# US 11,896,566 B2 · Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof

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- Number: US 11,896,566 B2
- Document ID: US11896566B2
- Status: Granted
- Kind: B2
- Application number: 16/583,903
- Filed: 2019-09-26
- Published: 2020-02-13
- Granted: 2024-02-13
- Earliest claimed: 2010-01-19
- Assignees: Catalent Ontario Limited
- Applicants: Catalent Ontario Limited
- Inventors: John Lopez; Peter Draper; Sankalp Vashishtha; Nancy Klassen; Christina Armstrong
- Web page: https://patentgrep.com/patent/US11896566B2

## CPC

- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 9/4833: {Encapsulating processes; Filling of capsules (mechanical aspects A61J3/07)}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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

This invention relates to a naproxen formulation suitable for encapsulation into a soft gel dosage unit by increasing the stability, concentration, and bioavailability of naproxen. Fill formulations of the invention may include other active pharmaceutical ingredients and combinations of two or more active pharmaceutical ingredients. This invention also provides for adjusting pH values of fill formulations without additional process steps. A process for increasing the achievable concentration of an active NSAID pharmaceutical ingredient, such as naproxen, relative to fill composition for dosage units is also provided. The highly concentrated formulation of this invention permits a reduction in the fill volume or dosage unit size, or an increase in concentration of the active pharmaceutical ingredient per dosage form. The invention also relates to a formulation of optimal stability suitable for supporting a fill composition compatible with the soft gel dosage unit.

## Claims

### Claim 1

A softgel dosage form, comprising:
a pharmaceutical fill formulation, consisting essentially of:
about 2% to about 25% of naproxen;
about 25% to about 2% of naproxen sodium, wherein the weight ratio of naproxen to naproxen sodium is about 9:1 to about 3:7;
about 40% to about 70% polyethylene glycol, wherein the polyethylene glycol is PEG 400;
about 1% to about 5% propylene glycol;
about 1% to about 6% povidone;
about 1% to about 10% water; and
phenylephrine hydrochloride,
wherein the total amount of naproxen and naproxen sodium ranges from about 22% to about 30% by weight of the total composition,
wherein the pH of the fill formulation is from about 4 to about 6,
wherein the fill formulation is free of a neutralization agent, and
wherein a volume of the fill formulation is less than a volume of a neutralized naproxen fill composition containing an equivalent dose of naproxen and naproxen sodium.

### Claim 2 (depends on 1)

The softgel dosage form of claim 1, wherein the phenylephrine hydrochloride is present in an amount ranging from about 0.01% to about 1% by weight of the total composition.

### Claim 3 (depends on 1)

The soft gel dosage form of claim 1, wherein the pharmaceutical fill formulation has a mass of not greater than about 900 mg.

### Claim 4 (depends on 1)

The softgel dosage form of claim 1, wherein the povidone is povidone K12.

### Claim 5 (depends on 1)

The softgel dosage form of claim 1, wherein the ratio of naproxen to naproxen sodium ranges from about 3:2 to about 2:3.

### Claim 6 (depends on 1)

The softgel dosage form of claim 1, wherein the ratio of naproxen to naproxen sodium is about 1:1.

### Claim 7 (depends on 1)

The softgel dosage form of claim 1, wherein the fill formulation is free of hydroxide ion.

### Claim 8 (depends on 1)

The softgel dosage form of claim 1, wherein the fill formulation comprises a mass of not greater than about 900 mg.

### Claim 9 (depends on 1)

The softgel dosage form of claim 1, wherein the softgel dosage form has a size of not greater than 14 oblong.

### Claim 10

A dosage form, comprising:
a pharmaceutical fill formulation of a non-steroidal anti-inflammatory drug (NSAID) suitable for encapsulation in a soft gel, consisting essentially of:
about 2% to about 25% of naproxen;
about 25% to about 2% of naproxen sodium, wherein the weight ratio of naproxen to naproxen sodium is about 9:1 to about 3:7;
about 40% to about 70% polyethylene glycol, wherein the polyethylene glycol is PEG 400;
about 1% to about 5% propylene glycol;
about 1% to about 6% povidone;
about 1% to about 10% water, and
wherein the total amount of naproxen and naproxen sodium ranges from about 22% to about 30% by weight of the total composition,
wherein the pH of the fill formulation is from about 2 to about 8,
wherein the fill formulation is free of a neutralization agent, and
wherein a volume of the fill formulation is less than a volume of a neutralized naproxen fill composition containing an equivalent dose of naproxen and naproxen sodium.

### Claim 11 (depends on 10)

The dosage form of claim 10, wherein the dosage form is a soft gel capsule.

### Claim 12 (depends on 10)

The dosage form of claim 10, wherein the dosage form has a size of not greater than 14 oblong.

### Claim 13 (depends on 10)

The dosage form of claim 10, wherein the ratio of naproxen to naproxen sodium ranges from about 3:2 to about 2:3.

### Claim 14 (depends on 10)

The dosage form of claim 10, wherein the ratio of naproxen to naproxen sodium is about 1:1.

### Claim 15 (depends on 10)

The dosage form of claim 10, wherein the formulation is free of hydroxide ion.

### Claim 16 (depends on 10)

The dosage form of claim 10, wherein the fill formulation comprises a mass of not greater than about 900 mg.

### Claim 17 (depends on 10)

The dosage form of claim 10, wherein the povidone is povidone K12.

### Claim 18

A pharmaceutical fill formulation, consisting essentially of:
about 2% to about 25% of naproxen;
about 25% to about 2% of naproxen sodium, wherein the weight ratio of naproxen to naproxen sodium is about 9:1 to about 3:7;
about 40% to about 70% polyethylene glycol, wherein the polyethylene glycol is PEG 400;
about 1% to about 5% propylene glycol;
about 1% to about 6% povidone;
about 1% to about 10% water, and
wherein the total amount of naproxen and naproxen sodium ranges from about 22% to about 30% by weight of the total composition,
wherein the pH of the fill formulation is from about 2 to about 8,
wherein the fill formulation is free of a neutralization agent, and
wherein a volume of the fill formulation is less than a volume of a neutralized naproxen fill composition containing an equivalent dose of naproxen and naproxen sodium.

### Claim 19 (depends on 18)

The pharmaceutical fill formulation of claim 18, wherein the povidone is povidone K12.

### Claim 20 (depends on 18)

The pharmaceutical fill formulation of claim 18, wherein the ratio of naproxen to naproxen sodium ranges from about 3:2 to about 2:3.

### Claim 21 (depends on 18)

The pharmaceutical fill formulation of claim 18, wherein the ratio of naproxen to naproxen sodium is about 1:1.

### Claim 22 (depends on 18)

The pharmaceutical fill formulation of claim 18, wherein the formulation is free of hydroxide ion.

### Claim 23 (depends on 18)

The pharmaceutical fill formulation of claim 18, comprising a mass of not greater than about 900 mg.