Infusion refers to a large dose of injection injected into the body by intravenous drip, which is one of the five commonly used clinical preparations. It provides water, electrolytes and nutrients required by patients, and can also be used as a carrier for intravenous drug delivery. Since the "ninth Five-Year Plan", China's infusion production has been steadily and healthily developed, the output has increased from 1.38 billion bottles (bags) in 1995 to 2.91 billion bottles (bags) in 2001, with an average annual growth of 16.1%, and the market capacity of infusion reached 3.5 billion bottles (bags) in 2003. At present, the packaging forms used in China's infusion production are: glass bottles, plastic bottles and plastic soft bag packaging, of which plastic soft bag packaging is divided into PVC (polyvinyl chloride) bags and non-PVC soft bag packaging.

1, glass bottle infusion packaging technology

Glass bottle infusion has long been the main form of infusion packaging in China, and 95% of infusion in China is still packed in glass bottles. As the traditional packaging form of infusion, glass bottle infusion has the following advantages:

1) The transparency of the glass bottle is good, which is conducive to the detection of insoluble particles for infusion.

2) The glass bottle has good thermal stability, which is conducive to the use of high temperature sterilization in the process of infusion production to remove bacteria and ensure the quality of infusion.

3) It has good chemical inertness, barrier property and airtightness, which ensures the stability of the quality of the drug during storage.

However, there are certain defects in the technology of glass bottle packaging for infusion, mainly:

1) Inconvenient transportation and limited geographical scope. The glass bottle is brittle and easy to break due to violent vibration and impact, so the glass bottle infusion is not suitable for long-distance transportation, which limits the geographical scope of its application.

2) The process is complex and the production efficiency is low. The infusion is packaged in glass bottles. Compared with other infusion packaging technologies, the complex processes of rubber plug, isolation film and glass bottle washing are added in the production process, and the process route is longer and the production cycle is relatively extended, so the production efficiency is low.

3) High production cost. Due to the complex process route, more equipment, a wide area, higher equipment investment costs and housing construction costs, and in the processing of packaging containers and auxiliary materials need to consume a lot of water, so the production cost is higher.

4) Clinical use, there are safety risks. When the medical staff insert the needle in the glass bottle infusion, it is necessary to Pierce the rubber plug and Pierce the polyester film, and insoluble particles are inevitably introduced into the infusion, which may block the human microcirculation and even cause thrombocytic bleeding <2>; In addition, in clinical application, in order to make the infusion process can proceed smoothly, it is necessary to insert the ventilation pipe to introduce air to the solution, resulting in a pressure difference, when the infusion is in a fully open state, dust and microorganisms in the air may enter the glass bottle and pollute the infusion, resulting in serious infusion reactions.

Glass bottles due to heavy quality, high brittleness, easy to break, inconvenient to carry and transport, therefore, in the 1960s, the international infusion with plastic containers as packaging containers, ending the situation of glass infusion packaging technology domination.

2, plastic bottle infusion packaging technology

Plastic bottle infusion packaging technology is mainly based on polypropylene (PP) and polyethylene (PE) as materials for packaging containers. In 1984, Tianjin Otsuka Pharmaceutical Company introduced polypropylene gum bottle packaging production technology to produce our country's PP bottle infusion. The advantages of plastic bottle infusion packaging technology are:

1) Light weight, the bottle weight is only 1/5 of the glass bottle weight, and is not easy to break, which is conducive to long-distance transportation.

2) The chemical stability, barrier property and compatibility with drugs of plastic bottles are good, which is conducive to the long-term preservation of pharmaceutical liquid.

3) Advanced technology, high production efficiency. In the production process of plastic bottle infusion, bottle making and filling are carried out in the same production area, or even in the same machine, the bottle only needs to be washed with sterile air, or even filled directly without washing, eliminating the complicated washing process of glass bottle infusion, shortening the production cycle and improving production efficiency.

Although plastic bottle packaging technology overcomes the shortcomings of glass bottle packaging technology, which is not easy to transport and low production efficiency, it must be seen that there are still some problems with plastic bottle infusion:

1) Clinical application, there are transfusion safety problems, plastic bottle infusion and glass bottle infusion, both belong to the open infusion method, the use of the process still need to insert the air needle, the establishment of air access, in order to make the infusion drip smoothly, microorganisms and particles in the air can still enter the infusion through the air needle, causing damage to the human body.

2) The transparency of plastic bottles is not as good as that of glass bottles, which is not conducive to the inspection of the clarity of infusion.

3) The thermal stability of plastic bottles is worse than that of glass bottles, PP plastic bottles are not resistant to low temperature,

It is easy to be brittle and cracked when cold, PE plastic bottles are not resistant to high temperature, and can not reach the 121℃ required by FDA when sterilizing.

3, plastic soft bag infusion packaging technology

In order to solve the safety problem of clinical application of bottled infusion, plastic soft bag infusion packaging technology came into being. The infusion using this packaging technology can achieve fully enclosed infusion. In clinical use, due to the self-shrinking of the soft bag, there is no need to form an air loop, and the extrusion of external atmospheric pressure can force the medicine to drop out, avoiding the safety risks of open infusion mode and improving the safety of infusion. Plastic soft bag infusion packaging technology is divided into PVC soft bag packaging technology and non-PVC soft bag packaging technology according to the material of the soft bag.

