What Is a Depot Injection?

Injection refers to sterile solutions (including emulsions and suspensions) made of drugs for injection into the body and sterile powders or concentrated solutions that are formulated into solutions or suspensions before use.

Injection refers to sterile solutions (including emulsions and suspensions) made of drugs for injection into the body and sterile powders or concentrated solutions that are formulated into solutions or suspensions before use.
The injection works quickly and reliably. It is not affected by pH, enzymes, food, etc., and has no first-pass effect. It can play a systemic or local positioning effect. It is suitable for patients who should not take drugs or not. Poor body adaptability and high cost.
Chinese name
injection
Foreign name
injection
Features
Fast and reliable, not affected by pH enzyme food, etc.
Suitable
Patients who should not take medicine or not

Injection characteristics

Injections work quickly

Reliable effect, whether injectable liquid injection or powder injection
injection
The agent is stored, and when it is used clinically, it is directly injected into the tissues, blood vessels or organs of the human body in a liquid state. So fast absorption and quick effect. Especially for intravenous injection, the medicinal solution can directly enter the blood circulation, which is more suitable for the rescue of critical illness. And because the injection does not pass through the gastrointestinal tract, it is not affected by the digestive system and food. Therefore, the dosage is accurate and the effect is reliable.

Injectables are highly practical

Applicable to patients who should not be administered orally: Patients who often encounter dizziness, convulsions, convulsions, etc. in clinically, or patients suffering from digestive system disorders, cannot be administered orally. Injection is an effective route of administration.
It is suitable for drugs that should not be taken orally. Some drugs are not easily absorbed by the gastrointestinal tract due to their nature; some are irritating; others are easily destroyed by digestive juices. If made into injections, it can be solved. Chinese medicine One example is the powder injection of crystalline protein from trichosanthin.
Allow individual drugs to play a targeted role
For example, procaine hydrochloride injection can be used for local anesthesia; Xiaozhiling injection can be used for hemorrhoid injection.
Acupoint injection can give play to its unique effects, such as angelica injection.

Injection is shelf-stable

Injectables are sealed in a special container from the outside air in a special container, and are sterilized or aseptically processed during manufacture. They are more resistant to storage than other liquid preparations.
Disadvantage
(1) The injection is inconvenient and the injection is painful.
(2) The manufacturing process of injections is complicated, the equipment and packaging of the workshop are high, the production cost is large, and the price is also high.
(3) The toxic side effect is large, because it is directly injected into the blood

Classification of injections

Classification of injections

Liquid injection: also known as injection, commonly known as "water injection". Is formulated as a solution (water
Injection work
(Non-aqueous or non-aqueous), suspensions or emulsions, preparations in ampoules or multi-dose containers. It is mainly determined according to the nature of the drug and medical requirements. Generally, water-soluble drugs are required to achieve rapid effects after injection, so they are usually formulated into aqueous solutions or composite solutions of water (such as ethanol, propylene glycol, glycerol, etc. in the aqueous solution). Some medicines should not be made into aqueous solution. For example, it is difficult to dissolve in water or it can prolong the effect after injection. It can be made into oil solution, water or oil suspension, and emulsion. However, these injections are generally for intramuscular use.
Liquid injections are divided into small volume injections (less than 20mL, conventionally 1, 2, 5, 10, 20mL) and large volume injections (more than 50mL, conventionally 50, 100, 250, 500mL, etc.).
Powder for injection: commonly known as "powder injection". Some drugs have poor stability and are easy to decompose and deteriorate after being made into a solution. Such drugs can generally be prepared by aseptic operation, and sterilized powdered drugs for injection are placed in ampoules or other suitable containers, and when used, they are dissolved or suspended in an appropriate solvent. Such as penicillin, streptomycin, phenobarbital sodium, etc. can be made into "powder injection." In recent years, a number of traditional Chinese medicine powder injections have been successfully developed at home and abroad, such as extracting refined crystalline toxin protein from trichosanthin, ginseng extract, Gegen decoction and other refined preparations to prepare injection powder injections. There are also some drugs, such as enzyme preparations (trypsin, -chymotrypsin, paroxin, coenzyme A, etc.). In order to maintain stability, they are often freeze-dried under sterile operations to make powder injections for injection; some biological products Powder injections are also made by freeze-drying, such as placenta albumin injections.
Tablets for injection: refer to the embossed tablets or machine-pressed tablets made by the aseptic method of medicines, and they are dissolved with water for injection for subcutaneous or intramuscular injection, such as morphine hydrochloride tablets. However, such preparations are currently rarely used.

Injection site

Intradermal injection: injected between the epidermis and dermis, usually at the forearm. A single injection dose is less than 0.2mL, which is often used for allergic tests or disease diagnosis, such as toxomycin skin test solution, diphtheria diagnostic toxin and so on.
Subcutaneous injection: injected into the soft tissue between the dermis and muscle, and the injection site is mostly in the upper arm
Before the injection
Outside, the general dosage is 1 ~ 2mL. Subcutaneous injections are mainly aqueous solutions, but the rate of drug absorption is slightly slower. Because people feel subcutaneously more sensitive than muscles, irritating drugs and suspensions of oil or water are generally not suitable for subcutaneous injection. Sometimes the patient's blood vessels are not easy to find or for other reasons, high-dose infusions can also be administered subcutaneously.
Intramuscular injection: injected into muscle tissue, most of the injection site is in the arm muscle or deltoid muscle of the upper arm. Intramuscular injection has less stimulation than subcutaneous injection, and the injection dose is generally 1 ~ 5mL. In addition to aqueous solution, intramuscular injection can also be injected with oil solution, suspension and emulsion. Oil injection is absorbed slowly and uniformly in the muscles, which can have a delaying effect.
Intravenous injection: Injecting the vein to make the drug directly into the blood, so the drug is the fastest, often used for first aid, body fluid supplement and nutrition. Because of the large volume of blood vessels, large doses of intravenous injections are also called "infusions". One dose is from several milliliters to several thousand milliliters, and most are aqueous solutions. Oil solutions and general suspensions or emulsions can cause capillary embolism, so they cannot be injected intravenously. However, in recent years, studies have shown that emulsions made of certain nutritional drugs and medicinal oils can be used to accelerate the absorption of drugs. The oil droplets of these emulsions should be smaller than red blood cells, and their average diameter is less than 1 m. Because the blood has a buffering effect, the pH value and osmotic pressure of the blood are not much affected when a small amount of slow injection is performed. If a large amount of injection solution is injected, the pH value and osmotic pressure must be considered. Intravenous injection is more effective than subcutaneous or intramuscular injection. Any medicinal solution that can cause red blood cell lysis or protein precipitation should not be administered intravenously. Therefore, intravenous injections should generally not be added with bacteriostatic agents.
Spinal cavity injection: injected into the subarachnoid space around the spine. Because nervous tissue is more sensitive, and spinal fluid circulation is slower. Therefore, the injection dose should not exceed 10 mL, and the purest aqueous solution is required. Its pH value is between 5.0 and 8.0, and the osmotic pressure should be equal to the spinal fluid. Otherwise, due to osmotic disturbance or other effects, adverse reactions such as headache and vomiting will soon be caused. In short, the preparation and application of spinal cavity injections should be strictly required.

