EP2563340A2 - Water soluble pharmaceutical composition - Google Patents
Water soluble pharmaceutical compositionInfo
- Publication number
- EP2563340A2 EP2563340A2 EP11720620A EP11720620A EP2563340A2 EP 2563340 A2 EP2563340 A2 EP 2563340A2 EP 11720620 A EP11720620 A EP 11720620A EP 11720620 A EP11720620 A EP 11720620A EP 2563340 A2 EP2563340 A2 EP 2563340A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- composition according
- range
- weight
- effervescent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 64
- 229960004002 levetiracetam Drugs 0.000 claims abstract description 29
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims abstract 5
- 239000003795 chemical substances by application Substances 0.000 claims description 33
- 239000011230 binding agent Substances 0.000 claims description 19
- 235000003599 food sweetener Nutrition 0.000 claims description 19
- 239000003765 sweetening agent Substances 0.000 claims description 19
- 230000002378 acidificating effect Effects 0.000 claims description 16
- 239000008187 granular material Substances 0.000 claims description 16
- 239000000796 flavoring agent Substances 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 10
- 235000013355 food flavoring agent Nutrition 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- 235000010356 sorbitol Nutrition 0.000 claims description 7
- 235000000346 sugar Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- 239000007938 effervescent tablet Substances 0.000 claims description 5
- 239000000832 lactitol Substances 0.000 claims description 5
- 235000010448 lactitol Nutrition 0.000 claims description 5
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 5
- 229960003451 lactitol Drugs 0.000 claims description 5
- 239000000845 maltitol Substances 0.000 claims description 5
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 5
- 235000010449 maltitol Nutrition 0.000 claims description 5
- 229940035436 maltitol Drugs 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 239000007909 solid dosage form Substances 0.000 claims description 5
- 229960002920 sorbitol Drugs 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- 239000000811 xylitol Substances 0.000 claims description 5
- 235000010447 xylitol Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- 229960002675 xylitol Drugs 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 238000007580 dry-mixing Methods 0.000 claims description 4
- -1 effervescent couples Substances 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000007911 effervescent powder Substances 0.000 claims description 3
- 239000004554 water soluble tablet Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 230000000181 anti-adherent effect Effects 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 238000007908 dry granulation Methods 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000004549 water soluble granule Substances 0.000 claims description 2
- 239000004552 water soluble powder Substances 0.000 claims description 2
- 206010010904 Convulsion Diseases 0.000 abstract description 17
- 206010015037 epilepsy Diseases 0.000 abstract description 5
- 208000034308 Grand mal convulsion Diseases 0.000 abstract description 4
- 206010061334 Partial seizures Diseases 0.000 abstract description 4
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 13
- 239000003826 tablet Substances 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 10
- 239000013543 active substance Substances 0.000 description 7
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 238000002156 mixing Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000009747 swallowing Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000019658 bitter taste Nutrition 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
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- 229940062717 keppra Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
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- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
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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Abstract
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.
Description
WATER SOLUBLE PHARMACEUTICAL COMPOSITION
Field of the Invention
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.
Background of the Invention
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.
(I)
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.
In the prior art, the pharmaceutical 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.
However, 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, on the other hand, 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.
When the prior art is taken into consideration, there is need for 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.
Detailed Explanation of the Invention
Therapeutically advantageous water soluble compositions comprising levetiracetam which are user-friendly and have fast dissolution and/or dispersion have been found in scope of the present invention.
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.
A characteristic feature of the compositions in scope of the present invention is their being in single dose solid dosage form and in water soluble form.
The term "water soluble" used in the text comprises effervescent tablets, effervescent granules, effervescent powders, water soluble tablets, water soluble powders and/or water soluble granules.
The term "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.
The 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.
According to an aspect, 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.
In another aspect, 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.
In another aspect, 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.
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.
In another aspect, 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.
In another aspect, 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.
The inventors have observed that bitter taste problem of levetiracetam is entirely eliminated and no negative feeling of bitter taste remains in patients in the case that a sugar derivative binder is used along with the sweetener in the range of 0.5% to 20% by weight in the compositions.
According to this, 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.
Another characteristic feature of the invention is that 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.
The pharmaceutical 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,
b) Dry mixing of levetiracetam on an effective amount and at least one pharmaceutically acceptable diluent, at least one sweetener and optionally at least one effervescent couple and another excipient,
c) Wet granulation of the dry mixture obtained in the second step with the granulation solution obtained in the first step,
d) Drying and sieving the granules,
e) Optionally adding at least one pharmaceutically acceptable lubricant and flavoring agent into the dry granules,
f) Turning the final granules into suitable dosage forms.
The compositions of the present invention can be produced by one of the methods of dry granulation and dry mixing. In the case that 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.
Optionally, 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.
The 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.
