Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

• the present invention relates to a novel dosage form and a process for the manufacturing the same. More specincally, the present invention relates to a controlled release oral dosage form comprising an antipsychotic agent.
• Quetiapine chemically designated as 2-[2-(4 ⁇ benzo[3 ⁇ 4 I[1 ]-hiazepin-ll-yl-l- piperazinyl) ethoxy]ethanol (also known as ll-[ -[2-(2-hydro yethoxy)ethyl]-l- piperazmyl]dibenzo-[b,f][l,4] thiazepine), is a compound of formula (I):
• Quetiapine has been employed as an antipsychotic or neuroleptic agent in the treatment of schizophrenia and bipolar mania, due to its antidopaminergic activity, as well as depressive episodes associated with bipolar disorder.
• Quetiapine is a drug of the dibenzothiazepirie class and belongs to a group of drugs known as '"atypical" or second generation antipsychotics which have become increasingly popular alternatives to "typical" antipsychotics.
• quetiapine When administered orally, quetiapine is rapidly absorbed and generally reaches a peak plasma level within about 1.5 hours. Quetiapine is highly metabolized, with elimination occurring mainly through hepatic metabolism in the liver. The plasma half-life of quetiapine is typically about 5 to about 7 hours. Quetiapine is currently marketed as a hemifumarate salt in the form of tablets of several doses, mduding 25 mg, 100 mg, 150 mg, 200 mg and 300 mg, 400 mg for adrrinistration two or three times per day.
• European Patent No. 1 218009 describes the preparation of granules containing quetiapine and a freely or very water-soluble binder for t eir use in suspensions or solutions.
• International Patent Application WO2003/ 039516 describes methods for improving the dissolution of poorly dispersible medicaments, including, for example, quetiapine. The dissolution is improved by means of preparing granules in which a floating agent is added to the medicament. Unfortunately, there is no indication about the release profile of these medicaments in the granulate formulations.
• United States Patent Apphcation 2007/0244093 describes a controlled release dosage form comprising quetiapine and at least one excipient, exhibiting a dissolution profile such that at 4 hours after combining the dosage form with a dissolution media 50 to 95% of the quetiapine, or the pharmaceutically acceptable salt thereof, is released.
• Examples 10, 12 and 13 are formulations of quetiapine where stearic acid is used as a lubricant and wherein the tablets may further be coated with ethylcellulose.
• United States Patent Application 2008/0287418 describes a formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is about 9.6% to about 10.4% by weight and wherein the formulation comprises about 30% hydroxypropyl methy .cellulose by weight and about 7.2% sodium citrate dehydrate by weight.
• the formulation further comprises 25.1% lactose monohydrate by weight, about 25.1% microcrystallme cellulose and about 1% magnesium stearate by weight.
• United States Patent Application 2009/0035370 describes an orally deliverable pharmaceutical dosage form comprising quetiapine and at least one pharmaceutically acceptable excipient, wherein quetiapine is in a form of free base and/or pharmaceutically acceptable salt thereof and comprising a major component in immediate release form and one or more minor components in delayed extended release or delayed pulsed-release form.
• International Patent Application WO2007/058593 relates to the a method of treating a patient suffering from or susceptible to a mood disorder or an anxiety disorder comprising acuximistering a sustained release pharmaceutical composition comprising a pharmaceutically effective amount ofquetiapine, or a pharmaceutically acceptable salt thereof, to the patient in need thereof.
• the compositions claimed display a particular mean Cmax characteristics.
• the proposed method to obtain controlled release of the active ingredient uses the conventional Methocel® excipients.
• compositions which incorporate quetiapine, or one of its pharmaceutically acceptable salts, and which provide desired release rates of the pharmaceutically active agent and a robust manufacturing process
• the formulations according to the present invention overcome the drawbacks of the prior art by providing a novel approach by the using at least one hydrophobic controlled release agent in achieving an extended release dosage form.
• the present invention provides a novel controlled release pharmaceutical dosage form comprising:
• the present invention provides a novel controlled release pharmaceutical dosage form wherein the content (in % by weight) of the at least one hydrophobic controlled release agent is in the range of about 4.5 to about 35% and the content of the at least one pH dependent polymer is in the range from about 15 to about 35%.
• a novel controlled release pharmaceutical dosage form wherein the ratio of the % by weight content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:3 to about 1:7.
• the ratio of the % by weight content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4 to about 1:6. More preferably, the ratio of the % by weight content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4.5 to about 1:5.5.
