EXTENDED RELEASE COMPOSITIONS AND METHODS FOR THEIR MANUFACTURE.

专利摘要:
The present invention relates to sustained release formulations of quetiapine and its pharmaceutically acceptable salts, and methods of making the formulations, which may include the use of polymers selected for their physical and chemical characteristics. The formulations may include polymers selected to cause solid dosage forms of the formulations to conform to predefined quetiapine release criteria. The formulations may include non-polymeric materials that may affect quetiapine release.
公开号:BE1018260A3
申请号:E2007/0555
申请日:2007-11-19
公开日:2010-08-03
发明作者:Daniel Brown；Donna Caster；Sandra Hopkins；Jennifer Llewelyn；Lisa Martin；Robert Timko；Husheng Yang；Brian Clark
申请人:Astrazeneca Ab；
IPC主号:

专利说明:

PROLONGED RELEASE COMPOSITIONS AND METHODS OF MAKING SAME
Cross-reference to a related application
This application is a non-provisional application for U.S. Provisional Application No. 60 / 930,643, filed May 16, 2007, which is presently incorporated by reference in its entirety.
Field of the invention
The present invention relates to a formulation of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine (quetiapine). More particularly, the invention relates to a sustained release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof.
Context
The compound 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine (see formula 1), having the common name "quetiapine", and its pharmaceutically acceptable salts, has a useful anti-dopaminergic activity and can be used, for example, as an antipsychotic agent (for example, for the control of the manifestations of psychotic disorders) or as a treatment of hyperactivity. The compound can be used as an antipsychotic agent with a substantial decrease in the risk of causing side effects such as acute dystonia, acute dyskinesia, Parkinson's syndrome and tardive dyskinesia, which may result from the use of the drug. antipsychotics or conventional neuroleptics.
The preparation, physical properties and beneficial pharmacological properties of quetiapine, and its pharmaceutically acceptable salts are described in European Patent Nos. 240,228 and 282,236 and in U.S.
No. 4,879,288, the contents of which are presently incorporated by reference in its entirety.
It is desirable in the treatment of several diseases, both therapeutically and prophylactically, to produce an active pharmaceutical component in a sustained release form. Sustained release can produce a generally uniform and constant release rate over a long period of time and can achieve a desired blood or plasma level of the active component without requiring frequent administration of the component.
Although there are many sustained-release compositions known in the art that utilize gelling agents, such as hydroxypropyl methylcellulose (also referred to herein as "HPMC" and "hypromellose"), it has proven difficult to formulate formulations. sustained release of soluble drugs and gelling agents, such as hypromellose, for several reasons. Primarily, it has proved difficult to obtain the desired dissolution profiles or to control the rate of release of active components that are soluble in aqueous medium (as is the case for quetiapine, which is slightly soluble in water). water and soluble in acids). Among other problems, such active components tend to generate a sustained release product that is susceptible to a phenomenon called "dose dumping". That is, the release of the active component is delayed for some time but once the release starts to occur the release rate is very high. In addition, fluctuations tend to occur in the plasma concentrations of the active component, which increases the likelihood of toxicity. In addition, a certain degree of diurnal variation in plasma concentration of the active component has also been observed.
Because of the many physical and chemical interactions between components of certain pharmaceutical compositions, it is also often difficult to combine the components in a manner that produces desirable physical or chemical characteristics of the formulation.
Accordingly, it would be desirable to provide sustained-release formulations of water-soluble drugs, such as 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof which exhibit improved performance and can resolve, or at least mitigate, one or more of the difficulties described above.
summary
Formulations comprising quetiapine and its pharmaceutically acceptable salts, and methods for preparing the formulations are provided.
A formulation may comprise a hydrophilic matrix comprising a gelling agent, 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine, or a salt pharmaceutically acceptable thereof, such as a hemifumarate salt, and one or more pharmaceutically acceptable excipients.
Examples of gelling agents that may be present in the embodiments of the invention include such substances. hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, methylcellulose, ethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, carbopol, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like, or mixtures thereof. them. In some embodiments, the gelling agent may comprise hypromellose.
The amount of gelling agent, in combination with the quetiapine and any excipients, may be chosen such that the active component is released from the formulation in a controlled manner over a period of about 24 hours.
The gelling agent may be present in a range of about 5 to 50% (by weight). The range can be about 5 to 10%. The range may be about 20 to 50%. The range may be about 25 to 50%. The range can be from 28 to 50%. The range can be 30 to 50%. (The percentages by weight, in the present context, relate to the weight of tablet core, excluding the weight of any coating, unless otherwise indicated).
Some embodiments of the invention may include hypromellose blends that include more than one polymer grade. Hypromellose polymers are marketed under a number of brand names, for example METHOCEL® E, F, J and K from Dow Chemical Company, USA and METOLOSE ™ 60SH, 65SH and 90SH from Shin-Etsu, Ltd., Japan. The grades may exhibit differences in methoxy and hydroxypropoxy contents as well as viscosity and other characteristics. Different batches of hypromellose, even if they are of the same quality, may show differences in methoxy and hydroxypropoxy contents, viscosity and other characteristics.
The formulation may contain a buffer or pH modifier, for example if the active component has a pH-dependent solubility, as is the case for quetiapine salts such as quetiapine fumarate.
The formulation, in general, contains one or more excipients. Such excipients may include diluents such as lactose, microcrystalline cellulose, dextrose, mannitol, sucrose, sorbitol, gelatin, gum arabic, dicalcium phosphate, tricalcium phosphate, monocalcium phosphate, sodium phosphate, and the like. sodium, sodium carbonate and the like, preferably lactose and microcrystalline cellulose; lubricants such as stearic acid, zinc, calcium or magnesium stearate and the like, preferably magnesium stearate; binders such as sucrose, polyethylene glycol, povidone (polyvinylpyrrolidone), cereal or corn starch, pregelatinized starch and the like; dyes such as ferric oxides, FD & C dyes, lacquers and the like; flavoring agents; and pH modifiers which comprise suitable organic acids or alkali metal salts (e.g. lithium, sodium or potassium) thereof, such as benzoic acid, citric acid, tartaric acid, succinic acid, adipic acid and the like or the corresponding alkali metal salts thereof, preferably the alkali metal salts of such acids and in particular the citric acid sodium salt (i.e. ie, sodium citrate). As is known, certain excipients have multiple functions, for example they are both diluents and binders.
In certain embodiments of the invention, the formulation may be present in a solid pharmaceutical form such as a tablet, capsule tablet or any other suitable form comprising hemifumarate of 11- [4 - [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine ("quetiapine fumarate"), from 6 to 18% by weight of sodium citrate dihydrate, 30.0% by weight weight of hydroxypropylmethylcellulose, where at 29 of the 30.0% is a first component of hydroxypropylmethylcellulose; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has a "bulk viscosity" (see below) of between 80 centipoise ("cp") and 120cp and a second hydroxypropylmethylcellulose which has a viscosity apparent between 3000 cp and 5600 cp. The tablet may comprise from 11 to 12% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. The tablet may comprise from 29.5 to 30.5% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] hemifumarate thiazepine. The tablet may comprise from 37.9 to 38.9% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] hemifumarate thiazepine. In some embodiments, the tablet comprises from 52.4 to 53.4% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] hemifumarate. [1,4] thiazepine.
In some embodiments, the viscosities of the hydroxypropyl methylcellulose are consistent with the apparent viscosities of the Ubbelohde viscometer of 2% by weight of hydroxypropyl methylcellulose in water at 20 °, as determined using the method described in the United States Pharmacopoeia ( USP30-NF25), United States Pharmacopoeia Convention, Inc. 2007, p. 2323.
In certain embodiments of the invention, the formulation comprises sodium citrate dihydrate present at about 7.2 to 12.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 7.2% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 11.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 12.5% by weight.
In some embodiments of the invention, the formulation comprises lactose monohydrate present up to about 30% by weight. In some embodiments, the formulation comprises lactose monohydrate present at 25.1% by weight. In some embodiments, the formulation comprises lactose monohydrate present at 13.0% by weight. In some embodiments, the formulation comprises lactose monohydrate present at 8.8 wt%. In some embodiments, the formulation comprises lactose monohydrate present at 1.8% by weight.
In some embodiments, the formulation comprises microcrystalline cellulose present up to about 30% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present at 25.1% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present at 13.0% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present at 8.8 wt%. In some embodiments, the formulation comprises microcrystalline cellulose present at 1.8% by weight.
In some embodiments, the tablet comprises an amount of magnesium stearate of from about 1% to 3% by weight. In some embodiments, the tablet comprises magnesium stearate present at 1.0% by weight. In some embodiments, the tablet comprises magnesium stearate present at 1.5% by weight. In some embodiments, the tablet comprises magnesium stearate present at 2.0% by weight.
In some embodiments, the hydroxypropyl methylcellulose comprises from 9.8 to 13.4% by weight of the hydroxypropyl methylcellulose, measured by nuclear magnetic resonance ("NMR"), of hydroxypropoxy. In some embodiments, the hydroxypropyl methylcellulose comprises from 26.4 to 29.2% by weight of the hydroxypropyl methylcellulose, measured by NMR, of methoxy. In some embodiments of the invention, the solid dosage form comprises 50 milligrams ("mg") of quetiapine, for example in a total core mass of 500 mg. In some embodiments, the solid dosage form comprises 150 mg of quetiapine, for example, in a total core mass of 575 mg. In some embodiments, the solid dosage form comprises 200 mg of quetiapine, for example in a total core mass of 600 mg. In some embodiments, the solid dosage form comprises 400 mg of quetiapine, for example in a total core mass of 870 mg.
In certain embodiments of the invention, the formulation is present in a solid pharmaceutical form comprising 50 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a plasma concentration, in nanograms of quetiapine per milliliter of plasma, which is up to approximately: 67.6 to 1 hour after ingestion; 124 at 4 hours after ingestion; 105 to 8 hours after ingestion; 74.3 to 12 hours after ingestion; and 236 to 16 hours after ingestion.
In some embodiments of the invention, the formulation is a solid pharmaceutical form comprising 200 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a plasma concentration, in nanograms of quetiapine by milliliter of plasma, which is: up to about 251 to 1 hour after ingestion; between about 32.2 and about 416 to 4 hours after ingestion; until about 496 to 8 hours after ingestion; between about 4.6 and about 323-12 hours after ingestion; and until about 251 to 16 hours after ingestion.
In certain embodiments of the invention, the formulation is a solid pharmaceutical form comprising 400 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a plasma concentration, in nanograms of quetiapine by milliliter plasma, which is: between about 15.9 and about 391 to 1 hour after ingestion; until about 1052-4 hours after ingestion; from about 63.1 to about 785 to 8 hours after ingestion; from about 11.1 to about 613-12 hours after ingestion; and up to about 448-16 hours after ingestion.
In some embodiments of the invention, a dosage form comprises: 30.0% by weight of hydroxypropyl methylcellulose and 7.2% by weight of sodium citrate dihydrate. In some embodiments, from 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80cp and 120cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000cp and 5600cp. In some embodiments, the viscosities of the dosage form are consistent with the Ubbelohde viscometer viscosities of 2% by weight of hydroxypropyl methylcellulose in water at 20 °, as determined using the method described in the United States Pharmacopoeia ( USP30-NF25), United States Pharmacopoeia Convention, Inc. 2007, p. In some embodiments, the first and second components, respectively, have viscosities of 80 to 120 cps and 3000 to 5600 cps.
In certain embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a quetiapine plasma concentration as a function of time, in nanograms. of quetiapine per milliliter of plasma, having a maximum value, Cmax, of up to about 239 and corresponds to a time tmax which is between 2 and 16 hours after ingestion. In some embodiments, the concentration has a C24 value of up to about 39.2 and corresponds to a time t24 at 24 hours after ingestion; and the Cmax: C24 ratio is up to about 35.2.
In certain embodiments of the invention, a solid dosage form comprises 200 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a quetiapine plasma concentration as a function of time, in nanograms of quetiapine per milliliter of plasma, having a maximum value, C ^ x, which is between about 3.9 and about 601 and corresponds to a time tmax which is between 2 and 8 hours after ingestion. In some embodiments, the concentration has a value of C24 value of up to about 156 and corresponds to a time t24 at 24 hours after ingestion; and the CmaX: C24 ratio is up to about 20.9.
In certain embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a quetiapine plasma concentration as a function of time, in nanograms. of quetiapine per milliliter of plasma, having a maximum value, C ^ x, which is between about 80 and about 1109 and corresponds to a time tmax which is between 3 and 8 hours after ingestion. In some embodiments, the concentration has a C24 value of up to about 265 and corresponds to a time t24 at 24 hours after ingestion; and the Cmax: C24 ratio is up to about 25.9.
In some embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have a maximum value Cave, max between about 5.1 and about 117 nanograms of quetiapine per milliliter of plasma, Cave, max corresponding to a time that is between 2.5 and 3.5 hours after ingestion. In some embodiments, the different concentrations have a mean value Cave, which is about 14.8 and corresponds to a time of 24 hours after ingestion; and Cave (inax: Cave, 24 is about 4.1.
In certain embodiments of the invention, a solid dosage form comprises 200 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have a maximum value CaVe, max which is up to about 550.4 nanograms of quetiapine per milliliter of plasma, Cave, max corresponding to a time which is between 5.5 and 6.5 hours after ingestion. In some embodiments, the distinct concentrations have a mean value Cave (24 gui is about 64.9 and corresponds to a time of 24 hours after ingestion, and the ratio Cave, max: Cave, 24 is about 4.0.
In certain embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have a maximum value Cave, max which is up to about 1062 nanograms of quetiapine per milliliter of plasma, Cave / max corresponding to a time which is between 2.5 and 3.5 hours after ingestion. In some embodiments, the discrete concentrations have a mean Cave value, which is about 114 and corresponds to a time of 24 hours after ingestion; and Cave, max: Cave, 24 is about 4.6.
In some embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have an area under the cumulative curve, ASCCum, which is: up to 46 to 1 hour after ingestion; between 8 and 352 at 4 hours after ingestion; between 34 and 789 at 8 hours after ingestion; between 83 and 1092 at 12 hours after ingestion; between 111 and 1396 at 16 hours after ingestion; and until 1935 at 24 hours after ingestion; where ASCCUm has units of (nanogram of quetiapine) x hour / mL.
In some modes of. In one embodiment of the invention, a solid dosage form comprises 200 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have an area under the cumulative curve, ASCcum 'which is: up to 177 at 1 hour after ingestion; between 35 and 1318 at 4 hours after ingestion; between 188 and 3115 at 8 hours after ingestion; between 251 and 4650 at 12 hours after ingestion; between 362 and 5666 at 16 hours after ingestion; and between 441 and 6899 at 24 hours after ingestion; where ASCCUm has units of (nanogram of quetiapine) x hour / mL.
In some embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have an area under the cumulative curve, ASCcum, which is between: 3 and 320 at 1 hour after ingestion; 143 and 2677 at 4 hours after ingestion; 575 and 6158 at 8 hours after ingestion; 916 and 8722 at 12 hours after ingestion; 1037 and 10685 at 16 hours after ingestion; 1031 and 13033; and 1031 and 13033 at 24 hours after ingestion; where ASCcum has units of (nanogram of quetiapine) x hour / mL.
In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxypropylmethylcellulose, wherein 15 to 29 of the 30.0% is a first hydroxypropylmethylcellulose component, so that the formulation satisfies a predetermined dissolution criterion; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components respectively correspond to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp.
In some embodiments, the formulation comprises from 11 to 12% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 29.5 to 30.5% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 37.9 to 38.9% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 52.4 to 53.4% by weight of quetiapine fumarate.
In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 9.6% to about 10.4% by weight and wherein the formulation comprises about 30% of hydroxypropyl methylcellulose by weight and about 7.2% of sodium citrate dihydrate by weight.
In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 25.6 to about 26.5% by weight and wherein the dosage form comprises about 30% of hydroxypropyl methylcellulose by weight and about 12.5% of sodium citrate dihydrate by weight.
In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 32.9% to about 33.8% by weight and wherein the dosage form comprises about 12%. , 5% sodium citrate dihydrate by weight and about 30% hydroxypropyl methylcellulose by weight.
In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 37.1% to about 38.0% by weight and wherein the dosage form comprises about 12%. , 5% sodium citrate dihydrate by weight and about 30% hydroxypropyl methylcellulose by weight and wherein about 15 to about 29 of the 30% hydroxypropyl methylcellulose is a first component of hydroxypropyl methylcellulose; the remaining 30% is a second component of hydroxypropyl methylcellulose; and the first and second components correspond, respectively, to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of from about 80cp to about 120cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of from about 3000cp to about 5600cp, wherein the ratio of the first grade of hydroxypropyl methylcellulose to the second grade of hydroxypropyl methylcellulose is not 25.0 to 5.0.
In some embodiments, the formulation comprises quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 45.5% to about 46.4% by weight and wherein the dosage form comprises about 11%. , 5% sodium citrate dihydrate by weight and about 30% hydroxypropyl methylcellulose by weight.
In some embodiments, the invention comprises a method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral sustained release dosage form containing quetiapine or a pharmaceutically acceptable salt thereof where the quetiapine content is 50 mg which, at equilibrium, has a time of onset of peak plasma concentration (t ^ x) of said antipsychotic of about 2 at approximately 16 hours, a peak plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of said antipsychotic at approximately 24 hours, and said pharmaceutical form produces an effective treatment of psychoses for approximately 24 hours or more after administration to the patient .
In some embodiments, the invention comprises a method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral sustained release dosage form containing quetiapine or a pharmaceutically acceptable salt thereof where the quetiapine content is 150 mg which, in equilibrium, has a maximum plasma concentration (tmax) onset time of said antipsychotic of about 2 to about 16 hours, a peak plasma concentration (Cmax) that is greater than or equal to four times the plasma concentration of said antipsychotic at about 24 hours, and said pharmaceutical form produces effective treatment of psychoses for about 24 hours or more after administration to the patient.
In some embodiments, the invention comprises a method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral sustained release dosage form containing quetiapine or a pharmaceutically acceptable salt thereof where the quétiapine content is 200 mg which, at equilibrium, has a maximum plasma concentration (tmax) onset time of said antipsychotic of about 2 to about 8 hours, a peak plasma concentration (Cmax) that is greater than or equal to four times the plasma concentration of said antipsychotic at about 24 hours, and said pharmaceutical form produces effective treatment of psychoses for about 24 hours or more after administration to the patient.
