Sustained release midodrine hydrochloride compositions and methods of use

Abstract

To provide a sustained release Midodrine Hydrochloride composition and a method for using the same.SOLUTION: The present disclosure provides a pharmaceutical composition comprising midodrine, a pharmaceutically acceptable salt thereof, desglymidodrine or a pharmaceutically acceptable salt thereof, administrable to a human subject in need thereof. The present disclosure also provides a pharmaceutical composition for treating orthostatic hypotension that can be administered once or twice daily.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 609,842, filed December 22, 2017, and U.S. Provisional Patent Application No. 62 / 618,374, filed January 17, 2018, the entire contents of which are incorporated herein by reference.

[0002]

[0002] The present disclosure relates to pharmaceutical compositions of midodrine, pharmaceutically acceptable salts of midodrine, its active metabolite desglymidodrine, pharmaceutically acceptable salts of desglymidodrine, or combinations thereof, methods for their preparation, and methods for their use in patients in need thereof. [Background technology]

[0003] Orthostatic hypotension (postural hypotension) is a drop in blood pressure that occurs when a person suddenly stands up or stretches. This hypotension is primarily caused by gravity-induced pooling of blood in the lower extremities, followed by impaired venous return, resulting in reduced cardiac output and a subsequent drop in arterial pressure.

[0004]

[0004] Midodrine hydrochloride (also known as midodrine HCl) is a peripherally selective alpha-1-adrenergic agonist indicated for the treatment of orthostatic hypotension. Midodrine hydrochloride may also be prescribed for patients with postural orthostatic tachycardia syndrome (POTS).

[0005]

[0005] Midodrine hydrochloride has the chemical name (±)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide monohydrochloride and has the structural formula shown below. [ka]

[0006] Currently, midodrine hydrochloride is available in the United States only as an immediate-release tablet in three strengths: 2.5 mg, 5 mg, and 10 mg. The U.S. FDA recommends administering up to 10 mg of midodrine hydrochloride three times daily. Tablets are taken approximately four hours apart, for example, in the morning upon awakening, midday, and late afternoon. Midodrine hydrochloride can cause a significant increase in supine blood pressure. To reduce the likelihood of supine hypertension during sleep, the FDA recommends administering the last dose before 6:00 PM and, in any event, more than four hours before bedtime. Summary of the Invention [Problem to be solved by the invention]

[0007] Midodrine HCl is a prodrug that is rapidly absorbed and converted to its active metabolite, desglymidodrine, upon oral administration. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% in oral tablets. The bioavailability of desglymidodrine is not affected by food. Pharmacokinetic studies have been conducted at 2.5 mg, 5 mg, and 10 mg doses. The linear kinetics of midodrine HCl at single doses of 10 mg and 10 mg have been shown. Furthermore, midodrine HCl has been found to have pH-independent solubility and to be absorbed throughout the gastrointestinal tract. Due to its high water solubility and high permeability, midodrine HCl is classified as a BCS Class I drug. [Means for solving the problem]

[0008] overview Certain aspects of the present disclosure relate to pharmaceutical compositions comprising a first release portion comprising an active agent in the range of about 20% to about 40% (w / w) of the total amount of active agent in the composition; and a second release portion comprising an active agent in the range of about 60% to about 80% (w / w) of the total amount of active agent in the composition, wherein the in vitro release rate of the active agent as measured by in vitro dissolution testing comprises (i) a first release that is relatively rapid and (ii) a second release without a second increase in release rate about 5 hours to about 10 hours after the start of the in vitro dissolution testing, wherein the active agent is selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and any combination thereof. In some embodiments, the second release is steady or slower than the first release. In some embodiments, the second release comprises a second increase in release rate occurring between about 2 and about 4.5 hours after the initiation of the in vitro dissolution test. In some embodiments, the second increase in release rate occurs between 2 and 4.5 hours after the initiation of the in vitro dissolution test. In a preferred embodiment, the in vitro dissolution test conditions are: 0-2 hours, 0.1 N HCl (pH 1.2); 2-4 hours, acetate buffer (pH 4.5); 4-16 hours, phosphate buffer (pH 6.8), in 900 mL, at 37°C, 100 rpm, USP Apparatus I (basket).

[0009]

[0009] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a first release portion comprising an active agent in the range of about 20% to about 40% (w / w) of the total amount of active agent in the composition; and a second release portion comprising an active agent in the range of about 60% to about 80% (w / w) of the total amount of active agent in the composition, wherein the in vitro release rate of the active agent as measured by in vitro dissolution testing comprises (i) a first release that is relatively rapid, (ii) a second release comprising a second increase in release rate that occurs about 2 hours to about 4.5 hours after the initiation of the in vitro dissolution testing, and (iii) a third release comprising a third increase in release rate that occurs about 5 hours to about 8 hours after the initiation of the in vitro dissolution testing, wherein the active agent is selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and any combination thereof. In some embodiments, the second increase in release rate occurs about 2 to about 4 hours after the start of the in vitro dissolution test. In some embodiments, the second increase in release rate occurs 2 to 4.5 hours or 2 to 4 hours after the start of the in vitro dissolution test. In some embodiments, the third increase in release rate occurs at least 6 hours after the start of the in vitro dissolution test.

[0010]

[0010] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a first release portion comprising about 1.5 mg to about 45 mg of active agent, the active agent being present in an amount of about 2% to about 40% of the total weight of the first release portion, and excipients, and a second release portion comprising about 3.5 mg to about 105 mg of active agent, the active agent being present in an amount of about 2% to about 20% of the total weight of the second release portion, and a rate control agent, wherein the amount of active agent in the second release portion relative to the amount of rate control agent is in a ratio of about 1:1 to about 1:30 (w / w), wherein the active agent is selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and any combination thereof.

[0011] In some embodiments, the pharmaceutical composition comprises midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, or The pharmaceutical composition contains a total of about 5 mg to about 150 mg of an active agent selected from any combination thereof. In some embodiments, the active agent is midodrine or a pharmaceutically acceptable salt of midodrine. In some embodiments, the active agent, e.g., midodrine or a pharmaceutically acceptable salt of midodrine, is present in a total amount of about 7.5 mg to about 120 mg. In some embodiments, the total amount of the active agent in the pharmaceutical composition is at least 15 mg (e.g., about 15 mg to 50 mg, about 18 mg to about 45 mg, or about 20 mg to about 30 mg). In some embodiments, the pharmaceutical composition is a tablet, capsule, or suspension.

[0012] In some embodiments, the active agent, e.g., midodrine or a pharmaceutically acceptable salt thereof, is present in the first release portion in an amount of about 1.5 mg to about 45 mg (e.g., about 4.5 mg to about 18 mg, or about 5 mg) and in the second release portion in an amount of about 3.5 mg to about 105 mg (e.g., about 10.5 mg to about 42 mg, or about 15 mg). In some embodiments, the first release portion is in the form of a capsule or suspension of a multilayer tablet or multiparticulates (e.g., pellets, particles, granules, beads, spheres, or minitablets).

[0013] In some embodiments, the in vitro release rate of the active agent, as measured by in vitro dissolution testing, has (i) a first release that is relatively rapid, and (ii) a second release that is steady or slower than the first release and is not accompanied by a second increase from about 5 hours to about 10 hours after initiation of the in vitro dissolution testing. In some embodiments, there is no second increase in release rate from 5 hours to 10 hours after initiation of the in vitro dissolution testing.

[0014] In some embodiments, the in vitro release rate of the active agent as measured by in vitro dissolution testing has (i) a first release that is relatively rapid, and (ii) a second release that includes a second increase in release rate that occurs between about 2 hours and about 4.5 hours after initiation of the in vitro dissolution testing, without the second increase, between about 5 hours and about 10 hours after initiation of the in vitro dissolution testing. In some embodiments, there is a second increase in release rate that occurs between 2 hours and 4.5 hours after initiation of the in vitro dissolution testing, and there is no second increase in release rate between 5 hours and 10 hours after initiation of the in vitro dissolution testing.

[0015] In some embodiments, the in vitro release rate of the active agent as measured by in vitro dissolution testing has (i) a first release that is relatively rapid, (ii) a second release that includes a second increase in release rate that occurs from about 2 hours to about 4.5 hours after the initiation of the in vitro dissolution testing, and (iii) a third release that includes a third increase in release rate that occurs from about 5 hours to about 8 hours after the initiation of the in vitro dissolution testing. In some embodiments, there is a second increase in release rate that occurs from 2 hours to 4.5 hours after the initiation of the in vitro dissolution testing, and there is a third increase in release rate that occurs from 5 hours to 8 hours after the initiation of the in vitro dissolution testing.

[0016] In some embodiments, substantially all of the active agent in the first release portion is released within about 45 minutes after the initiation of the in vitro dissolution test. In some embodiments, substantially all of the active agent in the first release portion is released within about 30 minutes after the initiation of the in vitro dissolution test. In some embodiments, substantially all of the active agent in the second release portion is released within 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, or 8 hours after the initiation of the in vitro dissolution test. In some embodiments, the in vitro dissolution test is performed using USP Apparatus I (basket) in 900 mL of: 0-2 hours, 0.1 N HCl (pH 1.2); 2-4 hours, acetate buffer (pH 4.5); 4-16 hours (or 4-12 hours), phosphate buffer (pH 6.8), at 37°C and 100 rpm.

[0017]

[0017] In some embodiments, at least about 20% of the total amount of active agent in the composition is released within about 1 hour after the start of the in vitro dissolution test, and at least about 80% of the total amount of active agent in the composition is released within about 12 hours. In some embodiments, the first release is characterized by the release of about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 25% to about 40%, about 25% to about 35%, or about 30% to about 40% (e.g., 20-40%, 20-35%, 20-30%, 25-40%, 25-35%, or 30-40%) (w / w) of the total amount of active agent in the pharmaceutical composition within about 1 hour after initiation of the in vitro dissolution testing, and the second release is characterized by a release rate of the remaining total amount of active agent in the pharmaceutical composition that is slower than the first release rate, wherein at least about 95% of the total amount of active agent in the pharmaceutical composition is released within about 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, or 8 hours after initiation of the in vitro dissolution testing.

[0018] In some embodiments, about 20% to about 40% (w / w) of the total amount of active agent in the pharmaceutical composition is released within about 1 hour after initiation of in vitro dissolution testing. In some embodiments, at least about 95% (w / w) of the total amount of active agent in the pharmaceutical composition is released within about 16 hours, about 15 hours, about 14 hours, about 13 hours, about 12 hours, about 11 hours, about 10 hours, about 9 hours, or about 8 hours after initiation of in vitro dissolution testing.

[0019] In some embodiments, the in vitro release rate of the active agent in the second release phase is slower than the in vitro release rate of the active agent released during the first phase. In some embodiments, there is no second increase in the in vitro dissolution release rate occurring 5 to 10 hours after the start of the in vitro dissolution test. In some embodiments, there is a second increase in the in vitro dissolution release rate occurring 2 to 4.5 hours after the start of the in vitro dissolution test.

[0020]

[0020] In some embodiments, substantially all of the active agent in the first release portion is released within about 1 hour after administration of the pharmaceutical composition to the subject; and substantially all of the active agent in the second release portion is released over a period of time from about 1 hour after administration of the composition to the subject to about 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, or 8 hours after administration of the composition to the subject.

[0021] In some embodiments, administration of about 15 mg of the extended release composition to a subject results in (i) a relatively rapid peak plasma concentration of desglymidodrine of at least about 12 ng / ml (e.g., at least 12 ng / ml, at least 13 ng / ml, or at least 14 ng / ml), and (ii) a plasma concentration of desglymidodrine of at least about 7 ng / ml (e.g., at least 7 ng / ml, at least 8 ng / ml, at least 9 ng / ml, or at least 10 ng / ml) for at least 8 hours or at least 10 hours. Administration of about 7.5 mg of the extended release composition to a subject is expected to result in about half of the peak plasma concentrations shown above, i.e., at least about 6 ng / ml (e.g., at least 6 ng / ml, at least 6.5 ng / ml, or at least 7 ng / ml). Similarly, administration of about 30 mg of the sustained release composition to a subject is expected to result in about twice the peak plasma concentration shown above, i.e., at least about 24 ng / ml (e.g., at least 24 ng / ml, at least 26 ng / ml, or at least 28 ng / ml).

[0022] In some embodiments, the pharmaceutical composition is in the form of a tablet, capsule, orally disintegrating tablet, chewable tablet, buccal patch, sublingual tablet, oral suspension, powder for oral suspension, or multiparticulates for oral suspension. In some embodiments, the pharmaceutical composition is in the form of a multi-layer tablet (e.g., a bi-layer or tri-layer tablet). In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is in the form of a suspension, e.g., multiparticulates (e.g., pellets, particles, granules, beads, spheres, or minitablets) in a liquid medium.

[0023] In some embodiments, the pharmaceutical composition comprises a rate controlling agent. In some embodiments, the rate controlling agent is present in a weight ratio of active agent in the second release portion of the composition to rate controlling agent of about 1:1 to about 1:30 (w / w), optionally 1:2 to 1:20 (w / w), 1:3 to 1:15 (w / w), 1:5 to 1:20 (w / w), or 1:5 to 1:15 (w / w). In some embodiments, the rate controlling agent is selected from the group consisting of water-soluble excipients, water-insoluble excipients, water-permeable excipients, and combinations thereof. In some embodiments, the pharmaceutical composition further comprises one or more of a binder, a diluent, a disintegrant, a surfactant, a dye, a lubricant, a glidant, a flavoring agent, a pH adjuster, a solubilizer, a wetting agent, a buffer, or any combination thereof.

[0024] In some embodiments, the first release portion herein comprises a rapid release portion, e.g., an immediate release or sustained release portion. In some embodiments, the second release portion herein comprises a sustained release portion.

[0025] In some embodiments, the pharmaceutical composition is a multi-layer tablet, e.g., a bi-layer tablet comprising a first release portion comprising a rapid-release (e.g., immediate-release) layer and a second release portion comprising a sustained-release layer, or a tri-layer tablet comprising a first release portion comprising a rapid-release (e.g., immediate-release) layer and a second release portion comprising two sustained-release layers. In some embodiments, the pharmaceutical composition is a capsule or suspension comprising a first release portion comprising rapid-release multiparticulates (e.g., immediate-release pellets) and a second release portion comprising sustained-release multiparticulates (e.g., sustained-release pellets).

[0026] In some embodiments, the portion is a layer of a multilayer tablet, such as a bilayer or trilayer tablet. In another embodiment, the pharmaceutical composition is a multilayer tablet for oral administration to a subject, comprising a first release layer (e.g., an immediate-release layer) and a second release layer (e.g., a sustained-release layer). In some embodiments, the multilayer tablet is a bilayer tablet. In some embodiments, the multilayer tablet is a trilayer tablet comprising two sustained-release layers. In some embodiments, the first release layer (e.g., an immediate-release layer) and one or more second release layers (e.g., sustained-release layers) each comprise an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof. In some embodiments, the first release layer comprises the active agent in an amount ranging from about 1.5 mg to 45 mg, and the one or more second release layers comprise the active agent in an amount ranging from about 3.5 mg to about 105 mg. In some embodiments, the first release layer is formulated to release about 20% to about 40% (e.g., about 30%) w / w of the total amount of active agent in the tablet within about 1 hour in an in vitro dissolution test; and the one or more second release layers are formulated to release about 60% to about 80% (e.g., about 70%) w / w of the total amount of active agent in the tablet over an extended duration from about 1 hour to at least about 8 hours, about 10 hours, about 12 hours, about 14 hours, or about 16 hours. In some embodiments, the active agent in the one or more second release layers is released starting about 1 hour after administration of the multilayer tablet to a subject, and at least about 95% of the active agent in the one or more second release layers is released up to about 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, or 8 hours after administration of the multilayer tablet to a subject.

[0027] In some embodiments, one or more second release (e.g., sustained release) layers of a multi-layer tablet or second release (e.g., sustained release) multiparticulates of a capsule or suspension further comprise a rate controlling agent. In some embodiments, the rate controlling agent is selected from the group consisting of water soluble, water insoluble, water permeable, or water impermeable excipients, and mixtures thereof. In some embodiments, the one or more sustained release layers are selected from the group consisting of: a water soluble excipient, a water insoluble excipient, a water permeable excipient, or a water impermeable excipient, and mixtures thereof. In some embodiments, the one or more sustained release layers are selected from the group consisting of: a water soluble excipient, a water insoluble excipient, a water permeable excipient, and mixtures thereof. In some embodiments, the ratio of the amount of active agent in the second release layer to the amount of rate controlling agent in the second release layer is at least 1:1 to 1:30 (e.g., 1:2 to 1:20 (w / w) ), 1:5 to 1:20 (w / w), or 1:5 to 1:15 (w / w)). The multilayer tablet, capsule, or suspension may also include one or more fillers, dyes, lubricants, glidants, binders, diluents, disintegrants, surfactants, flavoring agents, pH adjusters, solubilizing agents, wetting agents, buffers, or combinations thereof.

