the present invention includes nimorazole or a pharmaceutically acceptable salt thereof,
a) Intragranular part containing 1-50% diluent, 0.5-15% disintegrant and 0.5-15% binder, and b) 0.5-50% diluent, disintegrant An extragranular portion containing 0.5-15%, a lubricant 0.5-3%, and a lubricant 0.5-3%, and c) a coating 0.5-5%
It further relates to a solid pharmaceutical composition comprising.

According to one embodiment, the present invention includes nimorazole or a pharmaceutically acceptable salt thereof,
a) 2-25% diluent, preferably 4-15%, more preferably 6-10%, preferably 7-8%, disintegrant 0.7-10%, preferably 1-8%, more Intragranular portion preferably containing 1.5-5%, preferably 2-3%, and 1-10%, preferably 2-8%, more preferably 3-6%, preferably 4-5% binder. And b) Diluent 0.7-25%, preferably 0.8-10%, more preferably 0.9-5%, preferably 1-2%, disintegrant 1-10%, preferably 2-8%, more preferably 4-7%, preferably 5-6%, lubricant is 0.6-2.5%, preferably 0.8-2%, more preferably 0.9-1.8 %, Preferably 1-1.5%, and lubricants 0.6-2.5%, preferably 0.8-2%, more preferably 0.9-1. An extragranular portion comprising 0.8%, preferably 1-1.5%, and c) 0.7-4%, preferably 1-3%, more preferably 1.5-2.5%, preferably coating Is 2-2.2%,
It further relates to a solid pharmaceutical composition comprising.

  According to one embodiment, the present invention relates to a pharmaceutical composition that is an immediate release tablet. Immediate release tablets disintegrate in water within 30 minutes.

  According to one embodiment, the present invention is administered to a patient via a tube that disintegrates to form a dispersion in water within 15 minutes, preferably within 10 minutes, more preferably within 5 minutes, preferably within 3 minutes. The present invention relates to a pharmaceutical composition or a tablet.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet in which the dispersion passes through a sieve screen with a nominal mesh opening of 710 μm.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet that disintegrates at 25 ° C., preferably 20 ° C., more preferably 15 ° C. using water within 10 minutes, preferably within 5 minutes.

  According to one embodiment, the present invention relates to a pharmaceutical composition that is a fast-disintegrating tablet. The expression “fast-disintegrating tablet” refers to a tablet that can be dispersed in water prior to administration to produce a uniform dispersion. Fast-disintegrating tablets disintegrate at 15-25 ° C. using water within 3 minutes. The fineness of the dispersion should follow a test that includes placing two tablets in 100 ml of water and stirring until completely dispersed. A smooth dispersion is produced which passes through a sieve screen with a nominal mesh opening of 710 μm.

  According to one embodiment, the present invention provides that one or more pharmaceutical compositions or tablets comprising a total of at least 1000 mg of nimorazole are stirred in 100 ml of water at 25 ° C. to produce a complete dispersion, thereby obtaining a dispersion. The dispersion passes through a sieve screen with a nominal mesh opening of 710 μm. According to an embodiment, the term “completely dispersed” means that at least 90%, more preferably at least 95%, preferably at least 98%, more preferably 99%, preferably 100% of nimorazole is dispersed or dissolved. Include.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for administration via a supply tube.

  According to one embodiment, the present invention is selected from the group consisting of a percutaneous endoscopic gastrostomy tube, a nasal feeding tube, a nasal jejunum feeding tube, a gastric feeding tube and a percutaneous jejunostomy feeding tube. It relates to a pharmaceutical composition or tablet for administration via a supply tube.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for administration via a percutaneous endoscopic gastrostomy (“PEG”) tube or nasal feeding (“NG”) delivery tube.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for the treatment of bedridden or geriatric patients. These patient groups often suffer from tablet dysphagia.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treating a patient who has undergone radiation therapy, in particular in the head and / or neck region.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treating an intubated patient, such as a patient having a tube inserted into the gastrointestinal tract. Individual differences can affect whether a patient is intubated and at what point in the treatment plan.

  According to one embodiment, the present invention is selected from at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times for cancer of the head and / or neck region. It relates to a pharmaceutical composition or tablet for treating patients who have received a certain number of radiation treatments.

  Nimorazole is usually administered from the first irradiation treatment, but the use of the tube is particularly relevant from the fifth to sixth irradiation treatments when the patient begins to experience problems with swallowing.

  Thus, dysphagia is usually not present in the early stages, so the need for administration of nimorazole via the supply tube usually does not occur before or after the fourth or fifth irradiation treatment. During the first approximately 4 divided doses of radiation treatment, direct oral administration, i.e. oral ingestion in the form of tablets, is preferred, but the need for administration via a supply tube is usually late, i.e. the 5th or 6th dose. Arising from radiation therapy.

  Thus, for nimorazole tablets used in conjunction with radiation therapy, it is convenient to have tablets that can be used both for direct oral administration and for making dispersions or solutions for administration via a supply tube. However, because of the unpleasant flavor of Nimorazole, it is preferred that the tablet includes a coating that masks the flavor. Conventional coatings suffer from the disadvantage that the coating makes it difficult to make a dispersion and that some of the coating can adhere to the supply tube.