In some embodiments, the invention comprises a method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral sustained release dosage form containing quetiapine or a pharmaceutically acceptable salt thereof where the quetiapine content is 400 mg which, in equilibrium, has a maximum plasma concentration (tmax) onset of said antipsychotic of about 3 to about 8 hours, a maximum plasma concentration (Cmax) that is greater than or equal to four times the plasma concentration of said antipsychotic at about 24 hours, and an area under the curve between the time of administration and 24 hours after administration (ASCCUm, 24 ) which is greater than or equal to about 6000 ng.h / ml, and said pharmaceutical form produces an effective treatment of psychoses for about 24 hours or more after administration to the patient.
In some embodiments, when the dissolution of the formulation is carried out in a basket apparatus having a rotation speed of 200 rpm and containing 900 milliliters of 0.05 molar sodium citrate and 0.09 molar sodium hydroxide 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide are added after 5 hours: no more than 20% of the quetiapine is dissolved during the first one-hour period of dissolution. . In some embodiments, 47 to 69% of the quetiapine is dissolved during the first 6 hour period of dissolution. In some embodiments, 65 to 95% of quetiapine is dissolved during the first 12 hour period of dissolution. In some embodiments, at least 85% of the quetiapine is dissolved during the first 20 hours of dissolution.
In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxypropylmethylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropylmethylcellulose, so that the formulation exhibits optimally at least one target solution; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components respectively correspond to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp.
In some embodiments, the formulation comprises from 11 to 12% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 29.5 to 30.5% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 37.9 to 38.9% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 52.4 to 53.4% by weight of quetiapine fumarate.
In some embodiments, a first target is, when the dissolution occurs in a basket apparatus having a rotation speed of 200 rpm and containing 900 milliliters of 0.05 molar sodium citrate and sodium hydroxide. , Normal, to which 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide are added after 5 hours: 58% of the quetiapine is dissolved in the first six-hour period of dissolution. In some embodiments, a second target is: 80% of quetiapine is dissolved in the first 12 hour period of dissolution.
In certain embodiments of the invention, a solid dosage form comprises a dose of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in plasma quetiapine concentrations over time, the average at a dose-related concentration, C / dose, which is between about 0.433 and about 0.678 at 1 hour after administration; about 1.01 and about 1.35 to 4 hours after administration; about 0.930 and about 1.35 to 8 hours after administration; about 0.590 and about 1.07 to 12 hours after administration; and about 0.204 and about 1.22 to 16 hours after administration; where the dose is between 49.5 mg and 249.5 mg and C is expressed in nanograms of quetiapine per milliliter of plasma.
In certain embodiments of the invention, a solid dosage form comprises a dose of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in plasma quetiapine concentrations over time, the average at a dose-related concentration, C / dose, which is between about 0.433 and about 0.678 at 1 hour after administration; about 1.01 and about 1.35 to 4 hours after administration; about 0.930 and about 1.35 to 8 hours after administration; about 0.590 and about 1.07 to 12 hours after administration; and about 0.204 and about 1.22 to 16 hours after administration; where the dose is greater than 350 mg and C is expressed in nanograms of quetiapine per milliliter of plasma.
In certain embodiments of the invention, a solid dosage form comprises an amount of quetiapine and 30.0% hydroxypropyl methylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose, so that the formulation optimally presents the ratio C: dose dependent on time; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components correspond, respectively, to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp; and C: dose is in a range defined by
where: C is the mean quetiapine plasma concentration, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; base is between, limits included, 0.1277 and 0.2428; Ke is between, limits included, 0.2344 and 0.2678; Ka is between, limits included, 0, 1396 and 0, 1592; and the dose is between 49.5 mg and 249.5 mg.
In some embodiments, a solid dosage form comprises a quantity of quetiapine and 30.0% hydroxypropyl methylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose, so that the formulation optimally presents a ratio C: dose dependent on time; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components correspond, respectively, to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp; and C: dose is in a range defined by
where: C is the mean quetiapine plasma concentration, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; base is between, limits included, 0.1277 and 0.2428; Ke is between, limits included, 0.2344 and 0.2678; Ka is between, limits included, 0,1396 and 0,1592; and the dose is greater than 350 mg.
The invention may include a method of making a solid dosage form having a composition that comprises an active component and first and second components. The active component may be quetiapine. In some embodiments of the invention, the method may include entering into a multivariate model first data corresponding to a first constituent; entering the data second model corresponding to a second constituent; using the model, identifying a ratio of a first amount of component to a second amount of component such that the dosage form meets a dissolution criterion when the composition comprises the first and second components proportionally to the ratio. This method can be used, for example, to determine a ratio of constituents to obtain a desired dissolution profile given variations in constituent properties, such as batch-to-batch or source-to-source variations, which can occur during the manufacture of the dosage form, such as commercial manufacture over a long period of time, or when identical component batches are not readily available.
In some embodiments, the first and second components comprise, respectively, first and second batches of hydroxypropyl methylcellulose. In some embodiments, the first and second batches have first and second viscosities, respectively, and the first viscosity is different from the second viscosity. In some embodiments, the first viscosity is in the range of 80 to 120 cp, and the second viscosity is in the range of 3000 to 5600 cp.
In some embodiments, the first and second data include measured viscosities corresponding to the first and second batches, respectively. In some embodiments, the first and second data include hydroxypropoxy contents of the first and second batches, respectively. In some embodiments, at least one of the hydroxypropoxy contents is measured using nuclear magnetic resonance. In some embodiments, at least one of the methoxy contents is measured using nuclear magnetic resonance.
In some embodiments, the first and second data comprise weight average molecular weights (hereinafter, "molecular weight" or "molecular weight," appropriately) corresponding to the first and second batches, respectively.
In some embodiments, the first and second data include methoxy levels of the first and second batches, respectively.
In some embodiments, the first and second data include particle size information corresponding to the first and second batches, respectively. The particle size information can be characterized as, for example, the 100 mesh percent through (an index that can be extracted from the supplier's certificate of analysis; the smaller mesh sizes of 3 1/2 mesh sizes). at 400 are referred to as the number of openings per linear inch in the sieve, thus a 100 mesh screen has 100 openings per inch, for example, a 100 mesh screen may have holes that are 149 x 149 microns. The% passing through a 100 mesh screen is the percentage by weight of particles that are less than 149 microns in diameter. The particle size can also be characterized by the median particle diameter (D50) and / or the particle size range, both of which can be determined using a laser diffraction technique.
In some embodiments, the first and second data comprise number average molecular weight information (hereinafter, "molecular number") corresponding to the first and second batches, respectively.
In some embodiments, the method comprises entering into the model a quetiapine salt content corresponding to the composition.
In some embodiments, the method comprises entering into the model an excipient content corresponding to the composition.
In some embodiments, the method comprises entering the pharmaceutical form weight into the model.
In some embodiments, the method comprises entering into the model an amount of quetiapine corresponding to the composition; wherein the first and second data include, for the first and second batches, respectively: hydroxypropoxy contents; and molecular weight information. In some embodiments, the hydroxypropoxy contents are characterized by percentages by weight of a total weight of hydroxypropyl methylcellulose.
In some embodiments, the ratio of the first to the second component has a minimum value of 15% by weight of composition: 15% by weight of composition; and a maximum value of 29% by weight of composition: 1% by weight of composition.
In some embodiments, the dissolution criterion is satisfied when the formulation in a solid dosage form, when subjected to predetermined conditions for a certain time, is dissolved to a degree that is within a predetermined range.
In some embodiments, the dissolution criterion is satisfied when the degree is optimal in the range.
In some embodiments, when the report is a first report, the use of the model includes the prediction of dissolution for a second report; and the degree of dissolution is optimal when the degree is closer to the center of the range than the dissolution corresponding to the second ratio.
The invention may include a method of manufacturing a pharmaceutical form by establishing for first and second properties of first and second components, respectively, a correlation between a ratio and dissolution profile information; wherein the ratio is between a first amount of component and a second amount of component such that the dosage form meets a dissolution criterion when the composition comprises the first and second components proportionally to the ratio.
In some embodiments, the first property promotes dissolution; and the second property delays dissolution. In some embodiments, the first property is the hydroxypropoxy content.
In some embodiments, the second property is viscosity, molecular weight, or molecular number.
In some embodiments, the first property is the hydroxypropoxy content and the second property is the viscosity.
In some embodiments, the dissolution profile information includes a first value corresponding to a time and a second value corresponding to the degree of dissolution at that time.
In some embodiments, the correlation can be performed in a multivariate model.
The method may comprise measuring hydroxypropoxy and methoxy of a plurality of hydroxypropyl methylcellulose batches. In some embodiments the measurement is performed using nuclear magnetic resonance (NMR). A first grade of the hypromellose has a first viscosity and a second grade may have a second viscosity. The method may include entering a multivariate model of the tablet dosage and the hydroxypropoxy content and molecular weight of each of the first quality and the second grade. The method may further include entering into the model a series of ratios between a quantity of the first quality and a quantity of the second quality. The method may further include identifying, using the model, an optimal ratio that corresponds to a predicted dissolution profile that has a smaller deviation from a target profile than the difference obtained using the other ratios. . Alternatively, the method may include identifying, using the model, at least one ratio that produces a formulation that satisfies a desired dissolution profile.
In some embodiments, the model may be an artificial neural network ("ANN") model.
In some embodiments, the correlation can be implemented in a conversion table.
Brief description of the figures
The above and other features of the present invention, its nature and various advantages will become more clearly apparent from the following detailed description, with reference to the accompanying drawings, and in which:
Figure 1 is a schematic diagram showing chemical structures that can be used according to the principles of the invention.
Fig. 2 is a flowchart showing a manufacturing method that can be used in accordance with the principles of the invention.
Fig. 3 is a graph showing clinical data based on a formulation according to the principles of the invention.
Fig. 4 is a graph showing clinical data based on a formulation according to the principles of the invention.
Fig. 5 is a graph showing clinical data based on a formulation that can be obtained using methods according to the principles of the invention.
Fig. 6 is a graph showing clinical data based on formulation according to the principles of the invention.
Figure 7 is a graph showing standardized clinical data from Figures 3 to 6.
Fig. 8 is a graph showing the effect of different factors on a property of a formulation according to the principles of the invention.
Fig. 9 is a graph showing a correlation between a polymer chemical attribute and a polymer characteristic.
Fig. 10 is a graph showing a correlation between a physical polymer attribute and a polymer characteristic.
Fig. 11 is a graph showing in vitro dissolution data based on formulations according to the principles of the invention.
Fig. 12 is a graph showing a characteristic of a gelling agent that can be used according to the principles of the invention.
Fig. 13 is a graph showing the release of hypromellose for different grades of hypromellose that can be used according to the principles of the invention.
Fig. 14 is a graph showing the release of hypromellose and a drug that can be used according to the principles of the invention.
Figure 15 is a schematic diagram showing the architecture of a multivariate model that can be used according to the principles of the invention.
Figure 16 is a schematic diagram of a multivariate model according to the principles of the invention.
Fig. 17 is a graph showing predictive data and acceptance criteria according to the principles of the invention.
Fig. 18 is a flowchart showing a method of using the model of Fig. 15.
Fig. 19 is a flowchart showing a method of using the model of Fig. 15.
Fig. 20 is a table of illustrative data according to the principles of the invention.
Fig. 21 is a graph of in vitro dissolution data based on a formulation according to the principles of the invention.
Fig. 22 is a graph of in vitro dissolution data based on a formulation according to the principles of the invention.
Fig. 23 is a graph of in vitro dissolution data based on a formulation according to the principles of the invention.
Fig. 24 is a graph of in vitro dissolution data based on a formulation according to the principles of the invention.
Figure 25 is a graph of in vitro dissolution data based on a formulation according to the principles of the invention.
Detailed Description of the Embodiments
Unless otherwise indicated, all technical and scientific terms have the same meaning as those commonly known to those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods and examples are illustrative only, and are not intended to be limiting, all of the publications, patents and other documents mentioned are presently incorporated by reference in their entirety.
In order to further define the invention, the following terms and definitions are currently defined.
The term "treat" or "treatment" is intended to include, but is not limited to, the reduction or alleviation of symptoms such as psychotic disorders or hyperactivity in a mammal such as a human.
The term "patient" refers to an animal comprising a mammal (eg, a human).
The term "bioavailability" includes, but is not limited to, reference to the rate and extent to which an active component or active fragment is absorbed from a pharmaceutical product and becomes available at the site of action.
The term "sustained release" includes, but is not limited to, reference to products that are formulated to render the drug available for extended periods of time after administration.
A formulation may comprise a hydrophilic matrix comprising a gelling agent, 11- [4- (2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine, or a pharmaceutically acceptable salt acceptable thereof, such as a hemifumarate salt, and one or more pharmaceutically acceptable excipients.
Examples of gelling agents which may be present in the embodiments of the invention include such substances as hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, methylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, and the like. carbopol, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like, or mixtures thereof. In some embodiments, the gelling agent may comprise hypromellose.
The amount of gelling agent, in combination with the quetiapine and any excipients, and any excipients, may be chosen so that the active component is released from the formulation in a controlled manner, in a period of about 24 hours. hours.
The gelling agent may be present in a range of about 5 to 50% (by weight). The range can be about 5 to 40%. The range can be from about 8 to 35%. The range can be from about 10 to 35%. The range can be 10 to 30%. The range can be from 15 to 30%. (The percentages by weight, in the present context, relate to the weight of tablet core, excluding the weight of any coating, unless otherwise indicated).
Certain embodiments of the invention may include mixtures of hypromelloses that comprise more than one polymer grade. Polymers are marketed under several brand names, for example METHOCEL® E, F, J and K from Dow Chemical Company, USA and METOLOSE ™ 60SH, 65SH and 90SH from Shin-Etsu, Ltd., Japan. The grades exhibit differences in methoxy and hydroxypropoxy contents as well as viscosity and other characteristics. Different batches of hypromellose, even if they are of the same quality, may show differences in methoxy and hydroxypropoxy contents, viscosity and other characteristics.
The formulation may contain a buffer or pH modifier, for example if the active component has a pH-dependent solubility, as is the case for quetiapine salts such as quetiapine fumarate.
The formulation, in general, contains one or more excipients. Such excipients may include diluents such as lactose, microcrystalline cellulose, dextrose, mannitol, sucrose, sorbitol, gelatin, gum arabic, dicalcium phosphate, tricalcium phosphate, monocalcium phosphate, sodium phosphate, and the like. sodium, sodium carbonate and the like, preferably lactose and microcrystalline cellulose; lubricants such as stearic acid, zinc, calcium or magnesium stearate and the like, preferably magnesium stearate; binders such as sucrose, polyethylene glycol, povidone (polyvinylpyrrolidone), cereal or corn starch, pregelatinized starch and the like; dyes such as ferric oxides, FD & C dyes, lacquers and the like; flavoring agents; and pH modifiers which comprise suitable organic acids or alkali metal salts (e.g. lithium, sodium or potassium) thereof, such as benzoic acid, citric acid, tartaric acid, succinic acid, adipic acid and the like or the corresponding alkali metal salts thereof, preferably the alkali metal salts of such acids and in particular the citric acid sodium salt (i.e. ie, sodium citrate). As is known, certain excipients have multiple functions, for example they are both diluents and binders.
In certain embodiments of the invention, the formulation may be present in a solid pharmaceutical form such as a tablet, capsule tablet or any other suitable form comprising hemifumarate of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine ("quetiapine fumarate"), from 6 to 18% by weight of sodium citrate dihydrate, 30.0% by weight weight of hydroxypropyl methylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components correspond, respectively, to a first grade of hydroxypropyl methylcellulose which has an "apparent viscosity" (see below) of between 80 centipoise ("cp") and 120 cp and a second hydroxypropyl methylcellulose which has an apparent apparent viscosity. between 3000 cp and 5600 cp. The tablet may comprise from 11 to 12% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] thiazepine hemifumarate. The tablet may comprise from 29.5 to 30.5% by weight of 11- [4- (2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1,4] hemifumarate thiazepine The tablet may comprise from 37.9 to 38.9% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1 hemifumarate, 4] Thiazepine In some embodiments, the tablet comprises from 52.4 to 53.4% by weight of 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [hemifumarate] b, f] [1,4] thiazepine.
Pharmaceutical forms can be manufactured in batches. A lot may comprise one or more constituents. A constituent can be marketed and obtained in batches. Pharmaceutical forms can be manufactured according to a "Batch Ratio Process", in which variations in hydroxypropoxy content, which should cause variations in active component release characteristics, can be compensated for by choosing an appropriate ratio ( the "polymer ratio") of hypromellose with high viscosity and low viscosity. The effects on the release of active component from variations in the properties of other constituents can be compensated in the same way.
In some embodiments, the viscosities of the formulation are consistent with Ubbelohde viscometer viscosities of 2% by weight of hydroxypropyl methylcellulose in water at 20 °, as determined using the method described in the United States Pharmacopoeia (USP30-). NF25), United States Pharmacopoeia Convention, Inc. 2007, p. 2323, which is presently incorporated by reference in its entirety.
