Inner page

Clinical Observation on the Efficacy of Zhitongning Aerosol in Treating Thrombosed External Hemorrhoids and Inflammatory External Hemorrhoids

Thrombosed external hemorrhoids and inflammatory external hemorrhoids are common and frequently occurring conditions in clinical proctology. Based on the principles of traditional Chinese medicine’s syndrome differentiation and treatment, we have achieved good therapeutic effects by using Zhutongning Aerosol to treat pain and edema caused by thrombosed external hemorrhoids and inflammatory external hemorrhoids. The results are reported as follows.

Keywords:

06-30

2020

Clinical Observation on the Treatment of Anal Pruritus with Zhitongning Aerosol

Anal pruritus is a common, localized skin condition characterized by intense itching. Due to its high prevalence, severe itching, and difficulty in cure, it significantly impairs rest and sleep. Therefore, in clinical treatment, there is a need for an external medication that offers rapid efficacy, a high cure rate, and ease of use. Since 1990, we have conducted comparative studies using Zhutongning aerosol and Mayinglong Musk Hemorrhoid Ointment for the treatment of anal pruritus, achieving satisfactory therapeutic outcomes.

Keywords:

06-30

2020

Production technology for water used in pharmaceutical manufacturing processes

Abstract: Pharmaceutical process water refers to the water used in pharmaceutical manufacturing processes, including drinking water, purified water (i.e., deionized water, distilled water, and water for injection). Keywords: Pharmaceutical process water; Production; Process technology 1. Preparation of Purified Water for Pharmaceutical Use Purified water is water prepared for pharmaceutical use by means of ion exchange, reverse osmosis, distillation, or other suitable methods, without any added substances. 1.1 Preparation Process of Purified Water. Currently, there are four main preparation processes for purified water used in pharmaceutical enterprises: 1.1.1 Pre-treatment Stage: The first step involves adding a coagulant to promote the aggregation of colloidal particles in the water, which can remove some iron, manganese, fluorine, and organic substances. Commonly used coagulants include ST high-efficiency coagulant and polyaluminum chloride; sometimes polyacrylamide is added to enhance the coagulation effect. 1.1.2 Surface Water Clarification Agent This process is suitable for river water with turbidity below 30 and ordinary tap water. After treatment, the turbidity of the clarified water can generally be reduced to below 1. 1.1.3 Simultaneous Removal of Turbidity, Organic Substances, and Residual Chlorine from Raw Water: If the raw water has high levels of organic substances (COD) and residual chlorine, the following process is adopted: Among these, the multi-media filter mainly removes suspended solids and mechanical impurities from the water, reducing the effluent turbidity to meet the water quality requirements for subsequent deep purification and desalination systems. The activated carbon filter uses granular activated carbon as the filter medium to adsorb organic substances, residual chlorine, and colloids, reducing color and turbidity and ensuring the normal operation of downstream systems. The precision filter, with filtration accuracies of 1 μm, 5 μm, and 10 μm, is a highly efficient and low-resistance deep filtration method that can be used as a security filter for membrane separation systems. 1.2 Equipment and Principles for Purified Water Production 1.2.1 Ion Exchange Column: For production capacities below 5 m³/h, commonly made of acrylic glass with a height-to-diameter ratio of 5:10; when the production capacity is larger, the material is often steel-reinforced acrylic glass or composite fiberglass-acrylic glass, with a height-to-diameter ratio of 2:5. The resin layer height accounts for about 60% of the cylinder height. The upper drain port is used to vent air during operation and to discharge waste during regeneration and backwashing. The lower drain port is used before operation to introduce compressed air to loosen the resin and during forward washing to discharge waste. The operation of cation and anion exchange columns can be divided into four steps: water production, backwashing, regeneration, and forward washing. 1.2.2 Electrodialyzer: Under the action of an external DC electric field, utilizing the selective permeability of ion exchange membranes to ions in the solution, positive and negative ions migrate through the anion and cation exchange membranes respectively, achieving desalination or concentration. The electrodialyzer consists of anion and cation exchange membranes, spacers, electrodes, and clamping devices. Ion exchange membranes can be classified into homogeneous membranes, semi-homogeneous membranes, and conductive membranes. Conductive membranes are used for pure water, made by hot-pressing ion exchange resin powder onto nylon mesh and fixing it onto a polyethylene membrane; the membrane thickness is typically 5 mm. The cation membrane is polyethylene-styrene sulfonic acid type, while the anion membrane is polyethylene-styrene quaternary ammonium type. The cation membrane allows only cations to pass through, while the anion membrane allows only anions to pass through. 1.2.3 Reverse Osmosis: Reverse osmosis actually removes impurities from water by passing it through a semi-permeable membrane, thus obtaining purified water. Although the conventional concept of osmosis refers to the natural movement of a concentrated solution toward a dilute solution, here it relies on external pressure to force water through the membrane, while impurities are blocked by the membrane, causing the concentration of impurities in the original water to increase continuously—hence the term "reverse osmosis." The structure of a reverse osmosis device is exactly the same as that of a general microporous membrane filtration device, but it requires higher pressure (typically 2.5–7 MPa), so its structural strength must be high. The water permeability is relatively low, so the membrane area per unit volume in a reverse osmosis device is usually large. 2. Preparation of Water for Injection Water for injection can be prepared using distillation machines or reverse osmosis. The purity of water for injection is similar to that of purified water, but the main difference is that water for injection contains no microorganisms or pyrogens. 