Risk Reviews of Preclinical Pharmaceutical Studies on Traditional Chinese Medicine Injection

YANG Na, CHEN Yu-wen(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Risk Reviews of Preclinical Pharmaceutical Studies on Traditional Chinese Medicine Injection

YANG Na, CHEN Yu-wen
(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Objective To analyze the risks of preclinical pharmaceutical research on TCM injections according to the application dossiers of traditional Chinese medicine (TCM). Methods Process of clinical pharmaceutical research on traditional Chinese medicine (TCM) injections and its potential risk control points were analyzed based on the cycle of research and development of TCM injections, expert consultations and literature reviews. Results and Conclusion Six research stages with high risks should be focused on in order to improve the R&D efficiency of traditional Chinese medicine injection.

traditional Chinese medicine injection; pharmaceutical research; risk

1 The risk factors in the preclinical study of TCM injections

1.1 The risk of Chinese medicinal materials

In the process of research and development of TCM injections, each risk factor will bring instability and uncertainty to the traditional Chinese medicinal materials and the efficacy of the medicine, and it can cause adverse reaction of Chinese medicine injection. Therefore, the source and identification of medicinal herbs should be attached importance to. The risk of Chinese medicinal materials for research and development of traditional Chinese medicine (TCM) injections includes the following parts.

1.1.1 The risk of differences of Chinese medicinal materials leading to the different purity of Chinese medicine liquid

The origin, varieties and harvest season of Chinese medicinal materials will greatly influence the quality of Chinese herbal medicine. In addition, the growth conditions such as sunshine, water, soil, climate changes and the picking time as well as the store time can lead to the differences of TCM injections quality. For example, the raw material for Houttuyina cordata injection should be fresh Houttuyina herbs according to the quality standard. Therefore, there must be strict control standards on the extraction of fresh Houttuyina cordata from picking, transportation to the production. Second, the differences of medicinal part, years of growth and processing methods of Chinese medicinal materials can also cause different purity of traditional Chinese medicine liquid[1].

1.1.2 The risk of wrong medicinal materials duo to the homonyms and synonyms of Chinese herbs

China is rich in herbal medicine resources and it is easy to have the problem of the homonyms or synonyms of Chinese herbs that can bring unexpected adverse reactions to traditional Chinese medicine injection. For example, the labiatae plants of the genus is called Qi Dan in “dictionary of Chinese medicine”, but it belongs to dry grass primulaceae in “Chinese pharmacopoeia”[2].

1.1.3 The risk of different contents of Chinese herbal medicine duo to the lack of standards

There are some provisions on the shape of Chinese herbal medicine, but there are rarely indicators of theingredient content, not to mention the heavy metals, pesticides and harmful substances in Chinese traditional medicine itself and the harmful effects caused by various exogenous pollution[3].

1.2 The risk of chemical composition of TCM injections

The chemical composition of TCM injections are divided into active ingredients and invalid ingredients. The active ingredients include the components directly exert on the body and some composition that indirectly function on the body. These components function indirectly, such as the native glycosides can work as the medicine, and another case is the lamp b polyethylene glycol[4], which plays a role in the metabolic product of native glycosides in the human body or biological products.

1.2.1 The risk of uncertain chemical composition of TCM injections

The uncertain chemical composition of traditional Chinese medicine injections is the cause of adverse reactions. Therefore, it is risky to have the research and development of traditional Chinese medicine (TCM) injection with the compatibility of Chinese herbs.

First, the single traditional Chinese herb contains a large number of the chemical components, and the current research bottleneck is that we just get to know part of the chemical components. For example, the active components of salvia miltiorrhiza injection are phenolic acid compounds, but the other ingredients will affect its purity and effectiveness. Secondly, in terms of compatibility of traditional Chinese medicine injection, the chemical components include impurities, allergen, tanning and hemolytic which is the main cause of allergic reactions[5]. In addition, it is easy for these chemical components in traditional Chinese medicine (TCM) to have reactions such as oxidation and hydrolysis, resulting in the quantity change of traditional Chinese medicine (TCM) injection.