In certain embodiments of the invention, the formulation comprises sodium citrate dihydrate present at about 7.2 to 12.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 7.2% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 11.5% by weight. In some embodiments, the formulation comprises sodium citrate dihydrate present at 12.5% by weight.
In some embodiments of the invention, the formulation comprises lactose monohydrate present up to about 30% by weight. In some embodiments, the formulation comprises lactose monohydrate present at 25.1% by weight. In some embodiments, the formulation comprises lactose monohydrate present at 13.0% by weight.
In some embodiments, the formulation comprises lactose monohydrate present at 8.8 wt%. In some embodiments, the formulation comprises lactose monohydrate present at 1.8% by weight.
In some embodiments, the formulation comprises microcrystalline cellulose present up to about 30% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present at 25.1% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present at 13.0% by weight. In some embodiments, the formulation comprises microcrystalline cellulose present at 8.8 wt%. In some embodiments, the formulation comprises microcrystalline cellulose present at 1.8% by weight.
In some embodiments, the tablet comprises an amount of magnesium stearate of from about 1% to 3% by weight. In some embodiments, the tablet comprises magnesium stearate present at 1.0% by weight. In some embodiments, the tablet comprises magnesium stearate present at 1.5% by weight. In some embodiments, the tablet comprises magnesium stearate present at 2.0% by weight.
In some embodiments, the hydroxypropylmethylcellulose comprises from 9.8 to 13.4% by weight of the hydroxypropylmethylcellulose, measured by nuclear magnetic resonance ("NMR"), of hydroxypropoxy. In some embodiments, the hydroxypropyl methylcellulose comprises from 26.4 to 29.2% by weight of the hydroxypropyl methylcellulose, measured by NMR, of methoxy.
In some embodiments of the invention, the solid dosage form comprises 50 milligrams ("mg") of quetiapine, for example in a total core mass of 500 mg. In some embodiments, the solid dosage form comprises 150 mg of quetiapine, for example, in a total core mass of 575 mg. In some embodiments, the solid dosage form comprises 200 mg of quetiapine, for example in a total core mass of 600 mg. In some embodiments, the solid dosage form comprises 400 mg of quetiapine, for example in a total core mass of 870 mg.
In certain embodiments of the invention, the formulation is present in a solid pharmaceutical form comprising 50 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a plasma concentration, in nanograms of quetiapine per milliliter of plasma, which is up to approximately: 67.6 to 1 hour after ingestion; 124 at 4 hours after ingestion; 105 to 8 hours after ingestion; 74.3 to 12 hours after ingestion; and 236 to 16 hours after ingestion.
In some embodiments of the invention, the formulation is a solid pharmaceutical form comprising 200 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a plasma concentration, in nanograms of quetiapine by milliliter of plasma, which is: up to about 251 to 1 hour after ingestion; between about 32.2 and about 416 to 4 hours after ingestion; until about 496 to 8 hours after ingestion; between about 4.6 and about 323-12 hours after ingestion; and until about 251 to 16 hours after ingestion.
In certain embodiments of the invention, the formulation is a solid pharmaceutical form comprising 400 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a plasma concentration, in nanograms of quetiapine by milliliter of plasma, which is: between about 15.9 and about 391 to 1 hour after ingestion; until about 1052-4 hours after ingestion; between about 63, 1 and about 785 to 8 hours after ingestion; from about 11.1 to about 613-12 hours after ingestion; and up to about 448-16 hours after ingestion.
In some embodiments of the invention, a dosage form comprises 30.0% by weight of hydroxypropyl methylcellulose and 7.2% by weight of sodium citrate dihydrate. In some embodiments, from 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80cp and 120cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000cp and 5600cp. In some embodiments,. the viscosities of the dosage form are consistent with Ubbelohde viscometer viscosities of 2% by weight of hydroxypropyl methylcellulose in water at 20 °, as determined using the method described in United States Pharmacopoeia (USP30-NF25), United States Pharmacopoeia Convention, Inc. 2007, p. In some embodiments, the first and second components, respectively, have viscosities of 80 to 120 cps and 3000 to 5600 cps.
In certain embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a quetiapine plasma concentration as a function of time, in nanograms of quetiapine per milliliter of plasma, having a maximum value, Cmax, of up to about 239 and corresponds to a time tmax which is between 2 and 16 hours after ingestion. In some embodiments, the concentration has a C24 value of up to about 39.2 and corresponds to a time t24 at 24 hours after ingestion; and the ratio C 1 X: C 24 is up to about 35.2.
In certain embodiments of the invention, a solid dosage form comprises 200 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a quetiapine plasma concentration as a function of time, in nanograms of quetiapine per milliliter of plasma, having a maximum value, Cmx, which is between about 3.9 and about 601 and corresponds to a time ίωχ which is between 2 and 8 hours after ingestion. In some embodiments, the concentration has a C24 value of up to about 156 and corresponds to a time t24 at 24 hours after ingestion; and the ratio: C24 is up to about 20.9.
In certain embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the pharmaceutical form, after ingestion under equilibrium conditions by a human, resulting in a quetiapine plasma concentration as a function of time, in nanograms of quetiapine per milliliter of plasma, having a maximum value, Cmax, which is between about 80 and about 1109 and corresponds to a time tmax which is between 3 and 8 hours after ingestion. In some embodiments, the concentration has a C24 value of up to about 265 and corresponds to a time t24 at 24 hours after ingestion; and the Cmax: C24 ratio is up to about 25.9.
In some embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have a maximum value Cave, max between about 5.1 and about 117 nanograms of quetiapine per milliliter of plasma, Cave <max corresponding to a time which is between 2.5 and 3.5 hours after administration. In some embodiments, the distinct concentrations have a mean Cave value (24 which is about 14.8 and corresponds to a time of 24 hours after ingestion, and the ratio Cave, max: Cave, 24 is about 4.1.
In certain embodiments of the invention, a solid dosage form comprises 200 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have a maximum value Cave, max which is up to about 550.4 nanograms of quetiapine per milliliter of plasma, CaVe, max corresponding to a time which is between 5.5 and 6.5 hours after administration. In some embodiments, the discrete concentrations have a mean Cave value, which is about 64.9 and corresponds to a time of 24 hours after ingestion; and the Cave, max: Cave, 24 ratio is about 4.0.
In certain embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have a maximum value Cave, max which is up to about 1062 nanograms of quetiapine per milliliter of plasma, Cave, max corresponding to a time which is between 2.5 and 4.5 hours after administration. In some embodiments, the discrete concentrations have a mean Cave value, which is about 114 and corresponds to a time of 24 hours after ingestion; and Cave, max: Cave, 24 is about 4.6.
In some embodiments of the invention, a solid dosage form comprises 50 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have an area under the cumulative curve, ASCCUiru which is: up to 46 to 1 hour after ingestion; between 8 and 352 at 4 hours after ingestion; between 34 and 789 at 8 hours after ingestion; between 83 and 1092 at 12 hours after ingestion; between 111 and 1396 at 16 hours after ingestion; and until 1935 at 24 hours after ingestion; where ASCCUm has units of (nanogram of quetiapine) X hour / mL.
In some embodiments of the invention, a solid dosage form comprises 200 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have an area under the cumulative curve, ASCcum, which is: up to 177 at 1 hour after ingestion; between 35 and 1318 at 4 hours after ingestion; between 188 and 3115 at 8 hours after ingestion; between 251 and 4650 at 12 hours after ingestion; between 362 and 5666 at 16 hours after ingestion; and between 441 and 6899 at 24 hours after ingestion; where ASCCUm has units of (nanogram of quetiapine) X hour / mL.
In certain embodiments of the invention, a solid dosage form comprises 400 mg of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in different plasma concentrations of quetiapine as a function of time, which have an area under the cumulative curve, ASCcum, which is between: 3 and 320 at 1 hour after ingestion; 143 and 2677 at 4 hours after ingestion; 575 and 6158 at 8 hours after ingestion; 916 and 8722 at 12 hours after ingestion; 1037 and 10685 at 16 hours after ingestion; 1031 and 13033; and 1031 and 13033 at 24 hours after ingestion; where ASCcum has units of (nanogram of quetiapine) X hour / mL.
In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxypropylmethylcellulose, wherein 15 to 29 of the 30.0% is a first hydroxypropylmethylcellulose component, so that the formulation satisfies a predetermined dissolution criterion; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components respectively correspond to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp.
In some embodiments, the formulation comprises from 11 to 12% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 29.5 to 30.5% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 37.9 to 38.9% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 52.4 to 53.4% by weight of quetiapine fumarate.
In some embodiments, when the dissolution of the formulation is carried out in a basket apparatus having a rotation speed of 200 rpm and containing 900 milliliters of 0.05 molar sodium citrate and 0.09 molar sodium hydroxide 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide are added after 5 hours: no more than 20% of the quetiapine is dissolved during the first one-hour period of dissolution. . In some embodiments, 47 to 69% of the quetiapine is dissolved during the first 6 hour period of dissolution. In some embodiments, from 65 to 95% of quetiapine is dissolved during the first 12 hour period of dissolution. In some embodiments, at least 85% of the quetiapine is dissolved during the first 20 hours of dissolution.
In some embodiments of the invention, a formulation comprises quetiapine fumarate and 30.0% hydroxypropyl methylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose, so that the formulation is optimally at least one target solution; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components respectively correspond to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp.
In some embodiments, the formulation comprises from 11 to 12% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 29.5 to 30.5% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 37.9 to 38.9% by weight of quetiapine fumarate. In some embodiments, the formulation comprises from 52.4 to 53.4% by weight of quetiapine fumarate.
In some embodiments, a first target is, when the dissolution is performed in a basket apparatus having a rotation speed of 200 rpm and containing 900 milliliters of 0.05 molar sodium citrate and sodium hydroxide. , Normal, to which 100 milliliters of 0.05 molar sodium phosphate and 0.46 normal sodium hydroxide are added after 5 hours: 58% of the quetiapine is dissolved in the first six-hour period of dissolution. In some embodiments, a second target is: 80% of quetiapine is dissolved in the first 12 hour period of dissolution.
In certain embodiments of the invention, a solid dosage form comprises a dose of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in plasma quetiapine concentrations over time, the average at a dose-related concentration, C / dose, which is between about 0.433 and about 0.678 at 1 hour after administration; about 1.01 and about 1.35 to 4 hours after administration; about 0.930 and about 1.35 to 8 hours after administration; about 0.590 and about 1.07 to 12 hours after administration; and about 0.204 and about 1.22 to 16 hours after administration; where the dose is between 49.5 mg and 249.5 mg and C is expressed in nanograms of quetiapine per milliliter of plasma.
In certain embodiments of the invention, a solid dosage form comprises a dose of quetiapine, the dosage form, after ingestion under equilibrium conditions by different humans, resulting in plasma quetiapine concentrations over time, the average at a dose-related concentration, C / dose, which is between about 0.433 and about 0.678 at 1 hour after administration; about 1.01 and about 1.35 to 4 hours after administration; about 0.930 and about 1.35 to 8 hours after administration; about 0.590 and about 1.07 to 12 hours after administration; and about 0.204 and about 1.22 to 16 hours after administration; where the dose is greater than 350 mg and C is expressed in nanograms of quetiapine per milliliter of plasma.
In certain embodiments of the invention, a solid dosage form comprises an amount of quetiapine and 30.0% hydroxypropyl methylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose, so that the formulation optimally presents the ratio C: dose dependent on time; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components correspond, respectively, to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp; and C: dose is in a range defined by
where: C is the mean quetiapine plasma concentration, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; base is between, limits included, 0.1277 and 0.2428; Ke is between, limits included, 0.2344 and 0.2678; Ka is between, limits included, 0, 1396 and 0, 1592; and the dose is between 49.5 mg and 249.5 mg.
In some embodiments, a solid dosage form comprises a quantity of quetiapine and 30.0% hydroxypropyl methylcellulose, wherein 15 to 29 of the 30.0% is a first component of hydroxypropyl methylcellulose, so that the formulation optimally presents a ratio C: dose dependent on time; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; the first and second components correspond, respectively, to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of between 80 cp and 120 cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of between 3000 cp and 5600 cp; and C: dose is in a range defined by
where: C is the mean quetiapine plasma concentration, in nanograms of quetiapine per milliliter of plasma, at time t after administration of quetiapine to a human; base is between, limits included, 0.1277 and 0.2428; Ke is between, limits included, 0.2344 and 0.2678; Ka is between, limits included, 0,1396 and 0,1592; and the dose is greater than 350 mg.
The invention may include a method of making a solid dosage form having a composition that comprises an active component and first and second components. The active component may be quetiapine. In some embodiments of the invention, the method may include entering into a multivariate model first data corresponding to a first constituent; entering the data second model corresponding to a second constituent; using the model, identifying a ratio of a first amount of component to a second amount of component such that the dosage form meets a dissolution criterion when the composition comprises the first and second components proportionally to the ratio. This method can be used, for example, to determine a ratio of constituents to obtain a desired dissolution profile given variations in constituent properties, such as batch-to-batch or source-to-source variations, which can occur during the manufacture of the dosage form, such as commercial manufacture over a long period of time, or when identical component batches are not readily available.
In some embodiments, the first and second components comprise, respectively, first and second batches of hydroxypropyl methylcellulose. In some embodiments, the first and second batches have first and second viscosities, respectively, and the first viscosity is different from the second viscosity. In some embodiments, the first viscosity is in the range of 80 to 120 cp, and the second viscosity is in the range of 3000 to 5600 cp.
In some embodiments, the first and second data include measured viscosities corresponding to the first and second batches, respectively. In some embodiments, the first and second data include hydroxypropoxy contents of the first and second batches, respectively. In some embodiments, at least one of the hydroxypropoxy contents is measured using nuclear magnetic resonance. In some embodiments, at least one of the methoxy contents is measured using nuclear magnetic resonance.
In some embodiments, the first and second data comprise molecular weights corresponding to the first and second batches, respectively.
In some embodiments, the first and second data include methoxy levels of the first and second batches, respectively.
In some embodiments, the first and second data include particle size information corresponding to the first and second batches, respectively. The particle size information can be characterized as, for example, the 100 mesh percent through (an index that can be extracted from the supplier's certificate of analysis; the smaller mesh sizes of 3 1/2 mesh sizes). at 400 are referred to as the number of apertures per linear inch in the sieve, thus a 100 mesh screen has 100 apertures per inch, for example, a 100 mesh screen may have holes that are 149 x 149 microns. The% passing through a 100 mesh screen is the percentage by weight of particles that are less than 149 microns in diameter. The particle size can also be characterized by the median particle diameter (D50) and / or the particle size range, both of which can be determined using a laser diffraction technique.
In some embodiments, the first and second data include molecular number information corresponding to the first and second batches, respectively.
In some embodiments, the method comprises entering into the model a quetiapine salt content corresponding to the composition.
In some embodiments, the method comprises entering into the model an excipient content corresponding to the composition.
In some embodiments, the method comprises entering the pharmaceutical form weight into the model.
In some embodiments, the method comprises entering into the model an amount of quetiapine corresponding to the composition; wherein the first and second data include, for the first and second batches, respectively: hydroxypropoxy contents; and molecular weight information. In some embodiments, the hydroxypropoxy contents are characterized by percentages by weight of a total weight of hydroxypropyl methylcellulose.
In some embodiments, the ratio of the first to the second component has a minimum value of 15% by weight of composition: 15% by weight of composition; and a maximum value of 29% by weight of composition: 1% by weight of composition.
In some embodiments, the dissolution criterion is satisfied when the formulation in a solid dosage form, when subjected to predetermined conditions for a certain time, is dissolved to a degree that is within a predetermined range. In some embodiments, the dissolution criterion is satisfied when the degree is optimal in the range.
In some embodiments, when the report is a first report, the use of the model includes the prediction of dissolution for a second report; and the degree of dissolution is optimal when the degree is closer to the center of the range than the dissolution corresponding to the second ratio.
The invention may include a method of manufacturing a pharmaceutical form by establishing for first and second properties of first and second components, respectively, a correlation between a ratio and dissolution profile information; wherein the ratio is between a first amount of component and a second amount of component such that the dosage form meets a dissolution criterion when the composition comprises the first and second components proportionally to the ratio.
In some embodiments, the first property promotes dissolution; and the second property delays dissolution. In some embodiments, the first property is the hydroxypropoxy content.
In some embodiments, the second property is viscosity, molecular weight, or molecular number.
In some embodiments, the first property is the hydroxypropoxy content and the second property is the viscosity.
In some embodiments, the dissolution profile information includes a first value corresponding to a time and a second value corresponding to the degree of dissolution at that time.
In some embodiments, the correlation can be performed in a multivariate model.
The method may comprise measuring hydroxypropoxy and methoxy of a plurality of hydroxypropyl methylcellulose batches. In some embodiments the measurement is performed using nuclear magnetic resonance (NMR). A first grade of the hypromellose has a first viscosity and a second grade may have a second viscosity. The method may include entering a multivariate model of the tablet dosage and the hydroxypropoxy content and molecular weight of each of the first quality and the second grade. The method may further include entering into the model a series of ratios between a quantity of the first quality and a quantity of the second quality. The method may further include identifying, using the model, an optimal ratio that corresponds to a predicted dissolution profile that has a smaller deviation from a target profile than the difference obtained using the other ratios. . Alternatively, the method may include identifying, using the model, at least one ratio that produces a formulation that satisfies a desired dissolution profile.
In some embodiments, the model may be an artificial neural network neuronal network ("ANN") model.
In some embodiments, the correlation can be implemented in a conversion table.
Exemplary formulations for 50 mg, 150 mg, 200 mg, 300 mg and 400 mg tablet strengths are shown in Tables 1 to 5, respectively:
Table 1
quetiapine fumarate contains 86.86% by weight of quetiapine
Table 2
Quetiapine fumarate contains 86.86% by weight of quetiapine
Table 3

