What are Aerosols?

Aerosol means that the medicine, emulsion or suspension is sealed in a pressure-resistant container with a special valve system together with a suitable propellant. When used, the contents are sprayed out in a mist by the pressure of the propellant. Inhaled in the lungs or sprayed directly to the mucosa, skin and space of the cavity.

Aerosol means that the medicine, emulsion or suspension is sealed in a pressure-resistant container with a special valve system together with a suitable propellant. When used, the contents are sprayed out in a mist by the pressure of the propellant. Inhaled in the lungs or sprayed directly to the mucosa, skin and space of the cavity.

Chinese name

aerosol

Foreign name

Aerosol

Time

1862

Origin

Lynde Rotheim

Make up

Drugs, pressure vessels, valve systems, etc.

Use

Local or systemic treatment

Aerosol Origin

The aerosol concept originated in 1862 when Lynde proposed the use of a saturated solution of gas to make pressurized packages. Until 1926, Norwegian chemical engineer Erik Rotheim used liquefied gases to prepare prototypes of modern aerosols.

aerosol

In 1943 Goodhue used dichlorodifluoromethane (trade name F12) as a propellant to prepare a portable insecticide aerosol, which should be the most practical and important progress in the development of aerosols. Insecticide aerosols were launched in 1947. At that time, very thick and heavy pressure vessels were needed. With the successful development of low-pressure propellants and low-pressure vessels, the cost of aerosols has been reduced and rapidly developed. In the 1950s, aerosols were used for skin diseases, trauma, burns, and local infections. In 1955, they were used for respiratory administration. In recent years, research in this field has become increasingly active, with more and more products, including topical therapies, antibiotics, and anti-illness herbs. In addition, in recent years, more and more new technologies have been applied to aerosols. The first is the improvement of the drug delivery system itself, such as new inhalation drug delivery devices, which make the application of aerosols more and more convenient and more acceptable to patients. . The second is the new preparation technology, such as the application of liposomes, prodrugs, polymer carriers, etc., which can prolong the residence time of the drug in the lungs and play a slow-release role.

Similar formulations to aerosols include sprays and powders. This chapter mainly introduces aerosols. The 2000 edition of the Chinese Pharmacopoeia contained six aerosols, and the 27th edition of the United States Pharmacopoeia contained 20 aerosols and 6 propellants.

Aerosol characteristics

Aerosols have the following advantages:

(1) The drug can go directly to the action site or absorption site, and has a very obvious fast-acting effect and positioning effect, especially in

Respiratory administration has the advantage that other dosage forms cannot be replaced.

aerosol

(2) The medicine is sealed in a sealed container, which can keep clean and sterile, reducing the chance of contamination of the medicine, and the remaining medicine after stopping is not easy to cause environmental pollution. In addition, the container is opaque, protected from light, and not in direct contact with oxygen and moisture in the air, which is conducive to improving the stability of the drug.

(3) Convenient to use, can be swallowed (sucked), suitable for all ages, help to improve the compliance of patients, especially for OTC drugs.

(4) Systemic administration can reduce the irritation of the gastrointestinal tract and avoid the first-pass effect of the liver.

(5) The medicinal aerosol is equipped with a quantitative valve, so the dosage is accurate.

The aerosol is different from most other dosage forms: the packaging of this kind of preparation requires pressure-resistant containers, valve systems and special production equipment, so the product cost is higher. In addition, propellants (mainly chlorochloroalkanes), which are important components of aerosols, can destroy the ozone layer, have serious environmental protection problems, and reach a certain concentration in the animal or human body can sensitize the heart and cause arrhythmia. . The Montreal Treaty signed by more than 140 countries requires a total ban on the use of HCFC propellants in 2005. Therefore, the development of non-HCFC propellants with excellent performance is facing severe challenges.

Aerosol classification

There are many classifications of aerosols. The common classification methods are as follows:

Aerosol press dispersion system

(1) Solution aerosol: solid or liquid medicine is dissolved in the propellant to form a homogeneous solution. After spraying, the propellant evaporates, and the drug reaches the action site in the state of solid or liquid particles.

aerosol

(2) Suspension aerosol: The solid drug is dispersed in the propellant in a particulate state to form a suspension. After spraying, the propellant volatilizes, and the drug reaches the action site in a solid particulate state. Such aerosols are also called powder aerosols.

(3) Emulsion aerosol: liquid medicine or drug solution and propellant (water-insoluble liquid) form W / O or O / W

Emulsion. O / W type sprays out in the form of foam with the vaporization of the internal phase propellant during injection, and W / O type follows

The external phase propellant vaporizes to form a liquid stream.