[0028] In some embodiments, the pharmaceutical composition comprises a first release portion and a second release portion. In some embodiments, the first release portion comprises about 4 mg of midodrine hydrochloride, and the second release portion comprises about 16 mg of midodrine hydrochloride. In some embodiments, the second release portion further comprises a rate controlling agent comprising a hydrophilic polymer and a non-polymeric agent. In some embodiments, the rate controlling agent comprises a methacrylic acid copolymer and a fatty acid ester. In some embodiments, the rate controlling agent comprises a methacrylic acid and ethyl acrylate copolymer (1:1) and glyceryl behenate.

[0029] A further aspect of the present disclosure is directed to a method for treating or reducing the incidence of orthostatic hypotension or postural orthostatic tachycardia syndrome (POTS) in a subject, comprising administering a pharmaceutical composition of the present disclosure, e.g., a multi-layer tablet, capsule, or suspension. In some embodiments, the pharmaceutical composition is administered once daily or twice daily.

[0030] In some embodiments, the single total daily dose of the pharmaceutical composition administered to a subject is greater (e.g., 10-40%, 10-35%, 10-30%, 15-40%, 15-35%, 15-30%, or about 25% greater) than the total daily dose of an immediate-release tablet (e.g., a 5 mg tablet) administered three times daily. For example, a 20 mg dose of the pharmaceutical composition disclosed herein can be administered once daily (total daily dose of 20 mg) instead of one 5 mg immediate-release tablet administered three times daily (total daily dose of 15 mg). In some embodiments, a 10 mg dose of the pharmaceutical composition disclosed herein can be administered once daily (total daily dose of 10 mg) instead of one 2.5 mg immediate-release tablet administered three times daily (total daily dose of 7.5 mg). In some embodiments, a 40 mg dose of a pharmaceutical composition disclosed herein can be administered once daily (40 mg total daily dose) instead of one 10 mg immediate-release tablet administered three times daily (30 mg total daily dose). In some embodiments, the 10 mg, 20 mg, or 40 mg dose is a multi-layer tablet (e.g., a bi-layer or tri-layer tablet) comprising a rapid-release portion and an extended-release portion.

[0031] In some embodiments, the subject suffers from orthostatic hypotension, autonomic neuropathy, postural orthostatic tachycardia syndrome (POTS), retrograde ejaculation or other disorders of ejaculation, Bradbury-Eggleston syndrome, Shy-Drager syndrome, diabetes, or Parkinson's disease. In some embodiments, the subject suffers from orthostatic hypotension due to autonomic failure.

[0032] In another embodiment, a kit is provided. In some embodiments, the kit includes the multiparticulates disclosed herein (e.g., pellets, particles, granules, beads, spheres, or minitablets) and a liquid medium, wherein the multiparticulates can be combined with the liquid medium to form a suspension. In some embodiments, the kit comprises a first formulation and a second formulation, wherein the first formulation and the second formulation are the same or different, and the first formulation is a composition comprising a first release portion and a second release portion, wherein both the first release portion and the second release portion comprise an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof; the active agent is present in the first release portion in a range of about 1.5 mg to 45 mg, and the active agent is present in the second release portion in a range of about 3.5 mg to about 105 mg; and the first release portion dissolves in about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 25% to about 40%, or about 50% of the total amount of active agent in the tablet within about 1 hour after the start of an in vitro dissolution test. %, about 25% to about 35%, about 30% to about 40%, or about 30% to 35% w / w; and the second release portion is formulated to release the remainder (e.g., about 60-80%, e.g., about 70%) of the total amount of active agent in the tablet over a period of about 1 hour to about 16 hours after the start of the in vitro dissolution test.

[0033]

[0033] In some embodiments, the second formulation of the kit may be an immediate release formulation containing an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof; wherein the active agent is present in the range of 2.5 mg to 20 mg and is formulated to release substantially all of the active agent within about 1 hour of administration of the second formulation to a subject. [Brief explanation of the drawings]

[0034] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0034] Figure 1 is a graph comparing the in vitro dissolution profiles (expressed as the percentage of active agent released over 12 hours) of 15 mg, 30 mg, and 45 mg midodrine HCl rapid release / sustained release bilayer tablet formulations. [Figure 2]

[0035] 1 is a graph illustrating the in vitro dissolution profile (shown as the amount of active agent (mg) released over 12 hours) for a rapid-release / sustained-release bilayer tablet formulation containing 30 mg of midodrine HCl. [Figure 3]

[0036] 1 shows the simulated 20-hour plasma concentration (ng / mL) profile of desglimidodrine (the active metabolite of midodrine HCl) following administration of a 5 mg immediate-release tablet (i.e., TID regimen) at 0, 4, and 8 hours. [Figure 4]

[0037] 1 shows the simulated 24-hour plasma concentration (ng / mL) profiles of desglimidodrine (the active metabolite of midodrine HCl) in 15 mg and 20 mg fast-release / extended-release formulations of the present disclosure compared to the simulated plasma profile of a 5 mg TID immediate-release tablet. [Figure 5]

[0038] 1 shows simulated dissolution profiles (showing percent drug released over time) for a 20 mg formulation of the present disclosure. [Figure 6]

[0039] 1 shows the simulated 20-hour plasma concentration (ng / mL) profile of desglymidodrine in a 20 mg once-daily formulation of the present disclosure compared to a 5 mg TID immediate-release tablet. [Figure 7]

[0040] 1 shows the simulated drug release profile over time (shown as % / hour) for a tri-layer tablet formulation containing 20 mg midodrine HCl. [Figure 8]

[0041] 1 is a graph illustrating the drug release rate over time (shown as % / hour) for a rapid release / sustained release tri-layer tablet formulation containing 20 mg midodrine HCl. [Figure 9]

[0042] 1 shows the dissolution profile of a 20 mg formulation of midodrine HCl of Example 17. DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description

[0043] Certain embodiments of the present disclosure are directed to pharmaceutical compositions comprising an active agent, e.g., midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, or any combination thereof (e.g., midodrine HCl or desglymidodrine), that initially release a portion of the active agent to a subject relatively rapidly, e.g., within at least the first hour after administration, and release a second (or remaining) portion of the active agent to a subject over an extended period of time, e.g., up to about 8, 10, 12, 14, or 16 hours after administration. The disclosed unique rapid-release / extended-release (FR+ER) formulations (i) provide plasma levels of desglymidodrine of at least 12 ng / mL (e.g., at least 14 ng / mL) within 1 hour, and (ii) provide plasma levels of desglymidodrine of at least 3 ng / mL, at least 7 ng / mL, at least 10 ng / mL, at least 12 ng / mL, or more. or at least 14 ng / mL of desglymidodrine can be maintained for a period of time, for example, from about 4 to about 12 hours (e.g., at least 8 hours) after administration of a single dose, and the blood pressure of a subject in need thereof (e.g., a patient with orthostatic hypotension) can be maintained within a desired level (e.g., greater than 90 mmHg systolic and greater than 60 mmHg diastolic, e.g., about 120 / 80 mmHg) throughout the day (e.g., at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, or at least 16 hours).

[0036]

[0044] In some embodiments, the present disclosure provides improved formulations of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, or any combination thereof (e.g., midodrine HCl or desglymidodrine) that deliver a higher dose initially, followed by a sustained release that maintains blood pressure within a desired range throughout the day.

[0037]

[0045] Upon oral administration of 10 mg immediate-release tablets, midodrine plasma levels peak after approximately 30 minutes and then decline, with a half-life of approximately 25 minutes, while the active metabolite, desglymidodrine, reaches its first peak blood concentration (e.g., approximately 10 ng / mL) approximately 1-2 hours after the initial administration of midodrine and has a half-life of approximately 3-4 hours. The short half-lives of midodrine and desglymidodrine associated with immediate-release tablets necessitate frequent dosing to maintain minimum effective blood concentrations of desglymidodrine (e.g., at least 3 ng / mL or 7 ng / mL) throughout the day.

[0038]

[0046] Patients suffering from orthostatic hypotension report more discomfort in the morning than in the afternoon and evening, even after taking the first dose of currently available 2.5 mg, 5 mg, and 10 mg immediate-release tablets (TID). For example, simulated plasma profiles of desglymidodrine (the active metabolite of midodrine HCl) in 5 mg immediate-release tablets administered three times daily at 4-hour intervals indicate that the first dose does not produce as high desglymidodrine levels as the third dose (see Figure 3). This modeling assay suggests that desglymidodrine levels increase with each dose, reaching a maximum concentration after the third dose. However, this simulated data suggests that, for example, in patients following a 5 mg immediate-release TID regimen after the first IR dose, plasma concentrations of at least about 12 ng / mL or about 14 ng / mL of desglymidodrine are not achieved. In some embodiments, the first-release / second-release formulations disclosed herein provide a plasma concentration of desglymidodrine of at least about 12 ng / mL or at least about 14 ng / mL within 1 hour of administration. In some embodiments, the first-release / second-release formulations disclosed herein maintain a plasma concentration of desglymidodrine of at least about 7 ng / mL or at least about 10 ng / mL for at least 8 hours, at least 10 hours, or at least 12 hours after administration. Thus, the first-release / second-release formulations disclosed herein offer improved properties over currently available IR (TID) formulations.

[0039]

[0047] In addition to frequent dosing (e.g., three times daily) as a result of short half-lives, another challenge with immediate-release formulations is that administration of multiple doses does not sufficiently maintain a patient's blood pressure over an extended period of time to manage patient symptoms, such as dizziness and / or lightheadedness, throughout the day. For example, multiple doses of immediate-release midodrine can cause repeated increases and decreases in a patient's blood pressure as the active agent is released and subsequently removed with each administration. In some embodiments, the first-release / second-release formulations disclosed herein alleviate patient symptoms, such as dizziness and / or lightheadedness, throughout the day.

[0040]

[0048] In addition, multiple dosing of immediate-release tablets (e.g., three times daily) may increase patient compliance. The lack of or delay in administration of an immediate release dose can result in a worsening and sometimes unmanageable patient condition. The present application provides a formulation of the drug that can be administered less frequently than immediate release tablets, for example, once daily, thereby improving patient compliance.

[0041] definition

[0049] As used herein, the following words and phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0042]

[0050] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0043]

[0051] As used herein, the term "about" means approximately ±10%. When the term "about" is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical value set forth. Generally, the term "about" is used herein to modify a numerical value by around 10 percent (higher or lower) from the stated value, i.e., ±10%, unless a different variation (e.g., ±30%, ±20%, ±5%, ±1%, etc.) is indicated.

[0044]

[0052] As used herein, "and / or" encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0045]

[0053] The term "active agent" refers to a substance useful for preventive and / or therapeutic treatment, such as a biologically active substance. Typically, an active agent is an organic molecule that is a drug compound, its salt, metabolite, or the like. In this disclosure, the term "active agent" can refer to midodrine, a pharmaceutically acceptable salt of midodrine, its active metabolite desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, or a combination thereof. For example, the active agent can be midodrine hydrochloride.

[0046]

[0054] The term "midodrine" refers to a compound having the following chemical structure: [ka]

[0047]

[0055] For purposes of this disclosure, unless otherwise indicated, when referring to a formulation or pharmaceutical composition containing "midodrine," it is understood that the embodiment may include midodrine or a pharmaceutically acceptable salt of midodrine, such as midodrine hydrochloride (midodrine HCl).

[0048]

[0056] The term "desglimidodrine" refers to the active metabolite of midodrine, which has the following chemical structure: [ka]

[0049]

[0057] For purposes of this disclosure, unless otherwise specified, when referring to a formulation or pharmaceutical composition comprising "desglimidodrine," it should be understood that the embodiment may include desglimidodrine or a pharmaceutically acceptable salt of desglimidodrine.

[0050]

[0058] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include, for example, salts with inorganic acids and organic acids. A compound described herein as an acid addition salt may be converted to the corresponding free base by basifying a solution of the acid salt. Conversely, addition salts, particularly pharmaceutically acceptable addition salts, may be produced by dissolving the corresponding free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. In one embodiment, the pharmaceutically acceptable salt of midodrine or desglymidodrine is the hydrochloride salt.

[0051]

[0059] The term "portion" as used herein refers to a portion, percentage, or share of a whole or total amount (e.g., a whole tablet or total amount of active agent).

[0052]

[0060] The term "substantially all," as used herein, refers to a majority of the total amount, for example, at least 80%, at least 85%, at least 90%, at least 95% of the total amount.

[0053]

[0061] The term "subject," as used herein, refers to a human, e.g., a human patient.

[0054]

[0062] The term "first release portion" or "rapid release portion," as used herein, refers to a portion of a pharmaceutical composition disclosed herein that releases the active agent contained therein relatively rapidly, for example, within about one hour, after the start of an in vitro dissolution test. In some embodiments, the first release portion comprises an immediate release delivery system.

[0055]

[0063] In some embodiments, the in vitro dissolution conditions for the rapid-release / sustained-release compositions disclosed herein are designed to mimic in vivo release conditions. In a preferred embodiment, the in vitro dissolution test conditions are: 0-2 hours, 0.1 N HCl (pH 1.2); 2-4 hours, acetate buffer (pH 4.5); 4-16 hours, phosphate buffer (pH 6.8), in 900 mL, at 37°C and 100 rpm, USP Apparatus I (basket).

[0056]

[0064] The term "immediate release," as used herein, refers to a delivery system in which at least a portion of an active agent is released from a pharmaceutical composition or formulation without delay. In some embodiments, the immediate release of the active agent is within about 30 minutes to about 1 hour after the start of an in vitro dissolution test. In some embodiments, the immediate release of the active agent is within about 1 hour after administration to a subject.

[0057]

[0065] The term "second release portion" or "sustained release portion," as used herein, refers to a portion of a pharmaceutical composition disclosed herein that releases an active agent contained therein over a period of time. In some embodiments, the second release portion comprises a sustained release delivery system.

[0058]

[0066] As used herein, the term "sustained release" refers to a delivery system by which an active agent is released over a specified period of time (i.e., a sustained-release period). In some embodiments, the pharmaceutical composition can extend the release of at least a portion of the active agent by up to about 8 hours, up to about 10 hours, up to about 12 hours, up to about 14 hours, up to about 16 hours, from about 1 hour to about 16 hours, from about 1 hour to about 14 hours, from about 1 hour to about 12 hours, from about 1 hour to about 10 hours, or from about 1 hour to about 8 hours from the start of an in vitro dissolution test. In some embodiments, the sustained release of the active agent extends over a period of up to about 8 hours, up to about 10 hours, up to about 12 hours, up to about 14 hours, up to about 16 hours, from about 1 hour to about 16 hours, from about 1 hour to about 14 hours, from about 1 hour to about 12 hours, from about 1 hour to about 10 hours, or from about 1 hour to about 8 hours after administration to a subject.

[0059]

[0067] The term "rate controlling agent" refers to an agent whose primary function is to modify the duration of release of an active drug substance from a dosage form.

[0060]

[0068] As used herein, "percent" or "%" refers to weight (w / w) percent unless otherwise specified.

[0061]

[0069] As used herein, the term "percent drug release" refers to the proportion (percentage) (w / w%) of an active agent released from a pharmaceutical composition at a specific time compared to the total amount of the active agent in the pharmaceutical composition. For example, if a pharmaceutical composition releases 20 wt% of the total active substance in 1 hour, 28 wt% in 2 hours, and 35 wt% in 3 hours in a dissolution test, the drug release percentage of this pharmaceutical composition is 20 (w / w)% in 1 hour, 28 (w / w)% in 2 hours, and 35 (w / w)% in 3 hours.

[0062]

[0070] The term "release rate" refers to the amount of active agent released from a pharmaceutical composition over a period of time. For example, the release rate can be reported as the amount of active agent released per hour (e.g., mg / hour) or the percentage of active agent released per hour (e.g., % / hour). The release rate can be measured by an in vitro test, such as an in vitro dissolution test, or an in vivo test. As described herein, the drug release rate can be measured by the approximate incremental increase in the percent drug released at a particular time point compared to the previous time point in an in vitro dissolution test. For example, if the percent drug release of a pharmaceutical composition is 20% (w / w) at 1 hour, 28% (w / w) at 2 hours, and 35% (w / w) at 3 hours, the drug release rate can be described as 20% / hour at 1 hour, 8% / hour at 2 hours, and 7% / hour at 3 hours.

[0063]

[0071] The term "release profile" refers to an in vitro dissolution curve that represents the amount or percentage of active agent measured at specific time points. Alternatively, the term "release profile" can also refer to an in vivo plasma curve that represents the active agent plasma concentration measured at specific time points.

