Fast-dissolving tablet comprising brotizolam

Abstract: The invention refers to a tablet comprising brotizolam as active agent, one or more filling and/or disintegrating agents, lubricants and optionally sweeteners, souring agents and/or flavouring agents, having a total weight of between 30 and 800 mg, a diameter of 4 to 15 mm and a hardness of 50 N to 100 N to allow disintegrating in a volume of aqueous liquids of maximum 2 ml within maximum 60 seconds.

Description: The present invention relates to a new easy-to-take tablet containing brotizolam rapidly disintegrating in small amounts of water, like for example the saliva of the mouth. Background to the invention Brotizolam is a diazepine with sedative and hypnotic effect. The substance itself and a first manufacturing procedure is disclosed in the German patent DE 2410030. Brotizolam is by far most used as sedative. A major group of customers are elderly people. Brotizolam is available on the market as a tablet that has to be taken orally. The tablet is such that it must be swallowed or chewed by the patient together with water. However, it turned out that the compliance of the elderly for the tablet reduces the more often it has to be taken, especially at night and/or together with water. Among others, this is because elderly people do not like to drink much, especially at night before going to bed and thus prefer taking tablets at night without water. Another field brotizolam can be used in is as sedative before surgical operations. The advantage of the use of brotizolam in such cases is obvious. However, the fact that it has to be taken together with water reduces the admissibility before operations. The present invention relates to a new formulation of brotizolam to overcome the aforementioned disadvantages of the present brotizolam tablet. The invention refers to a brotizolam tablet well disintegrating with saliva in the oral cavity and thus being swallowable without the use of water. While in the state of the art well disintegrating tablets are known, said tablets have several disadvantages. Normally those tablets are very porous and thus not very hard. As a consequence they cannot be broken into two or more pieces, which renders them useless for regiments wherein only one half of a tablet shall be taken at a time. Additionally, these porous tablets tend to be very sensitive to humidity. As a consequence they cannot be stored for some days once the blister is opened. Another disadvantageous feature of these tablets concerns the manufacturing process. Normally, they are made by compressing wet mass at low pressure followed by drying, for example freeze drying, what is not only rather lavish but also expensive. Summary of the invention Objective of the present invention is to create a tablet containing brotizolam as active ingredient, which easily disintegrates in small amounts of a pharmacologically acceptable aqueous liquid, such as the saliva in the oral cavity while being stable enough for transport and commercial use and which overcomes the disadvantages known in the state of the art. Another objective of the present invention is to create a tablet containing brotizolam as active ingredient, that easily disintegrates with saliva of the oral cavity while being hard enough to be broken into two stable pieces. Another object of the present invention is to create a tablet containing brotizolam as active ingredient, that easily disintegrates in saliva in the oral cavity and that resists humidity for several days without taking up moisture or breaking apart if unblistered. Another object of the present invention is to create a tablet containing brotizolam as active ingredient, which easily disintegrates in saliva in the oral cavity into a well tasting solution or suspension, preferred into a suspension. The well taste of the tablet does not only improve compliance but also minimise the risk that the tablet might be given to a person under misuse intention. Description of the invention The present invention relates to a tablet consisting of brotizolam as active agent, lactose, crystalline cellulose, corn, maize or potato starch as filling and/or disintegrating agents, magnesium stearate, optionally in combination with light anhydrous silicic acid as lubricant and a sweetener being selected from the group of