In an aspect, the present invention provides a pharmaceutical composition comprising an effective amount of levetiracetam along with pharmaceutically acceptable excipients.
In another aspect, 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.
One characteristic feature of the present invention is that 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.
In another aspect, 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.
It was observed that the dissolution profile is improved and the formulation is dissolved in water at room temperature in less than 5 minutes when these characteristics are provided.
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.
In another aspect, a characteristic feature of the effervescent compositions of the present invention is that said compositions comprise; a) levetiracetam in the range of 10% to 50% by weight,
b) at least one acidic agent in the range of 25% to 60% by weight,
c) at least one basic agent in the range of 10% to 25% weight,
d) at least one diluent in the range of 1% to 10% by weight,
e) at least one binder in the range of 1% to 20%,
f) at least one sweetener in the range of 0.5 to 20% and optionally,
g) at least one more pharmaceutically acceptable excipient in the range of 1 to 50%.
The production method preferred for effervescent compositions of the present invention, on the other hand, is as follows: a) Preparation of the granulation solution prepared by mixing at least one pharmaceutically acceptable binder and the solution,
b) Dry mixing of levetiracetam on an effective amount and at least one pharmaceutically acceptable diluent, at least one sweetener and at least one effervescent couple, c) Wet granulation of the dry mixture obtained in the second step with the granulation solution obtained in the first step,
d) Drying and sieving the granules,
e) Optionally adding at least one pharmaceutically acceptable lubricant and flavoring agent into the dry granules obtained,
f) Turning the final granules into suitable dosage forms.
The inventors have found that the desiccation temperature of the granules plays a significant role for the final product to attain to sufficient dissolution in the effervescent compositions produced by wet granulation method given above. 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.
The pharmaceutical compositions and preparation methods for said compositions of the present invention can be explained with, but not limited to, the examples below.
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. Optionally, 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.
Claims
1. A pharmaceutical composition comprising levetiracetam characterized in that said composition is in single dose solid dosage form and in water soluble form.
2. The pharmaceutical composition according to claim 1 characterized in that the percentage of levetiracetam in total composition is in the range of 0.1% to 60% by weight.
3. The pharmaceutical composition according to claim 2 characterized in that the percentage of levetiracetam in total composition is in the range of 10% to 50% by weight.
4. The pharmaceutical composition according to claims 1 to 3 characterized in that said composition is in effervescent tablet, effervescent granule, effervescent powder, water soluble tablet, water soluble powder and/or water soluble granule form.
5. The pharmaceutical composition according to claims 1 to 4 characterized in that said composition comprises at least one pharmaceutically acceptable excipient 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 nonaqueous solvents or combinations thereof.
6. The pharmaceutical composition according to claim 5 characterized in that said composition comprises 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.
7. The pharmaceutical composition according to claim 6 characterized in that said composition comprises at least one pharmaceutically acceptable sweetener at least in the range of 0.5% by weight.
8. The pharmaceutical composition according to claim 7 characterized in that said composition comprises at least one pharmaceutically acceptable sweetener in the range of 0.5% to 20 % by weight.
9. The pharmaceutical composition according to claim 8, characterized in that said composition comprises at least one pharmaceutically acceptable sweetener in the range of 0.5% to 10 % by weight.
10. The pharmaceutical composition according to claim 9 characterized in that said composition comprises at least one pharmaceutically acceptable sweetener in the range of 0.5% to 4 % by weight.
11. The pharmaceutical composition according to claim 6 characterized in that said composition comprises at least one binder selected from the group comprising mannitol, sorbitol, xylitol, lactitol, maltitol, sugar and/or maltodextrin.
12. The pharmaceutical composition according to claim 11 characterized in that said binder is sorbitol.
13. The pharmaceutical composition according to claims 7 to 12 characterized in that the ratio of the sweetener to the binder is in the range of 1 :20 to 20: 1.
14. The pharmaceutical composition according to any one of the preceding claims characterized in that said composition is in effervescent tablet, effervescent granule and/or effervescent powder form.
15. The pharmaceutical composition according to claim 14 characterized in that said composition comprises at least one pharmaceutically acceptable effervescent couple, at least one binder, at least one flavoring agent, at least one diluent, at least one lubricant, at least one sweetener and other pharmaceutically acceptable excipients.
16. The pharmaceutical composition according to claim 15 characterized in that the effervescent couple used is composed of the combination of an acidic agent and a basic agent.
17. The pharmaceutical composition according to claim 16 characterized in that the percentage of the acidic agent comprised in the effervescent couple in total composition is in the range of 15% to 75% by weight.
18. The pharmaceutical composition according to claim 17 characterized in that the percentage of the acidic agent comprised in the effervescent couple in total composition is in the range of 25% to 60% by weight.
19. The pharmaceutical composition according to claim 18 characterized in that the percentage of the basic agent comprised in the effervescent couple in total composition is in the range of 0.1 % to 35% by weight.
