Modified release trazodone dosage forms

Abstract

The present disclosure is based on a surprising finding that a pH sensitive modified release dosage form is a suitable platform for trazodone therapy. Herein is described a pH sensitive modified release dosage form for once-a-day oral administration of trazodone, or a derivative thereof, comprising from 20% to 50% by weight of the trazodone or the derivative thereof, and from 10% to 80% of a release modifying excipient, which is a hydrogel-forming excipient. The present disclosure is also based on a surprising finding that dosage forms comprising trazodone have particular particle size distribution features that are advantageous for uniform release properties, even upon subdivision. In one such embodiment, less than 35% of the particles are 355μm to 500μm, greater than 5% of the particles are 250μm to 355μm, greater 2% of the particles are 75μm to 150μm, and greater than 5% of the particles are less than 38μm.

Description

MODIFIED RELEASE TRAZODONE DOSAGE FORMSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 558,241 filed February 27, 2024 entitled MODIFIED RELEASE TRAZODONE DOSAGE FORMS, the entirety of which is hereby incorporated by reference.FIELD

[0002] The present disclosure related to trazodone formulations. More particularly, the present disclosure related to modified-release trazodone formulations.BACKGROUND

[0003] 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. 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).

[0004] Formula I depicts the structure of trazodone as the hydrochloride salt.

[0006] 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 oftrazodone required to inhibit SERT may not be needed to alleviate depression. Instead, 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.

[0007] 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.

[0008] Along with an early onset of action, for example during or after only one week of treatment, another method of avoiding treatment failures is to mitigate the emergence of sideeffects early in treatment. This may be achieved by dose titration, that is a slow progressive increase in administered dose allowing tolerance to occur at low drug doses before stepping up to a higher dose where side-effects might otherwise occur. This "start-low, go-slow", titrationbased approach to treatment, that also allows physicians to prescribe in a more patient-specific or personalized manner, is facilitated by the availability of a series of different tablet doses (or strengths) with small incremental differences in dose between them. This, in turn, requires that multiple different strength formulations are developed and that the patient must obtain multipledifferent strength prescriptions from their physician which is both inconvenient and costly for the patient. Breakable, long lasting, release-modifying formulations of 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.

[0009] Developing release modifying formulations of trazodone that provide constant low levels of trazodone in the blood for example over about 24hr is, however, problematic because 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) will experience conditions of diminishing drug solubility and therefore diminishing bioavailability during their intended period of efficacy; achieving constant levels of trazodone in the blood over prolonged periods as will benefit the patient is therefore challenging when delivering a pH sensitive drug such as trazodone.

[0010] 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 Contramid™) for pH independent release of trazodone from the composition and, in some way, pH independent, consistent trazodone bioavailability. As stated in U.S Patent No. 9,439,866, after oral administration the described controlled release excipient overcomes the pH sensitivity of trazodone to provide a substantially pH independent controlled release of trazodone so that trazodone remains soluble for absorption during passage through both the upper and lower gastrointestinal tracts.

[0011] U.S. Patent No. 7,829,120 disclose the same 150mg and 300mg Contramid™ 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.

[0012] The formulations described by U.S Patent Nos. 9,439,866 and 7,829,120 have been commercialized as Oleptro™ (Angelini Labopharm), with U.S. Patent No. 7,829,120 listed in the Orange Book of the U.S. Food and Drug Administration (FDA) for Oleptro™. The 300mg strength tablet of Oleptro™ comprises, as per its package insert hydroxypropyl distarch phosphate (i.e., Contramid™), 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.

[0013] The same Contramid™-based trazodone formulations are additionally available for purchase in the European Union under trade name Trittico XR (Angelini Pharma). Reference to the package insert of Trittico XR confirms that Trittico XR tablets comprise: granulated Contramid™ (gelatinized modified starch), hypromellose, anhydrous colloidal silicon dioxide, sodium stearyl fumarate, and a coating comprising yellow Opadry™ II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow, iron oxide red).

[0014] Existing release-modifying formulations are technologically complex, relying on specialized controlled release technologies imparted by a specially prepared release modifying excipient. It would be advantageous to have simpler alternatives.SUMMARY

[0015] It is an object of the present disclosure to obviate or mitigate at least one disadvantage of previous approaches.

[0016] In one aspect, there is provided 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.

[0017] In one aspect, there is provided 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.

[0018] In one aspect, there is provided 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.

[0019] In one aspect, there is provided 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.

[0020] In one aspect, there is provided 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.

[0021] In one aspect, there is provided 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.

[0022] In one aspect, there is provided 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.

[0023] In one aspect, there is provided 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 treatment of depression in a subject.

[0024] In one aspect, there is provided 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 treatment of insomnia in a subject.

[0025] In one aspect, there is provided 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 treatment of anxiety in a subject.

[0026] In one aspect, there is provided a use of the 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.