aspartame and mono ammonium glycyrrhizinate and optionally souring agents selected from the group of mono sodium fumarate and/or citric acid and/or flavouring agents I-menthol, and/or mannitol, the tablet having a total weight of between 30 and 800 mg, a diameter of 4 to 15 mm and a hardness of 50 N to 100 N to allow disintegrating in up to 2 ml of water or saliva within a maximum of 60 seconds and the tablet being preparable by directly compressing the ingredients at a pressure of 5900 N to 15700 N without using any granulation processes. The tablet is such that it disintegrates already within up to 60 seconds, more preferred within up to 30 seconds and most preferred within up to 15 seconds. The disintegration process will already take place in a volume of said liquid of up to 2 ml, preferably between 0,5 ml and 2 ml, most preferably already in a volume of 1 ml. In order to meet the above-mentioned advantages of the tablet, namely being rapidly disintegrating on one hand and being hard enough to be breakable into two pieces, transported and commercialised on the other hand, the tablet must have a certain hardness. It was shown that a hardness of 50 N to 100 N is well suited for the aforementioned purpose. Preferred are tablets with a hardness of 60 N to 90 N, most preferred with a hardness of 65 N to 85 N. The tablet has a total weight of 30 mg to 800 mg and a diameter of 4 to 15 mm. Preferred are tablets having a total weight of 40 mg to 400 mg and a diameter of 5 mm to 10 mm, preferably 8 mm. Also preferred are tablets with a total weight of 50 mg to 100 mg and a diameter of 5 mm to 7 mm, preferably 6 mm. Most preferred are tablet having a total weight of 150 mg or 170 mg and a diameter of 8 mm and tablets having a total weight of 80 mg or 85 mg and a diameter of 6 mm. The tablet contains one or more filling and/or disintegrating agent(s). These agents are useful to produce tablets of a certain, size and to support the disintegrating step and are well known in the state of the art. The filling and/or disintegrating agent(s) are selected from the group of lactose, microcrystalline cellulose, starch, preferably corn, maize or potato starch. The tablet also contains one or more lubricant(s). Lubricants are well known in the state of the art. Among them, the lubricant(s) are selected from the group of light anhydrous silicic acid and/or magnesium stearate. The lubricant may also have a humidity binding effect. To improve the taste of the tablet it comprises one or more sweetener(s). Theses sweeteners are selected from the group of aspartame and monoammoniumglycyrrhizinate. Additionally to the sweetener the tablet may optionally comprise one or more souring agent(s), Theses may be selected from the group of mono sodium fumarate and citric acid. Additionally to the sweetener and souring agent(s), the tablet may optionally comprise one or more flavouring agent(s). The flavouring agents also give the impression of a cooling effect. The flavouring or cooling agent(s) is (are) selected from the group of l-menthol, and/or mannitol. The tablet is made by using a direct tabletting process, this means that all ingredients are compressed without any granulation processes. The tablet is compressed at a pressure of 5900 N to 15700 N, preferred at a pressure of 7800 N to 14000 N. A tablet with a total weight of 170 mg and a diameter of 8 mm made at a pressure of 9800 N to 12000 N will have a hardness of about 80 N. The tablet with the aforementioned features and made by the aforementioned process can be used as sedative or in any other indication in that brotizolam may be useful. The tablet may also be used for rapidly preparing a solution or suspension of brotizolam in an aqueous liquid, within up to 60 seconds, more preferably within a up to 30 seconds, most preferably within up to 15 seconds. Examples Example 1 brotizolam 0,250 mg lactose 86,820 mg crystalline cellulose 30,000 mg corn starch 30,000 mg aspartame 0,225 mg monosodium fumarate 0,750 mg light, anhydrous silicic acid 1,500 mg l-menthol 0,007 mg magnesiumstearate 0,450 mg total 150 mg Example 2 brotizolam 0,250 mg lactose 88,320 mg crystalline cellulose 30,000 mg corn starch 30,000 mg aspartame 0,225 mg monosodium fumarate 0,750 mg l-menthol 0,007 mg magnesiumstearate 0,450 mg total 150 mg Example 3 brotizolam 0,250 