Composition for preparing tretinoin soft capsule

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a composition for preparing a tretinoin soft capsule, the composition is prepared by mixing tretinoin, soybean oil and beeswax according to a certain proportion and then preparing a soft capsule content, the content can uniformly mix the tretinoin in an oily matrix, and the tretinoin soft capsule has better stability and redispersibility, so that the soft capsule can be used for preparing soft capsules. The method can be used for preparing tretinoin soft capsules, does not cause medicine sedimentation, and is stable and controllable in quality. The tretinoin soft capsule preparation prepared by the invention is suitable for clinical application, and lays a foundation for developing the tretinoin soft capsule which can be orally taken by children.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a composition for preparing retinoic acid soft capsules. The composition comprises retinoic acid, soybean oil and yellow beeswax mixed in a certain proportion and used to prepare soft capsule contents. The contents can mix retinoic acid in an oily matrix and have good stability and redispersibility. The composition can be used for the preparation of retinoic acid soft capsules without drug sedimentation and with stable and controllable quality. Background Art

[0002] According to the definition of the World Health Organization (WHO), rare diseases are diseases with a prevalence of 0.65 to 1‰ of the total population. Due to the small number of patients, it is difficult to conduct relevant pathological research, resulting in the treatment and drug development of such rare diseases still being a major problem worldwide. [1-2] It is especially difficult to develop drugs for rare diseases in children. Strengthening the development of children's health is of great significance to protecting and improving people's livelihood and improving the health quality of the whole people. [3] .

[0003] According to research reports, the rare disease, such as acute promyelocytic leukemia (APL), clinically belongs to the M3 type of acute non-lymphocytic leukemia (ANLL), which was once the most dangerous type of leukemia. [4] Clinical practice shows that the combination of arsenic trioxide and retinoic acid has greatly improved the prognosis of ANLL and has become the best treatment for ANLL. Although major breakthroughs have been made in the treatment of APL, the development of related drugs for children has not yet been seen in clinical research practice. [5] .

[0004] In addition, according to records, children's medicines have long been in short supply, with a single dosage form, irregular medication, and inadequate safety evaluation. The damage caused by this has been shown to be very serious in clinical practice. [6-7] . It is known in the industry that the absorption and metabolic systems of children are not fully developed, and their pharmacodynamics, pharmacokinetic, and toxicokinetic characteristics are significantly different from those of adults. Psychologically, children have higher requirements for the color, smell, appearance, and compliance of drugs. Whether from a physiological or pharmacological perspective, children are not just smaller versions of adults, and the dosage should be adjusted based on the corresponding clinical trial data. Difficulties in children's medication compliance and quantitative accuracy remain two major challenges in the development of pediatric drugs, and are also major obstacles to the development of "child-friendly" drug dosage forms. Among them, the development of retinoic acid oral soft capsules that can be used for rare diseases in children is one of the problems that need to be solved urgently in clinical and social practice.

[0005] It is known that retinoic acid, also known as retinoic acid, is an intermediate metabolite of vitamin A in the body. It mainly affects bone growth and epithelial metabolism, promotes epidermal cell proliferation, differentiation, keratin dissolution, and inhibits tumors. It participates in regulating epidermal cell proliferation, differentiation, apoptosis, immune regulation, and inhibits sebaceous gland secretion and other biological effects. Retinoic acid is mainly used in the treatment of various skin diseases such as psoriasis, acne, skin T lymphocytoma, skin photoaging, keratotic skin diseases, and epidermal tumors. [8] .

[0006] Studies have shown that because retinoic acid is a polyene compound, it is almost insoluble in water, unstable when exposed to light, air and oxidants, and is prone to isomerization. These properties bring certain difficulties to retinoic acid preparations. [9] At present, the common clinical dosage forms of retinoic acid include creams, pills, soft capsules, etc. There are also studies reporting that it can be prepared into self-microemulsions, nanosuspensions, etc. [10-15] Based on the current state of the art, the inventors of this application intend to provide a composition for preparing tretinoin soft capsules, and further prepare tretinoin soft capsule preparations to improve their stability for clinical application, and lay the foundation for the development of tretinoin soft capsules that are suitable for oral administration by children.

[0007] References related to the present invention include:

[0008] 1. Shao Wenbin, Li Yangyang, Wang Fei, et al. Current status and solutions for accessibility of rare disease drugs in China. China Food and Drug Administration. 2019, 2: 8-15.

[0009] 2. Ji Xiwei, Liang Jiabin, Ji Shuangmin. Research status of rare disease treatment at home and abroad. Chinese Journal of Clinical Pharmacology. 2019, 3: 305-308.

[0010] 3. Xu Haopeng, Zhu Chong, Gong Mengchun, et al. Current status and future of rare disease research in China. Peking Union Medical College Journal. 2018, 1: 5-9.

