# US 2007/0178147 A1 · Liposomal compositions

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- Number: US 2007/0178147 A1
- Document ID: US20070178147A1
- Status: Published application
- Kind: A1
- Application number: 11/636,378
- Filed: 2006-12-08
- Published: 2007-08-02
- Earliest claimed: 2005-12-08
- Inventors: Narendra Desai; Hemlata Dalal; Richard Saunders
- Web page: https://patentgrep.com/patent/US20070178147A1

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1277: Preparation processes; Proliposomes
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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: 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

## Abstract

This invention relates generally to liposomal pharmaceutical compositions and related methods.

## Claims

### Claim 1

A lyophilized liposomal composition comprising
(i) a hydrophobic therapeutic agent;
(ii) a first component; and
(iii) a second component;
wherein, when the composition is contacted with water, the first component and the second component interact to form a substantially homogeneous liposomal solution of the hydrophobic therapeutic agent.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the composition comprises from about 20 weight percent to about 40 weight percent of the first component and the second component.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the weight per cent ratio of the second component to the first component is from about 1 to about 7.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the number of moles of the first component is about the same as the number of moles of the hydrophobic therapeutic agent, and the number of moles of the second component is from about 2 to about 15 times greater than the number of moles of the hydrophobic therapeutic agent.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the number of moles of the first component is from about 1.5 to about 6 times greater than the number of moles of the hydrophobic therapeutic agent, and the number of moles of the second component is from about 2 to about 15 times greater than the number of moles of the hydrophobic therapeutic agent.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the weight per cent ratio of the first component and the second component to the hydrophobic therapeutic agent is from about 10 to about 50.

### Claim 7 (depends on 1)

The composition of claim 1, wherein each of the first component and the second component is, independently, a natural lecithin or phospholipid.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the first component is egg phosphatidyl glycerol and the second component is soy phosphatidyl choline.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the composition comprises from about 0.05 weight percent to about 10 weight percent of the hydrophobic therapeutic agent.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the composition further comprises a cryoprotectant.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the cryoprotectant is a sugar.

### Claim 12 (depends on 11)

The composition of claim 11, wherein the cryoprotectant is lactose.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the composition further comprises an anti-oxidant.

### Claim 14 (depends on 13)

The composition of claim 13, wherein the composition comprises two anti-oxidants.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the two anti-oxidants are BHT and ascorbyl palmitate.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the composition further comprises a cryoprotectant, a first anti-oxidant, and a second anti-oxidant.

### Claim 17 (depends on 16)

The composition of claim 16, wherein the composition comprises:
Ingredient
Amount % (w/w)
Hydrophobic therapeutic agent
about 0.500 to about 2.500
First Component
about 5 to about 15
Second Component
about 15 to about 25
First Anti-oxidant
about 0.005 to about 0.020
Second Anti-oxidant
about 0.025 to about 0.050
Cryoprotectant
about 50 to about 75

### Claim 18 (depends on 16)

The composition of claim 16, wherein the cryoprotectant is lactose, the first anti-oxidant is BHT, and the second anti-oxidant is ascorbyl palmitate.

### Claim 19 (depends on 1)

The composition of claim 1, wherein the hydrophobic therapeutic agent has a water solubility of from about 5 nanograms/mL to about 5 milligrams/mL.

### Claim 20 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent has a molecular weight of from about 100 Daltons to about 1,000 Daltons.

### Claim 21 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent lacks ionizable groups.

### Claim 22 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent further comprises an acidic group having a pKa of from about 2 to about 11.

### Claim 23 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent further comprises a basic group, wherein the pKa of the basic group's conjugate acid is from about 3 to about 12.

### Claim 24 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent is a zwitterion.

### Claim 25 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent is a crystalline solid.

### Claim 26 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent further comprises two rings, wherein each ring is, independently, an aromatic ring or a heteroaromatic ring.

### Claim 27 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent further comprises a condensed bicyclic, tricyclic or polycyclic ring system.

### Claim 28 (depends on 19)

The composition of claim 19, wherein the hydrophobic therapeutic agent is a water insoluble fungal antibiotic or complex macrocycle of synthetic, semi-synthetic, or natural origin.

### Claim 29 (depends on 1, 19)

The composition of claims 1 or 19, wherein the hydrophobic therapeutic agent has a log P value of from about 1.0 to about 5.0.

### Claim 30 (depends on 1, 19)

The composition of claims 1 or 19, wherein the hydrophobic therapeutic agent has a log P value of from about 2.0 to about 5.0.