2.1 Preparation Process of Water for Injection Process I uses purified water as feedwater and prepares distilled water for injection by distillation, which is included in pharmacopoeias of various countries and is the most commonly used method for preparing water for injection abroad. Distillation effectively removes bacteria, pyrogens, and most other organic substances from water. China is currently replacing the original single-effect tower distillation machines with multi-effect distillation machines, greatly reducing steam and cooling water consumption, meeting GMP requirements, and offering a simple, reliable, and easy-to-implement method whose indicators all comply with Chinese pharmacopoeia standards. Process II is a new technology developed in the 1970s, which uses reverse osmosis combined with ion exchange to produce high-purity water, then employs ultrafiltration to remove pyrogens, followed by UV sterilization and finally microfiltration through a microporous membrane to obtain water for injection. This process has lower operating costs, but is affected by membrane technology levels; it has not yet been widely used for preparing injectable solutions in China, though it can be applied for washing vials or preparing animal injections. The U.S. Pharmacopoeia [19th Edition] has already included the reverse-osmosis method for preparing water for injection. 2.2 Equipment for Water for Injection: Distillation machines can be divided into two major categories: multi-effect distillation machines and atmospheric-pressure distillation machines. Multi-effect distillation machines can further be classified into tube-type, coil-type, and plate-type. Plate-type machines are not yet widely used. 2.2.1 Tube-Type Multi-Effect Distillation Machine: The tube-type multi-effect distillation machine is equipment that uses multi-effect evaporation in tubular form to produce distilled water. The number of effects in multi-effect distillation machines is usually between 3 and 5; when there are more than 5 effects, the reduction in steam consumption is not significant. 2.2.2 Tower-Type Multi-Effect Distillation Machine: This type of evaporator is a shell-and-tube falling-film evaporator, also known as a coil-type multi-effect distillation machine. The evaporation heat transfer surface is in the form of a coil, with a feed-water distributor at the top of the coil to evenly distribute the feed water over the outer surface of the coil. After absorbing heat, part of the water evaporates, and the secondary steam, after being separated from mist droplets by a demister, is sent through a conduit to serve as the heat source for the current effect. The unevaporated water flows down through a throttling hole at the bottom into the distributor of the next effect, where it continues to evaporate. This distillation machine has advantages such as high heat transfer coefficient, no need for support brackets during installation, and stable operation. 2.2.3 Atmospheric-Pressure Distillation Machine: The atmospheric-pressure distillation machine treats raw water that has already reached drinking water standards. The raw water enters the preheater through the inlet pipe and is pumped into the tubes of the evaporation-condensation unit, where it is heated and evaporated. 2.2.4 Ultrafiltration: Ultrafiltration is a selective membrane separation process whose filtering medium is called an ultrafiltration membrane, generally made of polymer materials. The pore size of ultrafiltration membranes is approximately 2–54 μm, lying between the pore sizes of microporous membranes and reverse osmosis membranes, and can effectively remove impurities from the source water, such as colloidal macromolecules and pyrogens. The filtration process of an ultrafiltration system uses tangential flow technology, also known as cross-flow technology, allowing the filtrate to flow tangentially across the membrane surface during filtration, significantly reducing the rate of membrane failure and facilitating backflush cleaning, thereby greatly extending the service life of the membrane and providing considerable regenerative and continuous operability. These characteristics indicate that ultrafiltration technology is highly effective when applied to water filtration processes. Unlike reverse osmosis, which relies on osmosis, ultrafiltration separates substances mechanically. Ultrafiltration membranes allow salts and other electrolytes to pass through, while colloids and substances with larger molecular weights are retained. Membrane cleaning for ultrafiltration: After prolonged operation, contaminants and gel-like deposits gradually accumulate on the membrane surface, becoming compacted under water pressure, increasing the operating resistance of the device and reducing the membrane's water permeability. Special chemical treatments are often required to clean the membrane surface. Cleaning methods include physical and chemical approaches. Physical methods mainly involve vigorous flushing and backwashing of the membrane surface. Chemical methods should only be used when physical cleaning cannot meet the requirements. Chemical cleaning methods, according to their nature of action, are divided into acidic cleaning, alkaline cleaning, redox cleaning, and enzymatic cleaning. Among them, acidic cleaning often uses 0.1 mol/L oxalic acid solution or 0.1 mol/L hydrochloric acid solution; alkaline cleaning mainly uses 0.1%–0.5% NaOH aqueous solution. Redox cleaning is mainly used to remove organic contamination, employing 1%–1.5% H₂O and 0.5%–1% NaCl; enzymatic cleaning is primarily used to remove oils and proteins, using trypsin and pepsin as cleaning agents. Key considerations for ultrafiltration systems include: the adaptability of membrane materials to disinfectants; the integrity of the membrane; contamination caused by particulates and microorganisms; retention of pollutants by cartridge filters; and the integrity of seals. References [1] Lin Hai. A Brief Analysis of Pharmaceutical Process Water (J). Chongqing Journal of Chinese Herbal Medicine Research, 1999(2). [2] Weng Liu Jing. Optimization and Improvement of Pharmaceutical Water System Design [D]. Tianjin: Tianjin University, 2004.

