Release from PLGA

Four possible drug release mechanisms-

  1. Diffusion through water-filled pores The most common way of transport through water-filled pores is diffusion,e. random movements of the molecules driven by the chemical potential gradient, which can often be approximated by the concentration gradient. Transport through water-filled pores are the most common way of release, as the encapsulated drug is usually a bio-pharmaceutical, such as a protein or a peptide, which are too large and too hydrophilic to be transported through the polymer phase.
  2. Osmotic pumping (Convection) through water-filled pores – The other way of transport through water-filled pores is convection, which is driven by a force such as osmotic pressure (Cussler, 1997). Osmotic pressure may be created by the influx of water into a non-swelling system. Drug transport driven by this force is called osmotic pumping (Hjärtstam, 1998), and is more common in drug delivery systems utilizing other polymers such as ethyl cellulose (Marucci, 2009).
  3. Diffusion through swelling polymerPLGAs that absorb a large amount of water also have mobile polymer chains and are prone to swell. As the volume of water inside increases, any significant increase in osmotic pressure will probably be compensated for by swelling and rearrangement of the polymer chains. Transport through the polymer phase may occur when the drug is small and hydrophobic (Raman et al., 2005). However, the drug must enter the water phase, either at the surface or in the pores inside the DDS, before being released.
  4. Erosion (due to dissolution of polymer, without any drug transport) The encapsulated drug may also be released without any transport due to dissolution of the polymer, i.e. erosion. Erosion also creates pores, thus increasing the rate of diffusion(diffusion-controlled release).

However, there is a difference between erosion leading to drug release without drug transport, and erosion that increases the rate of drug transport.

  • Unlike diffusion through water-filled pores, diffusion through
    the polymer is not particular dependent on the porous structure.The diffusion coefficient did not increase as PLGA degraded or when the pore-forming substance MgCO3 was encapsulated together with bovine serum albumin (BSA). However, the dffusion coefficient varied considerably with the temperature. These results clearly indicate that most diffusion took place in the polymer.
  • The rate of diffusion through a polymer is very dependent on the physical state, and for a small molecule, may increase by several orders of  magnitude at the transition from the vitreous to the rubbery state. PLGAs typically show a glass transition temperature in the range of 40-60 °C.(The value of Tg depends on the mobility of the polymer chains)
  • The glass transition temperature (Tg)of PLGA in a DDS may also be lower than that of the original polymer due to degradation during the manufacturing process and the plasticizing effects of additives or residual water.
  • However, swelling may also cause pore closure in low-Mw and relatively hydrophilic PLGAs with high polymer chain mobility, as swelling may enable the rearrangement of the polymer chains and the formation of
    a homogeneous swollen polymer mass without distinct pores.

Swelling was found to cause burst release in a study in which:

  • drug release was monitored using confocal microscopy,
  • pore size was analyzed using SEM and
  • diffusion of water was measured using NMR (Messaritaki et al., 2005). 

Molecular weight and pore formation:

  • Water absorption or swelling occurs immediately upon immersion
    in water or administration in vivo. This has been found to create pores in the polymer matrix increasing the rate of drug diffusion.
  • The pores in the low-molecular-weight polymer with highly mobile polymer chains and low hydrophobicity, seemed to be closed by diffusion/rearrangement of polymer chains that covered the pores, forming a more swollen and homogeneous polymer structure. This was facilitated at high temperature.
  • The initial porosity of a drug delivery system is very important when using a high-molecular weight-PLG with a relatively high degree of hydrophobicity, as pores are formed slowly due to slow degradation and
    water absorption. Pore will not close, and if the porosity is high, the release may be faster than when using a low-molecular-weight PLG.
  • The solubility of the drug, drug–drug interactions, polymer–drug interactions, hydrolysis, pore formation and pore closure, all depend on the pH, which depends on the rate of hydrolysis, water absorption and transport out of the

Proton Donor Strength: pKa

  • The pKa measures how tightly a proton is held by a Bronsted acid.
  • A pKa may be a small, negative number, such as -3 or -5. It may be a larger, positive number, such as 30 or 50.
  • The lower the pKa of a Bronsted acid, the more easily it gives up its proton. The higher the pKa of a Bronsted acid, the more tightly the proton is held, and the less easily the proton is given up.
  • When a compound gives up a proton, it retains the electron pair that it formerly shared with the proton. It becomes a conjugate base. Looked at another way, a strong Bronsted acid gives up a proton easily, becoming a weak Bronsted base. The weak Bronsted base does not easily form a bond to the proton. It is not good at donating its electron pair to a proton. It does so only weakly.
  • In a similar way, if a compound gives up a proton and becomes a strong base, the base will readily take the proton back again. Effectively, the strong base competes so well for the proton that the compound remains protonated. The compound remains a Bronsted acid rather than ionizing and becoming the strong conjugate base. It is a weak Bronsted acid.