* Lefumaratede quétiapin contains 86.86% by weight of quetiapine
Table 4
Quetiapine fumarate contains 86.86% by weight of quetiapine
Table 5

quetiapine fumarate contains 86.86% by weight of quetiapine
Figure 1 shows substituted anhydroglucose units which constitute hypromellose and are involved in dissolution processes which are described in more detail below with reference to certain exemplary embodiments.
The formulations can be used in 50, 150, 200, 300 and 400 mg sustained release tablets that can be manufactured using one or more of the following devices and methods: high shear granulation, drying processes fluidized bed, grinding, mixing, compression, aqueous coating, and any other suitable methods that are identical or similar to other manufacturing processes generally used in the pharmaceutical industry.
The raw materials can be transferred to the high shear granulator and can be mixed for 10 minutes. All excipients (with the exception of magnesium stearate) can be added to the high shear granulator. A dry mixing time of 10 minutes can be used.
During the wet granulation step water can be added to the dry mix to complete the granulation. There may be a range of amount of water added to the granulation and rate of addition of water to obtain an acceptable product. Wet milled material can be dried in a fluidized bed drier. For each batch a target moisture of <3% loss on drying (LOD) can be obtained.
A hammer mill can be used to reduce the size of the aggregate to achieve adequate flow and compression characteristics.
A lubricant mixing time of 3 minutes can be used.
Illustrative tablet manufacturing parameters for two different commercial plants are shown in Table 6.