[0027] In one aspect, there is provided a use of the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for treatment of depression in a subject.

[0028] In one aspect, there is provided a use of the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for treatment of insomnia in a subject.

[0029] In one aspect, there is provided a use of the 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.

[0030] In one aspect, there is provided a use of the 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.

[0031] In one aspect, there is provided a use of the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceuticaldosage form as described herein for preparation of a medicament for treatment of depression in a subject.

[0032] In one aspect, there is provided a use of the 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.

[0033] In one aspect, there is provided a use of the 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.

[0034] In one aspect, there is provided a kit 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.

[0035] In one aspect, there is provided a kit 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.

[0036] In one aspect, there is provided a kit 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.

[0037] In one aspect, there is provided a kit 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.

[0038] In one aspect, there is provided 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.

[0039] In one aspect, there is provided 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.

[0040] In one aspect, there is provided 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.

[0041] In one aspect, there is provided 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.

[0042] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached figures.

[0044] 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.

[0045] FIG. 2 shows the progressive release of trazodone from tablets of Composition A using the using water as the incubation medium.

[0046] 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.

[0047] FIG. 4 depicts progressive release of trazodone from tablets of Composition B when tested using water as the incubation medium.

[0048] 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.

[0049] 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.

[0050] FIG. 7 illustrates an aspect of the subject matter in accordance with one embodiment.

[0051] 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.

[0052] FIG. 9 depicts drug PSD of the six batches of trazodone hydrochloride used in the analysis (Batches A to F).

[0053] FIG. 10 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch A. Tablet to tablet variation was very low.

[0054] FIG. 11 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch B. Tablet to tablet variation was very low.

[0055] FIG. 12 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch C. Tablet to tablet variation was very low.

[0056] FIG. 13 depicts dissolution profiles for the whole (intact) tablets taken made with drug from Batch D. Tablet to tablet variation was very low.

[0057] 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.

[0058] 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.DETAILED DESCRIPTION

[0059] The present disclosure is based on the surprising finding that a pH sensitive modified release dosage form is a suitable platform for trazodone therapy. Herein is described 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. Despite conventional teaching indicating that a pH insensitive composition is required, embodiments described herein exhibit properties indicating that they will maintainsubstantially constant and effective plasma concentrations of trazodone in a subject across a dosing period. In addition, 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.

[0060] pH sensitive modified release trazodone dosage forms

[0061] In one aspect, there is provided 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.

[0062] By "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. A “release modifying excipient” is, therefore, an excipient that achieves these effects when present in such a composition.

[0063] By "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.

[0064] In one embodiment, the release modifying excipient comprises a hydrogel-forming excipient.

[0065] By "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.

[0066] In one embodiment, the hydrogel-forming excipient comprises hydroxypropyl methylcellulose (HPMC).

[0067] In one embodiment, the hydrogel-forming excipient comprises a hydroxypropyl di starch phosphate (HPDP) mixture.

[0068] In one embodiment, the hydrogel -forming excipient comprises both the HPMC and the hydroxypropyl distarch phosphate (HPDP) mixture.

[0069] In one embodiment, 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 substantiallyfree of crosslinks between amylose and amylopectin subunits and substantially free of crosslinks between amylose and amylose subunits.

[0070] In one embodiment, 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.

[0071] In one embodiment, 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.

[0072] In one embodiment, the release modifying excipient may be as defined in International Patent Publication No. WO2019 / 071348, which is hereby incorporated by reference in its entirety.

[0073] By “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.

[0074] By “high amylose starch” (HAS) is meant a starch comprising of at least 50% amylose (wt / wt). Examples of commercially available HAS include Hylon VII™ AmyloGel™ 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.

[0075] In one embodiment, the HAS comprises AmyloGel™ 03003.

[0076] By “amylopectin” will be understood 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.

[0077] By “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 nativeamylopectin is substituted with hydroxypropyl groups. For example, hydroxypropylation may increase the gel stability, water solubility, digestibility, and storage stability of the native molecules. Examples include Utra-Tex4™, Pure-Gel B990™, Polar Tex-instant 12640™, and Polar-Tex-instant 12643™.

[0078] In one embodiment, the cross-linked hydroxypropylated amylopectin comprises PolarTex-Instant™ 12640.

[0079] By “pre-gelatinized common starch” (PGS) is meant 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. Examples include Starch 1500™, SuperStarch 200™, and National 78-1551™.

[0080] In one embodiment, the PGS comprises Starch 1500™.

[0081] In one embodiment, 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.

[0082] In one embodiment, 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. In one embodiment, 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 about275mg of the trazodone. In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises about 300mg of the trazodone. In one embodiment, 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.

[0083] In one embodiment, 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.

[0085] In one embodiment, 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.

[0086] In one embodiment, 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.

[0087] In one embodiment, 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.

