# US 10,925,835 B2 · Celecoxib and amlodipine formulation and method of making the same

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- Number: US 10,925,835 B2
- Document ID: US10925835B2
- Status: Granted
- Kind: B2
- Application number: 17/006,959
- Filed: 2020-08-31
- Published: 2020-12-17
- Granted: 2021-02-23
- Earliest claimed: 2017-07-06
- Assignees: Dexcel Ltd.; Kitov Pharmaceuticals Ltd.
- Applicants: Dexcel Ltd.; Kitov Pharmaceuticals
- Inventors: Yitshak Itsik Efrati
- Web page: https://patentgrep.com/patent/US10925835B2

## CPC

- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- 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 31/415: 1,2-Diazoles
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61K 47/38: Cellulose; Derivatives thereof
- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- A61K 31/4422: 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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

Provided herein is a celecoxib and amlodipine composition and method of making the same. The composition contains granules containing celecoxib. The amlodipine is incorporated into the composition as an extragranulate.

## Claims

### Claim 1

A method for treating pain and/or hypertension, and ameliorating celecoxib-induced elevation of blood pressure in a subject, comprising providing to the subject a pharmaceutical composition comprising
(i) an admixture comprising
a dry granulate comprising celecoxib or a pharmaceutically acceptable salt, wherein said dry granulate has a loss on drying (LOD) % of about 2.5% or less, wherein said dry granulate does not include amlodipine; and
an extragranulate comprising amlodipine or a pharmaceutically acceptable salt thereof admixed with the dry granulate; and
(ii) one or more excipients selected from the group consisting of a diluent, a disintegrant, a surfactant, a binder, a glidant, a lubricant, and combinations thereof, wherein the amount of celecoxib is sufficient to cause elevation in blood pressure, and wherein the amount of amlodipine is sufficient to ameliorate blood pressure elevation.

### Claim 2 (depends on 1)

The method of claim 1, wherein each of the dry granulate and the extragranulate includes at least one of the one or more excipients, and wherein the at least one of the one or more excipients in the dry granulate and the at least one of the one or more excipients in the extragranulate are the same or different.

### Claim 3 (depends on 1)

The method of claim 1, wherein the one or more excipients includes a diluent selected from the group consisting lactose, sucrose, mannitol, sorbitol, calcium phosphate, cellulose, kaolin, sodium chloride, and starch.

### Claim 4 (depends on 1)

The method of claim 1, wherein the one or more excipients includes a disintegrant selected from the group consisting of cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, pregelatinized starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, and magnesium aluminum silicate.

### Claim 5 (depends on 1)

The method of claim 1, wherein the one or more excipients includes a surfactant selected from the group consisting of stearyl triethanolamine, sodium lauryl sulfate, sodium taurocholate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and polyvinyl alcohol.

### Claim 6 (depends on 1)

The method of claim 1, wherein the one or more excipients includes a binder selected from the group consisting of polyvinylpyrrolidone (povidone; PVP), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate, alginic acid, guar gum, acacia gum, xanthan gum, carbopol, carboxymethyl cellulose, ethyl cellulose, maltodextrin, vinylpyrrolidone/vinyl acetate copolymer, microcrystalline cellulose, starch, and methyl cellulose.

### Claim 7 (depends on 1)

The method of claim 1, wherein the one or more excipients includes a glidant selected from the group consisting of corn starch, colloidal silicon dioxide, silica anhydrous, and talc.

### Claim 8 (depends on 1)

The method of claim 1, wherein the one or more excipients includes a lubricant selected from the group consisting of magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, talc, polyethylene glycol, and hydrogenated vegetable oil.

### Claim 9 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is in the form of a tablet, a caplet, or a capsule.

### Claim 10 (depends on 1)

The method of claim 1, wherein the dry granulate has LOD % in the range of from about 0.5% to about 2%.

### Claim 11 (depends on 1)

The method of claim 1, wherein the dry granulate has LOD % in the range of from about 0.5% to about 1.5%.

### Claim 12 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition comprises 200 mg celecoxib and 2.5, 5, or 10 mg amlodipine.

### Claim 13 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.

### Claim 14 (depends on 1)

The method of claim 1, wherein the dry granulate comprises celecoxib, a diluent, a disintegrant, a binder, and a surfactant; and wherein the extragranulate comprises amlodipine besylate, a diluent, a disintegrant, a glidant, and a lubricant.

### Claim 15

A method for treating pain and/or hypertension, and ameliorating celecoxib-induced elevation of blood pressure in a subject, comprising providing to the subject a pharmaceutical composition comprising a combination of celecoxib and amlodipine, wherein the pharmaceutical composition is prepared from a wet granulation of celecoxib or a pharmaceutically acceptable salt thereof and one or more excipients to obtain a wet granulate, wherein said wet granulate does not include amlodipine, wherein the wet granulate was dried to obtain a dry granulate, wherein the dry granulate has a loss on drying (LOD) % of about 2.5% or less, wherein the dry granulate was admixed with an extragranulate comprising amlodipine or a pharmaceutically acceptable salt thereof and optionally one or more excipients, wherein the amount of celecoxib is sufficient to cause elevation in blood pressure, and wherein the amount of amlodipine is sufficient to ameliorate blood pressure elevation.

### Claim 16 (depends on 15)

The method of claim 15, wherein the dry granulate has LOD % in the range of from about 0.5% to about 2%.

### Claim 17 (depends on 15)

The method of claim 15, wherein the dry granulate has LOD % in the range of from about 0.5% to about 1.5%.

### Claim 18 (depends on 15)

The method of claim 15, wherein the wet granulation was formed by dry mixing celecoxib or a pharmaceutically acceptable salt thereof and one or more excipients to obtain a dry mixture, and spraying the dry mixture with a granulation solution or suspension to obtain a wet granulate.

### Claim 19 (depends on 18)

The method of claim 18, wherein the granulation solution or suspension comprises an aqueous medium.

### Claim 20 (depends on 18)

The method of claim 18, wherein the granulation solution or suspension comprises an organic medium.

### Claim 21 (depends on 15)

The method of claim 15, wherein the extragranulate comprises one or more excipients, and wherein the one or more excipients in the wet granulate and the one or more excipients in the extragranulate are the same or different selected from the group consisting of a diluent, a disintegrant, a surfactant, a binder, a glidant, a lubricant, and combinations thereof.

### Claim 22 (depends on 15)

The method of claim 15, wherein the dry granulate was milled to produce a milled dry granulate prior to being admixed with the extragranulate.

### Claim 23 (depends on 15)

The method of claim 15, wherein the pharmaceutical composition was compressed to obtain a tablet or a caplet.

### Claim 24 (depends on 15)

The method of claim 15, wherein the subject has osteoarthritis.