Figure 2 is an illustrative flowchart for the manufacture of quetiapine fumarate tablets. The manufacturing method 200 may comprise a process scheme 210 and a manufacturing equipment 250. The process flow may comprise dry mixing and wet granulation 212 using a high shear granulator 252, wet milling 214, and using a sieve mill 254, a drying 216 using a fluid bed drier 256, a milling 218 using an impact or sieve mill 258, a mixture 220 using a diffusion mixer 260, the compression 222 using a rotary press 262 and a coating 224 using a turbine coating machine 264. Scheme 210 and material 250 are only exemplary and other suitable process steps and other suitable manufacturing equipment may be used.
For step 253 an exemplary list of constituents for dry blending and wet granulation by a high shear granulator 252 is presented. Magnesium stearate 263 may be added through a screen 265 during mixing 220. A coating suspension 267 may be included in the coating process 224.
The following protocol was used to determine plasma active component concentrations in patients. Figures 3 to 6 show plasma concentration - time (mean and range) plots.
An open, multi-center, multi-dose study was conducted to evaluate the steady-state pharmacokinetics of commercially available tablets comprising study formulations ("SF") with the following quetiapine dosages: 50 mg, 200 mg, 300 mg, and 400 mg . The study formulations have compositions which are shown in Tables 1 to 5. Following a 2-day wash-out period, patients received oral doses of the study formulations and an immediate release drug ("IR Sold under the brand name "Seroquel" (marketed by Astra-Zeneca Pharmaceuticals, Wilmington, Delaware) once a day as follows: 50 mg SF on days 1 to 4, 200 mg SF on days 5 to 7, 300 mg SF at days 8-11, 400 mg SF at days 12-14 and 300 mg IR at days 15-17. On days 4 and 11, patients consumed a standardized high-fat breakfast 10 minutes before or after their dose planned. Day 3 (50 mg, Figure 3), Day 7 (200 mg, Figure 4), Day 10 (300 mg, Figure 5), and Day 14 (400 mg, Figure 6) data were used. is assumed that equilibrium has been reached for each dose level. On each plot (Figures 3 to 6), the bars correspond to the 95% prediction interval.
Data from the study are presented in Tables 6A and 6B. In Table 6A, Ct is the concentration, in nanograms per milliliter of plasma, at a time, t, which is expressed in hours after ingestion of the tablet. ASCcumt is the area under the cumulative concentration curve, in (nanogram of quetiapine) x hour / mL, at a time t, which is expressed in hours after ingestion of the tablet. The amounts shown in Table 6Δ that are derived from Ct and ASCCUI "t are explained above.
Table 6Ά
1 Lower confidence limit for individual subject data (two-sided, p = 0.05, n = 12) 2 Average for individual subject data (n = 12) 3 Upper confidence limit for individual subject data ( bilateral, p = 0.05, n = 12) 4 Minimum, most frequent and maximum values observed 5 Peak C> ve, mean plasma concentration for all subjects at one time
In Table 6B, C / doset is an independent report of the dosage concentration, in nanograms of quetiapine per milliliter of plasma, at tablet dosage, in mg of quetiapine, at a time, t, which is expressed in hours after ingestion tablet.
Table 6B
Lower confidence limit for C / dose calculated from C.ve for each assay for each time (bilateral, p = 0.05, n = 4) 2 Overall C average / dose calculated from Cavc for each assay for each time (n = 4)
3 Upper confidence limit for C / dose calculated on the same basis as LCL
Each plot (Figures 3 to 6) further represents a regression curve based on a pharmacokinetic ("PK") model using first-order drug absorption and elimination constants Ke and Ka, respectively, with 'equation
(See, for example, "The
Time Course of Drug Action, "Neubig, R.R., in Principles of Drug Action, Pratt, W, B., Taylor, P., (Eds), 3rd Edition, Churchill Livingstone, Inc. 1990.)
PK model parameters, regression values and standard errors ("SE"), as well as the 95% confidence interval, for active component quantities of 50 mg, 200 mg, 300 mg and 400 mg, respectively, are shown in Tables 7 to 10, which correspond to the data presented in Figures 3 to 6, respectively.
The PK model parameters, regression values, and standard errors (95% confidence interval) for the dose-normalized curve are presented in Table 11, which corresponds to the data presented in Figure 7. The bars are the 95% confidence interval.
Table 11
Hypromellose hydrates rapidly after ingestion to form a continuous gel layer. The gel layer initially acts to prevent wetting and subsequent disintegration of the tablet core, which would lead to rapid and complete release of the drug, and then to control drug release through a complex mechanism that implements the inward extension of the hydrated gel layer, the swelling, the diffusion of the drug through the gel to the surrounding medium, and the erosion that results in the release of active component and hypromellosis from the outer surface . See "Using Dow Excipients for Controlled Release of Drugs in Hydrophilic Matrix Systems." Technical Guide published by the Dow Chemical Company, September, 2006, which is presently incorporated by reference in its entirety.
Hypromellose is a cellulose ether derived by chemical modification of cellulose, a naturally occurring carbohydrate that contains a repeated structure of anhydroglucose units. Cellulose itself is an insoluble fibrous polymer; however, each anhydroglucose unit contains 5 reactive hydroxyl groups, two of which are used in chain propagation, leaving three sites for chemical substitution. For pharmaceutical applications, the most commonly used substituents are methyl, ethyl, and hydroxypropyl. Ethylcelluloses are insoluble in water but are soluble in certain organic solvents and are useful, alone or in combination with other excipients, as tablet coatings or in the manufacture of hydrophobic matrix tablets. Methylcelluloses are generally soluble in water, while hydroxypropylcelluloses are soluble in water and some organic solvents. Hypromellose can be substituted with methyl and hydroxypropyl groups, thus allowing fine adjustment of properties for applications such as use in hydrophilic matrix tablets (see Figure 1).
Hypromellose concentration is an important consideration in the design of a hydrophilic controlled release matrix tablet. The hypromellose concentration should be high enough to ensure that a continuous gel layer is formed immediately after exposure to an aqueous medium. Once such a concentration has been exceeded, however, an increase in the hypromellose concentration leads to a decrease in release rate due to an increase in the time required for the hypromellosis to be disentangled on the tablet surface. At a certain stage, the disentangling effect reaches a plateau so that a further increase in hypromellose concentration does not result in a further decrease in the drug release rate. This is because the drug release does not result exclusively from the erosion of the hypromellose, but also from the diffusion of solubilized drug into the hydrated matrix. The precise position of the lower concentration threshold and the upper plateau concentration depends on the characteristics and the load of the drug and other excipients, but generally the hypromellose concentration should be in the range of 20% to 50%. Hypromelloses can be characterized by the following parameters:
Degree of substitution ("DS"). DS denotes the level of substitution in terms of the number of substituted hydroxyl groups, regardless of the nature of the substituent group, expressed on average. For hypromellose, DS is usually redefined to reflect only the methoxyl substitution. In all cases, the total number of hydroxyl groups available is 3, therefore DS is between 0 and 3, but is most often between 1.3 and 2.6.
Molar substitution ("MS"). For hypromellose, MS refers to the degree of hydroxypropyl substitution in terms of moles per mole of anhydroglucose, and is expressed on average. Typical values are in the range of 0.2 to 0.4. Since each hydroxypropyl group contains a hydroxy group, there is no theoretical upper limit for MS.
Title. The title refers to the content of methoxy (-OCH3) and hydroxypropoxy (-OCH2CHOHCH3), expressed as a percentage.
Chemistry. The chemistry is defined by the title values and is important in the determination of hydrophilicity and therefore the solubility of hypromellose. Hypromellose which is marketed under the brand name METHOCEL® (The Dow Chemical Company, Michigan, USA) is available in four defined grades which are differentiated by their chemistry, as described in Table 12.
Table 12
For a controlled release matrix tablet formulation, a rapid hydration / gelation rate for the release control polymer, such as hypromellose, can provide the formulation with a protective layer around the tablet core. The hydration levels of the different grades of hypromellose differ because of the difference in chemistry. It has been postulated that a hydroxypropyl group acts as a hydrophilic substituent that contributes greatly to the level of hydration, while a methoxyl group is relatively hydrophobic and does not contribute to the hydration rate. Therefore, it is believed that the hydration rate of the different hypromellose chemistries is dependent on the hydroxypropoxyl to methoxyl substitution ratio, the higher ratio chemistries having faster hydration / gelation. Therefore, chemistry products K and E are most frequently used in controlled release matrix tablets.
The hydroxypropoxy and methoxy contents of the hypromellose are most commonly measured using a modification of the Zeisel alkoxy reaction, which uses hydroiodic acid treatment followed by gas chromatographic determination of the methyl iodides and hydrogen iodide. Isopropyl liberated (see, for example, The United States Pharmacopoeia (USP30-NF25), United States Pharmacopoeia Convention, Inc., 2007, 2323 and DOW Analytical Method DOWM 100755-ME00B, The Dow Chemical Company, 2002). Sample preparation is long, involves the use of hazardous reagents at high temperature and pressure, and requires careful control for accurate results to be obtained.
Proton nuclear magnetic resonance spectrometry (1H NMR) was used to measure the hydroxypropoxy content of O- (2-hydroxypropyl) cellulose (see, for example, Determination of Substitute Distribution in Cellulose ethers by 13C- and 1H-NMR acetylated derivatives: O- (3-hydroxypropyl) cellulose,
Tezuka, Y .; Irnai, K.; Oshima, M. and Ciba, T., Carbohydr. Res. 196, 1 (1990)). A similar procedure, employing the preparation of an acetyl derivative of the intact polymer to confer solubility in NMR solvents in a wide range of substitution, has been developed for hypromellose (see, for example, NMR method 1, below) . This method has a higher accuracy than the USP method, but the sample preparation is long (the acetylation reaction lasts 3 days). Determination of hydroxypropoxy content of hydroxypropylcellulose without derivatization, using deuterated chloroform as a solvent, has been described (see, for example, Determination of molar substitution and degree of substitution of hydroxypropyl cellulose by nuclear magnetic resonance spectrometry. , FF-L., Kohler, RR, Ward, GA, Anal Chem 44, 178 (1972)); however, a recent evaluation of this procedure has demonstrated poor reproducibility (see, eg, Determination of hydroxypropoxy content in hydroxypropyl cellulose by 1H NMR, Andersson, T., Richardson, S., Erikson, M., Pharmeuropa , 271 (2003)). Further work has been conducted to develop a method for determining the undiluted hypromellose hydroxypropoxy and methoxy content, using a D20 / DMSO solvent, which is suitable for routine use (see NMR Method 2, below). ). NMR method 1. The degree of substitution is indirectly determined on samples acetylated by proton nuclear magnetic resonance (1 H NMR). Acetylation of the samples is performed by dissolving 75 mg of each of the polymer samples in 2.25 ml of acetic anhydride and 0.75 ml of pyridine. The solutions are heated to 90 ° C with stirring for 6 hours and then dialyzed against demineralised water in a Spectra / Por dialysis membrane (having a 10 kDa molar mass threshold) for 24 hours. The samples are dried before dissolution in deuterated chloroform (0.8 mg / ml). The 1H NMR spectra are recorded on a Varian 500 Inova spectrometer (United States) operating with a magnetic field of 11.7 T and equipped with a probe of 5 mm inverse detection gradient 1H. The free induction decay is recorded with at least 16 scans and the spectral window is between -1 and 16 ppm, with reference to the CDCI3 solvent signal. The spectra are recorded at 50 ° C. The percentages by weight of methoxy (MeO) and hydroxypropyl (HP) groups are calculated according to the following formula:
where DS, the degree of substitution, and MS, the molar substitution, are obtained from the NMR spectra (see, for example, Determination of hydroxypropoxy content in hydroxypropyl cellulose by 1H NMR, Andersson, T., Richardson, S., Erikson, M., Pharmeuropa 15, 271 (2003)).
NMR method 2. The hydroxypropoxy and methoxy contents are determined directly by nuclear magnetic resonance spectrometry as follows. 3.5 to about 4.5 mg of hypromellose are dissolved in a solvent, which is 99.96% D20. Hypromellose is heated at about 105 ° C for about 30 minutes before dissolution in the solvent. Hypromellose is heated at about 80 ° C for about 15 minutes after dissolution in the solvent. The nuclear magnetic resonance spectrometer comprises a reverse detection probe 1H {X}. The temperature is about 353K. The pulse is about 45 °. The spectrum width is about -2.5 to 13.5 ppm. The pulse repetition is about 15 seconds. The exponential line broadening is about 1.0 Hz. The spectrum is referenced to the residual dimethylsulfoxide (DMSO) peak at 2.70 ppm. The baseline of the nuclear magnetic resonance spectrum is corrected. The number of scans is chosen so that the ratio signal: noise at 200 Hz for the peak at 1.2 ppm is greater than 500. The number of time domain data points is about 65,000. The number of points processed data is approximately 250,000.
Table 13 shows contents of hydroxypropoxy ("HP") and methoxy ("MeO"), expressed as percentages by weight of 18 solid dosage forms of a formulation, as determined using the method of the United States Pharmacopoeia (" USP "), the NMR Method 1 and the NMR Method 2.
Table 13
Multivariate analysis determined that the hydroxypropoxy content of hypromellose is the most important uncontrolled factor in determining the release of active component from the formulations. FIG. 8 presents multivariate analysis results which identify the hydroxypropyl content of low and high viscosity SP 2208 hypromellose chemistry as the most important uncontrolled factors affecting the release of active component from solid dosage forms of the formulations. . The vertical axis represents the influence of variable on projection, VIP, which is a measure of the relative importance of factors, listed on the horizontal axis, that may affect the release, (see, for example, PLS.Wold, S., Johansson, E., Cocchi, M. in 3D-QSAR in Drug Design, Theory, Methods and Applications, Kubinyi, H., (ed.), ESCOM Science, Ledien, pp. 523-550, 1993).
The factors, in the order shown in Figure 8, are: the polymer ratio (controlled factor used to compensate for variation in hypromellose lot characteristics), the hydroxypropoxy content of low viscosity hypromellose ("100 cP HP "), the hydroxypropoxy content of the high viscosity hypromellose (" 4000 cP HP "), the number average molecular weight of the high viscosity hypromellose (" 4000 cP Mn "), the average molecular weight of weight of high viscosity hypromellose ("4000 cP Mw"), viscosity of low viscosity hypromellose ("100 cP Viscosity"), methoxy content of low viscosity hypromellose ("100 cP MeO") ), the 100 mesh cross-over of high viscosity hypromellose ("4000 cP 100 mesh"), the average particle diameter of the low viscosity hypromellose ("100 cP PS D50"), the weight average molecular weight of low viscosity hypromellose ("100 cP Mw "), the 100 mesh cross-over of the low viscosity hypromellose (" 100 cP 100 mesh "), the average particle diameter of the high viscosity hypromellose (" 4000 cP PS D50 "), the average molecular weight in number of the low viscosity hypromellose ("100 cP Mn"), the methoxy content of the high viscosity hypromellose ("4000 cP MeO"), the particle size range of low viscosity hypromellose ( "100 cP PS range"), the high viscosity hypromellose particle size range ("4000 cP PS range"), and the viscosity of high viscosity hypromellose ("4000 cP Viscosity"). Given the importance of the hydroxypropoxy content, it is important to use the best possible test method. The NMR Method 2, although less robust than the NMR Method 1 (especially with respect to inter-laboratory transfer), has been optimized for the determination of hydroxypropoxy and is considered suitable for use in routine by a person skilled in the art at the same location. The 1-NMR method is useful as a reference method or when multiple-site use is required, whereas the USP method is suitable for determining compliance with pharmacopoeial standards but is considered to be too variable to be used. singly as a tool for batch selection of hypromellose. Accordingly, unless otherwise indicated, HPMC NMR characterization refers to the NMR Method 2.
Cloud point. Aqueous hypromellose solutions undergo a phenomenon known as thermal gelation, wherein upon heating gelling occurs at a specific temperature determined by the hypromellose chemistry and the solution concentration. This effect is attributed to a progressive loss of the water of hydration when the temperature increases, which results in a progressive decrease of the viscosity. Once dehydration has reached a critical point, hydrophobic (polymer-polymer) interactions are predominant, leading to an extensive network structure and a marked increase in viscosity. The temperature at which the optical transmissivity reaches 50% of its initial value is called the cloud point. The start of gelation can also be measured (temperature at 95% transmission) as well as a temperature profile - complete transmission.
An illustrative protocol for determining the cloud point is as follows: 50 ml of citric acid (0.05 M) / sodium hydroxide (0.09 M) buffer (pH 4.70 - 4.90) in a container of 100 ml are heated to 75 ± 5 ° C and 500 ± 2 mg of the hypromellose test sample are added with rapid stirring. Stirring is maintained for about 5 minutes to ensure complete dispersion. The vessel is transferred to an ice bath and slow stirring is maintained for another 20 minutes. The resulting solution is then refrigerated overnight to ensure complete dissolution.
The cloud point is measured using a cloud point analyzer, such as the Mettler-Toledo FP900 Thermosystem, which includes a Mettler-Toledo FP90 central processor and a Mettler-Toledo FP81C clarity and cloud point measuring cell. Sample capillaries (Fisher Cat. No. UC-18572 or equivalent) are filled with sample solution at a height of approximately 10 mm using a Pasteur pipette, taking care to avoid trapping air, and placed in the measuring cell. The optical transmission is measured continuously while the samples are heated in the temperature range of 40 to 80 ° C at a rate of 1 ° C per minute with a waiting time of 30 s. Each test is performed in triplicate and the average values for Tcp96 (the temperature at which light transmission is 96% of the value at 40 ° C) and Tcp50 (the temperature at which the transmittance is 50% of the value at 40 ° C) are recorded.
Table 14 shows the cloud point measurements for 16 solid dosage forms of a formulation having a hydroxypropoxy content in the range of 10.2 to 13.7%.
Table 14
Figure 9 represents, on the basis of the data presented in Table 14, a weak correlation between the cloud point and the hydroxypropoxy content.
Since the cloud point is related to the hydrophilicity of hypromellose, a property which is highly dependent on the degree of hydroxypropoxy and methoxy substitution, it is possible that the cloud point is useful as an active component release factor. , and serves as a substitute for more complex and expensive NMR methods. Viscosity. The viscosity of a 2% hypromellose solution (weight of hypromellose / weight of water) in water can be measured by a Ubbelohde viscometer and expressed in centipoises (cp). Additional information can be found in C.M. Keary, Characterization of METHOCEL cellulose ethers by aqueous SEC with multiple detectors, Carbohydrate Polymers 45 (2001) 293-303, which is presently incorporated by reference in its entirety.
The viscosity and percent through 100 mesh are determined by hypromellose suppliers (e.g., Dow Chemical and Shin-Etsu Chemical Companies). The viscosity can be determined using a method of the hypromellose monograph of the US Pat. Pharmacopoeia.
Erosion. Solid dosage forms can release an active component by erosion of a hypromellose tablet, which can be measured as follows. Hypromellose tablets, which may include Methocel K100 and Metolose SR [Type 90SH] (Hypromellose 2208 USP, 100cP), are prepared by direct compression. Hypromellose is mixed with magnesium stearate (1.5%) in a small V-blender for 2 minutes. Tablets are prepared using a press F (0.3 x 0.748 "forming tool) at a target weight of 640 mg (± 10 mg) and a target hardness of 20 to 25 Kp. Regular weight and hardness is done by determining the weight and hardness of 5 individual tablets before operating the press and once the press has started random samples are taken to check the pattern.
Erosion studies can be carried out in triplicate using a USP I basket apparatus in 0.05 M citric acid / 0.09 M NaOH pH 4.8 buffer (900 ml) maintained at 37 ° C and stirred at a temperature of speed of 100 rpm. Each tablet is weighed before starting the test. The baskets are removed from the medium at 16 hours and dried at 60 ° C in an oven for a period of 24 hours. The residues are then cooled on a desiccant before weighing.
The percentage of erosion is calculated as follows:
where W1 is the tablet weight before testing and W2 is the cooled residue weight.
Table 15 shows the percent erosion for 20 solid dosage forms of a formulation.
Table 15

