ABSTRACT: This paper summarizes the characteristics and classification of traditional Chinese medicine sprays, the research progress of sprays and related fields, and introduces the quality control methods of sprays, with emphasis on the inspection methods of droplet size.
Key words: spray; particle test; laser particle size analyzer
1. Current situation of pharmaceutical spray industry
Medical sprays have developed rapidly in recent years. Their mechanism of action and low toxicity and side effects have been favored by more and more people. Packaging containers, production equipment, process and technology have also been constantly improved, and their application scope and product types have been increasing. As a kind of non-injection drug delivery system for peptide and protein drugs, medical sprays have been paid more and more attention by researchers and are widely used in the field of medicine. [1,2]
Aerosol, aerosol and powder aerosol are closely related and have great differences. Aerosol is driven by ejector; powder spray is driven by human breath and mainly inhaled; spray is a unique dosage form, which has the advantages and characteristics of atomization, and avoids the use of ejector, especially for skin, mucosa, limb surface, cavity and so on. With the banning of aerosol ejector Freon in recent years, many aerosol products are also learning the process ideas of aerosol, and the development of aerosol has been rapid.
Traditional Chinese medicine spray is a unique formulation in China. It can not only give full play to the advantages of traditional Chinese medicine, but also show the characteristics of micro-droplet delivery. It has convenient clinical application and exact curative effect and is generally recognized. According to statistics, by the end of 2007-02, the State Food and Drug Administration had issued 43 registration certificates for traditional Chinese medicine sprays, of which 3 were burns sprays and 4 were stomatitis sprays, which were the most declared among the same varieties. The rest of the varieties had corresponding one approval. From the perspective of varieties, there are many kinds of Chinese traditional medicine sprays, which cover a wide range of varieties and are comparable to chemical sprays. [3] From the practical point of view, Chinese traditional medicine sprays have the following characteristics.
1. Indications are widely distributed. Among all kinds of traditional Chinese medicine sprays, 11 were used to treat oral and pharyngitis, including 7 for promoting blood circulation and relieving pain, 7 for treating falls and injuries, 3 for treating angina pectoris, 4 for burns and scalds, 4 for rhinitis, 3 for gynecological drugs, 4 for cold drugs, 1 for hemorrhoids and 1 for skin diseases. It embodies the characteristics and expertise of traditional Chinese medicine. The main usage is external use and cavity.
2. The formula is rough and the quality standard is not high. Because the spray is mostly delivered in solution, suspension and emulsion, the formula is relatively simple, and the quality control index is more rough than chemical spray.
3. Small-scale varieties, no Big Mac products. Thirty-eight varieties are produced in 35 pharmaceutical factories, and their output value and profit are slight. They are generally insignificant compared with other varieties in enterprises.
2. Development prospects of traditional Chinese medicine sprays
Traditional Chinese medicine decoction and powder have become increasingly difficult to adapt to the fast-paced life style of modern society and the needs of clinical application. To some extent, various newly developed formulations have replaced the use of traditional Chinese medicine decoction pieces. In China, the spray of traditional Chinese medicine started late, but developed rapidly. This year, with the development of the Chinese medicine industry, the spray container is becoming more and more perfect. The preparation technology of Chinese medicine spray is becoming more and more mature. It has been applied more widely in the aspects of local, systemic and respiratory diseases treatment, showing its unique advantages and becoming an important branch in the field of Chinese herbal medicine.
2.1 New Projection System
The traditional ejector is Freon, which is banned because of its destruction of the ozone layer. Major pharmaceutical companies at home and abroad have done a lot of research on new projectiles [4.5], mainly concentrated on fluoroalkanes without chlorine and low molecular weight liquefiable alkanes. The former can be used as an ejector for inhalation of aerosols; the latter can only be used for external or environmental disinfection and sterilization of aerosols. Among them, the local application of aerosols for treating burns, minor traumas, infections, asthma, sterilization and disinfection, various skin diseases and so on. The State Food and Drug Administration has approved the design and use of sevofluoropropane, tetrafluoroethane and dimethyl ether for medicinal aerosols.