[0011] 4. Jing Li, Wang Qin, Yuan Kaifeng. Observation on the short-term and long-term efficacy of different regimens in the treatment of acute promyelocytic leukemia. Chinese Journal of Frontier Medicine. 2015, 8: 48-51.

[0012] 5. Han Binghong, Wang Dianzhi, Wang Zhanying, et al. Clinical observation of low-dose arsenite / retinoic acid regimen in the treatment of myelodysplastic syndrome in children. Chinese Journal of Traditional Chinese Medicine and Pharmacy. 2015, 6: 664-666.

[0013] 6. Wang Feng. Progress in the development of dosage forms of Chinese medicine preparations for children. Chinese Medical Abstracts: Pediatrics. 2008, 3: 195-197.

[0014] 7. Yu Kunjiao. Current status and dosage form design of pediatric pharmaceutical preparations. Shanghai Medicine. 201, 38(15): 91-94.

[0015] 8. Zhou Xin, Zhang Xibao. Current status and progress of clinical application of retinoic acid in dermatology. Journal of Clinical Dermatology. 2011, 40(11): 706-709.

[0016] 9. Zhang Yanmei, Hu Yongfu, Zhang Lihua. Research progress of retinoic acid preparations in China. Hebei Medicine. 2006(10):986-987.

[0017] 10. Yan Zhuoli, Li Daicheng. Preparation and quality control of compound retinoic acid cream. Chinese Pharmacy, 2006, 17: 269. 11. Yu Xiangan, Jiang Yina. Preparation and clinical application of compound retinoic acid ointment. Chinese Journal of Drugs and Clinics, 2004, 4: 51-52.

[0018] 12. Liu Fuzhen, Wang Zhiyuan, Deng Wenhua. Preparation of retinoic acid dripping pills. Chinese Journal of New Drugs, 2003, 12: 635-637.

[0020] 13. Quan Dongqin, Xu Guixia. In vitro and in vivo evaluation of self-emulsifying drug delivery system of all-trans retinoic acid. Acta Pharmaceutica Sinica, 2005, 40: 76-79.

[0022] 14. Quan Dongqin, Xu Guixia. In vitro dissolution of retinoic acid self-emulsifying soft capsules and pharmacokinetics in beagle dogs. Journal of Shenyang Pharmaceutical University, 2004, 21: 408-411.

[0024] 15. Duan Lei, Xia Qiang, Ma Quanhong, et al. Preparation and characterization of retinoic acid nanoparticle suspension. Journal of Southeast University (Natural Science Edition), 2004, 34: 344-345. Summary of the invention

[0025] The purpose of the present invention is to provide a composition for preparing tretinoin soft capsules based on the current state of the prior art, and to further prepare tretinoin soft capsule preparations to improve their stability for clinical application, and to lay a foundation for the development of tretinoin soft capsules that are suitable for oral administration by children.

[0026] Specifically, the present invention provides a composition for preparing tretinoin soft capsules, wherein the composition comprises tretinoin, soybean oil and yellow beeswax mixed in a certain proportion and used to prepare soft capsule contents, wherein the contents can mix tretinoin in an oily matrix and have good stability and redispersibility, and are further used for the preparation of tretinoin soft capsule preparations, without drug sedimentation, and with stable and controllable quality.

[0027] More specifically,

[0028] The present invention adopts modern technical means to provide an excellent retinoic acid soft capsule content prepared according to a certain ratio. The content consists of retinoic acid, soybean oil and yellow beeswax, and the ratio of the three can be changed within the following range: retinoic acid 1-6%, soybean oil 91-98%, and yellow beeswax 1-3%.

[0029] In the present invention, within the ratio range of the above contents, a more preferred ratio range is: retinoic acid 1-4%, soybean oil 94-98%, and yellow beeswax 1-2%.

[0030] Using the above-mentioned contents and their component ratio range system as the soft capsule contents can obtain better stability and redispersibility, which is conducive to the preparation of stable soft capsule preparations.

[0031] The present invention adopts the following method to prepare the retinoic acid soft capsule preparation: according to the above-mentioned content prescription and its component ratio, the retinoic acid soft capsule preparation is prepared according to the following process method:

[0032] First, add yellow beeswax to soybean oil, dissolve and mix in a 70°C water bath, and when cooled to room temperature, add retinoic acid raw materials and stir thoroughly to obtain retinoic acid soft capsule contents; place the above contents in a soft capsule pressing machine and press at a gelatin: glycerol: water ratio of 1: (0.4-0.5): 1 to obtain a retinoic acid soft capsule preparation.

[0033] The present invention conducts an experiment on the effect of yellow beeswax content on the sedimentation volume ratio of the suspension of soft capsule contents, and the results show that the addition of yellow beeswax can significantly improve the stability of the prescription. When the proportion of yellow beeswax in the prescription is higher than 1%, the prescription stability is better, and there is no obvious sedimentation within 24 hours.