Keywords:

06-30

2020

Tablet Manufacturing Process Technology, Procedures, and Cleanroom Zoning

Abstract: This paper mainly analyzes the production technology, process flow, and cleanroom zoning techniques for tablet manufacturing. Keywords: Tablet production; Process flow; Cleanroom 1 Overview of Tablets Tablets refer to solid dosage forms made by compressing medicinal extracts or a mixture of medicinal extracts and fine powdered medicinal materials combined with suitable excipients into round or irregularly shaped tablets. They include semi-solid tablets, semi-solid tablets, and fully powdered tablets. Tablets can be produced by compression or molding methods and may or may not contain diluents. Since the 19th century, tablets have been widely used and remain popular. Although the basic operational procedures for tablet production have remained largely unchanged, the tablet manufacturing processes have significantly improved. Continuous efforts have been made to further understand the physical properties of powders and factors affecting the bioavailability of dosage forms after oral administration. Equipment has also been continuously upgraded, particularly in terms of tablet compression speed and uniformity. Although tablet shapes vary widely—ranging from round, oval, rectangular, cylindrical, to triangular—they differ greatly in size and weight depending on the dose of the active ingredient and the intended method of administration. Based on whether they are compressed or molded, tablets can be divided into two main categories. Compressed tablets are typically produced on a large scale, while molded tablets are usually manufactured on a smaller scale. Due to their lower production volume and the need for drying or sterile conditions during manufacture, molded tablets have gradually been replaced by other production methods or dosage forms and are now relatively rare. 1.1 Characteristics of Tablets. Tablets offer numerous advantages, including: (1) Accurate dosing—The dose and content of the drug within each tablet strictly adhere to the prescription, with minimal variation in content, ensuring patients take the correct dose; pharmaceutical manufacturers can also press grooves onto tablets, allowing them to be split into halves or quarters, making it easy to take smaller doses without losing accuracy; (2) Stable quality—Tablets remain intact and do not deform during normal transportation and storage, maintaining their drug content over an extended period. As dry solid dosage forms, tablets have a small volume after compression, and their surface area exposed to light, air, moisture, and dust is relatively small, thus minimizing stability issues; (3) Convenient administration—Tablets contain no solvents and are compact in size, making them easy to swallow and carry; their surfaces are generally smooth and attractive, and drugs with unpleasant colors, flavors, or odors can be coated to mask these characteristics; (4) Easy identification—Tablets can be stamped with the name and content of the active ingredient, or colored differently for easy recognition; (5) Low cost—Tablets can be mass-produced using automated machinery, hygiene conditions are easy to control, and packaging costs are low. However, tablets also have several drawbacks, such as: (1) Not suitable for children and unconscious patients to swallow; (2) If prepared or stored improperly, they may gradually degrade, leading to poor disintegration or dissolution in the gastrointestinal tract; (3) Tablets containing volatile ingredients may lose potency over time if stored for too long. 1.2 Quality Requirements for Tablets. High-quality tablets generally require: (1) Accurate content and minimal weight variation; (2) Proper hardness and disintegration time; (3) Uniform color and attractive appearance; (4) Stability over the specified period; (5) Compliance with dissolution rate and bioavailability requirements; (6) Compliance with hygienic inspection standards. These requirements include specific requirements for individual products, clearly stipulated in pharmacopoeias and national drug standards, thereby ensuring medication quality. 2 Tablet Production Technology and Process Flow The properties of a tablet are influenced by both its formulation and manufacturing method, and there is considerable similarity between these two factors. An appropriate formulation can produce satisfactory tablets; therefore, it must be designed according to the required specifications, favorable conditions, manufacturing methods, and available equipment. The main unit operations involved in tablet preparation include crushing, sieving, weighing, mixing (solid-solid, solid-liquid), granulation, drying, tableting, coating, and packaging. The preparation methods can be categorized into wet granulation, dry granulation, and direct compression. Since the preparation process involves crushing, sieving, and tableting, temperature and humidity must be controlled in the production environment. For some products, temperatures must be kept at low levels, and cross-contamination between materials during crushing should be carefully avoided. 2.1 Crushing and Sieving 2.1.1 Crushing. Crushing is primarily the mechanical process of breaking down large solid materials into particles of an appropriate size. In the pharmaceutical industry, other methods can also be used to reduce solid drugs to fine powders. 