Production process of capsule-in-capsule composite dosage form suitable for multi-dosage form compatibility

Abstract

The application belongs to the technical field of capsule preparation, and particularly relates to a production process of a capsule-in-capsule composite dosage form suitable for multiple dosage form compounding. For the production of the capsule-in-capsule composite dosage form, the production of a soft bag soft production line and a hard capsule production line is controlled according to a compounding scheme. The state of the soft inner capsule is characterized from different dimensions through a water content prediction value, a deformation rate prediction value and a surface activity prediction value, which jointly determine whether the soft inner capsule is suitable for secondary compression. Thus, the production schedule of each production line is reasonably arranged. In addition, the secondary compression parameters are dynamically adjusted according to the predicted state of the soft inner capsule, so that the soft inner capsule can still complete high-quality secondary forming after a certain degree of state change.

Description

Technical Field

[0001] This invention belongs to the field of capsule formulation technology, specifically relating to the production process of capsule-in-capsule composite dosage forms suitable for multi-dosage form compatibility. Background Technology

[0002] Encapsulation-in-a-capsule formulations are drug delivery systems that isolate one or more active ingredients through multiple layers of capsule shells. They are mainly classified into three types: soft-encapsulated-soft, soft-encapsulated-hard, and hard-encapsulated-soft. The core value of this technology lies in its ability to achieve combined encapsulation of incompatible components through physical isolation, and to achieve programmed release through differentiated design of the inner and outer capsules.

[0003] Currently, soft-pack production lines and hard capsule production lines operate largely independently in actual production, each undertaking different capsule-in-capsule preparation tasks, but there are significant problems in terms of operational efficiency and resource utilization.

[0004] The preparation of soft capsule formulations requires two pressing processes on the same production line: the first pressing prepares the inner soft capsule, and the second pressing prepares the outer soft capsule. Between the two pressing processes, the inner capsule needs to undergo temporary storage, transfer, and refeeding. Taking a soft capsule production line as an example, when it is dedicated to the production of soft capsules, its effective output will be greatly affected by the state of the inner soft capsule during the temporary storage period. Summary of the Invention

[0005] To address the problems in the prior art, this invention provides a production process for capsule-in-capsule composite dosage forms suitable for multi-dosage form compatibility.

[0006] The technical solution of the present invention is as follows: This invention provides a manufacturing process for a capsule-in-capsule composite dosage form suitable for multi-dosage form compatibility, comprising: S1: Based on production needs and the physicochemical properties of active ingredients, set the formulation scheme as either soft-pack soft or hard-pack soft, and save the formulation parameters; S2: The soft packaging production line performs one pressing according to the compatibility scheme to prepare soft inner capsules, and automatically records the corresponding formula parameters and production timestamp when each batch of soft inner capsules is produced. S3: Each batch of soft inner capsules is stored in the transit buffer area, and the temperature and humidity of the storage environment are monitored, and the storage time of each batch of soft inner capsules is recorded; S4: Select the production path according to the compatibility scheme: If the compatibility scheme is hard-pack soft, the soft inner capsule is supplied across the production line to the hard capsule production line, and the hard capsule production line performs the filling and packaging operation. If the formulation is soft-pack soft, then the current state of the soft inner capsule is determined based on the formula parameters and storage time of the soft inner capsule; the current state of the soft inner capsule is used to determine whether the batch of soft inner capsules meets the conditions for secondary pressing. If the conditions for secondary pressing are met, the soft inner capsule will enter the secondary pressing process of the soft packaging production line. S5: Adjust the secondary compression parameters of the soft inner capsule production line according to the current soft inner capsule status.

[0007] Based on the above-described production process for capsule-in-capsule composite dosage forms suitable for multi-dosage form compatibility, step S4, which determines the current state of the soft inner capsule based on the formulation parameters and storage time, specifically involves: Based on the formulation parameters of the soft inner capsules and the temperature and humidity of the storage environment monitored by S3, the corresponding rate constants are retrieved from the mapping relationship library. Combined with the storage time of this batch of soft inner capsules, the predicted values ​​of water content, deformation rate and surface activity of this batch of soft inner capsules are calculated.

[0008] Furthermore, based on the production process of the capsule-in-capsule compound dosage form applicable to multiple dosage forms described above, the predicted water content value is obtained through the formula: To calculate; In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted water content of the capsule shell at that time This indicates the initial water content of the capsule. This represents the water migration rate constant. This indicates the first-time index.

