WO2013095312A1 - Formulations comprising quetiapine fumarate - Google Patents

Formulations comprising quetiapine fumarate Download PDF

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Publication number
WO2013095312A1
WO2013095312A1 PCT/TR2012/000215 TR2012000215W WO2013095312A1 WO 2013095312 A1 WO2013095312 A1 WO 2013095312A1 TR 2012000215 W TR2012000215 W TR 2012000215W WO 2013095312 A1 WO2013095312 A1 WO 2013095312A1
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Prior art keywords
quetiapine
granules
excipient
active agent
optionally
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Application number
PCT/TR2012/000215
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French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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Publication of WO2013095312A1 publication Critical patent/WO2013095312A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

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 of bipolar disorders.
  • Quetiapine was first disclosed in the application numbered US4879288. In said document, it was disclosed that quetiapine is effective in schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and continuous treatment of bipolar disorders.
  • Quetiapine is available in film coated tablet forms comprising 25, 100, 200, 300 mg of quetiapine or prolonged release tablet forms comprising 50, 200, 300, 400 mg of quetiapine on the market.
  • formulation mixtures do not have proper flow due to the reasons that free flow of the obtained granules cannot be enabled and/or possible friction between granule particles cannot be reduced, therefore homogeneity cannot be provided in the pharmaceutical composition obtained and the mixture loses its homogeneity during preparation of the formulations comprising quetiapine. Therefore, the abovementioned problems cause weight changes in the end product and increase in relative standard deviation values during forming the formulations into any dosage form. Weight and content uniformity cannot be provided in the end product due to these variations observed in weight of the end product obtained and failure to ensure formulation homogeneity.
  • the present invention relates to pharmaceutical formulations comprising quetiapine and methods for preparation of these formulations. Surprisingly, it has been observed that in the case that the formulations wherein the granules comprising quetiapine, at least one excipient and optionally a second active agent and having an average particle size in the range of 300- 2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ are formed into any solid dosage form, relative standard deviation thereof remains low, a homogeneous pharmaceutical composition is obtained, weight and content uniformity are provided by preventing weight changes.
  • the subject of the present invention is that the average particle size of the granules comprising quetiapine, at least one excipient and optionally a second active agent is in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ during preparation of the formulations comprising quetiapine.
  • average particle size refers to volumetric average particle size and is shown with d 5 o in short.
  • d 50 signifies that half of the said substance by volume has a particle size above the value stated with d 50 and the other half of the substance by volume has a particle size below the value stated with d 50 .
  • D 50 value can be measured by one of the known measuring devices, for instance by a device measuring particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
  • the pharmaceutical formulations prepared according to the process of the present invention can comprise various excipients in addition to the active agent quetiapine.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, optionally effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, antiadherant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent.
  • the granules should not agglomerate during their preparations.
  • the inventors have observed that when the granules comprise quetiapine, disintegrant, binder and diluent, the granules do not agglomerate during the preparation and more homogeneous pharmaceutical composition is obtained, resulting in an effective treatment.
  • the present invention relates to a process that shall be used in production of granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ characterized in that said granules comprise quetiapine, disintegrant, binder and diluent.
  • the present invention relates to a process that shall be used in production of granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ which comprise quetiapine, at least one excipient and optionally a second active agent characterized in that said granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350- 2000 ⁇ , more preferably in the range of 500-1750 ⁇ are obtained by
  • the pharmaceutical formulation of the present invention can be obtained by a method comprising the steps of;
  • the pharmaceutical formulation of the present invention is preferably obtained by a method comprising the steps of;
  • the inventors have also observed that in the case that 45-90% of the amount of disintegrant is added to the process intragranularly before granulation and 10-55% of the amount of disintegrant is added to the process extragranularly after granulation, a homogenous quetiapine composition is obtained and weight and content uniformity are provided.
  • the present invention relates to a process for the preparation of the quetiapine formulation wherein 45-90% of the amount of disintegrant is added to the process intragranularly before granulation and 10-55% of the amount of disintegrant is added to the process extragranularly after granulation.
