Sustained-release properties of injectables
Sustained-release parenteral injections can be divided into several types: oil-based injectable solutions, injectable-drug
suspensions, polymer-based microspheres and polymer-based in-situ formings. Oil-based injectable solutions and injectable drug suspensions control the release for weeks while polymer-based
microspheres and in-situ gels are claimed to last for months (1, 7).
Oil-based injectable solutions and injectable drug suspensions.
Conventional long-acting injections consist either of lipophilic drugs in aqueous solvents as suspensions or of lipophilic
drugs dissolved in vegetable oils. The administration need for these long-acting formulations only takes place every few weeks
or so. In the suspension formulations, the rate-limiting step of drug absorption is the dissolution of drug particles in the
formulation or in the tissue fluid surrounding the drug formulation. Poorly water-soluble salt formations can be used to control
the dissolution rate of drug particles to prolong the absorption, and olanzapine pamoate is an example of a poorly water-soluble
salt form of olanzapine. Certain drugs for long-acting formulations are synthesized by esterification of the parent drug to
a long-chain fatty acid. Based on its extremely low water solubility, a fatty acid ester of a drug dissolves slowly at the
injection site after IM injection and is hydrolyzed to the parent drug. Once the ester is hydrolyzed intramuscularly, the
parent drug becomes available in the systemic circulation. The release rate of paliperidone palmitate from long-acting injectable
suspension is governed by this mechanism. In many formulations, a fatty acid ester of a drug is used to prepare an oil-based
parenteral solution, and the drug-release rate from solution is controlled by the drug partitioning between the oil vehicle
and the tissue fluid and by the drug bioconversion rate from drug esters to the parent drug. However, several other factors
such as injection site, injection volume, the extent of spreading of the depot at the injection site, and the absorption and
distribution of the oil vehicle per se might affect the overall pharmacokinetic profile of the drug. Decanoic acid esters of antipsychotic drugs are widely used
for these oil-based IM injections.
Polymer-based microspheres and in-situ formings. The development of polymer-based long-acting injectables is one of the most suitable strategies for macromolecules such as
peptide and protein drugs. Advantages of polymer-based formulations for macromolecules include: in vitro and in vivo stabilization of macromolecules, improvement of systemic availability, extension of biological half life, enhancement of
patient convenience and compliance, and reduction of dosing frequency.
Among the various approaches to deliver macromolecules parenterally, biodegradable microsphere systems are the most commercially
successful. The most crucial factor in the design of injectable microspheres is the choice of an appropriate biodegradable
polymer. The release of the drug molecule from biodegradable microspheres is controlled by diffusion through the polymer matrix
and polymer degradation. The nature of the polymer, such as composition of copolymer ratios, polymer crystallinities, glass-transition
temperature, and hydrophilicities plays a critical role in the release process. Although the microspheres structure, intrinsic
polymer properties, core solubility, polymer hydrophilicity, and polymer molecular weight influence the drug-release kinetics,
the possible mechanisms of drug release from microsphere are as follows: initial release from the surface, release through
the pores, diffusion through the intact polymer barrier, diffusion through a water-swollen barrier, polymer erosion, and bulk
degradation. All these mechanisms together play a part in the release process (2).
Another intensively studied polymeric injectable depot system is an in-situ-forming implant system. In situ-forming implant systems are made of biodegradable products, which can be injected via a syringe into the body, and once injected, congeal to form a solid biodegradable implant. This article will briefly summarize
the types of in situ-forming implants because the topic has been intensively reviewed elsewhere (3–5). Biodegradable injectable in situ-forming implants are classified into five categories based on the mechanism of depot formation: thermoplastic pastes, in situ cross-linked polymer systems, in situ polymer precipitation, thermally induced gelling systems, and in situ solidifying organogels. The mechanism of depot formation of thermoplastic pastes is to form a semisolid upon cooling to body
temperature after injection into the body in the molten form. Cross-linked polymer networks can be achieved in situ in various ways, forming solid polymer systems or gels. Methods for in situ cross-linked systems include free radical reactions, usually initiated by heat or absorption of photons, or ionic interactions
between small cations and polymer anions. In situ formings can be produced by causing polymer precipitation from solution. A water-insoluble and biodegradable polymer are solubilized
in a biocompatible organic solvent to which a drug is added which forms a solution or suspension after mixing. When this formulation
is injected into the body, the water-miscible organic solvent dissipates and water penetrates into the organic phase. This
leads to phase separation and precipitation of the polymer forming a depot at the site of injection. This method has been
designed as Atrigel technology (QLT, Vancouver, Canada), which used as a drug-carrier system for Eligard. Thermally induced
gelling systems show thermo-reversible sol/gel transitions and are characterized by a lower critical solution temperature.
They are liquid at room temperature and produce a gel at and above the lower critical solution temperature. In situ solidifying organogels are composed of water-insoluble amphiphilic lipids, which swell in water and form various types of
lyotropic liquid crystals.