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WO2025179377A1 - Formes posologiques de trazodone à libération modifiée - Google Patents

Formes posologiques de trazodone à libération modifiée

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Publication number
WO2025179377A1
WO2025179377A1 PCT/CA2025/050243 CA2025050243W WO2025179377A1 WO 2025179377 A1 WO2025179377 A1 WO 2025179377A1 CA 2025050243 W CA2025050243 W CA 2025050243W WO 2025179377 A1 WO2025179377 A1 WO 2025179377A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
pharmaceutical dosage
trazodone
release
sensitive
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CA2025/050243
Other languages
English (en)
Inventor
Damon Smith
Marc Lemieux
Bradut Mitrasca
Sonia Gervais
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Altus Formulation Inc
Original Assignee
Altus Formulation Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Altus Formulation Inc filed Critical Altus Formulation Inc
Publication of WO2025179377A1 publication Critical patent/WO2025179377A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure related to trazodone formulations. More particularly, the present disclosure related to modified-release trazodone formulations.
  • Trazodone is a triazolopyridine derivative antidepressant that at the time of its discovery in the 1960’s was classed a SARI (serotonin antagonist reuptake inhibitor) mechanism drug.
  • SARI serotonin antagonist reuptake inhibitor
  • Antagonism of serotonin receptors and inhibition of the serotonin reuptake transporter (SERT) were considered essential for antidepressant efficacy despite the very large, approximately 20- fold, differences in affinity that trazodone displays for these two receptor types (viz. circa 15nM for serotonin 5-HT2A receptors verses circa 280nM for SERT).
  • Formula I depicts the structure of trazodone as the hydrochloride salt.
  • Trazodone still ranks amongst the top 50 most prescribed drugs and, today, its mechanism is better understood. Thus, recent studies have revealed its therapeutic value to be multi-modal such that its effects differ depending on drug concentrations achieved within different areas of the brain. For example, it is now understood that the high concentrations of trazodone required to inhibit SERT may not be needed to alleviate depression.
  • the molecule may exhibit antidepressant properties at lower concentrations via i) 5-HT2A and a -1 !- adrenergic receptor antagonism, and consequent reductions gaberinergic tone to increase serotonin levels in the prefrontal cortex, and; ii) antagonism of inter alia 5-HTiA and 5- HTID receptors in the dorsal raphe nucleus to reduce serotonin levels in this region. Both mechanisms may work in concert to bring about improvements in mood and reduce anxiety both also relying on constant receptor occupancy to effect rapid receptor remodeling and therapeutic changes in serotonin levels.
  • Sustained or release-modifying formulations of trazodone that maintain constant and relatively low levels of trazodone in the blood, enable such constant receptor occupancy and therefore benefit depressed and anxious patients by, for example, reducing the time required to see an improvement in symptoms, for example after only 1 week of dosing in the case of depressed patients, or during the first week of dosing in the case of insomniac patients [Walsh et al. 1998], Patients who experience an early improvement in their symptoms due to these sustained low levels of trazodone are less likely to cease taking their medications and, thereby, losing the benefits of antidepressant and or hypnotic therapy. The levels of trazodone in the blood of patients required to achieve constant receptor occupancy are therefore important.
  • Constant and relatively low concentrations of trazodone can also avoid the unwanted pharmacological effects occurring when higher concentrations of the drug are experienced by patients, again for example, those generated by repeat dosing of immediate release, or short duration formulations, including daytime somnolence.
  • the levels of trazodone in the blood of patients required to achieve constant receptor occupancy yet avoid unwanted pharmacological effects are, therefore, also important.
  • trazodone that, by breaking into segments provide doses, for example 2 or 3 doses, of equal, but lower strength, provide a simple method to generate the multiple doses needed for dose titration without the need for multiple prescriptions and the associated cost.
  • Such features are important since they promote patient compliance and improved treatment outcomes.
  • Such trazodone formulations can also have value for the treatment of, for example, agitation in dementia, hyperkinetic delirium, bulimia, alcohol abuse, schizophrenia and diabetic neuropathy which may require doses different from those used to treat depression and insomnia.
  • trazodone is a pH sensitive drug with a pKa of approximately 6.7 in water. This means that in low pH media the drug is highly soluble and therefore available for absorption by the body; the drug is bioavailable under these conditions. If exposed to media with a pH close to, or above its pKa however, trazodone becomes highly insoluble and unavailable for absorption; trazodone under these conditions may be said to be non-bioavailable.
  • This pH-sensitivity is a problem when developing formulations intended to generate constant drug concentrations in the body since the pH of the gastrointestinal tract through which any orally administered pharmaceutical composition must pass, varies from the very low values found in the stomach, to which an orally administered composition is first exposed, (pH 1 - 2 in the fasted state), to the neutral conditions of the upper intestines experienced as the composition moves through the gastrointestinal system, (the duodenal pH can reach pH 6.7 in the fasted state) and finally the alkaline condition of the caecum (up to about pH 7.5) and colon (also up to about pH 7.5). Because the approximate gastrointestinal transit time for an orally administered pharmaceutical composition is greater than 6 hours then formulations designed to provide constant blood concentrations from e.g.
  • 6-12hr or 12-24hr i.e. twice daily and once daily formulations
  • trazodone a pH sensitive drug such as trazodone
  • U.S Patent No. 9,439,866 describes one means of addressing this problem through the development of a ‘pH independent’ controlled release orally administered formulations of trazodone which rely on a certain pH insensitive controlled release hydrogel excipient (a cross- linked high amylose starch trade name ContramidTM) for pH independent release of trazodone from the composition and, in some way, pH independent, consistent trazodone bioavailability.
  • a pH insensitive controlled release hydrogel excipient a cross- linked high amylose starch trade name ContramidTM
  • U.S. Patent No. 7,829,120 disclose the same 150mg and 300mg ContramidTM formulations as U.S Patent No. 9,439,866 and again states that these trazodone compositions, when comprising 300mg of trazodone, like those in the ‘866, maintain a substantially constant effective plasma concentration between about 50 ng/mL and about 3000 ng/mL from at least about one hour to at least about 24 hours after initial administration. Should there be any doubt, these statements confirm that the trazodone compositions of U.S Patent Nos. 9,439,866 and 7,829,120 are the same.
  • OleptroTM Angelini Labopharm
  • U.S. Patent No. 7,829,120 listed in the Orange Book of the U.S. Food and Drug Administration (FDA) for OleptroTM.
  • the 300mg strength tablet of OleptroTM comprises, as per its package insert hydroxypropyl distarch phosphate (i.e., ContramidTM), hypromellose, sodium stearyl fumarate, and colloidal silicon dioxide.
