# US 2015/0147282 A1 · Topical bioadhesive formulations

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- Number: US 2015/0147282 A1
- Document ID: US20150147282A1
- Status: Published application
- Kind: A1
- Application number: 14/551,761
- Filed: 2014-11-24
- Published: 2015-05-28
- Earliest claimed: 2005-01-14
- Assignees: Camurus AB
- Applicants: Camurus AB
- Inventors: Fredrik JOABSSON; Margareta LINDEN; Krister THURESSON; Fredrik TIBERG
- Web page: https://patentgrep.com/patent/US20150147282A1

## CPC

- A61K 38/22: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35)
- A61K 8/0295: {Liquid crystals}
- A61K 8/21: Fluorides; Derivatives thereof
- A61K 8/34: Alcohols
- A61K 8/37: Esters of carboxylic acids
- A61K 8/375: {the alcohol moiety containing more than one hydroxy group}
- A61K 8/494: {with more than one nitrogen as the only hetero atom}
- A61K 8/553: {Phospholipids, e.g. lecithin}
- A61K 8/92: Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0043: {Nose}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/0063: {Periodont}
- A61K 9/12: Aerosols; Foams {(A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015)}
- A61K 9/1274: Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases
- A61K 9/7015: {Drug-containing film-forming compositions, e.g. spray-on}
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/191: having two or more hydroxy groups, e.g. gluconic acid
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 38/23: Calcitonins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- 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)
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 5/28: Antiandrogens
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/10: Anti-acne agents
- A61P 25/22: Anxiolytics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61Q 11/00: Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
- A61Q 17/04: Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
- A61Q 19/00: Preparations for care of the skin
- A61K 2800/48: Thickener, Thickening system
- A61K 2800/59: Mixtures
- 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
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

The present invention relates to topical bioadhesive formulations comprising low viscosity, non-liquid crystalline, mixtures of: a) at least one neutral diacyl lipid and/or at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The invention additionally relates to a method of delivery of an active agent comprising administration of a preformulation of the invention, a method of treatment comprising administration of a preformulation of the invention and the use of a preformulation of the invention in a method for the manufacture of a medicament.

## Claims

### Claim 1

A pre-formulation comprising a low viscosity mixture of:
a) at least one neutral lipid component comprising a polar head group linked to at least one non-polar tail group by an ester, and optionally at least one tocopherol;
b) at least one phospholipid;
c) 2 to 30 wt. % of at least one biocompatible, oxygen containing organic solvent selected from alcohols, amides, sulfoxides and mixtures thereof;
optionally including at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid and/or body surface.

### Claim 2 (depends on 1)

A pre-formulation as claimed in claim 1 wherein said polar head group is a polyol.

### Claim 3 (depends on 2)

A pre-formulation as claimed in claim 2 wherein the polyol is selected from glycerol, diglycerol or a sugar moiety.

### Claim 4 (depends on 3)

A pre-formulation as claimed in claim 3 wherein the sugar moiety is selected from an inositol or glucosyl based moiety.

### Claim 5 (depends on 1)

A pre-formulation as claimed in claim 1 wherein the polar head group is an esterified polyol, such as the acetate or succinate ester of a polyol.

### Claim 6 (depends on 1)

A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises a fatty acid ester of a polyol.

### Claim 7 (depends on 6)

A pre-formulation as claimed in claim 6 wherein the neutral lipid component comprises a fatty acid ester of a sugar.

### Claim 8 (depends on 1)

A pre-formulation as claimed in claim 1 wherein the neutral lipid component a) comprises at least one C6 to C32 alkyl or alkenyl group.

### Claim 9 (depends on 1)

A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises at least one non-polar tail group selected from caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups.

### Claim 10 (depends on 1)

A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises a sugar head group, and at least one fatty acid tail group selected from caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2) and linolenoyl (C18:3) groups.

### Claim 11 (depends on 1)

A pre-formulation as claimed in claim 1 wherein the neutral lipid component comprises a sugar head group, and at least one fatty acid tail group selected from palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2) and linolenoyl (C18:3) groups.

### Claim 12 (depends on 1)

A pre-formulation as claimed in claim 1 wherein component a) comprises two apolar tail groups.

### Claim 13 (depends on 1)

A pre-formulation as claimed in claim 1 further comprising a drug agent selected from drugs which act on cells and receptors, peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulation system, endocrine and hormone system, blood circulatory system, synoptic sites, neuroeffector junctional sites, the immunological system, the reproductive system, the skeletal system, autacoid system, the alimentary and excretory systems, the histamine system, and the central nervous system.

### Claim 14 (depends on 1)

The pre-formulation as claimed in claim 1 wherein said tocopherol is present and is selected from vitamin E, salts thereof and an analogues thereof.

### Claim 15 (depends on 1)

A pre-formulation as claimed in claim 1 wherein said liquid crystalline phase structure is bioadhesive.

### Claim 16 (depends on 1)

A pre-formulation as claimed in claim 1 wherein component b) is phosphatidylcholine.

### Claim 17 (depends on 1)

A preformulation as claimed in claim 1 having a viscosity of 0.1 to 5000 mPas.

### Claim 18 (depends on 1)

A preformulation as claimed in claim 1 having a molecular solution, L2 and/or L3 phase structure.

### Claim 19 (depends on 1)

A preformulation as claimed in claim 1 having 35 to 60% by weight a), 20 to 50% by weight b) and 10 to 20% by weight c).

### Claim 20 (depends on 1)

A preformulation as claimed in claim 1 wherein component c) is selected from an alcohol, ethanol, dimethylacetamide, N-methyl pyrrolidone and dimethylsulfoxide.

### Claim 21 (depends on 1)

A preformulation as claimed in claim 1 wherein said active agent is selected from corticosteroids, nonsteroidal anti-inflammatory compounds, local inhibitors of inflammatory pathways, phospholipase inhibitors, antioxidants, antiinfectives, cytokines and cytokine inducers/supressors.

### Claim 22 (depends on 1)

A preformulation as claimed in claim 1 which is administrable by rinsing, spraying, gargling, as a patch, by suppository or by enema.

### Claim 23 (depends on 1)

A topical formulation as claimed in claim 1 for dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is selected from UV absorbing agents.

### Claim 24 (depends on 1)

A method of delivery of a bioactive agent to a human or non-human animal (preferably mammalian) body, this method comprising administering a pre-formulation as claimed in claim 1.

### Claim 25 (depends on 1)

A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a preformulation as claimed in claim 1.

### Claim 26 (depends on 25)

A method as claimed in claim 25 for the treatment of inflammation and/or irritation at a body surface and/or in a body cavity.

### Claim 27 (depends on 26)

The method as claimed in claim 26 wherein said inflammation is caused by Crohn's disease, ulcerative collitus or oral mucositis.

### Claim 28

(canceled)

### Claim 29 (depends on 1)

Method for the treatment of oral mucositis in a human or animal subject comprising administration of a preformulation as claimed in claim 1, said composition comprising 40 to 60 wt % GDO, 20 to 35% PC, 5 to 25% ethanol, and 1 to 8% bezydamine, or a derivative thereof.

### Claim 30 (depends on 1)

The pre-formulation as claimed in claim 1 further comprising a UV absorbing agent.