[0009] Furthermore, based on the production process of the capsule-in-capsule composite dosage form applicable to multiple dosage forms described above, the predicted deformation rate is obtained through the formula: To calculate; In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted value of deformation rate at time Represents the deformation rate constant. This indicates the second time index.

[0010] Furthermore, based on the production process described above for capsule-in-capsule composite dosage forms suitable for multi-dosage form compatibility, the predicted surface activity value is obtained through the formula: To obtain; In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted surface activity values ​​at that time This indicates the initial surface activity value of the soft capsule. This represents the surface oxidation rate constant.

[0011] Furthermore, based on the production process of capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility described above, the mapping relationship library is pre-established through the following steps: For each combination of formulation parameters, the changes in water content, deformation rate, and surface activity of the soft inner lining over time were measured under multiple preset temperature and humidity conditions. Regression was performed on each temperature and humidity condition group to determine the rate constant and time exponent of the formulation parameter combination under that temperature and humidity condition. The formulation parameter combination, temperature and humidity condition group, and corresponding rate constant and time exponent were associated and stored to form a mapping relationship library.

[0012] Furthermore, based on the production process of the capsule-in-capsule composite dosage form applicable to multiple dosage forms described above, in step S4, the determination of whether the batch of soft inner capsules meets the secondary pressing conditions based on the current soft inner capsule state involves comparing the predicted values ​​of water content, deformation rate, and surface activity of the batch of soft inner capsules with the water content threshold, deformation rate threshold, and surface activity threshold, respectively.

[0013] Furthermore, based on the production process of the capsule-in-capsule composite dosage form applicable to multiple dosage forms described above, the secondary pressing conditions mentioned in S4 are that the predicted water content of this batch of soft inner capsules is not lower than the water content threshold, the predicted deformation rate is not higher than the deformation rate threshold, and the predicted surface activity is not lower than the surface activity threshold.

[0014] Based on the above-described production process for capsule-in-capsule composite dosage forms applicable to multiple dosage forms, the soft-pack production line includes at least: a gelling device, a soft capsule pressing device, and a shaping and drying device; the soft capsule pressing device has primary pressing and secondary pressing functions, and the shaping and drying device is used to perform preliminary shaping of the soft inner capsules after primary pressing.

[0015] Based on the above-described production process for capsule-in-capsule composite dosage forms applicable to multiple dosage forms, the hard capsule production line includes at least: a hard capsule directional separation device, a material filling device, and a capsule closing device; the hard capsule production line receives soft inner capsules from the soft packaging production line through a cross-line supply channel, and encapsulates the soft inner capsules as filling material inside the hard capsule shell.

[0016] Beneficial effects For the production of multi-dosage-formula capsule-in-capsule composite dosage forms, this invention controls the production of soft-pack and hard-capsule production lines based on the formulation scheme. By using predicted values ​​for moisture content, deformation rate, and surface activity, the state of the soft inner capsule is characterized from different dimensions, collectively determining whether the soft inner capsule is suitable for secondary pressing, thereby rationally scheduling the production of each line. Furthermore, the secondary pressing parameters are dynamically adjusted according to the predicted state of the soft inner capsule, ensuring that the soft inner capsule can still achieve high-quality secondary molding even after a certain degree of state change. Detailed Implementation

[0017] The following examples are intended to illustrate the present invention, and not to further limit the invention.

[0018] Example 1 This invention provides a manufacturing process for a capsule-in-capsule composite dosage form suitable for multi-dosage form compatibility, comprising: S1: Based on production needs and the physicochemical properties of active ingredients, set the formulation scheme as either soft-pack soft or hard-pack soft, and save the formulation parameters.

[0019] To ensure the operational efficiency of both the soft capsule production line and the hard capsule production line, determining the compatibility scheme is a prerequisite for the entire production process of this invention, and the compatibility scheme determines the destination of the soft inner capsules.

[0020] In actual production, the formulation is a soft-pack soft compound dosage form, with the inner capsule containing sea buckthorn seed oil and the outer capsule containing sea buckthorn fruit oil, to better retain and exert the comprehensive activity of sea buckthorn oil as a health food. The formulation is also a hard-pack soft compound dosage form, with the inner capsule containing sea buckthorn seed oil and the outer capsule being a hard capsule shell, to achieve sequential release of the contents of the soft inner capsule.