[0064]

[0072] The term "increase" as used herein refers to an increase in in vitro dissolution and release properties. "Increase" refers to an increase in the rate of release of an active agent from a composition relative to a peak (or shoulder or plateau) in the in vivo release profile, and / or the term "increase" may also refer to an increase in the active agent plasma concentration relative to a peak (or shoulder or plateau) in the in vivo release profile. As discussed above, the rate of release of an active agent in an in vitro dissolution test can generally be described by a gradual increase in the percent active agent released at a particular time point in the dissolution test compared to the preceding time point.

[0065]

[0073] The term "secondary increase," as used herein, refers to an increase in the rate of active agent release from a composition after an initial release or first increase. In some embodiments, the disclosed formulations do not have a secondary increase after 5 hours (e.g., between about 5 and 10 hours) from the start of an in vitro dissolution test.

[0066]

[0074] The term "third increase," as used herein, refers to an increase in the rate of active agent release from a composition after the initial release (or first increase) and after the second increase.

[0067]

[0075] The term "treatment" or "treating" means any treatment of a disease in a mammal, including: (i) preventing or reducing the incidence of disease by preventing the development of clinical symptoms of the disease; (ii) inhibiting the disease by preventing the onset of clinical symptoms of the disease; and / or (iii) Relieving the disease by reversing the clinical symptoms of the disease.

[0068]

[0076] An "effective amount" is the amount of a compound or formulation that, when administered to a subject suffering from or at risk of suffering from the condition being treated, will achieve a beneficial clinical outcome. A "beneficial clinical outcome" may include one or more of a reduction in the number or severity of symptoms in a subject, such as elimination of elevated blood pressure, dizziness, and / or mild headaches.

[0069]

[0077] As used herein, "multi-particulates" (used interchangeably with "a multi-particulate") refer to small discrete drug units exhibiting desired characteristics that form a multi-unit drug delivery system. Multiparticulates can be in the form of, for example, drug particles, granules, pellets, beads, spheres, or minitablets.

[0070]

[0078] For any embodiment described herein using the language "comprising," analogous embodiments are also provided that are described using the terms "consisting of" and / or "consisting essentially of." To the extent the terms "include" or "including" are used in this specification or in the claims, they are intended to be inclusive in a manner similar to the term "comprising," as that term is interpreted when used as a transitional term in the claims.

[0071]

[0079] As used herein, the terms "optional" and "optionally" mean that the subsequently described circumstance may or may not occur, and thus the description includes cases where the circumstance occurs and cases where it does not occur.

[0072]

[0080] Furthermore, to the extent the term "or" is used (e.g., A or B), this term is intended to mean "A or B or both." If applicant intends to indicate "A or B only, but not both," then "A or B only, but not both" is also acceptable. The term "or" is used in this specification, but not in its entirety. Therefore, the use of the word "or" herein is inclusive and not exclusive. See Bryan A. Gamer, "A Dictionary of Modern Legal Usage 624" (2nd ed., 1995). Also, to the extent the terms "in" or "into" are used in this specification or claims, they are intended to further mean "on" or "onto."

[0073]

[0081] Furthermore, when features or aspects of the present disclosure are described in terms of a Markush group, those skilled in the art will understand that the disclosure also describes any individual member or subgroup of members of the Markush group. As will be understood by those skilled in the art, all ranges disclosed herein, for any and all purposes, including providing a written description, also encompass any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as fully describing and enabling ranges that subdivide the same range into at least one-half, one-third, one-quarter, one-fifth, one-tenth, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, upper third, etc. As will be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc., are inclusive of the recited numbers and refer to ranges that can then be subdivided into the subranges described above. Finally, as will be understood by those skilled in the art, a range includes each individual member. For example, a group having 1 to 3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 1 to 5 members refers to groups having 1, 2, 3, 4, or 5 members, etc. While various aspects and embodiments are disclosed herein, other aspects and embodiments will be apparent to those skilled in the art.

[0074] Pharmaceutical Composition

[0082] In some embodiments, the pharmaceutical compositions disclosed herein may contain one or more active agents. The active agent may be selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof. In one embodiment, the active agent is midodrine or a pharmaceutically acceptable salt thereof, such as midodrine hydrochloride (HCl). In another embodiment, the active agent is desglymidodrine or a pharmaceutically acceptable salt thereof.

[0075]

[0083] In some embodiments, the pharmaceutical compositions disclosed herein can be, but are not limited to, tablets, capsules, orally disintegrating tablets, chewable tablets, buccal patches, sublingual tablets, oral suspensions, or powders, granules, or multiparticulates for oral suspension.

[0076]

[0084] In some embodiments, pharmaceutical compositions contemplated herein with unique release characteristics include, but are not limited to, 1. A bilayer tablet containing a rapid-release layer and a sustained-release layer; 2. A triple-layer tablet containing a rapid-release layer and two sustained-release layers; 3. Rapid release coating on sustained release core tablets; 4. A tablet-in-tablet dosage form containing an extended-release tablet within a rapid-release tablet; 5. Compression-coated tablets with a sustained-release core and a rapid-release coating; 6. A rapid release core coated with a sustained release coating and then a further rapid release coating; 7. Capsules filled with or tablets compressed from multiparticulates (e.g., pellets, particles, granules, beads, spheres, or minitablets) having a sustained-release core and a rapid-release coating; 8. Rapid release and sustained release drugs that may be filled inside capsules or compressed into tablets Sustained-release multiparticulate mixture; 9. A mixture of rapid-release and sustained-release multiparticulates that may be suspended in a suitable delivery vehicle known in the art or filled into a sachet for reconstitution; and 10. Sustained-release osmotically controlled tablets with a layer coating of rapid-release agents may include:

[0077]

[0085] In some embodiments, the rapid-release and sustained-release portions each comprise midodrine hydrochloride. In some embodiments, the rapid-release portion of the pharmaceutical composition comprises about 20% to about 45%, about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 30% to about 50%, or about 30% to about 35% (e.g., 20-45%, 20-40%, 25-40%, 30-50%, 30-40%, or 30-35%) (w / w) of the midodrine hydrochloride in the composition. The pharmaceutical compositions disclosed herein can be formulated for oral administration, for example, in the form of a tablet, suspension, or multiparticulate-filled capsule.

[0078]

[0086] In some embodiments, the pharmaceutical compositions disclosed herein may comprise multiple distinct portions, which may comprise the same or different excipients. In one embodiment, the pharmaceutical composition may comprise a rapid-release portion and a sustained-release portion (e.g., where the rapid-release and sustained-release portions each comprise midodrine hydrochloride). In some embodiments, the pharmaceutical compositions disclosed herein may be multi-layer compositions, e.g., multi-layer tablets comprising two or more drug-containing layers. In certain embodiments, the pharmaceutical composition is a bi-layer or tri-layer tablet. In certain embodiments, the pharmaceutical composition is a capsule filled with rapid-release and sustained-release multiparticulates.

[0079]

[0087] In some embodiments, the pharmaceutical compositions disclosed herein contain an active agent in an amount of about 5 mg to about 150 mg, about 7.5 mg to about 150 mg, about 7.5 mg to about 120 mg, about 5 mg to about 100 mg, about 7.5 mg to about 100 mg, about 7.5 mg to about 75 mg, about 7.5 mg to about 50 mg, about 10 mg to about 100 mg, about 15 mg to about 100 mg, about 20 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 15 mg to about 75 mg, about 15 mg to about 50 mg, about 20 mg to about 75 mg, about 20 mg to about 50 mg, about 10 mg to about 20 mg, about 25 mg to about 35 mg, or about 40 mg to about 50 mg. In one embodiment, the pharmaceutical composition can contain about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, or about 150 mg of the active agent. In some embodiments, the active agent is midodrine hydrochloride. In some embodiments, the pharmaceutical compositions disclosed herein contain a total amount of about 20 mg of midodrine hydrochloride per dosage unit (e.g., a single tablet, capsule, or suspension). In some embodiments, the pharmaceutical compositions disclosed herein contain a total of about 10 mg of midodrine hydrochloride per dosage unit (e.g., a single tablet, capsule, or suspension). In some embodiments, the pharmaceutical compositions disclosed herein contain a total of about 40 mg of midodrine hydrochloride per dosage unit (e.g., a single tablet, capsule, or suspension).

[0080]

[0088] In some embodiments, the pharmaceutical compositions disclosed herein comprise a rapid-release portion and a sustained-release portion, in which the rapid-release portion comprises about 15% to about 50%, about 20% to about 45%, about 20% to about 40%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 30% to about 45%, about 30% to about 40%, or about 30% to about 35% (w / w) of the active agent of the total amount of active agent in the composition. In another embodiment, the rapid release portion comprises about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 40%, about 45%, or about 60% of the total amount of active agent in the composition. The active agent may be present in an amount of about 50% (w / w). In some embodiments, the active agent is midodrine hydrochloride.

[0081]

[0089] In another embodiment, the rapid release portion can contain the active agent in an amount ranging from about 0.75 mg to about 75 mg, from about 1 mg to about 60 mg, from about 2 mg to about 50 mg, from about 2.25 mg to about 36 mg, from about 3 mg to about 12 mg, from about 4 mg to about 20 mg, from about 4.5 mg to about 18 mg, from about 6 mg to about 24 mg, from about 3 mg to about 6 mg, from about 7.5 mg to about 10.5 mg, or from about 12 mg to about 15 mg. In other embodiments, the rapid release portion is about 1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, The active agent can include about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 24 mg, about 27 mg, about 30 mg, about 36 mg, about 40 mg, about 45 mg, about 48 mg, about 54 mg, or about 67.5 mg. In some embodiments, the active agent is midodrine hydrochloride.

[0082]

[0090] In some embodiments, the sustained-release portion comprises an active agent in an amount (w / w) of about 50% to about 85%, about 55% to about 80%, about 55% to about 75%, about 60% to about 80%, about 60% to about 75%, about 55% to about 70%, about 65% to about 70%, or about 60% to about 70% of the total amount of active agent in the composition. In other embodiments, the sustained-release portion comprises an active agent in an amount (w / w) of about 50%, about 55%, about 65%, about 65%, about 70%, about 75%, about 80%, or about 85% of the total amount of active agent in the composition. In some embodiments, the active agent is midodrine hydrochloride.

[0083]

[0091] In another embodiment, the sustained release portion comprises the active agent in an amount ranging from about 2.5 mg to about 127.5 mg, about 3 mg to about 110 mg, about 3.75 to about 102 mg, about 3.75 to about 102 mg, about 5.25 mg to about 84 mg, about 12 mg to about 96 mg, about 10.5 mg to about 84 mg, about 9 to about 72 mg, about 7 mg to about 14 mg, about 17.5 mg to about 24.5 mg, or about 28 mg to about 35 mg. In another embodiment, the sustained release portion provides the active agent in an amount of about 2.5, about 5 mg, about 6 mg, about 7 mg, about 7.5, about 8 mg, about 8.5 mg, about 9 mg, about 9.625 mg, about 10 mg, about 10.5 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about In some embodiments, the active agent is midodrine hydrochloride.

[0084]

[0092] In some embodiments, the rapid-release portion contains about 3 mg to about 9 mg of midodrine hydrochloride, and the sustained-release portion contains about 9 mg to about 21 mg of midodrine hydrochloride. In some embodiments, the rapid-release portion and the sustained-release portion contain about 5 mg and about 15 mg of midodrine hydrochloride, respectively. In some embodiments, the rapid-release portion and the sustained-release portion contain about 6 mg and about 9 mg of midodrine hydrochloride, respectively. In some embodiments, the rapid-release portion and the sustained-release portion contain about 4 mg and about 16 mg of midodrine hydrochloride, respectively.

[0085]

[0093] The sustained-release portion of the pharmaceutical composition disclosed herein may comprise an effective amount of one or more rate-controlling agents. The rate-controlling agent may be, for example, a water-soluble, water-insoluble, water-permeable, water-impermeable excipient, or a mixture thereof. The rate-controlling agent may be a polymeric or non-polymeric agent. The rate-controlling agent may be a hydrophilic or hydrophobic polymer. In some embodiments, the rate-controlling agent is incorporated into the pharmaceutical composition. In one embodiment, the rate-controlling agent is incorporated into the sustained-release portion. In another embodiment, the sustained-release portion of the pharmaceutical composition is coated with the rate-controlling agent.

[0086]

[0094] In some embodiments, the rate-controlling agent is a hydrophilic polymer selected from hypromellose; hydroxypropyl cellulose (HPC); hydroxyethyl cellulose (HEC); polyethylene oxide; polyvinyl alcohol; povidone; xanthan gum; guar gum; chitosan; chitosan derivatives; carbomer; carrageenan; carboxymethyl cellulose; sodium alginate; polyglycolized glycerides; polyethylene glycol; polyvinyl acetate dispersions; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose triacetate; methacrylic acid copolymers; hypromellose acetate succinate; and combinations thereof. In one embodiment, the rate-controlling agent is hypromellose. In another embodiment, the rate-controlling agent is hypromellose (e.g., USP hypromellose 2208) or METHOCEL™ K4M (COLORCON®). In some embodiments, the rate controlling agent is a methacrylic acid copolymer, such as a 1:1 copolymer of methacrylic acid and ethyl acrylate (e.g., Eudragit L100-55®). In some embodiments, the rate controlling agent is hypromellose acetate succinate (e.g., AquaSolve® LG).

[0087]

[0095] In other embodiments, the rate controlling agent is a hydrophobic polymer selected from poly(methyl methacrylate); poly(ethyl methacrylate); poly(methyl acrylate); poly(isopropyl acrylate); poly(isobutyl acrylate); poly(octadecyl acrylate); ethyl cellulose; cellulose propionate; cellulose acetate propionate; and combinations thereof.

[0088]

[0096] In some embodiments, the rate controlling agent is a non-polymeric agent selected from waxes, fatty alcohols, fatty acid esters, hydrogenated vegetable oils, and combinations thereof. In some embodiments, the rate controlling agent is glyceryl behenate.

[0089]

[0097] In some embodiments, the sustained release portion may contain a rate controlling agent in a weight ratio of active agent to rate controlling agent in the sustained release portion of about 1:1 to about 1:30 (w / w), about 1:1 to about 1:20 (w / w), about 1:2 to about 1:15 (w / w), about 1:3 to about 1:15 (w / w), about 1:5 to about 1:15 (w / w), or about 1:5 to about 1:10 (w / w). In another embodiment, the sustained release portion comprises a rate controlling agent in a weight ratio of active agent to rate controlling agent in the sustained release portion of about 1:5 (w / w), about 1:7 (w / w), about 1:10 (w / w), about 1:12 (w / w), about 1:15 (w / w), about 1:20 (w / w), about 1:25 (w / w), or about 1:30 (w / w).

[0090]

[0098] In some embodiments, the sustained release portion may comprise a combination of two or more rate controlling agents. In some embodiments, the sustained release portion may comprise a combination of two rate controlling agents. In some embodiments, the sustained release portion may comprise methacrylic acid copolymer and glyceryl behenate as rate controlling agents. In some embodiments, the sustained release portion may comprise methacrylic acid and ethyl acrylate copolymer (1:1) and glyceryl behenate as rate controlling agents.

[0091]

[0099] The pharmaceutical compositions disclosed herein may contain one or more fillers, binders, diluents, disintegrants, The composition may include a surfactant, a dye, a lubricant, a glidant, a flavoring agent, a pH adjuster, a solubilizing agent, a wetting agent, a buffer, or any combination thereof.

[0092]

[0100] Examples of binders include, but are not limited to, gum acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (Type I), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, microcrystalline cellulose, polymethacrylate, povidone, pregelatinized starch, sodium alginate, starch, zein, etc., or mixtures thereof. In one embodiment, the binder is hydroxypropylmethylcellulose, microcrystalline cellulose, or povidone.

[0093]

[0101] Examples of diluents include, but are not limited to, microcrystalline cellulose, lactose, starch, sucrose, anhydrous and dibasic calcium phosphate, mannitol, sorbitol, xylitol, maltitol, ammonium alginate, calcium carbonate, calcium lactate, calcium silicate, calcium sulfate, cellulose powder, silicified microcrystalline cellulose, compressible sugar, confectioner's sugar, corn starch, pregelatinized starch, Dextrates, dextrin, glucose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, isomalt, lactitol monohydrate, magnesium carbonate, magnesium oxide, maltose, medium chain triglycerides, polydextrose, polymethacrylate, simethicone, sodium alginate, sodium chloride, sterilized corn and combinations thereof.

[0094]

[0102] Examples of disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, calcium alginate, powdered cellulose, glycine, sodium starch glycolate, starch, hydroxypropyl cellulose, and the like, or mixtures thereof.