[0034] The invention conducts an experiment on the influence of the yellow beeswax content of the soft capsule content on the uniformity of the suspension. The result shows that adding yellow beeswax to the prescription can significantly improve the uniformity of retinoic acid. When the yellow beeswax ratio is between 1% and 2%, the medicine is basically completely mixed and the content difference is less than 3%.

[0035] The present invention conducts an experiment on the effect of yellow beeswax content on the redispersibility of a suspension of soft capsule contents, and the results show that yellow beeswax can significantly improve the redispersibility of the suspension, and as the proportion of yellow beeswax in the prescription increases, the redispersibility also increases accordingly. When the proportion of yellow beeswax in the prescription is between 1% and 2%, the suspension has good redispersibility and can be completely dispersed by slight shaking.

[0036] The present invention conducts an experiment on the influence of drug content on the sedimentation volume ratio of the suspension of soft capsule contents, and the results show that when the suspension matrix is ​​soybean oil: yellow beeswax at a ratio of 1:100, the sedimentation volume ratio of the suspension decreases as the proportion of retinoic acid in the prescription increases, and when the drug content does not exceed 6%, the sedimentation volume ratio is greater than 0.9 within 8 hours.

[0037] The present invention provides a composition for preparing tretinoin soft capsules, and further prepares tretinoin soft capsule preparations, which can improve the stability of the tretinoin soft capsule preparations and make them suitable for clinical application, and lay a foundation for developing tretinoin soft capsules suitable for oral administration by children.

[0038] Table 1 shows the effect of the amount of yellow beeswax added on the sedimentation volume ratio of the suspension of soft capsule contents.

[0039] Table 2 shows the effect of yellow beeswax content on the uniformity of the drug suspension in the soft capsule content.

[0040] Table 3 shows the effect of yellow beeswax content on the redispersibility of the soft capsule suspension.

[0041] Table 4 shows the effect of retinoic acid content on the sedimentation volume ratio of the suspension of soft capsule contents.

[0042]

[0043] Table 2 Effect of yellow beeswax content on drug uniformity of soft capsule suspension

[0044]

[0045]

[0046] Table 3 Effect of beeswax content on the redispersibility of soft capsule suspension

[0047]

[0048] Table 4 Effect of retinoic acid content on sedimentation volume ratio of soft capsule suspension

[0049] BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 This is a UV scan of retinoic acid.

[0051] Figure 2 This is a UV scan of soybean oil.

[0052] Figure 3 This is a UV scan of yellow beeswax.

[0053] Figure 4 This is the UV scan of blank solvent. DETAILED DESCRIPTION

[0054] The present invention is further explained below by means of specific examples, but is by no means intended to limit the present invention.

[0055] [Example 1] Effect of yellow beeswax content on the sedimentation volume ratio of soft capsule content suspension

[0056] Take 0, 30, 50, 100, 150, and 200 mg of yellow beeswax and add them to 10 g of soybean oil. Heat in a 70°C water bath and stir evenly. After cooling, add 500 mg of retinoic acid API, stir well again, pour into a 10 ml graduated cylinder to the 10 ml mark, wrap the mouth of the graduated cylinder with sealing film, and let it stand. Observe and record the stratification at 1, 2, 4, 6, 8, 12, and 24 hours, and calculate the sedimentation volume ratio.

[0057] From the results in Table 1, it can be seen that the addition of yellow beeswax can significantly improve the stability of the prescription. When the proportion of yellow beeswax in the prescription is higher than 1%, the prescription stability is better, and there is no obvious sedimentation within 24 hours.

[0058] [Example 2] Effect of yellow beeswax content in soft capsules on the uniformity of the suspension

[0059] Take 0, 30, 50, 100, 150, 200 mg of yellow beeswax and add them to 10 g of soybean oil, heat in a 70°C water bath and stir evenly. After cooling, add 500 mg of retinoic acid API, stir thoroughly and pour into a 10 ml measuring cylinder to the 10 ml mark, use a pipette to take 100 ul of suspension from the upper layer (8 ml mark), middle layer (5 ml mark), and lower layer (2 ml mark), wipe off the liquid attached to the outer layer with paper, add to a 10 ml volumetric flask, flush the inner wall of the pipette tip with isopropanol: acetonitrile (7:3) solution, combine the washing liquid, make up to volume with isopropanol: acetonitrile (7:3) solution, and ultrasonicate for 10 minutes. Take 100ul of liquid in a 10ml volumetric flask, dilute to volume with isopropanol:acetonitrile (7:3) solution, use isopropanol:acetonitrile (7:3) solution as blank control, measure absorbance at 350nm, and calculate the RSD value of the upper, middle and lower layers. From the results in Table 2, it can be seen that adding yellow beeswax to the prescription can significantly improve the uniformity of retinoic acid. When the proportion of yellow beeswax is between 1% and 2%, the drug is basically completely mixed, and the content difference is less than 3%.