  • the inventors have observed relative standard deviation of the weight by changing the average particle size values of the granules in order to find the effect of the average particle sizes of the granules sieved after granulation and drying processes on weight changes in solid dosage form obtained and therefore on weight uniformity. According to this, the average particle size values of the granules obtained after the sieving process and relative standard deviation values (RSD %) observed in accordance with these are given in Table 1.
  • RSD% values are around 2% or less when the average particle sizes of the granules obtained are in the range of 300-2500 ⁇ , particularly in the range of 500-2000 ⁇ . According to this, it has been found that the solid dosage forms of the formulations prepared with the granules having an average particle size in the range of 300-2500 ⁇ and more preferably in the range of 500-2000 ⁇ have low relative standard deviation and therefore weight uniformity is ensured.
  • the inventors have seen that the parameters such as drying temperature and moisture content of the obtained granules are important for obtaining optimum values of hardness, brittleness and stability of the granules obtained during preparation of the formulations comprising quetiapine and the end product in solid form prepared with the said granules and therefore important for preventing possible problems that can be encountered during quality control and using phases.
  • the inventors have surprisingly seen that the granules obtained according to the process of the present invention by drying the granules at 10-120°C, preferably at 20-100°C and more preferably at 25-70°C have proper flow and the solid forms prepared with these granules have desired hardness and brittleness.
  • the present invention relates to drying the granules comprising quetiapine, at least one excipient and optionally the second active agent at a temperature in the range of 10-120°C, preferably at a temperature in the range of 20-100°C and more preferably at a temperature in the range of 25-70°C during preparation of the formulations comprising quetiapine.
  • the present invention relates to drying the granules comprising quetiapine, at least one excipient and optionally the second active agent in the manner that they have moisture content less than 1% by weight, preferably in the range of 0.1-0.9% by weight during preparation of the formulations comprising quetiapine.
  • Quetiapine comprised in the pharmaceutical formulations prepared according to the process of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in terms of polymorphic structure it is in amorphous form or crystalline form or the combination thereof.
  • Quetiapine is preferably in quetiapine fumarate form.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be prepared in any solid 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 prepared according to the process of the present invention and comprising quetiapine are preferably in powder, tablet and granule forms, more preferably in film coated tablet or effervescent tablet forms.
  • the pharmaceutical formulation obtained according to the present invention 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 a 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 a combination thereof.
  • 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.
  • the disintegrant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 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 prepared according to the process of the present invention and comprising quetiapine can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic 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 prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
  • the surfactant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
  • the antiadheant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be selected from talc, starch, colloidal silica, sodium sulphate and streates.
  • the stabilizing agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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.
  • flavouring agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be selected from flavours such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can comprise quetiapine in the range of 0.1 to 99.9 % by weight, preferably in the range of 1 to 99% by weight, more preferably in the range of 5 to 95% by weight.
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine 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 formulations prepared according to the process of the present invention and comprising a second active agent in addition to quetiapine can be prepared in any solid dosage forms 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 in the case that two active agents are comprised in the same formulation; in dosage forms such as layered tablet, capsule in the case that the two active agents are in different formulations but in the same dosage form; in treatment package form comprising a combination of the solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet or in the forms of micro tablet and/or capsule comprising micropellet in the case that the two active agents are in different formulations and in different dosage forms.
  • a granulation solution comprising the binder is prepared. Quetiapine fumarate, the binder, the disintegrant and the diluent are granulated with the granulation solution. The granules obtained are dried and sieved in the manner that they have an average particle size of 800 ⁇ . The granules sieved are mixed with the glidant, the disintegrant and the antiadherent. The lubricant is added into this mixture and the final mixture obtained is compressed in tablet form.

Abstract

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 continuous treatment of bipolar disorders and preparation methods of these formulations.