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

  The tablets are specifically applied to swallow or disintegrate in water or an aqueous medium at the discretion of the person administering the tablets.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet further comprising a coating that facilitates swallowing and masks the flavor of Nimorazole.

  The flavor of Nimorazole is uncomfortable for most patients. Thus, without the coating, many patients feel uncomfortable swallowing Nimorazole tablets. However, the coating tends to prevent tablet disintegration in water. Surprisingly, it was possible to devise a coating that facilitates swallowing, masks the flavor of nimazole, and can quickly create a dispersion in water.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for curative treatment or reirradiation of cancer.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for the initial irradiation treatment of a cancer intended for healing or the subsequent re-irradiation treatment of cancer intended for healing and / or alleviation.

  According to one embodiment, the present invention provides a pharmaceutical composition for curative or palliative treatment of cancer for patients who have undergone radiation therapy, particularly for patients with cancer in the head and / or neck region. Product or tablet.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treating a patient with hypoxic cancer. Methods for testing whether a cancer is hypoxic are known in the art.

  According to one embodiment, the present invention is selected from breast cancer, head / neck cancer, esophageal cancer, lymphoma, cervical cancer, colon cancer, brain tumor, lung cancer, bladder cancer and prostate cancer. The present invention relates to a pharmaceutical composition or a tablet for treating an indication. The present invention is particularly relevant to patients with dysphagia that may be caused by or not due to radiation therapy. Cancer treatment may or may not be combined with chemotherapy.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treating head / neck cancer.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treating cervical cancer or inoperable lung cancer.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treating non-smokers. Nimorazole appears to have little or no effect on the effectiveness of radiation therapy for cancer in patients who have not quit smoking during treatment. According to one embodiment, cessation of smoking throughout therapy is natural.

  According to one embodiment, the present invention relates to a pharmaceutical composition comprising at least 250 mg of nimorazole or a pharmaceutically acceptable salt thereof.

  According to one embodiment, the present invention provides a pharmaceutical composition comprising 10-2500 mg, more preferably 100-2000 mg, preferably 300-1500 mg, more preferably 400-1000 mg, preferably 500 mg of nimorazole or a pharmaceutically acceptable salt thereof. About.

  According to one embodiment, the present invention provides that 3-5 said pharmaceutical compositions or tablets are 15, preferably 10, more preferably 5 at 25 ° C., preferably 20 ° C., more preferably 15 ° C. in 2 dl of water. Relates to a pharmaceutical composition or tablet according to the condition that it can be dispersed preferably within 3 minutes.

  According to one embodiment, the present invention relates to 1500-2500 mg, preferably 2000 mg of nimorazole in 2 dl of water at 25 ° C., preferably 20 ° C., more preferably 15 ° C., preferably 15, 10, more preferably 5, Preferably it relates to a pharmaceutical composition or tablet which can be dispersed within 3 minutes.

  According to one embodiment, the present invention relates to a pharmaceutical composition or tablet for treatment alone or in combination with chemotherapy. According to one embodiment, the present invention relates to a tablet for treatment alone or in combination with chemotherapy, for a patient who has received a total of ≧ 40 Gray during a course of treatment.

  According to one embodiment, the invention relates to 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 one embodiment, the present invention relates to a method for producing a pharmaceutical composition comprising wet granulation of nimorazole.

  According to one embodiment, the present invention is a wet granulation step performed using a high speed mixer granulator, or a high speed mixer granulator, an oscillating granulator (Oscillating Granulator). ), A wet granulation step performed using an apparatus selected from the group consisting of an in-line homogenizer, Caleva Mini Mixer, and High Shear Mixers.

  According to one embodiment, the present invention provides a wet granulation step in which dry mixing is preceded in a granulator, or said dry mixing is performed by a Conta blender, an Octagonal blender, a double cone blender (Double cone blender). The present invention relates to a method for producing a pharmaceutical composition, which can be carried out using an apparatus selected from the group consisting of blenders, conical blenders and multi mills.

  According to one embodiment, the present invention relates to a method for producing a pharmaceutical composition comprising the step of drying a wet granulation mass resulting from wet granulation until a predetermined loss on drying (% LOD) is obtained.

  According to one embodiment, the present invention provides a wet granulation mass resulting from wet granulation, wherein said LOD% is 0 to 10%, preferably 0.5 to 5.0%, more preferably 1.5 to 3.0. The method of manufacturing a pharmaceutical composition comprising the step of drying to the extent of%.

  According to one embodiment, the present invention relates to a method for producing a pharmaceutical composition comprising the step of screening all granules through a # 20 (20 #) or finer screen prior to compression.

  According to one embodiment, the present invention relates to a process for producing a pharmaceutical composition comprising the step of screening all extragranular raw materials through a 20 #, preferably 25 #, more preferably 30 # or finer screen prior to compression. .

  According to one embodiment, the present invention combines radiation therapy with the administration of at least one tablet according to the invention, said at least one tablet being disintegrated in water or an aqueous medium and administered via a tube. , Relating to cancer treatment. This method is particularly preferred for patients with dysphagia who are treated with Nimorazole.

