Liposome is a type of artificial cell membrane with an onion-like closed spherical structure that can protect drugs within its structure, exert directional effects, and is particularly suitable as a carrier for anticancer drugs to improve their therapeutic effects and reduce side effects. Liposomes consist of phospholipids as the skeletal membrane material and additives. The phospholipids used to prepare liposomes include natural phospholipids and synthetic phospholipids. Natural phospholipids, mainly phosphatidylcholine (PC), are derived from egg yolk and soybean, and are neutral, contain many impurities, and are easily oxidized and degraded. Liposomes composed of natural phospholipids have greater drug leakage and are not easily preserved. Synthetic phospholipids, including DPPC, DPPE, DSPC, etc., belong to hydrogenated phospholipids and have stable properties, strong antioxidant properties, and stable finished products. They are currently the preferred excipients abroad.
To prepare liposomes, some additives are also required, such as cholesterol HP, which is also an amphiphilic substance, mixed with phospholipids to prepare stable liposomes. Its role is to regulate the fluidity of the bilayer and reduce the permeability of the liposome membrane. Other additives include octadecylamine, phosphoric acid, etc. These two additives can change the surface charge properties of the liposome. When preparing, salts or buffer salts such as sodium chloride are also used as solvents or stabilizers.
In long-circulating liposomes, PEG lipids are used, such as DSPE-MPEG2000, etc. In the liposome process, special excipients are also used, such as the liposome Erythecan of Taiwan's Zhijing Company, which uses sucrose octasulfate gradient loading. Sugars or trehalose are generally used as lyophilized protective agents for liposomes.
There are 2015 FDA Liposome Drug Products liposome pharmaceutical industry guidelines draft in foreign countries.
The requirements for excipients are as follows: Control of lipid components:
The quality of lipid components, including modified lipids (eg, polyethylene glycol-modified lipids, PEG), may affect the quality and performance of liposomal drug products. When using a novel lipid, the lipid should be submitted with the same level of detail in the submission as for the drug. In addition, the following lipid-specific information should be submitted:
Properties and characteristics of lipid components
If the selected lipid is synthetic or semi-synthetic, such as dimyristoylphosphatidylcholine (DMPC), structural proof should be submitted, including fatty acid composition and specific conformation. Specific lipid composition (eg, percentages of various lipids and fatty acids, specific configuration of acyl chains, and degree of saturation of fatty acids) should be submitted. If it is a lipid mixture from natural sources (such as lecithin), the percentage range of each single lipid and its fatty acids should be submitted.
Production of lipid components
Whether synthetic, semi-synthetic or naturally derived, manufacturing information for lipid components should be submitted. For synthetic and semi-synthetic lipids, we recommend submitting the following information: i. If applicable, a complete description of the synthesis process and purification process ii. Starting materials, specifications for raw materials, solvents and reagents iii. Critical steps and intermediates The controls, if applicable, should include side chain acyl configuration-specific production controls.
Quality Standards for lipid components
The following information covered in the specification for each lipid component used in the manufacture of the drug product should be provided. The criteria include:
The identification test should be able to distinguish the target lipid composition from lipids with similar structure.
Content analysis should be based on the analysis method of stability indication.
The analysis process should be validated (validation data should be submitted).
Impurity testing should be included (see below).
Additional examples that should be covered for naturally derived lipid mixtures such as organic egg yolk lecithin. The tests are as follows: 1. Unsaturation of fatty acid side chains. 2. Counter ion content and limit of divalent cations.
For synthetic lipids or lipid mixtures, the tests indicated below should be included: 1. Trans fatty acids 2. Free fatty acids 3. Peroxides 4. Lysophospholipids 5. Counterion content and divalent cation limits.