Route of injection

(1) Intradermal injection
(2) Subcutaneous injection
(3) Intramuscular injection
(4) Intravenous injection
(5) Intra-arterial injection
(6) Others (intracardiac injection, intra-articular injection, subcutaneous infusion, etc.)

Technical requirements for injections

In addition to the general requirements for preparations, all injections must meet the following quality requirements:
Sterility; the injection should not contain any living microorganisms, and must meet the requirements of sterility inspection of the Chinese Pharmacopoeia.
No pyrogen: The pyrogen should not be contained in the injection, especially the injection for more than 5mL at a time, for intravenous or spinal injection, must be qualified for pyrogen inspection.
Clarity: solution type injections must not contain visible foreign bodies or suspensions,
Injection
Should comply with the relevant provisions of the Ministry of Health on clarity inspection.
Safety: The injection must be non-toxic and irritating to the body.
Isotonicity: For injections with large dosages and for intravenous injection, they should have the same or slightly higher osmotic pressure as plasma.
pH: The injection should have a pH value equal to or similar to that of blood.
Stability: The injection must have the necessary physical and chemical stability to ensure that the product is safe and effective during storage.
In addition, some injections should also be checked for hemolytic and sensitizing effects, and their use is not strictly prohibited.

Composition of injection

Aqueous solvent for injection

The most commonly used is water for injection. Purified water is distilled water, and its pH value should be 5.0 ~ 7.0. Ammonia, chloride, sulfate and calcium salt, nitrate and nitrite, carbon dioxide, easy oxide, non-volatile matter and heavy metals, bacteria. Toxins and microbiological examinations should comply with the provisions of the 2005 edition (Part 2) of the Chinese Pharmacopoeia. Generally, purified water is used to prepare pure water by ion exchange method, electrodialysis method and other methods, and the obtained pure water is then prepared by distillation to obtain water for injection. At present, tower distillation or multi-effect distillation is commonly used to prepare water for injection. The preparation of injection solution usually uses freshly prepared water for injection. The storage time of water for injection generally does not exceed 12 hours, and the storage time after sterilization should not exceed 24 hours.

Non-aqueous solvent for injection

Vegetable oil is commonly used, mainly soybean oil for injection. Its quality should meet the "Chinese Pharmacopoeia" 2005 edition (Part II) "soy oil (for injection)" standard; others also include ethanol, propylene glycol, polyethylene glycol and other solutions. Soybean oil (for injection) is a clear yellow liquid with an acid value of not more than 0.1, a saponification value of 188 to 195, and an iodine value of 126 to 140.

Injection supplement

"Chinese Pharmacopoeia" stipulates that in addition to the main drug, other substances can be added according to the preparation and medical needs to increase the effectiveness, safety and stability of the injection. Such substances are collectively referred to as injection additives. The choice of species and the concentration used are non-toxic to the body, and are not compatible with the main, and do not affect the main efficacy and content determination. The finished product specification should also indicate the different uses of the additives.

Additives that increase the solubility of the main drug

The methods to increase the solubility of the main drug are:
Use mixed solvents or non-aqueous solvents.
Add acid or alkali to make the insoluble drug form a soluble salt.
Introduce hydrophilic groups on the molecular structure of the main drug.
Add solubilizers, such as Tween-80 and bile. However, when using Tween-80, the effects of acidic drugs, benzyl alcohol, and trichloro-tert-butyl alcohol may be weakened, so it should be noted.
Add co-solvent.
Commonly used are:
1. Tween-80: commonly used solubilizer, the commonly used amount is 0.5% ~ 1%. It is mainly used for intramuscular injection, with slight hypotensive and hemolytic effects. Use with caution. Note: tanning or phenolic ingredients, the solution is acidic, and turbidity will appear when adding Tween-80. Contains phenolic ingredients, adding Tween-80 to reduce sterilization effect. During the Tween-80 sterilization process, turbidity will appear. Usage: First mix the solubilized drug with Tween-80, and then dissolve.
2. Sodium salt of bile bile acids, commonly used 0.5 ~ 1.0%. Commonly used are beef bile, pig bile, sheep bile, etc., which have impurities and require processing. Note: The pH of the medicinal solution is greater than 6.9, and its properties are stable.
The pH is less than 6.0, which reduces the solubilizing effect and affects the clarity of the preparation.
3. Glycerin: a good solvent for tannins and phenolic ingredients. The dosage is generally 15% ~ 20%.
4. Others: Co-solvents such as organic acids and their sodium salts, amides and amines. Compound solvent system.