Aerosols by route of administration

(1) Inhalation aerosol: Refers to a medicated solution, suspension or emulsion, which is packaged with a suitable propellant or liquefied mixed propellant in a pressure-resistant container with a quantitative valve system and a certain pressure. The pressure of the propellant sprays out the contents as a mist and inhales the preparation deposited in the lungs through the mouth, which is also commonly referred to as a metered dose inhaler. The pressure valve releases the active substance quantitatively, the drug is dispersed into particles or mist droplets, and it is inhaled through the respiratory tract to exert local or systemic therapeutic effects.

(2) Non-inhalation aerosols: such as aerosols for skin and mucous membranes. Skin aerosols are mainly used for protecting wounds, cleaning and disinfecting, local anesthesia and hemostasis. Nasal aerosol refers to a preparation deposited in the nasal cavity by nasal inhalation. Aerosols for nasal mucosa are used for the administration of some protein and peptide drugs and can exert systemic effects. O / W foam aerosols for vaginal mucosa are commonly used. They are mainly used to treat vaginitis caused by microorganisms, parasites, etc., and can also be used for birth control.

(3) External aerosol: refers to an aerosol used for skin and space disinfection ^[1] .

Aerosol composition by prescription

(1) Two-phase aerosol: a solution type aerosol, which is composed of a homogeneous liquid phase formed by the drug and the propellant and a gas phase formed by the propellant partially volatilized propellant.

(2) Three-phase aerosol: two phases are propellants, that is, a solution of the propellant and a liquid formed by a partially volatile propellant. According to the situation of the drug, there are three types: an aqueous solution of the drug and a liquefied propellant. A W / O emulsion is formed, and the other phase is a partially vaporized propellant; an aqueous solution of the drug and a liquefied propellant form an O / W emulsion, and the other phase is a partially vaporized propellant; solid drug particles are suspended in the propellant Medium solid, liquid and gas three phases.

In addition, aerosol can be divided into quantitative aerosol and non-quantitative aerosol according to whether a quantitative valve system is used. Among them, quantitative aerosol is mainly used in the lungs, oral cavity and nasal cavity, while non-quantitative aerosol is mainly used for local treatment of skin, vagina and rectum.

Aerosol use

Aerosols can be used for local or systemic therapeutic effects. Local therapeutic effects such as: Yan Su Kang aerosol for the treatment of sore throat, compound naphthozoline spray for the treatment of rhinitis, compound metronidazole aerosol for the treatment of vaginitis, local analgesic lidocaine aerosol, etc .; Systemic therapeutic effects such as: glucocorticoid budesonide aerosol, anti-angina nitroglycerin aerosol, antipyretic and indomethacin aerosol.

aerosol

The use of aerosols for the administration of peptides and proteins is compelling. Peptide and protein drugs are difficult to absorb from the gastrointestinal tract due to their large molecular weight, and they cannot tolerate the destruction of gastrointestinal enzymes. They can only be administered by injection, which is very painful for patients who have been taking drugs for a long time. In recent years, the non-injection route of peptide and protein drugs has progressed rapidly. Among them, it is more successful to make them into aerosols, powders or sprays, and to administer them through the lungs, mouth or nasal cavity. Nasal delivery systems for drugs such as calcitonin have been marketed; several pulmonary, oral or nasal delivery systems for insulin have entered clinical research.

Aerosol composition

Aerosols consist of drugs, additives, propellants, pressure vessels and valve systems.

Aerosol drugs and additives

Liquid, semi-solid and solid drugs can be developed into aerosols. In addition to propellants, aerosols often need to add additional solvents such as latent solvents that are miscible with the propellant, antioxidants that increase drug stability, and surfactants required for emulsification. Additives should be determined on a case-by-case basis.

Solution-type aerosol, using propellant as solvent, if necessary, add appropriate amount of ethanol. Sometimes, in order to make the drug and the propellant miscible, organic solvents such as propylene glycol and polyethylene glycol may be added, but attention should be paid to the effects of the amount of ethanol, propylene glycol, etc. on the irritation of the lungs and the aerosol stability. If necessary, add antioxidants and preservatives.

Suspension aerosol is suitable for the case where the drug is insoluble or poorly soluble in the propellant and is not dissolved by a suitable latent solvent. Compared with the solution aerosol, the suspension aerosol has good drug stability, but has high preparation requirements. Suspension aerosols commonly used excipients are: solid wetting agents, such as talcum powder, colloidal silica, etc .; surfactants, low HLB value surfactants and higher fatty alcohols can make the drug easily dispersed in Among the propellants, oleic acid, Span 85, oleyl alcohol, and lauryl alcohol are commonly used, and they can also lubricate the valve system; moisture regulators, such as anhydrous calcium sulfate, anhydrous calcium chloride, and anhydrous sodium sulfate Add to control the water content below 300 × 10-6, use the concentration of 0.1% to 0.5%; specific gravity correction agent, such as ultra-fine powder of sodium chloride, sodium sulfate, sodium hydrogen phosphate, sodium hydrogen sulfite, lactose and sulfuric acid The specific gravity of the drug can be adjusted to make it close to the specific gravity of the propellant.