Description

FORMULATIONS COMPRISING QUETIAPINE FUMARATE
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 of bipolar disorders. Quetiapine was first disclosed in the application numbered US4879288. In said document, it was disclosed that quetiapine is effective in schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and continuous treatment of bipolar disorders.
Figure imgf000002_0001
Quetiapine is available in film coated tablet forms comprising 25, 100, 200, 300 mg of quetiapine or prolonged release tablet forms comprising 50, 200, 300, 400 mg of quetiapine on the market.
It is seen that formulation mixtures do not have proper flow due to the reasons that free flow of the obtained granules cannot be enabled and/or possible friction between granule particles cannot be reduced, therefore homogeneity cannot be provided in the pharmaceutical composition obtained and the mixture loses its homogeneity during preparation of the formulations comprising quetiapine. Therefore, the abovementioned problems cause weight changes in the end product and increase in relative standard deviation values during forming the formulations into any dosage form. Weight and content uniformity cannot be provided in the end product due to these variations observed in weight of the end product obtained and failure to ensure formulation homogeneity. This situation poses problems for producers during production and quality control phases and also patients cannot take same amount of drug during the treatment, which results in decrease in treatment efficiency due to loss of weight and content uniformity observed in the dosage forms obtained. As it is seen, there is still need to develop new approaches so as to obtain homogeneous quetiapine formulations produced in the manner that no change weight is observed in unit dosage for the purpose of performing an effective treatment by preventing the changes observed in weight and content of the end product obtained and preventing the problems arising from loss of weight uniformity during quality and control phases.
As a result of the studies they conducted in line with this requirement, the inventors have found that some physical characteristics of the formulations they have developed in order to prepare the dosage forms comprising quetiapine are effective on relative standard deviation in dosage weight of the drug obtained and said problems encountered during both phases of quality control and use can be solved with these formulations developed by adjusting physical characteristics.
Description of the Invention The present invention relates to pharmaceutical formulations comprising quetiapine and methods for preparation of these formulations. Surprisingly, it has been observed that in the case that the formulations wherein the granules comprising quetiapine, at least one excipient and optionally a second active agent and having an average particle size in the range of 300- 2500 μπι, preferably in the range of 350-2000 μιη, more preferably in the range of 500-1750 μηι are formed into any solid dosage form, relative standard deviation thereof remains low, a homogeneous pharmaceutical composition is obtained, weight and content uniformity are provided by preventing weight changes.
In this respect, the subject of the present invention is that the average particle size of the granules comprising quetiapine, at least one excipient and optionally a second active agent is in the range of 300-2500 μπι, preferably in the range of 350-2000 μιη, more preferably in the range of 500-1750 μηι during preparation of the formulations comprising quetiapine.
The term "average particle size" refers to volumetric average particle size and is shown with d5o in short. In this sense, the term d50 signifies that half of the said substance by volume has a particle size above the value stated with d50 and the other half of the substance by volume has a particle size below the value stated with d50.
D50 value can be measured by one of the known measuring devices, for instance by a device measuring particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
The pharmaceutical formulations prepared according to the process of the present invention can comprise various excipients in addition to the active agent quetiapine. The pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, optionally effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, antiadherant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent.
In order to obtain a homogeneous pharmaceutical composition, it is also required that the granules should not agglomerate during their preparations. The inventors have observed that when the granules comprise quetiapine, disintegrant, binder and diluent, the granules do not agglomerate during the preparation and more homogeneous pharmaceutical composition is obtained, resulting in an effective treatment.
In another aspect, the present invention relates to a process that shall be used in production of granules having an average particle size in the range of 300-2500 μηι, preferably in the range of 350-2000 μπι, more preferably in the range of 500-1750 μπι characterized in that said granules comprise quetiapine, disintegrant, binder and diluent.
In another aspect, the present invention relates to a process that shall be used in production of granules having an average particle size in the range of 300-2500 μηι, preferably in the range of 350-2000 μηι, more preferably in the range of 500-1750 μπι which comprise quetiapine, at least one excipient and optionally a second active agent characterized in that said granules having an average particle size in the range of 300-2500 μηι, preferably in the range of 350- 2000 μιη, more preferably in the range of 500-1750 μπι are obtained by
• sieving said granules with a proper sieve or
• grinding said granules with devices such as impact mill, jet mill, blade mill etc.