[0088] In one embodiment, 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 thetrazodone 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.

[0089] In one embodiment, 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.

[0090] In one embodiment, 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.

[0091] In one embodiment, 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.

[0092] In one embodiment, 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.

[0093] In one embodiment, the pH sensitive release modifying pharmaceutical dosage form is bisectable.

[0094] In one embodiment, the pH sensitive release modifying pharmaceutical dosage form comprises trazodone formed of particles.

[0095] In one embodiment, 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.

[0096] In one embodiment, 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.

[0097] In one embodiment, 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.

[0098] 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. In one embodiment, 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. In one embodiment, 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.

[0099] In one embodiment, 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.

[0100] In one embodiment, 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.

[0101] In one embodiment, 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.

[0102] In one embodiment, 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.

[0103] In one embodiment, 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.

[0104] In one embodiment, 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. In one embodiment, 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.

[0105] In one embodiment, 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.

[0106] In one embodiment, 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. In one embodiment, 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.

[0107] Modified release dosage forms comprising trazodone having particle size distribution properties

[0108] In one aspect, there is provided 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.

[0109] In one embodiment, 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.

[0110] In one embodiment, less than 20% (wt / wt) of the particles are 355pm to 500pm in size. In one embodiment, greater than 15% (wt / wt) of the particles are 250pm to 355pm in size. In one embodiment, greater than 8% (wt / wt) of the particles are 75pm to 150pm in size. In one embodiment, 5% to 20% (wt / wt) of the particles are less than 38pm in size. In one embodiment, a combination of these particle size distribution features may apply.

[0111] In one embodiment, the release modifying excipient comprises a hydrogel-forming excipient.

[0112] In one embodiment, the hydrogel-forming excipient comprises hydroxypropyl methylcellulose (HPMC).

[0113] In one embodiment, the hydrogel-forming excipient comprises a hydroxypropyl di starch phosphate (HPDP) mixture.

[0114] In one embodiment, the hydrogel -forming excipient comprises both the HPMC and the hydroxypropyl distarch phosphate (HPDP) mixture.

[0115] In one embodiment, 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.

[0116] In one embodiment, 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.

[0117] In one embodiment, 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.

[0118] In one embodiment, the release modifying excipient may be as defined in International Patent Publication No. WO2019 / 071348

[0119] In one embodiment, 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.

[0121] In one embodiment, 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.

[0122] In one embodiment, 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.

[0123] In one embodiment, 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.

[0124] In one embodiment, 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.

[0125] In one embodiment, 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. In one embodiment, the dosage form, upon subdivision into subunits from an intact dosage form, exhibits less than 3% variation in releaseof the trazodone by the subunits as compared to the intact dosage form at a time during a 20- hour dissolution test period.

[0126] In one embodiment, 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.

[0127] In one embodiment, 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. In one embodiment, 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.

[0128] Methods, Products for Use, Uses, Kits, and Commercial Packages

[0129] In one aspect, there is provided 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.

[0130] In one aspect, there is provided 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.

[0131] In one aspect, there is provided a method of treating insomnia in a subject in need thereof comprising administering to the subject the pH sensitive release modifyingpharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein.

[0132] In one aspect, there is provided 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.

[0133] In one aspect, there is provided the 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.

[0134] In one aspect, there is provided the 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.

[0135] In one aspect, there is provided 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 treatment of insomnia in a subject.

[0136] In one aspect, there is provided 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 treatment of anxiety in a subject.

[0137] In one aspect, there is provided a use of the 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.

[0138] In one aspect, there is provided a use of the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for treatment of depression in a subject.

[0139] In one aspect, there is provided a use of the pH sensitive release modifying pharmaceutical dosage form of as described herein or the modified release pharmaceutical dosage form as described herein for treatment of insomnia in a subject.

[0140] In one aspect, there is provided a use of the 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.

[0141] In one aspect, there is provided a use of the 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.

[0142] In one aspect, there is provided a use of the 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.

[0143] In one aspect, there is provided a use of the 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.

[0144] In one aspect, there is provided a use of the 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.

[0145] In one aspect, there is provided a kit 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.

[0146] In one aspect, there is provided a kit 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.

[0147] In one aspect, there is provided a kit 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.

[0148] In one aspect, there is provided a kit 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.

[0149] In one aspect, there is provided 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.

[0150] In one aspect, there is provided 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.

[0151] In one aspect, there is provided 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.

[0152] In one aspect, there is provided 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.

[0153] It is to be appreciate that the amount used, for use, or administered is an effective amount for treatment of the respective condition in the subject.EXAMPLESIntroduction to the Examples

[0154] 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. As the pH of the tract varies throughout its length however, for example between about pH 1.2 and about pH 7.4 [Fallingborg 1999][Evans et al. 1988 ] then the solubility and therefore bioavailability of trazodone would be expected to change being more soluble and bioavailable in regions with pH distant from the pKa, that is, the lower pH of the upper gastrointestinal tract.