1.2.2 The risk of sensitization duo to large or small molecules

Chemical composition of TCM injections can be divided into large molecules and small molecules. In terms of large molecules, it also has the nature of polysaccharide and protein. Due to the insufficient research on allergen of TCM injections, it is possible that the large molecules as antigen can cause allergic reaction[6]. And as to small molecules, more than 99% chemical components in traditional Chinese medicine (TCM) injection were found to be small molecules. The risk factors in research and development include the following such as the main components of the TCM injections, trace elements, alkaloids, flavonoids, effective components and impurities. And these risk factors are easy to cause allergic reaction in the process of research and development.

1.2.3 The risk of residual macromolecular substance

The residue of TCM injections is the macromolecular substance, such as tanning, phlegmatic, protein, starch, pigment and resin, etc., which will become precipitated for long time storage. For instance, polysorbate 80, a solubilizer, can cause adverse reactions such as low blood pressure, hemolysis or even an allergic reaction if it is not used appropriately[7].

1.3 The risk of preparation technology

The research on preparation technology of traditional Chinese medicine injection is to analyze the active ingredients and harmful material in the process of preparation to determine the risk factors of TCM injection. The preparation process of traditional Chinese medicine (TCM) injection generally includes extraction, refining, compounding, filling and sealing, sterilization and packing.

1.3.1 The risk of improper extraction method

Water alcohol method, alcohol water method and distillation are commonly used for the extraction. However, the current extraction method can not solve the problem of the complexity and unpredictability of TCM injections, and different method has different risk. (1) Water alcohol method can extract the effective components but there are still many impurities which can cause more adverse reactions. In addition, some active ingredients get lost and the injection has poor stability and long heating time for solution. (2) Alcohol water method has the similar risk to the water alcohol method. (3) Distillation method is easy to damage the sensitive components duo to its long heating time. The effective composition of volatile oil is a mixture, and the extraction quantity measure of the volatile components is not clear now. Therefore, it is possible to destroy the volatile oil in the process of extraction[8].

1.3.2 The risk caused by the defects in refined method

The common refined methods include water extractalcohol precipitation, lime sulfur method, active carbon adsorption method and ultrafiltration membrane filtration method. The purpose is to remove sensitization ingredients such as tanning, polysaccharide and protein. However, these methods are difficult to achieve the objectives. (1) Water extract-alcohol precipitation method can not get rid of sensitization ingredients such as polysaccharide and protein composition in injection. (2) Lime sulfur method is to remove impurities through adjusting pH value in the lime milk and sulphuric acid. But the acid base tends to destroy the active ingredients in traditional Chinese medicine injection which results in the uncertainty of effective component. (3) Activated carbon adsorption method is usually used to remove the pyrogen, but due to the change of the environment, the components of the injection is polluted which reduces the content of active ingredients. (4) Ultrafiltration law is likely to reduce the active ingredients because of the ultrafiltration membrane[9].

1.3.3 The other risks in the process of preparation of traditional Chinese medicine (TCM) injection

(1) The risk of inappropriate processing raw materials. The allergen in the raw materials is the risk factors in the preliminary processing. (2) The risk of low clarity in Chinese medicine injection. Traditional Chinese medicine injections have colloid such as resin, starch, protein and other impurities, and the change of temperature or pH value will affect the clarity of Chinese medicine injection. (3) The risk of pH adjustment. The solubility of many effective ingredients of traditional Chinese medicine is vulnerable to the pH change, which makes the active ingredients precipitated and affects the content of the effective components. (4) The risk of local irritation. A large proportion of the active components of TCM injections contain volatile oil and it is irritating because of its properties, so the patient may feel irritated or uncomfortable after the injection[10].

1.4 The risk of selecting auxiliary materials

In the process of TCM injections R&D, due to the particularity of the injection route, we must improve monitoring level of the solubility and stability of the effective components. Traditional Chinese medicine injections may produce hemolysis, allergies and other adverse reactions when solubilizer and other auxiliary materials are added to the injections. Because we do not have provisions on injection level such as the uncertainty of purity and the microbial limit that results in the risks in the research and development of TCM injections[11]. In addition, because of the complexity of the chemical composition in traditional Chinese medicine injection, it is possible that the auxiliary materials react with chemical composition or they prompt some of the chemical reaction, and it makes injection composition more complex[12].

