Naoxuekang dropping pill placebo as well as preparation method and application thereof
By using polyethylene glycol, caramel coloring, and compound flavoring to prepare a placebo for Naoxuekang Dripping Pills, the problems of insufficient simulation accuracy and pharmacological activity interference in existing technologies were solved, achieving highly consistent placebo preparation that meets the needs of clinical trials.
Patent Information
- Application Number
- CN202610063559.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-19
- Publication Date
- 2026-02-24
AI Technical Summary
The existing placebo of Naoxuekang Dripping Pills lacks sufficient accuracy in simulating sensory and physical properties, making it difficult to meet the stringent requirements of double-blind, randomized controlled clinical trials. Furthermore, it poses a potential risk of interfering with pharmacological activity, affecting the reliability of trial data.
Using polyethylene glycol, caramel coloring, and compound flavoring as raw materials and excipients, a placebo with no pharmacological activity was prepared by controlling the pill weight, shape, color, odor, and taste to be highly consistent with the original drug.
It improves the sensory and physical properties matching between the placebo and the original drug, ensuring the reliability and safety of clinical trials, meeting food additive standards, and not producing significant adverse reactions.
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Abstract
Description
Technical Field
[0001] This application relates to the technical field of pharmaceuticals, specifically to a placebo of Naoxuekang Dripping Pills, its preparation method, and its application. Background Technology
[0002] Naoxuekang Dripping Pills, a commonly used traditional Chinese medicine for promoting blood circulation and removing blood stasis, has its main ingredient derived from leeches. With the deepening of evidence-based medicine in the field of traditional Chinese medicine and the increasing requirements for the standardization of clinical trial design, the use of high-quality placebo controls has become a necessary design step in order to scientifically verify the true efficacy of Naoxuekang Dripping Pills, eliminate subjective perception bias of efficacy, and accurately distinguish between adverse drug reactions and placebo effects.
[0003] However, the current placebo preparation technology for Naoxuekang Dripping Pills still faces significant bottlenecks, making it difficult to meet the stringent requirements of double-blind, randomized controlled clinical trials. This is mainly reflected in the following aspects: (1) Insufficient accuracy in simulating sensory and physical properties: Naoxuekang Dripping Pills have a unique brownish-red appearance and a slight fishy smell (derived from animal drug components). Existing placebos are mostly prepared directly using simple excipients (such as starch, dextrin, and pigments). Although they can roughly imitate color and shape, they differ significantly from the original drug in terms of odor reproduction (such as the inability to accurately simulate the slight fishy smell of natural animal drugs, or the artificial addition of fragrances leading to odor deviation) and key indicators. This can easily lead to "blinding" by subjects or researchers, seriously affecting the reliability of experimental data. (2) Potential risk of pharmacological activity interference: In order to pursue physical properties similar to the original drug, some placebos may use excipients with weak physiological activity, resulting in the placebo itself having a trace amount of blood-activating and stasis-removing activity, thereby affecting the experimental results.
[0004] In summary, to meet the clinical research needs of Naoxuekang Dripping Pills, developing a dedicated placebo that is pharmacologically inactive, has sensory and physical properties highly similar to the original drug, and is stable over a long period has become a key technical requirement for breaking through the bottleneck of its clinical trial design and promoting the standardization of the efficacy evaluation system of traditional Chinese medicine. This is of great significance for improving the level of evidence-based treatment for Naoxuekang Dripping Pills and ensuring the safety of clinical medication. Summary of the Invention
[0005] To address the aforementioned technical problems, this application provides a placebo of Naoxuekang Dripping Pills, its preparation method, and its application.
[0006] In one aspect, this application provides a placebo of Naoxuekang Dripping Pills, specifically comprising the following components in parts by weight: 7000-13000 parts of matrix, 100-600 parts of pigment, and 50-300 parts of compound fragrance; The matrix is polyethylene glycol; the pigment is caramel pigment; the compound flavor is composed of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol in a weight ratio of 1500-3000:1000-4000:1-50:1-50:10-100:1000-3000:99500000-100000000 by weight.