mg lactose 89,070 mg crystalline cellulose 30,000 mg corn starch 30,000 mg aspartame 0,225 mg l-menthol 0,007 mg magnesiumstearate 0,450 mg total 150 mg Example 4 brotizolam 0.250 mg lactose 99.330 mg microcrystalline cellulose 34.032 mg corn starch 34,000 mg aspartame 0.260 mg mono sodium fumarate 0.850 mg light anhydrous silicic acid 0.570 mg l-menthol 0.008 mg magnesium stearate 0.700 mg total 170 mg Example 5 brotizolam 0.250 mg lactose 100.180 mg microcrystalline cellulose 34.032 mg corn starch 34.000 mg aspartame 0.260 mg Light anhydrous silicic acid 0.570 mg l-menthol 0.008 mg magnesium stearate 0.700 mg total 170 mg Example 6 brotizolam 0.25 mg lactose 99.338 mg microcrystalline cellulose 34.032 mg corn starch 34 mg aspartame 0.26 mg mono sodium fumarate 0.85 mg light anhydrous silicic acid 0.57 mg magnesium stearate 0.7 mg total 170 mg Example 7 brotizolam 0.250 mg lactose 99.330 mg microcrystalline cellulose 34.032 mg corn starch 34.000 mg monoammonium 0.260 mg glycyrrhizinate mono sodium fumarate 0.850 mg light anhydrous silicic acid 0.570 mg l-menthol 0.008 mg magnesium stearate 0.700 mg total 170 mg Example 8 brotizolam 0.250 mg lactose 99.330 mg microcrystalline cellulose 34.032 mg corn starch 34.000 mg aspartame 0.260 mg citric acid 0.850 mg light anhydrous silicic acid 0.570 mg l-menthol 0.008 mg magnesium stearate 0.700 mg total 170 mg Example 9 brotizolam 0.250 mg lactose 89.410 mg microcrystalline cellulose 34.032 mg corn starch 34.00 mg aspartame 0.260 mg mono sodium fumarate 0.850 mg light anhydrous silicic acid 0.570 mg mannitol 10.000 mg magnesium stearate 0.700 mg total 170 mg

Claims: Tablet consisting of brotizolam as active agent, lactose, crystalline cellulose, corn, maize or potato starch as filling and/or disintegrating agents, magnesium stearate, optionally in combination with light anhydrous silicic acid as lubricant and a sweetener being selected from the group of aspartame and mono ammonium glycyrrhizinate and optionally souring agents selected from the group of monosodium fumarate and/or citric acid and/or flavouring agents I-menthol, and/or mannitol, the tablet having a total weight of between 30 and 800 mg, a diameter of 4 to 15 mm and a hardness of 50 N to 100 N to allow disintegrating in up to 2 ml of water or saliva within a maximum of 60 seconds and the tablet being preparable by directly compressing the ingredients at a pressure of 5900 N to 15700 N without using any granulation processes. Tablet according to claim 1, characterised in that it has a hardness of 60 N to 90 N. Tablet according to claim 1, characterised in that it has a hardness of 65 N to 85 N. Tablet according to any of claims 1 to 3, characterised in that the starch is corn, starch. Tablet according to any of claims 1 to 4, characterised in that the tablet comprises light anhydrous silicic acid. Tablet according to any of claims 1 to 5, characterised in that the tablet comprises aspartame. Tablet according to any of claims 1 to 6, characterised in that the tablet comprises citric acid. Tablet according to any of claims 1 to 7, characterised in that it has a total weight of 130 mg to 180 mg and a diameter of 5 mm to 10 mm, preferably 8 mm. Tablet according to any of claims 1 to 7, characterised in that it has a total weight of 150 mg or 170 mg and a diameter of 8 mm. Tablet according to any of claims 1 to 7, characterised in that it has a total weight of 50 mg to 100 mg and a diameter of 5 mm to 7mm, preferably 6 mm. Method for preparing a tablet according to any one of claims 1 to 10, by directly compressing the ingredients at a pressure of 5900 N to 15700 N without using any granulation processes. Method according of claim 11, characterised in that the pressure is 7800 N to 14000 N. Use of a tablet according to any of claims 1 to 10 for the manufacture of a medicament for sedation. Use of a tablet according to any of claims 1 to 10 to be dissolved or suspended in up to 2 ml, preferably 1 ml of water or saliva within up to 60 seconds, preferably within up to 30 seconds.

Inventors: KUROSAKI SEISUKE, OHKI TOSHIMITSU, WADA KOICHI, KUROSAKI, SEISUKE, OHKI, TOSHIMITSU, WADA, KOICHI
Applicants: BOEHRINGER INGELHEIM INT, BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Application year: 2000
Main classification: A61K9
IPC codes: A61K47, A61K9, A61K31, A61P25