3.1 PVC soft bag infusion packaging technology

PVC soft bag packaging technology, compared with glass bottles, plastic bottles infusion packaging technology, has the following advantages:

1) The use of PVC soft bag packaging, small size, light weight, lighter than the quality of plastic bottles, saving the storage space of hospitals and manufacturers, more conducive to transportation and carrying, it overcomes the glass bottle infusion weight, large volume, easy to break inconvenient transportation and carrying, and bottle containers need more storage space shortcomings.

2) PVC soft bag has the characteristics of pressure resistance and strong anti-fall force, which is easy to transport and use in time and space in emergency situations, which is an important feature of soft bag packaging that is different from bottled infusion.

3) Good transparency, although worse than glass bottles, but better than plastic bottles, does not affect the clarity inspection, can overcome the shortcomings of poor clarity of plastic bottles infusion.

4) The fully closed infusion method is realized, which can be used clinically, overcome the secondary pollution problem of bottled infusion, and improve the safety of infusion.

5) Simple process, high efficiency and low cost. The bag-making, filling and sealing process of PVC bag infusion is completed in the bag-making, filling and sealing machine under the 10000 level control environment (the filling and sealing are carried out under the local 100 level laminar flow protection), and the bag is filled directly without cleaning after the bag is made, which saves the complicated rubber plug, polyester film and glass bottle cleaning process compared with the glass bottle packaging technology. The production process is greatly shortened and the production efficiency is improved. At the same time, it saves a lot of washing water and the land area of the production plant (glass bottle storage, cleaning workshop, glue plug storage, cleaning workshop, etc.) in the production of glass bottle infusion, and the price of PVC material is low, and the production cost of infusion is reduced.

Although PVC soft bag infusion packaging technology has many of the above advantages, there are still fatal weaknesses that limit the promotion of PVC soft bag packaging technology:

1) The barrier of PVC soft bag to water, wet steam and air is poor, easy to be permeated by water, wet steam and air, which is not conducive to the long-term storage of liquid medicine.

2) PVC soft bag on some drugs such as: oil soluble vitamins, insulin, isosorbide nitrate, chlorpromazine, there is a certain absorption, reduce the efficacy of drugs.

3) There are more dissolved substances in PVC soft bags, and the number of insoluble particles of 2 to 5μm is more than that of other packaging containers, which may cause vascular embolism, venous inflammation, and allergic reactions.

4) There is potential harm to human health and the environment, the plasticizer phthalate (DHEP) added in the production process of PVC soft bag, although it can make PVC flexible packaging soft and elastic. However, studies have found that this substance is a carcinogen, which may dissolve in the infusion and cause damage to the health of patients. As a disposable product, PVC infusion soft bag produces harmful gas dioxins when incinerated after disposal to pollute the atmosphere, causing great harm to the environment. In view of this, the National Drug Control Administration has clearly stopped the approval of new PVC soft bag packaging infusion manufacturers.

3.2 Non-PVC soft bag infusion packaging technology

Although the above three infusion packaging technologies have their own advantages, but there are certain shortcomings, so is there a new infusion packaging technology, with the advantages of these three packaging technologies, but without its defects? This is the non-PVC soft bag packaging technology developed by developed countries in Europe and the United States in the 1990s. In Japan, non-PVC soft bag infusion currently accounts for 60% of the entire infusion market.

Non-pvc soft bag packaging technology has experienced two stages of development, one is the polyolefin composite film packaging technology from the 1980s to the 1990s, soft bags are made of different film processing fusion, generally 3 to 5 layers. Polyolefin composite film light weight, high transparency, good barrier to water, moisture, air, heat resistance, chemical stability and drug compatibility, is a relatively ideal packaging material, but because in the process of preparing composite film, the use of adhesive between the layers of the film is not conducive to the stability of the film, and there is a potential impact on the stability of the liquid medicine. Therefore, the application of this technology in infusion production has been affected to a certain extent; The second is the polyolefin multi-layer co-extruded film packaging technology, which has been improved on this technology in recent years. In the process of making soft bags, multi-layer polyolefin materials are fused and crosslinked at the same time, without adding adhesives, and the adverse effects of adhesives on the stability of film materials and pharmaceutical liquid are eliminated.

At present, the more popular polyolefin multilayer co-extruded film generally has a three-layer structure. Commonly used polyolefin multilayer co-extruded film has two types, one is the inner layer, the middle layer of polypropylene and different proportions of elastic materials mixed, non-toxic, inert and has good heat sealing property, the outer layer of high mechanical strength polypropylene or polyester material; The second type is a mixture of polypropylene and styrene butene styrene (SEBS) copolymer in the inner layer, SEBS in the middle layer and polypropylene in the outer layer.

Polyolefin multi-layer co-extruded film soft bag, the bag making process does not use adhesives, plasticizers, and the film material does not dissolve out, no chips, for the safe use of infusion soft bag provides a guarantee, the film material is easy to heat seal, good elasticity and impact resistance, wide temperature tolerance range, not only high temperature can be sterilized at 121℃, but also low temperature (-40℃). High transparency, conducive to clarity inspection; Chemical inertness, good drug compatibility suitable for packaging various infusion; Chloride-free post-treatment is environmentally friendly; Simple production process, high degree of automation; In clinical infusion, the soft bag can be completely self-shrinking to achieve fully closed infusion, avoiding secondary pollution during infusion, and high transfusion safety. At present, the shortage is that the film price is high, and the special bag making and filling equipment are mostly imported, and the price is high, so the production cost is higher than other packaging technologies. However, fortunately, recently, the domestic Hunan Qianshan company has developed similar equipment to reach the international level, the price is 1/3 of the imported, with the continuous digestion and absorption of the domestic technology, the production cost will continue to decline.