  • Excipients used for an optional non-functional aesthetic coating to the tables include: iron oxide yellow, iron oxide red, talc, polyethylene glycol 3350, titanium dioxide, and polyvinyl alcohol.
  • Trittico XR Angelini Pharma
  • Reference to the package insert of Trittico XR confirms that Trittico XR tablets comprise: granulated ContramidTM (gelatinized modified starch), hypromellose, anhydrous colloidal silicon dioxide, sodium stearyl fumarate, and a coating comprising yellow OpadryTM II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow, iron oxide red).
  • a pH sensitive modified release pharmaceutical dosage form for once-a-day oral administration of trazodone, or a derivative thereof which comprises from about 20% to about 50% by weight of the trazodone or the derivative thereof, and from about 10% to about 80% of a release modifying excipient.
  • a modified release pharmaceutical dosage form for once-a-day oral administration of trazodone comprising: from about 20% to about 50% by weight of the trazodone or the derivative thereof, and from about 10% to about 80% of a release modifying excipient, wherein the trazodone is formed of particles, wherein: less than 35% of the particles are 355pm to 500pm in size, greater than 5% of the particles are 250pm to 355pm in size, greater than 2% of the particles are 75pm to 150pm in size, and greater than 5% of the particles are less than 38pm in size, wherein the dosage form exhibits less than 10% variation in release rate of the trazodone over a dissolution test period as compared to the mean release rate determined for a plurality of said dosage forms.
  • a method of delivering trazodone to a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.
  • a method of treating depression in a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.
  • a method of treating insomnia in a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.
  • a method of treating anxiety in a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.
  • the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for use in delivery of trazodone to a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for use in treatment of depression in a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for use in treatment of insomnia in a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for use in treatment of anxiety in a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for delivery of trazodone to a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for treatment of anxiety in a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for delivery of trazodone to a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for treatment of depression in a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for treatment of insomnia in a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for treatment of anxiety in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for delivery of trazodone to a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of depression in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of insomnia in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of anxiety in a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for delivery of trazodone to a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of depression in a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of insomnia in a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of anxiety in a subject.
  • FIG. 1 shows the amounts of trazodone released from tablets of Composition A after 12hr of dissolution testing at various pH. The amount of trazodone release increases up to pH 6 and then diminishes.
  • FIG. 2 shows the progressive release of trazodone from tablets of Composition A using the using water as the incubation medium.
  • FIG. 3 depicts amounts of trazodone released from tablets of Composition B after 12hr of dissolution testing at various pH. The amount of trazodone release increases up to pH 6 and then diminishes.
  • FIG. 4 depicts progressive release of trazodone from tablets of Composition B when tested using water as the incubation medium.
  • FIG. 5 depicts dissolution profiles of the trazodone tablets of Composition A in the presence (unbroken line) and absence (dotted line) of 40% ethanol. Dissolution profiles are largely unchanged.
  • FIG. 6 depicts dissolution profiles of the trazodone tablets of Composition A after bisecting lengthways across their short axis in the presence (unbroken line) and absence (dotted line) of 40% ethanol. Dissolution profiles are largely unchanged by alcohol or by bisecting the tablets.
  • FIG. 7 illustrates an aspect of the subject matter in accordance with one embodiment.
  • FIG. 8 depicts dissolution rates of tablet bisected into two equal segments across their short axis, in the presence and absence of 40% volume/volume ethanol.
  • FIG. 9 depicts drug PSD of the six batches of trazodone hydrochloride used in the analysis (Batches A to F).
  • FIG. 10 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch A. Tablet to tablet variation was very low.
  • FIG. 11 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch B. Tablet to tablet variation was very low.
  • FIG. 12 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch C. Tablet to tablet variation was very low.
  • FIG. 13 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch D. Tablet to tablet variation was very low.
  • FIG. 14 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch E. Tablet to tablet variation was greater than seen with tablets made with drug from Batches A-D.
  • FIG. 15 depicts dissolution profiles for whole and split tablets segments of tablets made with drug from Batch F. Tablet segment to segments variation was high for intact or whole tablets and even higher for the tablet segments.
  • a pH sensitive modified release dosage form is a suitable platform for trazodone therapy.
  • a pH sensitive release modifying pharmaceutical composition for once-a-day oral administration of trazodone (or derivative thereof) comprising from about 20% to about 50% by weight trazodone or derivative thereof, and between 10% to 80% of a pH sensitive release modifying excipient.
  • trazodone or derivative thereof
  • embodiments described herein exhibit properties indicating that they will maintain substantially constant and effective plasma concentrations of trazodone in a subject across a dosing period.
  • the present disclosure is also based on the surprising finding that dosage forms comprising trazodone of particular particle size distributions have advantageously uniform release properties, even upon subdivision.
  • pH sensitive modified release trazodone dosage forms [0060] pH sensitive modified release trazodone dosage forms
  • a pH sensitive modified release pharmaceutical dosage form for once-a-day oral administration of trazodone, or a derivative thereof which comprises from about 20% to about 50% by weight of the trazodone or the derivative thereof, and from about 10% to about 80% of a release modifying excipient.
  • release modifying is meant a composition that, in respect of an API incorporated therein, releases the API at a rate that is at least two-fold slower than would be achieved compared to an immediate release (IR) dosage form.
  • IR immediate release
  • a “release modifying excipient” is, therefore, an excipient that achieves these effects when present in such a composition.
  • pH sensitive in the context of an excipient for composition, is meant that when tested in vitro, the composition comprising the excipient exhibits different rates of release of the active pharmaceutical ingredient according to the pH of the in vitro test conditions.
  • the release modifying excipient comprises a hydrogel-forming excipient.
  • hydrogel-forming is meant a material comprising hydrophobic, hydrophilic, amphiphilic polymer chains, or a mixture thereof, which, when in contact with water, absorb and retain water to form a gel comprising the polymer chains and water.
  • the hydrogel-forming excipient comprises hydroxypropyl methylcellulose (HPMC).
  • the hydrogel-forming excipient comprises a hydroxypropyl di starch phosphate (HPDP) mixture.
  • HPDP hydroxypropyl di starch phosphate
  • the hydrogel -forming excipient comprises both the HPMC and the hydroxypropyl distarch phosphate (HPDP) mixture.
  • the hydrogel-forming excipient comprises a hydroxypropyl distarch phosphate (HPDP) mixture comprising 35% to 95% (wt/wt) of a high amylose starch, 1% to 40% (wt/wt) of a cross-linked hydroxypropylated amylopectin, and 1% to 30% (wt/wt) of a pre-gelatinized common starch, wherein the release modifying excipient is substantially free of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.