[0021] S2: The soft packaging production line performs one pressing according to the compatibility scheme to prepare soft inner capsules, and automatically records the corresponding formula parameters and production timestamp when each batch of soft inner capsules is produced.

[0022] The formulation parameters include at least the oil-to-water ratio of the contents and the proportion of plasticizer in the capsule shell. These two parameters directly affect the state of the soft capsule: the driving force of oily contents on water migration in the capsule shell is weaker than that of aqueous contents, and the proportion of plasticizer affects the flexibility and water retention capacity of the capsule shell. These parameters are recorded for subsequent matching of the corresponding rate constants.

[0023] S3: Each batch of soft inner capsules is stored in the transit buffer area, and the temperature and humidity of the storage environment are monitored, and the storage time of each batch of soft inner capsules is recorded.

[0024] Temperature and humidity in the storage environment are external factors that affect the condition of the soft inner capsules. Continuous monitoring during the production process avoids prediction deviations caused by environmental fluctuations and facilitates the retrieval of rate constants that match the current environmental conditions from the mapping database, ensuring that the predicted values ​​reflect the actual condition of this batch of soft inner capsules under the current environment.

[0025] S4: Select the production path according to the compatibility scheme: If the compatibility scheme is hard-pack soft, the soft inner capsule is supplied across the production line to the hard capsule production line, and the hard capsule production line performs the filling and packaging operation. If the formulation is soft-pack soft, then the current state of the soft inner capsule is determined based on the formula parameters and storage time of the soft inner capsule; the current state of the soft inner capsule is used to determine whether the batch of soft inner capsules meets the conditions for secondary pressing. If the conditions for secondary pressing are met, the soft inner capsule will enter the secondary pressing process of the soft packaging production line.

[0026] Preferably, determining the current state of the soft capsule based on its formulation parameters and storage time specifically involves: Based on the formulation parameters of the soft inner capsules and the temperature and humidity of the storage environment monitored by S3, the corresponding rate constants are retrieved from the mapping relationship library. Combined with the storage time of this batch of soft inner capsules, the predicted values ​​of water content, deformation rate and surface activity of this batch of soft inner capsules are calculated.

[0027] The mapping relationship library is pre-established through the following steps: For each combination of formulation parameters, the changes in water content, deformation rate, and surface activity of the soft inner lining over time were measured under multiple preset temperature and humidity conditions. Regression was performed on each temperature and humidity condition group to determine the rate constant and time exponent of the formulation parameter combination under that temperature and humidity condition. The formulation parameter combination, temperature and humidity condition group, and corresponding rate constant and time exponent were associated and stored to form a mapping relationship library.

[0028] Specifically, the water content of the soft inner capsule shell is determined using an infrared halogen moisture analyzer during production and quality control.

[0029] The deformation rate is calculated by setting a fixed compressive load and measuring the deformation of the soft inner bladder under that load.

[0030] The surface activity value is determined by briefly contacting the surface of the soft inner capsule with a texture analyzer under simulated secondary compression temperature conditions, and then pulling it apart at a constant speed. The maximum force during the separation process is measured, and this force value can be used as a quantitative indicator of surface activity.

[0031] The moisture content of the soft inner capsule shell is a crucial determinant of its adhesive activity. When the moisture content is too low, the shell becomes brittle, loses sufficient adhesive activity, and cannot reliably fuse with fresh adhesive. Therefore, moisture content is the primary indicator for determining whether a soft inner capsule can still be re-pressed.

[0032] Therefore, in the specific implementation process, the predicted moisture content value is obtained through the formula: This can be calculated.

[0033] In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted water content of the capsule shell at that time This indicates the initial water content of the capsule. This represents the water migration rate constant. This indicates the first-time index.

[0034] Because the soft inner bladder will creep and deform due to gravity during storage, if the deformation rate is too large, the soft inner bladder cannot be accurately positioned in the secondary pressing mold, resulting in uneven wall thickness of the soft outer bladder or eccentricity of the soft inner bladder, which affects the quality of the finished product.

[0035] Therefore, in the specific implementation process, the predicted deformation rate is obtained through the formula: This can be calculated.

[0036] In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted value of deformation rate at time Represents the deformation rate constant. This indicates the second time index.

[0037] During storage, the gelatin molecules on the shell surface come into contact with oxygen in the air, undergoing an oxidative cross-linking reaction to form a low-activity film. With decreased surface activity, even if the water content and deformation rate are within acceptable ranges, the interfacial bonding between the soft inner shell and the fresh gelatin solution may still be insufficient, leading to delamination and shell separation.

