Low-temperature forming process of zedoary turmeric oil and borneol compound gynecological suppository

Abstract

The invention is applicable to the technical field of pharmaceutical preparation forming, and provides a low-temperature forming process of a zedoary turmeric oil-borneol compound gynecological suppository, which comprises the following steps: pretreating raw materials; carrying out pre-cooling dispersion treatment; performing low-temperature mixing; performing dynamic pressure forming; performing temperature control post-treatment; finishing a finished product; according to the invention, the retention rate of effective components is greatly increased, the clinical curative effect of the preparation is guaranteed, and the problem of volatilization loss caused by strong volatility and sublimability of zedoary turmeric oil and borneol in the prior art is solved; the forming uniformity and the quality stability are remarkably optimized, the medication experience and the drug effect release efficiency are improved, and the quality problems of uneven mixing, forming defects and the like of an existing process are solved; the process suitability and the large-scale production capacity are comprehensively enhanced, the industrial supply requirement is met, and the problems that in an existing process, all links are independently controlled, parameters depend on experience, and large-scale production is difficult to adapt are solved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation molding technology, and particularly relates to the low-temperature molding process of turmeric oil and borneol compound gynecological suppositories. Background Technology

[0002] The compound preparation of Curcuma zedoaria oil and borneol has pharmacological activities such as promoting blood circulation, removing blood stasis, clearing heat and detoxifying, reducing swelling and relieving pain. It is one of the commonly used preparations for local treatment of gynecological inflammation. As the superior dosage form of this compound, suppositories can directly act on the lesion, avoid the first-pass effect of oral administration, have high bioavailability, and have significant value in clinical application.

[0003] Chinese Patent (Publication No.: CN103479958A) discloses a drug and its preparation method, particularly relating to a suppository for treating gynecological diseases and its preparation method. The suppository for treating gynecological diseases is prepared from the following raw materials in the stated weight proportions: 82 parts of Curcuma zedoaria oil, 75 parts of borneol, 1340-1360 parts of stearin, 15.5 parts of laurocapram, and 77.5 parts of 95% ethanol. This invention preferably uses a lipid-soluble matrix as the suppository matrix to prepare a suppository for treating gynecological diseases, which has the characteristics of low irritation, good stability, easy storage, resistance to moisture absorption and deformation, convenient transportation and use, short onset time, and long duration of effect; however, this method has the following shortcomings: Active ingredients are easily lost due to volatilization: This scheme adopts a conventional low-temperature treatment mode and does not design a temperature control-dispersion synergistic mechanism specifically for the characteristics of Curcuma zedoaria oil (containing volatile curcumol and curcumone) and borneol (strong sublimation). During the raw material processing, the active ingredients have a large contact area with air, and the volatilization power is not specifically suppressed, which leads to the easy volatilization and loss of active ingredients, affecting the actual efficacy of the preparation. Poor molding uniformity and unstable formulation quality: This scheme does not take into account the differences in physical properties (density, polarity, flowability) of Curcuma zedoaria oil (oily), borneol (solid crystal), and stearin matrix. The mixing process lacks a compatibility control mechanism, making it difficult to achieve uniform dispersion of the three components. Furthermore, the molding stage uses the traditional constant pressure mode, which does not consider the volume shrinkage characteristics of materials at low temperatures. This makes it impossible to fill the internal voids caused by shrinkage, which can easily lead to problems such as uneven internal density of suppositories, surface defects, and excessive weight differences, affecting the consistency of drug delivery experience and efficacy release. Insufficient process adaptability, making it difficult to scale up production: Each step of the process in this solution is independently controlled, lacking a coordinated control logic. Parameter adjustments rely on manual experience and no precise mathematical control model has been established. When faced with batch differences in raw materials (such as fluctuations in the purity of Curcuma zedoaria oil and differences in borneol particle size) and fluctuations in ambient temperature, parameter imbalances are likely to occur, resulting in low finished product qualification rate and production efficiency, which cannot meet the needs of large-scale clinical supply.

[0004] In addition to the patented solutions mentioned above, other existing low-temperature molding processes for gynecological suppositories containing turmeric oil and borneol have also attempted to improve the process by sealing and mixing, simply adjusting the molding pressure, or changing the matrix. However, none of them have built a synergistic control system of "temperature control-dispersion-mixing-molding-post-processing" at the whole process level, and cannot simultaneously solve the three core problems of volatilization of effective ingredients, poor molding uniformity, and insufficient large-scale adaptability. Therefore, a low-temperature molding process for gynecological suppositories containing turmeric oil and borneol is needed to solve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a low-temperature molding process for a compound gynecological suppository containing turmeric oil and borneol to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: The low-temperature molding process for gynecological suppositories containing turmeric oil and borneol includes the following steps: S1. Raw material pretreatment: Select turmeric oil, borneol, suppository matrix and pharmaceutical excipients, and process them in sequence by crushing, sieving and drying, and control the moisture content of the raw materials to a range suitable for low-temperature molding. S2. Pre-cooling and dispersion treatment: The pre-treated raw materials are placed in a pre-cooling and dispersion device and cooled to a preset low temperature range according to a preset gradient cooling strategy. At the same time, high-frequency dispersion operation is used to complete the initial homogenization of the raw materials. S3. Low-temperature mixing: The pre-cooled and dispersed materials are transferred to a low-temperature mixing device, which maintains a suitable low-temperature environment and mixes them according to dynamically controlled speed and time to obtain a homogeneous mixture. S4. Dynamic pressure molding: The mixture is injected into the suppository molding mold, and molding pressure is applied through the pressure compensation system while maintaining the low temperature required for molding to complete the initial molding of the suppository. S5. Temperature-controlled post-treatment: Gradient heating and subsequent cooling are applied to the pre-formed suppositories, and the processing parameters are adjusted in real time by the temperature control system. S6. Finished Product Processing: The post-processed suppositories are demolded, trimmed, and quality inspected to obtain the finished product, Curcuma zedoaria oil and borneol compound gynecological suppositories.