Additives that help suspend or emulsify the main medicine

Suspension, emulsifier:
Suspensions and emulsifiers should meet the following quality requirements: no antigenicity, no toxicity, no pyrogens, no irritation, no hemolysis; heat resistance, no failure under sterilization conditions; highly dispersed and Stability can be achieved with a small amount; Suspending agents and emulsifiers for intravenous injection must strictly control their particle size, which should generally be less than 1nm, and individual particle sizes are not greater than 5nm.
Commonly used suspending agents:
Tween-80, Span-85, Proloni F-68, carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, gelatin, mannitol, sorbitol, aluminum monostearate, silicone oil, etc.
Common emulsifiers:
Lecithin, soy lecithin, Protoni F-68, oxyethylene propylene polymer, etc.

Additives to prevent oxidation of the main drug

Purpose: To prevent the unstable phenomenon caused by the oxidation of the main drug in the injection. In addition to reducing the temperature of the main drug, avoiding light, driving out oxygen, adjusting to a stable pH value, and controlling trace metal ions, the addition of antioxidants also plays an important role.
Common antioxidants and dosage:
Principle: Antioxidants are a class of oxidizing reducing agents.
Sodium metabisulfite (0.1% ~ 0.2%), sodium bisulfite (0.1% ~ 0.2%), sodium sulfite (0.1% ~ 0.2%), sodium thiosulfate (0.1%), thiourea (0.05% ~ 0.1%), Ascorbic acid (0.05% ~ 0.2%), etc.
Common metal complexing agents:
Principle: Metal ions accelerate the oxidative decomposition of certain chemical components, leading to deterioration of the preparation. Forms stable complexes with metal complexing agents.
Disodium edetate or calcium edetate is commonly used at 0.01% to 0.05%. In addition, sodium cyclohexanediamine tetraacetate, N-hydroxyethylenediamine triacetic acid, and the like can also be used.
Inert gas to drive out oxygen:
The high-purity inert gas N 2 or CO 2 is passed into the water for injection or the prepared medicinal solution to saturate it to drive out dissolved oxygen. After the medicinal solution is filled into the ampoule, N 2 or CO 2 is passed in to replace the oxygen in the surface space of the medicinal solution, and then sealed.

pH Additive for pH adjustment of injection

Includes: acids, bases and buffers.
Objective: To reduce local irritation to the body, increase the stability of the medicinal solution and accelerate the absorption of the medicinal solution.
Considering the adaptability and stability of the body, the medicinal solution should be adjusted to a suitable pH range. Under the premise of good drug stability, the pH value of the medicinal solution is preferably about 7.4, or between 7.0 and 7.6. There are only a few varieties that allow pH values between 4 and 9.
Commonly used additives to adjust the pH value: hydrochloric acid, sulfuric acid, citric acid, sodium (potassium hydroxide), sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the like.

Additive for injection to inhibit microbial reproduction

In order to prevent the contamination of microorganisms during the manufacture and use of injections, in particular injections prepared by low-temperature sterilization, filtration or sterilization, or multi-dose injections, appropriate bacteriostatic agents should be added. However, bacteriostatic agents must not be added to injections used for intravenous or spinal injection; special care should be taken when administering bacteriostatic agents with injections exceeding 5 mL.
The bacteriostatic agent should meet the following requirements: (1) reliable bacteriostatic efficacy; (2) non-toxic to human body; (3) no contraindication to compatibility with the main drug, which does not affect the efficacy and quality inspection; (4) stable in nature and not easily Temperature, pH, etc. affect the bacteriostatic effect; (5) Does not react with rubber stoppers.
Bacteriostatic agents and dosages commonly used in injections: phenol (0.25% ~ 0.5%), cresol (0.25% ~ 0.3%), chlorocresol (0.05% ~ 0.2%), trichlorotert-butanol (0.25% ~ 0.5 %), Phenylmercury nitrate (0.001% ~ 0.002%), benzyl alcohol (1% ~ 3%), parabens (about 0.1%), etc.

Injectables for pain relief

In order to alleviate the pain caused by the injection, topical analgesics should be added as appropriate.
Commonly used analgesics and dosage: benzyl alcohol (about 1%), procaine hydrochloride (0.5% ~ 2.0%), lidocaine hydrochloride (0.2% ~ 1.0%), trichloro-tert-butanol (0.3% ~ 0.5 %).

Additive for regulating osmotic pressure of injection

Maintaining the osmotic pressure of plasma is not only necessary for the survival of cells, but also related to maintaining the water balance in the body. Therefore, the osmotic pressure of the injection should be as equal to the plasma as possible. Any solution with the same osmotic pressure as plasma and tear is called an isotonic solution, for example: 0.9% sodium chloride solution and 5% glucose injection. Injecting a hypertonic solution, red blood cells atrophy due to water exudation, but the body has a certain regulating function on osmotic pressure, as long as the input amount is not too large, the speed is not too fast, and no adverse effects will occur. Therefore, intravenous injection of 10%, 50% glucose and other hypertonic solutions is harmless. However, injecting a large amount of hypotonic solution may cause hemolysis, which must be avoided. 0.45% sodium chloride solution can cause hemolysis, and 0.35% sodium chloride solution can completely hemolyze. For intravertebral injection, an isotonic solution must be used.
Common osmotic pressure regulators: glucose, sodium chloride, phosphate or citrate.
The most commonly used calculation methods for regulating isotonicity : the freezing point reduction data method and the sodium chloride isotonic equivalent method.
(I) Freezing point data reduction method: The freezing point of plasma is -0.52 ° C. The freezing point of any solution is reduced to -0.52 ° C, which is isotonic with plasma. example:
(II) Sodium chloride isotonic equivalent method: Sodium chloride isotonic equivalent refers to the isotonic effect of 1g of drug equivalent to the number of grams of sodium chloride.
(3) Isotonic solution and isotonic solution: Isotonic solution: A solution with an osmotic pressure equal to that of plasma. Some isotonic solutions (boric acid, ephedrine hydrochloride, cocaine hydrochloride, ethylmorphine hydrochloride) do not keep the volume and shape of red blood cells normal. Isotonic solution: A solution with the same tension as the membrane of red blood cells. The red blood cells in the isotonic solution can maintain normal volume and shape, and will not cause hemolysis.

