Gel plug butylation: drug pack mandatory "upgrade procedure"

As a packaging material directly in contact with drugs, the quality of the medical plug directly determines and affects the quality of the drug. As early as the 1960s, developed countries had used butyl rubber plugs to encapsulate medicines. However, due to limitations in the level of scientific and technological development and understanding, China has been using traditional natural rubber stoppers, which is not conducive to ensuring the quality of medicines. Therefore, it is imperative for China to promote the butylation process of medical rubber plugs.

Medical stopper "Link" drug quality

The cleanliness of the appearance of the medical stopper is crucial for the drug. For example, a needle-pointed white spot, dark spot, and the thickness of a hair fiber can be seen everywhere in our daily drinking water and delicacies, but it has little effect on health. However, in medicines, especially infusion products and injection preparations, such insoluble particles are extremely harmful. The light will cause patients with long-term drug-induced diseases, such as cerebral thrombosis, myocardial infarction, etc. In severe cases, they will even block blood vessels, leading to death of patients.

The various raw materials in the medical rubber plug formulation component and the raw materials in the production process will directly affect the safety of the drug. Cleaning agents such as cleaning agents, plastic bags for packaging, and various release agents must be non-toxic, non-adverse side effects; this is especially true of the various raw materials in the formulation components. Both raw rubber and various additives must be guaranteed to contain as few heavy metal ions, bacteria, etc. as possible.

The extract of medical stoppers is closely related to the stability and shelf life of the drug. Any rubber product undergoes high-temperature cooking in acids, alkalis, and organic solvents, all have different degrees of precipitation, and the less precipitated material, the more complete the cross-linking and the more stable the structure. The process of contact between the rubber stopper and the drug itself is a process of mutual penetration and mutual leaching. The only slower the reaction is, the less the material is precipitated, the better the drug efficacy is maintained, and the longer the shelf life will be.

In addition, the physical properties of the pharmaceutical butyl plugs such as acupuncture, etc., also directly affect the safety of the drug.

Rubber plug material "renewal" is reasonable

Natural rubber stoppers have four major drawbacks:

- Poor biological safety. Natural rubber is made from latex, where rubber hydrocarbons only account for 92%-95% and non-rubber hydrocarbons account for 5%-8%. These non-rubber components contain the lipids and their decomposition products, proteins and small amounts of calcium phosphate, magnesium phosphate and other salts left in the latex. The presence of certain proteins makes the rubber easy to absorb moisture and mold and provide mold growth. Suitable conditions. Tests by relevant agencies have shown that the dissolution of heterologous proteins from natural rubber plugs is one of the important factors that cause human heat sources; dissolved acridine compounds are prone to cause cancer, teratogenicity, and mutagenesis.

- The chemical properties are relatively lively and easily interact with drugs. Natural rubber is mainly composed of isoprene molecules. Each molecular chain contains an unsaturated double bond and has a low bond energy. Therefore, it is easy to react with other substances and has poor stability.

- Poor air tightness. Hermeticity is characterized by permeability. The permeability of the gas to the polymer depends on the diffusion rate of the gas in the polymer. Studies have shown that if the polymer molecular chain is flexible and free volume is large, it is conducive to diffusion. Natural rubber macromolecules have a high flexibility and have a high diffusivity for various gases, thereby deciding that natural rubber plugs have poor airtightness.

- The use of complex technology. Because the natural rubber plug has a poor environment in the production process and has a lot of extraneous pollution. In addition, the formulation components are more complicated. Therefore, the pharmaceutical factory must carry out acid and alkali treatment before packaging the medicine so as to reduce the rubber plug to the liquid medicine as much as possible. Pollution. In addition, in order to ensure its tightness, pharmaceutical companies have to undergo surface chlorination on natural rubber plugs and seal them after packing. Even so, natural rubber seals are still poorly sealed.

The five major advantages of butyl rubber plugs are obvious:

- good airtightness. The permeability of natural rubber to oxygen is 17 times that of butyl rubber, the permeability to carbon dioxide is 25 times that of the latter, and the permeability to hydrogen is 6 times that of the latter, visible butyl rubber is excellent The tightness makes it the preferred material for rubber stoppers.

- Good chemical stability.

Compared with natural rubber stoppers, butyl rubber is highly inert.

- Higher cleanliness.

In natural rubber, non-rubber components such as protein, water-soluble matter, ash, etc. account for 5%-8%, while butyl rubber accounts for only 0.9%. These non-rubber components, commonly referred to as impurities, are highly likely to be smoked. Proposed to contaminate the drug. In addition, butyl rubber plugs are mostly formulated with zinc-free or non-sulfur formulations. Traditionally, they do not use traditional thiurams or thiazole-based accelerators, and their formulation components are small. Therefore, there are fewer precipitates than natural rubber plugs.

The higher cleanliness of the production environment ensures that the external contamination of the butyl rubber plug is far less than that of the natural rubber plug. Since the butyl rubber plug pays great attention to the cleanliness of the factory environment during the production process, the degree of cleanliness is controlled step by step from the curing section, and finally a hundred-layer laminar flow hood under the finished product is packaged, thereby greatly improving the surface of the rubber plug. Cleanliness.
- With a more concise handling and use of technology. The butyl rubber stopper can be sterilized by simply rinsing with injection water in the pharmaceutical factory, which can reduce the production cost of the pharmaceutical factory, increase the labor production efficiency, and reduce the labor intensity of the operator.

