Aliphatic polyesters

PLA (poly(lactic acid), polylactide); PLGA (poly(lactic-co-glycolic acid), poly(lactide-co-glycolide)); PGA (polyglycolide); PCL (poly(ε-caprolactone)); Expansorb; Lactel; Purasorb; Resomer

Homopolymers and copolymers of lactic acid, glycolic acid, ε-caprolactone and related hydroxy acids · [—]

repeat units: lactide (C3H4O2)n; glycolide (C2H2O2)n; ε-caprolactone (C6H10O2)n · typically ≈ 2 000 to > 100 000, depending on grade

Release-modifying polymer

Typical concentrations: — · Dosage forms: Sterile (parenteral/ophthalmic)

Biodegradable, biocompatible polymers used mainly for parenteral controlled release: injectable microspheres, implants and in situ forming depots that release peptides, proteins and small molecules over weeks to months. Examples include long-acting leuprorelin, goserelin, octreotide, triptorelin and risperidone products. They are also used for absorbable sutures, orthopaedic devices and tissue-engineering scaffolds. The polymer usually forms most of the matrix, with drug loadings commonly in the range of a few per cent up to about 30–40%.

White to off-white or pale yellow-amber powders, granules or pellets, depending on composition and molecular weight. Properties depend on monomer ratio (for example lactide:glycolide 50:50 to 100:0), stereochemistry (L- or DL-lactide), molecular weight, crystallinity and the chemistry of the end groups (free carboxylic acid or ester-capped).

Glass transition temperature

PLGA and poly(DL-lactide) about 40–60 °C; PCL about −60 °C

Melting point

amorphous grades (DL-lactide, most PLGA) have none; crystalline poly(L-lactide) about 170–180 °C; PGA about 220–230 °C; PCL about 60 °C

Inherent viscosity

commonly about 0.1–2 dL/g, used as a measure of molecular weight

Degradation time in vivo

from weeks (low-molecular-weight 50:50 PLGA, acid end-capped) to more than a year (high-molecular-weight PLA, PCL)

Solubility

PLGA and DL-PLA soluble in dichloromethane, chloroform, ethyl acetate and (for lactide-rich grades) acetone; PGA and crystalline PLLA insoluble in most common solvents; all practically insoluble in water

These polymers degrade by hydrolysis of the ester bonds, which is accelerated by moisture, heat and acidic or basic conditions and is autocatalysed by the acidic degradation products. Store in tightly sealed containers, protected from moisture, preferably refrigerated or frozen; allow containers to reach room temperature before opening to avoid condensation. Gamma irradiation, often used for terminal sterilisation, lowers the molecular weight.

Basic drugs and excipients, and some metal salts, catalyse hydrolysis; amine-containing drugs can be acylated by the polymer or its degradation products. The acidic microclimate that develops inside degrading PLGA can destabilise peptides and proteins.

High-molecular-weight grades are made by ring-opening polymerisation of the cyclic dimers (lactide, glycolide) or of ε-caprolactone, usually with a tin(II) 2-ethylhexanoate catalyst and an alcohol initiator; low-molecular-weight grades can be made by direct polycondensation. The polymers are purified to remove residual monomer, catalyst and solvent.

Generally biocompatible; they degrade to lactic acid, glycolic acid or 6-hydroxyhexanoic acid, which are metabolised or excreted. Implants and microspheres may cause transient local inflammation or a foreign-body reaction at the injection site, and rapid degradation of large implants can produce local acidity.

Observe normal precautions for the quantity handled. Minimise exposure to humid air during weighing and processing; gloves and eye protection are recommended, and the organic solvents used to process the polymers require their own precautions.

Used in many FDA- and EU-approved parenteral depot products and implants, and in absorbable medical devices. Included in the FDA Inactive Ingredient Database (intramuscular and subcutaneous injections and implants).

Polyglactin (lactide–glycolide suture material); PEG–PLA and PEG–PLGA block copolymers; polyanhydrides; polyorthoesters.

Release from PLGA systems is usually triphasic (initial burst, lag, then erosion-controlled release), and it is very sensitive to polymer composition, molecular weight, end-group chemistry and particle morphology. Grades should therefore be specified precisely, and changing supplier or grade requires re-evaluation of release.