Preparation method of injection

Process for preparing injections

Preparation and handling of raw and auxiliary materials, preparation, potting, sterilization, inspection and packaging.

Preparation of injection materials for traditional Chinese medicine injections

Formulated raw materials:
Use the active ingredients of the monomers extracted from Chinese medicine as raw materials
Use the effective part extracted from Chinese medicine as raw material
The total extracts extracted from Chinese medicines are used as raw materials (status quo)
(1) Pretreatment of Chinese medicinal materials
The species and source of the medicinal materials must be determined. After the identification meets the requirements, pretreatment (selection, washing, cutting, drying, crushing, sterilization).
(Two) the preparation of traditional Chinese medicine injection liquid
1. Requirement: Remove impurities to the greatest extent and retain effective ingredients.
2. Selection basis of extraction and purification route:
(1) According to the basic physical and chemical properties of the ingredients contained in the drug in the prescription composition;
(2) Combining functional indications and modern pharmacological research determined by the theory of traditional Chinese medicine;
(3) Traditional usage and dosage of prescription;
(4) Application site and action time after injection.
3. Uses:

Preparation method of water for injection

Distillation is the most reliable and classic method for preparing water for injection. The Pharmacopoeia requires that the source of water for injection preparation for distillation should be purified water, so the raw water must be purified after filtration, deionization and other processes before use.
Preparation process of water for injection:
(1) Raw water treatment. Raw water is usually pre-treated tap water, and its quality should meet the national sanitary standards for drinking water. Raw water contains impurities such as suspended particles, soluble inorganic salts, organic matter, microorganisms, pyrogens, and volatile gases. It must be treated as purified water before it can be used as a source of water for injection preparation by distillation. Raw water treatment methods include ion exchange, electrodialysis, and reverse osmosis.
Ion exchange method The raw water is treated by ion exchange resin. The most commonly used ion exchange resins are 732 styrene strongly acidic cation exchange resin and 717 styrene strongly basic anion exchange resin. Generally, a combination of a cationic resin bed, an anionic resin bed, and a mixed resin bed is used in series. A degassing tower is added after the cationic resin bed to remove carbon dioxide in the water to reduce the burden on the anionic resin. The water obtained by this method has high chemical purity, and the specific resistance can reach more than 1 million · cm. The equipment is simple, saves fuel and cooling water, and the cost is low; after a period of ion exchange, the resin ages and the quality of the effluent is unqualified. Continue to use after regeneration.
Electrodialysis The electrodialysis method removes ions according to the directional migration of ions under the action of an electric field and the selective permeability of the exchange membrane. This method does not require the consumption of acids and bases used in the regeneration of ion exchange resin, which is more economical than the ion exchange method, but the water produced has a lower purity, and the specific resistance is generally 50,000 to 100,000 · cm;
A reverse osmosis method is provided with a semi-permeable membrane in a u-shaped tube, and a salt solution and pure water are respectively placed on both sides of the semi-permeable membrane. Water molecules on the pure water side are transferred to the salt solution side through the semi-permeable membrane to make the salt solution liquid. The surface rises, this is the osmosis. The pressure created by the height difference between the two liquid columns is the osmotic pressure that this salt solution has. If a pressure greater than the osmotic pressure of the salt solution is applied to the salt solution, the water molecules in the salt solution permeate to the pure water side to achieve the separation of salt and water. This is reverse osmosis. The semi-permeable membranes generally used for the purification of raw water by reverse osmosis method are cellulose acetate membrane and polyamide membrane.
(2) Distillation. Small-scale production is generally used for tower distilled water, which mainly includes three parts: evaporation pot, frothing device and condenser. For mass production, multi-effect distilled water or air pressure type distilled water is commonly used. The distilled water device for the preparation of water for injection shall be equipped with an effective frothing device to ensure that it does not bring in pyrogens. (3) Collection and storage of water for injection. The initial distillate was discarded, and after passing the inspection, it was collected in a closed collection system with a sterile filtration device, stored in a heat preservation cycle above 80 ° C, a heat preservation cycle above 65 ° C, or a sterile state below 4 ° C, and used within 12 hours of preparation.

Container and treatment of injection

1.Physical inspection
Appearance: The ampoule's body length, body thickness, silk thickness, and silk length meet the requirements; the appearance is free of crooked silk, crooked bottom, color, pits, grit, pimple, fine seam, oil stain and rust pink.
Cleanliness: The clean and dried ampoules are filled with qualified water for injection and sealed. Those who pass the inspection shall be sterilized by autoclaving at 121 for 30 minutes, and then the clarity shall be in accordance with the regulations.
Heat resistance: Wash the ampoule, fill it with water for injection, seal it, and check the damage rate of the ampoule after autoclaving. The ampoule of 1 ~ 2mL shall not exceed 1%, and the ampoule of 5 ~ 20mL shall not exceed 2%.
2. Chemical inspection
Acid resistance: take 110 ampoules, wash and dry, fill with 0.01mol / L hydrochloric acid solution to the normal volume, seal, remove ampoules containing foreign matter such as glass shavings, fibers and white spots, and sterilize by autoclaving at 121 ° C After 30 minutes, take out and check, all ampoules must not have visible flakes.
Alkali resistance: Wash and dry 220 ampoules, inject 0.004% sodium hydroxide solution to the normal filling amount, seal them, remove ampoules containing foreign matter such as glass chips, fibers, and white spots, and heat-extinguish at 121 ° C. Remove the bacteria for 30 minutes for inspection, and all ampoules should not have visible slices.
Neutral inspection: Take 11 ampoules and wash them with boiling cold distilled water. Into ten ampoules, methyl red acid solution was filled to the normal volume, and sealed. The other 1 ampoule was filled with a mixed solution of 10 mL of methyl red acid solution and 0.1 mol / L sodium hydroxide solution 0.1 mL to a normal volume, and then sealed. The 10 ampoules were autoclaved at 121 ° C for 30 minutes, and then left to cool. The ampoules were taken out and compared with the solution in the ampule which had not been hot-pressed.