[0060] [Example 3] Effect of yellow beeswax content on the redispersibility of soft capsule suspension

[0061] Take 0, 30, 50, 100, 150, and 200 mg of yellow beeswax and add them to 10 g of soybean oil. Heat in a 70°C water bath and stir evenly. After cooling, add 500 mg of retinoic acid API, stir thoroughly and pour into a 10 ml measuring cylinder to the 10 ml mark. Wrap the measuring cylinder mouth with sealing film and let it stand for 24 hours. Rotate the measuring cylinder upside down 180°, turn it upside down once, and stay for 5 seconds, which is counted as one shake. Record the number of rotations required for redispersion.

[0062] It can be seen from the results in Table 3 that yellow beeswax can significantly improve the redispersibility of the suspension, and as the proportion of yellow beeswax in the prescription increases, the redispersibility also increases. When the proportion of yellow beeswax in the prescription is between 1% and 2%, the suspension has good redispersibility and can be completely dispersed by slight shaking.

[0063] [Example 4] Effect of drug content on the sedimentation volume ratio of the soft capsule suspension

[0064] Take 600 mg of yellow beeswax and add it to 60 g of soybean oil. Heat it in a 70°C water bath and stir it evenly. After cooling, weigh 5 portions of 10 g of the mixed liquid and add 300, 400, 500, 600, and 700 mg of retinoic acid API respectively. Stir and mix thoroughly and pour into a 10 ml graduated cylinder to the 10 ml mark. Wrap the mouth of the graduated cylinder with sealing film and let it stand. Observe and record the stratification at 1, 2, 4, 6, and 8, and calculate the sedimentation volume ratio.

[0065] From the results in Table 4, it can be seen that when the suspension matrix is ​​soybean oil: yellow beeswax at a ratio of 1:100, the sedimentation volume ratio of the suspension decreases as the proportion of retinoic acid in the prescription increases. When the drug content does not exceed 6%, the sedimentation volume ratio is greater than 0.9 within 8 hours.

[0066] [Example 5] UV scanning of yellow beeswax, retinoic acid, and soybean oil

[0067] Take 5mg of yellow beeswax, 5mg of retinoic acid, and 100mg of soybean oil and place them in a 10ml measuring cylinder, dilute with isopropanol:acetonitrile (7:3) solution, and ultrasonicate for 10min. Take 200ul in a 25ml volumetric flask and dilute with isopropanol:acetonitrile (7:3) solution. Use isopropanol:acetonitrile (7:3) solution as blank solution, set the absorbance at 800nm ​​to 0, and scan the UV spectrum of the three substances and the blank solvent from 200-800nm.

Claims

1. A composition for preparing retinoic acid soft capsules, characterized in that: The composition is composed of three substances: retinoic acid, soybean oil and yellow beeswax, wherein the proportions of the three substances are respectively: 1-6% of retinoic acid, 91-98% of soybean oil and 1-3% of yellow beeswax.

2. The composition for preparing retinoic acid soft capsules according to claim 1, characterized in that: The three substances account for 1-4% of retinoic acid, 94-98% of soybean oil and 1-2% of yellow beeswax.

3. Use of the composition according to claim 1 or 2 in the preparation of tretinoin soft capsule preparations.

4. The use according to claim 4, wherein: The retinoic acid soft capsule preparation is prepared by the following method: Add yellow beeswax to soybean oil, dissolve and mix in a 70°C water bath, add retinoic acid raw materials when cooled to room temperature, and stir thoroughly to obtain retinoic acid soft capsule contents; place the prepared contents in a soft capsule pressing machine, press at a gelatin: glycerol: water ratio of 1: (0.4-0.5): 1 to obtain a retinoic acid soft capsule preparation.

5. The use according to claim 4, characterized in that In the retinoic acid soft capsule preparation, when the proportion of yellow beeswax is higher than 1%, the prescription stability is significantly improved.

6. The use according to claim 4, characterized in that In the retinoic acid soft capsule preparation, when the proportion of yellow beeswax is 1-2%, the uniformity of retinoic acid is significantly improved.

7. The use according to claim 4, characterized in that In the retinoic acid soft capsule preparation, when the yellow beeswax accounts for 1-2%, the redispersibility of the suspension is significantly improved.

8. The use according to claim 4, characterized in that In the retinoic acid soft capsule preparation, when the suspension matrix is ​​soybean oil: yellow beeswax at a ratio of 1:100, the sedimentation volume ratio of the suspension decreases as the proportion of retinoic acid increases.

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