2.2 New Products
Aerosol products have increased from the original asthma treatment drugs to antibiotics, cardiovascular drugs, antiviral drugs, analgesics, sedatives, topical anti-inflammatory analgesics, phytohormones and other aerosols [6-9]. Aerosol is used for inhalation or nasal administration of peptides and proteins, thus replacing the route of injection. At present, the technology of mixing drug and propellant in pressure vessel and filling suspension directly into aerosol vessel through valve is being studied in the world, and the research of traditional Chinese medicine aerosol is also a hot spot.
2.3 Pharmacokinetics and bioavailability of pulmonary drug delivery
Medical aerosols inhaled through the lungs need to quantify the amount of drugs inhaled through the lungs. The distribution of aerosols in the lungs and the amount of aerosols reaching the deep lung (pulmonary bioavailability) have an important impact on their efficacy. Therefore, more and more studies have been conducted on the bioavailability and pulmonary pharmacokinetics. The study of lung drug delivery absorption enhancers includes the selection of enhancers, the principle of action, toxicity and irritation. Liposomes, proteins, microspheres and macromolecule materials are used to prolong the duration of drug residence and release in the lung.
2.4 New pressure-resistant packaging system, powder inhalants and aerosol additives
At present, the research focuses on the new valve system, dose control valve, manual valve device, binary tank device, automatic inhalation touch device, new powder inhalation device and so on.
2.5 Aerosol Container
The materials used for aerosol containers are tinplate, galvanized iron, aluminium, resin, rubber, glass and composite materials. The research on the structure of aerosol containers (such as whole, two-piece, three-piece, double-layer, double-container), specifications, shape and functions has also made progress. Aerosol containers made of resins, rubber and other materials are gradually recognized and accepted by people, and will also have new development.
3. Opportunities and Challenges of Traditional Chinese Medicine Spray
3.1 Difficulties and Challenges
3.1.1 quality standard Chinese medicine spray is difficult due to the complexity of quality standards and components [10]. Quality standard is the standard of product quality. Without strict quality standard, it is difficult to talk about the great development of traditional Chinese medicine spray.
3.1.2 Absorption and mechanism of action, such as nasal ciliary movement, nasal mucosal toxicity, external spray transdermal process, etc. [11].
3.1.Formula and process formulation involve rational and scientific identification of pharmacodynamics; process design includes enrichment, protection and delivery of active ingredients, and multiple factors such as containers, valves, delivery pumps, materials, etc.
3.2 Opportunities and Prospects
3.2.1 opportunities for Chinese medicine spray are facing opportunities: (1) the form of aerosolization is unique and irreplaceable; the technology is simple for [12] first; second, aerosol is difficult because of the replacement of propellant; third, the powder fog agent has difficulties to overcome in the aspects of micronization, stability and delivery reliability. It comes from a wide range of sources.
Good prospects for 3.2.2 have made important spray a hot topic in recent research and development. It has broad prospects: 1) Chinese herbal sprays will have great development in recent years, and sprays will become the dominant drug delivery system. (2) Active components and natural extracts suitable for spraying emerged in batches. With the rapid development of phytochemistry, many active components or extracts have been discovered. Sprays can be considered to exert unique delivery effects. For example, podophyllotoxin spray [13]. (3) It is a shortcut to change famous and excellent traditional Chinese medicine into spray. Some people use propolis film-forming fast, bactericidal and promote the role of mucosal regeneration, with other ingredients, Title spray way, to treat oral ulcer [14]. Compound Achyranthes bidentata oral spray [15], Qingkailing spray [16] are examples under development. (4) Traditional Chinese medicine sprays will first make breakthroughs in the treatment of oral pharyngitis, rhinitis, burns and colds.