2.1.2 Sieving. (1) Sieving. After crushing, drug powders vary greatly in particle size. To meet requirements and separate coarse and fine particles, the operation of separating them is called sieving, and the mesh-like tool used is called a sieve or strainer. (2) Types of drug sieves. Drug sieves refer to standardized sieves uniformly used across the country for pharmaceutical production as specified in pharmacopoeias, also known as standard sieves. In actual production, except for certain research purposes, industrial sieves are also commonly used. The selection of such sieves should closely match the standards of drug sieves and not affect the quality of the pharmaceutical product. The performance and standards of drug sieves depend mainly on the sieve mesh. According to the manufacturing method, sieves can be divided into woven sieves and punched sieves. Woven sieves are made by weaving copper wire, iron wire, stainless steel wire, nylon wire, or silk thread; some are even woven from horsehair or bamboo strips. During use, the wires of woven sieves tend to shift, so the intersections of metal wires are often flattened and fixed. Punched sieves are made by punching circular or polygonal holes into metal plates; these sieves are sturdy and durable, with stable hole sizes, but cannot have very fine pores and are mostly used in high-speed crushing and sieving machines. Fine powders are generally screened using woven sieves or air classification methods. 2.2 Blending and Mixing. In tablet production, the active pharmaceutical ingredient powder and excipients must be weighed according to the prescription and then mixed several times to ensure tablet quality. Variations in tablet content, disintegration time, hardness changes, and segregation phenomena are often caused by improper mixing. The active pharmaceutical ingredient and excipients are not uniformly mixed in one step. First, an appropriate amount of diluent is added for dry mixing, followed by the addition of binders and wetting agents for wet mixing, producing a soft and pliable material. 2.3 Granulation. Except for certain crystalline drugs or powders suitable for direct compression, most powdered drugs must first be granulated before being compressed into tablets. This is because: (1) There is a certain amount of air trapped between powder particles; when the punch applies pressure, some of this air cannot escape in time and gets compressed into the tablet. When the pressure is removed, the air inside the tablet expands, causing the tablet to crack; (2) Some fine drug powders are loose and tend to clump together, with poor flowability, making it difficult for them to smoothly enter the die cavity through the feed hopper, thus affecting weight uniformity and leading to inaccurate tablet content; (3) If the prescription contains several raw and excipient powders with significant density differences, during compression, the vibration of the tablet press can cause heavier particles to sink and lighter ones to rise, resulting in layering and inaccurate content; (4) The airflow generated during compression can easily cause fine powders to fly around, and sticky fine powders tend to adhere to the punch surface, often causing sticking. Therefore, it is essential to reasonably select excipients based on the different properties of the drug, equipment conditions, and climate to produce granules of appropriate coarseness and firmness to overcome these problems. 2.4 Drying. Drying is a process that uses thermal energy to remove moisture or other solvents from wet solid materials or pastes, obtaining dried products. In pharmaceutical production, drying is used to remove water from fresh herbs, dehydrate raw and excipient materials, and prepare aqueous solutions, tablets, and granules (instant powders). Within a reasonable range, increasing the humidity of the air can raise the surface temperature of the material, accelerating the evaporation rate and facilitating drying. However, the appropriate drying temperature must be selected according to the nature of the material to prevent the destruction of heat-sensitive components. The lower the relative humidity of the air, the faster the drying rate. Reducing the relative humidity in a confined space can improve drying efficiency. In actual production, desiccants such as quicklime or silica gel are often used to absorb water vapor from the space, or ventilation and blowing devices are employed to renew the air flow. The higher the air flow rate, the faster the drying rate. However, the air flow rate has almost no effect on the falling-rate drying stage. This is because increasing the air flow rate reduces the thickness of the gas film and lowers the resistance to surface vaporization, thus increasing the drying rate during the constant-rate stage. The air flow rate does not affect internal diffusion and is therefore irrelevant to the drying rate during the falling-rate stage. 3 Cleanroom Zoning for Tablet Production Tablet workshops can be divided into "controlled areas" and "general production areas" according to their process flow. The "controlled area" includes production zones for crushing and blending, mixing, tableting, coating, and packaging. Other production areas belong to the "general production area." All air entering the "controlled area" must pass through primary and secondary double-effect filters to remove dust. According to GMP requirements, the cleanliness level of the "controlled area" must not exceed Class 300,000. References [1] Tian Yingna, Zhao Tongshuang, Sun Jianxun. FMEA Analysis of Granulation Process Risks in Oral Solid Dosage Forms [C]. Proceedings of the 2012 Annual Meeting of the Pharmaceutical Management Professional Committee of the Chinese Pharmaceutical Association and the Academic Symposium on the Scientific Development of Pharmaceuticals during the 12th Five-Year Plan (Volume II), 2012. [2] Zhao Yu, Peng Xiaoxia. Common Methods for Masking Unpleasant Odors in Oral Preparations [J]. Gansu Science and Technology Review, 2007(1).

