Clobazam formulation in capsule form

Abstract

The present invention relates to a pharmaceutical capsule formulation comprising clobazam. The formulation comprises lactose monohydrate or mannitol as diluent, corn starch as disintegrant, talc and colloidal silicon dioxide as glidant, and magnesium stearate as lubricant.

Description

[0001] CLOBAZAM FORMULATION IN CAPSULE FORM

[0002] Technical Field

[0003] The present invention relates to a pharmaceutical capsule formulation comprising clobazam.

[0004] Prior Art

[0005] Clobazam is a 1 ,5-benzodiazepine derivative (Formulation 1 ) with antiepileptic and antipsychotic properties. Chemical name for Clobazam is 7-Chloro-1-methyl-5- phenyl-1 ,5-benzodiazepine-2,4(3H)-dione. Its molecular weight is 300.7.

[0006] Formula 1

[0007] Clobazam is used for the adjunctive treatment of seizures associated with Lennox- Gastaut syndrome (LGS) in patients two years of age and older. There are tablets sold under the brand name ONFI in the USA and FRISIUM in Europe. There is also an oral film form with the brand name Sympazan.

[0008] Each ONFI tablet contains 10 mg or 20 mg of clobazam and com starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc. It is also available as ONFI oral suspension, containing clobazam at a concentration of 2.5 mg / mL. The suspension contains magnesium aluminum silicate, xanthan gum, citric acid monohydrate, disodium hydrogen phosphate dihydrate, simethicone emulsion, polysorbate 80, methylparaben, propylparaben, propylene glycol, sucralose, maltitol solution, blackberry flavor, purified water.

[0009] Clobazam is almost completely absorbed after oral administration (87% of the dose). Food do not affect absorption. It reaches maximum blood concentration in 1-3 hour(s). The clobazam molecule is disclosed in patent US3984398 (A).

[0010] CN106176643 (A) discloses a tablet prepared by dry granulation containing clobazam with a particle size of 5-50 pm

[0011] CN109846841 A relates to a rapid-acting oral formulation containing lyophilized clobazam.

[0012] US2018344648 (A1 ) relates to the pharmaceutical formulation containing clobazam with a particle size of 2-170 pm.

[0013] US10449201 B2 relates to the transdermal clobazam formulation.

[0014] FR2531866 (A1 ) relates to rapidly disintegrating benzodiazepine compounds, and clobazam is listed among the benzodiazepine compounds.

[0015] A major problem encountered in tablet manufacturing is that tablets are subject to breakage or crumbling in blister packs when they are not of sufficient hardness. In addition, if it is not of sufficient hardness, it will cause capping when compressed into tablets under high pressure to increase hardness.

[0016] The developed capsule formulation eliminates various disadvantages encountered in tablet production as a simple and economically applicable manufacturing process.

[0017] Description of the invention:

[0018] The present invention relates to capsule formulations comprising clobazam that do not present stability and incompatibility problems. The formulations are preferably in dosages of 5mg, 10mg and 20mg, and the proportions of excipients used in the formulations are the same according to the capsule content. The formulation relates to a pharmaceutical capsule composition comprising clobazam or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutical excipients in an amount preferably between about 6-10%, most preferably about 8.6% (8.62%), with respect to the capsule content.

[0019] The one or more pharmaceutically acceptable excipients used according to the invention are inactive ingredients such as fillers / diluents, disintegrants, glidants, lubricants, etc., which are conventionally used for capsule formulations.

[0020] Suitable fillers / diluents according to the invention include mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, sugar alcohols, dextrates, dextrin, calcium carbonate, calcium sulphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch, and the like. Lactose monohydrate or mannitol is selected as the diluent in the formulation of the invention. Pharmaceutical grade lactose monohydrate is available in the market under brand names such as Pharmatose, Lacochem. The amount of lactose or mannitol in the formulation is preferably between about 75-85% by weight. Most preferably, it is about 82% (82.07%) by weight.

[0021] Suitable disintegrants according to the invention include corn starch, carboxymethyl cellulose salts, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low substituted hydroxypropyl cellulose, cross-linked polypyrrolidone, sodium starch glycolate. Partially gelatinized corn starch, available in the market under the brand name Starch RX 1500, is selected as the disintegrant in the formulation of the invention. It is preferably present between about 2-6% by weight with respect to the capsule content in the formulation. Most preferably, it is used at a ratio of about 4.3% (4.31 %) by weight. Suitable glidants according to the invention include silica; colloidal silica, e.g. colloidal silica anhydrous (Aerosil® 200), magnesium trisilicate, powdered cellulose, starch, and talc. Preferably colloidal silicon dioxide and talc are used. Talc ratio is preferably between 3-5% by weight with respect to the capsule content in the formulation. Most preferably, talc is used at a ratio of about 4.3% (4.31 %) by weight.

[0022] Colloidal silicon dioxide is preferably between 0.1-1% by weight with respect to the capsule content in the formulation. Most preferably, colloidal silicon dioxide is used about 0.4% (0.43%) by weight.

[0023] Mg, Al or Ca stearate, PEG 4000 - 8000, talc, sodium benzoate, glyceryl mono fatty acid, glycerylmonostearate, glyceryl dibehenate, glyceryl palmitostearic ester, polyoxyethylene glycol, hydrogenated cottonseed oil, castor seed oil can be used as lubricants. Preferably magnesium stearate is selected. It is preferably between 0.1 - 0.5% by weight with respect to the capsule content in the formulation. Most preferably, it is used about 0.25% (0.26%) by weight.

[0024] The ingredients that go into the capsule formulation are mixed appropriately and the powder mixture is filled into capsules. The primary packaging of capsule powder content is two-piece hard gelatin capsules, namely cap and body. Transparent PVC- PVDC bottom foil and aluminum top foil are used as secondary packaging for filled capsules.

[0025] Examples:

[0026] Example 1. Example 2.

[0027] Formulations are preferably prepared according to the following process.

[0028] 1. Aerosil 200, Talc, Corn starch are sieved through a 1.0 sieve, put into a mixer and mixed for 5 minutes. 2. Clobazam and Lactose monohydrate are sieved through a 1.0 mm sieve, put into a mixer and mixed for 10 minutes.

[0029] 3. Magnesium stearate is sieved through a 0.8 mm sieve, put into the mixer and mixed for 3 minutes.

[0030] 4. Filling into capsules is performed.

Claims

CLAIMS1. A capsules formulation comprising clobazam, characterized in that it comprises lactose monohydrate or mannitol as diluent, corn starch as disintegrant, talc and colloidal silicon dioxide as glidant, and magnesium stearate as lubricant.

2. A capsule formulation comprising clobazam according to claim 1 , comprising 75- 85% lactose monohydrate by weight with respect to capsule content.

3. A capsule formulation comprising clobazam according to claim 1 , comprising 2-6% com starch by weight with respect to capsule content.

4. A capsule formulation comprising clobazam according to claim 1 , comprising 3-5% talc by weight with respect to capsule content.

5. A capsule formulation comprising clobazam according to claim 1 , comprising 0.1- 1 % colloidal silicon dioxide by weight with respect to capsule content.

6. A capsule formulation comprising clobazam according to claim 1 , comprising 0.1 - 0.5% magnesium stearate by weight with respect to capsule content.

7. A capsule formulation comprising clobazam according to claim 1 , characterized in that it comprises about 82% by weight lactose monohydrate as diluent, about 4.3% by weight com starch as disintegrant, about 4.3% by weight talc and about 0.4% by weight colloidal silicon dioxide as glidant, and about 0.25% by weight magnesium stearate as lubricant, with respect to capsule content.

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