Classifications

• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem

Definitions

• the present invention relates to pharmaceutical formulations comprising quetiapine that shall be used in schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and in continuous treatment of bipolar disorders.
• Quetiapine was first disclosed in the application numbered US4879288. In said document, it has been disclosed that quetiapine is effective in schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and in continuous treatment of bipolar disorders.
• Quetiapine is available in film tablet forms comprising 25, 100, 200, 300 mg quetiapine or prolonged release tablet forms comprising 50, 200, 300, 400 mg quetiapine on the market.
• the present invention relates to pharmaceutical formulations comprising quetiapine and preparation methods for said formulations.
• the formulations comprising quetiapine comprise talc, magnesium stearate, PEG 6000, silicone dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearyl fumarate and/or a combination thereof as the lubricant, the formulation does not adhere to the punch and inner walls of the die; wear and corrosion resulting from the possible friction in said machine parts are decreased.
• the present invention relates to quetiapine formulations wherein talc, magnesium stearate, PEG 6000, silicone dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearyl fumarate and/or a combination thereof is used as the lubricant.
• the lubricant used is magnesium stearate.
• d 100 value of magnesium stearate used is in the range of 30-250 ⁇ , preferably in the range of 50-200 ⁇ , more preferably in the range of 75-150 ⁇ .
• magnesium stearate is used as the lubricant and di 00 value of magnesium stearate used is in the range of 30-250 ⁇ , preferably in the range of 50-200 ⁇ , more preferably in the range of 75-150 ⁇ .
• the amount of the lubricant used for preparation of the formulations comprising quetiapine is an important parameter among characteristics of the formulation to be obtained. In the case that the lubricant is used less than the required amount, this results in adhesion of the formulation prepared to the machine parts and its binding to the hollow punches. Using lubricant more than the required amount, on the other hand, causes increase in dissolution times of the dosage forms obtained.
• formulations are not observed to adhere to the machine parts during preparation and the dosage forms obtained do not have long dissolution times in the case that the amount of the lubricant in the formulations comprising quetiapine is in the range of 1-20%, preferably in the range of 1- 10%, and more preferably in the range of 1-5 % in proportion to total weight of the formulation.
• the amount of the lubricant in the formulations comprising quetiapine is in the range of 1-20%, preferably in the range of 1- 10%, and more preferably in the range of 1-5 % in proportion to total weight of the formulation.
• the present invention relates to formulations comprising lubricant in the range of 1-20%, preferably in the range of 1-10% and more preferably in the range of 1-5% in proportion to total weight of the formulation.
• the formulations comprising quetiapine are characterized in that said formulations comprise magnesium stearate in the range of 1- 20%, preferably in the range of 1-10% and more preferably in the range of 1-5%.
• the ratio of di 00 value of quetiapine to d 100 value of the lubricant is in the range of 9:1 to 1 : 1 , preferably in the range of 8: 1 to 1 : 1 , and more preferably in the range of 6: 1 to 2: 1.
• a pharmaceutical composition comprising quetiapine is characterized in that said composition comprises lubricant in the range of 1-20 %, preferably in the range of 1-10%, more preferably in the range of 1-5% and
• the ratio of d 100 value of quetiapine to d 10 o value of the lubricant is in the range of 9: 1 tol :l, preferably in the range of 8:1 to 1 :1, and more preferably in the range of 6:1 to 2: 1 in said composition.
• the pharmaceutical composition comprising quetiapine is characterized in that
• - magnesium stearate is used in the range of 1-20%, preferably in the range of 1-10%, more preferably in the range of 1-5% in said composition and - the ratio of d 10 o value of quetiapine to d 100 value of the lubricant is in the range of 9: 1 to 1 : 1, preferably in the range of 8:1 to 1 :1 and more preferably in the range of 6: 1 to 2: 1.
• Percentage values of amounts given in scope of the present invention are calculated in proportion to unit dosage weight.
• Quetiapine comprised in the pharmaceutical formulations of the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in crystalline, amorphous forms or combinations thereof in terms of polymorphic structure.
• Quetiapine is preferably in quetiapine fumarate form.
• the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be prepared in any dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.
• the pharmaceutical formulations of the present invention comprising quetiapine and lubricant are preferably in powder, tablet and granule forms, more preferably in form of tablet, film tablet or effervescent tablet.
• the present invention relates to the pharmaceutical formulations comprising quetiapine and lubricant in form of tablet, film tablet or effervescent tablet.
• the pharmaceutical formulation obtained can be formed into any abovementioned dosage forms.
• the tablets obtained can be treated with film coating agents, for instance sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating compositions comprising any combination thereof.
• Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof as the sugar based coating agent.
• the water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
• cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
• synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
• the enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
• cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
• acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
• the delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
• compositions of the present invention comprising quetiapine and lubricant can comprise various excipients in addition to the active agent quetiapine and the lubricant.