4. Quality Control of Traditional Chinese Medicine Spray
The Chinese Pharmacopoeia stipulates that the liquid of solution spray should be clarified, the droplets of emulsion spray should be evenly dispersed in the medium, and the fine powder of suspension spray should be fully mixed with the additives. Non quantitative valve sprays should be inspected for injection rate and total ejection. Quantitative valve spray should be checked for the total lift of each bottle, the amount of spray per shot or the content of each main ingredient. Inhalation of aerosol should be inspected by particle size. See Annex I for details. This paper mainly introduces the method and significance of particle size inspection of sprays.
The formation of inhalation aerosols and their deposition in human lungs depend on many factors, such as the physical and chemical properties of aerosol particles, the design principles and characteristics of drug release devices, the respiratory patterns of patients and the morphology of human lungs. The characteristics of aerosols include particle size distribution, aerosol velocity and expiratory humidity. The appendix of the second part of the 2010 edition of the Chinese Pharmacopoeia stipulates that the particle size of aerosols for inhalation should be less than 10-mu; M. At present, the measurement methods of inhalant particle size distribution include micro-mirror method, inertial impactor method, laser scattering method and time-of-flight aerodynamic particle size distribution method.
Microscopic method is the oldest and most direct method for particle size measurement. It is also the only way to observe and measure individual particles. It is the most basic method for particle size measurement. The test range of optical microscopy is 0.3-200μ m, and that of transmission electron microscopy is 1-5μ m, and that of scanning electron microscopy is more than 10 nm. The amount of samples measured by microscopy is very small. When sampling and making samples, it is necessary to ensure that the samples are sufficiently representative and well dispersed. However, it is difficult to represent the average level of the measured particles because of the small sample size.
Inertial Impinger method is a method of separating drug particles according to particle size by using the principle of inertial impingement. Compared with other methods, it can quantify active drug components in different particle size ranges. The measured droplet size distribution means that the aerodynamic droplet diameter released from the inhaler is less than a certain size of the drug. The ratio of substance to drug content in each dose.
The instrumentation is shown in Figure 1 below.

Fig. 1. Device diagram for measuring droplet (particle) distribution
A: Rubber interface, connecting inhalation device. B: The simulated throat is made of an improved 50ml round bottom flask with 29/32 grinding pipe at the inlet and 24/32 grinding plug at the outlet. C: Simulated neck. D: First-class distribution bottle, made of 24/29 grinding orifice 100ml round bottom flask, with 14/23 grinding orifice outlet. E: Connecting pipe, connected with D by 14 grinding plugs. F: Outlet, flow meter, with plastic threaded caps (with gaskets) to seal E and F. G: The nozzle is made of polypropylene filter. There are four nozzles with diameter of 1.85 mm & plusmn at the bottom of the filter. There is a projection with diameter of 2 mm and protrusion of 2 mm at the center of the nozzle. H: Two-stage distribution bottle, 24 250ml conical bottles.
Impactor method is the most classical method for in vitro droplet distribution determination of inhalation preparations, and it is also recommended by pharmacopoeia of various countries to evaluate the droplet distribution of inhalation preparations. But the workload is large and time-consuming, and the air velocity is the main factor affecting the measurement.
Time-of-flight aerodynamic particle size distribution measurement is a real-time measurement of particle aerodynamic particle size by precise time-of-flight technology. The measurement range of particle size is 0.5-20 & mu; M. Because aerodynamic particle size counts based on flight time are only related to particle shape, the interference of refractive index is avoided.
Laser scattering method is mainly tested by laser particle size analyzer. Laser particle size analyzer is based on the principle of laser scattering. When the incident light irradiates on the particles, it will scatter a certain frequency of scattered light, which is related to the particle size. The particle size information can be obtained by calculating the scattered light.