The choice of emulsifier in emulsion aerosol is more critical. The selection of emulsifier should achieve the following properties: it can fully emulsify and form very fine droplets when shaken; it can be sprayed at the same time as the liquid medicine, and the appearance of the spray foam is white, uniform, delicate, soft, and has Required stability. Emulsifiers can be used as single or mixed surfactants. At present, emulsion aerosols mostly use an aqueous matrix as the external phase and a propellant as the internal phase. In recent years, non-ionic surfactants of such O / W type aerosols have been used more often.

Typical non-ionic surfactants used in such aerosols include polysorbates, fatty acid sorbitans, fatty acid esters, and alkylphenoxyethanol. In addition to emulsifiers, it is often necessary to add preservatives, fragrances, softeners, lubricants, and the like. Note that the selected additives should be non-irritating at the site of application.

Aerosol propellant

Propellants are substances that directly provide power to aerosols, and can sometimes double as solvents or diluents for drugs.

Due to the high vapor pressure of the propellant, the liquefied gas has a boiling point below atmospheric pressure at normal pressure. Therefore, once the valve system is opened, the pressure suddenly decreases and the propellant evaporates sharply. The medicine liquid in the container can be dispersed into very fine particles and sprayed out through the valve system to reach the function or absorption site. The ideal propellant should have the following characteristics: it must have an appropriate boiling point, and its vapor pressure should be appropriately greater than atmospheric pressure at room temperature; non-toxic, non-allergenic and irritating; non-flammable and explosive; non-reactive with drugs or containers; no Color, odorless, tasteless; cheap and easily available.

Aerosol container

The aerosol container should be stable in content, able to withstand working pressure, and have a certain pressure safety factor and impact resistance. Materials used to prepare pressure vessels include glass and metal. The chemical properties of the glass container are relatively stable, but the pressure resistance and impact resistance are poor. Therefore, the outside of the glass bottle needs to be lined with a plastic layer; metal materials such as aluminum, tinplate, and stainless steel have strong pressure resistance, but they are resistant to drug solutions. The stability is unfavorable, so epoxy resin, polyvinyl chloride or polyethylene is usually used for surface treatment in the container. When choosing a pressure-resistant container, we must pay attention not only to its pressure-resistant performance, portability, price, and chemical inertness, but also to its aesthetic effects. More commonly used pressure-resistant containers include glass bottles, aluminum containers, tinplate containers, etc.

Aerosol valve system

The basic function of the valve system is to control the dose of drug injection in a closed condition. Materials such as plastic, rubber, aluminum, or stainless steel used in the valve system must be inert to the contents. All components need to be precisely processed to have and maintain appropriate strength. The swelling properties must be kept within certain limits during the storage period to ensure that Accuracy of spray dose. The valve system is generally composed of a valve stem, a rubber seal, a spring, an immersion tube, a dosing chamber and a push button, and the valve system is fixed on a pressure-resistant container by an aluminum cap.

Aerosol aerosol filling machine

(1) Cap: its role is to fix the valve on the container, usually aluminum products, if necessary, coated with epoxy film.

(2) Valve stem: It is the shaft core part of the valve, usually made of nylon or stainless steel, including the inner hole and expansion chamber. If it is a quantitative valve, there should be a thin groove (drainage tank) at the lower end for the drug solution to enter the quantitative chamber. The inner hole is a very small hole that communicates with the inside and outside of the container. It is located next to the valve stem and is usually sealed by an elastic rubber seal, making the inside and outside of the container impassable. When the push button is pushed down, the inner hole is the same as the medicinal solution, and the contents are immediately ejected through the valve. The expansion chamber is located inside the valve stem above the inner bore. When the contents of the container enter the chamber through the inner hole, it suddenly expands, causing the propellant to boil and vaporize, dispersing the drug, and increasing the fineness of the particles when sprayed.

(3) Rubber sealing ring: It is a control ring that closes or opens the inner hole of the valve. It is usually made of nitrile rubber. There are two sealing rings for the liquid outlet and the liquid inlet, which are respectively placed on the valve stem and positioned in the quantitative chamber. The upper and lower ends respectively control the contents from the quantitative chamber into the inner hole and from the container into the quantitative chamber.

(4) Spring: Provides the spring force for the push button to rise. It is sleeved on the lower part of the valve stem (or quantitative chamber). It needs to be made of stainless steel with stable quality, such as electrostatic vacuum furnace steel (Cr17Ni12Mo2T).