[0007] This application uses safe, non-toxic, and harmless polyethylene glycol, caramel, and compound flavoring as raw and auxiliary materials for preparing the placebo of Naoxuekang Dripping Pills, which complies with relevant legal standards. The formulation does not contain any medicinal ingredients, and the amount of caramel and compound flavoring used is within the applicable range for food additives. It will not produce obvious adverse reactions or harm human health.
[0008] The placebo of Naoxuekang Dripping Pills provided in this application has a high degree of consistency with the original drug sample in terms of characteristics such as pill weight, appearance, color, smell and taste. It has been demonstrated through clinical trials that it can be used as a placebo in clinical practice.
[0009] Preferably, the placebo of Naoxuekang Dripping Pills specifically comprises the following components in parts by weight: 10,000-12,000 parts of matrix, 200-400 parts of pigment, and 100-200 parts of compound fragrance.
[0010] In one specific implementation, the weight parts of the matrix in the Naoxuekang Dripping Pill placebo can be 10,000, 11,000, or 12,000 parts, the weight parts of the pigment can be 200, 300, or 400 parts, and the weight parts of the compound fragrance can be 100, 150, or 200 parts.
[0011] Experimental analysis shows that by controlling the dosage of each raw material component within the above-mentioned range, the overall performance of the Naoxuekang Dripping Pill placebo can be further improved.
[0012] Preferably, the polyethylene glycol is selected from any one or more of polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 8000.
[0013] Preferably, the compound fragrance is composed of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol in a weight ratio of 1500-2000:3000-4000:10-30:30-50:50-80:1000-2000:99500000-100000000 by weight.
[0014] Preferably, the preparation method of the compound fragrance is as follows: propylene glycol solvent is heated to 50-60°C according to the formula amount, p-cresol is added, and stirred until completely dissolved; the remaining propionic acid, isovaleric acid, 2-methylpyrazine, 2,3-dimethylpyrazine, and limonene are added according to the formula, and the mixture is stirred and mixed evenly. The mixture is then allowed to stand at room temperature for 10-15 hours to obtain the final product.
[0015] In the preparation of compound fragrance, propylene glycol is used as a solvent. The solid fragrance is first added to the solvent and completely dissolved, and then the remaining liquid fragrance is added. This can effectively ensure the comprehensive performance of the placebo of Naoxuekang Dripping Pills.
[0016] Preferably, the placebo weight of the Naoxuekang Dripping Pills is 30-40 mg / pill.
[0017] Secondly, this application provides a method for preparing the placebo of the aforementioned Naoxuekang Dripping Pills, comprising the following steps: Heat polyethylene glycol until it is completely melted, then add pigments and compound fragrances, stir evenly, and keep warm at 70-85℃ for more than 30 minutes to obtain a mixture. Then, drop the mixture at a dripping temperature of 52-67℃ into liquid paraffin at a cooling temperature of 1-8℃. After forming, remove the pellets and absorb the liquid paraffin from the surface of the pellets to obtain the final product.
[0018] Preferably, the dripping temperature of the mixture is 55-65°C, and the cooling temperature of the liquid paraffin is 2-6°C.
[0019] Preferably, the dripping temperature of the mixture is 57-63°C, and the cooling temperature of the liquid paraffin is 3-5°C.
[0020] In one specific implementation, the dripping temperature of the mixture is 60°C and the cooling temperature of the liquid paraffin is 4°C.
[0021] Experimental analysis shows that, in the preparation method of Naoxuekang Dripping Pills placebo, by controlling the dripping temperature of the mixture and the cooling temperature of the liquid paraffin within the above-mentioned range, the overall performance of Naoxuekang Dripping Pills placebo can be further improved.
[0022] Thirdly, this application provides the use of the aforementioned Naoxuekang Dripping Pill placebo in the preparation of Naoxuekang medicine.
[0023] In summary, the technical solution of this application has the following effects: The placebo ingredients for the Naoxuekang Dripping Pills provided in this application are polyethylene glycol, caramel, and compound flavoring. These ingredients are safe, non-toxic, and harmless, and comply with relevant legal standards. The formulation does not contain any medicinal ingredients, and the amount of caramel and compound flavoring used is within the applicable range for food additives. They will not produce obvious adverse reactions or harm human health.
