# US 2014/0193347 A1 · Lipid depot formulations

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- Number: US 2014/0193347 A1
- Document ID: US20140193347A1
- Status: Published application
- Kind: A1
- Application number: 14/017,823
- Filed: 2013-09-04
- Published: 2014-07-10
- Earliest claimed: 2004-06-04
- Assignees: Camurus AB
- Applicants: Camurus AB
- Inventors: Krister THURESSON; Fredrik TIBERG; Markus JOHANSSON; Ian HARWIGSSON; Fredrik JOABSSON; Markus JOHNSSON
- Web page: https://patentgrep.com/patent/US20140193347A1

## CPC

- A61K 9/1274: Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases
- A61K 8/0295: {Liquid crystals}
- A61K 8/046: {Aerosols; Foams}
- A61K 8/37: Esters of carboxylic acids
- A61K 8/375: {the alcohol moiety containing more than one hydroxy group}
- A61K 8/498: {having 6-membered rings or their condensed derivatives, e.g. coumarin}
- A61K 8/553: {Phospholipids, e.g. lecithin}
- A61K 8/678: {Tocopherol, i.e. vitamin E}
- A61K 8/68: Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
- A61K 8/922: {of vegetable origin}
- A61K 9/0002: {Galenical forms characterised by the drug release technique; Application systems commanded by energy}
- 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 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/0043: {Nose}
- 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 9/7015: {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 31/198: 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 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 31/5685: having an oxo group in position 17, e.g. androsterone
- A61K 38/23: Calcitonins
- A61K 38/27: Growth hormone [GH], i.e. somatotropin
- A61K 38/31: Somatostatins
- 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
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/34: Tobacco-abuse
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61Q 3/02: Nail coatings
- 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 2800/10: General cosmetic use
- A61K 2800/592: Mixtures of compounds complementing their respective functions
- 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 pre-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 preformulations are suitable for generating parenteral, non-parenteral and topical depot compositions for sustained release of active agents. 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, non-liquid crystalline, 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;
wherein at least one bioactive agent is optionally dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, at least one liquid crystalline phase structure upon contact with an aqueous fluid.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a) consists essentially of diacyl glycerols, especially glycerol dioleate.

### Claim 4 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a) consists essentially of at least one tocopherol.

### Claim 5 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component a) consists essentially of a mixture of GDO and tocopherol.

### Claim 6 (depends on 1)

The pre-formulation as claimed in claim 1 wherein component b) is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and a mixture thereof.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

The preformulation as claimed in claim 1 having a ratio of a) to b) of between 95:5 and 5:95 by weight.

### Claim 10 (depends on 1)

The preformulation as claimed in claim 1 having 0.5 to 50% component c) by weight of components a)+b)+c).

### Claim 11 (depends on 1)

The preformulation as claimed in claim 1 wherein component c) is selected from the group consisting of alcohol, ketone, ester, ether, amide, sulphoxide and a mixture thereof.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

The preformulation as claimed in claim 1 wherein said active agent is present and is selected from the group consisting of drug, antigen, nutrient, cosmetic, fragrance, flavouring, diagnostic agent, vitamin, dietary supplement and a mixture thereof.

### Claim 14 (depends on 13)

The preformulation as claimed in claim 13 wherein said drug is selected from the group consisting of hydrophilic small molecule drug, lipophilic small molecule drug, amphiphilic small molecule drug, peptide, protein, oligonucleotide and a mixture thereof.

### Claim 15 (depends on 13)

The preformulation as claimed in claim 13 wherein said drug is selected from the group consisting of somatostatin related peptide, interferon, glucagon-like peptide 1, glucagon-like peptide 2, GnRH agonist, GnRH antagonist, bisphosphonates bisphosphonate, chlorhexidine and a mixture thereof.

### Claim 16 (depends on 1)

The preformulation as claimed in claim 1 which is administrable by injection.

### Claim 17 (depends on 1)

The preformulation as claimed in claim 1 which is administrable by spraying, dipping, rinsing, application from a pad or ball roller, painting, dropping, aerosol spraying or pump spraying.

### Claim 18 (depends on 1)

An injectable preformulation as claimed in claim 1 which forms a depot providing continuous release of active agent for at least two weeks, wherein said active agent is present and comprises at least one selected from the group consisting of
i. octreotide,
ii. human growth hormone,
iii. interferon alpha,
iv. leuprolide, and
v. a mixture thereof.

