# US 11,077,096 B2 · Modified release compositions comprising tacrolimus

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- Number: US 11,077,096 B2
- Document ID: US11077096B2
- Status: Granted
- Kind: B2
- Application number: 15/677,938
- Filed: 2017-08-15
- Published: 2018-08-16
- Granted: 2021-08-03
- Earliest claimed: 2003-08-29
- Assignees: Veloxis Pharmaceuticals, Inc.
- Applicants: Veloxis Pharmaceuticals A/S
- Inventors: Per Holm; Tomas Norling
- Web page: https://patentgrep.com/patent/US11077096B2

## 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 9/10: Dispersions; Emulsions
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- 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 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- 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 9/2846: {Poly(meth)acrylates}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61P 31/04: Antibacterial agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61K 9/1611: {Inorganic compounds}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2095: {Tabletting processes}
- A61K 9/2893: {Tablet coating processes (mechanical aspects A61J3/06)}
- 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

A modified release composition comprising tacrolimus releases less than 20% w/w of the active ingredient within 0.5 hours when subjected to an in vitro dissolution test using USP Paddle method and using 0.1 N HCl as dissolution medium and has increased bioavailability by effectively reducing or even avoiding the effects of CYP3A4 metabolism. The modified composition may be coated with an enteric coating; and/or may comprise a solid dispersion or a solid solution of tacrolimus in a hydrophilic or water-miscible vehicle and one or more modifying release agents; and/or may comprise a solid dispersion or a solid solution of tacrolimus in an amphiphilic or hydrophobic vehicle and optionally one or more modifying release agents.

## Claims

### Claim 1

A method of preparing an oral extended release pharmaceutical composition of tacrolimus, the method comprising:
(i) dissolving or dispersing tacrolimus in a vehicle to form a first composition, wherein the vehicle is a hydrophilic or water-miscible vehicle;
(ii) spraying the first composition onto carrier particles; and
(iii) blending the product of step (ii) with one or more modifying release agents.

### Claim 2 (depends on 1)

The method of claim 1, wherein the hydrophilic or water-miscible vehicle is selected from polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone, and mixtures thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the hydrophilic or water-miscible vehicle is selected from polyvinylpyrrolidones, polyvinyl-polyvinylacetate copolymers (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic polymers, cellulose derivatives including hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, pectins, cyclodextrins, galactomannans, alginates, carragenates, xanthan gums and mixtures thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the hydrophilic or water-miscible vehicle comprises polyethylene glycol (PEG).

### Claim 5 (depends on 4)

The method of claim 4, wherein the polyethylene glycol has an average molecular weight of at least 1500.

### Claim 6 (depends on 4)

The method of claim 4, wherein the polyethylene glycol has an average molecular weight of about 6000.

### Claim 7 (depends on 1)

The method of claim 1, wherein the hydrophilic or water-miscible vehicle comprises polyethylene glycol (PEG) and poloxamer.

### Claim 8 (depends on 7)

The method of claim 7, wherein poloxamer is poloxamer 188.

### Claim 9 (depends on 7)

The method of claim 7, wherein the weight ratio of polyethylene glycol to poloxamer is between 1:3 and 10:1.

### Claim 10 (depends on 1)

The method of claim 1, wherein the modifying release agents are selected from hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, poly (N-vinyl-2-pyrrolidinone) (PVP), poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, and any combination of any of the foregoing.

### Claim 11 (depends on 10)

The method of claim 10, wherein the modifying release agent is hydroxypropyl methyl cellulose (HPMC).

### Claim 12 (depends on 1)

The method of claim 1, wherein the carrier particles comprise lactose.

### Claim 13 (depends on 1)

An oral extended release pharmaceutical composition prepared by the method of claim 1.