# US 2016/0250232 A1 · A delayed release drug formulation

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- Number: US 2016/0250232 A1
- Document ID: US20160250232A1
- Status: Published application
- Kind: A1
- Application number: 15/028,863
- Filed: 2013-10-29
- Published: 2016-09-01
- Earliest claimed: 2013-10-29
- Assignees: Tillotts Pharma AG
- Applicants: Tillotts Pharma AG
- Inventors: Felipe Jose Oliveira VARUM; Roberto Carlos BRAVO GONZALEZ; Thomas BUSER; Abdul Waseh BASIT; Ana Cristina FREIRE
- Web page: https://patentgrep.com/patent/US20160250232A1

## CPC

- A61K 31/606: having amino groups
- A61J 3/005: {Coating of tablets or the like (coating of sweetmeats or confectionery A23G3/20; coating of granules in general B01J2/006)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2886: {having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer (of the type active core-drug layer-inactive layer A61K9/209)}
- A61K 9/2893: {Tablet coating processes (mechanical aspects A61J3/06)}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- 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)
- A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In a delayed release formulation comprising a core containing a drug and a delayed release coating for providing intestinal release, release of the drug in the colon is accelerated by including an isolation layer between the core and the delayed release coating. The delayed release coating comprises an inner layer and an outer layer. The outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above. The inner layer comprises a soluble polymeric material which is soluble in intestinal fluid or gastrointestinal fluid, said soluble polymeric material being selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralised, and a non-ionic polymer, provided that, where said soluble polymeric material is a non-ionic polymer, said inner layer comprises at least one additive selected from a buffer agent and a base.

## Claims

### Claim at position 1

1-49. (canceled)

### Claim 50

A method of producing a delayed release drug formulation for oral administration, wherein said formulation provides accelerated release of a drug in the intestine of a subject, said method comprising:
providing a core comprising said drug;
coating said core with an isolation layer to produce an isolated core; and
coating said isolated core with an outer coating for providing intestinal release of said drug, said outer coating comprising an outer layer and an inner layer,
wherein the outer layer comprises a pH dependently soluble polymeric material which has a pH threshold at about pH 5 or above, and
wherein the inner layer comprises a soluble polymeric material which is soluble in intestinal fluid or gastrointestinal fluid, said soluble polymeric material being selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralised, and a non-ionic polymer, provided that, where said soluble polymeric material is a non-ionic polymer, said inner layer comprises at least one additive selected from a buffer agent and a base.

### Claim at position 3

51-63. (canceled)

### Claim 64 (depends on 50)

The method of claim 50, wherein intestinal release of said drug from said formulation is accelerated compared to an equivalent formulation without said isolation layer.

### Claim 65 (depends on 50)

The method of claim 50, wherein said formulation is for use in accelerating drug release in the colon of said subject.

### Claim 66 (depends on 50)

The method of claim 50, wherein lag time (Tlag) of said formulation in vitro in Krebs buffer at pH 7.4 after 2 h at 0.1M HCl is reduced by at least 10%.

### Claim 67 (depends on 50)

The method of claim 50, wherein lag time (Tlag) of said formulation in vitro in Krebs buffer at pH 7.4 after 2 h at 0.1 M HCl is reduced by at least 10 minutes.

### Claim 68 (depends on 50)

The method of claim 50, wherein said formulation accelerates drug release in the small intestine of said subject.

### Claim 69 (depends on 50)

The method of claim 50, wherein said formulation accelerates drug release in the proximal small intestine of said subject.

### Claim 70 (depends on 50)

The method of claim 50, wherein said isolation layer has a coating amount from about 1 mg polymer/cm2 to about 5 mg polymer/cm2.

### Claim 71 (depends on 50)

The method of claim 50, wherein said isolation layer has a thickness from about 5 μm to about 100 μm.

### Claim 72 (depends on 50)

The method of claim 50, wherein said isolation layer comprises at least one non-ionic polymer.

### Claim 73 (depends on 50)

The method of claim 50, wherein said isolation layer comprises at least one polymer selected from the group consisting of methylcellulose (MC); hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol; polyvinylpyrollidone (PVP); and polyvinyl alcohol (PVA).

### Claim 74 (depends on 50)

The method of claim 50, wherein said isolation layer comprises HPMC.

### Claim 75 (depends on 50)

The method of claim 50, wherein said isolation layer comprises PVA.

### Claim 76 (depends on 74)

The method of claim 74, wherein HPMC is the sole film-forming polymeric material in the isolation layer.

### Claim 77 (depends on 75)

The method of claim 75, wherein PVA is the sole film-forming polymeric material in the isolation layer.

### Claim 78 (depends on 50)

The method of claim 50, wherein said core is acidic.

### Claim 79 (depends on 50)

The method of claim 50, wherein said drug, or any other component in the core, comprises at least one acidic group.

### Claim 80 (depends on 50)

The method of claim 50, wherein said drug is an anti-inflammatory agent.

### Claim 81 (depends on 50)

The method of claim 50, wherein said drug is 5ASA.