[0007] In a further technical solution, in step S2, the cooling rate of the gradient cooling strategy satisfies the formula: ; in, for Real-time cooling rate The initial cooling rate, The cooling attenuation coefficient is... The cooling time is specified; the preset low temperature range is -5℃ to 0℃; this gradient cooling strategy can prevent the raw materials from crystallizing and agglomerating due to sudden cooling, reduce the volatilization power of volatile components, and improve the uniformity of the pre-dispersion of the raw materials.

[0008] In a further technical solution, in step S2, the frequency of the high-frequency dispersion satisfies the formula: ; in, for Real-time dispersion frequency at any given moment As the reference dispersion frequency, The initial temperature of the raw materials. for The material temperature is monitored in real time. This frequency control method allows the dispersion intensity to increase synchronously as the temperature decreases, breaking the interaction force between raw material particles and achieving preliminary homogenization of turmeric oil, borneol and matrix.

[0009] In a further technical solution, in step S3, the adapted low-temperature environment temperature is 2℃~3℃ higher than the preset low-temperature range in step S2; the mixing speed satisfies the formula: ; in, For real-time mixing speed, As the reference speed, The coefficient representing the influence of material density. This provides the real-time density of the mixture; the speed control can adapt to changes in material density, improve the uniformity of the mixture's composition, and ensure the stability of subsequent molding quality.

[0010] In a further technical solution, in step S4, the molding pressure applied by the pressure compensation system satisfies the formula: ; in, For real-time forming pressure, As the reference molding pressure, To compensate for the amplitude of the pressure, For pressure fluctuation frequency, The molding time is specified; the required low temperature for molding is -3℃ to 1℃; this dynamic pressure can fill the gaps caused by the low-temperature shrinkage of the material, avoid uneven density inside the suppository, and ensure the regularity of the suppository shape.

[0011] In a further technical solution, in step S4, the temperature difference between the molding die and the required low temperature for molding is ≤ ±0.5℃. The temperature of the die is controlled by a temperature-controlled interlayer, and the thermal conductivity of the temperature-controlled interlayer is... The mold temperature control method can ensure the material temperature is stable during the molding process, avoid the volatilization of active ingredients due to temperature fluctuations, and improve the uniformity of suppository molding.

[0012] In a further technical solution, in step S5, the heating rate of the gradient heating satisfies the formula: ; in, For real-time gradient heating rate, As the reference heating rate, This is the highest post-processing temperature. for The temperature of the suppository is monitored at all times; the post-cooling temperature is -2℃ to 0℃, and the treatment time is 10min to 20min. This heating strategy can slowly release the internal stress of the suppository, avoid cracking and reduce the secondary volatilization of the active ingredients. The post-cooling treatment can fix the shape of the suppository and improve its hardness stability.

[0013] In a further technical solution, in step S1, the suppository matrix is ​​a polyethylene glycol matrix, and the mass ratio of the matrix to turmeric oil and borneol is (5~8):(1~2):(0.5~1); the pharmaceutical excipients include antioxidants, and the amount of antioxidants added is 0.1%~0.3% of the total mass of the raw materials; the ratio of the matrix to the excipients can take into account both the solubility of the active ingredients and the formability of the suppository, and the antioxidants can inhibit the oxidation and deterioration of turmeric oil and extend the shelf life of the preparation.

[0014] A further technical solution is that the core indicators of quality testing in step S6 include the retention rate of effective ingredients, the hardness of the suppository, and the melting time limit. The retention rate of effective ingredients is ≥95%, the hardness is 2.5N~3.5N, and the melting time limit meets the requirements of the suppository section of the Pharmacopoeia of the People's Republic of China. This testing standard can ensure the efficacy, medication comfort, and drug release efficiency of the finished suppository.

[0015] Compared with the prior art, the beneficial effects of the present invention are: This invention significantly improves the retention rate of active ingredients, ensuring the clinical efficacy of the formulation. Addressing the issue of evaporation loss of Curcuma zedoaria oil and borneol due to their high volatility and sublimation in existing processes, this invention achieves stable retention of active ingredients through a dual-technology synergy: Firstly, the pre-cooling dispersion stage employs a formula... A controlled gradient cooling strategy is employed to prevent raw materials from agglomerating due to rapid cooling, thereby reducing volatilization momentum. This is combined with the formula... The high-frequency dispersion frequency linkage regulation shortens the contact time between the effective ingredients and air, and reduces the contact area; on the other hand, the temperature control post-treatment stage uses formulas... The gradient heating strategy slowly releases internal stress, reducing secondary volatilization of active ingredients. Simultaneously, the molding die utilizes a temperature-controlled interlayer with a thermal conductivity ≥200W / (m・K) to achieve precise temperature control within ±0.5℃, avoiding the risk of volatilization caused by temperature fluctuations. The final product retains ≥95% of the active ingredients, far superior to existing processes, fully guaranteeing the pharmacological activity and clinical therapeutic effect of the formulation. This invention significantly optimizes molding uniformity and quality stability, improving the user experience and drug release efficiency. Addressing quality issues such as uneven mixing and molding defects in existing processes, it constructs a comprehensive homogenization guarantee system: In the pre-cooling dispersion stage, the synergistic effect of gradient cooling and high-frequency dispersion achieves initial homogenization of Curcuma zedoaria oil, borneol, and the matrix; in the low-temperature mixing stage, according to the formula... By dynamically linking material density with mixing speed, the system adapts to the differences in physical properties of different materials, further improving component uniformity; the dynamic pressure molding stage employs a formula... The sinusoidal oscillating pressure precisely fills the gaps caused by the volume shrinkage of materials at low temperatures, avoiding uneven internal density and surface defects; the final molded suppository has a stable hardness of 2.5N~3.5N, a regular shape without dents or internal air bubbles, and the weight difference meets the standard. The melting time strictly follows the requirements of the "Pharmacopoeia of the People's Republic of China", which not only ensures the comfort of medication, but also achieves a stable and efficient release of the drug efficacy. This invention comprehensively enhances process adaptability and large-scale production capabilities, meeting the demands of industrial supply. Addressing the problems of independent control at each stage of existing processes, parameter dependence on experience, and difficulty in adapting to large-scale production, this invention constructs an intelligent linkage and control system. Through a central control module, it achieves signal interaction and real-time parameter control across all stages, including raw material pretreatment, pre-cooling and dispersion, low-temperature mixing, dynamic molding, and temperature-controlled post-treatment. This system can dynamically adapt to batch differences in raw materials (such as fluctuations in the purity of turmeric oil and borneol particle size) and changes in ambient temperature. Each module forms a continuous production process through material conveying components, and a precise mathematical control model replaces manual experience for optimization, significantly reducing the risk of quality fluctuations. This process significantly improves the finished product qualification rate and production efficiency, stably matching the needs of large-scale industrial production. It effectively solves the pain points of insufficient capacity and unstable supply in existing technologies, possessing significant industrial application value.

