Consideration of safety of gelatin hollow capsules in relevant laws and regulations (1)

Capsules are an ancient dosage form whose application can be traced back to ancient Egypt in 1500 BC. With many advantages such as good taste masking effect, better bioavailability, and beautiful appearance and easy to swallow, capsules have gradually become one of the dosage forms favored by consumers. As an important auxiliary material for capsules, hollow capsules have been produced and used for more than 100 years, and gelatin has always been the main raw material for hollow capsules. At present, gelatin hollow capsules are widely used in the field of food and medicine. The United States Pharmacopoeia (USP), European Pharmacopoeia (EP), Japanese Pharmacopoeia (JP) and related food regulations have clear regulations on this type of product or the gelatin used to reduce product safety risks. This article will analyze the relevant laws and regulations of the United States, the European Union, Japan and my country, combined with pharmacological and toxicological studies, and discuss the safety considerations of the relevant laws and regulations for the gelatin hollow capsules.
Heavy metal
Heavy metals generally refer to mercury (Hg), cadmium (Cd), lead (Pb), chromium (Cr), and metal-like arsenic (As) with heavy metal characteristics, and other heavy elements with significant biological toxicity. Sometimes it also refers to copper (Cu ), zinc (Zn), cobalt (Co), nickel (Ni) and other general heavy metals. Some of these are trace elements necessary for human health, but if they accumulate in the body beyond the limit, they also show virality. Studies have shown that the accumulation of heavy metals in the body can cause diseases such as the nervous system, immune system, and cardiovascular system.
USP and JP respectively stipulate that the total amount of heavy metals in gelatin should be less than 50ppm, of which the arsenic content should be less than 0.08ppm (USP) and 1ppm (JP), respectively, and the mercury content should be less than 0.1ppm. EP does not regulate the total amount of heavy metals, but separately regulates the content of iron, zinc and chromium, which shall not exceed 30 ppm, 30 ppm and 10 ppm. It is worth mentioning that JP classifies gelatin, where the heavy metal limit of refined gelatin is set at 20 ppm. The Chinese Pharmacopoeia (CP) 2000 edition of the hollow capsule product's total heavy metal regulations are consistent with USP and JP, but the arsenic content is relaxed to 2ppm. The CP 2010 version of "Gelatin for Capsules" has been revised to limit the content of heavy metals to 30ppm, and the content of arsenic must not exceed 1ppm. At the same time, the "Gelatin Hollow Capsules" consultation draft also changed the limit of heavy metals to 40ppm.
In September 2007, the "Gelatin Hollow Capsules" Association Standard issued by the China Pharmaceutical Packaging Association added the detection of the chromium content limit, and it was specified to be less than 2ppm, which is significantly lower than the EP. This is mainly to control the use of inferior "blue alum skin glue". Since 2004, CCTV and other media have exposed the use of scraps from the tanning industry to produce edible and medicinal gelatin, which caused a great sensation. Some organizations have sampled and tested the gelatin hollow capsules on the Chinese market, and found that some samples had chromium content as high as tens of ppm, even as high as several hundred ppm. In April this year, the Southern Metropolis Daily and other media once again exposed the hydrolyzed protein produced by a company in Zhejiang that added leather scraps to dairy products, indicating that the use of inferior gelatin for profiteering has never completely disappeared.
"Blue alum leather" is leather scraps tanned with heavy metals, with a high content of hexavalent chromium ions. Cr6+ is the most toxic type of chromium ions. It easily enters cells and is reduced to trivalent chromium, producing intermediate pentavalent chromium and active free radicals, causing damage to DNA, irritation to the respiratory and digestive tracts, and to the liver and kidneys. There is obvious damage, and the degree of damage is related to the content of chromium ion; there is significant carcinogenic, teratogenic, and reproductive toxicity. Since conventional methods cannot remove hexavalent chromium ions in blue alum skin, the limit of chromium content in hollow capsules in the standard of my country Medical Packaging Association is an effective way to restrict the use of such inferior gelatin in hollow capsules. The CP 2010 version of "Hollow Gelatin Capsules" and "Gelatin for Capsules" have both increased the detection of chromium content, with a limit of 2ppm, in order to reduce the safety risk of hollow capsules in my country.