  According to one embodiment, the present invention comprises the step of administering nimorazole, wherein the administration provides a solid pharmaceutical composition comprising nimorazole or a pharmaceutically acceptable salt thereof, said solid pharmaceutical composition in water or an aqueous medium To obtain a dispersion, and to administer the dispersion via a tube to make the hypoxic tumor cells radiosensitive.

  Patients who receive nimorazole in tablet form may have difficulty swallowing. A new route or method of administration of nimorazole that is particularly suitable for these patients is suggested. There is a need for a pharmaceutical composition that can be administered via a tube and does not require the tablet to be crushed. The dispersion to be administered can be prepared easily by the patient, especially without the need to grind the tablets. Therefore, this is for outpatient administration, i.e. patients who are given nimorazole as part of their portable treatment, e.g. patients who are required to receive treatment at home or treatment facilities such as hospitals are receiving radiation therapy In particular, it is particularly appropriate for patients who are required to receive treatment on their way to pathogenesis. Furthermore, there is a need for a pharmaceutical composition or tablet comprising nimorazole that is masked in flavor.

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

  According to one embodiment, the present invention provides an aqueous solution comprising nimorazole or a pharmaceutically acceptable salt thereof wherein at least a portion of nimorazole or a pharmaceutically acceptable salt thereof is dispersed in water or an aqueous medium in the form of solid particles. It relates to a pharmaceutical composition.

  According to one embodiment, the present invention relates to an aqueous pharmaceutical composition obtainable by dispersing the pharmaceutical composition in water or an aqueous medium.

  According to one embodiment, the present invention relates to an aqueous pharmaceutical composition wherein nimorazole or a pharmaceutically acceptable salt is present at a concentration of more than 5 mg / water or 1 ml of aqueous medium.

  The term “concentration” refers to the abundance of a component divided by the total volume of the mixture. The term is applicable to any kind of mixture and is not limited to solutes and solvents in solution.

According to one embodiment, the present invention provides:
i) Nimorazole or a pharmaceutically acceptable salt thereof,
ii) disintegrants,
iii) optionally one or more additional excipients, and iv) a coating,
Can be administered orally, preferably as a tablet, and alternatively, prior to administration via a supply tube, the pharmaceutical composition may disintegrate in water or an aqueous medium to produce a dispersion that is administered via the supply tube. Relates to a solid pharmaceutical composition allowing administration via a supply tube.

  According to one embodiment, the present invention relates to a pharmaceutical composition wherein the further excipients include diluents, binders, lubricants and lubricants.

According to one embodiment, the present invention provides:
1-50 wt% diluent,
0.5-15 wt% disintegrant,
0.5-15 wt% binder,
0.5-3 wt% of lubricant,
Lubricant, 0.5-3wt%,
Optionally one or more additional excipients, as well as 0.5-5 wt% coating,
It is related with the pharmaceutical composition containing.

According to one embodiment, the present invention provides:
7-9 wt% diluent,
7-8 wt% disintegrant,
4-5 wt% binder,
1-1.5 wt% of lubricant,
1-1.5 wt% of lubricant,
Optionally, one or more additional excipients, as well as the coating,
It is related with the pharmaceutical composition containing.

According to one embodiment, the present invention provides:
Intragranular portion containing diluent, disintegrant and binder,
Extragranular parts including diluents, disintegrants, lubricants and lubricants, and coatings,
The present invention relates to a pharmaceutical composition comprising

  According to one embodiment, the present invention relates to a pharmaceutical composition formulated as a tablet, immediate release tablet or fast disintegrating tablet.

  According to one embodiment, the present invention relates to a pharmaceutical composition that disintegrates in water at 20 ° C. within 5 minutes.

  According to one embodiment, the present invention relates to a pharmaceutical composition that passes through a nominal 710 μm sieve screen after disintegration in water or an aqueous medium.

  According to one embodiment, the present invention relates to a pharmaceutical product which can be dispersed to provide at least 1000 mg of nimolazole in 100 ml of water by stirring within 25 minutes at 25 ° C., said dispersion passing through a sieve screen with a nominal aperture of 710 μm. .

  According to one embodiment, the invention provides that the supply tube is selected from the group consisting of a percutaneous endoscopic gastrostomy tube, a nasal feeding tube, a nasal jejunum supply tube, a gastric supply tube, and a percutaneous jejunostomy supply tube The pharmaceutical composition to be used.

  According to one embodiment, the present invention relates to a pharmaceutical composition wherein the coating facilitates swallowing and masks the flavor of nimorazole.

  According to one embodiment, the present invention relates to a pharmaceutical composition comprising at least 250 mg of nimorazole or a pharmaceutically acceptable salt thereof per dosage unit.

  According to one embodiment, the present invention relates to a pharmaceutical composition which 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 one embodiment, the present invention relates to a kit of parts comprising instructions for preparing a dispersion of the pharmaceutical composition for administration to a patient via the pharmaceutical composition and a supply tube.

According to one embodiment, the present invention provides:
a)
i) Nimorazole or a pharmaceutically acceptable salt thereof,
ii) disintegrants,
iii) optionally one or more additional excipients, and iv) a coating,
A solid pharmaceutical composition that can be administered to a patient via a supply tube by disintegrating the solid pharmaceutical composition in water or an aqueous medium to produce a dispersion that is administered via the supply 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 supply tube;
Relates to a kit of parts including

  According to one embodiment, the present invention relates to a pharmaceutical composition made by a method comprising the step of performing wet granulation of a composition comprising nimorazole or a pharmaceutically acceptable salt thereof.