[0095]

[0103] Examples of lubricants include, but are not limited to, starch, talc, silicon dioxide, such as colloidal silicon dioxide, or mixtures thereof.

[0096]

[0104] Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, medium chain triglycerides, myristic acid, palmitic acid, poloxamer, sodium benzoate, sodium stearyl fumarate, zinc stearate, and the like, or mixtures thereof.

[0097]

[0105] In some embodiments, the pharmaceutical compositions disclosed herein can be further coated with a film coating so that the film coating does not modify the release characteristics of the composition. Suitable materials that can be used to film coat the composition include, but are not limited to, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, ready-made premixes such as Opadry® (hypromellose, PEG) (Colorcon), Opadry® II (polyvinyl alcohol, PEG, talc, and titanium dioxide), and mixtures thereof.

[0098]

[0106] The pharmaceutical compositions disclosed herein can be prepared by any number of manufacturing processes known in the art, including, but not limited to, dry granulation, wet granulation, roller compaction, extrusion / spheronization, rotary pelletization, hot melt extrusion, fluidized bed granulation, fluidized bed coating, compression coating, powder coating, and the like.

[0099]

[0107] In some embodiments, the pharmaceutical compositions disclosed herein comprise (1) a rapid-release layer comprising about 4 mg of midodrine HCl, microcrystalline cellulose, croscarmellose sodium or sodium starch glycolate, yellow or red iron oxide, talc, and magnesium stearate, and (2) a sustained-release layer comprising about 16 mg of midodrine HCl, methacrylic acid and ethyl acrylate copolymer (1:1) or hypromellose acetate succinate, glyceryl behenate, povidone, and magnesium stearate. In some embodiments, the rapid-release layer comprises about 4 mg of midodrine HCl, about 135 mg of microcrystalline cellulose, about 9 mg of croscarmellose sodium, about 0.75 mg of red iron oxide, about 0.75 mg of talc, and about 0.75 mg of magnesium stearate. In some embodiments, the sustained-release layer comprises about 16 mg of midodrine HCl; about 100-340 mg of 1:1 methacrylic acid and ethyl acrylate copolymer or hypromellose acetate succinate; about 10-40 mg of glyceryl behenate; about 10-40 mg of povidone; and about 0.6-1.8 mg of magnesium stearate. In some embodiments, the sustained-release layer comprises about 16 mg of midodrine HCl; about 262 mg of 1:1 methacrylic acid and ethyl acrylate copolymer; about 20 mg of glyceryl behenate; about 20 mg of povidone; and about 1.5 mg of magnesium stearate.

[0100]

[0108] In some embodiments, the pharmaceutical compositions disclosed herein provide for in vivo release of an active agent (e.g., midodrine hydrochloride) over a period of up to about 16 hours, up to about 15 hours, up to about 14 hours, up to about 13 hours, up to about 12 hours, up to about 11 hours, up to about 10 hours, up to about 9 hours, or up to about 8 hours after administration to a subject, and can be characterized by a release profile in an in vitro dissolution test that includes (i) a first phase, which is a rapid release of the active agent, and (ii) a second phase, which is a sustained release of the active agent. In some embodiments, the release in the second phase is steady or slower than the first (rapid) release. In some embodiments, the second phase includes a second increase in release rate about 2 to about 4.5 hours after the start of the in vitro dissolution test. In some embodiments, the second phase does not include a second increase after 5 hours from the start of the in vitro dissolution test (e.g., a second increase does not occur between 5 and 10 hours). In some embodiments, the second stage comprises in vitro b) a third increase in release rate at least about 6 hours after the start of the dissolution test.

[0101]

[0109] In some embodiments, the first phase is characterized by release of substantially all, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or all of the active agent (e.g., midodrine hydrochloride) in the rapid-release portion at about 2 hours, about 90 minutes, about 1 hour, about 55 minutes, about 50 minutes, about 45 minutes, about 40 minutes, about 35 minutes, about 30 minutes, about 25 minutes, about 20 minutes, or about 15 minutes after the start of the in vitro dissolution test.

[0102]

[0110] In some embodiments, the first phase releases about 15% to about 55%, about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 25% to about 40%, about 30% to about 50%, or about 30% to about 40% (e.g., 15-55%, 20-55%, 20-50%, 20-45%, 20-40%, 25-40%, 30-50%, or 30-40%) of the total amount of active agent (e.g., midodrine hydrochloride) in the composition at about 2 hours, about 90 minutes, about 1 hour, about 55 minutes, about 50 minutes, about 45 minutes, about 40 minutes, about 35 minutes, about 30 minutes, about 25 minutes, about 20 minutes, or about 15 minutes after the start of the in vitro dissolution test. In another embodiment, the first phase is characterized by the release of about 15% to about 55%, about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 25% to about 40%, about 30% to about 50%, or about 30% to about 40% (e.g., 15-55%, 20-55%, 20-50%, 20-45%, 20-40%, 25-40%, 30-50%, or 30-40%) of the total amount of active agent in the composition in less than 1 hour, less than 55 minutes, less than 50 minutes, less than 45 minutes, less than 40 minutes, less than 35 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, or less than 15 minutes after the start of the in vitro dissolution test.

[0103]

[0111] In another embodiment, the second phase is characterized by release of substantially all, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or all of the active agent (e.g., midodrine hydrochloride) in the sustained-release portion over an extended or prolonged period of about 8 to about 16 hours, about 10 to about 16 hours, about 12 to about 16 hours, about 14 to about 16 hours, about 8 to about 14 hours, about 8 to about 12 hours, about 8 to about 10 hours, about 10 to about 14 hours, about 10 to about 12 hours, or about 12 to about 14 hours (e.g., about 16 hours, about 15 hours, about 14 hours, about 13 hours, about 12 hours, about 11 hours, about 10 hours, or about 8 hours) after initiation of in vitro dissolution testing. In one embodiment, the second phase is characterized by the release of substantially all, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or all of the active agent (e.g., midodrine hydrochloride) in the sustained release portion over an extended or prolonged period of about 8 to about 12 hours, about 9 to about 12 hours, about 10 to about 12 hours, about 11 to about 12 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, or about 14 hours after the start of an in vitro dissolution test.

[0104]

[0112] In some embodiments, the first phase is relatively rapid and the second phase is more steady or slower than the first phase, and may be greater than about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, between about 4 and about 12 hours, between about 4 and about 11 hours, between about 4 and about 10 hours, between about 4 and about 9 hours, between about 4 and about 8 hours, or There is no second increase between about 4.5 and about 12 hours, between about 4.5 and about 11 hours, between about 4.5 and about 10 hours, between about 4.5 and about 9 hours, between about 4.5 and about 8 hours, between about 5 and about 12 hours, between about 5 and about 11 hours, between about 5 and about 10 hours, between about 5 and about 9 hours, between about 5 and about 8 hours, between about 6 and about 12 hours, between about 6 and about 11 hours, between about 6 and about 10 hours, and between about 6 and about 9 hours.

[0105]

[0113] In some embodiments, the first phase is relatively rapid, the second phase is steady or slower than the first phase, and the second increase in release rate occurs at about 3 hours to about 5 hours, about 3 hours to about 4.5 hours, about 3.5 to about 4.5 hours, about 4 to about 4.5 hours, about 4 hours, about 4.5 hours, before about 5 hours, or before 5 hours after the start of the in vitro dissolution test.

[0106]

[0114] In some embodiments, the pharmaceutical compositions disclosed herein comprise a rapid-release portion and a sustained-release portion and are characterized by an in vitro dissolution release profile in which about 45% to about 75%, about 45% to about 70%, about 45% to about 65%, about 55% to about 65%, or about 60% to about 70%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70% of the total amount of active agent (e.g., midodrine hydrochloride) in the composition is released within about 2 hours after initiation of the dissolution test. In further embodiments, about 55% to about 85%, about 55% to about 80%, about 55% to about 77%, or about 58% to about 77% of the total amount of active agent in the composition is released within about 4 hours after initiation of the dissolution test. %, about 70% to about 80%, about 75% to about 85%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85% of the total amount of active agent in the composition is released within about 6 hours after initiation of the dissolution test. In another embodiment, about 65% to about 90%, about 65% to about 87%, about 65% to about 85%, at least about 80% to about 90%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% of the total amount of active agent in the composition is released within about 8 hours after initiation of the dissolution test. In another embodiment, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the total amount of active agent in the composition is released within about 8 hours after initiation of the dissolution test. In another embodiment, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or all of the total amount of active agent in the composition is released within about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, or about 11.5 hours after the start of the dissolution test. In another embodiment, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or all of the total amount of active agent in the composition is released within 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, or 16 hours after the start of the dissolution test.

[0107]

[0115] In some embodiments, the sustained-release portion releases the remainder of the total weight of the active agent (e.g., midodrine hydrochloride) in the pharmaceutical composition at a rate slower than the release rate of the rapid-release portion. In some embodiments, a second increase in the active agent release rate, as measured in an in vitro dissolution test, does not occur for 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, or 6 hours after the start of the dissolution test. In another embodiment, the second increase occurs at about 4 to about 16 hours, about 4 to about 15 hours, about 4 to about 14 hours, about 4 to about 14 hours, about 4 to about 12 hours, about 4 to about 11 hours, about 4 to about 10 hours, about 4 to about 9 hours, about 4 to about 8 hours, about 4.5 to about 16 hours, about 4.5 to about 15 hours, about 4.5 to about 14 hours, about 4.5 to about 13 hours, about 4.5 to about 12 hours, about 4.5 to about 11 hours, about 4.5 to about 10 hours, about 4.5 to about 5 hours, about 4.5 to about 6 hours, about 4.5 to about 7 hours, about 4.5 to about 8 hours, about 4.5 to about 9 hours, about 4.5 to about 10 hours, about 4.5 to about 16 hours, about 4.5 to about 15 hours, about 4.5 to about 14 hours, about 4.5 to about 13 hours, about 4.5 to about 12 hours, about 4.5 to about 11 hours, about 4.5 to about 10 hours, about 4.5 to about 12 hours, about 4.5 to about 11 hours, about 4.5 to about 10 hours, about 4.5 to about 14 hours, about 4.5 to about 16 hours, about 4.5 to about 15 hours, about 4.5 to about 14 hours, about 4.5 to about 13 hours, about 4.5 to about 12 hours, about 4.5 to about 11 hours, about 4.5 to about 10 hours, about 4.5 to about 14 hours, about 4.5 to about 14 hours, about 4.5 to about 14 hours, about 4.5 to about 14 hours does not occur within about 9 hours, about 4.5 to about 8 hours, about 5 to about 16 hours, about 5 to about 15 hours, about 5 to about 14 hours, about 5 to about 13 hours, about 5 to about 12 hours, about 5 to about 11 hours, about 5 to about 10 hours, about 5 to about 9 hours, about 5 to about 8 hours, about 6 to about 16 hours, about 6 to about 15 hours, about 6 to about 14 hours, about 6 to about 13 hours, about 6 to about 12 hours, about 6 to about 11 hours, about 6 to about 10 hours, about 6 to about 9 hours, or about 6 to about 8 hours.

[0108]

[0116] In some embodiments, the second increase in the active agent release rate, as measured by in vitro dissolution testing, occurs 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, or 4.5 hours after the start of the dissolution test, but not 5 hours after the start of the dissolution test. In other embodiments, the second increase occurs between about 3 and about 5 hours, between about 3 and about 4.5 hours, between about 3.5 and about 4.5 hours, or between about 4 and about 4.5 hours after the start of the dissolution test.

[0109]

[0117] In some embodiments, the release rate of the active agent (e.g., midodrine hydrochloride) does not substantially decrease during the sustained-release period, e.g., when the decrease in the release rate of the sustained-release portion is less than the decrease in the release rate of the rapid-release portion (e.g., occurring about 15 minutes to about 1 hour after the start of the in vitro dissolution test). In some embodiments, the decrease in the release rate of the active agent (e.g., midodrine hydrochloride) during the sustained-release period occurs at about 1 hour to about 16 hours, about 1 hour to about 15 hours, about 1 hour to about 14 hours, about 1 hour to about 13 hours, about 1 hour to about 12 hours, about 1 hour to about 11 hours, about 1 hour to about 10 hours, about 1 hour to about 14 hours, about 1 hour to about 16 hours, about 1 hour to about 18 hours, about 1 hour to about 19 hours, about 1 hour to about 20 hours, about 1 hour to about 21 hours, about 1 hour to about 22 hours, about 1 hour to about 23 hours, about 1 hour to about 24 hours, about 1 hour to about 25 hours, about 1 hour to about 26 hours, about 1 hour to about 27 hours, about 1 hour to about 28 hours, about 1 hour to about 29 hours, about 1 hour to about 30 hours, about 1 hour to about 31 hours, about 1 hour to about 32 hours, about 1 hour to about 33 hours, about 1 hour to about 34 hours, about 1 hour to about 35 hours, about 1 hour to about 36 hours, about 1 hour to about 37 hours, about 1 hour to about 38 hours, about 1 hour to about 39 hours, about 1 hour to about 40 hours, about 1 hour to about 41 hours, about 1 hour to about 42 hours, about 1 hours to about 9 hours, about 1 hour to about 8 hours, about 1.5 hours to about 12 hours, about 1.5 hours to about 11 hours, about 1.5 hours to about 10 hours, about 1.5 hours to about 9 hours, about 1.5 hours to about 8 hours, about 2 hours to about 12 hours, about 2 hours to about 11 hours, about 2 hours to about 10 hours, about 2 hours to about 9 hours, about 2 hours to about 8 hours, about 2.5 hours to about 12 hours, about 2.5 hours to about 11 hours, about 2.5 hours to about 10 hours, about 2.5 hours to about 9 hours, about 2.5 hours to about The rate of change occurs at less than about 10% / hour, less than about 9% / hour, less than about 8% / hour, less than about 7% / hour, less than about 6% / hour, less than about 5% / hour, less than about 4% / hour, or less than about 3% / hour within 8 hours, about 3 hours to about 12 hours, about 3 hours to about 11 hours, about 3 hours to about 10 hours, about 3 hours to about 9 hours, about 3 hours to about 8 hours, about 4 hours to about 12 hours, about 4 hours to about 11 hours, about 4 hours to about 10 hours, about 4 hours to about 9 hours, or about 4 hours to about 8 hours.

[0110]

[0118] In some embodiments, the pharmaceutical compositions disclosed herein provide for in vivo release of an active agent (e.g., midodrine hydrochloride) over a period of up to about 16 hours, up to about 15 hours, up to about 14 hours, up to about 13 hours, up to about 12 hours, up to about 11 hours, up to about 10 hours, up to about 9 hours, or up to about 8 hours after administration to a subject, and can be characterized by (i) a first phase comprising a peak plasma concentration of desglymidodrine, and (ii) a second phase comprising a therapeutically effective plasma concentration of desglymidodrine. In some embodiments, the plasma concentration of desglymidodrine in the second phase remains steady or lower than the peak plasma concentration of the first phase. In some embodiments, the second phase comprises a second increase in the plasma concentration of desglymidodrine between about 2 hours and about 4.5 hours after administration of the pharmaceutical composition to a subject. In some embodiments, the second phase does not comprise a second increase in the plasma concentration of desglymidodrine after 5 hours after administration of the pharmaceutical composition to a subject (e.g., no second increase occurs between 5 and 10 hours). In some embodiments, the second phase comprises a third increase in the plasma concentration of desglymidodrine at least about 6 hours after administration of the pharmaceutical composition to the subject. In some embodiments, the first phase peak plasma concentration of desglymidodrine is at least 10 ng / mL, at least 11 ng / mL, at least 12 ng / mL, at least 13 ng / mL, or at least 14 ng / mL. In some embodiments, the plasma concentration of desglymidodrine is maintained at a level of at least 7 ng / mL, at least 8 ng / mL, at least 9 ng / mL, at least 10 ng / mL, at least 11 ng / mL, at least 12 ng / mL, at least 13 ng / mL, or at least 14 ng / mL for at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours after administration of the pharmaceutical composition to the subject.

[0111]

[0119] In some embodiments, the pharmaceutical compositions disclosed herein can be characterized by a release profile following administration to a subject that includes: (i) a first phase that is a rapid release of the active agent (e.g., midodrine HCl), and (ii) a second phase that is a sustained release of the active agent.

[0112]

[0120] In some embodiments, the first phase of the in vivo release profile can be characterized by the release of up to about 20%, up to about 30%, up to about 35%, up to about 40%, up to about 45%, up to about 50%, or up to about 55% (w / w) of the total amount of active agent in the composition within about 30 minutes, about 45 minutes, about 1 hour, about 90 minutes, about 2 hours, about 15 minutes to about 2 hours, about 30 minutes to about 2 hours, about 30 minutes to about 90 minutes, or about 30 minutes to 60 minutes after administration of the composition to a subject.