[0024] The placebo of Naoxuekang Dripping Pills provided in this application has a high degree of consistency with the original drug sample in terms of characteristics such as pill weight, appearance, color, smell and taste. It has been demonstrated through clinical trials that it can be used as a placebo in clinical practice. Detailed Implementation
[0025] The present application will be further described in detail below with reference to embodiments, comparative examples and performance test results. These embodiments should not be construed as limiting the scope of protection claimed in this application.
[0026] Example
[0027] Examples 1-5 Examples 1-5 provide a placebo of Naoxuekang Dripping Pills and its preparation method.
[0028] The difference in the above embodiments is that the amount of each raw material component is different, as shown in Table 1.
[0029] The preparation method of the compound fragrance in the above embodiments is as follows: Propylene glycol solvent is added according to the formula amount, heated to 55°C, solid fragrance p-cresol is added, and stirred until completely dissolved; the remaining propionic acid, isovaleric acid, 2-methylpyrazine, 2,3-dimethylpyrazine, and limonene liquid fragrance are added according to the formula, and stirred thoroughly to ensure uniform aroma and density. The mixture is then aged at room temperature (25°C) for 12 hours to obtain the final product. The weight ratio of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol is 1500:4000:10:50:50:2000:100000000.
[0030] The preparation method of the placebo for Naoxuekang Dripping Pills in the above embodiments is as follows: Polyethylene glycol 6000 is placed in a preparation tank and heated and melted. After the polyethylene glycol has completely melted, pigments and compound fragrances are added, stirred evenly, kept at 80°C for 60 minutes, and cooled to 60°C. Then, the mixture with a dripping temperature of 60°C is dripped into liquid paraffin with a cooling temperature of 4°C. After forming, the pills are taken out, and the liquid paraffin on the surface of the dripping pills is absorbed to obtain the product.
[0031] Table 1. Amounts of each raw material component in Examples 1-5 and Comparative Example 1
[0032] Examples 6-9 Examples 6-9 provide a placebo of Naoxuekang Dripping Pills and its preparation method.
[0033] The difference between the above embodiments and Embodiment 3 is that the composition or preparation method of the compound fragrance is different, as shown below.
[0034] In Example 6: In the compound fragrance, the weight ratio of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol is 2000:3000:30:30:80:1000:100000000.
[0035] In Example 7: In the compound fragrance, the weight ratio of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol is 3000:1000:50:1:100:1000:100000000.
[0036] In Example 8: In the compound fragrance, the weight ratio of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol is 1500:4000:1:50:10:3000:100000000.
[0037] In Example 9: The preparation method of the compound fragrance is as follows: First, add propylene glycol solvent according to the formula amount, heat to 55°C, add solid fragrance p-cresol, and stir until completely dissolved; add the remaining propionic acid, isovaleric acid, 2-methylpyrazine, 2,3-dimethylpyrazine, and limonene liquid fragrance according to the formula, and stir thoroughly to make the aroma and density uniform. Let it stand at 55°C for 12 hours to obtain the final product.
[0038] All other process parameters in the above embodiments are the same as those in Embodiment 3.
[0039] Examples 10-13 Examples 10-13 respectively provide a placebo of Naoxuekang Dripping Pills and its preparation method.
[0040] The difference between the above embodiments and Embodiment 3 is that the preparation method of the placebo for Naoxuekang Dripping Pills is different, as shown below.
[0041] In Example 10: the dripping temperature of the mixture was 52°C.
[0042] In Example 11: the dripping temperature of the mixture is 55°C.
[0043] In Example 12: the dripping temperature of the mixture is 65°C.
[0044] In Example 13: the dripping temperature of the mixture was 67°C.
[0045] All other process parameters in the above embodiments are the same as those in Embodiment 3.
[0046] Comparative Example Comparative Example 1 Comparative Example 1 provides a placebo and its preparation method.