[0155] Previous reports of trazodone, and its effectiveness as an antidepressant, state that minimum and preferably essentially constant blood levels of trazodone are necessary to bring about the key improvements in depressive symptoms in a patient, such blood levels being in turn dependent on constant, that is continuous and unchanging absorption of trazodone throughout the gastrointestinal tract. The pH dependent bioavailability of trazodone, if delivered by a modified release composition that was itself pH sensitive would, therefore, not be expected to achieve the blood levels of the drug necessary for therapeutic effect. Indeed, U.S. Patent Nos. 9,439,866 and 7,829,120 teach that substantially pH independent release of trazodone is required to achieve such constant blood levels.

[0156] The following examples describe the preparation of 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. Despite this, when tested in vitro using methods generally accepted as predictive of trazodone pharmacokinetics in a person, 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. Surprisingly, when ingested by humans, the compositions will generate concentrations of trazodone in the blood known to exert an antidepressant effect in humans.Example 1: Composition A Dissolution Properties

[0157] A first modified release tablet composition comprising 300mg of trazodone (Composition A) was prepared having the composition provided in Table 1.

[0158] Table 1: Composition ARaw Materials mg / tab% / tabTrazodone hydrochloride 300.0 49Hydroxypropyl Di starch Phosphate (HPDP) 200.0 32.7Hydroxypropyl methylcellulose K100M (HPMC) 100.0 16.3Colloidal silicon dioxide 3.0 0.5Sodium stearyl fumarate 9.0 1.5Total: 612 100

[0159] The HPDP was a blend of 75% (wt / wt) of high amylose starch (AmyloGel™ 03003), 15% (wt / wt) of cross-linked hydroxypropylated amylopectin (PolarTex-Instant™ 12640), and 10% (wt / wt) of pre-gelatinized common starch (Starch 1500™).

[0160] Trazodone in this example accords with Batch C discussed in Example 7.

[0161] 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.

[0162] 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.

[0163] Table 2: Dissolution Media BuffersBuffer Concentration pHHydrochloric acid / sodium chloride 0.05 M 1.2Acetic acid / sodium acetate 0.05 M 4.5Monobasic / dibasic potassium phosphate 0.05M 6.0Monobasic / dibasic potassium phosphate 0.05 M 7.0

[0164] The amount of trazodone released after 12hr of testing under each of these conditions is shown in FIG. 1 as a representation of the release rates from the tablets up to this point.

[0165] 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

[0166] A second modified release tablet composition comprising 150mg of trazodone (Composition B) was prepared having the composition provided in Table 3.

[0167] Table 3: Composition BRaw Materials mg / tab % / tabTrazodone hydrochloride 150.0 27.8Hydroxypropyl Di starch Phosphate (HPDP) 252.8 46.8Hydroxypropyl methylcellulose K100M (HPMC) 126.4 23.4Colloidal silicon dioxide 2.7 0.5Sodium stearyl fumarate 8.1 1.5Total: 540 100.0

[0168] As with Example 1, the HPDP was a blend of 75% (wt / wt) of high amylose starch (AmyloGel™ 03003), 15% (wt / wt) of cross-linked hydroxypropylated amylopectin (PolarTex- Instant™ 12640), and 10% (wt / wt) of pre-gelatinized common starch (Starch 1500™).

[0169] Trazodone in this example accords with Batch C discussed in Example 7.

[0170] 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.

[0171] 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.

[0172] The amount of trazodone released after 12hr of testing under each of these conditions is shown in FIG. 3.

[0173] As may be seen in FIG. 3, 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. Unexpectedly however, rather than progressively less trazodone being released as the pH of the medium increases towards the pKa, here 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.

[0174] 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.Example 3: Friability Testing of Composition A

[0175] The hardness of a pharmaceutical composition such as the matrix tablets of Composition A 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 friableand 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.

[0176] 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.

[0177] Table 4: Friability Testing of Composition A300 mg Trazodone CompositionCompression parameters / Tablet (Composition A)CharacteristicsLow Hardness High HardnessCompression force (kN)14.06 - 14.38 22.21 - 22.67(min-max)55 84Tablet hardness (N) (min-max)(51 - 59) (78 -93)Whole tablet friability (%) 0.3 0.0

[0178] It is generally accepted by those in the art, as described for example in USP general chapter < 1216> (Tablet Friability) that tablets acceptable for human administration must display friability of less than 1.0%. Tablets of both low and high hardness displayed acceptable levels of friability.

[0179] The rates of trazodone release from the Composition A tablets of low and high hardness were determined using the aforementioned dissolution conditions with water being employed as the incubation medium. Tablets of both low and high hardness released not more than about 30% of the active ingredient 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.

[0180] 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.Example 4: Friability Testing of Composition B

[0181] 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.