[0113]

[0121] In some embodiments, the second phase of the in vivo release profile is characterized in that about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 85% (w / w) or less of the total active agent in the composition is released within about 30 minutes to about 16 hours, about 45 minutes to about 16 hours, about 1 hour to about 16 hours, about 90 minutes to about 16 hours, about 2 hours to about 16 hours, about 30 minutes to about 14 hours, about 45 minutes to about 14 hours, about 1 hour to about 14 hours, about 90 minutes to about 14 ... after administration. The active ingredient can be characterized by being released over an extended period of time, such as from about 1 hour to about 14 hours, from about 30 minutes to about 12 hours, from about 45 minutes to about 12 hours, from about 1 hour to about 12 hours, from about 90 minutes to about 12 hours, from about 2 hours to about 12 hours, from about 30 minutes to about 10 hours, from about 45 minutes to about 10 hours, from about 1 hour to about 10 hours, from about 90 minutes to about 10 hours, from about 2 hours to about 10 hours, from about 30 minutes to about 8 hours, from about 45 minutes to about 8 hours, from about 1 hour to about 8 hours, from about 90 minutes to about 8 hours, or from about 2 hours to about 8 hours. In other embodiments, the second phase of the in vivo release profile can be characterized by about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 85% (w / w) or less of the total active agent in the composition being released over an extended period of time, such as about 30 minutes to about 12 hours, about 45 minutes to about 12 hours, about 1 hour to about 12 hours, about 90 minutes to about 12 hours, or about 2 hours to about 12 hours, after administration. In other embodiments, the second phase of the in vivo release profile can be characterized by about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 85% (w / w) or less of the total active agent in the composition being released over an extended period of time, such as about 8 hours to about 16 hours, about 8 hours to about 14 hours, about 8 hours to about 12 hours, about 8 hours to about 10 hours, or about 6 hours to about 8 hours after administration. In some embodiments, the in vivo release profile is: (i) formulated to release about 20% to about 45%, about 20% to about 40%, about 20% to about 30%, about 25% to about 40%, about 25% to about 35%, or about 30% to about 40% w / w of the total amount of active agent within about 1 hour after administration of the pharmaceutical composition; and (ii) The composition is formulated so that the remaining total amount of active agent is released over a period of about 6 to 12 (e.g., about 8 to 10) hours after administration of the pharmaceutical composition. can be characterized by

[0114]

[0122] In some embodiments, the first phase is relatively rapid and the second phase is steady or slower than the first phase, and the second increase does not occur for 5 to 10 hours (e.g., about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, or about 8 hours) after administration of the pharmaceutical composition to the subject. In some embodiments, the first phase is relatively rapid and the second phase is steady or slower than the first phase, and the second increase does not occur for about 4.5 to about 16 hours, about 4.5 to about 15 hours, about 4.5 to about 14 hours, about 4.5 to about 13 hours, about 4.5 to about 12 hours, about 4.5 to about 11 hours, about 4.5 to about 10 hours, about 4.5 to about 9 hours, about 4.5 to about 8 hours, about 5 to about 16 hours, about 5 to about 18 hours, or about 19 hours after administration of the pharmaceutical composition to the subject. The second increase does not occur for about 15 hours, about 5 to about 14 hours, about 5 to about 13 hours, about 5 to about 12 hours, about 5 to about 11 hours, about 5 to about 10 hours, about 5 to about 9 hours, about 5 to about 8 hours, about 6 to about 16 hours, about 6 to about 15 hours, about 6 to about 14 hours, about 6 to about 13 hours, about 6 to about 12 hours, about 6 to about 11 hours, about 6 to about 10 hours, about 6 to about 9 hours, or about 6 to about 8 hours.

[0115]

[0123] In some embodiments, the release rate of the active agent (e.g., midodrine HCl) in the sustained-release portion of the pharmaceutical composition results in a second increase in the plasma concentration of desglymidodrine over a period of about 2 to about 4.5 hours after administration of the pharmaceutical composition to a subject. In some embodiments, the sustained-release portion does not result in a second increase in the plasma concentration of desglymidodrine over a period of 5 hours after administration of the pharmaceutical composition to a subject (e.g., no second increase occurs for 5 to 10 hours). In some embodiments, the sustained-release portion results in a third increase in the plasma concentration of desglymidodrine for at least about 6 hours after administration of the pharmaceutical composition to a subject.

[0116]

[0124] In some embodiments, the rapid release portion of the about 15 mg sustained release composition provides a first-phase peak plasma concentration of desglimidorine of at least 12 ng / mL, at least 13 ng / mL, or at least 14 ng / mL within about 1 hour. In some embodiments, the rapid release portion of the about 7.5 mg sustained release composition provides a first-phase peak plasma concentration of desglimidorine of at least 12 ng / mL, at least 13 ng / mL, or at least 14 ng / mL within about 1 hour. In some embodiments, the rapid release portion of the sustained release composition of about 30 mg provides a first-phase peak plasma concentration of desglimidodrine of at least 24 ng / mL within about 1 hour. In some embodiments, the pharmaceutical composition provides a plasma concentration of desglimidodrine of at least 7 ng / mL, at least 8 ng / mL, at least 9 ng / mL, at least 10 ng / mL, at least 11 ng / mL, or at least 12 ng / mL for at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours after administration of the pharmaceutical composition to a subject.

[0117] How to use

[0125] The present disclosure provides methods of using the pharmaceutical compositions disclosed herein. Some aspects of the present disclosure are directed to methods of treating or reducing the incidence of orthostatic hypotension in a human subject in need thereof, comprising administering a pharmaceutical composition described herein to the subject. In some embodiments, the pharmaceutical compositions disclosed herein increase systolic blood pressure measured one minute after standing. In some embodiments, the composition is administered once daily. In some embodiments, the pharmaceutical composition maintains the subject's blood pressure within a desired level throughout the day, for example, greater than 90 mmHg systolic and greater than 60 mmHg diastolic, e.g., about 120 / 80 mmHg.

[0118]

[0126] The pharmaceutical compositions of the present disclosure can be used to treat or reduce the incidence of disorders including at least one of orthostatic hypotension; postural orthostatic tachycardia syndrome (POTS); autonomic neuropathy; symptoms of chronic orthostatic hypotension corresponding to autonomic failure associated with Bradbury-Eggleston syndrome, Shy-Drager syndrome, diabetes, and Parkinson's disease; and retrograde ejaculation. In some embodiments, the pharmaceutical compositions of the present disclosure can be used to treat orthostatic hypotension in subjects suffering from Parkinson's disease. In some embodiments, the pharmaceutical compositions of the present disclosure can be used to treat subjects suffering from or at risk of suffering from Postural Orthostatic Tachycardia Syndrome (POTS).

[0119]

[0127] In certain aspects, the methods are directed to treating a subject suffering from or at risk of suffering from orthostatic hypotension due to autonomic failure, and comprise administering to a subject in need thereof an effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the subject suffers from Bradbury-Eggleston syndrome, Shy-Drager syndrome, diabetes, or Parkinson's disease.

[0120]

[0128] In certain aspects, the method is directed to treating a subject with Parkinson's disease who is suffering from or at risk of suffering from orthostatic hypotension, and comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition disclosed herein.

[0121]

[0129] In certain embodiments, the method is directed to treating a subject with postural orthostatic tachycardia syndrome (POTS), suffering from or at risk of suffering from orthostatic hypotension, and comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition disclosed herein.

[0122]

[0130] In some embodiments, the subject is between 10 and 50 years old, 10 and 25 years old, e.g., between 13 and 18 years old, 13 and 21 years old, or 13 and 25 years old. In some embodiments, the subject is male or female. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is a female between 13 and 25 years old and suffers from POTS. In some embodiments, the subject suffers from Parkinson's disease. In some embodiments, the subject suffers from early-onset Parkinson's disease (e.g., under age 50). In some embodiments, the subject is over 50 years old.

[0123]

[0131] The method of treatment can include administering a single dose of a pharmaceutical composition disclosed herein to a subject. The administration can be effective to provide rapid release of the active agent into the subject's plasma (e.g., within 2 hours, 90 minutes, 1 hour, 45 minutes, 30 minutes, or 15 minutes) and sustained release of the active agent into the subject's plasma (e.g., for at least 8 hours, at least 10 hours, at least 12 hours, or at least 14 hours). The active agent can include one or more of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, or a combination thereof.

[0124]

[0132] In some embodiments, the method comprises administering a pharmaceutical composition disclosed herein in a single total daily dose that is greater than the corresponding total daily dose of an immediate-release tablet administered three times daily, for example, a pharmaceutical composition disclosed herein can be administered in a single 20 mg dose instead of a 5 mg immediate-release tablet administered three times daily (i.e., a total daily dose of 15 mg dose of IR). In some embodiments, the 20 mg dose is a multi-layer tablet (e.g., a bi-layer or tri-layer tablet) comprising a rapid-release portion and an extended-release portion.

[0125]

[0133] In some embodiments, administration of a single dose can effectively increase blood pressure in a subject (e.g., to at least 12 ng / mL or at least 14 ng / mL) during the rapid-release period and maintain blood pressure in the subject (e.g., at a level of at least 7 ng / mL, at least 8 ng / mL, at least 9 ng / mL, or at least 10 ng / mL) during the sustained-release period. A single dose may contain the active agent in an amount of about 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg , 72.5 mg, 75 mg, 77.5 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg, for example, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 45 mg, or an amount ranging from about 5 mg to about 150 mg, about 5 mg to about 120 mg, about 5 mg to about 100 mg, about 5 mg to about 75 mg, about 10 to about 70 mg, about 4 mg to about 50 mg, or about 18 mg to about 25 mg.

[0126]

[0134] In some embodiments, the pharmaceutical composition is an oral suspension, and the dose can be titrated to an effective level for the subject.The subject can be started with an initial dose of the active agent, and subsequent doses can be adjusted based on the subject's response to the initial dose.Dose titration can be conveniently achieved by adjusting the volume of the oral suspension to be administered to the subject in oral suspension dosage form.

[0127]

[0135] In some embodiments, the methods of the present application not only allow the active agent (e.g., midodrine hydrochloride) to be administered less frequently than an immediate release dose, but also maintain blood pressure in a clinically acceptable range throughout the day, e.g., greater than 90 mmHg systolic and greater than 60 mmHg diastolic, e.g., about 120 / 80 mmHg.

[0128]

[0136] The method can include administering a single dose to a subject according to any of the embodiments of the pharmaceutical compositions described herein. For example, the method can include administering a single dose to a subject in a dosage form that includes at least one of: a multi-layer tablet, such as a bi-layer or tri-layer tablet, including a rapid-release layer and a sustained-release layer; a sustained-release core coated with a rapid-release coating; a combination of a rapid-release tablet and a sustained-release tablet; a plurality of microparticles, including a rapid-release population and a sustained-release population, designed to be dispersed in a liquid carrier (or suspension medium) suitable for oral administration; or a plurality of multiparticulate (e.g., particles, granules, beads, spheres, or minitablets) pellets that are a rapid-release population and a sustained-release population. The method can include administering a single dose to a subject in a dosage form that includes at least one of: a multi-layer tablet, such as a bi-layer or tri-layer tablet, including a rapid-release layer and a sustained-release layer; a sustained-release core coated with a rapid-release coating; a combination of a rapid-release tablet and a sustained-release tablet; a plurality of microparticles, including a rapid-release population and a sustained-release population, designed to be dispersed in a liquid carrier (or suspension medium) suitable for oral administration; or a plurality of multiparticulate (e.g., particles, granules, beads, spheres, or minitablets) pellets that are a rapid-release population and a sustained-release population. The present invention can further include combining a plurality of microparticles (e.g., multiparticulates disclosed herein) dispersed in a liquid carrier suitable for oral administration with a liquid and then orally administering the mixture to a subject.

[0129]

[0137] In some embodiments, the method can include administering a single dose to a subject such that the sustained release of the active agent into the subject's plasma over a sustained-release period is characterized by a sustained-release rate. The method can include administering a single dose to a subject such that greater than about 50% (w / w) of the active agent in the pharmaceutical composition is released to the subject over the sustained-release period. The sustained-release period can be within a few hours, or at least one of or at least about one of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 hours, e.g., about 12 hours, or a range between any two of the preceding values, e.g., between about 4 hours and about 12 hours, between 6 hours and 12 hours, between 8 hours and 12 hours, between 8 hours and 14 hours, or between 8 hours and 16 hours.

[0130]

[0138] In one embodiment, the pharmaceutical composition disclosed herein, such as a tablet, capsule, or suspension, is administered to a human subject in need thereof once or twice daily. In another embodiment, the pharmaceutical composition is administered to a human subject in need thereof once daily. The administered dose may be sufficient to obtain a suitable therapeutic response in the subject.

[0131]

[0139] In one embodiment, the present disclosure provides a method of treating orthostatic hypotension in a human subject in need thereof, comprising: a rapid-release portion comprising about 1.5 mg to about 45 mg (e.g., about 2 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, or about 5 mg to about 10 mg) of an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof; and a sustained-release portion comprising about 3.5 mg to about 105 mg (e.g., about 4 mg to about 75 mg, about 5 mg to about 50 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 7.5 mg to about 15 mg, or about 10 mg to about 15 mg) of an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof; and administering to a human subject a pharmaceutical composition comprising:

[0132]

[0140] In some embodiments, the pharmaceutical composition has in vitro dissolution release characteristics such that up to about 20%, up to about 30%, up to about 35%, up to about 40%, up to about 45%, up to about 50%, or up to about 55% (w / w) of the total amount of active agent in the composition is released within 1 hour, and at least about 95% of the total amount of active agent in the composition is released within 8, 10, 12, 14, or 16 hours.

[0133]

[0141] In another embodiment, the method includes administering a rapid-release portion comprising about 1.5 mg to about 45 mg (e.g., about 2 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, or about 5 mg to about 10 mg) of midodrine hydrochloride, a binder, a glidant, and a lubricant, wherein the midodrine hydrochloride is present in an amount of up to 40%, up to 35%, up to 30%, up to 25%, about 2% to about 30%, about 2% to about 20%, or about 2% to about 10% of the total amount of the rapid-release portion; and about 3.5 mg to about 105 mg (e.g., about 4 mg to about 75 mg, about 5 mg to about 15 mg). and a sustained-release portion comprising midodrine hydrochloride (about 60%, about 65%, about 70%, about 75%, about 80%, about 2% to about 30%, about 2% to about 20%, or about 2% to about 10% of the total amount of the sustained-release portion), and a rate control agent, wherein the midodrine hydrochloride is present in an amount of up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, about 2% to about 30%, about 2% to about 20%, or about 2% to about 10% of the total amount of the sustained-release portion, and wherein the weight ratio of midodrine hydrochloride to rate control agent is about 1:1 to about 1:30. nothing.

[0134]

[0142] In some embodiments, the rapid-release portion comprises about 1% to about 40%, about 2% to about 40%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 2% to about 5%, about 3% to about 15%, about 3% to about 10%, about 3% to about 10%, or about 3% to about 5% of the total amount of midodrine hydrochloride in the rapid-release portion. In some embodiments, the rapid-release portion comprises about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the total amount of midodrine hydrochloride in the rapid-release portion.

[0135]

[0143] In some embodiments, the sustained-release portion comprises about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 3% to about 15%, about 3% to about 10%, about 3% to about 5%, about 4% to about 10%, about 4% to about 8%, or about 4% to about 6% of midodrine hydrochloride based on the total amount of the sustained-release portion. In some embodiments, the sustained-release portion comprises about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the total amount of midodrine hydrochloride based on the total amount of the sustained-release portion. In some embodiments, the weight ratio of midodrine hydrochloride in the sustained-release portion to the rate controlling agent in the sustained-release portion is about 1:1 to about 1:20, about 1:1 to about 1:10, about 1:1 to about 1:8, about 1:1 to about 1:7, about 1:1 to about 1:6, or about 1:1 to about 1:5. In some embodiments, the weight ratio of midodrine hydrochloride in the sustained-release portion to the rate controlling agent in the sustained-release portion is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0136]

[0144] In some embodiments, the rapid-release portion contains about 2% to about 10% or about 3% to about 5% of midodrine hydrochloride by total amount of the rapid-release portion, the sustained-release portion contains about 2% to about 15% or about 4% to about 6% of midodrine hydrochloride by total amount of the sustained-release portion, and the weight ratio of midodrine hydrochloride in the sustained-release portion to rate controlling agent in the sustained-release portion is about 1:4 to about 1:5.

