Lipid system An artificial cell membrane with an onion-like closed spherical structure that enables drugs to be protected in its structure and to play a directional role, especially suitable as a carrier for anticancer drugs to improve their therapeutic effects and reduce toxic and side effects. Liposomes are composed of phospholipid as framework membrane material and additive. Phospholipids used in the preparation of liposomes include natural phospholipids and synthetic phospholipids. Natural phospholipids are mainly lecithin (phosphatidylcholine, PC), derived from egg yolk and soybean, neutral, containing a lot of impurities, easy oxidation, and degradation, liposomes composed of natural phospholipids, drug leakage is large, not easy to preserve. Synthetic phospholipids mainly include DPPC, DPPE, DSPC, etc., all of which belong to hydrogenated phospholipids, with stable properties, strong oxidation resistance, stable finished products, etc., and are the preferred excipients in foreign countries at present.
Preparation of liposomes, also need some additional agents, such as cholesterol, which is also an amphiphilic substance, and phospholipid mixed with the preparation of stable liposomes, its role is to adjust the fluidity of the bilayer, reduce the permeability of the liposome membrane. Other additives include octadecylamine and phosphatidic acid, which can alter the surface charge properties of liposomes. Sodium chloride and other salts or buffer salts are also used as solvents or stabilizers.
PEG lipids, such as DSPE-MPEG2000, are used in long-cycle liposomes. In the liposome process, special excipients will also be used, such as Onivyde®, irinotecan liposome developed by Taiwan Zhiqing Company, China, using sucrose octasulfate gradient drug delivery. Sucrose or trehalose are commonly used as lyophilized protectants.
Overseas, there are 2015 FDA draft pharmaceutical Industry Guidelines for Liposome Drug Products.
Requirements for excipients are as follows: control of lipid components:
The quality of lipid components, including modified lipids (e.g., polyethylene glycol-modified lipids, PEG), may affect the quality and performance of liposome drug products. When a brand new lipid is used, the level of detail in the submitted application should be the same as that of the drug. In addition, the following specific lipid-related information should also be submitted:
A. Characters and characteristics of lipid components
Proof of structure, including fatty acid composition and specific conformation, should be submitted if a lipid is selected as synthetic or semi-synthetic, such as dimyristoyl phosphatidylcholine (DMPC). Specific lipid composition (e.g., percentage of various lipids and fatty acids, the particular configuration of acyl chains, and saturation of fatty acids) should be submitted. If it is a mixture of lipids of natural origin (e.g. lecithin), the percentage range for each individual lipid and its fatty acid should be submitted.
B. Production of lipid components
Whether synthetic, semi-synthetic, or naturally extracted, information on the production of lipid components should be submitted. For synthetic and semi-synthetic lipids, we recommend submitting the following information: I. A complete description of the synthesis process and purification process, where applicable ii. Quality standard for Starting Materials, Raw materials, solvents, and reagents III. control of key steps and intermediates, where applicable, shall include side-chain acyl configuration-specific production control.
C. Quality standards for lipid composition
The following information covered in the quality standards for each lipid component used in the manufacture of drug products should be provided. The standard contains I. Identification tests should distinguish between target lipid components and lipids with similar structures. Ii. The content analysis shall be based on analysis methods indicating stability. Iii. The analysis process shall be validated (validation data shall be submitted). Iv. Tests for impurities shall be included (see below). V. Other examples that should be covered for mixtures of lipids of natural origin, such as lecithin. The tests are as follows: 1. Unsaturation of fatty acid side chain. 2. Limit equilibrium ion content and a divalent cation. Vi. For synthetic lipids or mixtures of lipids, the following tests shall be included: 1. Trans-fatty acids 2. Free fatty acid 3. Peroxide 4. Lysophospholipid 5. Limit of equilibrium ion content and a divalent cation.