# US 12,213,953 B2 · Extended release midodrine hydrochloride compositions and methods of use

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- Number: US 12,213,953 B2
- Document ID: US12213953B2
- Status: Granted
- Kind: B2
- Application number: 16/956,273
- Filed: 2018-12-21
- Published: 2020-10-29
- Granted: 2025-02-04
- Earliest claimed: 2017-12-22
- Assignees: Xenamed Corp.
- Applicants: Xenamed Corp.
- Inventors: Yogesh Dandiker; Maulik Kiritkumar Panchal; Xiao Yu
- Web page: https://patentgrep.com/patent/US12213953B2

## CPC

- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 9/0004: {Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/205: {Polysaccharides, e.g. alginate, gums; Cyclodextrin}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 9/2095: {Tabletting processes}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

This disclosure provides pharmaceutical compositions comprising midodrine, a pharmaceutically acceptable salt thereof, desglymidodrine, or a pharmaceutically acceptable salt thereof, that can be administered to a human subject in need thereof. The disclosure also provides pharmaceutical compositions for treatment of orthostatic hypotension that can be administered once or twice a day.

## Claims

### Claim 1

A pharmaceutical composition comprising:
a first release portion comprising an active agent in a range of about 20% to about 40% (w/w) of a total amount of the active agent in the composition;
a second release portion comprising the active agent in a range of about 60% to about 80% (w/w) of the total amount of the active agent in the composition; and
a rate controlling agent, 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 a combination thereof, and wherein the rate controlling agent is present in a weight ratio of the active agent in the second release portion of the composition to the rate controlling agent of about 1:1 to about 1:30 (w/w);
wherein the in vitro release rate of the active agent, measured by an in vitro dissolution test comprises (i) a first release that is relatively fast and (ii) a second release, wherein the second release does not include a second rise in release rate that takes place about 5 hours to about 10 hours after 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; and
wherein the second release comprises a second rise in release rate that takes place about 2 to about 4.5 hours after start of the in vitro dissolution test.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, further comprising:
(iii) a third release which includes a third rise in release rate that takes place about 5 hours to about 8 hours after start of the in vitro dissolution test, and
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.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the first release portion comprises about 1.5 mg to about 45 mg of active agent and an excipient, 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 comprises about 3.5 mg to about 105 mg of 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 amount of active agent in the second release portion to the amount of rate controlling agent is a ratio of about 1:1 to about 1:30 (w/w), and the total amount of the active agent is about 5 mg to about 150 mg.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, 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 a subject; and substantially all of the active agent in the second release portion is released over a period of time between about 1 hour after administration of the composition to the subject and up to about 16 hours after administration of the composition to a subject.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the in vitro dissolution test was performed with USP Apparatus I (baskets) at 100 rpm in 900 mL at 37° C. for 0-2 hours in 0.1N HCl (pH 1.2); for 2-4 hours in acetate buffer (pH 4.5); and for 4-16 hours or 4-12 hours in phosphate buffer (pH 6.8).

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the active agent is present in a total amount of about 7.5 mg to about 120 mg.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the in vitro release rate of the active agent during the second release phase is slower compared to the in vitro release rate of the active agent released during the first release phase.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a multilayer tablet, or a capsule comprising a plurality of fast release pellets and a plurality of extended release pellets.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, 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.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition to a subject provides (i) a relatively fast peak plasma concentration reaching at least about 12 ng/ml of desglymidodrine within about 1 hour and (ii) a plasma concentration of desglymidodrine 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.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a multi-layer tablet, a capsule, or suspension, wherein:
the first release portion comprises an amount of the active agent in the range of about 1.5 mg to 45 mg; the second release portion comprises an amount of the active agent in the range of about 3.5 mg to about 105 mg; and
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 slower rate than the release rate of the first release portion in an in vitro dissolution test.

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13, wherein the second release portion comprises a rate controlling agent, 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 a combination thereof, and wherein the amount of active agent in the second release portion to the amount of rate controlling agent is a ratio of about 1:1 to about 1:30 (w/w), optionally about 1:5 to about 1:15 (w/w).

### Claim 15 (depends on 13)

The pharmaceutical composition of claim 13, wherein the second release portion further comprises a-rate controlling agent comprises comprising a methacrylic acid copolymer and a fatty acid ester.

### Claim 16 (depends on 1)

A method for treating orthostatic hypotension or postural orthostatic tachycardia syndrome (POTS) in a subject comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein a single dose of the pharmaceutical composition comprises about 10% to 70% more than the total amount of active agent in three 2.5 mg, 5 mg, or 10 mg immediate release tablets.

### Claim 18 (depends on 1)

A kit comprising:
a first formulation and a second formulation, wherein the first and second formulations comprise the same active agent or different active agents, and
the first formulation comprises a pharmaceutical composition of claim 1.