  • HPDP hydroxypropyl distarch phosphate
  • the HPDP mixture comprises 70% to 80% (wt/wt) of the high amylose starch, 10% to 20% (wt/wt) of the cross-linked hydroxypropylated amylopectin, and 5% to 15% (wt/wt) of the pre-gelatinized common starch, wherein the release modifying excipient is substantially free of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.
  • the HPDP mixture comprises about 75% (wt/wt) of the high amylose starch, about 15% (wt/wt) of the cross-linked hydroxypropylated amylopectin, and about 10% (wt/wt) of the pre-gelatinized common starch, wherein the release modifying excipient is substantially free of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.
  • the release modifying excipient may be as defined in International Patent Publication No. WO2019/071348, which is hereby incorporated by reference in its entirety.
  • amylose will be understood the component starch that is a helical polymer made from a-D-glucose units, bonded to each other through a(l— >4) glycosidic bonds.
  • Amylose is a linear carbohydrate, and is generally of lower molecular weight than amylopectin.
  • high amylose starch is meant a starch comprising of at least 50% amylose (wt/wt).
  • HAS high amylose starch
  • examples of commercially available HAS include Hylon VIITM AmyloGelTM 03003, Hylon V, High Maize, Amylose Maize N400 and Eurylon G.
  • the high amylose starch may be non-chemically modified, i.e. free of chemical modification. For example, it may be noncrosslinked.
  • the HAS comprises AmyloGelTM 03003.
  • amlopectin the component starch is a polysaccharide and highly branched polymer of glucose. Glucose units are linked in a linear way with a(l— >4) glycosidic bonds. Branching takes place with a( l ⁇ 6) bonds occurring typically every 24 to 30 glucose units.
  • cross-linked hydroxypropylated amylopectin (a type of cross-linked modified amylopectin, or “CMAP”) is meant amylopectin that has been chemically modified to form covalent bonds between (and/or within) amylopectin molecules, and in which native amylopectin is substituted with hydroxypropyl groups.
  • hydroxypropylation may increase the gel stability, water solubility, digestibility, and storage stability of the native molecules. Examples include Utra-Tex4TM, Pure-Gel B990TM, Polar Tex-instant 12640TM, and Polar-Tex-instant 12643TM.
  • the cross-linked hydroxypropylated amylopectin comprises PolarTex-InstantTM 12640.
  • pre-gelatinized common starch a starch comprising not more than 50% amylopectin (wt/wt) that is subject to gelatinization, a process of breaking down the intermolecular bonds of starch molecules in the presence of water and heat, allowing the hydrogen bonding sites (the hydroxyl hydrogen and oxygen) to engage more water.
  • PGS pre-gelatinized common starch
  • the PGS comprises Starch 1500TM.
  • the hydrogel -forming excipient comprises about 50-80% (wt/wt) of the HPDP mixture, and about 20-50% (w/wt) of the HPMC. In one embodiment, the hydrogel -forming excipient comprises about 60-70% (wt/wt) of the HPDP mixture, and about 30-40% (w/wt) of the HPMC. In one embodiment, the hydrogel-forming excipient comprises about two thirds (wt/wt) of the HPDP mixture, and about one third (wt/wt) of the HPMC.
  • the pH sensitive release modifying pharmaceutical dosage form comprises from 50mg to 500mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 50mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 75mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about lOOmg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 125mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 150mg of the trazodone.
  • the pH sensitive release modifying pharmaceutical dosage form comprises about 175mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 200mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 225mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 250mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 275mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 300mg of the trazodone.
  • the pH sensitive release modifying pharmaceutical dosage form comprises about 325mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 350mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 375mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 400mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 425mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 450mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 475mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 500mg of the trazodone.
  • the pH sensitive release modifying pharmaceutical dosage form comprises about 75mg of the trazodone or the derivative thereof. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 150mg of the trazodone or the derivative thereof. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 300mg of the trazodone or the derivative thereof. [0084] In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 75mg of the trazodone, about 127mg of the HPDP mixture, and about 63mg of the HPMC.
  • the pH sensitive release modifying pharmaceutical dosage form comprises about 150mg of the trazodone, about 253mg of the HPDP mixture, and about 126mg of the HPMC.
  • the pH sensitive release modifying pharmaceutical dosage form comprises about 150mg of the trazodone, about lOOmg of the HPDP mixture, and about 50mg of the HPMC.
  • the pH sensitive release modifying pharmaceutical dosage form comprises about 300mg of the trazodone, about 200mg of the HPDP mixture, and about lOOmg of the HPMC.
  • the pH sensitive release modifying pharmaceutical dosage form releases at least 55% of the trazodone or the derivative thereof at pH 1.2, at least 65% of the trazodone or the derivative thereof at pH 4.5, at least 75% of the trazodone or the derivative thereof at pH 6, and less than 35% of the trazodone or the derivative thereof at pH 7, after 12 hours of dissolution testing using a USP paddle method (apparatus type II as described in U.S.P. XXVI) at 50 revolutions per minute and at 37 ⁇ 0.5° C.
  • the pH sensitive release modifying pharmaceutical dosage form releases up to about 30% of the trazodone or the derivative thereof by 1 hour, about 45% to about 65% of the trazodone or the derivative thereof by 6 hours, up to 90% of the trazodone or the derivative thereof by 12 hours, and greater than 90% of the trazodone or the derivative thereof by 20 hours, wherein release of the trazadone or the derivative thereof is determined over 20 hours in vitro in water, using a USP paddle method (apparatus type II as described in U.S.P. XXVI) at 50 revolutions per minute and at 37 ⁇ 0.5° C.
  • the pH sensitive release modifying pharmaceutical dosage form releases less than 30% of the trazodone or the derivative thereof within 2 hours, when tested in vitro in water, using a USP paddle method (apparatus type II as described in U.S.P. XXVI) at 150 revolutions per minute and at 37 ⁇ 0.5° C.
  • the pH sensitive release modifying pharmaceutical dosage form having a hardness of 50N to 99N.
  • the pH sensitive release modifying pharmaceutical dosage form wherein the hardness is 5 IN to 93N.
  • the pH sensitive release modifying pharmaceutical dosage form having a friability of less than 1%.
  • the pH sensitive release modifying pharmaceutical dosage form which releases less than 50% of the trazodone or the derivative thereof into solution upon incubation for two hours in 40% (v/v) alcohol in 0.1N HC1 using a U.S.P. paddle method apparatus type II (as described in U.S.P. XXVI) at 100 revolutions per minute, at 37 ⁇ 0.5° C.
