# US 2010/0166876 A1 · Loading of hydrophobic drugs into hydrophilic polymer delivery systems

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- Number: US 2010/0166876 A1
- Document ID: US20100166876A1
- Status: Published application
- Kind: A1
- Application number: 12/278,827
- Filed: 2007-02-09
- Published: 2010-07-01
- Earliest claimed: 2006-02-10
- Assignees: Biocompatibles UK Limited
- Inventors: Andrew Lennard Lewis; Yiqing Tang; Maria Victoria Gonzalez Fajardo
- Web page: https://patentgrep.com/patent/US20100166876A1

## CPC

- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- 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 9/1682: {Processes}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A process is described for loading hydrophilic polymer particles with a water-insoluble solvent-soluble drug. The particles are preferably embolic agents. The method provides particles having little or no drug at the surface and in a surface layer, whereby the burst effect is minimised. The drug is precipitated in the core of the particle, leading to extended release. The drug is, for instance, paclitaxel, rapamycin, dexamethasone or ibuprofen.

## Claims

### Claim 1

A process for forming drug-loaded polymer particles comprising the steps:
a) providing particles comprising a matrix of water-insoluble polymer, which, when neat, are swellable in phosphate buffered saline (PBS) at room temperature to an equilibrium water content in the range of from 40% to 99% by weight based on polymer plus PBS;
b) providing a solution of a drug having a water solubility of less than 10 g/l at room temperature, in a first organic solvent is selected to be capable of swelling neat particles;
c) containing the particles with the solution of drug whereby a solution of drug in solvent becomes impregnated into the particles;
d) separating drug solution which has not impregnated the particles in step c) from the impregnated particles and recovering the impregnated particles;
e) contacting the impregnated particles with aqueous liquid whereby drug is precipitated in the core of the particles;
f) providing a volatile, second solvent in which the particles are less swellable, relative to their swellability in water, and which is a solvent for the drug, wherein the drug solubility in the second solvent is at least 0.1 g/l; and
g) rinsing the particles produced in step e) with the second solvent whereby drug on and close to the surface of the particles is removed with the second solvent; and, optionally
h) drying the drug-loaded polymer particles by vacuum, or freeze drying, or air flow to remove the second solvent.

### Claim 2 (depends on 1)

A process according to claim 1, wherein the particles swell in step c) when the solution of drug becomes impregnated into the particles.

### Claim 3 (depends on 2)

A process according to claim 2, wherein the particles are swollen to equilibrium when the solution of drug becomes impregnated into the particles.

### Claim 4

(canceled)

### Claim 5

(canceled)

### Claim 6

(canceled)

### Claim 7

(canceled)

### Claim 8

(canceled)

### Claim 9 (depends on 1)

A process according to claim 1, in which the first and second solvents are the same.

### Claim 10 (depends on 1)

A process according to claim 1, in which the first and second solvents are different to one another.

### Claim 11 (depends on 1)

A process according to claim 1, in which the first and/or second solvent is miscible with water.

### Claim 12 (depends on 1)

A process according to claim 1, wherein the second solvent has a boiling point of less than 90° C.

### Claim 13 (depends on 1)

A process according to claim 1, in which the ratio of drug solubilities at room temperature in the first organic solvent and water is in the range 10:1 to 106:1.

### Claim 14 (depends on 1)

A process according to claim 1, in which the drug is selected from the group consisting of rapamycin analogues, esters and salts thereof which have water solubility less than 0.1 g/l; paclitaxel; analogues, esters and salts thereof which have water solubility less than 0.1 g/l; dexamethasone and ibuprofen.

### Claim 15 (depends on 1)

A process according to claim 1, in which the first solvent is an aprotic solvent, from dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidinone (NMP), dimethyl formamide (DMF) and dioxane.

### Claim 16 (depends on 3)

A process according to claim 3, in which the polymer matrix is formed from a polyvinyl alcohol macromer, having more than one ethylenically unsaturated pendant group per molecule, by radical polymerisation of the ethylenic groups.

### Claim 17 (depends on 16)

A process according to claim 16, in which the macromer is copolymerised with ethylenically unsaturated monomers.

### Claim 18 (depends on 1)

A process according to claim 1, in which the particles used in step a) have a mean particle size in the range 50 to 1500 μm, when fully swollen with PBS at room temperature.

### Claim 19

Drug loaded polymer particles having a homogeneous polymer composition from the centre to the periphery, having precipitated drug in a core region thereof, which drug has a water solubility of less than 0.1 g/l at room temperature; and having a surface layer in the range of from 1 to 100 μm thick, wherein the ratio of the concentration of drug in the core:concentration of drug in the surface layer is at least 2:1.

### Claim 20 (depends on 19)

Particles according to claim 19, in which the drug has a solubility in a solvent selected from dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidinone (NMP), dimethyl formamide (DMF) and dioxane to a concentration of at least 101, a times its solubility in water at room temperature.

### Claim 21 (depends on 15)

A process according to claim 15 in which the first solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidinone (NMP), dimethyl formamide (DMF) and dioxane.

### Claim 22 (depends on 1)

A process according to claim 1 in which the water insoluble polymer is a polyvinyl alcohol.

### Claim 23 (depends on 22)

A process according to claim 22 in which the water insoluble polymer is a covalently cross-linked polyvinyl alcohol.

### Claim 24 (depends on 17)

A process according to claim 17 in which the ethylenically-unsaturated monomer is selected from non-ionic monomers, and ionic monomers and mixtures thereof.

### Claim 25 (depends on 17)

A process according to claim 17 in which the monomers include anionic monomers.

### Claim 26 (depends on 18)

A process according to claim 18 in which the mean particle size is in the range 50 to 1500 μm.

### Claim 27 (depends on 19)

Drug loaded polymer particles according to claim 19 in which the said ratio is at least 10:1.

### Claim 28 (depends on 20)

Particles according to claim 20 in which the said solubility of the drug in the solvent is at least 102 times its solubility in water.