[0137]

[0145] In some embodiments, the method involves administering a pharmaceutical composition with a rapid-release portion and a sustained-release portion, wherein both the rapid-release portion and the sustained-release portion comprise an active agent (e.g., midodrine hydrochloride). In some embodiments, the active agent in the rapid-release portion is released within about 60 minutes, about 50 minutes, about 45 minutes, about 40 minutes, about 35 minutes, about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, or about 5 minutes after the start of an in vitro dissolution test. In some embodiments, the active agent in the rapid-release portion is released within about 90 minutes, about 60 minutes, about 50 minutes, about 45 minutes, about 40 minutes, about 35 minutes, about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, or about 5 minutes after administration to a subject. In some embodiments, at least a portion of the active agent is released over a period of about 1 hour to about 16 hours, about 1 hour to about 15 hours, about 1 hour to about 14 hours, about 1 hour to about 13 hours, about 1 hour to about 12 hours, about 1 hour to about 11 hours, or about 1 hour to about 10 hours after initiation of an in vitro dissolution test. In some embodiments, at least a portion of the active agent is released over a period of about 1 hour to about 16 hours, about 1 hour to about 15 hours, about 1 hour to about 14 hours, about 1 hour to about 13 hours, about 1 hour to about 12 hours, about 1 hour to about 11 hours, or about 1 hour to about 10 hours after administration to a subject.

[0138]

[0146] In some embodiments, administration of the pharmaceutical composition results in a maximum plasma concentration (Cmax) of midodrine hydrochloride or its active metabolite in the range of about 2 ng / mL to about 100 ng / mL, about 2 ng / mL to about 50 ng / mL, about 2 ng / mL to about 25 ng / mL, about 2 ng / mL to about 15 ng / mL, or about 2 ng / mL to about 10 ng / mL after oral administration of the pharmaceutical composition to a subject. In one embodiment, administration of the pharmaceutical composition results in a maximum plasma concentration (Cmax) of midodrine hydrochloride or its active metabolite in the range of about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 10 hours in a subject. It can result in plasma levels of the active metabolite, desglimidodrine, of at least 3 ng / mL, at least 4 ng / mL, at least 5 ng / mL, at least 6 ng / mL, at least 7 ng / mL, at least 8 ng / mL, at least 9 ng / mL, at least 10 ng / mL, at least 11 ng / mL, at least 12 ng / mL, at least 13 ng / mL, at least 14 ng / mL, at least 15 ng / mL, or at least 14 ng / mL for at least about 12 hours, or at least about 16 hours.

[0139]

[0147] In some embodiments, the method involves providing a bilayer or trilayer tablet comprising a rapid-release layer containing an active agent (e.g., midodrine hydrochloride) in the range of about 1.5 mg to about 45 mg (e.g., about 4 mg to about 75 mg, about 5 mg to about 50 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 7.5 mg to about 15 mg, or about 10 mg to about 15 mg) and a sustained-release layer containing an active agent (e.g., midodrine hydrochloride) in the range of 3.5 mg to about 105 mg (e.g., about 2 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, or about 5 mg to about 10 mg). The rapid-release layer of the tablet can be configured to release up to about 20%, up to about 30%, up to about 35%, up to about 40%, up to about 45%, up to about 50%, or up to about 55% (w / w) of the active agent within about 1 hour in an in vitro dissolution test. The sustained-release layer(s) can be configured to release the remaining amount of active agent over an extended period of about 1 hour to about 8 hours, about 1 hour to about 10 hours, about 1 hour to about 12 hours, or about 1 hour to about 16 hours after the start of the dissolution test.

[0140] dose

[0148] The pharmaceutical composition disclosed herein can be administered to a human subject in need thereof once or twice a day.In one embodiment, the pharmaceutical preparation is a tablet that can be administered to a human subject in need thereof once a day.The administered dose can be effective to cause the desired therapeutic and / or preventive response in the subject. In some embodiments, the pharmaceutical composition comprises a dose of about 5 mg to about 150 mg, about 5 mg to about 120 mg, about 7.5 to about 150 mg, about 7.5 mg to about 120 mg, about 5 mg to about 100 mg, about 7.5 mg to about 100 mg, about 7.5 mg to about 75 mg, about 7.5 mg to about 50 mg, about 10 mg to about 100 mg, about 15 mg to about 100 mg, about 20 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 15 mg to about 75 mg, about 15 mg to about 50 mg, about 20 mg to about 75 mg, about 20 mg to about 50 mg, about 18 mg to about 25 mg, or about 20 to about 25 mg of active agent (e.g., midodrine hydrochloride), which is administered once or twice daily. In one embodiment, the pharmaceutical composition comprises a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 18 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, or about 150 mg of an active agent (e.g., midodrine hydrochloride) administered once or twice daily.

[0141]

[0149] In some embodiments, the pharmaceutical compositions disclosed herein comprise a once-daily dosage form, wherein the total amount of active agent (e.g., midodrine HCl) in the dosage form is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 60%, or at least 70% greater than the total amount of active agent (e.g., midodrine HCl) in three immediate-release tablets (e.g., three IR tablets of 2.5 mg, 5 mg, or 10 mg). In some embodiments, the once-daily dosage form is Less than 70%, Less than 60%, Less than 50%, Less than 45%, Less than 40%, Less than 35%, Less than 30%, Between 10-70%, Between 10-55%, Between 10-50%, Between 10-40%, Between 10-35%, Between 10-30%, Between 15-50%, Between 15-40%, Between 15-35%, Between 15-30%, Between 20-50%, Between 20 The compositions may contain up to 40%, 20-35%, 20-30%, 25-50%, 25-40%, 25-35%, 25-30%, 30-50%, 30-45%, 30-40%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% more active agent (e.g., midodrine HCl). For example, a single 10 mg dosage form of the pharmaceutical compositions disclosed herein may be administered once daily (10 mg total daily dose) instead of a 2.5 mg immediate-release tablet administered three times daily (7.5 mg total daily dose). A single 20 mg dosage form of the pharmaceutical compositions disclosed herein may be administered once daily (20 mg total daily dose) instead of a 5 mg immediate-release tablet administered three times daily (15 mg total daily dose). A single 40 mg dosage form of the pharmaceutical compositions disclosed herein can be administered once daily (40 mg total daily dose) instead of a 10 mg immediate-release tablet administered three times daily (30 mg total daily dose). In some embodiments, the 10 mg, 20 mg, or 40 mg dose for once-daily administration is a multi-layer tablet (e.g., a bi-layer or tri-layer tablet) comprising a rapid-release portion and an extended-release portion. Production method

[0142]

[0150] In some aspects, the present application is directed to making a pharmaceutical composition as disclosed herein. In some embodiments, the pharmaceutical composition is prepared for oral delivery. In some embodiments, the pharmaceutical composition is a tablet, capsule, orally disintegrating tablet, chewable tablet, buccal patch, sublingual tablet, oral suspension, or powder, granules, or multiparticulates for oral suspension.

[0143]

[0151] In certain embodiments, the method of making comprises making a pharmaceutical composition comprising a multi-layer tablet (e.g., a bi-layer tablet or a tri-layer tablet) having a rapid-release layer and an extended-release layer, a tablet having an extended-release core and a rapid-release coating on the extended-release core, a tablet-in-tablet having an extended-release tablet within a rapid-release tablet, a compression-coated tablet having an extended-release core and a rapid-release coat, a rapid-release core coated with an extended-release coating and then a rapid-release coating, a capsule filled with multiparticulates (e.g., pellets, particles, granules, beads, spheres, or minitablets) having an extended-release core and a rapid-release coating, a mixture of fast- and extended-release multiparticulates compressed into a tablet, a mixture of fast- and extended-release multiparticulates filled into a sachet for reconstitution, or an extended-release osmotic controlled tablet with a layer coating of fast-release agent.

[0144]

[0152] In some embodiments, a method for making a pharmaceutical composition includes a drug-layered dispersion containing an active agent layered onto microcrystalline cellulose spheres in a fluidized bed processor by bottom spraying. A first portion (e.g., at least about 30%, at least about 40%, at least about 50%, at least about 60%, or about 70%) of the drug-layered multiparticulates is coated with a rate-controlling agent (e.g., ethyl cellulose and oleic acid) to form a first extended-release multiparticulate portion; a second portion (e.g., at least about 15%, at least about 20%, at least about 25%, or about 20%) of the drug-layered multiparticulates is coated with a rate-controlling agent (e.g., Eudragit® L 30D 55) to form a second extended-release multiparticulate portion; and the rapid-release (uncoated drug-layered multiparticulates), first extended-release multiparticulates, and second extended-release multiparticulates are lubricated (e.g., with talc and magnesium stearate) and filled into capsules.

[0145]

[0153] In some embodiments, methods for making the pharmaceutical composition include one or more of dry granulation, wet granulation, roller compaction, extrusion / spheronization, rotor granulation, hot melt extrusion, fluidized bed granulation, fluidized bed coating, compression coating, powder coating, and the like.

[0146] kit

[0154] In one embodiment, a kit is provided. In some embodiments, the kit comprises multiparticulates (e.g., pellets, particles, granules, beads, spheres, or minitablets) disclosed herein and a liquid medium, where the multiparticulates can be combined with the liquid medium to form a suspension. In some embodiments, the kit comprises a first pharmaceutical composition and a second pharmaceutical composition comprising the same or different active agents. In one embodiment, the first pharmaceutical composition comprises a rapid-release portion and a sustained-release portion, where both the rapid-release portion and the sustained-release portion comprise an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, and a pharmaceutically acceptable salt of desglymidodrine. In one embodiment, the active agent is present in the rapid release portion in a range of about 1.5 mg to about 45 mg (e.g., about 4 mg to about 75 mg, about 5 mg to about 50 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 7.5 mg to about 15 mg, or about 10 mg to about 15 mg), and the active agent is present in the sustained release portion in a range of about 3.5 mg to about 105 mg (e.g., about 2 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, or about 5 mg to about 10 mg). In another embodiment, the rapid-release portion releases about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 25% to about 40%, about 30% to about 50%, or about 30% to about 40% (e.g., 20 to 55%, 20 to 50%, 20 to 45%, 20 to 40%, 25 to 40%, 30 to 50%, or 30 to 40%) w / w of the total amount of active agent in the composition within about 1 hour, and the sustained-release portion releases the remaining total amount of active agent in the composition over about 1 hour to about 16 hours, about 1 to about 14 hours, about 1 to about 12 hours, about 1 to about 10 hours, or about 1 to about 8 hours.

[0147]

[0155] In certain embodiments, the second composition may be a rapid-release composition comprising an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, and a pharmaceutically acceptable salt of desglymidodrine. In one embodiment, the active agent is present in a range of 2.5 mg to 20 mg, and substantially all of the active agent is released within about 1 hour of administration of the second composition to a subject. In another embodiment, the first composition and the second composition are administered to a subject simultaneously. In yet another embodiment, the first composition and the second composition are administered to a subject sequentially, with the second composition being administered after the first composition.

[0148] Combination therapy

[0156] Certain aspects of the present application are directed to methods for treating a subject, comprising administering a pharmaceutical composition disclosed herein and a pharmaceutical composition further comprising an additional active agent. The additional active agent can be any active substance that can be advantageously used in combination with midodrine, a pharmaceutically acceptable salt thereof, desglimidodrine, a pharmaceutically acceptable salt thereof, or a combination thereof. Non-limiting examples of additional active agents include hydrocortisone, fludrocortisone, octreotide, etc. In some embodiments, the pharmaceutical composition can be administered concomitantly with one or more pharmaceutical compositions containing other active agents, for example, by simultaneous administration of the active agents in the same dosage form, simultaneous administration of the active agents in different dosage forms, or by separate administration of the active agents. [Example]

[0149]

[0157] The present disclosure is further illustrated by the following examples, which are provided merely for illustrative purposes and are not intended to limit the scope thereof. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present disclosure. The present disclosure provides, but is not limited to, the following formulation examples.

[0150] Example 1 Preparation and in vitro dissolution test of bilayer tablets of midodrine HCl

[0158] Midodrine hydrochloride bilayer tablets (15 mg, 20 mg, 30 mg, and 45 mg) containing a rapid-release layer and a sustained-release layer were prepared using the ingredients shown in Table 1. Midodrine HCl was blended with microcrystalline cellulose and a colorant. The mixture was then lubricated with colloidal silicon dioxide and magnesium stearate. For the sustained-release layer, midodrine HCl, microcrystalline cellulose, and hydroxypropyl cellulose were mixed and granulated with purified water. The granules were dried and lubricated with colloidal silicon dioxide and magnesium stearate. The rapid-release and sustained-release layers were compressed into bilayer tablets using a bilayer tablet press.

[0151] [Table 1]

[0152]

[0159] In vitro dissolution tests for the bilayer tablets of Example 1 were conducted under USP Apparatus I (basket) conditions in 900 mL of 0.1 N HCl (pH 1.2) for 0-2 hours; acetate buffer (pH 4.5) for 2-4 hours; and phosphate buffer (pH 6.8) for 4-16 hours at 37°C and 100 rpm. Similar dissolution profiles were observed with different buffers and agitation speeds (75 and 150 rpm). These results indicate that the drug release rate of midodrine is independent of simulated rapid, food-induced dissolution conditions, suggesting the absence of a food effect in vivo.

[0153]

[0160] Figure 1 shows the in vitro dissolution profiles of the tablets in Table 1. Tablets containing 30 mg and 45 mg midodrine HCl demonstrate rapid release of approximately 40% to 50% of the active agent from the rapid-release layer within approximately 1 hour, and sustained release of the remaining active agent over the 12-hour test period.

[0154]

[0161] The dissolution profile of a 30 mg midodrine HCl tablet is shown in Figure 2. These data demonstrate that a rapid release / sustained release composition containing 30 mg midodrine HCl exhibits a rapid release of the active agent followed by a sustained release of the active agent over a period of at least 10 hours.

[0155]

[0162] The in vitro dissolution data for the bilayer tablets tested in Example 1 supports the use of the disclosed pharmaceutical formulations in vivo in an effective rapid release period followed by a steady sustained release period.

[0156] Example 2 Simulated desglymidodrine plasma characteristics

[0163] The plasma profile of desglymidodrine (the active metabolite of midodrine HCl) after administration of a 5 mg immediate-release tablet (i.e., a TID regimen) at 0, 4, and 8 hours was simulated using known modeling methods. The simulated desglymidodrine plasma concentrations (ng / mL) versus time (hours) for the 5 mg immediate-release tablet (TID) is shown in Figure 3. From the simulation, it can be seen that the first immediate-release TID dose does not result in as high levels of desglymidodrine as the third immediate-release TID dose. As shown in the simulation, after administration of the third dose, desglymidodrine levels increase with each dose, reaching a maximum concentration (approximately 14 ng / mL).

[0157]

[0164] Using the same modeling method, the plasma profile of desglymidodrine was simulated for 15 mg and 20 mg rapid-release / extended-release tablets (formulations shown in Table 1) (FR+ER) of the present disclosure after administration at 0, 4, and 8 hours (i.e., TID regimen) compared with a 5 mg immediate-release tablet. The simulated desglymidodrine plasma concentrations (ng / mL) versus time (hours) for these formulations are shown in Figure 4. As shown in Figure 4, when the FR+ER 15 mg tablet was simulated and compared with the TID immediate-release 5 mg tablet, it initially (within approximately 1 hour) yielded desglymidodrine levels greater than 14 ng / mL. An additional FR+ER formulation at a higher strength, i.e., 20 mg, also achieved (simulated) this high initial peak desglymidodrine concentration. These FR+ER tablets exhibited rapid initial drug release in vitro (approximately 40% within 30 minutes) and no secondary increase after the initial release.

[0158] Example 3 Simulated dissolution and desglymidorine plasma properties

[0165] 20 mg FR+ER formulations were designed as shown in Example 7 (Table 5), and the dissolution and plasma profiles were simulated for once-daily doses of these formulations. Briefly, the 20 mg formulations are prepared as extended-release tri-layer tablets containing a rapid-release layer and an extended-release layer.

[0159]

[0166] As shown in Figure 5, the simulated dissolution profile for the 20 mg FR+ER formulation has a sustained drug release phase with a rapid second increase after about 2-4 hours and a slow-steady release followed by a third increase after about 6 hours. The rate dissolution profile also shows drug release for up to about 8 hours.

[0160]

[0167] Using the same modeling methodology used in Example 2, the plasma profile of desglymidodrine after administration of a 20 mg FR+ER tablet at 0, 4, and 8 hours (i.e., TID regimen) was simulated compared to a 5 mg immediate-release tablet. The simulated desglymidodrine plasma profile for the 20 mg FR+ER tablet also showed a significant improvement over the 5 mg immediate-release tablet within 1 hour. The 20 mg FR+ER tablet achieved higher initial desglimidorine plasma levels (greater than 14 ng / mL) compared to the simulated plasma profile for TID. Furthermore, the 20 mg FR+ER tablet maintained desglimidorine levels of at least about 10 mg / mL for at least about 10 hours, as shown in FIG.

