Correspondence: Lipoid GmbH, Frigenstraße 4, D-67065 Ludwigshafen, Germany, Tel: +49 621 53819 301, p.hoelig@lipoid.com

Peter Hölig, Pharma Insights Contributor, Lipoid GmbH, Frigenstrasse 4, Ludwigshafen am Rhein, Germany

The pharmaceutical industry has two main ways to generate new products. The first option is to look for new drug substances. A second option is to employ better formulations of an existing drug product. Such reformulated products are called Pharmaceutical Form Line Extensions. As part of such a product lifecycle management strategy, the profitability of sales of a drug substance facing generic competition may be extended

 The new products may be protected by dosage form patents. Line extensions require less research and development compared to development of new chemical entities

. Examples of commercially successful product line extensions can be found in the literature

Successful reformulations require suitable excipients with a broad scope of use. Phospholipids fulfil these requirements because they can be used in many dosage form types

. In addition, they are biocompatible, safe in use, and available at large scale in pharmaceutical grades known to regulatory authorities. The molecular structure of phospholipids comprises a glycerol backbone, which is esterified in positions 1 and 2 with fatty acids and in position 3 with phosphate (

This short review illustrates the many options which exist to make Pharmaceutical Form Line Extensions with phospholipids as key excipients. For extensive information, see Van Hoogevest et al.

Oral products can be reformulated to generate an intravenous injectable enabling, e.g., emergency treatment. An example is Aprepitant (EMEND® oral tablets converted into Cinvanti, oil-in-water emulsions with Egg-PC as emulsifier). The therapeutic index of intravenous drug products can be optimized by encapsulating drug substances in liposomes, which are mainly composed of phospholipids. The liposomes reach the disease target more efficiently and/or can avoid organs which are sensitive to the toxicity of the drug substances, compared to the original product. In the case of lipophilic drugs, liposomes can be used as solubilizers and replace synthetic detergents in the original products with allergenic properties

. Examples of such line extensions are Doxil® (doxorubicin liposomes), AmBisome® (amphotericin B liposomes), and Lipusu® (paclitaxel liposomes). Also, mixed micelles, comprising phospholipids and bile salts, or oil-in-water emulsions, with egg phospholipids as emulsifier, are used in line extensions as solubilizing vehicles to replace alternative detergents.

Specific liposomes, multivesicular liposomes, based on DepoFoam® technology, are used as depot, slow release vehicles after local injection of hydrophilic drugs

. These liposomes have large sizes to maintain the injectable at the injection site, a prerequisite for a depot effect. An example of such a product is Exparel® (bupivacaine liposomes).

Encapsulation of antibiotics in liposomes in nebulized formulations is used to reduce the frequency of administration and to target bacterial pathogens located in lung macrophages, which specifically take up the liposomes. An example of such a product is Arikayce® (amikacine liposomes)

. Furthermore, saturated phospholipids are used as alterative technological aid to, e.g., lactose to convert a nebulizer formulation into a dry powder for inhalation. An example is Tobi Podhaler® (tobramycin, PulmoSpheres®)

Liposomes are also used in dermatological formulations to enhance the skin interaction of drug substances to optimize dermal products, or to convert injectables into dermal extensions. An example is heparin for the treatment of deep venous thrombosis

Line extension products with phospholipids as key excipients may enable the application of a drug substance for another administration route or show an increased efficacy and/or reduced toxicity of the formulated drug substances, or enable a more convenient use, through reduction of dosing frequency. In these products, natural phospholipids (from soybean or egg yolk) and synthetic phospholipids (mainly used in parenteral formulations) are employed

. The patents related to the reformulated product may generate an additional market exclusivity period, enabling at least a return on investment to develop the line extensions. Parenteral line extensions using non-toxic phospholipid-based solubilizing formulations are clearly a better alternative to products with solubilizing synthetic detergents having anaphylactic properties.

A.C. Fowler. Pharmaceutical Line Extensions in the United States - A Primer on Definitions and Incentives. [PDF file] 2017 (accessed Mar 28, 2022); 

http://www.nber.org/aging/valmed/WhitePaper-Fowler10.2017.pdf

European Journal of Lipid Science and Technology

WebMD. Aqua-Mephyton Solution. [Phytonadione (Vitamin K1)] (accessed Mar 28, 2022); 

https://www.webmd.com/drugs/2/drug-9003/aqua-mephyton-injection/details

Insmed. Insmed Incorporated and Transave, Inc. Announce Business Combination. 2010 (accessed Mar 28, 2022); 

https://investor.insmed.com/2010-12-02-Insmed-Incorporated-and-Transave-Inc-Announce-Business-Combination

Tobi. Podhaler (Tobramycin Inhalation Powder). 2022 (accessed Mar 28, 2022); 

https://www.tobipodhaler.com/en/why-tobi-podhaler/what-are-the-benefits

Articles

Phospholipids in Pharmaceutical Form Line Extensions

In pharmaceutical formulations, phospholipids obtained from plant or animal sources as well as synthetic phospholipids are used. Synthetic phospholipids possessing natural stereochemical configuration are preferably synthesized from 

-glycero-3-phosphocholine (GPC), using acylation and enzyme catalyzed reactions. The precursor GPC can be obtained from naturally occurring phospholipids.

In addition to natural phospholipids, synthetic phospholipids are becoming increasingly important in drug delivery, as can be seen from the number of drug products containing synthetic phospholipids. They mainly play a role in parenteral administration and inhalation dosage forms. Parenteral and inhalation products with synthetic phospholipids comprise liposomal formulations, lipid nanoparticles, diagnostic products, and dry powders for inhalation, respectively. Examples of intravenous products are provided in 

Synthetic phospholipids are used in parenteral depot formulations as well 

Synthetic phospholipids can also be found in vaccines, in the form of lipid nano particles (LNPs) or liposomes in recently developed vaccine formulations for intramuscular administration for the delivery of messenger ribonucleic acid (mRNA) and a disease-related antigen, respectively. LNPs are also used for maintenance treatment of patients with chronic obstructive pulmonary disease intravenous administration of small interfering RNA (siRNA) in the treatment of rare diseases (

).

Synthetic phospholipids in relevant inhalation products are listed in 

. Interestingly, the phospholipids are used in several types of formulations suitable for commonly used inhalation devices.



In the future, synthetic phospholipids and designer lipids may play a more important role in sophisticated drug delivery systems.



van Hoogevest P, Luciani P. Recent Advances in the Use of Phospholipid Excipients in Local or Injectable Depot Formulations.
Pharm. Ind. 2018, 8:1104.

van Hoogevest P, Tiemessen H, Metselaar JM, Drescher S, Fahr A. The Use of Phospholipids to make Pharmaceutical Form Line Extensions. Eur. J. Lipid Sci. Technol. 2021, 2000297.

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