Keywords:

06-30

2020

Mado Ming Aerosol for Relief of Angina Pectoris and Hemodynamic Observations

　　Molidomine (molydomicine, molisidomine) is an imine-based vasodilator. There are numerous reports on its oral administration for the treatment of angina pectoris and heart failure; however, there have been no reports yet on its use via aerosol to relieve angina attacks. This study aims to verify its efficacy and explore its underlying mechanisms. Subjects and Methods 1.1 Subjects From February to June 1995, 73 hospitalized patients at our hospital were selected according to the International Society and Association for Cardiology and WHO criteria for ischemic heart disease. The patients included 40 cases of stable exertional angina, 20 cases of worsening exertional angina, and 13 cases of mixed-type angina. They were randomly divided into two groups: the Molidomine group (n=39), aged 57±10 (39–69) years, with 21 cases having a history of old myocardial infarction; and the Yishunmai group (n=34), aged 58±9 (37–72) years, with 17 cases having a history of old myocardial infarction. Among the 73 patients, 23 had coronary angiography showing stenosis of at least one coronary vessel lumen diameter ≥50%, including 3 cases with single-vessel disease, 6 cases with double-vessel disease, and 14 cases with triple-vessel disease. Another 21 patients with coronary heart disease underwent left ventricular and coronary angiography, with left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg serving as the criterion for observing hemodynamic changes. These patients were also randomly divided into the Molidomine group (n=12) and the Yishunmai group (n=9). The ages of the two groups were 53±10 (38–69) years and 51±13 (33–67) years, respectively, and they had 9 and 6 cases of old myocardial infarction, respectively. 1.2 Observation Methods 1.2.1 Study Drugs: Molidomine aerosol as the test drug, and Yishunmai aerosol (Xinxintong, manufactured by Mahler Pharma, Germany) as the control drug. 1.2.2 Observation Period: All patients continued their regular anti-anginal medications without any changes. When an angina attack occurred, heart rate and blood pressure were immediately measured, and an electrocardiogram was recorded. Patients in each group received either Molidomine aerosol at a dose of 1.0–1.4 mg or Yishunmai aerosol at a dose of 1.25–2.5 mg, according to random assignment. After symptom relief, heart rate, blood pressure, and ECG were re-measured. If symptoms did not improve within 10 minutes after medication, sublingual nitroglycerin or Xintong was immediately administered, or analgesics were given. 1.2.3 Hemodynamic Measurements: A 6F or 7F pigtail catheter was inserted through the femoral artery into the left ventricle to measure pressure. For patients with LVEDP ≥16 mmHg, Molidomine or Yishunmai aerosol was administered according to random group assignment at the same doses as before. Left ventricular pressure curves were recorded at baseline, and at 2, 5/7, and 10 minutes after medication. 1.3 Evaluation of Anti-Anginal Drug Efficacy In this group, the degree of angina improvement after medication was classified as follows: Excellent: Complete relief of symptoms; Effective: Significant relief of symptoms without the need for a second medication; Ineffective: No obvious relief of symptoms, requiring additional anti-anginal measures. 1.4 Statistical Methods Changes in the same indicators before and after medication were analyzed using repeated-measures ANOVA. Group differences were compared using t-tests and ANOVA. Results 2.1 Symptom Relief and ST-Segment Shift Changes The fastest onset time for Molidomine aerosol was 70 seconds, while that for Yishunmai aerosol was 55 seconds. Comparing the two groups in terms of angina relief and ST-segment shift recovery, there were no significant differences between the groups (P>0.05). 2.2 Heart Rate and Blood Pressure Changes During angina attacks and after symptom relief, the heart rates in the Molidomine group were 75±10 and 73±11 beats/min, respectively, while those in the Yishunmai group were 78±19 and 75±9 beats/min. There were no significant differences in heart rate between the two groups during or after symptom onset (P>0.05). During angina attacks and after medication, blood pressures in the Molidomine group were 130±20/79±10 mmHg and 126±19/77±11 mmHg, respectively, while those in the Yishunmai group were 132±20/79±8 mmHg and 125±16/76±13 mmHg. The only significant difference was observed in systolic blood pressure between the two groups during and after symptom onset (P<0.05). The product of heart rate and systolic blood pressure (HR×SBP-2) showed significant differences between the two groups during and after symptom onset: 97.50±22 and 91.98±24 in the Molidomine group (P<0.05), and 102.96±31 and 93.75±22 in the Yishunmai group (P<0.05). 2.3 Left Ventricular Pressure Changes Compared with the Yishunmai group, the Molidomine group showed no significant differences in heart rate, left ventricular systolic pressure (LVSP), and LVEDP changes after medication (P>0.05). There was no significant difference in LVSP between the two groups before medication (P>0.05). After medication, the Molidomine group showed a decrease of 10.5 mmHg at 5 minutes (P>0.05), while the Yishunmai group showed a decrease of 9.5 mmHg. Compared with baseline, both groups showed significant pressure reductions (P<0.05 and P<0.01). The maximum pressure reduction was greater in the Yishunmai group than in the Molidomine group: 6.6 mmHg in the Molidomine group versus 13.4 mmHg in the Yishunmai group, indicating that the Yishunmai group had a significantly greater pressure-lowering effect than the Molidomine group (P<0.05). 2.4 Side Effects In the Molidomine group, 2 cases and in the Yishunmai group, 4 cases reported mild dizziness, which quickly resolved. One case in the Yishunmai group reported mild headache 3 minutes after medication, but no other side effects were reported. Discussion Molidomine is a non-nitrate vasodilator. In this study, the dosage used via aerosol, the onset time for angina relief, the effectiveness rate, and the improvement in ECG findings were similar to those of Yishunmai. After medication, Molidomine caused a slight drop in blood pressure compared to the angina attack, but the blood pressure remained within the normal range. The drop in blood pressure might be due to the combined effects of the drug's dilation of resistance arterioles and the reduced sympathetic nerve activity after symptom relief. The mechanism by which Molidomine relieves angina is generally recognized as similar to that of nitrates. Its main action is to strongly dilate venous vessels, reducing left ventricular preload and myocardial oxygen consumption. It also dilates narrowed coronary arteries and collateral vessels. In this study, the decrease in LVEDP and myocardial oxygen consumption after Molidomine administration were consistent with those observed after Yishunmai, supporting the above view. However, the cellular mechanisms differ: nitrates dissociate into inorganic nitrites, requiring sulfhydryl (SH) groups to form nitric oxide (NO), which activates intracellular guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) and thereby reducing intracellular calcium levels and relaxing smooth muscle. In contrast, the metabolite of Molidomine (R-NNO) releases NO without the need for SH groups. Some authors suggest that one of the mechanisms behind nitrate tolerance is the depletion of SH groups; therefore, there is no cross-tolerance between these two drugs. When patients develop tolerance to nitrates, Molidomine can be tried instead. Molidomine has a longer duration of action—up to 6–7 hours—allowing it to provide prolonged preventive effects after symptom relief, whereas Yishunmai has a shorter duration of action, lasting only 30–60 minutes. Although Molidomine’s reduction in LVEDP is less pronounced than that of Yishunmai, in patients with chronic left ventricular dysfunction who have developed tolerance to Yishunmai over time, Molidomine can be used in combination with Yishunmai. In summary, Molidomine aerosol demonstrates definite clinical efficacy, rapid onset of action, long-lasting effects, few adverse reactions, mild symptoms, no development of tolerance, and is safe for long-term use.

Keywords:

06-30

2020

Discussion on the non-carcinogenic risk of Mordom.