[0038] Therefore, in the specific implementation process, the predicted surface activity value is obtained through the formula: To obtain.

[0039] In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted surface activity values ​​at that time This indicates the initial surface activity value of the soft capsule. This represents the surface oxidation rate constant.

[0040] This invention characterizes the state of the soft inner capsule from different dimensions by predicting the moisture content, deformation rate, and surface activity, which together determine whether the soft inner capsule is suitable for secondary pressing, thereby rationally arranging the production schedule of each production line.

[0041] Next, the step of determining whether the batch of soft inner capsules meets the secondary pressing conditions based on the current soft inner capsule status involves comparing the predicted values ​​of water content, deformation rate, and surface activity of the batch of soft inner capsules with the water content threshold, deformation rate threshold, and surface activity threshold, respectively.

[0042] Next, the conditions for satisfying the secondary pressing are that the predicted water content of the batch of soft inner capsules is not lower than the water content threshold, the predicted deformation rate is not higher than the deformation rate threshold, and the predicted surface activity is not lower than the surface activity threshold.

[0043] The steps for optimizing production line scheduling are as follows.

[0044] Based on the current load status of the soft packaging production line, the remaining processing time for each batch of soft inner capsules is calculated. The remaining processing time is determined by the minimum of the following: the remaining time for the predicted moisture content to reach the moisture content threshold, the remaining time for the predicted deformation rate to reach the deformation rate threshold, and the remaining time for the predicted surface activity to reach the surface activity threshold. All batches of soft inner capsules are scheduled according to the remaining processing time from smallest to largest. When the difference between the remaining processing time of two or more batches does not exceed the set tolerance, it indicates that the urgency is similar. The absolute value of the difference between the minimum and the second smallest value of the remaining processing time in the three dimensions of each batch is calculated, and the absolute values ​​are sorted from largest to smallest, so that batches with risk concentrated in a single dimension are given priority to enter the secondary compression.

[0045] This invention calculates the remaining processing time for each batch of soft inner capsules and generates a secondary pressing batch scheduling instruction, thereby minimizing the expiration and scrapping of soft inner capsules due to production line scheduling and improving the scientific nature and overall efficiency of production line scheduling.

[0046] In addition, regarding the production line configuration of each production line in this embodiment, the soft packaging production line includes at least: a gelling device, a soft capsule pressing device, and a shaping and drying device; the soft capsule pressing device has primary pressing and secondary pressing functions, and the shaping and drying device is used to perform preliminary shaping of the soft inner capsule after primary pressing.

[0047] The hard capsule production line includes at least: a hard capsule orientation separation device, a material filling device, and a capsule closing device; the hard capsule production line receives soft inner capsules from the soft packaging production line through a cross-line supply channel, and encapsulates the soft inner capsules as filling material inside the hard capsule shell.

[0048] In the hard-pack soft-path, the soft inner capsule does not undergo secondary pressing, and its surface activity is not involved in the process judgment; the soft inner capsule is directly supplied across lines after being produced by the first pressing, and the transit buffer time is controlled by the hard capsule production line, without a separate status judgment step.

[0049] S5: Adjust the secondary compression parameters of the soft inner capsule production line according to the current soft inner capsule status.

[0050] To flexibly address the process requirements posed by changes in the state of the soft inner capsule, in this invention, key parameters such as pressing temperature, moisture content of the outer capsule adhesive, pressing gap, and holding time are dynamically adjusted according to the predicted state of the soft inner capsule, so that the soft inner capsule can still complete high-quality secondary molding even after a certain degree of state change.

[0051] In this embodiment, for every 0.5% decrease in water content below the water content threshold, the water content of the outer capsule adhesive is increased by 0.3 percentage points, and the pressing temperature is increased by 1.5°C. For every 1% increase in deformation rate above the deformation rate threshold, the standard pressing gap is reduced by 1%, and the holding time is extended by 0.2 seconds. For every 10% decrease in surface activity below the surface activity threshold, a spray activation treatment is performed before the second pressing, and the concentration of the spray activation solution is increased by 0.2 percentage points.

