The cyclodextrin inclusion process is a cyclic oligosaccharide compound made by the hydrolysis of starch under the action of a cyclodextrin glycosyltransferase and is linked by an alpha-1,4 sugar hydrazone bond, that is, β cyclodextrin (β -CD) Preparation techniques for a class of non-bonded compounds formed by the entrapment of drug molecules in whole or in part. After inclusion of β-cyclodextrin, the drug can increase drug solubility and dissolution rate, increase drug stability, reduce drug irritation, improve bad odor, and broaden drug dosage forms. It is a research concern of pharmaceutical workers in recent years. Question. Domestic research has also made significant progress. It is summarized as follows:
Chemical synthesis drug inclusion studies According to the physicochemical properties and pharmacological effects of chemical drugs, they are often prepared as inclusion compounds in order to improve their own unfavorable factors, so as to be well utilized. For example, in order to improve Nap's solubility, dissolution rate, promote absorption, and reduce gastric mucosal irritation after oral administration, the solubility and thermodynamic parameters of Nap in different concentrations of β-CD solutions were studied. The change in ultraviolet absorption spectrum was measured, and the molar ratio of the composition of the composition was measured by a continuous gradient method. Experiments have proved that the molar ratio of the inclusion complexes is 1:1, the temperature increases, the binding constant of the Nap·β-CD inclusions decreases, the inclusion complex generation energy increases, and the reaction heat is −2.92 kJ/mol. The process is an exothermic process. The third-generation non-steroidal anti-inflammatory drug diclofenac sodium (DFS), due to its poor water solubility, is irritating to the gastrointestinal tract and affects its widespread use. Beijing Medical University Gu Fugen and other coprecipitation method for the preparation of DFS · β-CD inclusion complex, that is, with DFS 5.13 grams, add the appropriate amount of ethanol microtherm to make it dissolve, another weighing beta-CD18.30 grams, add water in a constant temperature water bath at 80 °C Made into a saturated solution. Under electric stirring, the DFS ethanol solution was gradually added to the β-CD solution, and the solution was stirred at a constant temperature for 1 hour. The heating was stopped and the mixture was stirred to room temperature to obtain a white suspension. The solution was stored in a refrigerator for 12 hours and filtered by suction to precipitate 60. °C dry, over 80 mesh sieve, dry after use. Infrared spectroscopy and differential scanning calorimetry indicated that DFS and β-CD can form a 1:1 molar ratio inclusion complex in aqueous solution, and inclusion complexes can significantly increase the solubility of DFS (increased by 1.77 compared to the original drug. Times), complete dissolution takes only 10 minutes (original drug nearly 30 minutes). They used orthogonal experiments to screen out the optimal conditions for the inclusion of the inclusion complexes. The inclusion temperature was 80°C, the inclusion time was 5 hours, and the stirring intensity was moderate. Retinoic acid (RA) is an intermediate metabolite of vitamin A in the body, mainly affecting bone growth and epithelial metabolism, and it is also a natural inhibitor of human cancer, but it has the disadvantages of poor water solubility, instability to light and heat, and easy oxidation. The third military medical university Zhang Enjuan and others used self-designed reverse mixing method to prepare RA·β-CD inclusion complex. Weigh RA300.44 mg and β-CD135.00 mg. RA is dissolved in 100 ml of anhydrous ethanol, stirred at 60°C on a constant temperature magnetic stirrer at approximately 60°C, and two batches of RA alcohol are slowly added dropwise with stirring. In the middle, the interval between 15 and 20 minutes, covered with stirring for 2 hours, a yellowish suspension was obtained. The lid was opened and the mixture was stirred for about 3 hours. After the warm suspension was concentrated to 30 ml, the refrigerator was placed overnight and the precipitate was filtered at low temperature. Protect from light and dry. The optimal preparation conditions of the host-to-molecule molar ratio of 1:1, the best stirring time is 5 hours, the inclusion rate of 6 batches of inclusions between 3.28% to 3.67%. Ket hydrochloride has been used as an intravenous anesthetic. If it is changed into sublingual for postoperative analgesia, it has the advantages of strong action, rapid onset, no addiction, and low toxic and side effects. And taste is hard. Yan Yaodong, an air force medical school, used aqueous solutions to prepare Ket β-CD inclusion complexes, which improved the above weaknesses. That is, 0.5 g of Ket and 4.4 g of β-CD were weighed and placed in a conical flask. 100 ml of distilled water was added. The aqueous solution was heated to 60° C., and after stirring, β-CD was dissolved and allowed to cool to 25° C., and the motor was stirred for 2.5 hours. After stirring, the β-CD was dissolved, cooled to 25° C., stirred for 2.5 hours with electric stirring, 15 ml of chloroform was added while stirring, stirring was continued for 0.5 hours to obtain a suspension, and the refrigerator was stored in the refrigerator for 24 hours and filtered to precipitate. Anhydrous ethanol was washed twice, dried and then crushed, passed through a 60-mesh sieve, and stored for future use. Orthogonal experiment was used to optimize the temperature, time and feed. The results showed that the mass ratio of host to guest was 1:2 and the motor was stirred at 25°C for 3 hours. The clathrate yield and yield were high and stable. High in sex, without bitterness and with sustained release properties.
Natural drug inclusion studies Natural drugs as the object is often a mixture of multiple groups, and there is a large difference in the physical and chemical properties and molecular structure between each component of the mixed object, these are the direct factors affecting the inclusion effect. Only when the physical and chemical properties of the object, the size and shape of the molecule are suitable for the space requirements provided by the subject, the inclusion effect is better. In this regard, domestic relevant researchers have also actively explored. For example, Hu Shilian of Anhui Provincial Hospital used orthogonal experiments to study the process of β-CD inclusion of mixed volatile oils of green and musk. By examining the utilization of volatile oil, the yield of inclusion compound and the oil content, the subject and guest were selected. The optimum conditions for the ratio of 6:1, the inclusion temperature of 55°C and the time of 3 hours. Shi Chenghe, Beijing Navy General Hospital, chose the legal method of ladle and grinding method to prepare the drained bile gall bladder β-CD inclusion compound, which effectively reduced the bitter taste of bear bile. The preferred process conditions are a host-to-guest ratio of 5:1 and a milling time of 20 minutes. The average yield of 5 batches of clathrate was 97.6%, and the average ursodeoxycholic acid content was 2.42% (RSD=0.83%). Houttuyfonate is poorly soluble and unstable in water and has a strong fishy odor. In order to improve this unfavorable nature, Wuhan Shi Tongji Medical University Wei Shichao, etc., took Houttuyfonate and β-CD by grinding with a molar ratio of 1:1 (mass ratio about 1:4), and set β-CD in the mortar. , Add appropriate amount of water to a uniform paste, add Houttuyfonate, fully grind evenly, suction filtration, the resulting low-temperature drying, 60 mesh sieve back. It was determined that the solubility of houttuyfonate increased 11.4 times, and the dissolution rate and stability increased, which masked the bad odor.