  According to one embodiment, the present invention relates to a method for producing a pharmaceutical composition comprising performing wet granulation of nimorazole or a pharmaceutically acceptable salt thereof.

According to one embodiment, the present invention provides radiation therapy,
i) Nimorazole or a pharmaceutically acceptable salt thereof,
ii) disintegrants,
iii) optionally one or more additional excipients, and iv) a coating,
Wherein the at least one solid pharmaceutical composition is disintegrated or dispersed in water or an aqueous medium and administered to the patient via a supply tube. To a method of treating cancer by making a hypoxic tumor cell radiosensitive.

  According to one embodiment, the present invention comprises the step of performing radiation therapy in combination with the administration of at least one solid pharmaceutical composition, wherein the at least one solid pharmaceutical composition is disintegrated or disintegrated in water or an aqueous medium. It relates to a method of treating cancer by dispersing and administering hypoxic tumor cells to a patient via a delivery tube to make them radiosensitive.

According to one embodiment, the present invention provides radiation therapy comprising:
Providing said solid pharmaceutical composition comprising nimorazole or a pharmaceutically acceptable salt thereof;
Dispersing a solid pharmaceutical composition in water or an aqueous medium to obtain a dispersion;
Administering the dispersion to the patient via a tube, as well as administering radiation to the patient;
Relates to a method comprising:

  According to one embodiment, the present invention relates to a method wherein the dispersion contains said nimorazole or a pharmaceutically acceptable salt thereof in a concentration greater than 5 mg / water or 1 ml of aqueous medium.

  According to one embodiment, the present invention relates to a method further comprising administering chemotherapy to the patient.

  According to one embodiment, the present invention provides that the cancer is breast cancer, head / neck cancer, esophageal cancer, lymphoma, cervical cancer, colon cancer, brain tumor, lung cancer, bladder cancer and prostate cancer. Relates to a method selected from the group consisting of

  According to one embodiment, the present invention comprises particulate nimorazole or a pharmaceutically acceptable salt thereof dispersed in water or an aqueous medium, wherein the concentration of nimorazole or its pharmaceutically acceptable salt is in water or an aqueous medium. It relates to a dispersion in which the solubility limit is exceeded and the dispersion is formulated for administration to a patient via a supply tube.

  According to one embodiment, the present invention relates to an aqueous dispersion in which the particulate nimorazole or a pharmaceutically acceptable salt thereof has an average diameter of less than 710 μm.

  All references cited are incorporated by reference.

  The accompanying drawings and examples are provided to illustrate the invention and not to limit it. It will be apparent to those skilled in the art that aspects, embodiments, and claims of the present invention can be combined.

  Unless otherwise specified, all percentages are w / w.

[Examples A1, A2, A3 and A4]
Tablet raw materials and manufacturing

  Unless otherwise specified, the environmental conditions are about 22 ° C. Crospovidone was replaced with sodium starch glycolate for tablet A1. Tablets were manufactured using the following steps.

i. Selection with vibratory shifter: Crospovidone was mixed with microcrystalline cellulose PH101 and finally with Nimorazole. The material was screened through a 30 # sieve using an oscillating shifter.
ii. Binder preparation and binder addition: Povidone K30 was dispersed in weighed purified water and a 20% w / w dispersion was prepared under stirring.
iii. Dry mixing in high speed mixing granulator: The sorted material from step i was charged into a Rapid Mixer Granulator and the material was dry mixed for 10 minutes with a low speed stirring blade and the chopper cut off.
iv. Wet mixing: Step ii. In step iii. Within 2 minutes with the chopper being cut off with a low speed stirring blade. Added to. If necessary, an additional sufficient amount of purified water was added within 1 minute.
v. Step iv. Were mixed with a low speed stirring blade and a low speed chopper for a maximum of 1 minute to obtain a uniform wet mass. The wet mass was discharged from the Rapid Mixer Granulator with a low speed stirring blade.
vi. Wet grinding in a co-mill: step v. The wet mass of was passed through a 8.00 mm screen using Comil at 700 RPM.
vii. Drying of the wet granule mass in a fluid bed processor / dryer was performed at an inlet temperature of 60 ± 10 ° C. to ensure uniform drying until a loss on drying (% LOD) was obtained. The percent loss on drying of the granules (% LOD) was automatically determined with a humidity analyzer at 105 ° C. and continued to dry until the% LOD reached the limit, ranging from 1.5 to 3.0%.
viii. Size processing: Step vii. The dried granules obtained in 1 were screened with a 20 # sieve using a vibratory shifter to obtain granules of uniform size.
ix. Step viii. The granules retained at 20 # were screened through 14 #. The granules retained at 14 # and the granules that passed through 14 # were collected separately.
x. Step ix. The granules retained by 14 # obtained in 1 were milled through a 2.0 mm SS screen using Comil at 700 PM. The milled granules were passed through a 20 # sieve using a vibroshifter.
xi. Step x. Both the oversized granule obtained in step 1 and the fraction passed through step ix 14 # and retained by 20 # were ground through a 1.0 mm SS screen using a comil at 700 RPM. The milled granules were passed through a 20 # sieve using a vibroshifter.
xii. All granules were finally screened through a 20 # SS sieve using an oscillating shifter.
xiii. Blending and lubrication in pillar bin blenders: Extragranular microcrystalline cellulose and crospovidone were screened through a 40 # sieve using an oscillating shifter. This was then blended with the selected granules for 10 minutes. Separately, anhydrous colloidal silica and magnesium stearate were screened through a 30 # sieve using a vibratory shifter. The mixture was added and lubrication was carried out for 3 minutes.
xiv. Compression in a rotary press tablet press. Tablets having an average weight of 650 mg and a disintegration time of 15 minutes or less were produced.
xv. Preparation of coating dispersion in stirrer: Opadry 03B57695 gray was dispersed in weighed purified water and a 10% w / w dispersion was prepared under stirring.
xvi. Coating in an automatic coating machine: The compressed core tablets were sprayed with the film coating dispersion. Curing was conducted at an inlet temperature of 45 ° C.
xvii. Packaged in a blister packing machine.

