# US 10,307,429 B2 · Complexes of celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them

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- Number: US 10,307,429 B2
- Document ID: US10307429B2
- Status: Granted
- Kind: B2
- Application number: 15/380,219
- Filed: 2016-12-15
- Published: 2018-01-04
- Granted: 2019-06-04
- Earliest claimed: 2015-12-16
- Assignees: Druggability Technologies IP Holdco Limited
- Applicants: Druggability Technologies IP Holdco Limited
- Inventors: Erzsébet Réka Angi; Tamás Jordán; Richárd Balázs Kárpáti; Gergo Patyi; Orsolya Basa-Dénes; Tamás Solymosi; Zsolt Ötvös; László Molnár; Hristos Glavinas; Genovéva Filipcsei
- Web page: https://patentgrep.com/patent/US10307429B2

## CPC

- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- 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 9/10: Dispersions; Emulsions
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers}
- A61K 31/415: 1,2-Diazoles
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- B01F 23/00: Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
- C07D 231/10: having two or three double bonds between ring members or between ring members and non-ring members
- 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 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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
- B01F: MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING (mixing paints B44D3/06)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed herein are stable complexes with controlled particle size, increased apparent solubility and increased dissolution rate comprising as active compound Celecoxib, its salts, or derivatives thereof, which is useful in the treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain especially in cancer related acute pain, primary dysmenorrhea. More specifically, the complexes possess instantaneous redispersibility, increased apparent solubility and permeability that provide faster onset of action for acute pain relief and lower GI related side effects. Further disclosed are methods of formulating and manufacturing the complexes described herein, pharmaceutical compositions, and uses and methods of treatment.

## Claims

### Claim 1

A stable complex comprising as active compound amorphous Celecoxib; at least one complexation agent that is vinylpyrrolidone/vinyl acetate copolymer; and at least one pharmaceutically acceptable excipient that is sodium lauryl sulfate; said complex characterized in that it
a) has a PAMPA permeability of at least 0.5×10−6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 1 month; and
b) has a dissolution of at least 90% at 10 minutes.

### Claim 2 (depends on 1)

The complex as recited in claim 1, wherein said complex has a controlled particle size in the range between 10 nm and 500 nm.

### Claim 3 (depends on 2)

The complex as recited in claim 2, wherein said particle size is between 10 nm and 200 nm.

### Claim 4 (depends on 1)

The complex as recited in claim 1, wherein said complex is shows earlier tmax and time to onset of action when compared to the current oral formulation.

### Claim 5 (depends on 1)

The complex as recited in claim 1, wherein said complex has an increased dissolution rate compared to Celebrex®.

### Claim 6

A stable complex comprising an active compound selected from the group of Celecoxib; at least one complexation agent that is copolymers of vinylpyrrolidone and vinyl-acetate; and at least one pharmaceutically acceptable excipient that is sodium lauryl sulfate; wherein said complex obtained via a mixing process.

### Claim 7 (depends on 6)

The complex as recited in claim 6, wherein said complex is obtained via a continuous flow mixing process.

### Claim 8 (depends on 1)

A complex according to claim 1 comprising a complexation agent that is a copolymer of vinylpyrrolidone and vinyl acetate; and a pharmaceutically acceptable excipient that is sodium lauryl sulfate; in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.

### Claim 9 (depends on 8)

The complex as recited in claim 8 wherein said complexation agent is a copolymer of vinylpyrrolidone and vinyl acetate; and pharmaceutically acceptable excipient that is sodium lauryl sulfate; comprise 50 weight % to about 95 weight % of the total weight of the complex.

### Claim 10 (depends on 6)

A process for the preparation of the complex according to claim 6, comprising the steps of mixing a solution comprising Celecoxib, and at least one complexation agent that is copolymers of vinylpyrrolidone and vinyl-acetate in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically accepted excipient that is-sodium lauryl sulfate.

### Claim 11 (depends on 10)

The process as recited in claim 10, wherein said process is performed in a continuous flow instrument.

### Claim 12 (depends on 11)

The process as recited in claim 11, wherein said continuous flow instrument is a microfluidic flow instrument.

### Claim 13 (depends on 10)

The process as recited in claim 10, wherein said pharmaceutically acceptable solvent is chosen from methanol, ethanol, 2-propanol, 1-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, and methyl-ethyl-ketone, or combinations thereof.

### Claim 14 (depends on 13)

The process as recited in claim 13 wherein said pharmaceutically acceptable solvent is chosen from methanol, 1-propanol, and 2-propanol.

### Claim 15 (depends on 10)

The process as recited in claim 10, wherein the solvent and the aqueous solution are miscible with each other.

### Claim 16 (depends on 10)

The process as recited in claim 10, wherein the aqueous solution comprises 0.1 to 99.9% weight of the final solution.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the complex according to claim 1 together with pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising the complex according to claim 1 wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.

### Claim 19 (depends on 18)

The pharmaceutical composition comprising the complex according to claim 18, wherein said composition is suitable for oral administration.

### Claim 20 (depends on 19)

The pharmaceutical composition comprising the complex according to claim 19, wherein said composition comprises liquid dispersible granules.

### Claim 21 (depends on 20)

The pharmaceutical composition comprising the complex according to claim 20, wherein said granules are suitable for the preparation of a sachet or buccal powder dosage forms.

### Claim 22 (depends on 1)

A method of treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain especially in cancer related acute pain, primary dysmenorrhea comprising administration of a therapeutically effective amount of the complex according to claim 1.

### Claim 23 (depends on 21)

A method for reducing tmax and time to onset of action when compared to the current oral formulation, said method comprising oral administration of a pharmaceutical composition according to claim 21.

### Claim 24

A stable complex comprising
a) 5-30% by weight of Celecoxib;
b) 40-80% by weight of a copolymer of vinylpyrrolidone and vinyl acetate; and
c) 1-30% by weight of sodium lauryl sulfate
wherein said complex has a controlled particle size in the range between 10 nm and 500 nm; and
wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.

### Claim 25 (depends on 1)

The complex as recited in claim 1, wherein said complex is instantaneously redispersable in physiological relevant media.

### Claim 26 (depends on 1)

The complex as recited in claim 1, wherein said complex is stable in solid form and in colloid solution and/or dispersion.

### Claim 27 (depends on 1)

The complex as recited in claim 1, wherein said complex has an apparent solubility in water of at least 1 mg/mL.