Abstract: Moxonidine can be used in the treatment of both chronic and acute heart failure and may help prevent myocardial infarction. Currently, foreign literature reports that moxonidine has carcinogenic effects; studies have shown that its metabolite, morpholine, is carcinogenic. Therefore, when using moxonidine as an active ingredient in pharmaceutical preparations, it is crucial to strictly control the content of the impurity morpholine and to choose sublingual or inhalation administration routes to avoid the formation of morpholine. Keywords: Moxonidine, Morpholine, Carcinogenicity Moxonidine, also known as Pulsedamine, Moadamine, Pulsumedamine, or Moketamine, has the chemical name N-(ethoxycarbonyl)-3-(4-morpholinyl)stevanilimine, with the molecular formula C9H14O4N4. It belongs to the imine class of compounds and is a calcium antagonist. This product has currently been approved for production in countries including China, Austria, Belgium, France, Germany, Italy, Spain, Switzerland, and Japan. I. Mechanism of Action of Moxonidine Moxonidine directly relaxes the smooth muscle of capacitance vessels, especially venous and small venous vessels, causing a mild decrease in blood pressure, reducing venous return and cardiac output, lowering the preload on the heart, decreasing left ventricular filling pressure and end-diastolic left ventricular pressure, reducing ventricular wall tension, and decreasing myocardial oxygen consumption. Moxonidine also dilates coronary arteries and arterioles, mildly reducing afterload on the heart and lowering pulmonary arterial pressure. The reduction in systolic blood pressure is more pronounced than that in diastolic blood pressure, increasing coronary blood flow, improving blood supply to the subendocardial myocardium, promoting collateral circulation, and animal experiments have confirmed its ability to reduce the area of experimental myocardial infarction. II. Clinical Applications of Moxonidine Moxonidine can be used in the treatment of both chronic and acute heart failure. According to Larbig et al. (1985), treating chronic heart failure with moxonidine at 4 mg four times daily can reduce pulmonary artery and pulmonary capillary congestion, adjust atrial blood pressure, and improve cardiac output without significantly altering systemic blood pressure. According to Reifart et al., in cases of acute left heart failure caused by myocardial infarction, moxonidine treatment has demonstrated beneficial hemodynamic effects, moderately reducing pulmonary artery and diastolic cardiac pressures, thereby alleviating disease symptoms. According to Gryglewaki et al. (1993)[1], moxonidine’s molecular formula is C9H14O4N4, and its structure contains multiple NO groups. Modern pharmacological studies have shown that NO groups possess various physiological activities, such as coronary vasodilation, nerve excitation, and anti-disease effects. Thus, moxonidine is an excellent supplier of NO groups, capable of treating myocardial ischemia and enhancing myocardial protective capacity. It can serve as a therapeutic agent for both acute and chronic heart failure. According to Polish scholar Giedrojc et al.[2], moxonidine is a blood vessel dilator, particularly acting as a specific endothelium-derived relaxing factor (EDRF). In experimental animals, moxonidine has shown good antithrombotic effects and ranks among the best compared to other drugs. According to Indian scholar Dikshit et al.[3], moxonidine has demonstrated good efficacy in treating pulmonary thrombosis in experimental animals. The Martindale's Pharmaceutical Reference also lists moxonidine as a drug for the prevention of myocardial infarction. III. Research on the Carcinogenicity of Moxonidine Currently, foreign literature reports that moxonidine has carcinogenic effects. The primary basis for this claim is that after oral administration, moxonidine is metabolized by the liver into morpholine, a compound that is carcinogenic. In response, foreign studies have conducted related research on the carcinogenicity and toxicity of morpholine. Experimental data show that when rodents—mice—are orally administered 2560 mg/kg of morpholine, it can induce