Based on the data in Table 15, there is a strong correlation between active component release rate from solid dosage forms containing low viscosity hypromellose (with high viscosity hypromellose and other excipients). ) and the erosion of low viscosity hypromellose tablets, as exemplified in Figure 10 for the 12 hour dissolution time. Therefore, the erosion test can be used as a performance test in the evaluation of new batches of low-viscosity hypromellose to identify and reject batches that would lead to tablets with release characteristics. unacceptable drug, or to determine an appropriate ratio of low viscosity hypromellose to high viscosity hypromellose which would result in tablets with acceptable release characteristics.
Particle size. The particle size can be measured by air-jet sieving.
Therefore, commercially available hypromellose products can be classified in terms of chemistry (methoxy and hydroxypropoxy content), viscosity and physical form (particle size). In the case of METHOCEL® products, the classification takes the following form: METHOCEL® X NY P, where X identifies the hypromellose as being E, F, or K; NY indicates the viscosity (N being a number and Y, if present, a letter indicating a multiplier, "C" representing 100 and "M" representing 1000, the multiplicative product being the apparent viscosity in mPa * s, solution at 2% in H2O at 20 ° C); P is a suffix that, if present, can be used to identify special products ("LV" means low viscosity, "CR" means controlled release quality, "EP" a product that meets the specifications of the European Pharmacopoeia, etc.).
A buffering agent (such as sodium citrate dihydrate) can increase the pH in a hydrated tablet core, so as to decrease the ring solubility in order to minimize diffusion release. For formulations, the selection of lactose, microcrystalline cellulose and magnesium stearate is conducted in accordance with industry practice. Formulations for different tablet strengths are shown in Table 16.
Table 16

The pigment mixtures with the indicated brightness and color are as follows: SSR 400 mg: 8146W (white); SSR 300 mg: 8580Y
(yellow); SSR 200 mg: 7757-Y (yellow); SSR 150 mg: 8146W (white); SSR 50 mg: 7756-OR (orange).
Studies have shown a variability of tablet dissolution in a lot of tablets that could not be attributed to any single factor, but depends on four hypromellose factors: viscosity / molecular weight, particle size, hydroxypropoxyl content, and the methoxyl content. It has been observed that the relative importance of these factors varies according to tablet dosage, and it has been observed that hypromelloses from different suppliers (for example, Dow Chemical Company and Shin-Etsu, Ltd.) have different behaviors.
An increase in viscosity (an increase in chain length and thus in molecular weight) leads to a reduction in the surface erosion rate and thus the drug release rate. There is evidence that this effect can reach a plateau at high viscosities. A mixture of high and low viscosity hypromellose to obtain an intermediate viscosity can be modeled using the Phillipof equation: η = (1 + KC) 8, where η = viscosity in cp, K = constant for each batch of polymer individual, and C = concentration expressed as a percentage. Formulations that include combinations of hypromellose qualities may be susceptible to variations in viscosity that may occur as a result of variability in hypromellose lot specifications.
The effect of deliberate variation in entrained viscosity by adjusting the proportions of low and high viscosity hypromellose grades 2208, characterized by the weight average molecular weight (Mw), for three batches of tablets, is shown in FIG. .
Smaller particles that have a higher surface area to mass ratio are hydrated faster than larger particles. This leads to a more effective formation of the protective gel barrier. In contrast, tablets made from larger hypromellose particles tend to disintegrate. This leads to rapid and uncontrolled drug release.
With respect to hydroxypropoxyl and methoxyl content, the formulation and methods of preparation are based on theories that disagree with widely accepted assumptions about hypromellose matrix chemistry (see, for example, Using Dow Excipients for Controlled Release of Drugs in Hydrophilic Matrix Systems, Dow Chemical Company, Midland, MI, 2006). It has previously been postulated, as previously mentioned, that the hydroxypropyl group acts as a hydrophilic substituent which contributes greatly to the level of hydration, whereas the methoxyl group acts as a relatively hydrophobic substituent and does not contribute to the hydration rate. . It has therefore been considered that the hydration rate of the different hypromellose chemistries depends on the ratio of hydroxypropoxyl: methoxyl substituent. Contrary to this assumption, cloud point measurements have shown that for the polymer batches studied, the methoxyl and hydroxypropoxyl groups both act as hydrophobic substituents, so that an increase in the content of one of the 'between them leads to a decrease in the cloud point. The inverse relationship between the hydroxypropyl content and the cloud point for batches of hypromellose having a similar rate of methoxy substitution is shown in Figure 12. In addition, when batches of hypromellose are used in the formulation, all other factors being equal, such a cloud point decrease leads to an increase in drug release rate, as described in Figure 13. Studies of the mechanism of release have demonstrated that quetiapine release from tablets is controlled exclusively by erosion, as illustrated by the coincident release profiles for quetiapine and hypromellose in Figure 14. Therefore, variations in methoxyl content and hydroxypropoxyl content affect the rate of erosion.
Methods for preparing a formulation include high to low viscosity hypromellose ratio batch to batch variation to compensate for normal variations in hydroxypropoxyl content, methoxyl content, and lot viscosity of hypromellose, which otherwise would lead to unacceptable variability in the quétiapine dissolution profile from tablets. The methods differ from the conventional "master formula" approach, in which each batch of a formulation is identically prepared by incorporating the active component and the excipients in fixed amounts and treating them in an identical manner. . In methods of the invention, the total hypromellose content can be fixed for all batches but the ratio of low and high viscosity hypromellose can be different in different batches, among which the ratio can vary between 15.0: 15.0 and 29.0: 1.0.
The methods of the invention can implement laboratory procedures (e.g., hydroxypropoxyl measurement by nuclear magnetic resonance) that may have reduced variability compared to simple test methods. The methods can implement predictive tools to determine the ratio of high and low viscosity hypromellose batches to obtain a dissolution profile for a formulation at a given dosage. The predictive tool can take the form of a conversion table (derived from historical data), a multivariate mathematical model, or any other suitable heuristic tool.
The methods can improve the frequency with which dosage forms meet drug release specifications for marketed products, support the use of a broad purchase specification for hypromellose lots consistent with the manufacturer's ability, allow the use of hypromellose from different suppliers, support the use of different sites and scales of manufacture, and / or support the manufacture of pharmaceutical form batches with faster or slower release profiles, as may be required for pharmacokinetic studies.
The methods can be applied to the above formulations and other formulations of quetiapine, or pharmaceutically acceptable salts thereof, or formulations comprising other active substances and a hypromellose content of between 15 and 55%.
Some embodiments of the invention include a multivariate model that can be used to correlate hypromellose properties and formulation information with in vitro tablet dissolution measurements. Hypromellose content and hypromellose viscosity have been determined to contribute to the quetiapine release rate from quetiapine sustained release tablet formulations. Unexpectedly, not only the hypromellose content and viscosity ratios affect the release rates, but also the polymer properties [e.g., the hydroxypropoxy content] affect the release rates.
The model may be an artificial neural network (ANN) model, which may have low prediction errors compared to other models. An ANN is a mathematical procedure for correlating variables to an output. The ANN develops a correlation between known inputs and known outputs in a process called "learning". A multi-layer positive reaction neuronal network ("NN") is described, for example, by Despagne, F. and D. Luc Massart, 1998, "Neural networks in multivariate calibration," Analyst, 123: 157R-178R, which is presently incorporated by reference in its entirety. A digital analytics platform marketed under the brand name MATLAB, which is marketed by MathWorks, Inc. of Natick, Mass., Is a commercialized tool for neural network learning and the use of neural networks defined for prediction. Positive feedback NN and fast back propagation are available through several commercial packages.
Figure 15 depicts a simplified representation of a positive reaction 1500 ANN with appropriate inputs and outputs for the formulations of the invention as presently described. Figure 15 shows an input layer 1502, a masked layer 1504, and an output layer 1506. The hypromellose properties and the formulation information are input into the input layer 1502.
Output 1506 is% dissolved, i.e., the% of quetiapine released for a single time. The dissolution curve of quetiapine extended release tablets as described herein, and other pharmaceutically acceptable salts, can be modeled using an independent neural network by dissolution sampling as a function of time. The results can be combined to obtain a dissolution profile that covers different times.
An example of ANN architecture for quetiapine formulations as described herein and other pharmaceutically acceptable salts is shown in Table 17. The elements referenced in Table 17 as well as the input parameters and dissolution results, define an ANN used for quetiapine tablets as described herein (and its pharmaceutically acceptable salts, more particularly the fumarate salt). A description of the architectures of ANN and the parameters presented in Table 17 is made, for example, in Despagne and Massart, 1998 (cited above). Model entries that may be appropriate for the formulations are presently described, and other model entries may be used for other embodiments of the invention, for example, embodiments of the invention that may be used for other pharmaceutical compositions.
Table 17
In some embodiments of the invention, there are two types of training information entered into the model 1500. The first type is information about the formulation, and the second type is data about properties. specific to hypromellosis.
Dosages of 50mg, 200mg, 300mg, and 400mg tablets were included in learning the 1500 model. Tablets were manufactured according to the protocol described in Example 2 below. The formulation components and tablet weights were included as inputs (see Table 18). The quantitative composition of components was expressed as the relative content (% by weight) of each component for each tablet dosage. For each batch of one tablet of any dosage, the only differences in formulation entries are the amounts of hypromellose at 100 cp and 4000 cp, but the total sum of hypromellose at 100 cp and 4000 cp is for each batch of 30% by weight of the formulation. All other formulation components remain fixed for each formulation dosage.
Table 18
Table 16 shows the quantitative composition of tablets of quetiapine formulations as herein described and other pharmaceutically acceptable salts of different weights.
The second type of learning information entered into the 1500 model is hypromellose property data. Although commercial data conform to pharmacopoeial specifications, these data alone are insufficient to understand the correlation between hypromellosis and dissolution results.
Eight hypromellose properties were chosen for the model (see Table 19). Values for hypromellose at 100 cp and 4000 cp for each property were included in the model.
Table 19
The hydroxypropoxy and methoxy contents can be determined by a nuclear magnetic resonance spectrometry protocol such as the NMR method 2.
Values for viscosity and particle size (% through 100 mesh) can be extracted directly from vendor certificates of analysis and used in the model.
The average particle diameter and the particle size range can be determined using a laser powder diffraction technique.
The number average molecular weight (Mn) and the weight average molecular weight (Mw) are determined using an aqueous SEC method using on-line light scatter detection for the direct determination of molecular weight. The units are daltons.
Inputs and outputs in ANN model learning data are centered on the mean and proportioned by range. By proportionalization, the maximums of the absolute value of the inputs centered on the mean are adjusted to the value one and the maximums of the absolute values of the outputs centered on the average are adjusted to the values 0.5, 0.5, 0.5, 0 , 5, 0.5, 0.5, 0.8, and 0.85 respectively.
Weights and biases are initialized with low random numbers between -0.05 and 0.05.
A back propagation algorithm that uses a pulse and an adaptive learning rate is described below. The algorithm is described by Martin T. Hagan, Howard B. Demuth, and Mark Beale, Neural Network Design, Boston: PWS Publishing Co., 1996, which is presently incorporated by reference in its entirety, and is summarized below. During the learning process, the weights and biases are adjusted according to the following formulas (some terms of which are more general than the corresponding terms that appear below with reference to the model after learning):
where λ is the learning rate, γ is the pulse factor, δ ± is the correction term that is calculated using the standard error backpropagation, Pj is the input to a neuron, and t represents the temporal sequence of the learning process.
The following rules were used to adjust the learning rate a during the learning process. The rules implement the calculation of a quadratic error, which can be the quadratic error of an individual prediction, the sum of the quadratic errors of individual predictions in a learning set, or any other suitable measure of the error between a predicted and real dissolution.
(1) If the squared error increases by more than 4% after a weight update, the weight update is rejected, the learning rate is multiplied by 0.7, and the pulse factor is set to zero; (2) If the squared error decreases after a weight update, the weight update is accepted, and the learning rate is multiplied by 1.05. If the pulse factor has been set to zero previously, it is reset to its original value; (3) If the squared error increases by less than 4% after a weight update, the weight update is accepted. The learning rate and the pulse factor keep the same values.
The learning is stopped when 400 learning periods or a sum of target square errors of 0.001 has been reached. The initial learning rate is set to 0.01 and the learning batch size is set to 10.
Model 1500 was trained using a set of training data of 177 batches of formulations as described herein. Tablets of all dosages, two different commercial sources of hypromellose, development and industrial fabrications, and three manufacturing sites were used for model learning. Tablets include 100 cp hypromellose to 4000 cp ratios in the range of 15:15 to 29: 1 (% 100 cp:% 4000 cp). The reports are also included in the template. Model 1600 (see Figure 16) is an illustrative after-learning prediction model based on the model architecture shown in Figure 15 and the training data set, which intrinsically reflects the characteristics of manufacturing equipment. which may differ between manufacturers and manufacturing sites. The 1600 model, therefore, can not predict the dissolution behavior of produced tablets using material that is different from the material used to make the currently described tablets. However, the 1600 model can be trained for tablets of different manufacturing processes, demonstrating that the ANN approach has general applicability, but the models must be trained on the same hardware that is to be used for commercial production. A caution against over-adjustment is to use the simplest possible ANN to adjust the data. The 1500 model is considered a simple simple ANN architecture because it contains a single masked layer with only 10 cells.
The learning is carried out by obtaining measurements of physical and chemical properties of hypromellose lot, input of measurements into the model, prediction of dissolutions, comparison of the predicted dissolution with the in vitro dissolution of batch tablets made from batches , and readjustment of model constants until model predictions are acceptable. The protocol for the in vitro dissolution test is described in Example 7. The predicted dissolution profile can be compared to a real tablet dissolution profile by calculating the RMSEP (RMSEP). The lower the RMSEP, the better the agreement between the real and predicted profiles.
For 100 cp and 4000 cp hypromellose lots, the 1500 model can be used to predict dissolution profiles for hypromellose ratios of 15:15 to 29: 1 (100 cp: 4000 cp) in ratio increments. 0.1 (eg 15.0: 15.0, 15.1: 14.9, 15.2: 14.8, etc.). Fig. 17 shows a set of curves 1702 which may include many predicted profiles corresponding to the incremental ratios. An optimal profile, and thus an optimal ratio, is identified by comparing the predicted dissolution results at the center points in the dissolution acceptance criteria ranges (bars 1704, FIG. 17) at 2 times, 6 and 12 hours. A comparison of the predicted results is performed by calculating a combined relative distance factor, d, using the equation:
where: P 6 is the% of dissolved quetiapine predicted at the time of 6 hours; Cb is the% of quetiapine dissolved at the midpoint in the dissolution acceptance criterion range at the time of 6 hours; R6 is the acceptance criteria range in% of quetiapine dissolved at 6 hours;
Ri2 is the range of acceptance criteria in% of quetiapine dissolved at 12 hours;
Pi2 is the% of dissolved quetiapine predicted at the time of 12 hours; C12 is the% of quetiapine dissolved at the midpoint in the dissolution acceptance criterion range at the 12 hour time.
The optimal ratio is identified by selecting the profile with the lowest value of d.
Since the slope of the dissolution profile varies according to the particular properties of the hypromelloses used, it is common that the profile with the optimal ratio identified may not pass through the central points of acceptance criterion (as described by the bars 1704 on the Figure 17) at 6 or 12 o'clock.
The details of the batch fabrication performed using the optimal ratio determination are presented above.
Twenty-four raw inputs 1610 are scaled to conform to a range of -1 to +1 by respective proportionalization factors 1612. Proportional inputs 1614 are input into input layer 1602. Proportional inputs 1614 are transformed into 10 masked layer values 1604 oq (j = 1 to 10) based on weights 1616 and bias 1618. Masked layer values 1604 are converted to output layer value 1606 aScaied based on weights 1620 and biasoutput 1622 The aSCaied value is then back-proportioned to the 1624 proportionalized output by using the 1624 scaling factor.
Table 20 shows illustrative physical parameters of 24 raw inputs 1610 for model 1600. Raw inputs # 1 to 16 and 19 to 24 are based on empirical measurements, estimates or descriptive statistics of formulation parameters and properties. of hypromellose.
Inputs No. 17 and 18 are percentages by weight of HPMC for HPMC at 100 and 4000 cp, respectively. Together, raw inputs 17 and 18 represent a ratio which is an independent variable to be optimized on the basis of the distance factor d. The sum of gross inputs 17 and 18 is kept constant at 30.0% and the ratios between gross inputs 17 and 18 vary in steps of 0.1 between 15.0: 15.0 and 29.0: 1.0.
Table 20
Table 20 furthermore presents the minimum and maximum values of each physical parameter raw input for which the model has been trained and has been validated.
Table 21 shows the corresponding minimum and maximum values of proportionate entries 1614.
Table 21
Model 1600 can be run once for each pair of raw inputs # 17 and 18 for each of the 8 beats to predict quétiapine fumarate dissolution% 1626 (see Figure 16) at times of 6 and 12 hours for the different reports. The ratio which minimizes the distance factor d can then be used as a ratio for the production of the currently described formulations.
Proportional inputs 1614 can be determined using the following equation.
where, for each raw entry, p is a raw entry 1610 and Pscaied is the scaled entry 1614. xMean and xScale for each raw entry are shown for exemplary model 1600 in Table 22.
Table 22