Laser scattering method is the most widely used particle size measurement method at present. Its advantages include: 1. It can measure particles of micron to nanometer scale in a wide range of measurements, which is the main range of particle size measurement nowadays; 2. Because of the transmittance of light, non-contact measurement can be realized, and the interference to the tested sample is very small, thus reducing. The systematic errors of the measurement are measured; 3. In the laser scattering method, the response time of the photoelectric conversion element is very short, which can realize the rapid measurement; 4. The laser scattering method is easy to realize the automation of the test process with the help of computer; 5. It has good repeatability, and the typical accuracy of the average particle size can be less than 1%; 6. It is easy to operate.
Laser particle size analyzer, which integrates laser technology, modern photoelectric technology, electronic technology, precision machinery and computer technology, is the main instrument in the field of particle testing. In the spray particle size distribution test, the domestic representative product is Winner31 produced by Ji'nan micro nano company.1XP. The instrument is specially designed and developed for the measurement of droplet size. The laser spray size meter is specially designed and developed. The principle of laser scattering is adopted to conduct non-contact measurement. It has the advantages of good repeatability, accurate data and simple operation. The test range of Winner 311xp is 0.1-100μ m, and the error of accuracy and repeatability is less than 3%. Winner311xp uses a semiconductor laser with a wavelength of 650nm, and the instrument adopts a tubular open structure, which ensures the smooth flow of the spray field, and is not easy to pollute and is easy to clean. Its working principle is as follows: Fig. 2.

Fig. 2: Principle block diagram of micro-nano laser particle size analyzer
A: Red dot laser, wavelength 650 nm. B: Beam expander. C: Fourier's mirror. D: Lens. E: Large lens. F: Small probe. G: Large probe.
Winner 311xp uses Mie scattering principle and unconstrained free inversion technology in the whole range, which can give real results for any particle group and effectively improve the practicability of the instrument. Fourier transform patented technology, single-beam double-lens technology and multi-angle auxiliary detector are used to collect scattered light from different angles of the measurement range, and to achieve the accuracy and reliability of the whole measurement range. Users can also customize the analysis parameters in the testing process, calculate the percentage according to the particle size, the percentage according to the percentage or the particle size interval, to meet the different characterization of particle size testing. [17]
Using laser particle size analyzer to measure the size distribution of droplets is simple and accurate. At present, it is gradually accepted by most enterprises. More and more enterprises begin to use laser particle size analyzer to control the size of droplets.
5. Summary
Traditional Chinese medicine spray has become a new way to treat emergencies because of its characteristics of small dosage, quick curative effect, convenient use, targeting effect, and being suitable for the treatment of upper respiratory tract diseases, various cavity diseases, traumatic internal injuries and systemic diseases. Pharmaceutical workers in China have done a lot of research work in this field in recent years. A number of products have been put on the market, and good economic and social benefits have been achieved.
Of course, there is still a lot of work to be done to give full play to the advantages of traditional Chinese medicine sprays in clinical practice. For example, the study of traditional Chinese medicine sprays should pay more attention to the optimization of traditional Chinese medicine formulation and technology. Traditional Chinese medicine prescriptions should not only consider the main function, but also the flavor, efficacy, dosage and activity of the ingredients contained in them, and select less and more refined drugs. The traditional process of removing crude and storing refined substances should be considered in the preparation method, and the special process of extracting active parts or active ingredients should also be considered. Only by choosing advanced and reasonable technological process can it be possible. It can prepare Chinese medicine spray with small dosage, strong efficacy and light color to ensure its clinical efficacy. We believe that as long as scientific methods are adopted and advanced high-tech technologies are actively used, new varieties of traditional Chinese medicine sprays will continue to emerge to meet the needs of clinical medication and gradually solve the problem of treating emergencies with traditional Chinese medicine.
In the aspect of spray droplet size measurement, the application of laser particle size analyzer will be more frequently used with the development of traditional Chinese medicine spray industry. With its advantages in particle size control, spray can get better particle size control and achieve better curative effect.
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