[0047] The difference between Comparative Example 1 and Example 3 is that the amounts of each raw material component are different, as shown in Table 1.
[0048] In Comparative Example 1, all other process parameters were the same as in Example 3.
[0049] Comparative Examples 2-4 Comparative Examples 2-4 each provide a placebo and its preparation method.
[0050] The difference between the above comparative example and Example 3 is that the composition of the compound fragrance is different, as shown below.
[0051] In Comparative Example 2: In the compound fragrance, propionic acid was used in place of p-isovaleric acid in equal amounts.
[0052] In Comparative Example 3: In the compound fragrance, propylene glycol was used as an equal amount of solvent instead of 2-methylpyrazine.
[0053] In Comparative Example 4: In the compound fragrance, the weight ratio of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol is 1000:4500:1:80:5:4000:100000000.
[0054] All other process parameters in the above comparative examples are the same as those in Example 3.
[0055] Comparative Examples 5-7 Comparative Examples 5-7 each provide a placebo and its preparation method.
[0056] The difference between the above comparative example and Example 3 is that the preparation method of the placebo of Naoxuekang Dripping Pills is different, as shown below.
[0057] In Comparative Example 5: the dropping temperature was 45℃.
[0058] In Comparative Example 6: the dropping temperature was 75℃.
[0059] In Comparative Example 7: the cooling temperature of the liquid paraffin was 12°C.
[0060] All other process parameters in the above comparative examples are the same as those in Example 3.
[0061] Performance testing Evaluation Method: This method uses pill weight, appearance, color, odor, and taste as indicators for scoring. The original drug sample was provided by Beijing Kang'erfu Pharmaceutical Co., Ltd.; pill weight: 35mg / pill; appearance: spherical; color: brownish-red; odor: fishy; taste: slightly astringent.
[0062] The pill weight score is calculated as follows: 10.0 - |5 × (placebo pill weight / original drug sample pill weight - 1)|. A score of 10.0 is given for appearance, color, odor, and taste being exactly the same as the original drug sample; 7.5 for similarity; 5.0 for uncertainty; 2.5 for significant difference; and 0 for complete difference. Scores in between are given based on the specific circumstances. Higher scores indicate greater similarity to the investigational drug. Twenty judges, randomly selected from clinical researchers (investigators, research nurses, quality control personnel, etc.) and patients, were involved. All judges signed informed consent forms. Each judge rated 10 Naoxuekang Dripping Pills placebos from the examples or comparative examples based on four aspects: appearance, color, odor, and taste. The average score across all five aspects was used as the overall score.
[0063] Test results are shown in Table 2.
[0064] Table 2 Performance evaluation results of Naoxuekang Dripping Pills placebo in the examples or comparative examples
[0065] As can be seen from the test results in Table 2 above, the placebo of Naoxuekang Dripping Pills prepared using the technical solution provided in this application has a high degree of consistency with the test original drug sample in terms of five characteristics: pill weight, appearance, color, smell and taste.
[0066] By comparing the test results of Examples 1-5 with Comparative Example 1, it can be seen that the amount of each raw material component has a significant impact on the performance of the placebo. In Comparative Example 1, the amount of pigment was relatively small while the amount of compound flavor was relatively large, resulting in a lower score for the color, odor, and taste of the prepared Naoxuekang Dripping Pills placebo. In contrast, the examples in this application, by screening and optimizing the amount of pigment and compound flavor, produced a Naoxuekang Dripping Pills placebo with excellent performance.
[0067] By comparing the test results of Examples 3, 6-9, and Comparative Examples 2-4, it can be seen that the composition of the compound flavoring has a significant impact on the performance of the placebo. In Comparative Example 2, the compound flavoring used an equal amount of propionic acid instead of p-isovaleric acid, and the resulting placebo for Naoxuekang Dripping Pills scored poorly in all five aspects: pill weight, appearance, color, odor, and taste. In Comparative Example 3, the compound flavoring used an equal amount of propylene glycol instead of 2-methylpyrazine, and in Comparative Example 4, the weight ratio of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol was 1000:4500:1:80:5:4000:100000000, resulting in a placebo for Naoxuekang Dripping Pills with low scores in both odor and taste. In contrast, the Naoxuekang Dripping Pills placebo prepared by the embodiments of this application through screening and optimization of the compound flavoring composition exhibits excellent performance.