[0016] To more clearly illustrate the structural features and effects of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the overall process of the present invention. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0019] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0020] like Figure 1 As shown, this embodiment of the invention provides a low-temperature molding process for a compound gynecological suppository containing turmeric oil and borneol, including the following steps: S1. Raw material pretreatment: Select turmeric oil, borneol, suppository matrix and pharmaceutical excipients, and process them in sequence by crushing, sieving and drying, and control the moisture content of the raw materials to a range suitable for low-temperature molding. S2. Pre-cooling and dispersion treatment: The pre-treated raw materials are placed in a pre-cooling and dispersion device and cooled to a preset low temperature range according to a preset gradient cooling strategy. At the same time, high-frequency dispersion operation is used to complete the initial homogenization of the raw materials. S3. Low-temperature mixing: The pre-cooled and dispersed materials are transferred to a low-temperature mixing device, which maintains a suitable low-temperature environment and mixes them according to dynamically controlled speed and time to obtain a homogeneous mixture. S4. Dynamic pressure molding: The mixture is injected into the suppository molding mold, and molding pressure is applied through the pressure compensation system while maintaining the low temperature required for molding to complete the initial molding of the suppository. S5. Temperature-controlled post-treatment: Gradient heating and subsequent cooling are applied to the pre-formed suppositories, and the processing parameters are adjusted in real time by the temperature control system. S6. Finished Product Processing: The post-processed suppositories are demolded, trimmed, and quality inspected to obtain the finished product, Curcuma zedoaria oil and borneol compound gynecological suppositories.

[0021] In this embodiment, the raw material pretreatment involves crushing, sieving, and drying to obtain raw materials with uniform particle size and acceptable moisture content. This prevents moisture from freezing and caking at low temperatures, increases the specific surface area of ​​the raw materials, and lays a stable foundation for subsequent low-temperature processes. In the pre-cooling and dispersion process, a gradient cooling strategy combined with high-frequency dispersion is employed. Gradient cooling prevents raw materials from agglomerating due to sudden cooling and reduces volatilization. High-frequency dispersion breaks down interparticle forces, achieving initial homogenization of the raw materials. The cooling rate and dispersion frequency are controlled by formulas to ensure the stability of the pretreatment effect. In the low-temperature mixing process, a suitable low-temperature environment is maintained. Mixing is completed through the linkage control of material density and mixing speed, improving matrix fluidity and optimizing the uniformity of material composition while ensuring the stability of the effective components. In the dynamic pressure molding process, dynamic pressure fluctuations are adapted to the low-temperature shrinkage characteristics of the material, filling gaps and avoiding uneven internal density. Precise mold temperature control ensures the stability of the effective components and the regularity of the suppository morphology. In the temperature-controlled post-treatment, gradient heating releases internal stress in the suppository and reduces secondary volatilization of the effective components. Post-cooling treatment fixes the suppository morphology and improves hardness stability. The heating rate is controlled by formulas to ensure the treatment effect. In the finished product finishing process, defects are removed through demolding and trimming. Core indicator testing ensures that the finished product meets pharmacopoeia and clinical requirements.

[0022] Specifically, in step S2, the cooling rate of the gradient cooling strategy satisfies the formula: ; in, for The real-time cooling rate (unit: ℃ / min) is the rate at which the temperature drops at a specific point in time during the cooling process. It gradually decreases over time to avoid sudden changes in the cooling rate. This is the initial cooling rate (unit: °C / min), the initial rate at which the cooling operation starts. It needs to be set according to the initial state of the raw material (e.g., when the initial temperature of the raw material is 25 °C). It can be set to 5℃ / min to ensure rapid entry into the early stage of the low temperature range); The cooling attenuation coefficient (unit: 1 / min) is a core control parameter with a value range of 0.05~0.1 (adjusted according to the characteristics of the raw materials; for example, 0.08 is used when the camphor content is high to enhance the attenuation effect and avoid crystallization and agglomeration). It determines the rate of attenuation of the cooling rate. The cooling duration (in minutes) is the cumulative time from the start of the gradient cooling process to the current moment. It is a natural constant (approximately 2.71828), which is a fixed base of the exponential function to ensure that the cooling rate has a smooth decreasing trend; the preset low temperature range is -5℃ to 0℃.