  • the pH sensitive release modifying pharmaceutical dosage form releases less than 40% of the trazodone or the derivative thereof into solution upon incubation for two hours in 40% (v/v) alcohol in 0.1N HC1 using a U.S.P. paddle method apparatus type II (as described in U.S.P. XXVI) at 100 revolutions per minute, at 37 ⁇ 0.5° C.
  • the pH sensitive release modifying pharmaceutical dosage form releases less than 30% of the trazodone or the derivative thereof into solution upon incubation for two hours in 40% (v/v) alcohol in 0.1N HC1 using a U.S.P. paddle method apparatus type II (as described in U.S.P. XXVI) at 100 revolutions per minute, at 37 ⁇ 0.5° C.
  • the pH sensitive release modifying pharmaceutical dosage form is bisectable.
  • the pH sensitive release modifying pharmaceutical dosage form comprises trazodone formed of particles.
  • less than 35% of the particles are 355pm to 500pm in size. In one embodiment, greater than 5% of the particles are 250pm to 355pm in size. In one embodiment, greater than 2% of the particles are 75pm to 150pm in size. In one embodiment, greater than 5% of the particles are less than 38pm in size. These values are expressed as (wt/wt). In one embodiment, a combination of these particle size distribution features may apply.
  • less than 30% of the particles are 355pm to 500pm in size. In one embodiment, greater than 10% of the particles are 250pm to 355pm in size. In one embodiment, greater than 6% of the particles are 75pm to 150pm in size. In one embodiment, 5% to 35% of the particles are less than 38pm in size. These values are expressed as (wt/wt). In one embodiment, a combination of these particle size distribution features may apply.
  • less than 20% of the particles are 355pm to 500pm in size. In one embodiment, greater than 15% of the particles are 250pm to 355pm in size. In one embodiment, greater than 8% of the particles are 75pm to 150pm in size. In one embodiment, 5% to 20% of the particles are less than 38pm in size. These values are expressed as (wt/wt). In one embodiment, a combination of these particle size distribution features may apply.
  • Release profiles can be compared using established statistical methods. For example, a similarity factor (f'2) may be calculated for two curves using established methods.
  • a release profile that that is “substantially the same” may have an fi value from 0 to 15 and an ? value from 50 to 100.
  • the release profile may have an f? value of 50 or greater.
  • the f? value may be above 60.
  • the f? value may 70 or greater.
  • the f? value may be 80 or greater.
  • the f? value may be 90 or greater.
  • the dosage form exhibits less than 10% variation in release of the trazodone at any one time over a dissolution test period as compared to the mean release rate determined for a plurality of said dosage forms at that same time.
  • the dosage form exhibits less than 5% variation in release of the trazodone at any one time over a a dissolution test period as compared to the mean release rate determined for a plurality of said dosage forms at that same time.
  • the dosage form exhibits less than 3% variation in release of the trazodone at any one time over a a dissolution test period as compared to the mean release rate determined for a plurality of said dosage forms at that same time.
  • the dissolution test period is 2 hours. In one embodiment, the dissolution test period is 4 hours. In one embodiment, the dissolution test period is 6 hours. In one embodiment, the dissolution test period is 8 hours. In one embodiment, the dissolution test period is 10 hours. In one embodiment, the dissolution test period is 12 hours. In one embodiment, the dissolution test period is 14 hours. In one embodiment, the dissolution test period is 16 hours. In one embodiment, the dissolution test period is 18 hours. In one embodiment, the dissolution test period is 20 hours. In one embodiment, the dissolution test period is 22 hours. In one embodiment, the dissolution test period is 24 hours.
  • the dosage form maintains an effect for at least 4 hours. In one embodiment, the dosage form maintains an effect for at least 6 hours. In one embodiment, the dosage form maintains an effect for at leasts hours. In one embodiment, the dosage form maintains an effect for at least 12 hours. In one embodiment, the dosage form maintains an effect for at least 24 hours.
  • the dosage form upon subdivision from an intact dosage form, exhibits less than 10% variation in release of the trazodone by the subunits as compared to the intact dosage form at a time during a 20-hour dissolution test period. In one embodiment, the dosage form, upon subdivision into subunits from an intact dosage form, exhibits less than 5% variation in release of the trazodone by the subunits as compared to the intact dosage form at a time during a 20-hour dissolution test period.
  • the dosage form upon subdivision into subunits from an intact dosage form, exhibits less than 3% variation in release of the trazodone by the subunits as compared to the intact dosage form at a time during a 20- hour dissolution test period.
  • the time within the 20-hour dissolution test period is 2 hours. In one embodiment, the time within the 20-hour dissolution test period is 4 hours. In one embodiment, the time within the 20-hour dissolution test period is 6 hours. In one embodiment, the time within the 20-hour dissolution test period is 8 hours. In one embodiment, the time within the 20-hour dissolution test period is 10 hours. In one embodiment, the time within the 20-hour dissolution test period is 12 hours. In one embodiment, the time within the 20-hour dissolution test period is 14 hours. In one embodiment, the time within the 20-hour dissolution test period is 16 hours. In one embodiment, the time within the 20-hour dissolution test period is 18 hours.
  • the time within the 20-hour dissolution test period is 20 hours.
  • the dosage form upon subdivision from an intact dosage form, exhibits less than 10% variation in release of trazodone by the subunits as compared to the intact dosage form at any one time during a 20-hour dissolution test period. In one embodiment, the dosage form, upon subdivision into subunits from an intact dosage form, exhibits less than 5% variation in release for the trazodone by the subunits as compared to the intact dosage form at any one time during a 20-hour dissolution test period.
  • the dosage form upon subdivision into subunits from an intact dosage form, exhibits less than 3% variation in release for the trazodone by the subunits as compared to the intact dosage form at any one time during a 20-hour dissolution test period.
  • Modified release dosage forms comprising trazodone having particle size distribution properties
  • a modified release pharmaceutical dosage form for once-a-day oral administration of trazodone comprising: from about 20% to about 50% by weight of the trazodone or the derivative thereof, and from about 10% to about 80% of a release modifying excipient, wherein the trazodone is formed of particles , wherein: less than 35% (wt/wt) of the particles are 355pm to 500pm in size, greater than 5% (wt/wt) of the particles are 250pm to 355pm in size, greater than 2% (wt/wt) of the particles are 75pm to 150pm in size, and greater than 5% (wt/wt) of the particles are less than 38pm in size, wherein the dosage form exhibits less than 10% variation in release of the trazodone over a dissolution test period as compared to the mean release rate determined for a plurality of said dosage forms.