[0182] Table 5: Friability Testing of Composition B150 mg Trazodone CompositionCompression parameters / Tablet (Composition B)CharacteristicsLow Hardness High HardnessCompression force (kN)14.35 - 14.43 22.45 - 22.64 (min-max)68.5 110Tablet hardness (N) (min-max)(62 - 78) (98 - 117)Whole tablet friability (%) 0.3 0.1

[0183] It is generally accepted by those in the art, as described for example in USP general chapter < 1216> (Tablet Friability) that tablets acceptable for human administration must display friability of less than 1.0%. Tablets of both low and high hardness displayed acceptable levels of friability.

[0184] The rates of trazodone release from the Composition B tablets of low and high hardness were determined using the aforementioned dissolution conditions with water being employed as the incubation medium. Tablets of both low and high hardness released not more than about 30% of the active ingredient 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.

[0185] 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.Example 5: Effects of Alcohol and Tablet Breakage on Tablets of Composition A

[0186] Modified release formulations intended to deliver pharmaceutical drugs slowly after oral administration, for example modified release trazodone formulations intended to produce a therapeutic effect over 24hrs, 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. Should 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. Such uncontrolled release is termed dose dumping and it is for this reason that conventional modified release formulations are labeled ‘do not break’ and do not administer with alcohol. It would be of benefit to the safety of patient therefore if a modified release formulation could be invented that could be broken or exposed to alcohol without the dangers of dose dumping. The ability to break tablets to generate segments of lower strength with essentially the same rate of drug release would also be an advantage allowing, as it would, dosing flexibility from a single tablet.

[0187] In this example it is shown for 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.

[0188] The modified release trazodone tablet compositions of Example 1 (Composition A) comprising 300mg of trazodone were manufactured as described previously and subjected to invitro 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.Example 6: Effects of Alcohol and Tablet Breakage on Tablets of Composition B

[0189] 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.

[0190] As may be seen from the Figures, neither exposing the tablets to ethanol nor breaking them and exposing them to ethanol caused changes to trazodone release rates which remained essentially the same.Example 7: Influence of Particle Size Distribution on Modified Release Performance

[0191] Background

[0192] 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.

[0193] 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. The difference in assay results, sample to sample, can then be expressed statistically as a measure of blend uniformity (so called ‘blend uniformity testing’). 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. Should the amount of drug in each tablet be uniform, given the amount of release controlling excipients is also uniform, then the amount of drug released over time from the each tablet would also be expected to be the same tablet to tablet at any one time i.e. in the case of a modified release trazodone tablet, 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).

[0194] There are a number of factors that can affect the uniform distribution of drug within a drug / excipient blend and therefore the amount of drug tablet to tablet. Arguably the most important of these is the size of the particles that comprise each excipient (the excipient particle size distribution or excipient PSD) and most importantly, since each tablet will contain a large amount of drug in relation to any one excipient, the particle size distribution of the drug, in this case trazodone hydrochloride (the drug PSD). It therefore also self-evident that, when selecting a source (i.e., a manufacturer) of a drug with which to make modified release tablets intended for human use, that the drug PSD must be carefully evaluated. 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 ofdrug 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.

[0195] 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. As will be seen, the influence of drug PSD on blend uniformity, content uniformity and tablet dissolution testing could not be predicted from review of sieve analysis results; surprisingly, the drug PSD required for manufacture of modified release trazodone hydrochloride tablets with uniform content and uniform drug release rate during tablet dissolution testing was only discovered by experimentation.

[0196] Methods

[0197] Six batches of trazodone hydrochloride (Drug batches A to F) having different particle size distributions were obtained and the drug PSD of each determined using sieve analysis as per <USP 786>. Results are provided in FIG. 9.

[0198] Batches of once-daily modified release trazodone tablets (Composition 2; Example 1) were then manufactured using the process described in Example 1. In brief, 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). Each of the blends was then compressed separately using a rotary tablet press to produce six different batches of modified release tablets.

[0199] 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. As the 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.

[0200] Results

[0201] Drug PSD

[0202] The drug PSD histograms of the six sources of trazodone hydrochloride, measured by sieve analysis, are shown in FIG. 9. As may be seen, with the exception of Batch D which contained a significant portion of very small particles (<38 micron) all other batches had similar PSD with the majority of particles being of between 500 microns to 75 microns in size. On the basis of these results all batches except Batch D might be expected to behave similarly with respect to blend uniformity, content uniformity and dissolution performance tablet to tablet.

[0203] Blend Uniformity

[0204] Mean 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 pharmaceuticalproducts, 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.