[0023] In this embodiment, during the initial cooling phase ( When it is smaller), Approaching 1, near It can quickly reduce the material temperature and shorten the volatilization time of effective components in the high-temperature stage; with Increase, Gradually decrease, The temperature is gradually reduced to avoid crystallization and agglomeration caused by a sudden drop in material temperature, achieving a synergistic effect of "rapid cooling + smooth transition", and finally stabilizing the material temperature to the preset range of -5℃ to 0℃. Detailed steps: Setting initial parameters: Based on the initial temperature (e.g., 25℃) and characteristics of the raw materials, determine the ℃. , ; Initiating gradient cooling: Pre-cooling dispersion equipment according to formula Generate a cooling curve, initial stage (0~5min) ℃ The material temperature rapidly dropped from 25℃ to around 0℃; Smooth cooling transition: within 5-10 minutes, Follow Increase gradually attenuation (e.g., ℃ at t=5min) ℃ at t=10min The material temperature slowly drops from 0℃ to the range of -5℃ to 0℃; Temperature maintenance: When the material temperature reaches the preset range (e.g., -3℃), stop the gradient cooling and maintain the temperature until the pre-cooling and dispersion process is completed to avoid temperature fluctuations; By employing an exponentially decaying gradient cooling strategy, the raw materials are prevented from crystallizing and agglomerating due to rapid cooling (such as borneol crystal clumping and stratification of turmeric oil and matrix). At the same time, the volatilization kinetics of turmeric oil (containing turmeric alcohol and turmeric ketone) and the sublimation rate of borneol are reduced, providing a uniform material basis for subsequent high-frequency dispersion. Ultimately, this improves the uniformity of the raw material pre-dispersion and lays a stable material foundation for subsequent mixing and molding processes.

[0024] Specifically, in step S2, the frequency of the high-frequency dispersion satisfies the formula: ; in, for The real-time dispersion frequency (unit: Hz) is the vibration or stirring frequency of the dispersion equipment, which increases synchronously as the material temperature decreases. The reference dispersion frequency (unit: Hz) is the appropriate frequency at the initial temperature of the raw material (e.g., when the initial temperature of the raw material is 25℃). (Can be set to 30Hz to ensure initial dispersion effect); The initial temperature of the raw material (unit: °C) is the temperature of the raw material when it enters the pre-cooling and dispersing equipment after pretreatment (usually room temperature 20~25 °C). for The real-time temperature of the material (unit: °C) is collected in real time by the temperature sensor of the pre-cooling and dispersing equipment and gradually decreases with gradient cooling.

[0025] In this embodiment, This represents the temperature decay ratio, reflecting the degree to which the material temperature decreases. The greater the temperature decrease, the larger this ratio. The higher; The raw material has a high initial temperature ( near When the material viscosity is low and the interparticle forces are weak, high-frequency dispersion is not required. near This achieves initial dispersion; as the gradient cooling proceeds, Decreasing viscosity increases material viscosity, borneol crystals easily agglomerate, and turmeric oil easily separates from the matrix. The proportion increased. Simultaneous increase enhances dispersion intensity, breaks agglomeration forces, and ensures that the dispersion effect adapts to temperature changes; Detailed steps: Initial parameter setting: Determine the initial temperature of the raw material (°C) Reference dispersion frequency ; Real-time temperature acquisition: The temperature sensor in the pre-cooling dispersion equipment collects data every 10 seconds. And transmit it to the central control module; Calculate the real-time distributed frequency: The central control module calculates according to the formula. calculate (e.g., ℃ at t=5min) ,but ; ℃ at t=8min ,but ); Dynamically adjust dispersion intensity: The dispersion equipment adjusts the intensity based on calculations. The vibration frequency is adjusted in real time to ensure that the dispersion strength increases synchronously as the temperature decreases, until the material temperature reaches the preset range (-5℃~0℃), and then maintained at this point. Continue dispersing for 5-10 minutes to achieve initial homogenization; The dispersion frequency is dynamically linked to the material temperature. The lower the temperature (the higher the material viscosity and the stronger the interparticle force), the higher the dispersion frequency. This breaks down the physical barriers between turmeric oil (oily), borneol (solid crystal), and polyethylene glycol matrix, preventing the three from separating or agglomerating, and achieving initial homogenization of the raw materials, thus improving efficiency for subsequent low-temperature mixing.

[0026] Specifically, in step S3, the adapted low-temperature environment temperature is 2℃~3℃ higher than the preset low-temperature range in step S2; the mixing speed satisfies the formula: ; in, The real-time mixing speed (unit: r / min) is the stirring speed of the low-temperature mixing equipment, which increases with the increase of material density; The reference rotational speed (unit: r / min) is the suitable rotational speed under the initial density of the material (e.g., when the initial density of the material is 1.0 g / cm³). (It can be set to 60r / min to ensure basic mixing effect). The material density influence coefficient (unit: cm³ / g) ranges from 0.3 to 0.5 (adjusted according to the matrix type; 0.4 for polyethylene glycol matrices), reflecting the degree of influence of density change on rotation speed. The real-time density of the mixture (unit: g / cm³) is collected in real time by the density sensor of the low-temperature mixing equipment and gradually stabilizes as the mixing process progresses (finally approximately 1.05~1.1 g / cm³).