In the case that blade mill is used, grinding is performed by the effect of rotating blades in the device.
In the case that impact mill is used, grinding is performed by the effect of rotating hammers in the device.
In the case that jet mill is used, grinding is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream. The pharmaceutical formulation of the present invention can be obtained by a method comprising the steps of;
• Homogeneously mixing the granules obtained after granulating the active agent quetiapine and, if available, the second active agent with the granulation solution comprising at least one of the excipients and drying the mixture obtained; if required, bringing it to an average particle size in the range of 300-2500 μηι by an appropriate method and optionally treating it with at least one other excipient or
• Homogeneously mixing the granules obtained after mixing the active agent quetiapine and, if available, the second active agent with one of the excipients and optionally granulating the mixture with the granulation solution comprising at least one excipient, and drying the mixture obtained; if required, bringing the granules to an average particle size in the range of 300-2500 μηι by an appropriate method and optionally treating them with at least one other excipient or
• Using any of the abovementioned methods separately for each active agent composition and combining the formulations obtained in the case that two active agents are used.
The pharmaceutical formulation of the present invention is preferably obtained by a method comprising the steps of;
• mixing quetiapine active agent with binder, disintegrant and diluents and granulating the mixture with the granulation solution comprising binder,
• drying and then sieving the granules obtained bringing them to an average particle size in the range of 300-2500 μηι,
• mixing dried and sieved granules with at least one excipient and adding lubricant into the mixture obtained and
• optionally compressing the resulting mixture into the tablet form.
The inventors have also observed that in the case that 45-90% of the amount of disintegrant is added to the process intragranularly before granulation and 10-55% of the amount of disintegrant is added to the process extragranularly after granulation, a homogenous quetiapine composition is obtained and weight and content uniformity are provided.
In another aspect, the present invention relates to a process for the preparation of the quetiapine formulation wherein 45-90% of the amount of disintegrant is added to the process intragranularly before granulation and 10-55% of the amount of disintegrant is added to the process extragranularly after granulation.The inventors have observed relative standard deviation of the weight by changing the average particle size values of the granules in order to find the effect of the average particle sizes of the granules sieved after granulation and drying processes on weight changes in solid dosage form obtained and therefore on weight uniformity. According to this, the average particle size values of the granules obtained after the sieving process and relative standard deviation values (RSD %) observed in accordance with these are given in Table 1. As seen in the table, RSD% values are around 2% or less when the average particle sizes of the granules obtained are in the range of 300-2500 μηι, particularly in the range of 500-2000 μηι. According to this, it has been found that the solid dosage forms of the formulations prepared with the granules having an average particle size in the range of 300-2500 μπι and more preferably in the range of 500-2000 μηι have low relative standard deviation and therefore weight uniformity is ensured.
Table 1: Average particle size of the granules and their relative standard deviation values accordingly
Figure imgf000006_0001
During the studies conducted, the inventors have seen that the parameters such as drying temperature and moisture content of the obtained granules are important for obtaining optimum values of hardness, brittleness and stability of the granules obtained during preparation of the formulations comprising quetiapine and the end product in solid form prepared with the said granules and therefore important for preventing possible problems that can be encountered during quality control and using phases. According to the studies conducted, the inventors have surprisingly seen that the granules obtained according to the process of the present invention by drying the granules at 10-120°C, preferably at 20-100°C and more preferably at 25-70°C have proper flow and the solid forms prepared with these granules have desired hardness and brittleness.
According to this, in another aspect, the present invention relates to drying the granules comprising quetiapine, at least one excipient and optionally the second active agent at a temperature in the range of 10-120°C, preferably at a temperature in the range of 20-100°C and more preferably at a temperature in the range of 25-70°C during preparation of the formulations comprising quetiapine.