[0161]

[0168] These simulated plasma profiles show that more rapid levels of desglymidodrine (greater than 14 ng / mL) were achieved within about 1 hour compared to the first dose of the 5 mg immediate-release TID regimen. The simulated plasma profiles also show sustained levels of desglymidodrine (at least 10 ng / mL) over about 10 hours.

[0162] Example 4 Midodrine HCl rapid release core coated with sustained release and rapid release coatings

[0169] A 45 mg rapid-release core coated with a sustained-release coating and then a rapid-release coating can be prepared using the ingredients shown in Table 2. Midodrine HCl is blended with microcrystalline cellulose and lubricated with colloidal silicon dioxide and magnesium stearate. This lubricated mixture is compressed into rapid-release core tablets. The tablets are coated with an aqueous ethylcellulose dispersion and hypromellose to form a sustained-release film. The coated sustained-release tablets are further coated with an aqueous solution of midodrine HCl and hypromellose to form an outer rapid-release coating on the tablets.

[0163] [Table 2]

[0164] Example 5 Midodrine HCl capsules filled with pellets having a sustained-release core and a rapid-release coating

[0170] A 30 mg capsule filled with pellets having a sustained-release core and a rapid-release coating can be prepared using the ingredients shown in Table 3. Midodrine HCl, microcrystalline cellulose, and hypromellose are blended and granulated with an aqueous solution of povidone in a high-shear granulator. The wet mass is extruded and spheronized using an extruder and spheronizer to form wet spherical pellets. These sustained-release matrix pellets are dried in a fluid-bed dryer and further coated with an aqueous solution of midodrine HCl and hypromellose to form an outer rapid-release layer. These pellets are filled into size 1 capsules using a capsule filling machine.

[0165] [Table 3]

[0166] Example 6 Bilayered sustained-release tablets of midodrine HCl with rapid and sustained-release layers prepared by direct compression

[0171] An 18 mg bilayer extended-release tablet having a rapid-release and a sustained-release layer can be prepared using the ingredients shown in Table 4. For the rapid-release layer, midodrine HCl, microcrystalline cellulose, sodium starch glycolate, and yellow iron oxide are blended and lubricated with talc and magnesium stearate. For the sustained-release layer, midodrine HCl, microcrystalline cellulose, and hypromellose are blended and lubricated with colloidal silicon dioxide and magnesium stearate. These lubricated layers are then compressed into a bilayer tablet using a bilayer tablet press.

[0167] [Table 4]

[0168] Example 7 Trilayer sustained-release tablets of midodrine HCl having a rapid-release layer and two sustained-release layers prepared by direct compression

[0172] A 20 mg trilayer extended-release tablet having one rapid-release layer and two sustained-release layers can be prepared using the ingredients shown in Table 5. For the rapid-release layer, midodrine HCl, microcrystalline cellulose, crospovidone, and yellow iron oxide are blended and lubricated with talc and magnesium stearate. For the first sustained-release layer, midodrine HCl, microcrystalline cellulose, hypromellose, and red iron oxide are blended and lubricated with colloidal silicon dioxide and magnesium stearate. For the second sustained-release layer, midodrine HCl, microcrystalline cellulose, and hypromellose are blended and lubricated with colloidal silicon dioxide and magnesium stearate. These lubricated layers are then compressed into a trilayer tablet using a multilayer tablet press. The drug release profile and release rate (% / hr) over time for the trilayer tablet formulation are shown in Figures 7 and 8, respectively.

[0169] [Table 5]

[0170] Example 8 A sustained-release hydrophilic matrix core of midodrine HCl prepared in a high-shear granulator by wet granulation, coated with a rapid-release coating by perforated pan coating.

[0173] 24 mg tablets with a sustained-release hydrophilic matrix core and a rapid-release coating on the sustained-release core can be prepared using the ingredients shown in Table 6. Midodrine HCl, microcrystalline cellulose, and hydroxypropyl cellulose are blended in a high-shear granulator. The mixture is wet-granulated with purified water. The granules are dried, milled, and lubricated with colloidal silicon dioxide and magnesium stearate. The lubricated mixture is compressed into sustained-release core tablets. These sustained-release core tablets are coated with a rapid-release coating solution containing midodrine HCl, hypromellose, polyethylene glycol, and purified water in a perforated coating pan.

[0171] [Table 6]

[0172] Example 9 A sustained-release hydrophilic matrix core of midodrine HCl prepared by direct compression, coated with a water-permeable functional coating and then with a rapid-release coating in a perforated coating pan.

[0174] 27 mg tablets with a sustained-release hydrophilic matrix core, a water-permeable functional coating, and a rapid-release coating are prepared using the ingredients shown in Table 7. Midodrine HCl, lactose monohydrate, and hypromellose are blended and lubricated with talc and magnesium stearate. The lubricated mixture is compressed into sustained-release core tablets. These tablets are coated with a functional coating containing an aqueous dispersion of Surelease® and Opadry® Clear. The tablets are further coated with a rapid-release coating containing midodrine HCl, croscarmellose sodium, hydroxypropyl cellulose, polyethylene glycol, and purified water.

[0173] [Table 7]

[0174] Example 10 A tablet-in-tablet of midodrine HCl having an extended-release core prepared by top-spray granulation and coated with a rapid-release coating by tablet-in-tablet compression.

[0175] A 15 mg tablet-in-tablet with an extended release core within a rapid release core can be prepared using the ingredients shown in Table 8. For the extended release core tablet, midodrine HCl and lactose monohydrate are blended and granulated with Surelease® by top spray granulation in a fluid bed processor. The granules are dried, milled, and then mixed with talc and stearic acid malate. The outer rapid-release tablet is lubricated with magnesium stearate. For the outer rapid-release tablet, a mixture of midodrine HCl, crospovidone, and red iron oxide is geometrically mixed with microcrystalline cellulose. The mixture is then lubricated with talc and magnesium stearate. A specially designed tablet-in-tablet press is used to compress the extended-release core tablet, and then the outer rapid-release tablet is compressed around the extended-release core tablet.

[0175] [Table 8]

[0176] Example 11 A sustained-release hydrophobic core of midodrine HCl prepared by melt granulation and coated with a rapid-release coating by compression coating.

[0176] 45 mg compression-coated tablets with a sustained-release hydrophobic core and a rapid-release outer coating can be prepared using the ingredients shown in Table 9. For the sustained-release core tablets, midodrine HCl, microcrystalline cellulose, and hydrogenated castor oil are blended in a steam-jacketed high-shear mixer granulator. The mixture is then granulated by melting the hydrogenated castor oil with the aid of steam. The granules are cooled, milled, and lubricated with sodium stearyl fumarate. For the rapid-release outer-coated tablets, a mixture of midodrine HCl, sodium starch glycolate, and red iron oxide is geometrically mixed with microcrystalline cellulose. The mixture is then lubricated with talc and magnesium stearate. The sustained-release core tablets are compressed, and then the outer rapid-release coated tablets are compressed using a specially designed compression machine.

[0177] [Table 9]

[0178] Example 12 Sustained-release capsules of midodrine HCl containing rapid- and sustained-release pellets prepared by drug layering and functional coating methods

[0177] 15 mg sustained-release capsules containing rapid-release pellets and functionally coated sustained-release pellets can be prepared using the ingredients shown in Table 10. A drug-layered dispersion containing midodrine HCl, hypromellose, and talc in purified water is layered onto microcrystalline cellulose spheres in a fluid-bed processor using a bottom spray method to prepare rapid-release pellets. A portion of these drug-layered pellets is coated with an ethanol solution of ethyl cellulose and oleic acid to form sustained-release pellets. The rapid-release and sustained-release pellets are then lubricated with talc and magnesium stearate and filled into capsules.

[0179] [Table 10]

[0180] Example 13 Sustained release capsules of midodrine containing rapid and sustained release pellets prepared by drug layering and functional coating methods

[0178] 20 mg extended-release capsules containing rapid-release pellets and functionally coated extended-release pellets can be prepared using the ingredients shown in Table 11. A drug-layered dispersion containing midodrine HCl, hypromellose, and talc in purified water is layered onto microcrystalline cellulose spheres in a fluid-bed processor by bottom spraying to prepare rapid-release pellets. A portion (50%) of these drug-layered pellets is coated with an ethanolic solution of ethyl cellulose and oleic acid to form a first population of extended-release pellets. A second portion (20%) of the drug-layered pellets is coated with an aqueous dispersion of Eudragit® L 30D 55 to form a second population of extended-release pellets. The rapid-release and extended-release pellets are then lubricated with talc and magnesium stearate and filled into capsules.

[0181] [Table 11]

[0182] Example 14 Orally disintegrating sustained-release tablets of midodrine HCl containing fast- and sustained-release pellets

[0179] Orally disintegrating 15 mg extended-release tablets containing rapid-release and functionally coated extended-release pellets can be prepared using the ingredients shown in Table 12. A drug-layered dispersion containing midodrine HCl, hypromellose, and talc in purified water is layered onto microcrystalline cellulose spheres in a fluid-bed processor using a bottom spray method to prepare drug-layered pellets. These pellets are then coated with an ethanolic solution of ethyl cellulose and oleic acid to form extended-release pellets. These extended-release pellets are further coated with a rapid-release coating using an aqueous dispersion containing midodrine HCl, hypromellose, and talc. The pellets are then blended with microcrystalline cellulose, mannitol, croscarmellose sodium, aspartame, and peppermint flavor and lubricated with magnesium stearate. The lubricated mixture is then compressed into orally disintegrating tablets.

[0183] [Table 12]

[0184] Example 15 Midodrine HCl sustained-release sachets for reconstitution containing sustained-release pellets coated with a rapid-release coating

[0180] A 30 mg extended-release sachet containing extended-release pellets coated with a rapid-release coating can be prepared using the ingredients shown in Table 13. Midodrine HCl, microcrystalline cellulose, and hypromellose are mixed and granulated with a non-aqueous solution of povidone in a high-shear granulator. The wet mass is extruded, and the extrudate is spheronized to form spherical pellets. These extended-release pellets are then dried, sized, and coated with a seal coating solution in a fluid-bed processor by a bottom spray method. The seal-coated pellets are further coated with a rapid-release coating. These pellets are then blended with xanthan gum, mannitol, orange flavor, and lubricated with magnesium stearate. The mixture is then filled into sachets. The contents of the sachet are reconstituted with water at the time of administration to form an extended-release suspension.

[0185] [Table 13]

[0186] Example 16 Sustained-release tablets of midodrine HCl based on osmotic drug delivery, prepared by top-spray granulation method, coated with a rapid-release coating agent in a perforated coating pan

[0181] A 60 mg sustained-release tablet based on osmotic drug delivery can be prepared using the ingredients shown in Table 14. For the sustained-release layer, midodrine HCl, microcrystalline cellulose, and polyethylene oxide are granulated in a fluid-bed processor using purified water by top-spray granulation. The granules are dried, milled, and lubricated with magnesium stearate. The push layer is also prepared by the same top-spray granulation method as for the sustained-release layer. Both layers are then compressed into a bilayer tablet using a multi-layer tablet press. These tablets are then coated with a functional coating solution of cellulose acetate and polyethylene glycol in an acetone and purified water mixture. These tablets are then passed through a laser perforator to drill an opening on the drug layer side. The tablets are then coated with an aqueous solution of midodrine HCl and hypromellose to form a rapid-release coating.

[0187] [Table 14]

[0188] Example 17 Bilayer sustained-release tablets of midodrine HCl having a rapid-release layer and a sustained-release layer prepared by the slug method

[0182] 20 mg bilayer extended-release tablets having rapid and sustained-release layers can be prepared by the slugging method using the ingredients shown in Table 15. For the rapid-release layer, midodrine HCl, silicified microcrystalline cellulose, croscarmellose sodium, and red iron oxide are blended and lubricated with talc and magnesium stearate. For the sustained-release layer, midodrine HCl, methacrylic acid and ethyl acrylate copolymer (1:1), and povidone are blended, lubricated with glyceryl behenate, and converted into slugs. The slugs are milled to the desired granule size and lubricated with magnesium stearate. The lubricated layers are then compressed into bilayer tablets.

[0189] [Table 15]

[0190]

[0183] Figure 9 shows the dissolution profiles for the 20 mg tablets of midodrine HCl discussed above using USP Apparatus 1 (basket) at 100 RPM in 900 mL at pH 1.2 (0.1 N hydrochloric acid), 0-2 hours; pH 4.5 (acetate buffer), 2-4 hours; and pH 6.8 (phosphate buffer), over 4 hours.

Claims

1. 1. A pharmaceutical composition comprising: a first release portion comprising an active agent in the range of about 20% to about 40% (w / w) of the total amount of the active agent in the composition; and a second release portion comprising the active agent in the range of about 60% to about 80% (w / w) of the total amount of the active agent in the composition; Including, wherein the in vitro release rate of the active agent, as measured by an in vitro dissolution test, comprises (i) a first release that is relatively rapid, and (ii) a second release that is not accompanied by a second increase in release rate from about 5 hours to about 10 hours after the start of the in vitro dissolution test; wherein the active agent is selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and any combination thereof. Pharmaceutical compositions.

2. 2. The pharmaceutical composition of claim 1, wherein the second release is constant or slower than the first release.

3. 10. The pharmaceutical composition of claim 1, wherein said second release comprises a second increase in release rate that occurs from about 2 to about 4.5 hours after the initiation of said in vitro dissolution test.

4. 1. A pharmaceutical composition comprising: a first release portion comprising an active agent in the range of about 20% to about 40% (w / w) of the total amount of the active agent in the composition; and a second release portion comprising the active agent in the range of about 60% to about 80% (w / w) of the total amount of the active agent in the composition; Including, wherein the in vitro release rate of the active agent, as measured by in vitro dissolution testing, comprises: (i) a first release that is relatively rapid; (ii) a second release comprising a second increase in release rate that occurs from about 2 hours to about 4.5 hours after initiation of said in vitro dissolution testing; and (iii) a third release comprising a third increase in release rate that occurs from about 5 hours to about 8 hours after initiation of said in vitro dissolution testing; wherein the active agent is selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and any combination thereof. Pharmaceutical compositions.

5. 5. The pharmaceutical composition of claim 3 or claim 4, wherein the second increase in release rate occurs from about 2 to about 4 hours after the start of the in vitro dissolution test.

6. 6. The pharmaceutical composition of claim 4 or claim 5, wherein the third increase in release rate occurs at least 6 hours after the start of the in vitro dissolution test.

7. the first release portion comprising about 1.5 mg to about 45 mg of an active agent and excipients, wherein the active agent is present in an amount of about 2% to about 40% of the total weight of the first release portion; and the second release portion comprising about 3.5 mg to about 105 mg of an active agent and a rate controlling agent, wherein the active agent is present in an amount of about 2% to about 20% of the total weight of the second release portion, and the ratio of the amount of active agent to the rate controlling agent in the second release portion is about 1:1 to about 1:30 (w / w), wherein the active agent is midodrine, ...

1. A pharmaceutical composition comprising an active agent selected from the group consisting of a pharmaceutically acceptable salt of desglimidodrine, desglimidodrine, a pharmaceutically acceptable salt of desglimidodrine, and any combination thereof, and wherein the total amount of the active agent is from about 5 mg to about 150 mg.

8. 8. The pharmaceutical composition of claim 7, wherein the in vitro release rate of the active agent, as measured by an in vitro dissolution test, has (i) a first release that is relatively rapid, and (ii) a second release that is steady or slower than the first release and is not accompanied by a second increase from about 5 hours to about 10 hours after the start of the in vitro dissolution test.

9. 8. The pharmaceutical composition of claim 7, wherein the in vitro release rate of the active agent, as measured by in vitro dissolution testing, has (i) a first release that is relatively rapid, (ii) a second release that comprises a second increase in release rate that occurs from about 2 hours to about 4.5 hours after the initiation of the in vitro dissolution testing, and (iii) a third release that comprises a third increase in release rate that occurs from about 5 hours to about 8 hours after the initiation of the in vitro dissolution testing.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein substantially all of the active agent in the first release portion is released within about 1 hour after administration of the pharmaceutical composition to the subject; and substantially all of the active agent in the second release portion is released over a period of from about 1 hour after administration of the composition to the subject to up to about 16 hours after administration of the composition to the subject.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the active agent is midodrine or a pharmaceutically acceptable salt of midodrine.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein substantially all of the active agent in the first release portion is released within about 45 minutes after the start of the in vitro dissolution test.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein substantially all of the active agent in the first release portion is released within about 30 minutes after the start of the in vitro dissolution test.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the in vitro dissolution tests were performed using USP Apparatus I (basket) in 900 mL of 0.1 N HCl (pH 1.2) for 0-2 hours; acetate buffer (pH 4.5) for 2-4 hours; phosphate buffer (pH 6.8) for 4-16 hours or 4-12 hours at 37°C and 100 rpm.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein substantially all of the active agent in the second release portion is released within 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, or 8 hours after the start of the in vitro dissolution test.