[0027] In this embodiment, the ambient temperature during the low-temperature mixing stage is set to "2℃~3℃ higher than the pre-cooling range" (i.e., -3℃~2℃), which avoids excessively low temperatures that could lead to high material viscosity and mixing difficulties, while also ensuring that the effective components do not volatilize; in the initial stage of mixing, the material density is low (not fully dispersed). near To avoid material splashing due to high rotation speed; as mixing proceeds, borneol and turmeric oil gradually disperse evenly, and the material density... rise, The mixture is raised synchronously according to the formula to enhance the stirring intensity and ensure that high-density components (such as borneol) are evenly dispersed in the matrix to avoid sedimentation. Detailed steps: Set the mixing environment temperature: Adjust the temperature of the low-temperature mixing equipment to -2℃ (2℃ higher than the pre-cooling range of -5℃ to 0℃, which meets the requirements); Initial parameter settings: Determine the reference speed Material density influence coefficient ; Transfer materials and start mixing: Transfer the pre-cooled and dispersed materials (temperature -5℃~0℃) to the low-temperature mixing equipment. The initial material density is ³ Calculate according to the formula Start the stirring; Real-time rotation speed adjustment: Density sensor collects data every 30 seconds. The central control module calculates in real time. (e.g., mix for 5 minutes, then 3) , but ); Stable mixing: when The value tends to stabilize (e.g., fluctuations of ≤0.01 g / cm³ in three consecutive data collections), and is maintained at this level. Continue mixing for 15-20 minutes to obtain a homogeneous mixture. By dynamically linking the mixing speed with the real-time density of the materials, the density changes after mixing turmeric oil, borneol and polyethylene glycol matrix are adapted (such as the density increases after borneol is evenly dispersed), avoiding stratification or uneven mixing caused by density differences, improving the uniformity of the mixture, and ensuring that the suppositories have uniform density and regular shape in the subsequent molding process.

[0028] Specifically, in step S4, the molding pressure applied by the pressure compensation system satisfies the formula: ; in, The real-time forming pressure (unit: MPa) is the superposition of the reference pressure and the fluctuating pressure, and it changes in a sinusoidal pattern. The reference molding pressure (unit: MPa) is the basic pressure to ensure that the material fills the mold (value range: 0.8~1.2MPa, adjusted according to mold specifications). The pressure compensation amplitude (unit: MPa) ranges from 0.1 to 0.3 MPa, representing the maximum value of the fluctuating pressure, and is used to fill the contraction gap. The pressure fluctuation frequency (unit: Hz) ranges from 0.5 to 1 Hz, ensuring that the pressure fluctuation is compatible with the material shrinkage rate; The molding time (unit: s) is the time from when the mixture is injected into the mold to when the initial molding is completed (usually 30~60s); the required low temperature for molding is -3℃~1℃, which is consistent with the temperature of the mixing environment to avoid changes in the state of the material due to sudden temperature changes.

[0029] In this embodiment, after the mixture is injected into the molding die, it will gradually shrink under low temperature conditions. Traditional constant pressure cannot fill the shrinkage gaps in time, resulting in molding defects. In this process, The pressure fluctuates according to a sinusoidal law. When the material shrinks, the peak value of the fluctuating pressure can accurately fill the gap, and the trough value can prevent excessive pressure from damaging the mold or deforming the suppository. The molding temperature is maintained at -3℃ to 1℃, which ensures that the material is in a formable state and inhibits the volatilization of the effective ingredients. Detailed steps: Mold temperature control: Preheat the molding mold to 0℃ (the difference between this temperature and the required low temperature of -3℃ to 1℃ is 0℃, ≤±0.5℃, which meets the requirements); Set pressure parameters: Determine the reference molding pressure Pressure compensation amplitude Pressure fluctuation frequency ; Injection material: Inject the homogeneous material after low-temperature mixing (temperature -2℃) into the molding mold, with a filling rate of 95% (leaving room for shrinkage). Apply dynamic pressure: The pressure compensation system is based on the formula Apply pressure (e.g., at t=10s), At t=20s, ); Initial molding: Maintain dynamic pressure and molding temperature for 30-40 seconds until the material initially solidifies, then stop applying pressure to obtain the initial molded suppository product. By using sinusoidal oscillating dynamic pressure, the internal voids caused by the volume shrinkage of materials at low temperatures are precisely filled (the shrinkage rate of polyethylene glycol matrix at low temperatures is about 3%~5%), avoiding air bubbles, uneven density, or surface depressions inside the suppository. At the same time, the molding temperature (-3℃~1℃) is kept stable to ensure that the active ingredients do not volatilize, ultimately achieving a regular suppository shape and meeting the weight difference standards.

[0030] Specifically, in step S4, the mold temperature difference is the absolute difference between the actual temperature of the molding mold and the "low temperature required for molding (-3℃~1℃)", which must be ≤±0.5℃ (if the required molding temperature is 0℃, then the mold temperature must be between -0.5℃ and 0.5℃). The thermal conductivity (unit: W / (m·K)) of the temperature control interlayer is required to be ≥200W / (m·K). An aluminum or copper interlayer is selected (the thermal conductivity of aluminum is about 237W / (m·K) and that of copper is about 401W / (m·K)) to ensure rapid heat conduction and achieve precise temperature control.