- Safer biological performance. Butyl rubber itself is a synthetic rubber, its impurity content is much lower than natural rubber, in particular it does not contain the opposite sex protein, thus the heat source is far less likely than natural rubber plugs. In addition, the butyl rubber stopper formula does not include thiuram, thiazole and various antioxidants, which greatly reduces the toxic side effects of rubber stoppers, making the bio-safety of butyl rubber stoppers further protected. .

Butyl rubber plug usage "Search"

Butyl rubber plugs should comply with the following principles when used:

- Choose according to the production process. When freeze-drying method is used to produce sterile powder for injection, the freeze-dried rubber plug must be selected; when using other methods such as sterile solvent crystallization method and spray drying method to produce sterile powder for injection, antibiotic rubber plug must be used (international standard) In the case of injectable rubber stoppers; for infusion products, infusion stoppers should be used.

- Select according to production equipment.

The running track of the imported rubber plug production line is generally applicable to rubber stoppers with a crown diameter of 18.8 mm, corresponding to the 20-A, 20-B1 type products in China's industry standards; whereas the domestic production lines previously using natural rubber plugs are generally applicable to the crown diameters. The 19.5 mm rubber plug corresponds to the 20-B2 product in China's industry standard. For the sucker capping machine, it is recommended to use a product with a circular spacer on the crown of the stopper, such as a 20-A type product; for any other type of capping machine, you can choose any one.

- Select according to the glass bottle selected.

Under normal circumstances, if you select the infusion bottle that meets GB2639-90, you can choose according to the bottle type, in which type A bottle can use the industry standard 32-A rubber plug, and type B bottle can use the industry standard 28-B type rubber. Plug. For molded antibiotic glass bottles that conform to GB2640-90, they can also be selected according to the bottle type. The inner diameter of the A bottle bottle mouth is 12.6 mm. It is recommended to use a product with a 13.2 mm plug diameter, such as a 20-A type product; B The inner diameter of the bottle bottle is 12.5 mm. It is recommended to use a product with a 13.0 mm plug diameter, such as 20-B1 and 20-B2 rubber plugs. For a controlled antibiotic glass bottle that complies with GB2641-90, the capacity is 5 ml, and the 13 series can be used; the capacity is 7-25 ml, and 20-B1 or 20-B2 rubber plugs can be used. In special circumstances, the size of the rubber plug chosen can be determined by the parties to the supply and demand.

- Select according to the compatibility test.

Since the butyl rubber plug is in direct contact with the drug, it will inevitably interact with certain drugs. Therefore, the drug manufacturer must conduct a compatibility test before confirming the supplier, and select the manufacturer for matching according to the test results.

When using butyl rubber plugs, pay attention to:

- The package should be opened in a clean area. Pharmaceutical manufacturers should open the packaging in the 100,000-class clean area and open the inner package in the 10,000-class clean area.

—— Use water for injection to clean, the number of cleaning should not exceed two times, it is best to use ultrasonic cleaning, avoid mixing during the cleaning process, should reduce the friction between the rubber plug as much as possible.

——Drying and sterilization is best done with moist heat sterilization method, 121°C for half an hour. If the conditions do not allow hygrothermal sterilization, only dry heat sterilization, it is best not to exceed two hours. During the process of drying and sterilizing the stopper, try to reduce the friction between the stoppers.

- Pharmaceutical companies can omit the silicidation process. Since the rubber stopper is already siliconized in the manufacturer, the pharmaceutical factory generally does not need to perform silicidation under the condition of satisfying the upper machine cover. If the machine is not running smoothly, consult with the supplier and adjust the amount of silicone oil.

Related standard "click"

International standards include ISO8536-2:1992 (infusion stopper), ISO8362-2:1988 (injection stopper), ISO8536-6:1995 (freeze-dried infusion stopper), ISO8362-5:1995 (freeze-dried infusion stopper) And ISO 8871:1990 (elastic parts for non-intestinal water preparations).

Industry standards are YY0169.1-94 (butyl rubber infusion bottle stopper), YY0169.2-94 (butyl rubber antibiotic stopper) and YY/T0169.3-94 (butyl rubber medical stopper chemical test method) .

The butyl rubber plugs are far superior to natural rubber stoppers in terms of bio-safety, airtightness, and chemical stability. In order to fully improve the quality of pharmaceutical packaging in China, the State Drug Administration has stipulated that from July 1, 2001, 13 drugs such as ceftazidime and cephalosporin sodium will still be packaged in common natural rubber stoppers. Sales and use. From January 1, 2002, biological products, blood products, and freeze-dried antibiotic injections must stop using natural rubber stoppers. From January 1, 2005, all other medicines will stop using natural rubber stoppers.

Eliminating outdated packaging is not only an improvement in the quality of pharmaceutical packaging and ensuring the safety of people's drug use, but also is one of the measures that pharmaceutical companies should take actively to face the challenges of accession to the WTO. Therefore, both pharmaceutical companies and manufacturers of rubber stoppers should seriously study the relevant laws and regulations of the State Food and Drug Administration and in-depth study of the various technical quality problems of butyl rubber plugs during production and use, in order to fully promote medical adhesives in China. The butylation process of the plug made its due contribution.