• the pharmaceutical formulations of the present invention comprising quetiapine and lubricant comprise at least one excipient selected from a group comprising disintegrant, diluent, glidant, binder, optionally effervescent couple comprising at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent, antiadherant in addition to the active agent quetiapine and the lubricant.
• excipient selected from a group comprising disintegrant, diluent, glidant, binder, optionally effervescent couple comprising at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent, antiadherant in addition to the active agent quetiapine and the lubricant.
• the disintegrant that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
• the diluent that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
• the glidant that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
• the binder that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
• the inventors have seen that using more than one binders in the formulation has an influence on the dissolution time of the resulting dosage form. It has been observed that when a binder combination comprising at least two binders is used, the obtained dosage form can be dissolved rapidly, thus a high absorption of the drug and an effective treatment can be provided.
• the present invention relates to the pharmaceutical formulations comprising quetiapine wherein said formulation comprises a binder combination comprising at least two binders.
• the obtained dosage form can dissolve rapidly resulting in a high absoption of quetiapine active agent.
• the present invention relates to the pharmaceutical formulations comprising quetiapine wherein said formulation comprises a binder combination comprising first and second binder and wherein the ratio of the first binder to the second binder is in the range of 25:1 to 1:1, preferably 20:1 to 2:1, more preferably 15:1 to 3:1 by weight.
• the first binder is starch.
• the second binder is povidone.
• the present invention relates to the pharmaceutical formulations comprising quetiapine wherein said formulation comprises a binder combination comprising starch and povidone and wherein the ratio of starch to povidone is in the range of 25:1 to 1 :1, preferably 20 : 1 to 2 : 1 , more preferably 15 : 1 to 3 : 1 by weight.
• the present invention relates to the pharmaceutical formulations comprising quetiapine wherein said formulation comprises a binder combination in an amount in the range of 5-40%, preferably 10-30% in proportion to the total weight of the pharmaceutical formulation.
• the acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
• the pH regulating agent that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
• the surfactant that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
• the stabilizing agent that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
• the sweetener and/or taste regulating agent that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
• the flavoring agent that can be used in the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can be selected from flavors comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavors.
• the antiadherant that can be used in the pharmaceutical formulations of the present invention can be selected from talc, starch, colloidal silica, L-leucine and sodium sulfate.
• the pharmaceutical composition comprising quetiapine is characterized in that
• the lubricant is used in the range of 1-20%, preferably in the range of 1-10%, more preferably in the range of 1-5 % in said composition and
• the ratio of d 100 value of quetiapine to d 100 value of the lubricant is in the range of 9:1 to 1 :1, preferably in the range of 8: 1 to 1 :1 and more preferably in the range of 6:1 to 2:1 in said composition
• composition comprises at least one excipient selected from a group comprising disintegrant, diluent, glidant, binder, optionally effervescent couple comprising at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent, antiadherant in addition to quetiapine and the lubricant.
• excipient selected from a group comprising disintegrant, diluent, glidant, binder, optionally effervescent couple comprising at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent, antiadherant in addition to quetiapine and the lubricant.
• the pharmaceutical composition comprising quetiapine is characterized in that - magnesium stearate is used in the range of 1-20%, preferably in the range of 1-10%, more preferably in the range of 1-5% in said composition and
• the pharmaceutical formulation of the present invention comprises at least one excipient selected from a group comprising disintegrant, diluent, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent in addition to quetiapine and magnesium stearate.
• the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can comprise quetiapine in the range of 0.1 to 99 % by weight, preferably in the range of 1 to 97 % by weight, more preferably in the range of 5 to 95% by weight.
• the pharmaceutical formulations of the present invention can comprise quetiapine in the range of 5 to 95%, lubricant in the range of 1-5% disintegrant in the range of 1-10%, diluent in the range of 5-30%, binder in the range of 10-30%, glidant in the range of 0.1-3%, antiadherant in the range of 0.2-5% in proportion to total weight of the formulation.
• the pharmaceutical formulations of the present invention comprising quetiapine and lubricant can optionally comprise a second active agent in addition to quetiapine.
• the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker
• the pharmaceutical formulation of the present invention can be used in treatment of schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and in continuous treatment of bipolar disorders.
• EXAMPLE Film coated tablets comprising quetiapine and their preparation methods
• quetiapine fumarate is mixed with the other excipients.
• Magnesium stearate is added into this mixture as the lubricant and the final mixture is compressed in tablet form.
• the tablets are optionally coated with film coating solution.

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Citations (7)

• 2012
  • 2012-12-27 WO PCT/TR2012/000235 patent/WO2013100879A1/fr not_active Ceased

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