(5) Immersion tube: It is connected to the lower part of the valve stem, and its function is to transport the contents to the valve system. If the immersion tube is not used and only the drainage tank is used, the container needs to be inverted. It is usually made of polyethylene or polypropylene.

(6) Dosing chamber: also known as dosing cup, plays the role of dosing spray. Its capacity determines that the aerosol gives an accurate dose at a time (usually 0.05 to 0.2 mL). The lower end of the dosing chamber has two small holes protruding into the container and sealed with a rubber gasket. When canned propellant, due to the high pressure of the canning machine system, the propellant can be injected into the container through the small hole. After the canning, the small hole is still sealed by the gasket, so that the contents cannot leak out.

(7) Push button: It is a device used to open or close the valve system. It has various shapes and has appropriate small holes connected to the nozzle to restrict the direction in which the content is ejected. Generally made of plastic.

Aerosol prescription design and examples

In addition to the selection of a suitable propellant, the aerosol prescription composition is mainly based on the physical and chemical properties of the drug, and the appropriate additional agent is selected and formulated into a certain type of aerosol to meet the requirements of clinical medication.

Aerosol solution type aerosol

If the drug itself can be dissolved in the propellant, it can be conveniently made into a solution type aerosol. However, since commonly used propellants (such as chlorochloroalkanes) are non-polar, a considerable part of commonly used drugs are difficult to be miscible with them. Therefore, an appropriate amount of ethanol or propylene glycol is generally added as a latent solvent to make the drug and the propellant miscible to become homogeneous Solution.

The choice of latent solvent is a key. Although ethanol, polyethylene glycol, propylene glycol, glycerol, ethyl acetate, acetone, etc. can be used as aerosol latent solvents, their toxicity and irritation must be paid attention to, especially for the oral cavity. , Inhalation or nasal aerosol.

Pay attention to the following issues when developing solution-based aerosols: the effect of the mixing of propellant and latent solvent on the solubility and stability of the drug; the size and surface tension of the ejected droplets; various additives such as antioxidants , Preservatives, latent solvents, etc. on the irritant part of the medication; whether the various additives in the inhalation can be metabolized or retained in the lungs.

Aerosol suspension type aerosol

When the drug is insoluble in the propellant or a mixed solution of the propellant and a latent solvent, or the selected latent solvent does not meet the requirements of clinical medicine, consider dispersing the fine powder of the drug in the propellant to make a suspension aerosol. .

There are certain difficulties in the preparation of suspension aerosols. The main problems include the increase of particle size, agglomeration, agglomeration, and clogging of valve systems. Therefore, when formulating the formulation of suspension aerosols, we must pay attention to improving the stability of the dispersion system. We must also pay attention to the following issues: The moisture content should be extremely low, should be below 0.03%, and usually controlled below 0.005%. In order to avoid agglomeration of drug particles in water; The particle size of inhaled drugs should be controlled below 5m and not more than 10m, and the maximum particle size of topical aerosols is generally controlled to 40-50m; under the premise of not affecting physiological activity , Select the drug derivative with the lowest solubility in the propellant (such as different bases) to prevent the drug crystallites from becoming coarse during storage; adjust the density of the propellant and / or suspended solids to make them as dense as possible Equal; Suspending agent that adds appropriate surfactant or dispersant to increase the stability of the formulation.

Aerosol emulsion

Milky aerosols contain, in addition to drugs and propellants, emulsifiers, aqueous and oily media. The drug can be dissolved in the water or oil phase according to its properties. The propellant cannot be miscible with water, but it can be miscible with the oily medium in the prescription. The internal phase (in this case, O / W type) or external phase ( (W / O type at this time). After the O / W emulsion is sprayed through the valve, the propellant in the dispersed phase expands and vaporizes immediately, so that the emulsion sprays out in a foam state, so it is called a foam aerosol. This type of aerosol is more commonly used.

Aerosols should be prepared in a germ-free environment. Various utensils, containers, etc. must be cleaned and disinfected by appropriate methods. The entire operation process should be careful to avoid microbial contamination.

Aerosol drug loading device

Pressurized metered-dose inhalers (pMDIs) generally consist of three parts: a pressure-resistant container, a metering valve, and a driving device. The medicated solution, emulsion or suspension is packaged in a pressure-resistant container with a suitable propellant. In the patient, the patient presses the driving device, and the drug is dissolved or dispersed in the small droplets formed by the propellant, and the rapid volatilization of the propellant causes the aerosol containing the drug particles to be subsequently sucked into the lungs. However, the large amount of drugs deposited in the oropharynx and the prone to denaturation when contacted with propellants make pMDIs not meet the requirements for pulmonary administration of protein and peptide drugs, and their application has been limited ^[1] .