### Claim 19 (depends on 1)

The preformulation as claimed in claim 1 which is injectable and which forms a depot providing continuous release of active agent for at least two weeks, wherein said active agent is present and comprises at least one selected from the group consisting of
i. risperidone
ii. olanzapine
iii. testosterone undecanoate and
iv. a mixture thereof.

### Claim 20 (depends on 1)

The formulation as claimed in claim 1 for topical intraoral administration which forms a bioadhesive, controlled release product, wherein said active agent is present and comprises at least one selected from the group consisting of
i. benzydamine,
ii. tramadol and
iii. a mixture thereof.

### Claim 21 (depends on 1)

The preformulation as claimed in claim 1 for topical intraoral administration for treatment of periodontal and topical infections, wherein the active agent is present and 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.

### Claim 22 (depends on 1)

The formulation as claimed in claim 1 for topical intranasal spray administration which forms a bioadhesive, controlled release product, wherein said active agent is present and comprises at least one selected from the group consisting of
i. fentanyl
ii. diazepam, and
iii. a mixture thereof.

### Claim 23 (depends on 1)

The formulation as claimed in claim 1 for ocular administration, wherein said active agent is present and comprises at least one selected from the group consisting of 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, indomethacin and a mixture thereof.

### Claim 24 (depends on 1)

The formulation as claimed in claim 1 for non-parenteral dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is present and is selected from the group consisting of
i. acyclovir
ii. testosterone undecanoate, and
iii. a mixture thereof.

### Claim 25 (depends on 1)

The formulation as claimed in claim 1 for topical dermatological administration which forms a bioadhesive, controlled release product, wherein the active agent is present and is selected from the group consisting of cosmetic agent, fragrance, flavouring, essential oil, UV absorbing agent and a mixture thereof.

### Claim 26

A method of delivery of a bioactive agent to a human or non-human animal body, this method comprising administering to said mammalian body 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.

### Claim 27 (depends on 1, 26)

The method as claimed in claim 26 wherein said preformulation is a preformulation as claimed in claim 1.

### Claim 28 (depends on 26)

The method as claimed in claim 26 wherein said pre-formulation is administered by a method selected the group consisting of from subcutaneous injection, intramuscular injection, intra-cavity injection through tissue, intra-cavity injection into an open cavity without tissue penetration, spraying, rolling, wiping, dabbing, painting, rinsing, dropping and a combination thereof.

### Claim 29

A method for the preparation of a liquid crystalline composition comprising exposing 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 optionally at least one bioactive agent dissolved or dispersed in the low viscosity mixture, to an aqueous fluid in vivo.

### Claim 30 (depends on 1, 29)

30) The method as claimed in claim 29 wherein said preformulation is a preformulation as claimed in claim 1.

### Claim 31

31) A process for the formation of a pre-formulation suitable for the administration of a bioactive agent to a mammalian subject, said process comprising forming 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 dissolving or dispersing at least one bioactive agent in the low viscosity mixture, or in at least one of components a, b or c prior to forming the low viscosity mixture.

### Claim 32 (depends on 1, 31)

32) The process as claimed in claim 31 wherein said preformulation is a preformulation as claimed in claim 1.

### Claim at position 33

33-34. (canceled)

### Claim 35 (depends on 1)

35) 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 36 (depends on 35)

36) The method of claim 35 for the treatment of a condition selected from the group consisting of bacterial infection, fungal infection, skin soreness, eye condition, genital soreness, infection and condition for the finger and/or toe nails, travel sickness, addiction including nicotine addiction, periodontal infection, conjunctivitis, glaucoma, hormone deficiency and hormone imbalance.

### Claim 37 (depends on 35)

37) The method of claim 35 for prophylaxis against at least one condition selected from the group consisting of infection during surgery, infection during implantation, sunburn, infection at the site of burns, cuts, abrasions, oral infection, genital infection and infection resulting from activities resulting in exposure to infective agent.

### Claim 38 (depends on 35)

The method of claim 35 for the treatment or prophylaxis of damaged, sensitized and/or infected mucosa.

### Claim 39 (depends on 20, 38)

The method of claim 38 comprising administration of the preformulation of claim 20.