Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

• the present invention relates to a water soluble pharmaceutical composition comprising levetiracetam, and use of said composition in the treatment of partial seizures, myoclonic seizures and tonic-clonic seizures of patients diagnosed with epilepsy.
• Epilepsy is a neurological disorder-disease which emerges as a result of an abnormal electrochemical discharge induced by neurons in the brain. It results from excessive and uncontrolled emission of electricity related to the brain operation. It frequently causes temporary loss of consciousness.
• Levetiracetam (Formula I), which is described in the patent numbered US 4,943,639, is a derivative of pyrrolidon ((S)-(-)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide)) and it does not have chemical resemblance to known antiepileptic drugs.
• Levetiracetam is supplied in tablet, delayed release tablet, solution forms and forms for injection under KEPPRA® trade mark.
• KEPPRA® is used in partial onset seizures of adult patients and pediatric patients older than 4 years; and as an add-on-therapy in myoclonic seizures of adolescent patients older than 12 years with juvenile myoclonic epilepsy and adult patients. It is also used as monotherapy in the treatment of partial onset seizures with or without secondary generalization of recently diagnosed patients aged 16 years and older.
• compositions comprising levetiracetam are prepared in tablet, solution and parenteral forms.
• Tablet or capsule dosage forms comprising levetiracetam are disclosed in the patent numbered EP 1,810,676.
• use of tablet dosage forms poses problems for patients having swallowing problems, for instance children, elderly patients and handicapped patients or for those who do not want to swallow these dosage forms and therefore, they are not preferred by most patients.
• Solution dosage forms are not preferred due to the reasons that they make the adaptation of patients to the therapy difficult as they cause uncontrolled dose intake, unpleasant taste, difficulty of use, and they have more inconvenient shelf life compared with solid dosage forms.
• compositions comprising levetiracetam which have fast dissolution and effects as well as having long shelf life and being user-friendly and appropriate for patients with swallowing difficulties.
• the characteristic feature of the present invention is being water soluble compositions which hold the advantages of both tablet and suspension forms and eliminating the problems encountered in these dosage forms.
• compositions in scope of the present invention are their being in single dose solid dosage form and in water soluble form.
• water soluble used in the text comprises effervescent tablets, effervescent granules, effervescent powders, water soluble tablets, water soluble powders and/or water soluble granules.
• single dose solid dosage forms used in the text comprises the composition comprising one dose of the active agent to be in solid dosage form for instance water soluble tablets, effervescent tablets or water soluble powder or granules stored as being filled in a suitable dosage pack.
• the levetiracetam compositions of the present invention formulated in water soluble form would have high stability as they will be in solid form during storage. No stability problem is experienced which may result from long-term contact with water since they dissolve in water immediately before use.
• Water soluble compositions of the present invention are stored in separate dosage forms comprising unit dose. Thus, each dose is freshly prepared before use.
• Levetiracetam comprised in the composition of the present invention can be in free base form, pharmaceutically acceptable salt, racemate, solvate, hydrate, different polymorphic form and amorphous form thereof, preferably in free base form.
• compositions of the present invention comprises high amount of levetiracetam as being more than 200 mg per dosage form.
• the ratio of the active agent in total composition is in the range of 0.1% to 60%, preferably in the range of 10% to 50% by weight.
• the present invention provides a method which includes delivering effective amounts of levetiracetam to a patient in need of treatment and treating partial seizures, myoclonic seizures and tonic-clonic seizures of patients.
• the present invention comprises use of compositions of the invention in prevention of seizures of patients diagnosed with epilepsy; in reducing the number of seizures or in the treatment of the disease.
• the present invention comprises preparation of the compositions of the invention as a medicament composition which is effective in the treatment of partial seizures, myoclonic seizures and tonic-clonic seizures of patients diagnosed with epilepsy.
• the pharmaceutical compositions pertaining to the present invention comprises levetiracetam as the active agent and one or more excipients selected from the group comprising pH adjusters, stabilizing agents, diluents, binders, coating materials developed to provide various release characteristics, disintegrants, anti-adhesive agents, plasticizers, rate control agents, filling substances, effervescent couples, flavoring agents, lubricants, glidants, coloring agents, aqueous or non-aqueous solvents or combinations thereof.
• excipients selected from the group comprising pH adjusters, stabilizing agents, diluents, binders, coating materials developed to provide various release characteristics, disintegrants, anti-adhesive agents, plasticizers, rate control agents, filling substances, effervescent couples, flavoring agents, lubricants, glidants, coloring agents, aqueous or non-aqueous solvents or combinations thereof.
• the water soluble compositions of the present invention preferably comprise at least one pharmaceutically acceptable diluent, at least one binder, at least one lubricant, at least one sweetener, at least one flavoring agent and optionally at least one effervescent couple.
• the pharmaceutically acceptable binders pertaining to the present invention can be selected from a group comprising ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxymethyl cellulose, mannitol, sorbitol, xylitol, lactitol, maltitol, sugar, maltodextrin, hydroxypropyl cellulose, gelatine, hypromellose, magnesium aluminum silicate, polyethylene oxide, povidone and water or combinations thereof.
• the pharmaceutically acceptable diluents pertaining to the present invention can be selected from a group comprising starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, lactitol, maltitol, sugar, maltodextrin or combinations thereof.
• the pharmaceutically acceptable lubricants pertaining to the present invention can be selected from a group comprising magnesium stearate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulphate, starch, talc or combinations thereof.
• the pharmaceutically acceptable flavoring agents can be selected from a group comprising sour cherry flavor, grapefruit flavor, grape flavor, pear flavor, orange flavor, apricot flavor or combinations thereof.