In line with the studies conducted, the inventors have seen that moisture content of the granules obtained during preparation of the formulations comprising quetiapine is effective on the end product obtained in solid form to have desired physical properties and on enabling weight certainty and stability of the product obtained.
According to this, in another aspect, the present invention relates to drying the granules comprising quetiapine, at least one excipient and optionally the second active agent in the manner that they have moisture content less than 1% by weight, preferably in the range of 0.1-0.9% by weight during preparation of the formulations comprising quetiapine.
Quetiapine comprised in the pharmaceutical formulations prepared according to the process of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in terms of polymorphic structure it is in amorphous form or crystalline form or the combination thereof. Quetiapine is preferably in quetiapine fumarate form.
The pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be prepared in any solid 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 prepared according to the process of the present invention and comprising quetiapine are preferably in powder, tablet and granule forms, more preferably in film coated tablet or effervescent tablet forms.
The pharmaceutical formulation obtained according to the present invention can be formed into any abovementioned dosage forms. In the case that the formulation is in tablet form, 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 a combination thereof.
As the sugar based coating agent, 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 a combination thereof.
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.
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.
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. The disintegrant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 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 prepared according to the process of the present invention and comprising quetiapine can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic 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 prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
The surfactant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents. The antiadheant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be selected from talc, starch, colloidal silica, sodium sulphate and streates.
The stabilizing agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine 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 prepared according to the process of the present invention and comprising quetiapine 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 flavouring agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can be selected from flavours such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
The pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine can comprise quetiapine in the range of 0.1 to 99.9 % by weight, preferably in the range of 1 to 99% by weight, more preferably in the range of 5 to 95% by weight. The pharmaceutical formulations prepared according to the process of the present invention and comprising quetiapine 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 and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin vitamin C, vitamin E, vitamin B6j vitamin B2; vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
The pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to quetiapine can be prepared in any solid dosage forms 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 in the case that two active agents are comprised in the same formulation; in dosage forms such as layered tablet, capsule in the case that the two active agents are in different formulations but in the same dosage form; in treatment package form comprising a combination of the solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet or in the forms of micro tablet and/or capsule comprising micropellet in the case that the two active agents are in different formulations and in different dosage forms. The pharmaceutical formulation of the present invention can be used in schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and in continuous treatment of bipolar disorders.
EXAMPLE: Tablets comprising quetiapine and preparation method thereof
Figure imgf000012_0001
In order to obtain the formulations of the present invention, a granulation solution comprising the binder is prepared. Quetiapine fumarate, the binder, the disintegrant and the diluent are granulated with the granulation solution. The granules obtained are dried and sieved in the manner that they have an average particle size of 800 μπι. The granules sieved are mixed with the glidant, the disintegrant and the antiadherent. The lubricant is added into this mixture and the final mixture obtained is compressed in tablet form.

Claims

A process that shall be used in preparation of the pharmaceutical formulations comprising quetiapine, characterized in that
- The granules comprising quetiapine, at least one excipient and optionally the second active agent are
- sieved or ground in the manner that they have an average particle size in the range of 300-2500 μη ,
- The granules are dried
- The granules are mixed with at least one excipient.
The process according to claim 1, characterized in that said process is sieving or grinding the granules comprising quetiapine, at least one excipient, that is selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, antiadheant, stabilizant, sweetener and/or taste regulating agent, flavouring agent and optionally the second active agent in the manner that they have an average particle size in the range of 350-2000 μηι.
The process according to claims 1-2, characterized in that said process is sieving or grinding the granules comprising quetiapine, at least one excipient and optionally the second active agent in the manner that they have an average particle size in the range of 500- 1750 μπι.
The process according to claims 1-3, characterized in that said process is sieving or grinding the granules comprising quetiapine, disintegrant, binder and diluent.
The process according to claims 1 - 4, characterized in that
- The granules comprising quetiapine, at least one excipient and optionally the second active agent are
- sieved in the manner that they have an average particle size in the range of 300-2500 μιη
- The granules are dried and
- The granules are mixed with at least one excipient.