carcinogenicity, leading to bronchial cancer and liver cancer (specific data are shown in Table 1 below). However, moxonidine itself does not have carcinogenic properties; only after oral administration and subsequent hepatic metabolism producing morpholine, and reaching a certain concentration of morpholine, can carcinogenic effects occur. Therefore, during the development of moxonidine raw materials, strict regulations are imposed on the impurity morpholine to minimize carcinogenic risk, requiring that the morpholine impurity level must not exceed 0.01%. During formulation development, to further reduce the carcinogenic risk of the product, administration routes that bypass hepatic metabolism and directly enter the bloodstream are adopted, such as rectal administration, respiratory administration, or mucosal administration. These administration routes do not involve hepatic metabolism, thus eliminating the carcinogenic risk of moxonidine. Currently, commonly available moxonidine formulations on the market include moxonidine tablets and moxonidine aerosols. The specification of moxonidine aerosol is 1%, with each bottle weighing 14 g and containing 200 puffs, each puff delivering 140 mg of moxonidine (0.7 mg per puff). Its active ingredient, moxonidine, is administered via the respiratory tract, absorbed by the alveoli, directly entering the bloodstream without undergoing hepatic metabolism, and being excreted directly by the kidneys without forming the metabolite morpholine. Therefore, moxonidine aerosol carries no carcinogenic risk and can be widely used for the prevention and treatment of angina pectoris, especially effectively reducing the frequency of angina attacks, bringing peace and relief to angina patients. Table 1: Toxicity Test Data for Morpholine | No. | Toxicity Type | Test Method | Test Subject | Dosage Used | Toxic Effects | |-----|---------------|-------------|--------------|-------------|---------------| | 1 | Acute Toxicity | Oral | Rodents—Rats | 1450 mg/kg | No detailed toxic side effects reported beyond lethal dose values | | 2 | Acute Toxicity | Inhalation | Rodents—Rats | 8000 ppm/8H | No detailed toxic side effects reported beyond lethal dose values | | 3 | Acute Toxicity | Oral | Rodents—Mice | 525 mg/kg | 1. Behavioral toxicity—Sleepiness<br>2. Behavioral toxicity—Lethargy | | 4 | Acute Toxicity | Inhalation | Rodents—Mice | 1320 mg/m3/2H | 1. Ocular toxicity—Tearing<br>2. Behavioral toxicity—Ataxia<br>3. Pulmonary, thoracic, or respiratory toxicity—Yellowing | | 5 | Multiple Dose | Oral | Rodents—Rats | 24 mg/kg/30D-I | 1. Gastrointestinal toxicity—Necrosis<br>2. Renal, ureteral, and bladder toxicity—Kidney, ureter, bladder (including acute renal failure, acute tubular necrosis)<br>3. Chronic disease-related toxicity—Death | | 6 | Multiple Dose | Inhalation | Rodents—Rats | 70 mg/m3/4H/17W-I | 1. Vascular toxicity—Reduced autonomic nervous regulation<br>2. Hematologic toxicity—Changes in white blood cell count | | 7 | Multiple Dose | Oral | Rodents—Guinea pigs | 13500 mg/kg/30D-I | 1. Gastrointestinal toxicity—Necrosis<br>2. Renal, ureteral, and bladder toxicity—Kidney, ureter, bladder abnormalities (including acute renal failure, acute tubular necrosis)<br>3. Chronic disease-related toxicity—Death | | 8 | Multiple Dose | Inhalation | Rodents—Guinea pigs | 70 mg/m3/4H/17W-I | 1. Hepatic toxicity—Liver function abnormalities<br>2. Renal, ureteral, and bladder toxicity—Changes in urinary components | | 9 | Carcinogenicity | Oral | Rodents—Mice | 2560 mg/kg/Y-C | 1. Carcinogenicity—Carcinogenesis<br>2. Pulmonary, thoracic, or respiratory toxicity—Bronchial cancer<br>3. Hepatic toxicity—Liver cancer | References [1] Gryglewaki, R. J, Swiee J, Chlopickis. Cardioprotective effect of moxonidine on iloprost-induced myocardial ischemia in cats. J PhyaiolPharmacol, 1993, 44(3):313. [2] Giedrojc Jan, Bielawiec Michal, Jaromin Jacek. The role of moxonidine combined with different antithrombotic agents in laser-induced thrombosis. Mater Med Pol (Engl. Ed), 1993, 25(3-4):153. [3] Dikshit M, Seth P, Srimal R C. Effect of moxonidine and free radical scavengers on pulmonary thromboembolism in mice. Thromb Rea, 1993(4):317.