The aerosol process is

Processing and assembly of container valve system drug preparation and dispensing filling propellant quality inspection packaging finished product

(I) Handling and assembly of container and valve systems

1. Glass bottle slush

The glass bottle was washed and dried, preheated to 120-130 ° C, and immersed in the plastic mucus while it was hot, so that a layer of plastic liquid was evenly adhered below the neck of the bottle, and dried at 150-170 ° C for 15 minutes after being inverted, and then set aside. The requirement for plastic coating is to tightly wrap the glass bottle, in case the bottle is broken, the glass will not splash, and the appearance is flat and beautiful.

2. Handling and assembly of valve systems

Treat the various parts of the valve separately: The rubber products can be immersed in 75% ethanol for 24 hours to remove the color and sterilize and dry for use; The plastic and nylon parts are washed and then immersed in 95% ethanol for use; stainless steel spring Boil in 1% to 3% lye for 10 to 30 minutes, wash it with water several times, and then wash it with distilled water two or three times until it is not greasy, soak it in 95% ethanol for later use. Finally, the above-mentioned processed parts are assembled according to the valve.

(II) Preparation and dispensing of drugs

Formulated according to prescription composition and required aerosol type. Solution-type aerosols should be made into clear liquids; suspension-type aerosols should be micronized and kept dry; emulsion-type aerosols should be made into stable emulsions. Quantitatively distribute the prepared qualified drug dispersion system in the prepared container, install a valve, and fasten the cap.

(Three) the filling of the propellant

There are two types of propellant filling: pressure irrigation and cold irrigation:

1. Pressure irrigation

First fill the prepared medicine solution (usually an ethanol solution or aqueous solution of the drug) into the container at room temperature, then install and tighten the valve, and then press the quantitative propellant (preferably the container first) The air is drawn out). The liquefied propellant is filtered by the sand rod and enters the press. The operating pressure is preferably 68.65 ~ 105.975kPa. When the pressure is lower than 41.19kPa, filling cannot be performed. When the pressure is low, the propellant steel bottle can be heated with hot water or infrared to make it reach the working pressure. When the container is pushed up, the filling needle is inserted into the valve stem, the press of the filling machine and the container is opened at the same time, and the liquefied propellant is expanded into the container by itself.

The equipment of the pressure irrigation method is simple, does not require low-temperature operation, and has less propellant loss. At present, this method is mostly used in China. However, the production speed is slow, and the pressure changes greatly during use. The production of aerosols abroad mainly adopts the process of high-speed rotary press-fitting propellants, with stable product quality and greatly improved production efficiency.

2. Cold irrigation

The chemical liquid is cooled to about -20 ° C by a cooling device, and the propellant is cooled to at least 5 ° C below the boiling point. Fill the container with the cooled solution first, and then add the cooled propellant (or both). Install and fasten the valve immediately. Operation must be completed quickly to reduce the loss of propellant.

The cold filling method is fast, has no effect on the valve, and the pressure of the finished product is relatively stable. However, refrigeration equipment and low-temperature operation are required, and the loss of propellant is large. This method is not suitable for water-containing products. After the filling of the propellant is completed (for the cold filling method, the valve must be installed and fastened with a cap), and finally, a push button must be installed on the valve, and a protective cover is generally added. This completes the preparation of the entire aerosol.

Aerosol quality evaluation

The appendix of the two parts of the 2015 edition of the Chinese Pharmacopoeia stipulates that the amount of the main drug released by the quantitative aerosol should be accurate, the spray droplets (granules) should be uniform, and the inhalation of the aerosol should ensure the uniformity of each content The finished aerosol should be checked for leakage to ensure its safe use; the aerosol should be stored in a cool and dark place, and avoid exposure to heat, heat, knock and impact. Quantitative aerosols should be marked: total volume of each bottle; content of main drug released from the valve per volume and content of main drug released from the mouthpiece per volume. In addition to meeting the requirements under the aerosol, inhalation aerosols should also meet the requirements under the relevant items of inhalation preparations (General Rule 0111); in addition to the requirements under the aerosol, nasal aerosols should also meet the nasal requirements. Requirements under applicable formulations (General Rule 0106).

Unless otherwise specified, inhaled aerosols should be checked accordingly.

1. Uniform delivery dose. Quantitative aerosols should be inspected according to the methods in the Pharmacopoeia inhalation preparations. Take 10 bottles for testing. The uniformity of the delivered dose should meet the requirements.

2. Total volume per bottle. For quantitative aerosols, take one bottle of test product for inspection according to the method in the Pharmacopoeia inhalation preparation. The total volume of each bottle should be not less than the total volume indicated. This test can be combined with a delivery agent uniformity test.