  Tablets A1, A2, A3 and A4 were all suitable for oral administration and dispersion in water prior to administration via a supply tube. The tablets differed with respect to the time required for dispersion and storage stability. Preliminary experiments show that the amount of coating provides a trade-off between storage stability and dispersion time. More coatings improve storage time but tend to take longer to disintegrate or disperse.

[Example B]
Nimorazole Coated Tablets with Crospovidone-General Formulation A dry mix containing nimorazole, microcrystalline cellulose, crospovidone was granulated using a granulating fluid, dried and sized. The granules were further blended with extragranular material, lubricated and compressed into tablets. The core tablet was further film coated. The tablet delivers 500 mg of Nimorazole.

[Example C]
Nimorazole Tablets Containing Sodium Starch Glycolate-General Formulation A dry mix containing nimorazole, microcrystalline cellulose, sodium starch glycolate was granulated using a granulating fluid, dried and sized. The granules were further blended with extragranular material, lubricated and compressed into tablets. The tablet delivers 500 mg of Nimorazole.

  These tablets do not have a coating. The absence of a coating generally means that the patient does not want to swallow the tablet due to the unpleasant flavor of the active ingredient.

[Example D]
Nimorazole oral powder A dry mix of nimorazole, anhydrous citric acid, aspartame, mannitol and sucrose was granulated using a granulating fluid to prepare granules. The granules were dried, sized and blended with flavoring. The blend was packaged in a single unit dosage form, ie a sachet. Dispersing one bag in 250 ml of water gives a dispersion that delivers 500 mg of Nimorazole.

  This oral powder is not very suitable for direct oral administration without being dispersed in water.

[Example E]
Nimorazole Oral Granules Nimorazole, microcrystalline cellulose, anhydrous colloidal silica, corn starch, hydroxypropyl cellulose, povidone were granulated by spraying the granulating fluid using a Top spray assembly. The granules were further coated with an aqueous alcohol solution of basic butylated methacrylate copolymer. An amount equivalent to a unit dose packaged in a sachet, dispersed in 250 ml of water, delivers 500 mg.

  When these granules are disintegrated or dispersed in water, they tend to clog the supply tube.

Disintegration and Solubility Experiments show that the solubility of Nimorazole in water is 4.91 mg / ml.

Tablet A1
Tablet A1 had a thickness of 5.61 to 5.65 mm. The disintegration time was measured as 2-3 minutes.

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

Dissolution Cumulative drug release% was measured in 900 ml of 0.1 N HCl for 30 minutes at 50 RPM on a USP Type II instrument and measurements were performed at 5, 10, 20 and 30 minutes.

  The use of crospovidone instead of sodium starch glycolate as a disintegrant reduced the disintegration time and provided a significant increase in dissolution rate, with more than 85% of the drug released within 5 minutes.

Tablet A4
Preliminary experiments show that tablet A4 disintegrates in less than 3 minutes. About 85% of the active ingredient Nimorazole dissolves before 10 minutes and the active ingredient dissolves almost completely before 30 minutes.

Comparison with Prior Art Tablets Dispersibility Tablet A1 (500 mg) of the present invention was compared with prior art tablet F4 (200 mg) (this tablet was described in the paper “Formation and In-Vitro Charactrization of Nitrozole Mouth Dissolving Tables”, Ratnaparkhi, Mukes R et al., Research Journal of Pharmaceutical, Biological and Chemical Sciences (2012), Volume 3, No. 3, pages 303-308.

  Dispersibility testing was performed at room temperature using water. To compare a mixture containing the active ingredient Nimorazole at the same concentration, tablet A1 (500 mg) was dispersed in 50 ml of water in a glass beaker, while tablet F4 (200 mg) was dispersed in 20 ml of water in a glass beaker. I let you. Stirring was continued for 3 minutes.

  After stirring, a uniform dispersion without precipitation was formed from tablet A1 (FIG. 1, right), while in the dispersion formed from tablet F4, phase separation was evident and the clear solvent phase was at the bottom of the beaker. Clearly above the visible precipitate (Figure 1, left). When the beaker is emptied, a negligible amount of residue remains in the beaker used for tablet A1 (FIG. 2, right), while the beaker used for tablet F4 still contains debris from precipitation. (Figure 2, left).

