Double Emulsion –solvent extraction
An aqueous solution of the peptide (which may contain excipients such as gelatin) is first emulsified in a polymer vehicle where the polyesters have been solubilized in an organic solvent (generally dichloromethane or ethyl acetate). This first emulsion is then poured into a second continuous aqueous phase containing a surfactant such as polyvinyl alcohol (PVA) from where the solvent will be extracted leading to the concomitant solidification of the microspheres.

Process limitations: Minimal solubility of the peptide in the organic solvent; shear stresses; the presence of residual solvent; the necessity of the aseptic process.

Example of manufactured product: Lupron Depot.

Nomisma`s Products for Lupron Depot: DLG752A(PLGA 75:25), DL1002A(DL-PLA), and DL1003A(DL-PLA).

Leuprolide acetate which is a highly active agonist of luteinizing hormone–releasing hormone (LH-RH) potently inhibits their secretion in the pituitary gland and it is useful in the treatment of hormone-dependent diseases in males and females. To eliminate the inconvenience of daily injection, Leuprolide acetate is available in the market, in the form of its depot for 1 month, 3 months, and 6 months, and depending upon the requirement of the patients, it is given as a parenteral solution.

To make this depot, one of the major and responsible ingredients required is Bioresorbable PLGA (Poly Lactic co glycolic acid) polymer, which is used to make microspheres of Leuprolide acetate along with this PLGA Polymer.

The higher level of free acid content in PLGA polymer causes an increase in the initial burst. If the free acid content is less than 0.1%, then the initial burst is less than 10%. These water-soluble acid fractions designated as free acid is ranging from heptamer to monomer/oligomer of lactic acid. These oligomers are assumed to interfere with the formation of the hydrophilic barrier by the arrangement of the polymer around the drug domains and increase the number of aqueous channels through the polymer barrier resulting in enhancement of the initial burst – called “tunnel effect”.

In order to have the quality of polymer i.e. free acid value in control, among all available in the market, Nomisma Healthcare Pvt. Ltd has produced PLGA polymers with optimum low-level free acid content value to control initial burst.

The drug release from the Leuprolide acetate depot mainly depends on the hydrolysis or degradation of PLGA (Poly lactic Co Glycolic acid) polymer involving diffusion and/or erosion either from its surface or from the mass.

The initial burst also depends upon the drug structure, drug concentration, hydrophilicity, or hydrophobicity.

According to solubility and water penetration into the polymer matrix, the drug on the surface in contact with the medium releases itself.

Random splitting of PLGA reduces molecular polymer weight considerably, but there is no considerable weight loss or soluble monomer substance.

The drug is gradually released through the second level’s thicker depleted sheet.

In the matrix, the polymer hydrolyzed into soluble monomeric and oligomeric components.

It permits the passage of a drug for release by erosive and diffusive processes prior to total polymer solvation.

The drug class also significantly contributes to the aqueous process’ matrix formation.