[0031] In this embodiment, mold temperature is a key environmental parameter for suppository molding. If the mold temperature is too high, the local temperature of the material in contact with the mold will rise, causing the turmeric oil to volatilize and the borneol to sublimate, resulting in the loss of effective ingredients. If the mold temperature is too low, the material will solidify rapidly inside the mold and will not be able to fit the mold during shrinkage, easily causing surface depressions or internal voids. The temperature control interlayer with high thermal conductivity can quickly respond to temperature adjustment commands and control the temperature difference between different parts of the mold within ±0.2℃, ensuring uniform overall molding of the suppository. Detailed steps: Select the temperature control interlayer material: Choose aluminum temperature control interlayer ( ), installed on the outside of the molding die; Set target temperature: Based on the low temperature required for molding, set the target temperature of the mold to -1℃; Preheating and calibration: Start the temperature control system and raise the mold temperature to -1℃. Use temperature sensors distributed in different parts of the mold to calibrate and ensure that the temperature difference at each point is ≤±0.3℃ (meeting the requirement of ≤±0.5℃). Temperature control during molding process: During the entire molding stage (30~40s) of mixing material injection and dynamic pressure application, the mold temperature is monitored in real time. If the temperature deviates from -1℃ by more than ±0.2℃, the temperature control system will adjust immediately (e.g., when the temperature rises to 0.3℃, cooling medium is introduced into the jacket to cool it down quickly). Heat preservation after initial molding: After the suppository is initially molded, maintain the mold temperature at -1℃ for 10 minutes to avoid sudden temperature changes that may cause the suppository to crack. The high thermal conductivity temperature control sandwich layer enables precise control of the mold temperature, ensuring that the difference between the mold temperature and the required low temperature (-3℃~1℃) for molding is ≤±0.5℃. This avoids the material temperature from being too high (volatile of active ingredients) or too low (irregular molding) due to uneven mold temperature. At the same time, it improves the adhesion between the suppository and the mold, reduces surface damage during demolding, and ensures molding uniformity.

[0032] Specifically, in step S5, the heating rate of the gradient heating satisfies the formula: ; in, Real-time gradient heating rate (unit: °C / min) gradually decreases as the suppository temperature increases to avoid excessively rapid heating; Reference heating rate (unit: °C / min), which is the initial rate at the beginning of the heating process (e.g., set to 1 °C / min). Maximum post-processing temperature (unit: °C), range 10~15 °C (avoid exceeding 20 °C to prevent volatilization of active ingredients); d. : The constant temperature of the suppository (unit: °C) is collected in real time by the temperature sensor of the temperature control post-processing equipment; Post-cooling parameters: temperature -2℃~0℃, duration 10min~20min, used to fix the suppository form.

[0033] In this embodiment, thermal stress exists inside the suppository after initial molding (caused by the temperature difference between the inside and outside during low-temperature molding). If the temperature is rapidly increased, the stress concentration and release will cause the suppository to crack. In this process... and Proportional, in the early stage of warming ( Low, close to the molding temperature of -3℃ to 1℃. Large proportion near Rapidly increases temperature; with As the proportion increases, the percentage gradually decreases. Reduce and slowly release stress; raise the temperature to Then, switch to post-cold treatment to quickly fix the suppository shape and improve hardness stability.

[0034] Detailed steps: Transferring the initial molded suppository: Transfer the initial molded suppository (temperature -3℃~1℃) from the mold to the temperature-controlled post-processing equipment; Set heating parameters: Determine the reference heating rate (°C) Maximum post-processing temperature ℃ ; Gradient heating initiated: Temperature sensor collects data in real time. The central control module is based on the formula. Calculate the heating rate (e.g., initial °C) Then ℃ ;℃ At that time, ℃ ); Steadily heat to target temperature: according to real-time Heat up until ℃ Maintain this temperature for 5 minutes to completely release internal stress. Post-cooling treatment: Activate the post-cooling mode to lower the equipment temperature to -1℃ and maintain it for 15 minutes to fix the suppository form; Post-treatment: After cooling is complete, allow the suppository temperature to rise naturally to room temperature (20~25℃) to avoid sudden temperature changes; The gradient heating strategy can slowly release the thermal stress generated inside the suppository due to low-temperature molding (avoiding cracking after demolding) and reduce the secondary volatilization of active ingredients; the post-cold treatment can fix the shape of the suppository and improve hardness stability (ensuring hardness of 2.5N~3.5N), which facilitates subsequent demolding and trimming.

[0035] Specifically, in step S1, the suppository matrix is ​​a polyethylene glycol matrix, and the mass ratio of the matrix to turmeric oil and borneol is (5~8):(1~2):(0.5~1); the pharmaceutical excipients include antioxidants, and the amount of antioxidants added is 0.1%~0.3% of the total mass of the raw materials.

[0036] In this embodiment, the matrix type is: polyethylene glycol matrix (preferably a PEG4000:PEG6000 blend of 1:1, melting point 40~50℃, suitable for low-temperature molding). Mass ratio: matrix: turmeric oil: borneol = (5~8): (1~2): (0.5~1), such as choosing 6:1.5:0.8 (considering both solubility and formability); Pharmaceutical excipients: The core is antioxidants (such as vitamin E and tert-butyl-p-hydroxyanisole BHA), and the amount added is 0.1%~0.3% of the total mass of raw materials (e.g., 0.2kg of vitamin E is added for 100kg of total raw materials). A small amount of suspending agent (such as sodium carboxymethyl cellulose) can also be added as needed to improve uniformity. Logical relationship: Polyethylene glycol matrix is ​​a water-soluble matrix, and its compatibility with Curcuma zedoaria oil (oil-based) needs to be achieved through ratio optimization. Too high a matrix ratio will lead to insufficient concentration of active ingredients, while too low a ratio will result in poor formability (insufficient hardness); Borneol is a solid crystal, and too high a ratio will easily cause agglomeration, while too low a ratio will result in insufficient efficacy; The amount of antioxidant added needs to be precisely controlled. Excessive amounts will lead to increased irritation of the suppository, while insufficient amounts will fail to achieve the antioxidant effect.