  • less than 30% (wt/wt) of the particles are 355pm to 500pm in size. In one embodiment, greater than 10% (wt/wt) of the particles are 250pm to 355pm in size. In one embodiment, greater than 6% (wt/wt) of the particles are 75 pm to 150pm in size. In one embodiment, 5% to 35% (wt/wt) of the particles are less than 38pm in size. In one embodiment, a combination of these particle size distribution features may apply.
  • the release modifying excipient comprises a hydrogel-forming excipient.
  • the hydrogel-forming excipient comprises hydroxypropyl methylcellulose (HPMC).
  • the hydrogel-forming excipient comprises a hydroxypropyl di starch phosphate (HPDP) mixture.
  • HPDP hydroxypropyl di starch phosphate
  • the hydrogel -forming excipient comprises both the HPMC and the hydroxypropyl distarch phosphate (HPDP) mixture.
  • the hydrogel-forming excipient comprises a hydroxypropyl distarch phosphate (HPDP) mixture comprising 35% to 95% (wt/wt) of a high amylose starch, 1% to 40% (wt/wt) of a cross-linked hydroxypropylated amylopectin, and 1% to 30% (wt/wt) of a pre-gelatinized common starch, wherein the release modifying excipient is substantially free of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.
  • HPDP hydroxypropyl distarch phosphate
  • the HPDP mixture comprises 70% to 80% (wt/wt) of the high amylose starch, 10% to 20% (wt/wt) of the cross-linked hydroxypropylated amylopectin, and 5% to 15% (wt/wt) of the pre-gelatinized common starch, wherein the release modifying excipient is substantially free of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.
  • the HPDP mixture comprises about 75% (wt/wt) of the high amylose starch, about 15% (wt/wt) of the cross-linked hydroxypropylated amylopectin, and about 10% (wt/wt) of the pre-gelatinized common starch, wherein the release modifying excipient is substantially free of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.
  • the release modifying excipient may be as defined in International Patent Publication No. WO2019/071348
  • the hydrogel -forming excipient comprises about 50-80% (wt/wt) of the HPDP mixture, and about 20-50% (w/wt) of the HPMC. In one embodiment, the hydrogel -forming excipient comprises about 60-70% (wt/wt) of the HPDP mixture, and about 30-40% (w/wt) of the HPMC. In one embodiment, the hydrogel-forming excipient comprises about two thirds (wt/wt) of the HPDP mixture, and about one third (wt/wt) of the HPMC. [0120] In one embodiment, the modified release pharmaceutical dosage form comprises about 75mg of the trazodone or the derivative thereof. In one embodiment, the modified release pharmaceutical dosage form comprises about 150mg of the trazodone or the derivative thereof. In one embodiment, the modified release pharmaceutical dosage form comprises about 300mg of the trazodone or the derivative thereof.
  • the dosage form exhibits less than 5% variation in release of the trazodone over a dissolution test period as compared to a mean release rate determined for a plurality of said dosage forms.
  • the dosage form exhibits less than 3% variation in release of the trazodone over a dissolution test period as compare a mean release rate determined for a plurality of said dosage forms.
  • the dissolution test period is 2 hours. In one embodiment, the dissolution test period is 4 hours. In one embodiment, the dissolution test period is 6 hours. In one embodiment, the dissolution test period is 8 hours. In one embodiment, the dissolution test period is 10 hours. In one embodiment, the dissolution test period is 12 hours. In one embodiment, the dissolution test period is 14 hours. In one embodiment, the dissolution test period is 16 hours. In one embodiment, the dissolution test period is 18 hours. In one embodiment, the dissolution test period is 20 hours. In one embodiment, the dissolution test period is 22 hours. In one embodiment, the dissolution test period is 24 hours.
  • the dosage form maintains an effect for at least 4 hours. In one embodiment, the dosage form maintains an effect for at least 6 hours. In one embodiment, the dosage form maintains an effect for at least 8 hours. In one embodiment, the dosage form maintains an effect for at least 12 hours. In one embodiment, the dosage form maintains an effect for at least 24 hours.
  • the dosage form upon subdivision from an intact dosage form, exhibits less than 10% variation in release of the trazodone by the subunits as compared to the intact dosage form at a time during a 20-hour dissolution test period. In one embodiment, the dosage form, upon subdivision into subunits from an intact dosage form, exhibits less than 5% variation in release of the trazodone by the subunits as compared to the intact dosage form at a time during a 20-hour dissolution test period.
  • the dosage form upon subdivision into subunits from an intact dosage form, exhibits less than 3% variation in release of the trazodone by the subunits as compared to the intact dosage form at a time during a 20- hour dissolution test period.
  • the time within the 20-hour dissolution test period is 2 hours. In one embodiment, the time within the 20-hour dissolution test period is 4 hours. In one embodiment, the time within the 20-hour dissolution test period is 6 hours. In one embodiment, the time within the 20-hour dissolution test period is 8 hours. In one embodiment, the time within the 20-hour dissolution test period is 10 hours. In one embodiment, the time within the 20-hour dissolution test period is 12 hours. In one embodiment, the time within the 20-hour dissolution test period is 14 hours. In one embodiment, the time within the 20-hour dissolution test period is 16 hours. In one embodiment, the time within the 20-hour dissolution test period is 18 hours. In one embodiment, the time within the 20-hour dissolution test period is 20 hours.
  • the dosage form upon subdivision from an intact dosage form, exhibits less than 10% variation in release of the trazodone by the subunits as compared to the intact dosage form at any one time during a 20-hour dissolution test period. In one embodiment, the dosage form, upon subdivision into subunits from an intact dosage form, exhibits less than 5% variation in release of the trazodone by the subunits as compared to the intact dosage form at any one time during a 20-hour dissolution test period.
  • the dosage form upon subdivision into subunits from an intact dosage form, exhibits less than 3% variation in release of the trazodone by the subunits as compared to the intact dosage form at any one time during a 20-hour dissolution test period.
  • a method of delivering trazodone to a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form described herein or the modified release pharmaceutical dosage form as described herein.
  • a method of treating depression in a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form described herein or the modified release pharmaceutical dosage form as described herein.
  • a method of treating insomnia in a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.
  • a method of treating axiety in a subject in need thereof comprising administering to the subject the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.
  • pH sensitive release modifying pharmaceutical dosage form described herein or the modified release pharmaceutical dosage form as described herein for use in delivery of trazodone to a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form described herein or the modified release pharmaceutical dosage form as described herein for use in treatment of depression in a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for use in treatment of insomnia in a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for use in treatment of anxiety in a subject is provided.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for delivery of trazodone to a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for treatment of anxiety in a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for delivery of trazodone to a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for treatment of depression in a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for treatment of insomnia in a subject.
  • pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for preparation of a medicament for treatment of anxiety in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for delivery of trazodone to a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of depression in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of insomnia in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of anxiety in a subject.
  • kits comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for delivery of trazodone to a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of depression in a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of insomnia in a subject.
  • a commercial package comprising the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein; together with instructions for treatment of anxiety in a subject.
  • the amount used, for use, or administered is an effective amount for treatment of the respective condition in the subject.
  • Trazodone hydrochloride is a low molecular weight (371.87 D) antidepressant of the SARI class displaying weak serotonin reuptake inhibition, and more potent 5-HT2A and aib adrenergic receptor antagonism.
  • the drug is pH sensitive with a pKa of approximately 6.7 so that its solubility varies according to the pH of an external medium into which it is placed. Should trazodone be formulated into a tablet designed to slowly release the drug over time, for example, over 24hrs, and the tablet be ingested orally then trazodone will be released over the entire length of the gastrointestinal tract.
  • trazodone tablet formulations that modify the release of trazodone so that it occurs slowly over approximately 20hrs.
  • the tablets display pH sensitive release of trazodone, with the rate of release changing as the pH of the external medium of the into which they are placed increases.
  • the rate of release of trazodone from the composition is, surprisingly, such that after oral administration to a person, the composition will maintain substantially constant plasma concentrations of trazodone in the person, of between about 50 ng/mL and about 3000 ng/mL from at least about one hour to at least about 24 hours after initial administration.
  • the compositions will generate concentrations of trazodone in the blood known to exert an antidepressant effect in humans.
  • Example 1 Composition A Dissolution Properties
  • composition A A first modified release tablet composition comprising 300mg of trazodone (Composition A) was prepared having the composition provided in Table 1.
  • HPDP Hydroxypropyl Di starch Phosphate
  • HPMC Hydroxypropyl methylcellulose K100M
  • HPDP was a blend of 75% (wt/wt) of high amylose starch (AmyloGelTM 03003), 15% (wt/wt) of cross-linked hydroxypropylated amylopectin (PolarTex-InstantTM 12640), and 10% (wt/wt) of pre-gelatinized common starch (Starch 1500TM).
  • Trazodone in this example accords with Batch C discussed in Example 7.
  • the modified release compositions were produced by blending the raw material components of Table 1 using a 16-qt V blender. The blended raw materials were then compressed using a rotary tablet press. The compressed tablets were optionally coated with a non-functional aesthetic film.
  • the rate of release of trazodone from the compressed tables over 20 hours was determined, in vitro, using a U.S.P. paddle method (apparatus type II as described in U.S.P. XXVI) at 50 revolutions per minute, at 37 ⁇ 0.5° C.
  • the rate of release of trazodone from the tablets was measured at four different pH these being; i) pH 1.2; ii) pH 4.5; iii) pH 6.0 and; iv) pH 7.
  • Buffers used as dissolution media in the testing of testing of the modified release compositions are set forth in Table 2.
  • FIG. 2 shows the release of trazodone from tablets of Composition A using the same apparatus and agitation rate as used previously but where water was used as the incubation medium. As can be seen, under these conditions not more than about 30% of the active ingredient was released by 1 hour after initiation of the experiment, about 45% to 65% of the active ingredient was released by 6 hours, not more than 90% of the active ingredient was released by 12 hours, and not less than 90% of the active ingredient was released by 20 hours.
  • Example 2 Composition B Dissolution Properties
  • composition B A second modified release tablet composition comprising 150mg of trazodone (Composition B) was prepared having the composition provided in Table 3.
  • HPDP was a blend of 75% (wt/wt) of high amylose starch (AmyloGelTM 03003), 15% (wt/wt) of cross-linked hydroxypropylated amylopectin (PolarTex- InstantTM 12640), and 10% (wt/wt) of pre-gelatinized common starch (Starch 1500TM).
  • Trazodone in this example accords with Batch C discussed in Example 7.
  • the modified release compositions were produced by blending the raw material components of Table 3 using a 16-qt V blender. The blended raw materials were then compressed using a rotary tablet press. The compressed tablets were optionally coated with a non-functional aesthetic film.
  • the rate of release of trazodone from the compressed tables over 20 hrs was determined, in vitro, using a U.S.P. paddle method (apparatus type II as described in U.S.P. XXVI) at 50 revolutions per minute, at 37 ⁇ 0.5° C.
  • the rate of release of trazodone from the tablets was measured at four different pH these being; i) pH 1.2; ii) pH 4.5; iii) pH 6.0 and; iv) pH 7.
  • Buffers used as dissolution media in the testing of testing of the modified release compositions are set forth in Table 2 above.
  • the amount of trazodone released from Composition B after 12hr of incubation is profoundly affected by the pH of the incubation medium, the amount released at, for example pH 6, a value close to the pKa of trazodone being greater than the amount released at pH 7, again a pH close to the pKa of the drug.
  • the converse is true, viz. the amount released at 12hr increases from pH 1.2 to pH 6, then drops 3-4-fold at pH 7, a feature of the release modifying nature of the hydrogel composition.
  • FIG. 4 shows the release of trazodone from tablets of Composition A using the same apparatus and agitation rate as used previously but where water is used as the incubation medium. As can be seen, under these conditions not more than about 30% of the active ingredient was released by 1 hour after initiation of the experiment, about 45% to 65% of the active ingredient was released by 6 hours, not more than 90% of the active ingredient was released by 12 hours, and not less than 90% of the active ingredient was released by 20 hours.
  • the hardness of a pharmaceutical composition is a feature of the nature of the composition and the degree of force with which it is compressed on a tablet press.
  • the hardness of a tablet will also influence its performance attributes. For example, tablet hardness will affect the durability a tablet, a low hardness tablet, being friable and therefore liable to fracture or chipping under routine handling making it unfit for purpose. Hardness may also affect the release rate of a drug incorporated in the tablet composition. For example, a tablet that is over compressed, and too hard, may release drug too slowly to achieve the desired pharmacological effect.
  • Tablets of Composition A were manufactured as described in Example 1 but compressed, on a rotary tablet press using different compression forces so as to generate tablets of different hardness. Tablets of low hardness (mean hardness 55N) and high hardness (mean hardness 84N) were generated. Tablet hardness was measured using a standard hardness tester and tablet friability was measured using a standard rotating friability tester. Table 4 describes the compression forces used to generate the tablets and the friability results.
  • Rates of release from the low and high hardness tablets were compared using similarity factor (/2) analysis resulting in a similarity factor of greater than 50 indicating tablets of low and high hardness will display equivalent pharmacokinetics in vivo.