### Claim 31 (depends on 1, 19)

The composition of claims 1 or 19, wherein the hydrophobic therapeutic agent has a log P value of from about 3.0 to about 5.0.

### Claim 32 (depends on 1, 19)

The composition of claims 1 or 19, wherein the hydrophobic therapeutic agent has a log P value of from about 4.0 to about 5.0.

### Claim 33 (depends on 1)

A process for preparing a composition of claim 1, the process comprising:
(i) combining a hydrophobic therapeutic agent, a first component, and a second component in an organic solvent to form a first combination;
(ii) combining the first combination with a water phase to form a second combination;
(iii) removing the organic solvent from the second combination to form a third combination; and
(iv) lyophilizing the third combination, thereby preparing the composition of claim 1.

### Claim 34 (depends on 33)

The process of claim 33, wherein the organic solvent is ethanol.

### Claim 35 (depends on 33)

The process of claim 33, wherein the water phase further comprises a cryoprotectant.

### Claim 36 (depends on 35)

The process of claim 35, wherein the cryoprotectant is lactose.

### Claim 37 (depends on 33)

The process of claim 33, wherein the first combination further comprises an anti-oxidant.

### Claim 38 (depends on 33)

The process of claim 33, wherein the second combination is a liposomal solution.

### Claim 39 (depends on 38)

The process of claim 38, wherein the process further comprises the step of reducing the particle size distribution of the liposomes.

### Claim 40 (depends on 38)

The process of claim 38, wherein the process further comprises the step of reducing the particle size distribution of the liposomes to a final particle size distribution of from about 5,000 nm to about 20 nm.

### Claim 41 (depends on 38)

The process of claim 38, wherein the process further comprises the step of reducing the particle size distribution of the liposomes to about 200 nm.

### Claim 42 (depends on 33)

The process of claim 33, wherein step (iii) comprises performing a tangential flow filtration.

### Claim 43 (depends on 42)

The process of claim 42, wherein the organic solvent is ethanol.

### Claim 44

A substantially homogeneous liposomal formulation comprising:
(i) a hydrophobic therapeutic agent;
(ii) a first component;
(iii) a second component; and
(iv) water.

### Claim 45 (depends on 44)

The formulation of claim 44, wherein the formulation comprises at least about 80 weight/volume per cent of water.

### Claim 46 (depends on 44)

The formulation of claim 44, wherein the formulation further comprises a cryoprotectant, a first anti-oxidant, and a second anti-oxidant.

### Claim 47 (depends on 46)

The formulation of claim 46, wherein the formulation comprises:
Ingredient
Amount % (w/v)
Hydrophobic therapeutic agent
about 0.050 to about 0.500
First Component
about 0.5 to about 5.0
Second Component
about 1.5 to about 6.0
First Anti-oxidant
about 0.001 to about 0.005
Second Anti-oxidant
about 0.004 to about 0.008
Cryoprotectant
about 5 to about 15
Water
about 70 to about 90

### Claim 48 (depends on 44)

The formulation of claim 44, wherein the formulation comprises about 2 mg/mL of the hydrophobic therapeutic agent.

### Claim 49 (depends on 44)

The formulation of claim 44, wherein the formulation is an intravenous formulation for administration to a human or animal subject.

### Claim 50 (depends on 1, 44)

The formulation of claim 44, wherein the formulation is prepared by contacting the lyophilized lipsomal composition of claim 1 with water.

### Claim 51 (depends on 44)

The formulation of claim 44, wherein the liposomes have an average particle size distribution of at most about 5,000 nm.

### Claim 52 (depends on 44)

The formulation of claim 44, wherein the liposomes have an average particle size distribution of from about 50 nm to about 200 nm.

### Claim 53 (depends on 44)

The formulation of claim 44, wherein the liposomes have an average particle size distribution of about 200 nm.

### Claim 54 (depends on 44)

The formulation of claim 44, wherein the formulation is capable of being diluted indefinitely with water without precipitation of the hydrophobic therapeutic agent.

### Claim 55 (depends on 44)

The formulation of claim 44, wherein the formulation rapidly releases the hydrophobic therapeutic agent into the bloodstream to associate with red blood cell (RBC), lipoproteins, HSA or WBC in blood upon in vivo administration.

### Claim 56 (depends on 1)

The composition of claim 1, wherein the number of moles of the first component is less than the number of moles of the hydrophobic therapeutic agent, and the number of moles of the second component is from about 2 to about 15 times greater than the number of moles of the hydrophobic therapeutic agent.