[0205] TABLE 6: Blend Assay Results and AV.Mean Drug ContentLocation in Blender (Percent of Expected Amount byAssay %)Location 1 102.45Location 2 103.5Location s 102.1Location 4 100.65Location s 101.2Location 6 101.65Average 101.95%RSD 1.5AV44.2

[0206] * Calculated as the arithmetic mean of the individual blend AV

[0207] As may be seen, all assay values met acceptance criteria as did the AV. Differences in drug PSD from the samples did not generate blends of different or unacceptable uniformity. Drug sources acceptable for future tablet manufacture could not be identified from blend uniformity testing.

[0208] Tableting

[0209] 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.

[0210] TABLE 7: Physicochemical characteristics of Trazodone Hydrochloride whole tablets of Composition 2 prepared from Batches A to F of the API

[0211] While review of Table 7 reveals no obvious trends or out of specification results Batches E and F had noticeably higher AV than tablets made with other sources of drug with Batch F displaying noticeably high weight perhaps supporting a change in blend flow characteristics and thereby increased flow rate of the blend from the hopper of the tablet press to the die table where compression occurs. Batch F also displayed the lowest thickness of the tablets tested and the highest hardness. These results may suggest that a degree of segregation of small and large particles in the drug / excipients blends occurs during compression but data are not in themselves sufficient to allow selection of drug sources suitable for once-daily trazodone tablet manufacture.

[0212] Dissolution Testing

[0213] 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 eachtablet 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.

[0214] As may be seen from FIG. 10 to FIG. 15, 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.

[0215] Tablets from batch F behaved differently, however. While whole tablet to whole tablet variation in dissolution rate was larger for batch F tablets than was seen with tablets made with drug from sources A to D (being similar to whole tablet to whole tablet variation seen in FIG. 14 for Batch E) variation in release rate between tablets segments reached 30%: the AV value for these segments was 23.

[0216] While results from tablet physicochemical testing indicated that drug Sources E and F were different from the other 4 sources of drug, the profound effect of the drug PSD on tablet dissolution performance elicited by these two Batches could only be discerned by dissolution testing. These effects, which were surprising, could not be deduced from initial review of drug PSD results or even blend uniformity results.

[0217] Returning to FIG. 9, these results indicate the trazodone having a PSD in which greater than 35% (w / w) of particle fall in the 355 to 500pm range should be avoided. It also appears desirable to have >5% (w / w) of particles in the 250-355pm size range. It also appears to be desirable to have at least 2% (w / w) in the 75-150pm range. In addition - and surprisingly - the negligible “fines” (particles < 38pm) of Batches E and F also appears to be undesirable when combined with other features; it appears that the trazodone should have at least 5% (w / w) of its particles < 38pm, keeping within accepted limitations. Combinations of these features appears to yield PSD profiles having the most promising results as far as performance upon tablet subdivision is concerned.Discussion of Examples

[0218] 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. This is surprising because two pharmaceutical compositions that display essentially the same dissolution rates (that is rates of trazodone release from the composition) at for example three, or four different pH that the two compositions are similar and will therefore generate levels of drug in the blood of equivalent safety and efficacy. Thus, contrary to previously approaches which indicate that a substantially pH insensitive or pH independent composition is required to achieve the constant low levels of trazodone of the plasma needed for rapid and effective antidepressant effects, the present examples demonstrate that a pH sensitive formulation can achieve the same benefits for patients because it behaves in the same manner as the substantially pH independent product under in vivo predictive conditions. This is both surprising and a benefit since the pH sensitive formulation does not require specialized pH insensitive cross linked high amylose starch used in the commercially available tablets.

[0219] 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.

[0220] As may be seen in FIG. 1, 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. Unexpectedly however, rather than progressively less trazodone being released as the pH of the medium increases towards that of the pKa, here 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.

[0221] It is also important when administering drug to a patient, especially when such a drug must be administered chronically, that the patient always receives the same amount of drug from each tablet. For a modified release tablet designed for once daily administration, it is alsoimportant that the drug contents of such tablets are released at the same rate so that blood levels are always the same throughout the day, every day. This in turn means that for a tablet manufacturing process relying on dry blending of powders, that the drug is uniformly distributed in drug / excipient blends and that such uniform blends are converted, during compression, into tablets with uniform amounts of drug that is always released at the same rate.

[0222] It is well known that drug PSD can have an affect on blend uniformity and so the amount of drug that is contained in each tablet. This is because particles of different sizes may segregate into different portions of a blend, large particles rising to the top of the vessel containing the blend and small ones falling to the bottom. Tablets made towards the end of the blend may then differ in drug content and release rate from those made when compression starts and blend from the top of the vessel is compressed because the dissolution rate of large particles of a drug is necessarily slower than that of small particles with a greater surface area to weight ratio.