3. Fine particle dose. Unless otherwise specified, aerosols should be checked for fine particle doses. Check the aerodynamic characteristics of the fine particles of the inhaled preparations (General Rule 0951) for inspection, and measure according to the law according to the devices and methods specified for each species. Calculate the dose of fine particles according to the provisions of each species. Unless otherwise specified, the percentage of fine drug particles shall not be less than 15% of the marked amount of the main drug content per mash. Breath-driven inhalation aerosols should be adjusted accordingly in accordance with the operating instructions for each type of item.

In the 2015 edition of the Chinese Pharmacopoeia ^[2] , the aerodynamic properties of fine particles of inhaled preparations were determined by the first method dual stage impactor, the second method Anderson cascade impactor and the third method new generation impactor. , To measure the aerodynamic particle size distribution of the drug. The collection and content analysis of particles at different levels can better reflect the particle size distribution of the particles.

4. Microbial limits. Unless otherwise specified, the inspection of non-sterile products based on microbial limits: the microbial counting method (General Rule 1105) and the control bacterium inspection method (General Rule 1106) and the non-sterile drug microbial limit standards (General Rule 1107) inspection shall comply with the regulations.

5. The content of the main drug in each tincture. According to the method of the Chinese Pharmacopoeia 2015 edition ^[2] aerosol related items, the quantitative content of the main drug of each aerosol should be 80% -120% of the labeled content of each main drug.

6. Spray rate. 4 bottles of non-quantitative aerosols were tested according to the method of the Pharmacopoeia, and the spraying rate should meet the requirements of various varieties.

7. The total amount of ejection. 4 bottles of non-quantitative aerosol were tested according to the method of the Pharmacopoeia, and the amount of plutonium emitted from each bottle should not be less than 85% of the stated volume.

8. Spray volume per grate. 4 bottles of quantitative aerosol were tested according to the pharmacopoeia method, and the quantitative aerosol was checked according to the following method. Unless otherwise specified, it should be 80% -120% of the indicated spray volume. For aerosols that are checked for uniformity of the delivered dose per batch, there is no longer a need to check the volume of each spray.

9. Granularity. Unless otherwise specified, suspension aerosols for inhalation should be examined for particle size if they are not measured for uniformity of delivered dose. Check 25 fields of view and count. The average drug particle size should be below 5µm, and no more than 10 particles with a particle size> 10µm.

10. Loading capacity. Unless otherwise specified, non-quantitative aerosols should be inspected for minimum loading (Pharmacopoeia General Rule 0942) and should meet the requirements.

11. Sterile. Unless otherwise specified, it is used for burns [except for milder burns (degrees or shallow )], severe trauma, or clinically necessary aerosols, which are inspected in accordance with the Aseptic Assay (General Rule 1101), meets the requirments.

Aerosol regulations

1. Aerosols should be formulated in a clean, germ-free environment. Various utensils, containers, etc. must be cleaned and sterilized by appropriate methods. Care should be taken to prevent microbial contamination throughout the operation.

2. When formulating an aerosol, an appropriate amount of an additional agent such as an antioxidant or a bacteriostatic agent can be added according to the nature of the drug. Inhalation aerosols, aerosols for skin and mucous membranes should be non-irritating.

3 The fineness of inhaled aerosol particles or drug particles should be controlled at 10 m, and most of the particles should be less than 5 m.

4 The commonly used propellants for aerosols are trichloromonofluoromethane (F11), dichlorodifluoromethane (F12), dichlorotetrafluoroethane (F114), and other compressed gases such as carbon dioxide and nitrogen. Depending on the required pressure of the aerosol, two or more propellants can be mixed and used in an appropriate ratio.

5. The aerosol container should not physically and chemically interact with the contents, and should be able to withstand the pressure required by the aerosol. Glass bottles or metal containers can be used. The outer wall of the glass bottles should be lined with a plastic protective layer of appropriate thickness. If the metal container is coated with a protective layer, the coating must not be softened, dissolved, or peeled off.

6. The spring, valve stem, metering cup, rubber washer and other components in the aerosol valve adjustment system should not physically and chemically interact with the medicinal solution, and its dimensional accuracy and swelling must meet the requirements. The quantitative valve used for inhaling aerosol should release uniform mist every time, and the dose should be accurate. The valve used for local aerosol should be able to continuously spray uniform mist.

7. Aerosols must be inspected for leaks and bursts by appropriate methods to ensure safe use.

8. The aerosol should be stored in a cool and dark place, and avoid exposure, heat, knock and impact.

9. Aerosols with a quantitative valve shall indicate the content of each bottle, the content of the main drug, the single spray dose or the total weight of the single spray contents.