[0052] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A production process for a capsule-in-capsule composite dosage form suitable for multi-dosage form compatibility, characterized in that, include: S1: Based on production needs and the physicochemical properties of active ingredients, set the formulation scheme as either soft-pack soft or hard-pack soft, and save the formulation parameters; S2: The soft packaging production line performs one pressing according to the compatibility scheme to prepare soft inner capsules, and automatically records the corresponding formula parameters and production timestamp when each batch of soft inner capsules is produced. S3: Each batch of soft inner capsules is stored in the transit buffer area, and the temperature and humidity of the storage environment are monitored, and the storage time of each batch of soft inner capsules is recorded; S4: Select the production path according to the compatibility scheme: If the compatibility scheme is hard-pack soft, the soft inner capsule is supplied across the production line to the hard capsule production line, and the hard capsule production line performs the filling and packaging operation. If the formulation is soft-pack soft, then the current state of the soft inner capsule is determined based on the formula parameters and storage time of the soft inner capsule; the current state of the soft inner capsule is used to determine whether the batch of soft inner capsules meets the conditions for secondary pressing. If the conditions for secondary pressing are met, the soft inner capsule will enter the secondary pressing process of the soft packaging production line. S5: Adjust the secondary compression parameters of the soft inner capsule production line according to the current soft inner capsule status.

2. The production process for capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility according to claim 1, characterized in that, S4 describes determining the current soft capsule status based on the soft capsule's formulation parameters and storage time, specifically as follows: Based on the formulation parameters of the soft inner capsules and the temperature and humidity of the storage environment monitored by S3, the corresponding rate constants are retrieved from the mapping relationship library. Combined with the storage time of this batch of soft inner capsules, the predicted values ​​of water content, deformation rate and surface activity of this batch of soft inner capsules are calculated.

3. The production process for capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility according to claim 2, characterized in that, The predicted moisture content is obtained using the formula: To calculate; In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted water content of the capsule shell at that time This indicates the initial water content of the capsule. This represents the water migration rate constant. This indicates the first-time index.

4. The production process for capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility according to claim 2, characterized in that, The predicted deformation rate is obtained through the formula: To calculate; In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted value of deformation rate at time Represents the deformation rate constant. This indicates the second time index.

5. The production process for capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility according to claim 2, characterized in that, The surface activity prediction value is obtained through the formula: To obtain; In the formula, This indicates that the soft capsule has a storage time of [duration]. Predicted surface activity values ​​at that time This indicates the initial surface activity value of the soft capsule. This represents the surface oxidation rate constant.

6. The production process for capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility according to claim 2, characterized in that, The mapping relationship database is pre-established through the following steps: For each combination of formulation parameters, the changes in water content, deformation rate, and surface activity of the soft inner lining over time were measured under multiple preset temperature and humidity conditions. For each temperature and humidity condition group, a regression is fitted to determine the rate constant and time exponent of the formula parameter combination under that temperature and humidity condition; the formula parameter combination, temperature and humidity condition group and the corresponding rate constant and time exponent are associated and stored to form a mapping relationship library.

7. The production process for capsule-in-capsule composite dosage forms applicable to multi-dosage form compatibility according to claim 2, characterized in that, S4 describes determining whether the batch of soft inner capsules meets the secondary pressing conditions based on the current soft inner capsule status. This involves comparing the predicted values ​​of water content, deformation rate, and surface activity of the batch of soft inner capsules with the water content threshold, deformation rate threshold, and surface activity threshold, respectively.

8. The production process for a capsule-in-capsule composite dosage form suitable for multi-dosage form compatibility according to claim 7, characterized in that, The conditions for satisfying the secondary pressing described in S4 are that the predicted water content of the soft inner capsules of this batch is not lower than the water content threshold, the predicted deformation rate is not higher than the deformation rate threshold, and the predicted surface activity is not lower than the surface activity threshold.

9. The production process for a capsule-in-capsule composite dosage form applicable to multi-dosage form compatibility according to claim 1, characterized in that, The soft capsule production line includes at least: a gelling device, a soft capsule pressing device, and a shaping and drying device; the soft capsule pressing device has primary pressing and secondary pressing functions, and the shaping and drying device is used to perform preliminary shaping of the soft capsules after primary pressing.

10. The production process for a capsule-in-capsule composite dosage form applicable to multi-dosage form compatibility according to claim 1, characterized in that, The hard capsule production line includes at least: a hard capsule orientation separation device, a material filling device, and a capsule closing device; the hard capsule production line receives soft inner capsules from the soft packaging production line through a cross-line supply channel, and encapsulates the soft inner capsules as filling material inside the hard capsule shell.