More generally, when the raw inputs are represented by the vector x, the proportionalization can be carried out as follows: for a given vector x (a column in the input data matrix), the mean of the vector (xMean) is computed in first, and x is then centered on the average as described below:
where I is the identity vector. Then, a predetermined xMax (1 for all raw inputs) can be used to compute a xScale proportional factor using the following equation
The data can then be scaled using the following equation
The output data can be similarly retro-proportioned.
The retro-proportional output 1626 can be determined using the following equation.
where oigcaied is the value in the output layer 1606, "backsoaied is the retro-scaled output 1626 and yScale and yMean are described in Table 23. yScale and yMean are analogous to xScale and xMean. yMax is analogous to xMax. yMax is also shown for the 1600 model in Table 23.
Table 23
The weights 1616 (a 10 x 24-element matrix), the 1618 biases (a 10 x 1 vector), the weights 1620 (a 1 x 10 vector) and the biasoutput 1622 (a scalar) for each of the 8 beats are presented in the table. Annex A, below.
The output layer ascending value 1606 for each of the times can be calculated as follows: an illustrative transfer function f is the hyperbolic tangent and is applied to each of the neurons in the layers 1604 and 1606. The hyperbolic tangent is defined as:
The value of each of the neurons in the masked layer 1604 is oq, where j = 1 to 10. The oq values are calculated as follows:
where Wji are the weights 1616, Pscaie ^ are the proportional inputs 1614, bj are the biases 1618 and f is defined by f (n) above.
The value of the neuron in the 1606 (ascaled) output layer is given by:
where Wj are the weights 1620, where are defined above, b2 is biasoutput 1622 and f is defined by f (n) above.
The 1600 model can be run in MATLAB® by loading the aforementioned scalar, vector and 2-D matrix variables into MATLAB® variables and performing the calculations defined by the equations above. It will appear that the model 1600 can be executed using a suitable digital analysis platform. The template can be run manually.
Model 1600 can be validated using a "leave-one-out" ("LOOCV") cross-validation in which a sample of the training data set is predicted using the remaining portion of the data set. 'learning. A lot of tablets was removed from the 1600 model, which was re-trained without the lot. The batch dissolution was then predicted using the 1600 model. The mean squared prediction error ("RMSEP") is then calculated by comparing the predicted dissolution profile with the actual dissolution profile at the specified times for profiles in which the Actual and / or predicted profiles meet the criteria for acceptance of dissolution. This procedure was repeated until all batches of tablets were successively removed and predicted. The mean squared error of cross validation (RMSECV) is the average of all individual RMSEPs.
The RMSECV for the 1600 model for the formulations is 2.9% operating within the acceptance criteria ranges. Hypromellose ratios can be determined by targeting the midpoints at 6 and 12 hour dissolution times. With acceptance criteria ranges of 22% and 30% at 6 and 12 hours, respectively, an RMSECV of 2.9% for the 1600 model is favorably comparable to the acceptance criteria ranges.
The 1600 model is a tool that can be used to increase batch performance, measured by in vitro dissolution of tablets. As a result, the model is considered verified if the tablets meet the criteria for acceptance of in vitro dissolution.
Twenty-four batches of tablets in total, 6 batches of each assay, are manufactured at 2 industrial sites using 100cp to 4000cp hypromellose ratios determined using ANN. The details of the manufacture are presented above.
All batches of tablets at a dosage of 200, 300 and 400 mg meet the criteria for acceptance of dissolution. Four of the 6 batches of tablets at a dosage of 50 mg meet the criteria for acceptance of dissolution. Two lots of 50 mg tablets do not meet the acceptance criteria, and these lots were manufactured from the same lots of 100 cp hypromellose and 4000 cp at each of the two industrial manufacturing sites. Since the model has been learned on the basis of the commercial source of hypromellose, hypromellose compositions are underrepresented in learning. For example, the hydroxypropoxy content (10%) of hypromellose at 4000cp of non-compliant lots is a level of content that is not correctly represented in the training tablets.
The development of the 1600 model demonstrated that the refinement of the model, for example, based on the increase in the number of hypromellose batches and batches of tablets, the variety of formulation assays, and possibly other variables , can increase the robustness of the model. The data corresponding to the tablets with which the 1600 model has been trained are shown below in Table 24.


Table 25 lists the characteristics of the 100 cp hypromellose lots used for learning the 1600 model.
Table 26 lists the characteristics of the 4000 cp hypromellose lots used for learning the 1600 model.

Figure 18 shows an illustrative method 1800 for formulating a sustained release formulation. The method may include step 1810 of assaying hydroxypropoxy and methoxy in a plurality of lots of hypromellose using nuclear magnetic resonance (NMR). Among this plurality, a first batch may have a first viscosity and a second batch may have a second viscosity. Step 1820 represents the entry into a multivariate model of the hydroxypropoxy content and the molecular weight of the first batch and the second batch and a tablet dosage. Step 1830 represents the entry into the model of a series of ratios between a quantity of the first batch and a quantity of the second batch. Step 1840 represents the identification, using the model, of an optimal ratio which corresponds to a predicted dissolution profile which has a deviation from a target profile, the difference being smaller than that of the other ratios.
Fig. 19 shows an illustrative method 1900. The method 1900 may comprise the step 1910 of identifying a plurality of formulation parameter values. The method 1900 may include the step 1920 of identifying a plurality of property parameter values.
Step 1930 represents the selection of a plurality of report values. Each ratio value may correspond to a ratio of the first constituent to the second constituent. Step 1940 represents the identification of a ratio value that minimizes the difference between a predicted dissolution fraction of a target constituent and a predetermined acceptable dissolution fraction of the target component.
Fig. 20 shows an illustrative conversion table 2000 which may be used to correlate the 2140 ratio of weight% of release control excipients 2120 and 2130 to active component release information 2150. The information 2150 may comprise a released percentage 2150 of active component at a time 2154. The information 2150 may be determined in whole or in part by one or more physical or chemical parameters 2122 and 2132 of release control excipients 2120 and 2130, respectively. Parameters 2122 and 2132 may be grouped into ranges such as ranges 2124 and 2134, respectively. The information 2150 can be determined in whole or in part by the dosage form dosage 2110. The conversion table 2000 can be powered by empirically determining the information 2150 for all combinations of assay values 2110, parameters such as 2122, parameters such as 2132 and the 2140 ratio. In some embodiments of the invention, the conversion table 2000 may be partially powered by empirically determining the information 2150 for the values and partly by estimating the values. For example, some information values 2150 may be calculated by interpolation or extrapolation based on near values.
In some embodiments of the invention, the release control excipients 2120 and 2130 may be hypromellose having nominal viscosities of 100 cp and 4000 cp, respectively. In certain embodiments of the invention, the active component may be quetiapine. In some embodiments of the invention, parameters such as 2122 and 2132 may correspond to entries in the 1600 model (shown in Figure 16, see, for example, entries 1 to 16 in Table 17).
Examples
Example 1: Determination of the hydroxypropyl (HP) content of hypromellose (hypromellose) by nuclear magnetic resonance
According to the NMR 2 method, 3.5 to about 4.5 mg of hypromellose are dissolved in a solvent, which is 99.96% D2O. Hypromellose is heated at about 105 ° C for about 30 minutes before dissolution in the solvent. Hypromellose is heated at about 80 ° C for about 15 minutes after dissolution in the solvent. The nuclear magnetic resonance spectrometer comprises a reverse detection probe 1H {X}. The temperature is about 353 K. The pulse is about 45 °. The spectrum width is about -2.5 to 13.5 ppm. The pulse repetition is about 15 seconds. The exponential line broadening is about 1.0 Hz. The spectrum is referenced to the residual dimethylsulfoxide (DMSO) peak at 2.70 ppm. The baseline of the nuclear magnetic resonance spectrum is corrected. The number of scans is chosen so that. the signal-to-noise ratio at 200 Hz for the peak at 1.2 ppm is greater than 500. The number of time domain data points is approximately 65,000. The number of data points processed is approximately 250,000. The NMR spectrum is phased so that the peaks at 4.5 ppm and 1.2 ppm are symmetrical.
The following regions are integrated: Region 1: 4.96-4.31, which is Area A; Region 2: 4.08-2.95, which is Area B; and Region 3: 1.47-0.92, which is Area C.
The content of hydroxypropoxy (weight% HP) is calculated by: Weight% HP = {(75 x MoleHP) / [162 + (58 x MoleHP) + (14 x
MoleMeO)]} x 100, where: MoleHP = C / (3 x A); MoleMeO = [B-C- (6 x A)] / (3 x A); and MeO is methoxy.
An exemplary procedure for analyzing the hydroxypropyl (HP) content of hypromellose by NMR is described below. According to the NMR 2 method, a 3.5 to 4.5 mg sample of hypromellose is heated at about 105 ° C for about 30 minutes. The 3.5 to 4.5 mg sample of hypromellose is dissolved in 99.96% D20. The dissolved hypromellose is heated at about 80 ° C for about 10 minutes. The dissolved hypromellose is analyzed by nuclear magnetic resonance as follows: (i) the nuclear magnetic resonance spectrometer comprises an inverse detection probe 1H {X}, (ii) the temperature is about 353K, (iii) pulse is about 45 °, (iv) the spectrum width is about -3.5 to 13.5 ppm, (v) the pulse repetition is about 15 seconds, (vi) the Exponential line widening is approximately 1.0 Hz, (vii) the number of scans is chosen so that the signal-to-noise ratio at 200 Hz for the peak at 1.2 ppm is greater than 500, (viii) the number of time domain data points is approximately 65,000, and (ix) the number of processed data points is approximately 250,000.
The nuclear magnetic resonance spectrum is phased so that the peaks at 4.5 ppm and 1.2 ppm are symmetrical. The spectrum is referenced to the residual DMSO peak at 2.70 ppm. The baseline of the spectrum nuclear magnetic resonance spectrum is corrected.
The following regions are integrated: Region 1: 4.96-4.31, which is Area A; Region 2: 4.31-4.08; Region 3: 4,08-2,95, which is Area B; Region 4: 2.95-2.45; and Region 5: 1.47-0.92, which is Area C.
The hydroxypropoxy content (% by weight HP) is calculated as% HP weight = {(75 × MoleHP) / [162 + (58 × MoleHP) + (14 × MoleMeO)]} × 100, where (i) MoleHP = C / (3 x A) and (ii) MoleMeO = [BC- (6 x A)] / (3 x A).
Example 2: Formulation of a 50 mg tablet
The following method was used to prepare sustained release formulations of quetiapine fumarate shown in Table 1.
1) Mix quetiapine fumarate, lactose, microcrystalline cellulose, Hypromellose 2208 (USP), and sodium citrate (eg, in a high shear granulator) until the uniformity of content obtained (for example, Fielder 600 1 for about 10 minutes); 2) Charging purified water (e.g., 37% by weight of the tablet) on the powder in the granulator (e.g., a spray nozzle) 5 to 6 minutes to form a granulate; 3) drying the granulate in a fluid bed dryer (for example, at a moisture content <or equal to 3% loss on drying); 4) Reduce the particles of the granulate to obtain a fluidity suitable for compression (for example, a Carr index which does not exceed 30 (for example, 20) using, for example, a sieve mill of 0.05 to 0.109 inch and 5) Mix the granulate with magnesium stearate for a time sufficient to avoid substantial lamination of the tablet punch (eg, 3 minutes in a V-blender, 2/3 full).
The resulting formulation of step 5 is compressed to form a tablet having a hardness of more than 16 kilograms-weight (especially about 28 kp) and a friability of less than 1%.
The tablets may further be coated by mixing all the coating components in the water until dissolved and spraying the resultant mixture onto the tablet (e.g. in a perforated turbine coating machine) until a uniform coating is obtained (for example, a target of 2.5% by weight).
Example 3: 150 mg tablet formulation
The procedure described in Example 2 is used to make tablets having the composition shown in Table 2.
Example 4: 200 mg Tablet Formulation
The procedure described in Example 2 is used to make tablets having the composition shown in Table 3.
Example 5: Formulation of 300 mg tablet
The procedure described in Example 2 is used to make tablets having the composition shown in Table 4.
Example 6: Formulation of 400 mg tablet
The procedure described in Example 2 is used to make tablets having the composition shown in Table 5.
Example 7 In Vitro Dissolution Test - 50 mg In Vitro Dissolution Protocol
The following method has been used for ANN training, control of formulations and as an in vivo release predictor. The dissolution process is carried out using the known basket apparatus at a rotation speed of 200 rpm. Initially, 900 ml of dissolution medium consisting of 0.05 M sodium citrate (molar) and 0.09 N sodium hydroxide (normal) are placed in each vessel. The pH of this medium is 4.8. At 5 hours, 100 ml of a medium consisting of 0.05 M sodium phosphate and 0.46 N sodium hydroxide are added to each vessel to bring the pH of the medium to 6.6 for the final period of time. dissolution analysis. Samples are taken over a 20 hour period and analyzed for quetiapine using ultraviolet spectrophotometric detection at 290 nm.
Figure 21 shows the results of the dissolution test. The error bars correspond to the range of individual measurements at each time.
Example 8 In Vitro Dissolution Test - 150 mg
In vitro dissolution protocol conducted as described in Example (7). Figure 22 shows the results of the dissolution test. The error bars correspond to the range of individual measurements at each time.
Example 9 In Vitro Dissolution Test - 200 mg
In vitro dissolution protocol conducted as described in Example (7). Figure 23 shows the results of the dissolution test. The error bars correspond to the range of individual measurements at each time.
Example 10 In Vitro Dissolution Test - 300 mg
In vitro dissolution protocol conducted as described in Example (7). Figure 24 shows the results of the dissolution test. The error bars correspond to the range of individual measurements at each time.
Example 11 In Vitro Dissolution Test - 400 mg
In vitro dissolution protocol conducted as described in Example (7). Figure 25 shows the results of the dissolution test. The error bars correspond to the range of individual measurements at each time.
Example 12: Plasma Protocol Studies
An open, multi-center, multi-dose study was conducted to evaluate the steady-state pharmacokinetics of commercially available tablets comprising study formulations ("SF") with the following quetiapine dosages: 50 mg, 200 mg, 300 mg, and 400 mg . The study formulations have compositions which are shown in Tables 1 to 5. Following a 2-day wash-out period, patients received oral doses of the study formulations and an immediate release drug ("IR Sold under the brand name "Seroquel" (currently marketed by Astra-Zeneca Pharmaceuticals, Wilmington, Delaware) once a day as follows: 50 mg SF on days 1 to 4, 200 mg SF on days 5 to 7, 300 mg SF on days 8-11, 400 mg SF on days 12-14 and 300 mg IR on days 15-17. On days 4 and 11, patients consumed a standardized high-fat breakfast 10 minutes before or after expected dose. Day 3 (50 mg, Figure 3), Day 7 (200 mg, Figure 4), Day 10 (300 mg, Figure 5), and Day 14 (400 mg, Figure 6) data were used. is assumed that equilibrium has been reached for each dose level. On each plot (Figures 3 to 6), the bars correspond to the prediction interval (p = 0.05) for the individual subject data. Each plot (Figs. 3-6) further has a regression curve calculated using first order drug absorption and elimination constants Ke and Ka, respectively, with the equation
The regression parameters for the different tablet assays are as follows: 50 mg: Base = 0.3773; Ke = 0.8421; Ka = 0.05765 (FIG. 3) 200 mg: Base = 25, 86; Ke = 0.3541; Ka = 0.1033 (FIG. 4) 300 mg: Base = 42.15; Ke = 0.2592; Ka = 0.1033 (FIG. 5) 400 mg: Base = 62, 96; Ke = 0.2959; Ka = 0.1395 (Figure 6)
Figure 7 shows the data of Figures 3 to 6.
Therefore, sustained release formulations comprising quetiapine and its pharmaceutically acceptable salts and methods of making the formulations have been proposed. It will be apparent to those skilled in the art that the invention may be practiced in the form of embodiments other than those presently described, which have been presented for purposes of illustration rather than limitation, and that the invention is limited only by the appended claims.
TABLE Al-5
Time: 1
Layer: 1604 (see Figure 16)