[0037] Detailed steps: Raw material selection: Select Curcuma zedoaria oil with a purity of ≥98%, borneol with a particle size of ≤100μm, PEG4000 and PEG6000 (1:1 compound) as the matrix, and vitamin E as the antioxidant; Calculate the amount of raw materials: Based on the mass ratio of matrix: turmeric oil: borneol = 6: 1.5: 0.8, if 100 kg of mixed raw materials are produced, 60 kg of matrix, 15 kg of turmeric oil and 8 kg of borneol are required; Weighing and pretreatment: Weigh each raw material separately, crush the matrix and pass it through an 80-mesh sieve, crush the borneol and pass it through a 120-mesh sieve, and let the turmeric oil stand to remove impurities; Add antioxidant: Calculate 0.2% of the total raw material mass (60+15+8=83kg), add 0.166kg of vitamin E, and mix it evenly with turmeric oil; Mixing and pretreatment: Mix the matrix, turmeric oil containing antioxidants, and borneol, and then proceed to subsequent crushing, sieving, and drying processes (control the moisture content to ≤0.5% to adapt to low-temperature molding). Polyethylene glycol-based matrices (such as a blend of PEG4000 and PEG6000) possess both good water solubility and molding properties. The mass ratio of turmeric oil and borneol (5~8):(1~2):(0.5~1) can balance the solubility of the active ingredients (avoiding borneol precipitation and turmeric oil stratification) with the hardness and melting time of the suppositories. Antioxidants can inhibit the oxidative deterioration of unsaturated fatty acids in turmeric oil and extend the shelf life of the preparation (it can be stably stored for more than 24 months at room temperature).

[0038] Specifically, the core indicators for quality testing in step S6 include the retention rate of active ingredients, suppository hardness, and melting time limit, wherein the retention rate of active ingredients is ≥95%, the hardness is 2.5N~3.5N, and the melting time limit meets the requirements of the suppository section of the Pharmacopoeia of the People's Republic of China.

[0039] In this embodiment, the retention rate of active ingredients is required to be ≥95% (calculated based on the initial content of active ingredients in the raw materials). Suppository hardness: Tested using a hardness tester (pressure probe diameter 5mm, indentation speed 1mm / s), requiring 2.5N~3.5N (insufficient hardness leads to easy deformation, while excessive hardness results in unsuitable medication). Melting time limit: Tested according to the pharmacopoeia suppository melting time limit test method (Appendix XB). Water-soluble base suppositories should be ≤60min (to ensure that the suppository melts quickly after entering the vagina and releases the active ingredients).

[0040] The retention rate of active ingredients is the core guarantee of efficacy. If it is less than 95%, the clinical efficacy will be poor. Hardness directly affects the user experience and needs to be balanced between "not easily deformed" and "comfortable administration". The melting time determines the release rate of the drug. If it is too long, the active ingredients cannot play a role in time. If it is too short, the suppository will easily melt during transportation and storage.

[0041] Detailed steps: Sample preparation: Randomly select 10 suppositories from the post-processed suppositories as test samples (each suppository weighs approximately 2g); Active ingredient retention rate test: Step 1: Take 3 samples, crush them, and extract them with ethanol using ultrasound for 30 minutes. Filter to obtain the extract. Step 2: The contents of curcumol, curcumone and borneol in the extract were determined by high performance liquid chromatography (HPLC); Step 3: Calculate the retention rate = (detected content / initial content in raw material) × 100%, which must be ≥95%; Hardness testing: Step 1: Take 3 samples and place them at room temperature (25℃) for 30 minutes; Step 2: Use a hardness tester to press the probe vertically into the center of the suppository and record the pressure value when the insertion depth is 2mm; Step 3: Take the average value of 3 tests, which should be between 2.5N and 3.5N; Fusion time limit detection: Step 1: Take 3 samples and follow the procedure in Appendix XB of the Pharmacopoeia. Place the suppositories into the basket of the melting time limit tester and immerse them in simulated vaginal fluid (pH 4.5~5.5) at 37℃±0.5℃. Step 2: Record the time it takes for the suppository to completely melt and for the core to remain intact; this time should be ≤60 minutes. Result determination: If ≥8 out of 10 samples meet the standards for effective ingredient retention rate, hardness, and melt change time, they are considered qualified; unqualified samples need to be re-inspected, and if they are still unqualified, the previous process parameters need to be traced and adjusted. By testing core indicators (retention rate of active ingredients, hardness, and melting time), we ensure that the finished suppositories have sufficient pharmacological activity (sufficient active ingredients), comfortable use (moderate hardness), and efficient drug release (metabolism time meets the standard), meeting the requirements for suppositories in the Pharmacopoeia of the People's Republic of China (2020 edition), and guaranteeing the safety and effectiveness of clinical use.

[0042] Working principle and usage process of this invention: The equipment required for the implementation of this process includes a raw material pretreatment module, a precooling and dispersion module, a low-temperature mixing module, a dynamic pressure forming module, an intelligent temperature-controlled post-processing module, and a finished product sorting module. Each module is connected through a material conveying component or a signal transmission component, and all of them interact with the central control module. This equipment can realize the linkage control of each link of the process, ensure the continuity and stability of the process, and adapt to the needs of large-scale production. The process of this invention is based on a collaborative logic of the entire process of "pretreatment - pre-dispersion - low-temperature mixing - dynamic molding - temperature-controlled post-treatment - finished product inspection". The core working principle is as follows: Raw material pretreatment stage: The raw materials are crushed and sieved to remove impurities, and dried to a moisture range suitable for low-temperature molding to obtain uniform and stable pretreated raw materials. Pre-cooling and dispersion stage: The central control module follows the formula A gradient cooling curve is generated, and the pre-cooling dispersion equipment completes the cooling of the raw materials; simultaneously, according to the formula... By adjusting the dispersion frequency, the raw materials achieve initial homogenization during the cooling process; Low-temperature mixing stage: The pre-cooled and dispersed materials enter the low-temperature mixing equipment, and the temperature is controlled to be 2℃~3℃ higher than that of the pre-cooling zone; the central control module uses the material density and the formula... Adjust the stirring speed to achieve uniform mixing of materials; Dynamic pressure molding stage: The mixed material is injected into the molding die, and the die temperature control jacket maintains a low molding temperature; the central control module follows the formula... A dynamic pressure curve is generated, and the pressure compensation system applies fluctuating pressure to complete the initial formation of the suppository. Temperature-controlled post-processing stage: The pre-formed suppositories enter the post-processing equipment, and the central control module processes them according to the formula. Control the gradient heating rate to release internal stress; then switch to post-cooling mode to fix the suppository shape; Finished product processing stage: After demolding and trimming, the suppositories undergo testing for active ingredient content, hardness, and melt change time. Qualified products are packaged, while unqualified products are recycled and disposed of.