• novel controlled release pharmaceutical dosage form can be optionally coated with a water insoluble/non gelling polymer,
• Another aspect of the present invention is to provide a controlled release pharmaceutical dosage form that allows a single daily administration with a prolonged effect, simplified production and is cost effective,
• Another aspect of the present invention is to provide a novel stable controlled release pharmaceutical dosage form comprising quetiapine or a pharmaceutically acceptable salt thereof, wherein said dosage form provides a dissolution of quetiapine or pharmaceutically acceptable salt thereof between about 30% and about 45% within 1 hour between about 45 and about 70 % within 6 hours and between about 75 and about 95 % within 16 hours as measured by Apparatus I USP (baskets) at 100 rpm, in lOOOmL of 0.1N HQ (1.2 pH) for the first hour, in lOOOmL of 4.5 pH acetate buffer for the 2 hour and subsequently in lOOOmL of 6.8 pH phosphate buffer.
• the dissolution rates for dosage forms of the present invention is between about 50% and about 60% (by t) of quetiapine or pharmaceutically acceptable salt thereof released after 2 hours; between about 60% and about 70% (by wt) after 4 hours; between about 65% and about 80% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 8 hours; between about 70% and about 80% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 12 hours; and over about 75% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 16 hours.
• Yet another aspect of the present invention is to provide a process for manufacturing the novel dosage form.
• active agent active ingredient
• active pharmaceutical ingredient active pharmaceutical ingredient
• drug drug
• pharmacologically active agent pharmaceutically acceptable active agent
• pharmaceutically acceptable active substance pharmaceutically acceptable active substance
• the pharmaceutically active substance is quetiapine (marketed as Seroquel®) or a pharmaceutically acceptable salt ester or solvate thereof.
• quetiapine as used herein includes all optical isomers, racemic mixtures and the like of the compound and all pharmaceutically acceptable salts, esters, amides, prodrugs and analogs thereof.
• a “pharmaceuticEilly acceptable salt” or a “pharmaceutically acceptable ester” of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable.
• an effective amount or “pharmaceutically effective amou t of an agent as provided herein are meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect The exact amount required will vary from subject to subject depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like. Thus, it is not W
• an appropriate "effective” amount in any individual case may be determined by a person of ordinary skill in the art using routine experimentation.
• ''excipient refers to a generally pharmaceutically inactive or inert substance used as a diluent or vehicle for a drug.
• a pharmaceutically acceptable excipient includes a "pharmaceutically acceptable carrier,”
• binders such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate.
• Capsules may contain additional excipients such as a liquid carrier.
• carrier a carrier comprised of a material that is not biologically or otherwise undesirable, .e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
• carrier is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus includes diluents, binders, lubricants, disintegrants, fillers, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
• the expression "dosage form” may consist of granules, spheroids, beads, pellets, capsules, tablets or any other suitable unit.
• the dosage form is preferably a tablet.
• the novel delayed release dosage form comprising a pharmaceutically acceptable active substance is characterized in the following way.
• Individual units for example granules, containing a pharmaceutically acceptable active substance are mixed with other pharmaceutically acceptable excipients and compressed into a final dosage form, preferably a tablet.
• granules containing a pharmaceutically acceptable active substance are mixed with other pharmaceutically acceptable excipients and compressed into a final dosage form, preferably a tablet.
• a final dosage form preferably a tablet.
• “mdividual units” is meant small beads, particles, granules or pellets. In the present invention, the preferred individual units are granules.
• the compaction process (or compression process) must not significanrly affect the chemical, i.e. degradation and/ or mechanical properties of the individual unit or the final dosage form, even if it were to be further layered with a coating layer.
• compositions such as fillers, binders, disintegrants, and other pharmaceutically acceptable additives can be envisaged, and compressed into tablets.
• the compressed tablet is optionally covered with one or more coating layers to obtain a smooth surface of the tablet and further enhances the stability of the tablet during packaging and transport.
• the granules or tablets may be covered with one or more coating layer (s).
• the coating layer(s) can be applied onto the tablets by coating or layering procedures in suitable equipments such as coating pan, 1 coating granulator or in a fluidized bed apparatus using water and/ or organic solvents for the coating or layering process,
• the materials for coating layers are chosen among pharmaceutically acceptable compounds such as, for instance methacrylic acid copolymer, ethylcellulose, used alone or in rnixtures.
• Additives such as plasticizexs, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the coating layer (s).
• the coating layer may further protect the tablet from environmental conditions.
• the coating layer is preferably made up of an aqueous dispersion of, for example, Eudragrt® (ie. methacrylic acid copolymer) or OPadry®, a plasticizer (i.e. triethyl citrate) and a diluent (i.e. colloidal silicon dioxide), which can be applied onto the final dosage form.