  • Tablets of Composition B were manufactured as described in Example 1 but compressed, on a rotary tablet press using different compression forces so as to generate tablets of different hardness. Tablets of low hardness (mean hardness 55N) and high hardness (mean hardness 84N) were generated. Tablet hardness was measured using a standard hardness tester and tablet friability was measured using a standard rotating friability tester. Table 5 describes the compression forces used to generate the tablets and the friability results.
  • Rates of release from the low and high hardness tablets were compared using similarity factor (/2) analysis resulting in a similarity factor of greater than 50 indicating tablets of low and high hardness will display equivalent pharmacokinetics in vivo.
  • Modified release formulations intended to deliver pharmaceutical drugs slowly after oral administration will by definition contain more trazodone than formulations of trazodone intended to produce the same therapeutic effect over a shorter period for example over 12hrs or 8 hrs.
  • the release technology that effects the slow release of the drug from a slow release composition become compromised however, for example by breaking the tablet or exposing it to alcohol, then the amount of drug intended to provide 24hr of therapeutic benefit can be released in an uncontrolled, or immediate release manner causing blood levels of the drug to rise to potentially dangerous levels if administered to a human.
  • modified release trazodone compositions comprising 150mg or 300mg of trazodone that, after exposing to alcohol, or breaking and exposing to alcohol, neither dose dump nor substantially change their rate of trazodone release.
  • Example 1 The modified release trazodone tablet compositions of Example 1 (Composition A) comprising 300mg of trazodone were manufactured as described previously and subjected to in vitro dissolution testing using a U.S.P. paddle method apparatus type II (as described in U.S.P. XXVI) at 100 revolutions per minute, at 37 ⁇ 0.5° C.
  • the rate of release of trazodone from the compositions was measured over 2hr using as the incubation medium either diluted hydrochloric acid solution (0.1M pH 1.2) or a diluted hydrochloric acid solution (0.1M pH 1.2) containing 40% volume/volume ethanol. Results are shown in FIG. 5. Dissolution rates of tablet bisected into two equal segments across their short axis, in the presence and absence of 40% volume/volume ethanol, are shown in FIG. 6.
  • composition B The modified release trazodone tablet compositions of Example 2 (Composition B) comprising 150mg of trazodone were manufactured as described previously and subjected to in vitro dissolution testing using a U.S.P. paddle method apparatus type II (as described in U.S.P. XXVI) at 100 revolutions per minute, at 37 ⁇ 0.5° C.
  • the rate of release of trazodone from the compositions was measured over 2hr using as the incubation medium either diluted hydrochloric acid solution (0.1M pH 1.2) or a diluted hydrochloric acid solution (0.1M pH 1.2) containing 40% volume/volume ethanol. Results are shown in FIG. 7. Dissolution rates of tablet bisected into two equal segments across their short axis, in the presence and absence of 40% volume/volume ethanol are shown in FIG. 8.
  • trazodone Once daily formulations of trazodone are used for the treatment of chronic major depressive disorder (MDD) and must therefore be taken by patients for many years. Given this long period of use it is critically important, if patients are to be treated safely and effectively, that they always receive the same dose of trazodone each day since it the dose of drug that patients take that controls the concentrations of trazodone in their blood over time and therefore the duration over which safety and efficacy must be maintained. It therefore stands to reason that each once daily tablet must contain not only the same amount of trazodone but also must release the trazodone contained within them at essentially the same rate over time. Different rates of release from different tablets may result in changes in safety, efficacy, and duration of action.
  • MDD chronic major depressive disorder
  • the amount of drug in a modified release tablet that is manufactured according to, for example, the process of blending and compressing of a mixture of drug (trazodone hydrochloride) and other raw materials (excipients) described in Example 1, is simple to measure. In the first place the amount of drug added to and blended with excipients can be carefully measured by accurate weighing of the drug to be added. Next, after blending of drug and excipients, multiple samples of the blended mixture can be taken from various positions in the vessel in which the blend is held, and the amount of drug in each sample (the blend sample ‘assay result’) can then be measured using methods known to those skilled in the art.
  • blend uniformity testing a measure of blend uniformity.
  • a uniform amount of drug in each of the blend samples will support the conclusion that, when this blend is compressed to form a sequence of consecutive tablets (using a rotary press for example), then each tablet will also contain the same amount of drug, i.e. that drug content per tablet will be uniform.
  • the amount of drug in each tablet may of course also be measured and any differences in drug content between them (so called ‘content uniformity’ testing) also evaluated statistically.
  • each tablet would be expected to display the same drug release rate, that is the same amount of trazodone would be expected to have been released at any one time, tablet to tablet, when tablet release rates are measured over time, in vitro, using suitable apparatus (tablet dissolution testing).
  • This may be performed by a number of methods known to those skilled in the art, including methods such as sieve analysis which, by separating particles of different sizes by passing them through a series of sieves of diminishing pore-size, allows the percentage of small, medium and large size particles within a sample of drug to be measured.
  • the effect of drug PSD on blend uniformity and content uniformity, for a particular source of drug may then be evaluated by accurately measuring the amount of drug to be used in blending and compression, and then performing blend uniformity and content uniformity testing for that particular drug source after mixing it with a common blend of excipients, thereby eliminating any effect of excipient PSD from the evaluation.
  • In vitro dissolution testing may then be undertaken, as described in Example 1, and the effect of drug PSD on the rate of drug release tablet to tablet assessed.
  • This example describes a series of tests to identify the drug (trazodone hydrochloride) PSD required to generate blends with uniform distribution of trazodone hydrochloride and tablets with uniform trazodone hydrochloride content and in vitro drug release rates.
  • Six different sources of trazodone hydrochloride were evaluated using sieve analysis to determine the drug PSD of each. Each sample was then blended with a common mixture of excipients to ensure excipient PSD did not mask the effect of drug PSD differences on blend uniformity, content uniformity and tablet dissolution testing.
  • composition 2 Batches of once-daily modified release trazodone tablets (Composition 2; Example 1) were then manufactured using the process described in Example 1.
  • samples from each source of drug were blended in a blender with a common mixture of excipients to form a Composition 2 blend.
  • Samples of these blends were then taken from six locations within the blender vessel and each subject to blend uniformity testing, the amount of trazodone hydrochloride in each being measured by RP-HPLC with UV detection; mean blend uniformity results are summarized in Table 5.
  • Results are expressed in terms of sample assay and Acceptance Value (AV) which was calculated according to the methods described in US Pharmacopoeia section ⁇ 905> (https://www.usp.org/sites/default/files/usp/document/harmonization/gen- method/q0304_stage_6_monograph_25_feb_201 l.pdf).