[0223] In Example 7, the effect of drug (trazodone hydrochloride) PSD on tablet drug content and tablet dissolution rate has been studied. Surprisingly, drug sources of similar drug PSD (Batches A-C) produced blends and tablets with very similar composition and release rates. One batch with a quite different PSD (batch D containing a large amount of small particles or ‘fines’) acted in a similar way to Batches A-C despite its differences. Two other batches (Batches E and F) though similar in some respects in PSD to batches A-C, generated tablets with mean dissolution performance similar to Batches A-D yet displayed release rates tablet to tablet (or, in the case of Batch F, tablet segment to tablet segment release rate) much greater than tablets made with Batch A-D tablets to the extent that they are not useful for producing tablets intended for human use. This was surprising and the results could not have been deduced from review of drug PSD alone. The PSD of these batches indicate PSD features that should be avoided in order to achieve a composition having desired properties.

[0224] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the embodiments. However, it will be apparent to one skilled in the art that these specific details are not required.

[0225] The above-described embodiments are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.REFERENCES

[0226] U.S. Patent No. 9,439,866.

[0227] U.S. Patent No. 7,829,120.

[0228] International Patent Publication No. WO2019 / 071348.

[0229] Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull. 1999 Jun;46(3): 183-96. PMID: 10421978.

[0230] Evans DF, Pye G, Bramley R, et al Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988;29: 1035-1041.

[0231] Walsh JK, Erman M, Erwin C, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII-R primary insomnia. Hum Psychopharmacol. 1998; 13(3): 191-198.

[0232] All references referred to herein are incorporated by reference in their entireties.

Claims

CLAIMS1. A pH sensitive modified release pharmaceutical dosage form for once-a-day oral administration of trazodone, or a derivative thereof, 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.

2. The pH sensitive release modifying pharmaceutical dosage form of claim 1, wherein the release modifying excipient comprises a hydrogel-forming excipient.

3. The pH sensitive release modifying pharmaceutical dosage form of claim 2, wherein the hydrogel -forming excipient comprises hydroxypropyl methylcellulose (HPMC).

4. The pH sensitive release modifying pharmaceutical dosage form of claim 2, wherein 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, and1% 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.

5. The pH sensitive release modifying pharmaceutical dosage form of claim 4, wherein 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.

6. The pH sensitive release modifying pharmaceutical dosage form of claim 5, wherein 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.

7. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 4 to 6, wherein the hydrogel-forming excipient further comprises hydroxypropyl methylcellulose (HPMC).

8. The pH sensitive release modifying pharmaceutical dosage form of claim 7, wherein the hydrogel -forming excipient comprises:- about 50-80% (wt / wt) of the HPDP mixture, and- about 20-50% (wt / wt) of the HPMC.

9. The pH sensitive release modifying pharmaceutical dosage form of claim 7, wherein the hydrogel -forming excipient comprises:- about 60-70% (wt / wt) of the HPDP mixture, and- about 30-40% (wt / wt) of the HPMC.

10. The pH sensitive release modifying pharmaceutical dosage form of claim 7, wherein the hydrogel -forming excipient comprises: about two thirds (wt / wt) of the HPDP mixture, and about one third (wt / wt) of the HPMC.

11. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 10, which comprises about 75mg of the trazodone or the derivative thereof.

12. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 10, which comprises about 150mg of the trazodone or the derivative thereof.

13. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 10, which comprises about 300mg of the trazodone or the derivative thereof.

14. The pH sensitive release modifying pharmaceutical dosage form of claim 7, which comprises: about 75mg of the trazodone, about 127mg of the HPDP mixture, and about 63mg of the HPMC.

15. The pH sensitive release modifying pharmaceutical dosage form of claim 7, which comprises:about 150mg of the trazodone, about 253mg of the HPDP mixture, and about 126mg of the HPMC.

16. The pH sensitive release modifying pharmaceutical dosage form of claim 7, which comprises: about 150mg of the trazodone, about lOOmg of the HPDP mixture, and about 50mg of the HPMC.

17. The pH sensitive release modifying pharmaceutical dosage form of claim 7, which comprises: about 3 OOmg of the trazodone, about 200mg of the HPDP mixture, and about lOOmg of the HPMC.

18. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to17, which 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.

19. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to18, which 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.

20. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to19, which 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 50 revolutions per minute and at 37±0.5° C.

21. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to20, having a hardness of 50N to 99N.

22. The pH sensitive release modifying pharmaceutical dosage form of claim 21, wherein the hardness is 5 IN to 93N.

23. The pH sensitive release modifying pharmaceutical dosage form of claim 21 or 22, having a friability of less than 1%.

24. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 23, 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.

25. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 23, which 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.

26. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 23, which 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.

27. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 26, which is bisectable.

28. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 27, which comprises trazodone formed of particles.

29. The pH sensitive release modifying pharmaceutical dosage form of claim 28, wherein less than 35% (wt / wt), preferably less than 30% (wt / wt), more preferably less than 20% (wt / wt) of the particles are 355pm to 500pm in size.

30. The pH sensitive release modifying pharmaceutical dosage form of claim 28 or 29, wherein the greater than 5% (wt / wt), preferably greater than 10% (wt / wt), more preferably greater than 15% (wt / wt) of the particles are 250pm to 355pm in size.

31. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 28 to30, wherein greater than 2% (wt / wt), preferably greater than 6% (wt / t), more preferably greater than 8% (wt / wt) of the particles are 75pm to 150pm in size.

32. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 28 to31, wherein greater than 5% (wt / wt), preferably 5% to 35% (wt / wt), more preferably 5% to 20% (wt / wt) of the particles are less than 38pm in size.

33. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 29 to32, wherein 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.

34. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 29 to 32, wherein the dosage form exhibits less than 5% 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.

35. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 29 to 32, wherein the dosage form exhibits less than 3% 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.

36. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 33 to 35, wherein the dissolution test period is 4 hours.

37. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 33 to 35, wherein the dissolution test period is 6 hours.

38. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 33 to 35, wherein the dissolution test period is 8 hours.

39. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 33 to 35, wherein the dissolution test period is 10 hours.

40. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 33 to 35, wherein the dissolution test period is 20 hours.

41. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 40, which produces an effect for at least 4 hours.

42. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 40, which produces an effect for at least 6 hours.

43. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 40, which produces an effect for at least 8 hours.

44. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 40, which produces an effect for at least 12 hours.

45. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 40, which produces an effect for at least 24 hours.

46. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 29 to 45, which, upon subdivision from an intact dosage form, exhibits less than 10% variation in release for the trazodone by the subunits as compared to the intact dosage form at a time during a 20-hour dissolution test period.

47. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 29 to 45, which, 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 a time during a 20-hour dissolution test period.

48. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 29 to 45, which, 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 a time during a 20-hour dissolution test period.

49. 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), preferably less than 30% (wt / wt), more preferably less than 20% (wt / wt) of the particles are 355pm to 500pm in size,- greater than 5% (wt / wt), preferably greater than 10% (wt / wt), more preferably greater than 15% (wt / wt) of the particles are 250pm to 355pm in size,- greater than 2% (wt / wt), preferably greater than 6% (wt / wt), more preferably greater than 8% (wt / wt) of the particles are 75pm to 150pm in size, and- greater than 5% (wt / wt), preferably 5% to 35% (wt / wt), more preferably 5% to 20% (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.

50. The modified release pharmaceutical dosage form of claim 49, wherein 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.

51. The modified release pharmaceutical dosage form of claim 49, wherein 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.

52. The modified release pharmaceutical dosage form of any one of claims 49 to 51, wherein the dissolution test period is 4 hours.

53. The modified release pharmaceutical dosage form of any one of claims 49 to 51, wherein the dissolution test period is 6 hours.

54. The modified release pharmaceutical dosage form of any one of claims 49 to 51, wherein the dissolution test period is 8 hours.

55. The modified release pharmaceutical dosage form of any one of claims 49 to 51, wherein the dissolution test period is 12 hours.

56. The modified release pharmaceutical dosage form of any one of claims 49 to 51, wherein the dissolution test period is at least every 20 hours.

57. The modified release pharmaceutical dosage form of any one of claims 49 to 56, which produces an effect for at least 4 hours.

58. The modified release pharmaceutical dosage form of any one of claims 49 to 56, which produces an effect for at least 6 hours.

59. The modified release pharmaceutical dosage form of any one of claims 49 to 56, which produces an effect for at least 8 hours.

60. The modified release pharmaceutical dosage form of any one of claims 49 to 56, which produces an effect for at least 12 hours.

61. The modified release pharmaceutical dosage form of any one of claims 49 to 56, which produces an effect for at least 24 hours.

62. The modified release pharmaceutical dosage form of any one of claims 49 to 61, which, upon subdivision from an intact dosage form, exhibits less than 10% variation in release rate for the trazodone by the subunits as compared to the mean release rate determined for a plurality of said dosage forms at that same time.

63. The modified release pharmaceutical dosage form of any one of claims 49 to 61, which, upon subdivision from an intact dosage form, exhibits less than 5% variation in release rate for the trazodone by the subunits as compared to the mean release rate determined for a plurality of said dosage forms at that same time.

64. The modified release pharmaceutical dosage form of any one of claims 49 to 61, which, upon subdivision from an intact dosage form, exhibits less than 3% variation in release rate forthe trazodone by the subunits as compared to the mean release rate determined for a plurality of said dosage forms at that same time.

65. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64 for use in delivery of trazodone to a subject.

66. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64 for use in treatment of depression in a subject.

67. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64 for use in treatment of insomnia in a subject.

68. The pH sensitive release modifying pharmaceutical dosage form of any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64 for use in treatment of anxiety in a subject.

69. 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 any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64.

70. 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 any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64.

71. 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 any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64.

72. 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 any one of claims 1 to 48 or the modified release pharmaceutical dosage form of any one of claims 49 to 64.

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