  Thus, it was shown that tablet A1 of the present invention produced a dispersion under stirring in water, while prior art tablet F4 did not produce a dispersion under stirring in water.

Sieve Inspection Tablet A1 (500 mg) of the present invention was compared to a prior art tablet, F4 (200 mg, ibid). A mixture of water and tablets at room temperature was prepared as the following tablets.

  Mixture I produced a stable and uniform dispersion with a milky appearance (FIG. 3, right). The dispersion of mixture I showed long-term stability. Mixture II (FIG. 3, left) and Mixture III both provided a non-homogenous mixture with a clear phase separation between the solvent and the precipitate.

  The mixture was poured into sieve screens # 20, # 30 and # 40 having openings of 900 μm, 600 μm and 400 μm, respectively. Mixture I passed through all three sieve screens, leaving no traces of precipitate in any of the sieve screens (FIG. 4, sieves # 20, # 30, # 40 from left to right). When Mixtures II and III were poured into the three sieve screens, in both cases the particles remained on all three sieve screens (FIGS. 5 and 6, sieves # 20, # 30, # 40 from left to right, respectively). ).

  Therefore, it was confirmed that Mixture I was a smooth dispersion, while Mixture II and Mixture III were not smooth dispersions.

  It is further noted that for Mixture I, a negligible amount of material was retained in the bottle used for mixing, whereas for Mixtures II and III, a clearly visible mass of tablets was retained. I want. This indicates that for Mixture II and Mixture III, not all of the active ingredient is present in the mixture poured from the bottle. Furthermore, the use of mixtures II and III increases the risk of blocking the supply tube, and the release of the active ingredient from mixtures II and III is due to the larger particle size resulting from the prior art tablet mixture production, It is slower than Mixture I.

In Vitro Dissolution Prior art tablet F4 (ibid) shows a slower dissolution rate in percentage than tablet A1 and A2 of the invention (see above) at all time points. Even more surprisingly, prior art tablet F4 contains 200 mg of active ingredient, while tablets A1 and A2 of the present invention contain 500 mg of active ingredient. This should be supported since the cumulative drug release% of tablet F4 as the actual concentration of the active ingredient nimorazole is lower in the USP device for 200 mg tablets.

  Thus, faster dissolution rates can be achieved in vitro, making it easier to achieve peak serum levels of active ingredients at specific time points, and in combination with radiation therapy, the serum peak levels of active ingredients can be further increased, This is an advantage of the tablet of the present invention.

Patient Compliance—Testing of Flavor Masking Properties of Coatings Tablet A1 (500 mg) of the present invention was compared to prior art tablet F4 (200 mg) (article “Formation and In-Vitro Charactorization of Nitroazole Dissolving Tables”, Ratnapurk, Ratnapark, R et al., Research Journal of Pharmaceutical, Biological and Chemical Sciences (2012), Vol. 3, No. 3, pages 303-308.

Two informed people (healthy volunteers) were requested and individual tablets were placed in the lower front for 30 seconds by pressing the tablets against the palate with the tongue. After 30 seconds, taste is graded from 1 to 10 for bitterness / taste.
The following steps were used:

In addition, taking into account that treatment involves 3-4 tablets per day for an average of 30 days, a subjective description of whether the flavor is considered to have an adverse effect on compliance with treatment is provided.
The results are shown in the table below.

  It was shown that dissolving tablet F4 in the mouth is not appropriate for patients without saliva. Furthermore, because of the very unpleasant flavor and the requirement for multiple tablets due to the large amount of active ingredients, the tablets are not suitable for combination with radiation therapy. The suggested mode of administration of F4 (ie, dissolution in the mouth) is therefore not appropriate for patient treatment.

Claims (54)