1.4.1 The R&D risk duo to the different auxiliary materials selection

In traditional Chinese medicine injections, isotonic regulators such as analgesic, solvent and pH regulator are frequently used as auxiliary materials, but preservatives, antioxidants, suspension agent and antibacterial agent are rarely used.

Of all the auxiliary materials, the choice of solubilizer and quality standard has been one of the bottlenecks in the development of TCM injections. In order to improve the rate of dissolution and the clarity of injection as well as preventing precipitation, polysorbate 80 is used as solubilizer at present in the injection. Another case in point, yamanashi ester 80 can’t increase the solubility of any active ingredients, but it can dissolve the active ingredients and impurities, or lead to hemolysis or allergic reaction with an excessive application[13].

Benzyl alcohol can affect the clarity of Chinese medicine injection, so we must strictly control its acting time as excipients[14].

The other two commonly used materials are pH regulator and adjusting agent. The R&D risk of pH regulator is that it is difficult to take the solubility, stability, effectiveness and physiological adaptability of traditional Chinese medicine (TCM) injections into account. As to adjusting agent, it is likely to affect some steps in the R&D such as identification, examination and content determination, and it is easy to have precipitation reaction with other chemical components which leads to the instability of TCM injections[15].

1.4.2 R&D risk caused by improper selection of auxiliary materials at the preparation stage

The choice of auxiliary materials should occur at the stage of extraction, separation and purification of traditional Chinese medicine (TCM). If the auxiliary materials areimproper, it is hard to extract the effective components and to get rid of the impurities and inactive ingredients. In selection of auxiliary materials for traditional Chinese medicine (TCM) injections, we should choose the same chemical components in that different components in the injection can also lead to physical turbidity, precipitation and oxidation[16].

Therefore, due to the lack of perfect system of selecting Chinese medicine injection auxiliary materials, solubilizer can work as auxiliary materials for TCM injections, which may lead to the potential hazard of TCM injections.

1.5 The risk of stability

The risk of stability in the study of TCM injections should screen effective index to reflect the stability of TCM injections based on its external and internal factors such as compatibility, preparation technology, impurities and quality control. As to the technical requirements for the study of stability, China has made requirements for the study of injection in terms of stability factors and long term stability test[17]. The followings are the overall analysis of the main risk factors which influence the stability of TCM injections.

1.5.1 The external risk factors influencing the stability of TCM injections

The external factors include production technology, physical and chemical properties. Production technology includes extraction, refining process and preparation process, etc. Physical and chemical conditions such as temperature, light and the type and intensity of pH values can provide the change of the chemical composition in traditional Chinese medicine injection with degradation conditions which becomes a leading factor for the variability of the chemical composition in TCM injections[18].

1.5.2 The inherent risk factors influencing the stability of TCM injections

Nowadays, because of the complexity of the chemical components of TCM injections, compounds containing multiple double bonds are prone to have oxidation reduction reaction. However, the current study of stability is limited to the physical and chemical properties of the known components.

The key factors are not only to purify the active components of traditional Chinese medicine injection and to maintain its steady state, but also to remove the impurities in a variety of chemical components. (1) The effective components of the physical and chemical properties: traditional Chinese medicine injections include unilateral and compound injections, which show the nature of the various active ingredients can determine the stability of TCM injections to a certain degree. Screening the right pH value, temperature and auxiliary materials such as solubilizer are the risk factors that influence the stability of TCM injections. (2) Removal of impurities: in the process of preparation most of the impurities can be removed. However, due to the dissolved impurities and effective components, it is hard to remove part of the impurities, and we must use the refined methods of preparation. Therefore, the removal of impurities can reduce the inherent risk of TCM injections and keep TCM injections stable[19].