TABLE Al-5 (continued)
TABLE Al-6
Time: 1
Layer: 1606 (see Figure 16)

Time: 2
Layer: 1604 (see Figure 16)
TABLE A2-5 (continued)
TABLE A2-6
Time: 2

TABLE A3-5
Time: 3
Layer: 1604 (see Figure 16)
TABLE A3-5 (continued)
TABLE A3 to 6
Time: 3
Layer: 1606 (see Figure 16)

TABLE A4-5
Time: 4
Layer: 1604 (see Figure 16)

TABLE A4-5 (continued)
TABLE A4-6
Time: 4

TABLE A5-5
Time: 5
Layer: 1604 (see Figure 16)
TABLE A5-5 (continued)
TABLE A5-6

TABLE A6-5
Time: 6
Layer: 1604 (see Figure 16)
TABLE A6-5 (continued)
TABLE A6-6
Time: 6
Layer: 1606 (see Figure 16)

TABLE A7-5
Time: 7
Layer: 1604 (see Figure 16)
TABLE A7-5 (continued)
TABLE A7-6
Time: 7
Layer: 1606 (see Figure 16)

TABLE A8-5
Time: 8
Layer: 1604 (see Figure 16)
TABLE A8-5 (continued)
O
TABLE A8-6
Time: 8

权利要求:
Claims (26)
[1]
A formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 9.6% to about 10.4% by weight and the formulation comprises about 30% hydroxypropyl methylcellulose by weight and about 7.2% sodium citrate dihydrate by weight.
[2]
The formulation of claim 1 wherein the quetiapine content is from about 49.5 to about 50.5 mg.
[3]
3. The formulation of claim 2 comprising 30.0% hydroxypropyl methylcellulose by weight.
[4]
The formulation of claim 3 wherein: about 15 to about 29 of the 30.0% hydroxypropyl methylcellulose is a first hydroxypropyl methylcellulose component; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of from about 80cp to about 120cp and a second hydroxypropylmethylcellulose having an apparent viscosity of from about 3000cp to about 5600cp.
[5]
The formulation of claim 4 further comprising: about 25.1% lactose monohydrate by weight; about 25.1% microcrystalline cellulose by weight; and about 1% magnesium stearate by weight.
[6]
A formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 25.6 to about 26.5% by weight and wherein the dosage form comprises about 30% hydroxypropyl methylcellulose by weight and about 12.5% sodium citrate dihydrate by weight.
[7]
The formulation of claim 6 wherein the quetiapine content is from about 149.5 to about 150.5 mg.
[8]
The formulation of claim 7 comprising 30.0% hydroxypropyl methylcellulose by weight.
[9]
The formulation of claim 8 wherein: about 15 to about 29 of the 30.0% hydroxypropyl methylcellulose is a first hydroxypropyl methylcellulose component; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of from about 80cp to about 120cp and a second hydroxypropylmethylcellulose having an apparent viscosity of from about 3000cp to about 5600cp.
[10]
The formulation of claim 8 further comprising: about 13.0% lactose monohydrate by weight; about 13.0% microcrystalline cellulose by weight; and about 1.5% magnesium stearate by weight.
[11]
A formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 32.9% to about 33.8% by weight and wherein the dosage form comprises about 12.5% citrate sodium dihydrate by weight and about 30% hydroxypropyl methylcellulose by weight.
[12]
The formulation of claim 11 wherein the quetiapine content is from about 199.5 to about 200.5 mg.
[13]
13. The formulation of claim 12 comprising 30.0% hydroxypropyl methylcellulose by weight.
[14]
The formulation of claim 13 wherein: about 15 to about 29 of the 30.0% hydroxypropyl methylcellulose is a first hydroxypropyl methylcellulose component; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of from about 80cp to about 120cp and a second hydroxypropylmethylcellulose having an apparent viscosity of from about 3000cp to about 5600cp.
[15]
The formulation of claim 11 further comprising: about 8.8% lactose monohydrate by weight; about 8.8% microcrystalline cellulose by weight; and about 1.5% magnesium stearate by weight.
[16]
A formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 37.1% to about 38.0% by weight and wherein the dosage form comprises about 12.5% citrate sodium dihydrate by weight and about 30% hydroxypropyl methylcellulose by weight and wherein about 15 to about 29 of the 30% hydroxypropyl methylcellulose is a first component of hydroxypropyl methylcellulose; the remaining 30% is a second component of hydroxypropyl methylcellulose; and the first and second components correspond, respectively, to a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of from about 80cp to about 120cp and a second hydroxypropylmethylcellulose which has an apparent viscosity of from about 3000cp to about 5600cp, where the ratio of the first grade of hydroxypropyl methylcellulose to the second grade of hydroxypropyl methylcellulose is not 25.0 to 5.0
[17]
A formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is from about 45.5% to about 46.4% by weight and wherein the dosage form comprises about 11.5% citrate sodium dihydrate by weight and about 30% hydroxypropyl methylcellulose by weight.
[18]
18. The formulation of claim 17 wherein the quetiapine content is from about 399.5 to about 400.5 mg.
[19]
19. The formulation of claim 18 comprising 30.0% hydroxypropyl methylcellulose by weight.
[20]
The formulation of claim 19 wherein: about 15 to about 29 of the 30.0% hydroxypropyl methylcellulose is a first hydroxypropyl methylcellulose component; the remaining 30.0% is a second component of hydroxypropyl methylcellulose; and the first and second components are, respectively, a first grade of hydroxypropylmethylcellulose which has an apparent viscosity of from about 80cp to about 120cp and a second hydroxypropylmethylcellulose having an apparent viscosity of from about 3000cp to about 5600cp.
[21]
The formulation of claim 17 further comprising: about 1.8% lactose monohydrate by weight; about 1.8% microcrystalline cellulose by weight; and about 2.0% magnesium stearate by weight.
[22]
22. The formulation of any one of claims 1, 6, 11, 16, 17 which satisfies the following dissolution criteria, when the dissolution occurs in a basket apparatus having a rotation speed of 200 rpm and containing 900 milliliters of 0.05 molar sodium citrate and 0.09 molar sodium hydroxide, to which 100 milliliters of 0.05 molar sodium phosphate and 0.46 molar sodium hydroxide are added after 5 hours: during the first 1 hour of dissolution, no more than 20% of the quetiapine is dissolved; during the first 6 hours of dissolution, 47 to 69% of quetiapine is dissolved; during the first 12 hour period of dissolution, 65 to 95% of quetiapine is dissolved; during the first 20 hours of dissolution, at least 85% of the quetiapine is dissolved.
[23]
23. A method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral prolonged release dosage form containing quetiapine or a pharmaceutically acceptable salt of which the quétiapine content is 50 mg which, in equilibrium, has a maximum plasma concentration (tmax) onset of said antipsychotic in about 2 to about 16 hours, a maximum plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of said antipsychotic at about 24 hours, and said pharmaceutical form produces effective treatment of psychoses for about 24 hours or more after administration to the patient.
[24]
24. A method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral prolonged release dosage form containing quetiapine or a pharmaceutically acceptable salt of the latter where the quétiapine content is 150 mg which, at equilibrium, has a maximum plasma concentration (tmaX) onset time of said antipsychotic in about 2 to about 16 hours, a maximum plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of said antipsychotic at about 24 hours, and said pharmaceutical form produces effective treatment of psychoses for about 24 hours or more after administration to the patient.
[25]
25. A method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral prolonged release dosage form containing quetiapine or a pharmaceutically acceptable salt of the latter where the quétiapine content is 200 mg which, at equilibrium, has a maximum plasma concentration (tmax) onset of said antipsychotic in about 2 to about 8 hours, a maximum plasma concentration (Cmax) which is greater than or equal to four times the plasma concentration of said antipsychotic at about 24 hours, and said pharmaceutical form produces effective treatment of psychoses for about 24 hours or more after administration to the patient.
[26]
26. A method for effectively treating psychoses in humans, comprising orally administering to a human patient on a once daily basis an oral prolonged release dosage form containing quetiapine or a pharmaceutically acceptable salt of which the quétiapine content is 400 mg which, at equilibrium, has a time of onset of peak plasma concentration (t ^ x) of said antipsychotic in about 3 to about 8 hours, a maximum plasma concentration ( Cmax) which is greater than or equal to four times the plasma concentration of said antipsychotic at approximately 24 hours, and an area under the curve between the time of administration and 24 hours after administration (ASCCUm, 24) which is greater than or equal to approximately 6000 ng.h / ml, and said pharmaceutical form produces effective treatment of psychoses for about 24 hours or more after administration to the patient.

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同族专利:

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公开号 | 公开日

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EP2160183A4|2013-02-13|

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CN101754752A|2010-06-23|

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CA2610652A1|2008-05-17|

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EP2160183A1|2010-03-10|

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DE102007054788A1|2008-07-03|

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FR2908657A1|2008-05-23|

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SE0702522L|2008-05-18|

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WO2008060228A1|2008-05-22|

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PT103884A|2008-05-19|

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US20080287418A1|2008-11-20|

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JP2010526874A|2010-08-05|

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NO20093540L|2009-12-16|

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US20110319383A1|2011-12-29|

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法律状态:
2011-05-31| RE| Patent lapsed|Effective date: 20101130 |

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