Spray test:

1. Non-quantitative valve aerosol: take 4 bottles of test product, wipe the valve for several seconds after spraying, and weigh it accurately, set it in a 25 + 1 water bath for half an hour, remove, wipe dry, and lift the valve to spray accurately After 5 minutes, wipe it, weigh it separately, and then place it in a 25 + 1 water bath. Repeat the operation 3 times according to the above method. Calculate the average spray rate per bottle in g / s. Under the regulations.

2. Aerosol with a quantitative valve: take 4 bottles of test product, spray them several times, clean, accurately weigh, spray once, and then weigh accurately, the difference between the two weights before and after is the amount of spray After three consecutive injections were measured according to the above method, the injection was continued for 10 times irrespective of weight. Then three consecutive injections were measured according to the above method, and then 10 consecutive injections were performed without any weight. Finally, four injections were measured according to the above method. the amount. Calculate the average of the spray volume before and after each bottle and compare it with the spray volume. The difference should be within + 20% of the spray volume.

Aerosol Drugs

Common name: Budesonide aerosol

Product Name: Jishu

English name: Budesonide Aerosol

Phonetic script (Hanyu Pinyin): Budinaide Qiwuji

Budesonide

Chemical name: 16, 17 (22R, S) -Butylenedioxoprogesterone-1,4-diene-11, 21-dihydroxy-3,20-dione.

Molecular formula: C25H34O6

Molecular weight: 430.5

Properties The medicine liquid in the pressure-resistant container is a white suspension liquid. When the valve is pressed, the medicine liquid is sprayed out as mist.

Indications for bronchial asthma.

Specifications Each bottle contains budesonide 20mg, each bottle 200 , each tin contains budesonide 0.1mg.

Aerosol usage and dosage

Administration by inhalation.

The dose of budesonide aerosol should be individualized. For patients with severe asthma and withdrawn or reduced oral hormones, the dose of budesonide aerosol to start is:

Adults: 200 1600g / day, divided into 2 4 times for use (200 800g / day for mild cases, 800 1600g / day for more severe cases).

Children 2 to 7 years old: 200 to 400 g / day, divided into 2 to 4 uses.

Children over 7 years: 200-800 g / day, divided into 2 to 4 times.

Administration twice daily (morning and evening) is generally sufficient. When the clinical effect has been achieved, the maintenance dose should be gradually reduced to the lowest dose that can control symptoms.

For patients who need to strengthen the therapeutic effect, the dose of budesonide aerosol can be increased, because the former has a lower incidence of systemic side effects compared with the treatment with oral hormones.

Non-hormonal dependent patients: The therapeutic effect is generally achieved within ten days. For patients with excessive mucus secretion from the bronchus, a short-term (about 2 weeks) oral hormone therapy can be given at the same time.

Hormone-dependent patients: The patient should be in a relatively stable phase when starting from oral hormones to budesonide aerosol. Large-dose budesonide aerosol should be combined with the previous oral hormone for about ten days, and then the oral hormone can be gradually reduced to the lowest dose (such as a monthly reduction of prednisolone 2.5mg or equivalent). In many cases, budesonide aerosols can completely replace oral hormones.

Aerosol adverse reactions

Mainly manifested as mild throat irritation, cough, and hoarseness. Pharyngeal Candida infections have been reported. A rash has been reported in rare cases.

Aerosol contraindications

1. Those who are allergic to the ingredients of this medicine should not use this product.

2. The initial stage of bronchospasm when more powerful treatment is needed.

3. When more powerful treatment is needed for acute asthma attacks.

Aerosol Precautions

1. Pulmonary tuberculosis, airway fungi and fungal infections should be used with caution.

2. In the process of replacing oral hormones with budesonide aerosol, patients will re-appear some early symptoms, such as rhinitis, eczema and muscle and joint pain, temporarily increasing the oral hormone dose in these cases is necessary.

3. In rare cases, if the following symptoms occur, such as fatigue, headache, nausea, and vomiting, the manifestation of systemic sex hormone deficiency should be expected.

4. In order to reduce thrush in the throat, patients should gargle after taking the medicine.

5, athletes use with caution.

Aerosol medication for pregnant and lactating women

The study of this product for pregnant women is not enough, so pregnant women should weigh the advantages and disadvantages when using this product. Unless there is a reason to use it, you should avoid using this product during pregnancy. During pregnancy, if the use of glucocorticoids cannot be avoided, inhaled sex hormones can be used because when the equivalent dose of anti-asthma is reached, the former has lower systemic side effects than oral hormones.

Adrenal insufficiency may occur in babies born to women who use this product during pregnancy, so infants should be carefully observed.

Because this product can be excreted into human milk, breastfeeding women avoid using this product and should stop breastfeeding when it must be used.