The inherent risk factors influencing TCM injections are the unique characteristics of TCM injections compatibility. The problems are summarized as follows: (1) Traditional Chinese medicine injection contains a large number of particles, and the unknown components in the liquid causes the adverse reaction of traditional Chinese medicine injection. The presence of the color also shows that there are particles in the traditional Chinese medicine injections and it is hard to determine their components. Experiments have confirmed that the insoluble particles increased a lot after the compatibility of traditional Chinese medicine injection and infusion. We can make the conclusion that a variety of chemical components in TCM injections were precipitated to a certain extent due to the change of physical properties, such as temperature, pH value, REDOX, polymerization and hydrolysis[20]. (2) The decreasing effective components after the compatibility[21]. (3) The appearance of turbidity and precipitation after the compatibility[22]. (4) The operating environment, preparation technology and equipment affect the clarity[23].

1.6 The risk of drug packaging materials

The wrong choice of drug packaging materials is likely to lead to the loss of medicinal effectiveness since the physical and chemical properties of the materials can absorb the active ingredients of the medicine, or more serious adverse reaction can occur to TCM injections.

The packaging materials of TCM injections include glass, plastic, rubber and metal. in traditional The packaging materials of Chinese medicine (TCM) injections should not only pay attention to the characteristics of injection such as the cleanliness of the external, but also the risks ofthe compatibility test. The followings are the risk analysis of packaging materials for Chinese medicine injection, including glass, plastic and rubber.

1.6.1 The risk of selecting glass materials

Three kinds of glass materials are widely used for traditional Chinese medicine injection, including I, II and none I II type. (1) Type I glass is used for alkaline injections because if other type glasses are used for packaging alkaline injections, particles are likely to fall off the container bottle in the process of storage and the liquids are in the muddy state. The more serious consequence is that these particles can enter human body that causes adverse reactions such as local blockages. (2) Type II is commonly known as soda lime glass, and it works as a neutral and weak acid injection packing material. Its water resistance and chemical corrosion resistance is poorer than other glasses, and the change of pH value will lead to the dissolution of alkaline ion in the glass. The performance of soda lime glass will decline due to the destruction of silicon layer in the process of preparation, so it is used as disposable injection containers. (3) None I and II type glass is a unique glass type in China, and it is commonly known as low borosilicate glass[24]. This kind of glass is frequently to break or crack, so it is a low-end packaging material for traditional Chinese medicine (TCM) injection.

In addition to the risk factors caused by different types of glass, a lot of glass materials can affect the quality of the injections. For example, in the process of clinical infusion, it is easy to introduce some kinds of pollution (bacteria, dust, etc.) into the glass bottles. It is easy to find glass debris in the solution when the ampoule small bottle is opened by the nurse. During the process of research and development, some wavelengths of light going through the glass with colorant can cause the decomposition of some drugs. Drug adsorbed on the inner glass walls can reduce the efficacy of the medicine[25].

1.6.2 The risk of selecting plastic materials

The risk of plastic materials includes the followings such as the adsorption of drugs by plastic materials, the influence of plasticizer on preparation technology, drugs affected by antioxidants and their decomposition, water vapor, the penetration of oxygen and moisture, the absorption of of volatile drugs and the sealing particles[26]. We must ensure that under the condition of appropriate sterilization, the thermal stability of the chemical composition of traditional Chinese medicine injection should be kept.

1.6.3 The risk of selecting rubber materials

Because of the characteristics of the rubber, there are the problems including penetration, absorption, dissolution, particle pollution, puncture exfoliation and chemical reaction[27,28]. Research should be focused on the risks of natural rubber stopper and the officinal butyl rubber plug. (1) When natural rubber plug is used for injection, its composition and drug particles will have chemical reaction which can cause allergy. (2) Medicinal butyl rubber plug will have some adsorption and penetration with drugs in the process of preparation due to the decomposition of sulfide material, and it will affect the efficacy of the injection[29].

2 Conclusions

Based on the analysis of the problems in the process of TCM new drug R&D, we recognized the sources of risk of TCM clinical pharmaceutical technology and determined the risk control methods.

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Author’s information: CHEN Yu-wen, Professor. Major research area: Pharmacy administration. Tel: 15940448000, E-mail: cywwyc@163. com