Injection solution

(1) Dilute formulation method: Add the raw materials to the required solvent once to prepare the required concentration of injection. This method is suitable for the preparation of small-dose injections with good raw materials.
(2) Concentrated formulation method: Partial solvent is added to the raw materials to prepare a concentrated solution, and after heating, dissolving and filtering, all the solvents are added to the filtrate to reach the specified concentration. This method is suitable for the preparation of high-dose injections with average quality of raw materials.
The quality of the concentrated solution can be guaranteed by heat treatment and cold storage. However, after heat treatment, boiling for 30 minutes or heating at 115 ° C for 15-20 minutes, it can destroy its colloidal state and cause it to aggregate. Refrigerating at 0 ° C to 4 ° C for 24 hours can reduce its kinetic stability and cause precipitation , Can be filtered to remove impurities.
The properties of several raw materials are different, and the dissolution requirements are different. They can be dissolved separately when mixed, mixed, and finally added the solvent to the full amount.

Injection filtration

Filtration is an important operation to ensure the clarity of injections, and is generally divided into primary filtration and fine filtration. If there are many precipitates in the drug solution, the drug solution specially treated with activated carbon must be filtered first before fine filtration. This will prevent precipitation from blocking the pores.
Filter materials commonly used in primary filtration are: filter paper, long-fiber absorbent cotton, silk, flannel, nylon, etc. Commonly used filters are: triangular glass funnel, Buchner funnel, filter rod. Commonly used filters for fine filtration are: fused glass funnels, microporous filters and filters. Sand filter rods are suitable for large-scale preliminary filtration (coarse filtration); vertical melting glass filters G3 atmospheric pressure filtration, G4 pressure or reduced pressure filtration, G6 sterilization filtration, such filters can be autoclaved and pumped with water after use Wash and immerse with cleaning solution or 1% ~ 2% sodium nitrate and sulfuric acid solution; plate and frame filter press is used for large-scale pre-filtration; microporous filter membrane is used for fine filtration (0.45 ~ 0.8m) or sterile filtration 0.22 ~ 0.3m). There are three filtering methods:
(1) Natural filtration: High-level static pressure filtration device is usually used. The device is suitable for a building, a liquid distribution room and a liquid storage tank upstairs. The liquid to be filtered passes the examination, the large collection and finishing pipeline flows into the filter naturally, and the filtrate flows into the liquid storage bottle below or directly into the container. The static pressure formed by the liquid level difference promotes natural filtering through the filter medium of the filter. This method is simple, stable pressure and good quality, but the filtration speed is slow.
(2) Decompression filtration device: It continuously extracts air from the filtrate reservoir to form a negative pressure, which promotes the liquid medicine above the filter to flow into the filtrate reservoir through the filter material.
(3) Pressure filtration device: The centrifugal pump is used to transport the chemical solution through the filter for filtration. Its characteristics are: stable pressure, fast filtration speed, good quality and high output. Because all the devices maintain a positive pressure, microorganisms and particles in the air cannot easily penetrate the filtration system, and the filter layer is not easy to loose, so the filtration quality is relatively stable. It is suitable for dosing, filtering and potting on the same plane.
No matter what kind of filtration method and device is used, because the pore size of the filter material cannot be exactly the same, the initial filtrate may not be clear. The initial filtrate needs to be filtered back until the filtrate clarity is fully qualified before it can be officially filtered. Potting.

Types and choices of injection filters

(1) Vertical melting glass filter: low adsorption, does not affect the pH of the chemical solution, easy to clean, but the price is high and easy to break. Filter No. 3 is used for atmospheric pressure, No. 4 is used for decompression or pressure, and No. 6 is used for sterile filtration.
(2) Sand filter rod: cheap and easy to obtain, but easy to remove sand, strong adsorption of medicinal solution, difficult to clean, suitable for primary filtration in large production. Medium (500 ~ 300mL / min) commonly used in injection production
(3) Plate-and-frame filter press: large area, high rejection, can be used for filtering various materials with large viscosity and filter cake compressibility, especially suitable for filtrate containing a small amount of particles, and is mostly used in the production of injection preparations. The disadvantage of filtration is that it is troublesome to assemble and clean and easy to leak.
(4) Microporous filter membrane: small pore diameter, strong retention ability; uniform pore size, no particle leakage; fast filtration speed; no medium migration, does not affect the pH of the drug solution; small adsorption, does not affect the content of the main drug ; Discard after use without pollution. However, it is easy to plug, and some filter membranes have unsatisfactory chemical properties.

Injection potting

The potting includes the pouring of the liquid medicine and the sealing of the container. The potting room is a critical area for the production of sterile preparations, and its cleanliness requirements are particularly strict, which should reach level 100.
(I) Filling of injection
In order to ensure that the injection has a sufficient dose to compensate for the loss caused by the adherence of the bottle wall and the syringe and needle during aspiration during the administration, the actual perfusion of the injection in the ampoule should be equal to the labeled amount plus the additional amount. The provisions of the Chinese Pharmacopoeia for additional injections are shown in Table 10-5 (P259).
When filling:
(1) The filling amount is accurate. Before each infusion, the capacity of the perfusion device must be corrected, and a few tubes must be tested. The filling amount should be checked in accordance with the "Pharmaceutical Filling Inspection Method" stipulated in the Chinese Pharmacopoeia.
(2) During infusion, care should be taken not to make the infusion needle collide with the inner wall of the ampoule neck as much as possible, so as to prevent the glass debris from falling into the ampoule;
(3) The liquid medicine should not adhere to the neck wall of the ampoule, so as to avoid scorching or bursting.
Filling method: manual filling and machine filling.
Commonly used perfusion devices are: manual vertical perfusion devices, manual horizontal perfusion devices, double or multi-needle perfusion devices, electric potting machines, etc.
If it is necessary to fill inert gas to prevent the chemical solution from oxidizing, it is necessary to completely replace the air in the ampoule with the inert gas. Generally, it is considered that twice aeration is better than one aeration.
(2) Sealing of injection solution
1. Requirements: The sealing of the ampoule should be tight, seamless and airtight; the seal of the ampoule should be the same length, the neck end should be round and smooth, and there should be no sharp and frangible tips and fragile globules.
2. Method:
(1) Manual fusion sealing: single flame method and double flame method, which belong to "waist sealing", and are produced in small quantities.
(2) Machine sealing: Automatic ampoule filling and sealing machine is mostly used for natural sealing at the top. However, at present, the pull-seal method is mostly adopted. When mass production is performed, the operation is convenient and the production efficiency is high.
During filling and sealing, some products whose main medicine is oxidized easily when exposed to air, should be filled with inert gas to replace the air in the ampoule. Commonly used are nitrogen and carbon dioxide.