• a significant problem encountered in oral solutions of levetiracetam is that this substance has a quite bitter taste and its taste lingers in users after use.
• the inventors have used at least 0.5% sweetener in the water soluble compositions comprising high amounts of active agent they prepared in order to prevent this problem.
• the present invention characterized by comprising at least one pharmaceutically acceptable sweetener in the range of 0.5% to 20%, preferably in the range of 0.5% to 10%, more preferably in the range of 1% to 4% by weight.
• the pharmaceutically acceptable sweeteners pertaining to the present invention can be selected from a group comprising acesulfame potassium, acesulfame, aspartame, fructose, dextrose, glucose, lactitol, maltitol, xylitol, sorbitol, maltose, saccharine, saccharine sodium, sodium cyclamate, sucralose, sucrose or combinations thereof.
• the present invention characterized by comprising aspartame in the range of 0.5% to 20%, preferably in the range of 0.5% to 10%, more preferably in the range of 1% to 4% by weight.
• another characteristic feature of the invention is to comprise preferably a sugar derivative binder such as at least one binder selected from the group comprising mannitol, sorbitol, xylitol, lactitol, maltitol, sugar and/or maltodextrin in the range of 1% to 20% by weight, more preferably sorbitol.
• a sugar derivative binder such as at least one binder selected from the group comprising mannitol, sorbitol, xylitol, lactitol, maltitol, sugar and/or maltodextrin in the range of 1% to 20% by weight, more preferably sorbitol.
• the ratio of the sweetener and the sugar derivative binder is in the range of 1:20 to 20:1, preferably in the range of 1 :10 to 10:1, more preferably in the range of 1 :3 to 3:1; for example 1:1, 1 :2, 1 :3, 2:1, 2:3, 3:1, 3:2.
• compositions of the present invention can be produced by any methods in the prior art, for instance by wet granulation method.
• Said production method basically comprises the following steps: a) Preparation of granulation solution by mixing at least one pharmaceutically acceptable binder and the solution,
• compositions of the present invention can be produced by one of the methods of dry granulation and dry mixing.
• the selected production method is dry blending, levetiracetam and pharmaceutically acceptable excipients are mixed; at least one pharmaceutically acceptable sweetener, at least one pharmaceutically acceptable flavoring agent and at least one pharmaceutically acceptable lubricant is added into the mixture. The final mixture is turned into a suitable dosage form.
• tablets are compressed of the water soluble compositions of the present invention.
• Compression force to compress tablets in the compositions of the present invention is in the range of 10 to 150 kN, preferably in the range of 20 to 150 kN, more preferably in the range of 30 to 150 kN. It has been observed that the tablets prepared by imposing this compression force do not undergo deformation in course of tube/blister filling and carrying.
• compositions according to the present invention can optionally be formulated in effervescent form.
• Effervescent formulations are especially beneficial for patients with swallowing difficulties and in pediatrics.
• the present invention provides a pharmaceutical composition comprising an effective amount of levetiracetam along with pharmaceutically acceptable excipients.
• the effervescent compositions comprise levetiracetam as the active agent and at least one effervescent couple that is composed of an acidic and a basic agent in order to provide water solubility.
• the acidic agent reacts with the basic agent and lead to carbon dioxide production. Therefore, a solution that can be easily taken by patients who do not like swallowing tablets or who have swallowing difficulties is obtained by dissolving and/or dispersing the pharmaceutical composition of the invention in an aqueous media like drinking water.
• the percentage of the acidic agent of the effervescent couple in the total weight of the composition is in the range of 15% to 75%, preferably in the range of 25% to 60% by weight while the percentage of the basic agent of the effervescent couple in the total weight of the composition is in the range of 0.1% to 35%, preferably in the range of 10% to 25% by weight.
• one characteristic feature of the present invention is that the ratio of the acidic agent of the effervescent couple to the basic agent is in the range of 1.6:1 to 3.5:1, preferably in the range of 2:1 to 2.9:1 by weight.
• the pharmaceutically acceptable acidic agent of the present invention can be selected from a group comprising other organic acids like citric acid and acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or combinations thereof. According to the present invention, it is preferred to be used citric acid anhydrous as the acidic agent.
• the pharmaceutically acceptable basic agent pertaining to the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate or combinations thereof. According to the present invention, it is preferred to be used sodium hydrogen carbonate as the basic agent.
• compositions of the present invention comprise; a) levetiracetam in the range of 10% to 50% by weight,
• At least one sweetener in the range of 0.5 to 20% and optionally,
• the production method preferred for effervescent compositions of the present invention is as follows: a) Preparation of the granulation solution prepared by mixing at least one pharmaceutically acceptable binder and the solution,
• Suitable desiccation temperature for the active agent granules obtained following the granulation is in the range of 20°C to 80 °C, preferably in the range of 20°C to 70 °C, more preferably in the range of 20°C to 60 °C.
• Example 1 Water soluble granule composition comprising levetiracetam
• the method for preparation of the water soluble composition comprising levetiracetam which is going to be produced according to the formulation given above can comprise granulating the active agent and the excipients with aqueous binder solution; adding sweetener and lubricant into the granules obtained; then mixing the blend, and optionally filling sachets.
• tablets can be compressed of the granules obtained.
• Example 2 Effervescent tablet composition comprising levetiracetam
• the mixture composed of levetiracetam, the acidic agent, the basic agent, the diluent and other excipients according to the formulation given above is granulated with the granulation solution obtained by mixing the binder and the pharmaceutically acceptable solvent; the granules are dried at 55°C.
• the final mixture is obtained after the other excipients are added and optionally tablets are compressed of the obtained mixture.

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• 2011
  • 2011-04-25 EP EP11720620A patent/EP2563340A2/de not_active Withdrawn
  • 2011-04-25 WO PCT/TR2011/000109 patent/WO2011136751A2/en active Application Filing

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