Keywords:

06-30

2020

< 1 > proceed page
Heilongjiang Fulekang Pharmaceutical Co., Ltd.

Contact Address: No. 3 Yingbin Road, Niuji Industrial Park, Hanan Industrial New City, Harbin City, Heilongjiang Province

Fax: 0451-55893328

Domestic:0451-55893326-6023 13354500470

International:0451-55893326-6020

Personnel:0451-55893326-6002

Mobile phone:18845760808(WeChat same number)

Email:978590540@qq.com

Postal Code: 150221

Heilongjiang Fulekang Pharmaceutical Co., Ltd.

Copyright © 2026 Heilongjiang Fulekang Pharmaceutical Co., Ltd.

COOKIES

Our website uses cookies and similar technologies to personalize the advertising shown to you and to help you get the best experience on our website. For more information, see our Privacy & Cookie Policy

COOKIES

Our website uses cookies and similar technologies to personalize the advertising shown to you and to help you get the best experience on our website. For more information, see our Privacy & Cookie Policy

These cookies are necessary for basic functions such as payment. Standard cookies cannot be turned off and do not store any of your information.

These cookies collect information, such as how many people are using our site or which pages are popular, to help us improve the customer experience. Turning these cookies off will mean we can't collect information to improve your experience.

These cookies enable the website to provide enhanced functionality and personalization. They may be set by us or by third-party providers whose services we have added to our pages. If you do not allow these cookies, some or all of these services may not function properly.

These cookies help us understand what you are interested in so that we can show you relevant advertising on other websites. Turning these cookies off will mean we are unable to show you any personalized advertising.

Website : 300.CN | SEO tags | Privacy Policy

Website : 300.CN | SEO tags | Privacy Policy

Business license