Type of injection

injection
According to the dispersion system, injections can be divided into four types:
1. Solution-type injections For drugs that are easily soluble in water and stable in water, they can be made into aqueous-type injections, such as sodium chloride injection, glucose injection, and the like. Some drugs that are unstable in aqueous solutions can be made into oil solution injections, such as progesterone injections, if they are soluble in oil. According to the size of molecular weight, it can be divided into low-molecular solution injection and high-molecular solution injection.
2. Suspension injection water-insoluble drugs or drugs that require prolonged efficacy after injection can be made into water or oil suspensions, such as cortisone acetate injection. Such injections are generally only for intramuscular injection. The solvent can be water or oil or other non-aqueous solvents.
3. Emulsion-type injections are water-insoluble liquid drugs or oil-based liquid drugs, which can be made into emulsion-type injections, such as intravenous fat emulsions, according to medical needs.
4. Sterile powder for injection Sterile powder for injection, also called powder needle, is to put sterile powdered medicine for injection into an ampoule or other suitable container, and add an appropriate solvent (usually sterilized injection) before use. Formulation prepared by dissolving or suspending in water). For example, sterile powders of water-resistant drugs such as the Na and K salts of penicillin G.

Injection

Traditional Chinese medicine injection refers to the active ingredients extracted from Chinese medicinal materials. It is a sterilized solution prepared by using modern science and technology and can be injected into the body including muscles, acupoints, intravenous injections and intravenous drips, and solutions prepared before use Sterilized powder or concentrate.
Injectables should meet the following relevant regulations during production and storage:
1. The solvents used in injections include aqueous solvents, vegetable oils and other non-aqueous solvents. The most commonly used aqueous solvent is water for injection. Sodium chloride injection or other suitable aqueous solution can also be used.
Commonly used oil solvents are sesame oil, tea oil, etc., in addition to complying with the requirements of each oil (see the text of this Pharmacopoeia), and should be refined to meet the following requirements.
(1) There should be no peculiar smell and no rancidity; unless otherwise specified, the color shall not be deeper than the yellow colorimetric standard 6 color liquid, and it shall be kept clear at 10 .
(2) Iodine value is 79-128; saponification value is 185-200; acid value is not more than 0.56.
Other solvents must be safe and harmless, and the amount should not affect the efficacy.
2. When formulating injections, suitable additives can be added according to the nature of the drug. When the additive is a bacteriostatic agent, the amount should be able to inhibit the growth of microorganisms in the injection. Commonly used bacteriostatic agents and dosage (g / mL) are 0.5% phenol, 0.3% cresol, 0.5% trichloro-tert-butanol and the like. Antibacterial injections should still be sterilized by appropriate methods. For injections with an injection volume exceeding 5mL, the added bacteriostatic agent must be selected with special care. Intravenous (unless otherwise specified) or injections for spinal canal injections must not contain bacteriostatic agents.
3. Unless otherwise specified, the container shall comply with the national standards for medical glass containers. Container rubber stoppers shall comply with relevant regulations.
4. When preparing the injection solution, the perfusion solution must be clear, and the container should be used clean and dry.
When preparing an oil solution for injection, the refined oil should be sterilized by dry heat at 150 ° C for 1 to 2 hours, and then allowed to cool to a suitable temperature.
Unless otherwise specified, the fineness of the drug in the suspension for injection should be controlled below 15 m, and 15-20 m (with some 20-50 m in between) should not exceed 10%.
Raw materials for direct packaging into sterile powders for injection should be sterile, and those who use freeze-drying methods should be sterile, and the difference in filling volume should be controlled within ± 4%.
Fifth, in the preparation of injections, we should strictly prevent deterioration and contamination of microorganisms and pyrogens. The prepared medicinal solution should be potted and sterilized within the same day. If it cannot be completed within the same day, the medicinal solution must be stored under the condition of non-deteriorating and non-reproductive microorganisms; injections for intravenous and spinal canal injection, Should be strictly controlled.
6. In the filling process, drugs that are easily deteriorated should be excluded from the container during the filling process and filled with carbon dioxide or nitrogen.
7. After welding or tightly sealing, a suitable method can be used for sterilization according to the nature of the drug, and the finished product must be sterile.
8. During or after sterilization of the sealed injection, the container should be leak-checked by decompression or other suitable methods.
Nine, the injection should be stored in a light-shielded condition according to the prescribed conditions.

Main products of injection

injection
Although injection is not a new preparation, in recent years there have been some important research advances in varieties and packaging types. For example, liposome injections, therapeutic monoclonal antibody injections, long-acting biodegradable microsphere injections, nanoparticle injections, depot-type controlled-release injections, gene therapy drug injections, gel injections, etc. have appeared successively in varieties; In terms of injection devices and packaging, single-dose / multi-dose needle-free injections, powder syringes, pre-filled injections, powder / liquid pre-mixed syringes, and syringes for subcutaneous implantation have appeared.