Including nimorazole or a pharmaceutically acceptable salt thereof,
Disintegrant,
Optionally one or more additional excipients, as well as a coating,
Further including
At least two different pathways:
i) oral administration, or ii) administration through a tube of the dispersion after the dispersion has been formed by disintegration in water or aqueous medium
A solid pharmaceutical composition that can be administered via Including nimorazole or a pharmaceutically acceptable salt thereof,
Diluent,
Disintegrant,
Binder,
Lubricant,
A lubricant, and optionally one or more additional excipients, and a coating,
A solid pharmaceutical composition further comprising: Including nimorazole or a pharmaceutically acceptable salt thereof,
1-50% diluent,
0.5-15% disintegrant,
0.5-15% binder,
0.5-3% lubricant
0.5-3% lubricant, and optionally one or more additional excipients, and 0.5-5% coating,
Further comprising a solid pharmaceutical composition. Including nimorazole or a pharmaceutically acceptable salt thereof,
2-25% diluent, preferably 4-15%, more preferably 6-10%, preferably 7-9%
1-12% disintegrant, preferably 3-10%, more preferably 5-9%, preferably 7-8%,
1-10% binder, preferably 2-8%, more preferably 3-6%, preferably 4-5%,
The lubricant is 0.6-2.5%, preferably 0.8-2%, more preferably 0.9-1.8%, preferably 1-1.5%,
0.6-2.5% lubricant, preferably 0.8-2%, more preferably 0.9-1.8%, preferably 1-1.5%, and optionally one or more Additional excipients, as well as the coating 0.7-4%, preferably 1-3%, more preferably 1.5-2.5%, preferably 2-2.2%,
Further comprising a solid pharmaceutical composition. Including nimorazole or a pharmaceutically acceptable salt thereof,
a. Diluent,
Disintegrant, and binder,
An intragranular portion comprising: b. Diluent,
Disintegrant,
Lubricant, and lubricant,
An extragranular portion comprising: c. coating,
A solid pharmaceutical composition further comprising: Including nimorazole or a pharmaceutically acceptable salt thereof,
a. 1-50% diluent,
0.5-15% disintegrant and 0.5-15% binder
An intragranular portion comprising, and b. 0.5-50% diluent,
0.5-15% disintegrant,
0.5-3% lubricant, and 0.5-3% lubricant
An extragranular portion comprising, and c. 0.5-5% coating,
Further comprising a solid pharmaceutical composition. Including nimorazole or a pharmaceutically acceptable salt thereof,
a. 2-25% diluent, preferably 4-15%, more preferably 6-10%, preferably 7-8%,
0.7-10% disintegrant, preferably 1-8%, more preferably 1.5-5%, preferably 2-3%, and 1-10% binder, preferably 2-8%, More preferably 3-6%, preferably 4-5% of the intragranular part, and b. 0.7-25% diluent, preferably 0.8-10%, more preferably 0.9-5%, preferably 1-2%
1-10% disintegrant, preferably 2-8%, more preferably 4-7%, preferably 5-6%,
The lubricant is 0.6-2.5%, preferably 0.8-2%, more preferably 0.9-1.8%, preferably 1-1.5%, and the lubricant is 0.6- An extragranular portion comprising 2.5%, preferably 0.8-2%, more preferably 0.9-1.8%, preferably 1-1.5%, and c. 0.7-4% coating, preferably 1-3%, more preferably 1.5-2.5%, preferably 2-2.2%,
Further comprising a solid pharmaceutical composition.   A solid pharmaceutical composition for treatment comprising disintegration of the pharmaceutical composition in water or an aqueous medium and administration via a tube comprising nimorazole or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition according to any of claims 1 to 8, for administration to a patient with dysphagia.   10. A pharmaceutical composition according to any one of claims 1 to 9 for administration to a patient with insufficient or no saliva.   The pharmaceutical composition according to any one of claims 1 to 10, which is a tablet.   The pharmaceutical composition according to any one of claims 1 to 11, which is an immediate release tablet.   13. A pharmaceutical composition according to any of claims 1 to 12, for administration to a patient via a tube that disintegrates in water within 15 minutes to form a dispersion.   14. The pharmaceutical composition according to claim 13, wherein the dispersion passes through a sieve screen with a nominal mesh opening of 710 [mu] m.   The pharmaceutical composition according to any of claims 1 to 14, which disintegrates in water at 20 ° C within 10 minutes, preferably within 5 minutes.   The pharmaceutical composition according to any one of claims 1 to 15, which is a rapidly disintegrating tablet.   17. The pharmaceutical composition according to any one of claims 1 to 16, wherein one or more pharmaceutical compositions comprising a total of at least 1000 mg of nimorazole are dispersed in 100 ml of water at 25 ° C. within 5 minutes of stirring, A pharmaceutical composition thereby producing a dispersion, which passes through a sieve screen with a nominal mesh opening of 710 μm.   18. A pharmaceutical composition according to any one of claims 1 to 17 for administration via a supply tube.   Claimed for administration via a feeding tube selected from the group consisting of a percutaneous endoscopic gastrostomy tube, a nasal feeding tube, a nasal jejunum feeding tube, a gastric feeding tube and a jejunostomy feeding tube Item 19. A pharmaceutical composition according to any one of Items 1 to 18.   The pharmaceutical composition according to any one of claims 1 to 19, for administration via a percutaneous endoscopic gastrostomy tube or a nasal feeding tube.   21. A pharmaceutical composition according to any of claims 1 to 20 for treating a patient who has received radiation therapy.   The pharmaceutical composition according to any one of claims 1 to 21, for treating an intubated patient.   23. A pharmaceutical composition according to any of claims 1 to 22, for swallowing or for disintegration in water or an aqueous medium and administration via a tube.   24. The pharmaceutical composition according to any of claims 1 to 23, further comprising a coating that facilitates swallowing and masks the flavor of Nimorazole.   25. A pharmaceutical composition according to any of claims 1 to 24 for curative treatment or reirradiation of cancer.   26. The pharmaceutical composition according to any one of claims 1 to 25, for the first irradiation treatment of cancer for the purpose of healing or the next re-irradiation treatment of cancer for the purpose of healing and / or alleviation.   