### Claim 82 (depends on 50)

The method of claim 50, wherein said soluble polymeric material of said inner layer is said polycarboxylic acid polymer that is at least partially neutralised.

### Claim 83 (depends on 82)

The method of claim 82, wherein at least 10% of the carboxylic acid groups of said polycarboxylic acid polymer are in the form carboxylate anions.

### Claim 84 (depends on 82)

The method of claim 82, wherein said polycarboxylic acid polymer is fully neutralised.

### Claim 85 (depends on 82)

The method of claim 82, wherein said pH dependently soluble polymeric material of said outer layer is based on the same polycarboxylic acid polymer as said soluble polymeric material of said inner layer, said the soluble polymeric material of said inner layer having a higher degree of neutralisation than said pH dependently soluble polymeric material of said outer layer.

### Claim 86 (depends on 82)

The method of claim 82, wherein said polycarboxylic acid polymer of said soluble polymeric material of said inner layer is polymethacrylate; cellulose acetate phthalate (CAP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose acetate succinate (HPMC-AS); cellulose acetate trimellitate (CAT); xanthan gum; alginate; or shellac.

### Claim 87 (depends on 82)

The method of claim 82, wherein said soluble polymeric material of said inner layer is an at least partially neutralised co-polymer of (meth)acrylic acid and a (meth)acrylic acid C1-4 alkyl ester.

### Claim 88 (depends on 82)

The method of claim 82, wherein said soluble polymeric material of said inner layer is a fully neutralised co-polymer of (meth)acrylic acid and (meth)acrylic acid methyl ester.

### Claim 89 (depends on 82)

The method of claim 82, wherein said inner layer comprises at least one additive selected from a buffer agent and a base.

### Claim 90 (depends on 50)

The method of claim 50, wherein said soluble polymeric material of said inner layer is said non-ionic polymer.

### Claim 91 (depends on 90)

The method of claim 90, wherein said non-ionic polymer of said inner layer is selected from HPMC; PVA; MC; HPC; poly(ethylene oxide)-graft-polyvinyl alcohol; and PVP.

### Claim 92 (depends on 50)

The method of claim 50, wherein the inner layer comprises a buffer agent and a base.

### Claim 93 (depends on 50)

The method of claim 50, wherein the buffer agent is selected from the group consisting of a carboxylic acid having from 1 to 16 carbon atoms, an alkali metal salt, an alkali earth metal salt, an ammonium salt and a soluble metal salt.

### Claim 94 (depends on 50)

The method of claim 50, wherein the buffer agent is a phosphate salt.

### Claim 95 (depends on 50)

The method of claim 50, wherein the buffer agent is potassium dihydrogen phosphate.

### Claim 96 (depends on 50)

The method of claim 50, wherein the buffer agent is present in the inner layer a total amount from about 0.1 wt % to about 50 wt % based on the dry weight of the soluble polymeric material of the inner layer.

### Claim 97 (depends on 50)

The method of claim 50, wherein the buffer agent is present in the inner layer in a total amount from about 0.1 wt % to about 20 wt % based on the dry weight of the at least partially neutralised polycarboxylic acid of the inner layer.

### Claim 98 (depends on 50)

The method of claim 50, wherein the buffer agent is present in the inner layer in a total amount from about 10 wt % to about 30 wt % based on the dry weight of the non-ionic polymer of the inner layer.

### Claim 99 (depends on 50)

The method of claim 50, wherein the base is selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates, or physiologically tolerated amines.

### Claim 100 (depends on 50)

The method of claim 50, wherein the base is a hydroxide base.

### Claim 101 (depends on 50)

The method of claim 50, wherein the base is sodium hydroxide.

### Claim 102 (depends on 50)

The method of claim 50, wherein the pH dependently soluble polymeric material of the outer layer is a blend of at least two different polymers having a pH threshold of about pH 5 and above.

### Claim 103 (depends on 102)

The method of claim 102, wherein the polymers in the blend are different polymethacrylate polymers.

### Claim 104 (depends on 102)

The method of claim 102, wherein there are two different polymers in the blend in a ratio from about 40:60 to about 60:40.

### Claim 105 (depends on 103)

The method of claim 103, wherein there are two different polymers in the blend in a ratio from about 40:60 to about 60:40.

### Claim 106 (depends on 50)

The method of claim 50, wherein said pH dependently soluble polymeric material is present in the outer layer as the sole film forming polymeric material.

### Claim 107 (depends on 50)

The method of claim 50, wherein said pH dependently soluble polymeric material is present in the outer layer in admixture with a digestible polymeric material which is susceptible to attack by colonic bacteria.

### Claim 108 (depends on 107)

The method of claim 107, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio of up to about 60:40.

### Claim 109 (depends on 107)

The method of claim 107, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio from about 25:75 to about 35:65.

### Claim 110 (depends on 108)

The method of claim 108, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio from about 25:75 to about 35:65.

### Claim 111 (depends on 107)

The method of claim 107, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio from about 40:60 to about 60:40.

### Claim 112 (depends on 108)

The method of claim 108, wherein said digestible polymeric material and said pH dependently soluble polymeric material are present in the outer layer in a ratio from about 40:60 to about 60:40.