Microsphere injection

Combining the drug in a microsphere carrier for subcutaneous or intramuscular administration can slowly release the drug, change its transport process in the body, and prolong the action time in the body (up to 1 to 3 months), greatly reducing the number of medications and significantly improving Patient compliance. At present, the backbone materials used to prepare sustained-release microspheres are mainly polylactic acid-polyglycolic acid (PLGA) and polylactic acid (PLA)-which are biodegradable materials approved by the US FDA for human use. Often used. In addition to its good biocompatibility, no immune response, and high safety, it is even more rare to adjust the degradation rate of the polymer in the body by changing the ratio of the two monomers and the polymerization conditions.
Microsphere injection of protein and peptide drugs Due to the limited dose of microsphere injection, some drugs with a small daily dose should be selected. Protein and peptide drugs are generally used in small doses and require long-term medication. The release pattern of microspheres should basically match the clinical needs of the drug. The encapsulation rate of the drug in the microspheres should be high, the burst release effect should be small when the drug is released, the release mode should be stable, and the release time must meet the requirements. In addition, there are many factors that affect the release of microspheres, including the type and proportion of matrix materials, preparation processes, microsphere morphology, structure, particle size and distribution, microsphere drug encapsulation rate and drug loading, and microsphere drugs Interaction between the state of the carrier and so on. Generally, microspheres are prepared by compound emulsion-liquid drying method, low temperature spray solvent extraction method, and the like. At present, many related products have been put on the market, and more products (including microspheres of macromolecules and small molecules) are under development or approval.
Microsphere injections of vaccines Microsphere injections of vaccines have received increasing attention due to their advantages of good biocompatibility and easy adjustment of drug release rate. At present, a research group led by the World Health Organization (WHO) has submitted the formula and animal experimental results of tetanus toxoid microsphere injection. The long-acting preparation is composed of two kinds of microspheres. One has a small particle size and high content. The ratio of two monomers in PLGA is 50:50. The other has a large particle size and low content. The ratio of two monomers in PLGA is 75:25; The drug is released twice after injection, one burst release, and the other is 3-11 weeks after injection. After inoculating the microsphere preparation, mice can produce higher antibody levels than the solution.

Liposome injection

Liposomes have attracted people's attention because of their good biocompatibility. After more than 20 years of research, researchers have successively overcome the quality problems of lipid materials, the problems of large-scale production processes, the problems of encapsulation efficiency, and stability issues. After the first product of amphotericin liposomes was launched abroad, doxorubicin and daunorubicin were approved for marketing. Econazole nitrate liposome gel was also launched in Europe. So far, liposome products registered in the US FDA include cisplatin, interleukin-2, insulin-like growth factor, prostaglandin E1, vincristine, and the like. The hydroxycamptothecin liposomes, ribavirin liposomes, and isoconazole nitrate liposomes are registered in the State Food and Drug Administration in China.
With the improvement of carrier materials and surface modification of liposomes, various types of liposome preparations have appeared successively, such as immunoliposomes, long-cycle liposomes, targeting peptide-coupled liposomes, and pH-sensitive lipids And heat-sensitive liposomes, magnetic liposomes, etc. Long-cycle liposomes embed hydrophilic macromolecules, such as polyethylene glycol (PEG) and its derivatives, on the liposome membrane through a lipid anchor, forming a hydrophilic layer on the surface of the liposome, thereby reducing The recognition and absorption of the reticuloendothelial system increases the circulation of liposomes in the body and prolongs the duration of drug action.
For example, doxorubicin common preparations need to be administered 3 times a week, while doxorubicin hydrochloride liposomes (Caelyx) can be encapsulated in doxorubicin hydrochloride by novel PEGylated liposomes, which can cause its retention in the body The time is longer than the common doxorubicin preparation, which is conducive to the effectiveness of the drug, and it is more convenient to use (once a month). Third-generation liposomes (targeting long-circulating liposomes) are now being researched and developed.

Nanoparticle injection

In January 2005, the US FDA approved the albumin-paclitaxel nanoparticle injection suspension for use in breast cancer that has relapsed after metastatic breast cancer combined chemotherapy failed or within 6 months of adjuvant chemotherapy. This indicates that a new class of "protein-bound particles" drugs can be prepared using ABI's patented nanoparticle albumin binding technology. This product is only composed of albumin and paclitaxel nanoparticles, and does not contain a serious adverse reaction surfactant. Thanks to the use of nanoparticle technology, therapeutic doses of even more paclitaxel can be released into the body through ordinary vein intubation for 30 minutes. Taxol, which uses Cremophor-EL as a surfactant, requires steroid hormones and antihistamines to prevent allergic reactions before use, and the infusion time is up to 3 hours. Magnetic nanoparticle injections for diagnosis have also been used clinically.

Depot type controlled release injection

Skyepharma researched and developed the depot foam type long-acting release patented technology which was successfully applied to cytarabine sustained-release injection, which is composed of matrix filled with dispersed water-filled compartment lipid particles. Fat particles have a particle size of 10-30 microns and are suspended in physiological saline. The suspension is like skim milk and can be injected with a fine needle. The water-filled compartment contains the drug and is the main body of lipid particles. Lipids use natural substances such as phospholipids and triglycerides, and the release time can be controlled from 1 to 30 days. After injection, the drug-containing particles gradually degrade, extending the release time of the drug, which can be injected once every two weeks, thereby greatly reducing the interference to the patient's life, reducing the danger caused by frequent injections, and reducing medical costs. Most importantly, sustained release keeps cytarabine in the cerebrospinal fluid at high concentrations, and it can also delay the exacerbation of the disease. Recently, the FDA also approved the release of a long-acting injection of morphine sulfate reservoir foam type for the treatment of pain after major surgery.