• Eudragrt® ie. methacrylic acid copolymer
• OPadry® i.e. triethyl citrate
• a diluent i.e. colloidal silicon dioxide
• novel drug dosage forms are to be achninistered orally to a mammal and can be used to administer the pharmaceutically acceptable active substance (ie. quetiapine or a pharmaceutically acceptable salt or solvate thereof) to treat or prevent a variety of disorders / conditions and diseases,
• administration, of quetiapine or a pharmaceutically acceptable salt or solvate thereof may be carried out in order to treat any disorder, condition or disease for which quetiapine is generally indicated.
• disorders, conditions and diseases include, for example:
• the novel controlled release pharmaceutical dosage form of the present invention provide a controlled release pharmaceutical dosage form that allows a single daily administration with a prolonged effect, simplified production, and is cost effective.
• the dosage forms of the present invention comprise a matrix comprising:
• o intragranular excipients comprising:
• the content (in % by weight) of the hydrophobic controlled release agent is in the range of about 4.5 to about 35 % and the content of the pH dependent polymer is in the range from about 15 to about 35 %.
• the ratio of the % by weight content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:3 to about 1:7. More preferably, the ratio of the % by weight content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4 to about 1:6. More preferably/ the ratio of the % by weight content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4.5 to about 1:5.5.
• the dosage forms for example a tablet, of the present invention were subjected to dissolution studies, using either Method 1 where the conditions are as follows:
• Apparatus 1 (USP baskets)
• Apparatus 1 (USP baskets)
• the dosage forms of the present invention provide a dissolution of quetiapine, or pharmaceutically acceptable salt thereof, when determined via Method 1, between about 30% and about 45% within 1 hour, between about 45% and about 70% within 6 hours and between about 75% and about 95% within 16 hours.
• the dosage forms of the present invention also have an in vitro dissolution rate, when determined by Method 2, of between about 50% and about 60% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 2 hours; between about 60% and about 70% (by wt) after 4 hours; between about 65% and about 80% (by wt) of quetiapine or pharmaceutically acceptable salt mereof released after 8 hours; between about 70% and about 80% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 12 hours; and over about 75% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 16 hours.
• the process for manufacturing the novel dosage form according to the present invention generally comprises the following steps:
• step (b) adding to the quetiapine or to the mixture obtained in step (a) a hydrophobic controlled release agent or sodium starch glycolate, and at least one diluent and a pH dependent polymer; and
• step (c) adding a solvent mixture, comprising a binder to the mixture obtained step ( );
• step (d) wet granulating the mixture obtained in step (c);
• step (e) drying the granules in step (d);
• step (g) blending the granules of step (f) with extragranular excipients in a suitable non shear blender;
• step (h) compressing the blend of step (g) into a tableted dosage form
• the at least one hydrophobic controlled release agent is stearic acid or Cutina® HR FH (Le. hydrogenated castor oil).
• the pH dependent polymer is Eudragit® (Le. a methacrylic acid copolymer), and more preferably, the pH dependent polymer is selected from Eudragit L 30 D-55, Eudragit L100-55, and mixtures thereof.
• the preferred manufacturing technique is direct compression. Tablets are the preferred dosage form of the present invention, however, other dosage forms can be envisaged.
• the dosage strength in the dosage forms can be any desired strength, for example, 50, 150, 200, 300, or 400 mg per tablet..
• Quetiapine Fumarate is equivalent to 200 mg Quetiapine
• step 4 Dry the granules and size. 5. Blend the granules of step 4 and extragranular ingredients in suitable non shear blender.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the grantdes of step 3 and extragrantdar ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 7 Coat the tablets of step 5 using the dispersion of step 6.
• Apparatus 1 (USP baskets)
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator,
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• Table 8 List of ingredients for the formulation of quetiapine tablets according to a preferred embodiment (Example 8)
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• step 4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
• Apparatus 1 (USP baskets)
• Examples 5, 6 and 8 to 12 are examples of the preferred emrxjdiments of the present invention, wherein the at least one hydrophobic controlled release agent and at least on pH dependent polymer are present at a weight % ratio of about 1:3 to about 1:7, and the dosage forms provide a dissolution of quetiapine or a pharmaceutically acceptable salt thereof, mat is within the preferred dissolution profile as discussed above.

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• 2010
  • 2010-05-27 CA CA2705685A patent/CA2705685A1/en not_active Abandoned
• 2011
  • 2011-05-27 EP EP11785946.2A patent/EP2575820A4/de not_active Withdrawn
  • 2011-05-27 WO PCT/CA2011/000620 patent/WO2011147025A1/en active Application Filing
  • 2011-05-27 CA CA2800910A patent/CA2800910A1/en not_active Abandoned
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