[0068] By comparing the test results of Examples 3, 10-13, and Comparative Examples 5-7, it can be seen that the preparation method of the Naoxuekang Dripping Pill placebo has a significant impact on the performance of the placebo. In Comparative Example 5, the dripping temperature of the mixture was 45°C; in Comparative Example 6, the dripping temperature of the mixture was 75°C; and in Comparative Example 7, the cooling temperature of the liquid paraffin was 12°C. The Naoxuekang Dripping Pill placebo prepared in these examples scored poorly in all five aspects: pill weight, appearance, color, odor, and taste. In contrast, in the preparation method of the Naoxuekang Dripping Pill placebo in this application, by controlling the dripping temperature of the mixture to 52-67°C and the cooling temperature of the liquid paraffin to 1-8°C, the finished Naoxuekang Dripping Pill placebo exhibited excellent performance.
[0069] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.
Claims
1. A placebo of Naoxuekang Dripping Pills, characterized in that, Specifically, it includes the following components by weight: 7000-13000 parts matrix, 100-600 parts pigment, and 50-300 parts compound fragrance; The matrix is polyethylene glycol; The pigment is caramel pigment; the compound flavor is composed of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol in a weight ratio of 1500-3000:1000-4000:1-50:1-50:10-100:1000-3000:99500000-100000000 by weight.
2. The placebo of Naoxuekang Dripping Pills according to claim 1, characterized in that, Specifically, it includes the following components by weight: 10,000-12,000 parts of matrix, 200-400 parts of pigment, and 100-200 parts of compound fragrance.
3. The placebo of Naoxuekang Dripping Pills according to claim 1, characterized in that, The polyethylene glycol is selected from any one or more of polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 8000.
4. The placebo of Naoxuekang Dripping Pills according to claim 1, characterized in that, The compound fragrance is composed of propionic acid, isovaleric acid, 2-methylpyrazine, p-cresol, 2,3-dimethylpyrazine, limonene, and propylene glycol in a weight ratio of 1500-2000:3000-4000:10-30:30-50:50-80:1000-2000:99500000-100000000 by weight.
5. The placebo of Naoxuekang Dripping Pills according to claim 1, characterized in that, The preparation method of the compound fragrance is as follows: propylene glycol is heated to 50-60℃ according to the formula, p-cresol is added and stirred until completely dissolved; the remaining propionic acid, isovaleric acid, 2-methylpyrazine, 2,3-dimethylpyrazine and limonene are added according to the formula, and the mixture is stirred and mixed evenly. The mixture is then aged at room temperature for 10-15 hours to obtain the final product.
6. The placebo of Naoxuekang Dripping Pills according to claim 1, characterized in that, The placebo of the Naoxuekang Dripping Pills weighs 30-40 mg per pill.
7. A method for preparing a placebo of Naoxuekang Dripping Pills as described in any one of claims 1-6, characterized in that, Includes the following steps: Heat polyethylene glycol until it is completely melted, then add pigments and compound fragrances, stir evenly, and keep warm at 70-85℃ for more than 30 minutes to obtain a mixture. Then, drop the mixture at a dripping temperature of 52-67℃ into liquid paraffin at a cooling temperature of 1-8℃. After forming, remove the pellets and absorb the liquid paraffin from the surface of the pellets to obtain the final product.
8. The method for preparing the placebo of Naoxuekang Dripping Pills according to claim 7, characterized in that, The dripping temperature of the mixture is 55-65℃, and the cooling temperature of the liquid paraffin is 2-6℃.
9. The method for preparing the placebo of Naoxuekang Dripping Pills according to claim 8, characterized in that, The dripping temperature of the mixture is 57-63℃, and the cooling temperature of the liquid paraffin is 3-5℃.
10. The use of a placebo of Naoxuekang Dripping Pills as described in any one of claims 1-6 in the preparation of Naoxuekang medicament.