Topical Bioadhesive Formulations

• US 20090155193A1
• Filed: 12/09/2005
• Published: 06/18/2009
• Est. Priority Date: 01/14/2005
• Status: Active Grant

• Current Assignee: Camurus AB
• Original Assignee: Camurus AB
• Inventors: Linden, Margareta, Tiberg, Fredrik, Thuresson, Krister, Joabsson, Fredrik
• Granted Patent: US 8,920,782 B2
• Time in Patent Office: Days
• US Class Current: 424/59
• CPC Class Codes: A61K 2800/48 Thickener, Thickening system
• CPC Class Codes: A61K 2800/59 Mixtures
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: 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
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: 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
• CPC Class Codes: A61K 8/0295 Liquid crystals
• CPC Class Codes: A61K 8/21 Fluorides; Derivatives thereof
• CPC Class Codes: A61K 8/34 : Alcohols
• CPC Class Codes: A61K 8/37 : Esters of carboxylic acids
• CPC Class Codes: A61K 8/375 : the alcohol moiety containing more than one hydroxy group
• CPC Class Codes: A61K 8/494 : with more than one nitrogen as the only hetero atom
• CPC Class Codes: A61K 8/553 : Phospholipids, e.g. lecithin
• CPC Class Codes: A61K 8/92 : Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0043 : Nose
• CPC Class Codes: A61K 9/0048 : Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/006 : Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/0063 : Periodont
• CPC Class Codes: A61K 9/12 : Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61K 9/1274 : Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
• CPC Class Codes: A61K 9/7015 : Drug-containing film-forming compositions, e.g. spray-on
• CPC Class Codes: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 : Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 15/08 : for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/10 : Anti-acne agents
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61Q 11/00 : Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: A61Q 17/04 : Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• CPC Class Codes: A61Q 19/00 : Preparations for care of the skin

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

1. A pre-formulation comprising a low viscosity mixture of:

a) at least one neutral diacyl lipid and/or a tocopherol;

b) at least one phospholipid;

c) at least one biocompatible organic solvent;

optionally including at least one bioactive agent 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.

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

3. A pre-formulation as claimed in claim 1, wherein component a) consists essentially of diacyl glycerols.

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

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

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

7. A preformulation as claimed in claim 6, having 35 to 60% by weight a), 20 to 50% by weight b) and 10 to 20% by weight c).

8. A preformulation as claimed in claim 7, wherein component c) is an alcohol.

9. A preformulation as claimed in claim 1, additionally comprising up to 10% by weight of a)+b) of a charged amphiphile.

10. A preformulation as claimed in claim 9, 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/suppressors.

11. A preformulation as claimed in claim 10, which is administrable by rinsing, spraying, gargling, as a patch, by suppository or by enema.

12. A preformulation as claimed in claim 11, comprising benzydamine

13. A topical formulation for intraoral administration which forms a bioadhesive, controlled release product and comprises a preformulation of claims 1, 6 or 9, wherein said active agent comprises at least one selected from;

benzydamine, tramadol, Acetaminophen, Ibuprofen, Propoxyphene, Codeine, Dihydrocodeine, Hydrocodone, Oxycodone, Nalbuphine, Meperidine, Leverorphanol, Hydromorphone, Oxymorphone, Alfentanil, Fentanyl and Sefentanil.

14. A topical preformulation as claimed in suitable for intraoral administration for treatment of periodontal and topical infections and comprising a preformulation of claims 1, 6 or 9, wherein the active agent is chlorhexidine gluconate, and where the preformulation is applied as a liquid product which forms a surface gel in situ between 1 second, and 5 min after application.

15. A topical formulation as claimed in suitable for ocular administration and comprising a preformulation of claims 1, 6 or 9, wherein said active agent comprises at least one selected from diclofenac, pilocarpine, levocabastine hydrochloride, ketotifen fumarate, timolol, betaxolol, carteolol, levobunolol, dorzolamide, brinzolamide, epinephrine, dipivefrin, clonidine, apraclonidine, brimonidine, pilocarpine, atanoprost, travoprost, bimatoprost, unoprostone, pilocarpine hydrochloride, dexamethasone, chloramphenicol, and indomethacin.

16. A topical formulation for dermatological administration which forms a bioadhesive, controlled release product and comprises a preformulation of claim 1, 6 or 9, wherein the active agent is selected from cosmetic agents, fragrances, flavourings, essential oils UV absorbing agents and mixtures thereof.

21. A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a preformulation as claimed in any of claims 1, 6 or 9.

22. A method for the treatment of a human or animal subject comprising administration of a preformulation as claimed in any of claims 1, 6 or 9.

23. A method as claimed in claim 22, for the treatment of inflammation and/or irritation at a body surface and/or in a body cavity.

24. The method as claimed in claim 23, wherein said inflammation is caused by Crohn'"'"'s disease, ulcerative colitis or oral mucositis.

26. A 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% benzydamine, or a derivative thereof.

17. A method of delivery of a bioactive agent to a human or non-human animal body, this method comprising administering a pre-formulation comprising a non-liquid crystalline, low viscosity mixture 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; and

at least one bioactive agent is dissolved or dispersed in the low viscosity mixture, whereby to form at least one liquid crystalline phase structure upon contact with an aqueous fluid in vivo following administration.

27. A method as claimed in claim 17, wherein in the pre-formulation:

the liquid crystalline phase structure is bioadhesive, component a) consists essentially of diacyl glycerols, component b) is phosphatidylcholine, and the viscosity ranges from 0.1 to 5000 mPas.

18. (canceled)

19. (canceled)

20. (canceled)

25. (canceled)