# US 10,864,199 B2 · Tacrolimus for improved treatment of transplant patients

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- Number: US 10,864,199 B2
- Document ID: US10864199B2
- Status: Granted
- Kind: B2
- Application number: 15/041,986
- Filed: 2016-02-11
- Published: 2016-08-25
- Granted: 2020-12-15
- Earliest claimed: 2007-05-30
- Assignees: Veloxis Pharmaceuticals A/S
- Applicants: Veloxis Pharmaceuticals A/S
- Inventors: Robert D. Gordon; Per Holm; Anne-Marie Lademann; Tomas Norling
- Web page: https://patentgrep.com/patent/US10864199B2

## CPC

- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- 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 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

An extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for a once daily immunosuppressive treatment of a patient in need thereof, preferable a kidney or liver transplant patient. The dosage form releases the active substance over an extended period of time. It also provides improved pharmacokinetic parameters due to an extended and constant in vivo release including substantial decreased peak concentrations, despite increased bioavailability, substantial extended times for maximal concentration, and higher minimal concentrations when compared with conventional immediate release dosage forms and a recent modified release tacrolimus dosage form.

## Claims

### Claim 1

A method of suppressing kidney rejection in a kidney transplant patient comprising orally administering once daily in the evening to the kidney transplant patient an extended release pharmaceutical composition comprising tacrolimus, wherein
(i) the in vivo release of the extended release pharmaceutical composition after oral administration takes place substantially in the colon,
(ii) the extended release pharmaceutical composition further comprises a modifying release agent,
(iii) the pharmaceutical composition provides a substantially zero order release profile, and
(iv) at least 8% w/w of the tacrolimus in the composition is released within 4 hours, 40% w/w of the tacrolimus is released within 10 to 14 hours, and less than 62% w/w of the tacrolimus in the composition is released within 15 hours, when subjected to an in vitro dissolution test using the USP II Paddle method at a rotation speed of 50 ppm in a 900 mL aqueous dissolution medium at pH 4.5 with 0.005% hydroxypropylcellulose.

### Claim 2 (depends on 1)

The method of claim 1, wherein the in vivo release of the extended release pharmaceutical composition after oral administration takes place substantially in one or more of the colon ascendens, colon transversum and colon descendens.

### Claim 3 (depends on 1)

The method of claim 1, wherein the oral administration of the composition results in a plasma concentration of about 5 ng/mL to about 20 ng/mL for at least about 24 hours.

### Claim 4 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is administered once daily for at least 7 days.

### Claim 5 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition administered comprises from 0.1 to 15 mg of tacrolimus.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition administered comprises from 0.5 to 5 mg of tacrolimus.

### Claim 7 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition administered comprises 1 mg of tacrolimus.

### Claim 8 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is orally administered without simultaneous food intake.

### Claim 9 (depends on 1)

The method of claim 1, wherein the patient is a de novo kidney transplant patient.

### Claim 10 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition further comprises a hydrophilic or water-miscible vehicle, and the tacrolimus in the pharmaceutical composition is present in the vehicle.

### Claim 11 (depends on 10)

The method of claim 10, wherein the vehicle is selected from a polyethylene glycol, a polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone, polyglycolized glycerides, polyvinylpyrrolidone, polyvinyl-polyvinylacetate copolymer, polyvinyl alcohol, polymethacrylic polymer hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, a pectin, a cyclodextrin, galactomannan, alginate, carragenate, xanthan gum, and mixtures thereof.

### Claim 12 (depends on 10)

The method of claim 10, wherein the vehicle comprises poloxamer.

### Claim 13 (depends on 10)

The method of claim 10, wherein the vehicle comprises a mixture of polyethylene glycol and poloxamer.

### Claim 14

A method of suppressing kidney rejection in a kidney transplant patient comprising orally administering once daily to the kidney transplant patient an extended release pharmaceutical composition comprising tacrolimus without restriction as to the time of day of administration, wherein
(i) the pharmaceutical composition was prescribed without restriction as to the time of day of administration,
(ii) the in vivo release of the extended release pharmaceutical composition after oral administration takes place substantially in the colon,
(iii) the extended release pharmaceutical composition further comprises a modifying release agent,
(iv) the pharmaceutical composition provides a substantially zero order release profile, and
(v) at least 8% w/w of the tacrolimus in the composition is released within 4 hours, 40% w/w of the tacrolimus is released within 10 to 14 hours, and less than 62% w/w of the tacrolimus in the composition is released within 15 hours, when subjected to an in vitro dissolution test using the USP II Paddle method at a rotation speed of 50 ppm in a 900 mL aqueous dissolution medium at pH 4.5 with 0.005% hydroxypropylcellulose.

### Claim 15 (depends on 9)

The method of claim 9, wherein the treatment is initiated at a starting daily dose of 0.14 mg/kg of tacroliumus.

### Claim 16 (depends on 14)

The method of claim 14, wherein the patient is a de novo kidney transplant patient and the treatment is initiated at a starting daily dose of 0.14 mg/kg of tacroliumus.

### Claim 17

A method of suppressing kidney rejection in a kidney transplant patient being treated with an immediate release oral tacrolimus product, the method comprising:
(a) discontinuing treatment of the kidney transplant patient with the immediate release oral tacrolimus pharmaceutical composition; and
(b) initiating once daily oral administration to the kidney transplant patient in the evening of an extended release pharmaceutical composition comprising tacrolimus, wherein
(I) the in vivo release of the extended release pharmaceutical composition after oral administration takes place substantially in the colon,
(II) the ratio of (i) tacrolimus previously administered daily with the immediate release pharmaceutical composition to (ii) tacrolimus initially administered daily with the extended release pharmaceutical composition is 1:0.66-0.80,
(III) the extended release pharmaceutical composition further comprises a modifying release agent,
(IV) the pharmaceutical composition provides a substantially zero order release profile, and
(V) at least 8% w/w of the tacrolimus in the composition is released within 4 hours, 40% w/w of the tacrolimus is released within 10 to 14 hours, and less than 62% w/w of the tacrolimus in the composition is released within 15 hours, when subjected to an in vitro dissolution test using the USP II Paddle method at a rotation speed of 50 ppm in a 900 mL aqueous dissolution medium at pH 4.5 with 0.005% hydroxypropylcellulose.

### Claim 18 (depends on 17)

The method of claim 17, wherein the ratio of (i) tacrolimus administered daily with the immediate release pharmaceutical composition to (ii) tacrolimus initially administered daily with the extended release pharmaceutical composition is 1:0.80.

### Claim 19 (depends on 17)

The method of claim 17, wherein the extended release pharmaceutical composition is orally administered without simultaneous food intake.