Needle-free injection drug delivery system

The drug release principle of the needle-free drug delivery system is to use a powder / liquid spray hand-held device for percutaneous drug release, using high-pressure gas (helium, etc.) to instantly accelerate the drug powder / droplet to 750 m / s, and enter the skin through the skin cells Inside. It can control the depth of drug release, and can release large molecules (such as antigens) directly into the epidermis, which is difficult to achieve with ordinary needle injection. If the vaccine is applied at the junction of the epidermis and the dermis, a strong immune response can be generated. Bioject has marketed a needleless applicator for the release of pediatric human growth hormone (produced by Serono). The Medical House PLC has also sold the novel Mhi-500 insulin needle-free injection delivery system in more than 30 countries including the United Kingdom, France, Germany, Ireland, and Italy. A single dose can release up to 70 of 100 insulin , Can replace the syringe or pen syringe to inject insulin.

- Injections -Other

[Filling volume of injection]
When filling the injection solution, the filling amount should be appropriately increased according to the following table to ensure that the injection amount is not less than the indicated amount. Unless otherwise specified, the injection volume for multiple injections shall not exceed 10 injection volumes per container, and the increased injection volume shall be sufficient for each injection.
Increase
Labeled quantity Flowable liquid Viscous liquid
0.5mL 0.10mL 0.12mL
1.0mL 0.10mL 0.15mL
2.0mL 0.15mL 0.25mL
5.0mL 0.30mL 0.50mL
10.0mL 0.50mL 0.70mL
20.0mL 0.60mL 0.90mL
50.0mL 1.0mL 1.5mL
Inspection method
The labeled volume of the injection is 2 mL or less for 5 test samples, 2 mL to 10 mL for 3 test samples, and 10 mL or more for 2 test samples; be careful to avoid loss when opening, and save the contents Use a dry syringe (pre-standardized) of the corresponding volume to draw up and inspect at room temperature; when measuring the amount of oil solution or suspension, you should first warm up and shake, then use the dry syringe to draw up and let cool View at room temperature. The amount of each injection should not be less than its labeled amount.
[Differences in the amount of sterile powder for injection] Unless otherwise specified, the limit of the difference in the amount of sterile powder for injection should meet the requirements in the table below.
------------------------------
Inspection method: take 5 bottles (pieces) for testing, average loading
Remove labels, aluminum caps, and use ethanol on the outer wall of the container
Wash, dry, and avoid glass when opening
Foreign materials such as crumbs fall into the container, and they are quickly refined below 0.05g or 0.0g respectively
Dense scale, pour out the contents, the container can use water, more than 0.05g to 0.15g
Wash with ethanol and dry under suitable conditions, 0.15g to 0.5g ± 7%
------------------------------
Then accurately weigh the weight of each container separately, and find the filling amount and average filling amount of each bottle (branch). Comparing the filling amount of each bottle (branch) with the average filling amount, it should meet the requirements in the table above. If 1 bottle (branch) does not meet the requirements, another 10 bottles (branch) shall be taken for re-tests, and all shall meet the requirements.
[Clarity of injection]
Inspection in accordance with the provisions of the Ministry of Health on the clarity of injections should comply with the regulations.
[Sterile]
Inspection according to the method under the sterility inspection method (Appendix XIIIB) shall comply with the regulations.
Development of Traditional Chinese Medicine Injection
There is no such injection form in the traditional formulation of traditional Chinese medicine. Due to the many unique advantages of the injection, some people started to develop the traditional Chinese medicine injection decades ago. As early as the 1930s, "Chaihu injection" has been successfully developed, and has been used to treat colds, fevers and other diseases with good results. After the founding of the People's Republic of China, the Chinese medicine injection was developed in the mid-1950s. At the beginning of the 1960s, "protest 601 injection", "yinhuanghuang injection", "201-2 (banlangen) injection and other twenty varieties" were developed. Most are used clinically, and some have been formally put into production and are still widely used to this day. Due to the continuous improvement of quality and stable efficacy, it has opened the way for the development of traditional Chinese medicine injections.
Traditional Chinese medicine injections were a period of great development in the 1970s. Not only were they developed by scientific research, teaching, and production units, but many urban and rural medical units also carried out trial production. According to statistics, the traditional Chinese medicine injection has undergone clinical trials during this period. There are more than 700 types that have been reported. The 1977 edition of the Pharmacopoeia of the People's Republic of China contains 23 types. Among them, there are dozens of species with good quality and reliable effects, such as Ding Gong Teng, horse chestnut, ginseng, rhubarb, total roots of trichosanthis, trichosanthin crystals, salvia miltiorrhizae, holly, total root of tangle , Angelica, Luying, Houttuynia, Andrographis paniculata, summer without, turmeric oil, antler essence, etc .; Compound injections have Shengmai, Angelica Safflower, Compound Chaihu, Compound Banlangen, Xiaozhiling, Qingkailing, Received good results in clinical. Some have significant effects, have been produced in batches, and have stable quality, which can meet the clinical requirements of traditional Chinese medicine, especially for emergency treatment.
The quality control of traditional Chinese medicine injections is a key issue, because the injections are taken by injection and directly enter the body without being absorbed by the digestive tract, so the quality control must be strict. However, most traditional Chinese medicine injections are prepared by extracting and refining medicinal materials or decoction pieces as raw materials. Objectively, there are impurities, significant differences in the content of effective substances, and they are easily brought into the pyrogen. A lot of in-depth research work has been done to solve specific problems one by one. For example, trichosanthin has been purified protein crystals, and Shengmai injection, Qingkailing injection and other specified content standards for strict pyrogen inspection; rhubarb, pasqueflower, and agaricin injections for stability experiments. In addition, according to the characteristics of traditional Chinese medicine injections, a series of routine quality inspection items and standards have been stipulated, so that the quality of some traditional Chinese medicine injections has passed. It shows that traditional Chinese medicine injection, as a dosage form of traditional Chinese medicine, has been basically finalized and shows its unique advantages. It is a promising type of traditional Chinese medicine. Especially in the development of traditional Chinese medicine and the treatment of emergency treatment of traditional Chinese medicine, it will be an indispensable main dosage form. Not only will the number of "small needles" be increased, but the infusion solution will gradually pass the customs, and then be put into production to meet the requirements of traditional Chinese medicine for clinical use.

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