16. 16. The pharmaceutical composition of any one of claims 1-15, wherein about 1.5 mg to about 45 mg of the active agent is released within about 1 hour after administration of the composition to a subject, and about 3.5 mg to about 105 mg of the active agent is released from about 1 hour to about 16 hours after administration of the composition to a subject.

17. the first release portion comprises from about 1.5 mg to about 45 mg of an active agent and excipients, wherein the active agent is present in an amount from about 2% to about 40% of the total weight of the first release portion; and The second release portion comprises from about 3.5 mg to about 105 mg of an active agent and a rate controlling agent.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the active agent is present in an amount of about 2% to about 20% of the total weight of the second release portion, and the ratio of the amount of active agent to the amount of rate controlling agent in the second release portion is about 1:1 to about 1:30 (w / w).

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein at least about 20% of the total amount of active agent in the composition is released within about 1 hour after the start of an in vitro dissolution test, and at least about 80% of the total amount of active agent in the composition is released within about 12 hours.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein about 20% to about 40% (w / w) of the total amount of the active agent in the pharmaceutical composition is released within about 1 hour after the start of the in vitro dissolution test.

20. 20. The pharmaceutical composition of any one of claims 1-19, wherein at least about 95% (w / w) of the total amount of the active agent in the pharmaceutical composition is released within about 15 hours, about 14 hours, about 13 hours, about 12 hours, about 11 hours, about 10 hours, about 9 hours, or about 8 hours after the start of the in vitro dissolution test.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the active agent is present in a total amount of from about 7.5 mg to about 120 mg.

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the active agent is present in a total amount of about 15 mg to about 100 mg.

23. 23. The pharmaceutical composition of any one of claims 1 to 22, wherein the active agent is present in a total amount of about 20 mg to about 35 mg.

24. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein the in vitro release rate of the active agent during the second release stage is slower than the in vitro release rate of the active agent released during the first release stage.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, in the form of a tablet, capsule, orally disintegrating tablet, chewable tablet, buccal patch, sublingual tablet, oral suspension, powder for oral suspension, or multiparticulates for oral suspension.

26. 26. The pharmaceutical composition of any one of claims 1 to 25, further comprising a rate controlling agent.

27. 27. The pharmaceutical composition of claim 26, wherein the rate controlling agent is present in a weight ratio of the active agent to the rate controlling agent in the second release portion of the composition of from about 1:1 to about 1:30 (w / w), optionally from about 1:5 to about 1:15 (w / w).

28. 28. The pharmaceutical composition of claim 26 or 27, wherein the rate-controlling agent is selected from the group consisting of a water-soluble excipient, a water-insoluble excipient, a water-permeable excipient, and combinations thereof.

29. The rate control agent is selected from the group consisting of hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and derivatives thereof, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate, polyethylene glycol, polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose triacetate, methacrylic acid copolymer, hypromellose acetate succinate, poly(methyl methacrylate), ...

29. The pharmaceutical composition of any one of claims 26 to 28, wherein the polyglyceryl stearate is selected from the group consisting of poly(acrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(methyl acrylate), beeswax, carnauba wax, paraffin wax, microcrystalline wax, ozokerite, cetostearyl alcohol, stearyl alcohol, cetyl alcohol, myristyl alcohol, glyceryl monostearate, glyceryl palmitostearate, glycerol monooleate, glyceryl behenate, cetyl esters, acetylated monoglycerides, tristearin, tripalmitin, hydrogenated vegetable oils, and combinations thereof.

30. The pharmaceutical composition of any one of claims 26 to 28, wherein the rate controlling agent is a polymer.

31. 31. The pharmaceutical composition of claim 30, wherein the rate-controlling agent is a hydrophilic polymer selected from hypromellose; hydroxypropyl cellulose (HPC); hydroxyethyl cellulose (HEC); polyethylene oxide; polyvinyl alcohol; povidone; xanthan gum; guar gum; chitosan; chitosan derivatives; carbomer; carrageenan; carboxymethyl cellulose; sodium alginate; polysaccharified glycerides; polyethylene glycol; polyvinyl acetate dispersions; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose triacetate; methacrylic acid copolymers; hypromellose acetate succinate; and combinations thereof.

32. 31. The pharmaceutical composition of claim 30, wherein the rate-controlling agent is a hydrophobic polymer selected from poly(methyl methacrylate); poly(ethyl methacrylate); poly(methyl acrylate); poly(isopropyl acrylate); poly(isobutyl acrylate); poly(octadecyl acrylate); ethyl cellulose; cellulose propionate; cellulose acetate propionate; and combinations thereof.

33. 29. The pharmaceutical composition of any one of claims 26 to 28, wherein the rate controlling agent is a non-polymeric agent selected from waxes; fatty alcohols; fatty acid esters; hydrogenated vegetable oils; and combinations thereof.

34. The pharmaceutical composition according to any one of claims 1 to 33, wherein the pharmaceutical composition is a multi-layer tablet.

35. 35. The pharmaceutical composition of claim 34, wherein the composition is a bilayer tablet comprising a first release layer and a second release layer.

36. 35. The pharmaceutical composition of claim 34, wherein the composition is a tri-layer tablet comprising a first release layer and a second release layer comprising a first sustained release layer and a second sustained release layer.

37. 37. The pharmaceutical composition of any one of claims 1 to 36, wherein the pharmaceutical composition is a capsule comprising a plurality of fast-release pellets and a plurality of sustained-release pellets.

38. 38. The pharmaceutical composition of any one of claims 1 to 37, further comprising one or more of a binder, a diluent, a disintegrant, a surfactant, a dye, a glidant, a glidant, a flavoring agent, a pH adjuster, a solubilizing agent, a wetting agent, a buffer, or any combination thereof.

39. The binder may be gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, cellulose acetate ...

39. The pharmaceutical composition of claim 38, comprising kistrin, methylcellulose, microcrystalline cellulose, polymethacrylate, povidone, pregelatinized starch, sodium alginate, starch, zein, or any combination thereof.

40. 40. The pharmaceutical composition of claim 38 or 39, wherein the disintegrant comprises alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, calcium alginate, powdered cellulose, glycine, sodium starch glycolate, starch, hydroxypropyl cellulose, or any combination thereof.

41. 41. The pharmaceutical composition of any one of claims 38 to 40, wherein the lubricant comprises starch, talc, colloidal silicon dioxide, or any combination thereof.

42. 42. The pharmaceutical composition of any one of claims 38-41, wherein the lubricant comprises magnesium stearate, stearic acid, talc, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, medium chain triglycerides, myristic acid, palmitic acid, poloxamer, sodium benzoate, sodium stearyl fumarate, zinc stearate, or any combination thereof.

43. 43. The pharmaceutical composition of any one of claims 1 to 42, wherein the active agent is present in the first release portion in an amount of about 1.5 mg to about 45 mg and in the second release portion in an amount of about 3.5 mg to about 105 mg.

44. 44. The pharmaceutical composition of claim 43, wherein the first release portion comprises from about 4.5 to about 18 mg of midodrine hydrochloride and the second release portion comprises from about 10.5 to about 42 mg of midodrine hydrochloride.

45. 45. The pharmaceutical composition of any one of claims 1 to 44, wherein administration of the pharmaceutical composition to a subject results in (i) a relatively rapid peak plasma concentration of desglimidodrine of at least about 12 ng / ml within about 1 hour, and (ii) a plasma concentration of desglimidodrine of at least about 7 ng / ml or at least about 10 ng / ml for at least about 8 hours or at least about 10 hours.

46. A multi-layer tablet, capsule, or suspension comprising a first release portion and a second release portion, wherein each of the first release and the second release portions comprises an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and any combination thereof; and the first release portion comprises the active agent in an amount ranging from about 1.5 mg to 45 mg; the second release portion comprises the active agent in an amount ranging from about 3.5 mg to about 105 mg; and A multi-layer tablet, capsule, or suspension, wherein, in an in vitro dissolution test, the first release portion releases at least about 20% to about 40% w / w of the total amount of the active agent in the tablet, capsule, or suspension within about 1 hour, and the second release portion releases the remaining total amount of the active agent in the tablet, capsule, or suspension at a rate slower than the release rate of the first release portion.

47. 47. The multi-layer tablet, capsule, or suspension of claim 34 or 46, comprising a bi-layer tablet or a tri-layer tablet.

48. 48. The multi-layer tablet, capsule, or suspension of claim 46 or 47, wherein substantially all of the total amount of the active agent in the pharmaceutical composition is released within about 16 hours, about 15 hours, about 14 hours, about 13 hours, about 12 hours, about 11 hours, or about 10 hours after the start of the in vitro dissolution test.

49. 49. The multi-layer tablet, capsule, or suspension of any one of claims 46 to 48, wherein the second release portion comprises a rate controlling agent.

50. 50. The multi-layer tablet, capsule, or suspension of claim 49, wherein the ratio of the amount of active agent to the amount of rate controlling agent in the second release portion is from about 1:1 to about 1:30 (w / w), optionally from about 1:5 to about 1:15 (w / w).

51. 51. The multi-layer tablet, capsule, or suspension of claim 49 or 50, wherein the rate-controlling agent is selected from the group consisting of water-soluble excipients, water-insoluble excipients, water-permeable excipients, and combinations thereof.

52. The rate control agent is selected from the group consisting of hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and derivatives thereof, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate, polyethylene glycol, polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose triacetate, methacrylic acid copolymer, hypromellose acetate succinate, poly(methyl methacrylate), poly(ethyl methacrylate), poly 52. The multi-layer tablet, capsule, or suspension of any one of claims 49 to 51, wherein the polyisoprene copolymer is selected from the group consisting of butyl methacrylate, poly(methyl acrylate), beeswax, carnauba wax, paraffin wax, microcrystalline wax, ozokerite, cetostearyl alcohol, stearyl alcohol, cetyl alcohol, myristyl alcohol, glyceryl monostearate, glyceryl palmitostearate, glycerol monooleate, glyceryl behenate, cetyl esters, acetylated monoglycerides, tristearin, tripalmitin, hydrogenated vegetable oils, and combinations thereof.

53. 52. The multilayer tablet, capsule, or suspension of any one of claims 49 to 51, wherein the rate controlling agent is a polymer.

54. 54. The multi-layer tablet, capsule, or suspension of claim 53, wherein the rate-controlling agent is a hydrophilic polymer selected from hypromellose; hydroxypropyl cellulose (HPC); hydroxyethyl cellulose (HEC); polyethylene oxide; polyvinyl alcohol; povidone; xanthan gum; guar gum; chitosan; chitosan derivatives; carbomer; carrageenan; carboxymethyl cellulose; sodium alginate; polysaccharified glycerides; polyethylene glycol; polyvinyl acetate dispersions; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose triacetate; methacrylic acid copolymers; hypromellose acetate succinate; and combinations thereof.

55. The rate control agent may be selected from the group consisting of poly(methyl methacrylate), poly(ethyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), ethyl cellulose, cellulose protease, and the like.

54. The multi-layer tablet, capsule, or suspension of claim 53, wherein the hydrophobic polymer is selected from the group consisting of cellulose acetate propionate; cellulose acetate propionate; and combinations thereof.

56. 52. The multi-layer tablet, capsule, or suspension of any one of claims 49 to 51, wherein the rate controlling agent is a non-polymeric agent selected from waxes; fatty alcohols; fatty acid esters; hydrogenated vegetable oils; and combinations thereof.

57. 57. The multilayer tablet, capsule, or suspension of any one of claims 46 to 56, wherein the first-release portion comprises from about 4.5 to about 18 mg of midodrine hydrochloride and the second-release portion comprises from about 10.5 to about 42 mg of midodrine hydrochloride.

58. 58. The multilayer tablet, capsule, or suspension of any one of claims 46-57, wherein there is no second increase in in vitro dissolution release rate from about 5 hours to about 10 hours after the start of the in vitro dissolution test.

59. 59. The multilayer tablet, capsule, or suspension of any one of claims 46 to 58, wherein the active agent is present in the first release portion in an amount of about 20% to about 40% of the total weight of the active agent in the composition, and the active agent is present in the second release portion in an amount of about 60% to about 80% of the total weight of the active agent in the composition.

60. 60. The multi-layer tablet, capsule, or suspension of any one of claims 46 to 59, wherein the first release portion comprises a rapid release layer and the second release portion comprises one or more sustained release layers.

61. 60. The multi-layer tablet, capsule, or suspension of any one of claims 46 to 59, wherein the composition contains no more than two or three drug-containing layers.

62. 62. The pharmaceutical composition or multi-layer tablet according to any one of claims 1 to 61, comprising a film coating.

63. 60. The multi-layer tablet, capsule, or suspension of any one of claims 46 to 59, wherein the first release portion comprises a plurality of rapid release pellets and the second release portion comprises a plurality of sustained release pellets.

64. 47. The multi-layer tablet, capsule, or suspension of claim 46, wherein the first-release portion comprises about 4 mg of midodrine hydrochloride and the second-release portion comprises about 16 mg of midodrine hydrochloride.

65. 65. The multi-layer tablet, capsule, or suspension of claim 64, wherein the second release portion further comprises a rate controlling agent comprising a hydrophilic polymer and a non-polymeric agent.

66. 66. The multi-layer tablet, capsule, or suspension of claim 65, wherein the rate controlling agent comprises a methacrylic acid copolymer and a fatty acid ester.

67. 66. The multi-layer tablet, capsule, or suspension of claim 65, wherein the rate controlling agent comprises methacrylic acid and ethyl acrylate copolymer (1:1) and glyceryl behenate.

68. 68. A method for treating orthostatic hypotension or postural orthostatic tachycardia syndrome (POTS) in a subject, comprising administering to a subject in need thereof the pharmaceutical composition, multi-layer tablet, capsule, or suspension of any one of claims 1 to 67.

69. 69. The method of claim 68, wherein the pharmaceutical composition, multi-layer tablet, capsule, or suspension is administered once or twice daily.

70. 69. The method of claim 68, wherein the pharmaceutical composition, multi-layer tablet, capsule, or suspension is administered once daily.

71. 71. The method of any one of claims 68 to 70, wherein the subject suffers from autonomic neuropathy, postural orthostatic tachycardia syndrome (POTS), retrograde ejaculation or other disorders of ejaculation, Bradbury-Eggleston syndrome, Shy-Drager syndrome, diabetes, or Parkinson's disease.

72. 72. The method of any one of claims 68 to 71, wherein the subject suffers from orthostatic hypotension resulting from autonomic failure.

73. 73. The method of any one of claims 68 to 72, wherein the subject suffers from Bradbury-Eggleston syndrome, Shy-Drager syndrome, diabetes, or Parkinson's disease.

74. 73. The method of any one of claims 68 to 72, wherein the subject suffers from Parkinson's disease.

75. 73. The method of any one of claims 68-72, wherein a single dose of the pharmaceutical composition, multi-layer tablet, capsule, or suspension of any one of claims 1-67 contains about 10% to 70% more active agent than the total amount of active agent in three immediate release tablets of 2.5 mg, 5 mg, or 10 mg.

76. 76. The method of claim 75, wherein the single dose of the pharmaceutical composition, multi-layer tablet, capsule, or suspension contains about 40% more active agent than the total amount of active agent in three immediate-release tablets of 2.5 mg, 5 mg, or 10 mg.

77. 77. The method of claim 75 or 76, wherein the single dose of the pharmaceutical composition, multi-layer tablet, capsule, or suspension contains 10 mg, 20 mg, or 40 mg of the active agent.

78. 68. A kit comprising a first formulation and a second formulation comprising the same or different active agents, wherein the first formulation comprises the pharmaceutical composition or multi-layer tablet of any one of claims 1 to 67.

79. 79. The kit of claim 78, wherein the second formulation is an immediate release formulation comprising an active agent selected from the group consisting of midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, and combinations thereof, wherein the active agent is present in an amount of about 2.5 mg to about 20 mg and is formulated to release substantially all of the active agent within about 1 hour of administration of the second formulation to a patient.

80. 80. The kit of claim 78 or 79, wherein the second formulation further comprises a second active agent.

81. 81. The kit of claim 80, wherein the second active agent is selected from the group consisting of hydrocortisone, fludrocortisone, octreotide, desglimidorine, pharmaceutically acceptable salts thereof, and any combination thereof.

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