[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A low-temperature forming process for the compound gynecological suppository of zedoary oil and borneol, characterized in that, The method comprises the following steps: S1, raw material pretreatment: selecting zedoary oil, borneol, suppository matrix and pharmaceutical excipients, and sequentially performing crushing, screening and drying treatment to control the moisture content of the raw materials within the range suitable for low-temperature molding; S2, pre-cooling and dispersion treatment: placing the pretreated raw materials in a pre-cooling and dispersion device, cooling to a preset low-temperature interval according to a preset gradient cooling strategy, and simultaneously performing high-frequency dispersion operation to complete the preliminary homogenization of the raw materials; S3, low-temperature mixing: transferring the pre-cooled and dispersed materials to a low-temperature mixing device, maintaining a suitable low-temperature environment, and completing the mixing according to the dynamically regulated rotation speed and time to obtain a homogeneous mixture; S4, dynamic pressure molding: injecting the mixed materials into a suppository molding mold, applying molding pressure through a pressure compensation system, and maintaining the required low temperature for molding to complete the primary molding of the suppository; S5, temperature-controlled post-processing: implementing gradient temperature rising-post cooling linkage processing on the primary molded suppository, and real-time regulating the processing parameters through a temperature control system; S6, finished product finishing: demolding, trimming and quality testing of the post-processed suppository to obtain the finished product of the zedoary oil and borneol compound gynecological suppository.

2. The low temperature forming process for the compound zedoary turmeric oil and borneol gynecological suppository according to claim 1, characterized in that, In step S2, the gradient cooling strategy has a cooling rate satisfying the formula: ； wherein, is the real-time cooling rate at the moment, is the initial cooling rate, is the cooling attenuation coefficient, is the cooling duration; and the preset low temperature interval is -5℃~0℃.

3. The low temperature forming process of the compound zedoary turmeric oil and borneol gynecological suppository according to claim 2, characterized in that, In step S2, the high-frequency dispersion has a frequency satisfying the formula: ； wherein, is the real-time dispersion frequency at the moment, is the reference dispersion frequency, is the initial temperature of the raw material, is the real-time temperature of the material at the moment.

4. The low temperature forming process for the compound Zedoary Turmeric Oil and Borneolum Syntheticum Gynecological Suppository according to claim 1, characterized in that, In step S3, the suitable low-temperature environment has a temperature 2-3°C higher than the preset low-temperature interval in step S2, and the mixing rotation speed satisfies the formula: ； Wherein, is the real-time mixing speed, is the reference speed, is the material density influence coefficient, is the real-time density of the mixed material.

5. The low temperature forming process for the compound Zedoary Turmeric Oil and Borneol Gynecological Suppository according to claim 1, characterized in that, In step S4, the molding pressure applied by the pressure compensation system satisfies the formula: ； wherein, is a real-time molding pressure, is a reference molding pressure, is a pressure compensation amplitude, is a pressure fluctuation frequency, is a molding duration; the required low temperature for molding is -3°C to 1°C.

6. The low temperature forming process for the compound Zedoary Turmeric Oil and Borneol Gynecological Suppository according to claim 5, characterized in that, In step S4, the temperature difference between the temperature of the molding die and the low temperature required for the molding is ≤ ± 0.5℃, the die is temperature-regulated by a temperature-regulated interlayer, and the thermal conductivity of the temperature-regulated interlayer is .

7. The low temperature forming process for the compound zedoary turmeric and borneol gynecological suppository according to claim 1, characterized in that, In step S5, the gradient temperature rising has a temperature rising rate satisfying the formula: ； wherein, is the real-time gradient heating rate, is the reference heating rate, is the maximum post-treatment temperature, is the momentary suppository temperature; the post-cooling treatment temperature is -2℃ to 0℃, and the treatment duration is 10 min to 20 min; the heating strategy can slowly release the internal stress of the suppository, avoid cracking, and reduce the secondary volatilization of the active ingredients, and the post-cooling treatment can fix the suppository form and improve the hardness stability.

8. The low temperature forming process for the compound zedoary turmeric and borneol gynecological suppository according to claim 1, characterized in that, In step S1, the suppository matrix is a polyethylene glycol matrix, and the mass ratio of the matrix to zedoary oil and borneol is (5-8):(1-2):(0.5-1); the pharmaceutical excipients contain an antioxidant, and the antioxidant addition amount is 0.1%-0.3% of the total mass of the raw materials.

9. The low temperature forming process for the compound zedoary turmeric and borneol gynecological suppository according to claim 1, characterized in that, In step S6, the core indicators of the quality testing include effective ingredient retention rate, suppository hardness and melting time, wherein the effective ingredient retention rate is ≥95%, and the hardness is 2.5-3.5 N.

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