27. A pharmaceutical composition according to any one of claims 1 to 26 for treating a patient having hypoxic cancer.   To treat an indication selected from breast cancer, head / neck cancer, esophageal cancer, lymphoma, cervical cancer, colon cancer, brain tumor, lung cancer, bladder cancer and prostate cancer, 28. A pharmaceutical composition according to any one of claims 1 to 27.   29. A pharmaceutical composition according to any of claims 1 to 28 for treating head / neck cancer.   30. The pharmaceutical composition according to any one of claims 1 to 29, for treating cervical cancer or inoperable lung cancer.   31. A pharmaceutical composition according to any of claims 1 to 30, comprising at least 250 mg of nimorazole or a pharmaceutically acceptable salt thereof.   32. A pharmaceutical composition according to any of claims 1 to 31, comprising 100-2000 mg, preferably 300-1500 mg, more preferably 400-1000 mg, preferably 500 mg of nimorazole or a pharmaceutically acceptable salt thereof.   33. Pharmaceutical composition according to any of claims 1 to 32, according to the condition that at least 4 pharmaceutical compositions can be dispersed in 2 dl of water at 25 [deg.] C within 5 minutes, preferably within 3 minutes.   34. A pharmaceutical composition according to any of claims 1 to 33, wherein 2000 mg of Nimorazole or a pharmaceutically acceptable salt thereof can be dispersed in 2 dl of water at 25 [deg.] C within 5 minutes.   35. The pharmaceutical composition according to any of claims 1-34, wherein 2000 mg of Nimorazole can be dispersed in 2 dl of water at 25 [deg.] C within 3 minutes.   36. A pharmaceutical composition according to any of claims 1 to 35 for treatment in combination with chemotherapy.   Fast-disintegrating tablets comprising nimorazole or a pharmaceutically acceptable salt thereof, including a flavor masking coating.   Fast-disintegrating tablets comprising nimorazole or a pharmaceutically acceptable salt thereof, which can be administered via a feeding tube after dispersion and which includes a coating that allows oral administration.   In 50 ml of water, 15-25 ° C. water is used to stir within 3 minutes with stirring to produce a uniform dispersion, passing through a sieve screen with a nominal aperture of 710 μm and masking the flavor. Further comprising a tablet comprising nimorazole or a pharmaceutically acceptable salt thereof.   40. A kit of parts comprising instructions for preparing a dispersion of a pharmaceutical composition according to any of claims 1 to 39 or a pharmaceutical composition for administration via tablets and tubes.   40. A method for producing a pharmaceutical composition or tablet according to any of claims 1 to 39, comprising wet granulation of a composition comprising nimorazole.   The wet granulation step is performed using a high speed mixer granulator (Rapid Mixer Granulator) or a fast mixer granulator (Oscillating Granulator), an in-line homogenizer, Caleva Mini. 42. The method for producing a pharmaceutical composition or tablet according to claim 41, carried out using an apparatus selected from the group consisting of a mixer and a high shear mixer.   The wet granulation step is preceded by dry blending in the granulator, or the dry blending is done by Conta blender, Octagonal blender, Double cone blender, Conical blender (Conical blender). 43. A method for producing a pharmaceutical composition or tablet according to claim 41 or 42, which can be carried out using an apparatus selected from the group consisting of blenders and multi mills.   44. A method of manufacturing a pharmaceutical composition or tablet according to any of claims 41 to 43, wherein the wet granule mass resulting from wet granulation is dried until a predetermined loss on drying (% LOD) is obtained.   The wet granule mass resulting from wet granulation is dried until the LOD% is in the range of 0 to 10%, preferably 0.5 to 5.0%, more preferably 1.5 to 3.0%. 45. A method for producing the pharmaceutical composition or tablet according to any one of claims 41 to 44.   46. A method of manufacturing a pharmaceutical composition or tablet according to any of claims 41 to 45, wherein all the granules are screened through a # 20 (20 #) or finer sieve before compression.   47. Pharmaceutical composition or tablet according to any of claims 41 to 46, wherein all extragranular ingredients are screened through a 20 #, preferably 25 #, more preferably 30 # or finer screen prior to compression. Manufacturing method.   Irradiation treatment is combined with administration of at least one pharmaceutical composition or tablet according to any of claims 1 to 39, wherein at least one pharmaceutical composition or tablet is disintegrated or dispersed in water or an aqueous medium; A method for treating cancer, which can be administered via a tube. Administering nimorazole,
Administration
Providing a solid pharmaceutical composition or tablet comprising nimorazole or a pharmaceutically acceptable salt thereof;
Dispersing a solid pharmaceutical composition or tablet in water or an aqueous medium to obtain a dispersion, and administering the dispersion via a tube;
A method for making hypoxic tumor cells radiosensitive.   50. The method of claim 48 or 49, comprising administering the pharmaceutical composition or tablet 30-60 minutes prior to radiation therapy.   40. Use of the pharmaceutical composition or tablet according to any of claims 1 to 39, wherein the pharmaceutical composition or tablet is dispersed in water or another aqueous medium and administered via a tube.   An aqueous pharmaceutical composition comprising nimorazole or a pharmaceutically acceptable salt thereof wherein at least a portion of nimorazole or a pharmaceutically acceptable salt thereof is dispersed in the form of solid particles in water or an aqueous medium.   40. An aqueous pharmaceutical composition obtainable by the step of dispersing the pharmaceutical composition or tablet of any one of claims 1 to 39 in water or an aqueous medium.   54. Aqueous pharmaceutical composition according to claim 52 or 53, wherein nimorazole or a pharmaceutically acceptable salt thereof is present in a concentration of more than 5 mg / water or 1 ml of aqueous medium.

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