Aerosol medication for children

The safety and effectiveness of this product for children under 2 years of age have not been studied and should be avoided. Studies of asthma in children have shown that the incidence of adverse events is the same in children aged 6-12 (172) and children aged 13-17 (124). Because oral corticosteroids can cause growth inhibition in children, children who take other corticosteroids to cause growth inhibition should consider that they may also have a higher sensitivity to this product.

Aerosol medication for the elderly

Clinical studies on the use of this product in 100 elderly patients over 65 years of age have shown that the efficacy and safety of this product for elderly patients are the same as for young patients.

Aerosol drug interactions

In clinical studies, given budesonide and other commonly used drugs for the treatment of asthma, the incidence of adverse reactions was not increased. Ketoconazole, a potent inhibitor of cytochrome P450 3A, can increase the blood concentration of budesonide and should be monitored clinically.

Aerosol overdose

Acute toxicity of this product is low when overdose, but long-term overdose may occur systemic glucocorticoid effects, such as hyperadrenal function.

Aerosol Pharmacology and Toxicology

The aerosol containing budesonide is a non-halogenated glucocorticoid. Due to the extremely high (approximately 90%) first-pass metabolic effects of the budesonide in the liver, the drug has a large dosage range It has good selectivity for local anti-inflammatory effects.

Induction tests in animals and patients show that budesonide has anti-allergic and anti-inflammatory effects and can relieve bronchial obstruction caused by immediate and delayed allergic reactions.

In highly reactive patients, budesonide has a reduced airway response to histamine and methacholine, and budesonide can also effectively prevent the onset of exercise-induced asthma.

Rabbit aerosol inhaled budesonide 400 g / day for one week without local irritation. The minimum lethal dose of this product in mice is 100mg / kg (approximately 250 times the maximum recommended daily inhalation dose for humans). The mice were orally administered budesonide 200 g / kg day (approximately 1/2 of the maximum recommended daily human inhaled dose) for 91 consecutive weeks without any carcinogenic effect. In the 104-week carcinogenicity study of Sprague-Dawley rats, the incidence of gliomas in male rats receiving oral doses of 50 g / kg / day (about 1/4 of the maximum recommended daily inhalation dose for humans) increased significantly. And statistically significant; and the oral dose for male rats receiving oral doses of 10, 25 g / kg / day (approximately 1/20 and 1/8 of the maximum recommended daily inhalation dose for humans, respectively) is 50 g / kg Male rats per day (approximately a quarter of the maximum recommended daily human inhaled dose) have not found a carcinogenic effect. Ames test, mouse micronucleus test, mouse lymphoma test, human lymphocyte chromosome aberration test, Drosophila melanogaster recessive lethal test, and rat liver cell culture DNA repair experiments confirm that budesonide has no mutagenic effect And cleavage effect. Rats were given subcutaneously 20 g / kg / day of budesonide (approximately 1/10 of the maximum recommended daily inhalation dose for humans). Maternal weight gain, prenatal survival rate, perinatal and lactation pup survival rates decreased. There is no such effect at a dose of 5 g / kg (approximately 1/40 of the maximum recommended daily human inhaled dose). Subcutaneous administration of budesonide to rabbits and rats at 25 and 500 g / kg / day (approximately 1/4 and 2.5 times the maximum recommended daily inhalation dose for humans, respectively) can result in stillbirth, weight loss and skeletal deformities. Rats inhaled budesonide at 100 to 250 g / kg / day (about 1/2 to 1/4 of the maximum recommended daily human inhaled dose) did not show teratogenic and lethal fetal effects.

Aerosol pharmacokinetics

After inhalation of this product, the absolute bioavailability is 39%. The maximum blood concentration reaches 30 minutes after inhaling 1 mg budesonide, and the Cmax is less than 0.01 mol / L. This product has a half-life of 2 to 3 hours, a distribution volume of 3 L / kg, and a plasma protein binding rate of 85 to 90%. The concentration of the drug in the lung 1.5 to 4 hours after inhalation of a single dose of 1600 g was 5.5 nmol / L, while the mean blood drug concentration was 0.63 nmol / L. After inhaling 500 g of this product, 32% of the drug is excreted in urine and 15% is excreted in feces. After inhalation, about 10% of the drug is deposited in the lungs, and about 90% of the swallowed residual drug is inactivated by the first pass metabolism of the liver. The main metabolites are 16-hydroxyprednisolone and 6-hydroxybudesonide .

Store tightly closed in a cool place (not more than 20 ° C).

Packing 20ml pressure-resistant aluminum cans, tank mouth locks with quantitative aerosol valve, cover driver. Carton packaging, 1 bottle / box.

The validity period is tentatively set for 24 months.

Implementation of the National Food and Drug Administration National Drug Standard YBH06092003.

Approved document number drug word H20030987.

manufacturer

Company Name: Lunan Bate Pharmaceutical Co., Ltd.