Release date:2021/7/30 8:57:58

Complex injections have been drawing much attention for their high technical barriers, obvious clinical advantages, good market performance and the ability to extend product life cycles. In this part, four complex injection preparations are further discussed, including liposome, microsphere, nanoparticle and suspension, and emulsion.

According to statistics, the FDA approved at dozens of liposome, microsphere, and nanoparticle injectable formulations.

FDA-approval drug products of injection delivery  (liposome, nanoparticle, nanosuspension, emulsion, microsphere).

Liposome Injection

Liposomes are microscopic vesicles composed of lipid membranes surrounding discrete aqueous compartments and are mainly prepared from natural or synthetic phospholipids (e.g. DLPC, DMPC, DPPC, etc.).  These vesicles are highly biocompatible and less toxic in nature as phospholipids used in fabrication are the components of biomembranes. Like polymeric carriers, liposomes also provide advantages of protecting therapeutic proteins from in vivo degradation, prolonging half-life, longer systemic circulation time and higher bioavailability. Furthermore, it is customary to develop liposomes with desired properties such as cationic, PEGylated liposomes by varying lipid compositions. For successful delivery, proteins and peptides can be either encapsulated into liposomes or adsorbed on the surface. Protein cargos loaded in liposomes have demonstrated excellent therapeutic efficacy on parenteral administration.

In 1995, the FDA approved the first liposome injectable drug, Doxil (doxorubicin HCl liposome injection ), for the treatment of ovarian cancer, AIDS-related Kaposi's sarcoma and multiple myeloma. Compared to free doxorubicin, the doxorubicin hydrochloride liposomes in Doxil show greater efficacy and lower cardiotoxicity due to the long-circulating half-life (45 hours) and passive targeting. In addition, Doxil targets tumors through enhanced permeability and retention (EPR) effects at the tumor site.

Doxil (marketed in the EU under the trade name Caelyx), which reached peak annual sales of $600 million in 2001, was a huge commercial success. This has led to the entry of many pharmaceutical companies into the liposome field.

Ambisome (liposomal amphotericin B injection) was approved in 1997 for the treatment of deep fungal infections. Depodur (morphine sulfate extended-release liposome injection, 2004) and Exparel (bupivacaine liposome injectable suspension, 2011) entered the market as anesthetics. Daunoxome (Liposomal daunorubicin, 1996, withdrawn from the market), Depocyt (cytarabine liposome injection, 1999), Marqibo kit (vinCRIStine sulfate LIPOSOME injection, 2012), Onivyde (irinotecan liposome injection, 2015) and Vyxeos (daunorubicin and cytarabine for injection, 2017) were approved for cancer treatment.

Microsphere Injection

Microspheres are small spherical particles, typically ranging from 1 µm to 300 µm in diameter. The key to developing sustained-release injectable microspheres is the selection of a suitable biodegradable polymer. The products currently marketed mainly use synthetic polymers, for example, PLGA and PLA are both biodegradable and biocompatible synthetic polymers.

The first FDA-approved sustained-release microspheres, Lupron depot (leuprolide acetate for depot suspension), were developed by Takeda (in collaboration with AbbVie). Lupron depot contains gonadotropin-releasing hormone (GnRH) agonists and is used for the palliative treatment of advanced prostate cancer. Currently, more than a dozen sustained-release microsphere injections have been approved for marketing by the FDA. For example, Sandostatin Lar (octreotide acetate for injectable suspension) addresses the short biological half-life of peptides, extending the dosing period to 4 weeks and improving patient compliance, and Risperdal Consta (risperidone long-acting injection) addresses the difficulties of medication and substance abuse in patients with psychiatric disorders.

Nanoparticle and Suspension Injections

Nanoparticles are colloidal carriers with size ranging from 10 to 1000 nm, and can be fabricated from lipids, polymers or metal. Since the 1990s, nanoparticle drug delivery systems have attracted a lot of attention in drug research.

Abraxane, a Cremophor-free, albumin-bound paclitaxel, has achieved significant commercial success in the treatment of recurrent breast cancer. In the formulation of Abraxane, paclitaxel has a significant advantage over pure paclitaxel. In addition, Abraxane does not contain phospholipids, which avoids the hemolytic reaction of liposomes. Today, more than a dozen nanoparticle injectable products are also approved for marketing in the United States. Among these products, several drugs with new technologies have attracted a lot of attention. Invega Trinza (paliperidone palmitate) with nanocrystal technology releases slowly over a long period of time, and Sublocade (buprenorphine extended-release Injection) with Atrigel technology in situ gel-forming system is considered to be a landmark product.

Emulsion Injections

Emulsion injection is a colloid system of two or more immiscible oil and water. The stability of emulsion depends on the interfacial tension between the oil and aqueous phase.

Intralipid® is the first FDA-approved injectable emulsion in 1975, which was used as a source of calories and essential fatty acids after intravenous administration. Intralipid® is a soybean oil-in-water formulation, stabilized by the egg phospholipid emulsifier. Multiple advantages of emulsions could be viewed, such as solubilization, buffering, passive targeting and improving stability.

Drug delivery systems play a more and more important role in pharmaceutical R&D. Advanced drug delivery systems not only promote the efficiency of drugs but also extend the life cycle of new molecular entities (NMEs). In the future, the R&D of advanced delivery technologies may make drug candidates into more therapeutically effective formulations.

Polyethylene glycol (PEG) is widely utilized in drug delivery and nanotechnology due to its reported “stealth” properties and biocompatibility. It is generally thought that PEGylation allows particulate delivery systems and biomaterials to evade the immune system and thereby prolong circulation lifetimes. Biochempeg is committed to providing innovative high-quality PEG derivatives and PEGylation services for our customers through discovering, developing, and manufacturing.

​Zhong H, Chan G, Hu Y, Hu H, Ouyang D. A Comprehensive Map of FDA-Approved Pharmaceutical Products. Pharmaceutics. 2018 Dec 6;10(4):263. doi: 10.3390/pharmaceutics10040263. PMID: 30563197; PMCID: PMC6321070.

Related Articles:
The Evolution of 5 Therapeutic Drug Delivery Technologies
Stealth Liposomes (PEGylated Liposomes) as Drug Carrier System for Drug Delivery
Liposomes vs. Lipid Nanoparticles: Which Is Best for Drug Delivery?
​Advantages and Disadvantages of PEGylated Liposomes in Drug Delivery System

Previous:The Evolution of 5 Therapeutic Drug Delivery Technologies Next:R&D of Peptide Drugs: Current Status