The process according to claim 5, characterized in that
- The granules comprising quetiapine, at least one excipient and optionally the second active agent are - ground in the manner that they have an average particle size in the range of 500-1750 μιη
- The granules are dried and
- The granules are mixed with at least one excipient.
7. The process according to claims 5 and 6, characterized in that grinding process is performed by impact mill, jet mill or blade mill.
8. The process according to claims 1-7-8, characterized in that the granules comprising quetiapine, at least one excipient and optionally the second active agent are dried at a temperature in the range of 10-120°C.
9. The process according to claim 8, characterized in that the granules comprising quetiapine, at least one excipient and optionally the second active agent are dried at a temperature in the range of 20-100°C.
10. The process according to claims 8-9, characterized in that the granules comprising quetiapine, at least one excipient and optionally the second active agent are dried at a temperature in the range of 25-70°C.
11. The process according to claims 1- 10, characterized in that the granules comprising quetiapine, at least one excipient and optionally the second active agent are dried in the manner that they have moisture content less than 1%.
12. The process according to claims 1-11, characterized in that the granules comprising quetiapine, at least one excipient and optionally the second active agent are dried in the manner that they have moisture content in the range of 0.1 - 0.9 %.
13. The process according to claims 1-12 characterized in that said process comprises the steps of;
mixing quetiapine active agent with binder, disintegrant and diluent and granulating the mixture with the granulation solution comprising binder, drying and then sieving the granules obtained bringing them to an average particle size in the range of 300-2500 μιη,
mixing dried and sieved granules with at least one excipient and adding lubricant into the mixture obtained and
optionally compressing the resulting mixture into the tablet form.
14. The process according to claims 1-13 characterized in that 45-90% of the amount of disintegrant is added to the process intragranularly before granulation and 10-55% of the amount of disintegrant is added to the process extragranularly after granulation.
15. A pharmaceutical formulation prepared in accordance with the process according to claim 1 -14, characterized in that
• Said formulation comprises granules comprising quetiapine, at least one excipient and optionally a second active agent and
• The granules comprising quetiapine, at least one excipient and optionally a second active agent have an average particle size in the range of 300-2500 μιη.
16. The pharmaceutical formulation comprising quetiapine according to claim 15, characterized in that
• Said formulation comprises granules comprising quetiapine, at least one excipient and optionally a second active agent and
• The granules comprising quetiapine, at least one excipient and optionally a second active agent have an average particle size in the range of 350-2000 μπι.
17. The pharmaceutical formulation comprising quetiapine according to claims 15 and 16, characterized in that
• Said formulation comprises granules comprising quetiapine, at least one excipient and optionally a second active agent and
• The granules comprising quetiapine, at least one excipient and optionally a second active agent have an average particle size in the range of 500-1750 μπι.
18. The pharmaceutical formulation according to claims 15-17, wherein said formulation is prepared in any dosage forms of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.
19. The pharmaceutical formulation according to claim 18, wherein said formulation is in film coated tablet or effervescent tablet form.
20. The pharmaceutical formulation according to claims 15- 19, wherein quetiapine is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.
21. The pharmaceutical formulation according to claims 15- 20, wherein said formulation comprises quetiapine as the active agent in the range of 0.1 to 99.9% by weight.
22. The pharmaceutical formulation according to claim 21, wherein said formulation comprises quetiapine as the active agent in the range of 1 to 99 % by weight.
23. The pharmaceutical formulation according to claim 22, wherein said formulation comprises quetiapine as the active agent in the range of 5 to 95% by weight.
4. The pharmaceutical formulation according to claims 15- 23, wherein the second active agent comprised in the formulation that can optionally be used in addition to quetiapine is selected from antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, 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 and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin vitamin C, vitamin E, vitamin B6; vitamin B2; vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
PCT/TR2012/000215 2011-12-19 2012-12-17 Formulations comprising quetiapine fumarate WO2013095312A1 (en)

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