Liposomes, Microencapsulation, Oil-Based, Nanocrystals for Long-Acting Formulations

What are Long-Acting Formulations?

A long-acting drug formulation is a form of drug designed to prolong the sustained release of a drug in the body, with the aim of reducing the frequency of use and improving therapeutic efficacy. Long-acting formulations can generally achieve slow release by different routes, including controlled release techniques, modified drug molecule structures or combination with carrier materials. One of the advantages of long-acting drug formulations is that they can reduce the side effects of the drug because the concentration of the drug is relatively more stable over the dosing interval.

Delivery Systems for Long-Acting Formulations

Long-acting formulations achieve sustained efficacy through controlled release strategies from drug delivery systems and include microencapsulation (microsphere) technology, liposome technology, oil-based formulation technology, nanocrystal technology, biomineralisation technology, long-acting hydrogel technology, long-acting microneedle technology, and long-acting implant systems.

Multivesicular Liposomes

Liposomes are widely used for drug delivery because of their biocompatibility and universality. The different assembly modes of lipid vesicles have important effects on drug release from liposomes. Generally, liposomes are stacked in a concentric manner, with phospholipid membranes assembled to form a monolayer or multilayer structure, so that the collapse or rupture of the inner lipid membrane leads to the accumulation of drug, which is rapidly released with the rupture of the outer lipid membrane. Adriamycin liposomal Doxil is the first PEGylated liposome approved by the FDA, which improves efficacy while reducing toxicity, but does not have a long-lasting effect because traditional liposome drug encapsulation technology does not allow for slow drug release. Multicapsular liposomes have an average particle size of 3-30 μm and consist of hundreds of non-concentric and polyhedral aqueous chambers, each separated by a continuous lattice of phospholipid membranes. Multivesicular liposomes achieve sustained drug release by gradually degrading the outermost vesicles. The inner vesicles are protected by the outer vesicles to avoid abrupt drug release behaviour. Factors such as the nature and composition of the lipid phase, the interaction of the lipid with the encapsulated drug, the composition of the aqueous phase and the osmotic pressure of the aqueous phase have an influence on the rate of drug release. Preparation of multivesicular liposomes involves a double emulsification process to form water-in-oil-in-water (W/O/W) emulsions. Multi-encapsulated liposomes provide a practical and long-lasting strategy for prolonging drug retention time due to their multi-chambered structure. Here are the advantages of liposomes in long-acting formulations applications.

1) Slow release and prolonged efficacy

2) Improvement of drug solubility

3) Reduced toxicity of the drug

4) Enhancement of stability

5) Achieve targeted delivery

6) Improve drug bioavailability

Micro-encapsulation Long-Acting Formulations

The process of micro-encapsulation refers to the dispersion or dissolution of a solid or liquid API in a polymeric material to form microspheres, or as a core encapsulated in a polymeric shell to form microcapsules. The first leuprolide extended-release injectable microspheres (Lupron Depot) based on the biodegradable material polylactic acid-hydroxyacetic acid copolymer (PLGA) were approved by the FDA in 1986 for the treatment of prostate cancer.The most recent microsphere product approved by the FDA is zilretta for the treatment of osteoarthritis (OA) pain of the knee, which can be released slowly over a period of 3 months in the joint of the OA. release of tretinoin for more than 3 months. Polymeric materials used to prepare microspheres include natural (e.g. gelatin, alginate, chitosan), semi-natural (cellulose acetate phthalate, ethylcellulose, methylcellulose) and synthetic (polylactic acid (PLA) and polylactic acid hydroxyacetic acid (PLA-HACOA) copolymers), with PLGA being the most commonly used biodegradable material for microsphere products, with a 46 per cent share of all markets. The drug release process can be regulated by controlling the molecular weight of PLGA, drug-polymer ratio, microsphere particle size, hydroxyacetic acid-lactic acid ratio, polymer ends and physicochemical properties of excipients. Five possible pathways exist for the mechanism of drug release as follows

• Initial release of drug from the microsphere surface.
• Release through pores in the microspheres
• Diffusion through the intact polymer membrane barrier
• Diffusion through the water swelling barrier.
• Erosion and degradation of polymers.

The above mechanisms work together to achieve sustained drug release from microspheres. In addition, novel polymers with potential alternatives to PLGA have been developed for loading drugs that are incompatible with PLGA, such as PCPP-SA, HA, and TEG-POE, all of which have similar biocompatibility and sustained controlled drug release. As far as the current technology is concerned, microspheres are a very promising strategy for long-lasting formulations even though they suffer from a number of challenges such as inhomogeneous particle size, poor injectability, limited drug loading capacity, and poor stability.

Oil-based Long-Acting Formulations

Oil-based parenteral long-acting formulations are formed by covalent attachment of fatty acid chains to the therapeutic drug to form a prodrug and are present in the oil phase. Decanoic, heptanoic and hexanoic acids are commonly used to form ester bonds with the prototype drug to increase its solubility in the oil phase and enhance its distribution in the adipose tissue. After intramuscular injection the formulation forms a drug reservoir in situ and slowly releases the prodrug into the surrounding bloodstream, where it is hydrolysed to release the active molecule. The rate of drug release from oil-based long-acting preparations depends not only on the slow release of the prodrug from the adipose tissue into the circulatory system, but also on the slow hydrolysis of the ester bond and the release of the prototype drug. In addition, parameters such as oil-phase drug concentration, surface area of the oil-phase reservoir, and partition coefficient between the tissue fluid and the oil-phase reservoir are crucial for controlling drug release. Oil-based parenteral long-acting formulations can be used for both systemic and topical drug delivery. Cost-effectiveness and simple manufacturing process are the main advantages of oil-based long-acting formulations.

Nanocrystalline Suspensions

Nanocrystalline strategies are widely used to improve the properties of insoluble drugs, and nano-formulations prepared by nanocrystallisation techniques have significant long-lasting effects and are used in the development of therapies for various diseases, such as antipsychotic and antiviral treatments. Various techniques are used to prepare nanocrystals such as top-down, bottom-up and combinatorial methods. The solubility of insoluble drugs can be increased by decreasing the particle size and increasing the specific surface area of the drug. It is also possible to modify the drug into a hydrophobic precursor before converting it into nanocrystals, which ultimately forms a nanocrystalline suspension. After high-pressure homogenisation or milling, nanoscale crystals of 50  - 1000 nm can be obtained, with high drug loading capacity and controllable particle size, and can be stored for a long time after lyophilization. The drug dissolution and absorption of nanocrystals are affected by a variety of factors, such as aqueous solubility, particle size, injection site and depth, macrophage phagocytosis efficiency, pre-drug degradation rate and lymphatic absorption efficiency.

Advantages of Long-Acting Formulations

• Ideally suited for formulation development for chronic diseases

Drug development for chronic diseases such as hypertension, diabetes, and rheumatoid arthritis requires ensuring efficacy while maintaining stable drug concentrations for effective disease management.

• Allow for personalized drug release mechanism customization

Long-acting formulations can be customized with different release mechanisms, such as gradual release, slow release or delayed release, to meet different drug characteristics and development needs.