20. The pharmaceutical composition according to claim 19 characterized in that the percentage of the basic agent comprised in the effervescent couple in total composition is in the range of 10% to 25% by weight.
21. The pharmaceutical composition according to claims 16 to 20 characterized in that the ratio of the acidic agent to the basic agent used is in the range of 1.6: 1 to 3.5: 1.
22. The pharmaceutical composition according to claim 21 characterized in that the ratio of the acidic agent to the basic agent used is in the range of 2: 1 to 2.9: 1.
23. The pharmaceutical composition according to claims 14 to 21 characterized in that the acidic agent used is selected from a group comprising citric acid, acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or combinations thereof.
24. The pharmaceutical composition according to claim 23 characterized in that the acidic agent used is citric acid anhydrous.
25. The pharmaceutical composition according to claims 14 to 24 characterized in that the basic agent used is selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium hydrogen carbonate or combinations thereof.
26. The pharmaceutical composition according to claim 25 characterized in that the basic agent used is sodium hydrogen carbonate.
27. The pharmaceutical composition according to claims 14 to 26 characterized in that said composition comprises;
a. levetiracetam in the range of 10% to 50% by weight,
b. at least one acidic agent in the range of 25% to 60% by weight,
c. at least one basic agent in the range of 10% to 25% weight,
d. at least one diluent in the range of 1 % to 10% by weight,
e. at least one binder in the range of 1 % to 20%,
f. at least one sweetener in the range of 0.5% to 20%, and optionally,
g. at least one more pharmaceutically acceptable excipients in the range of 1% to 50%.
28. The pharmaceutical composition according to claim 1 characterized in that said composition is produced by one of the methods of dry mixing, dry granulation or wet granulation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201003234 | 2010-04-26 | ||
| PCT/TR2011/000109 WO2011136751A2 (en) | 2010-04-26 | 2011-04-25 | Water soluble pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2563340A2 true EP2563340A2 (en) | 2013-03-06 |
Family
ID=44626494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP11720620A Withdrawn EP2563340A2 (en) | 2010-04-26 | 2011-04-25 | Water soluble pharmaceutical composition |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2563340A2 (en) |
| WO (1) | WO2011136751A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI2790695T1 (en) | 2011-12-16 | 2016-09-30 | Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. | Pharmaceutical composition comprising (s)-2-(2-oxopyrrolidin-1-yl)butanamid |
| US9339489B2 (en) | 2013-03-15 | 2016-05-17 | Aprecia Pharmaceuticals Company | Rapid disperse dosage form containing levetiracetam |
| HK1216513A1 (en) * | 2013-03-15 | 2016-11-18 | 阿普雷奇亚制药有限责任公司 | Rapid disperse dosage form containing levetiracetam |
| CN110193008A (en) * | 2018-11-21 | 2019-09-03 | 武汉兴华智慧医药科技有限公司 | A kind of Levetiracetam oral administration solution and preparation method thereof |
| ES2945809T3 (en) * | 2019-10-02 | 2023-07-07 | Intas Pharmaceuticals Ltd | Effervescent solid pharmaceutical compositions practically without sodium |
| CN115350178B (en) * | 2022-08-24 | 2024-04-26 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing levetiracetam |
| EP4570243A1 (en) * | 2023-12-13 | 2025-06-18 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Effervescent tablet formulation of brivaracetam |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8412357D0 (en) | 1984-05-15 | 1984-06-20 | Ucb Sa | Pharmaceutical composition |
| WO2006088864A1 (en) * | 2005-02-16 | 2006-08-24 | Elan Pharma International Limited | Controlled release compositions comprising levetiracetam |
| JP2009524658A (en) | 2006-01-24 | 2009-07-02 | テバ ファーマシューティカル インダストリーズ リミティド | Levetiracetam preparation and method for producing the same |
| CN101172105A (en) * | 2007-11-27 | 2008-05-07 | 北京润德康医药技术有限公司 | Use of levetiracetam in preparing intelligence benefiting medicament |
| WO2009135646A2 (en) * | 2008-05-05 | 2009-11-12 | Farmaprojects, Sa | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
| JP2010024156A (en) * | 2008-07-16 | 2010-02-04 | Ucb Pharma Sa | Pharmaceutical composition comprising levetiracetam |
| US20100055177A1 (en) * | 2008-08-29 | 2010-03-04 | Dafna Arieli | Modified release composition of levetiracetam and process for the preparation thereof |
-
2011
- 2011-04-25 WO PCT/TR2011/000109 patent/WO2011136751A2/en not_active Ceased
- 2011-04-25 EP EP11720620A patent/EP2563340A2/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2011136751A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011136751A3 (en) | 2011-12-29 |
| WO2011136751A2 (en) | 2011-11-03 |
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