  • AV Acceptance Value
  • Each of the blends was then compressed separately using a rotary tablet press to produce six different batches of modified release tablets.
  • Samples of tablets made with each blend were then subject to physical analysis the results of which are included in Table 6. Tablets made from each blend were then subject to tablet dissolution testing using USP Type II apparatus. Briefly, six tablets were randomly selected from the bulk tablets made with each source of drug.
  • Dissolution tests were conducted using USP Type II dissolution apparatus employing water as the dissolution medium as described in Example 1. After adding the tablets to be tested to separate vessels within the apparatus the dissolution medium was then stirred. Individual samples were then taken from the dissolution medium in each vessel at various intervals over a 20-hour period, the trazodone hydrochloride concentrations in the samples being assessed using RP-HPLC with UV detection. The drug release rate of each individual tablets was then assessed and the mean rate of release of all six was also calculated.
  • modified release once-daily trazodone formulation of the present invention are intended to be administered whole or as a segment, produced by breaking the tablet in to two equal halves (thereby representing 50% of the whole tablet dose) the rate of release of six compressed tablets broken into two equal halves was also measured by in vitro dissolution testing. Results are provided in Figures 2-7. The drug content of six tablets segments (produced by breaking six tablets in half and measuring the content of each half tablet) was also calculated to assess the content uniformity of tablet segments.
  • Blend uniformity results from blends comprising drug from different sources calculated by measuring drug content in blend samples taken from 6 locations in the blender vessel are provided in Table 6. Results are expressed in terms of assay results and AV. To be passed as acceptable by governmental authorities responsible for approving pharmaceutical products, blend uniformity results must typically display assay results from each location +/- 5% from the expected result (i.e., versus the measured amount of drug first added to the blend) and a RSD of less than 5%. AV must be below 15.
  • Tableting The physicochemical properties of tablets produced by compression of the various blends on a rotary tablet press are provided in Table 7. All tablets were compressed using the same press operating parameters so tablets could be compared solely on the basis of their source of drug. Tablet AV was calculated by assay of ten separate tablets according to USP ⁇ 905>. Friability was determined according to USP method ⁇ 1216> and tablet thickness and weight were determined by calibrated calipers and balances.
  • Dissolution testing was performed using USP Type II dissolution apparatus using 900mL of distilled water at 37°C as the dissolution medium which was stirred with a paddle at 50rpm. Tests were performed on 6 tablets from each batch of tablets with samples of the dissolution medium being taken at regular intervals and assessed for drug content. As above, tests were also performed on 6 tablet segments. Mean dissolution rates for tablets from each tablet batch were calculated. These dissolution profiles of drug/released over time are shown in FIG. 10 to FIG. 15 where the maximum and minimum values from the six tablets tested are also shown.
  • tablets manufactured using drug sources A - D generated highly similar mean tablet dissolution profiles, each releasing about 80% of their drug content after 12hrs of incubation. Tablet to tablet variation differed considerably between batches however with batch A-D displaying very low tablet to tablet variation but batch E tablets varying in amount of drug released over time by ten percentage points maximum to minimum. Tablet segments generated by splitting in half tablets from these batches produced similarly small differences in dissolution rate segment to segment.
  • Example 1 to 6 The results presented herein in Examples 1 to 6 reflect the surprising discovery that it is possible to develop a release modifying trazodone composition for administration to a person that, while pH sensitive, exhibits trazodone release rates that are essentially the same as those of a commercially available substantially pH independent formulation of trazodone which maintains substantially constant plasma concentrations of trazodone of between about 50 ng/mL and about 3000 ng/mL from at least about one hour to at least about 24 hours, which is used for treating inter alia, depression and insomnia.
  • FIG. 1 shows the amounts of trazodone released from tablets of Composition A after 12hr of dissolution testing at various pH. The amount of trazodone release increases up to pH 6 and then diminishes.
  • the amount of trazodone released from Composition A after 12hr of incubation is profoundly affected by the pH of the incubation medium, the amount released at, for example pH 6, a value close to the pKa of trazodone, being greater than the amount released at pH 7, again a pH close to the pKa of the drug.
  • the converse is true, viz. the amount released at 12hr increases from pH 1.2 to pH 6, then drops 3-4-fold at pH 7, a feature of the release modifying nature of the hydrogel composition.
  • Example 7 the effect of drug (trazodone hydrochloride) PSD on tablet drug content and tablet dissolution rate has been studied.
  • drug sources of similar drug PSD Batches A-C
  • One batch with a quite different PSD batch D containing a large amount of small particles or ‘fines’

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Abstract

La présente divulgation est basée sur une découverte surprenante selon laquelle une forme posologique à libération modifiée sensible au pH est une plateforme appropriée pour une thérapie par trazodone. L'invention concerne une forme posologique à libération modifiée sensible au pH pour une administration orale une fois par jour de trazodone, ou d'un dérivé de celle-ci, comprenant de 20% à 50% en poids de la trazodone ou de son dérivé, et de 10% à 80% d'un excipient de modification de libération, qui est un excipient formant un hydrogel. La présente divulgation est également basée sur une découverte surprenante selon laquelle des formes posologiques comprenant de la trazodone ont des caractéristiques de distribution de taille de particule particulières qui sont avantageuses pour des propriétés de libération uniforme, même lors de la subdivision. Dans un tel mode de réalisation, moins de 35% des particules sont de 355 µm à 500 µm, plus de 5% des particules sont de 250 µm à 355 µm, plus de 2% des particules sont de 75 µm à 150 µm, et plus de 5% des particules sont inférieures à 38 µm.
PCT/CA2025/050243 2024-02-27 2025-02-25 Formes posologiques de trazodone à libération modifiée Pending WO2025179377A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829120B2 (en) * 2005-09-09 2010-11-09 Labopharm Inc. Trazodone composition for once a day administration
US9439866B2 (en) * 2005-09-09 2016-09-13 Angelini Pharma, Inc. Trazodone composition for once a day administration
WO2019071348A1 (fr) * 2017-10-13 2019-04-18 Altus Formulation Inc. Excipients modificateurs de libération à base d'amidon et compositions pharmaceutiques dérivées de ceux-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829120B2 (en) * 2005-09-09 2010-11-09 Labopharm Inc. Trazodone composition for once a day administration
US9439866B2 (en) * 2005-09-09 2016-09-13 Angelini Pharma, Inc. Trazodone composition for once a day administration
WO2019071348A1 (fr) * 2017-10-13 2019-04-18 Altus Formulation Inc. Excipients modificateurs de libération à base d'amidon et compositions pharmaceutiques dérivées de ceux-ci

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