Valerian self-microemulsifying drop pills and preparation method thereof

Abstract

The present application belongs to the field of natural medicine, and provides a valerian self-microemulsion drop pill and a preparation method thereof, which is prepared from the following components by weight: valerian volatile oil 20-40 parts, valerian extract powder 8-10 parts, oil phase 10-30 parts, emulsifier 40-80 parts, co-emulsifier 10-50 parts, and base 200-650 parts. The volatile oil and alcohol-soluble components of valerian are extracted, and are prepared into self-microemulsion together with oil ester, emulsifier and co-emulsifier, so as to increase the drug solubility, promote the absorption of the drug, and improve the bioavailability. Then, the self-microemulsion is solidified in the form of drop pill, so as to obtain the valerian self-microemulsion drop pill with high drug solubility, high bioavailability and good stability. By controlling the mass ratio of the base and the valerian self-microemulsion, the heating temperature of the drug-containing base, and the drop distance, the forming rate of the drop pill can reach more than 90%.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and more specifically relates to a valerian microemulsion droplet and its preparation method. Background Technology

[0002] Self-emulsifying drug delivery systems refer to emulsion drug delivery systems that spontaneously form oil / water (O / W) or water / oil (W / O) emulsions with a particle size of less than 5 μm within the gastrointestinal tract or at ambient temperature (usually body temperature 37°C) with gentle stirring. With increasing emulsifier dosage, these self-emulsifying systems can spontaneously form microemulsions with a particle size of less than 100 nm within the gastrointestinal tract, and are thus called self-microemulsifying drug delivery systems. Traditional self-emulsifying formulations are liquid dosage forms, often encapsulated in soft or hard capsules. However, in actual production and use, liquid self- (micro)emulsifying formulations have some drawbacks: such as compatibility issues between the formulation components and the capsule shell, rapid drug release after oral administration, unsuitability for poorly soluble water-soluble drugs requiring frequent administration, or those that are highly irritating to the stomach or unstable in the stomach. Solid self-microemulsifying drug delivery systems are prepared by mixing self- (micro)emulsifying components with suitable solid materials to create solid dosage forms, aiming to combine the advantages of both self-emulsifying and solid dosage forms while overcoming the disadvantages of traditional liquid self-emulsifying formulations. Compared with traditional self-microemulsification drug delivery systems, it has advantages such as increased stability, extended storage time, reduced gastrointestinal irritation, and convenient administration. It can also be conveniently prepared into sustained-release formulations by adding various solid excipients or using coating technology. It provides a new platform for formulation development for drugs that are poorly soluble in water and have low oral bioavailability.

[0003] Valerian is the dried rhizome and root of *Valeriana pseudofcinalis* CYCheng et HHChen, a plant in the Valerianaceae family. It is pungent, sweet, and warm in nature. It enters the heart and liver meridians. Its functions and indications include calming the mind, regulating qi, and relieving pain. It is used for restlessness, palpitations, insomnia, depression, epilepsy, abdominal distension and pain, lower back and leg pain, and traumatic injuries. Valerian is sweet in taste and primarily enters the heart and liver meridians. It has calming, qi-regulating, and depression-relieving effects, treating restlessness, palpitations, depression, and epilepsy. Modern pharmacological experiments show that it has sedative, antidepressant, anti-anxiety, anti-epileptic, anticonvulsant, memory-improving, and anti-cerebral ischemia-related central nervous system effects. It also has antiarrhythmic, lipid-lowering, and kidney-protective pharmacological effects. Valerian extract capsules are available in China, with the function of relieving pain and used for stomach pain due to qi stagnation. It has good therapeutic effects, but because the active ingredients are volatile oils and alcohol-soluble active ingredients, the bioavailability is low. There are no reports in the existing literature on solid self-microemulsion drug delivery formulations of valerian. Summary of the Invention

[0004] In view of the above-mentioned prior art, the present invention provides a valerian self-microemulsion droplet and its preparation method. The present invention extracts the volatile oil and alcohol-soluble components of valerian, and combines them with oil esters, emulsifiers, and co-emulsifiers to prepare a self-microemulsion, which increases drug solubility, promotes drug absorption, and improves bioavailability. Then, the self-microemulsion is solidified in the form of droplets to obtain valerian self-microemulsion droplets with high drug solubility, bioavailability, and good stability.

[0005] The present invention is achieved through the following technical solution: The present invention provides a valerian self-microemulsion droplet, which is made of the following components in parts by weight: 20-40 parts of valerian volatile oil, 8-10 parts of valerian extract powder, 10-30 parts of oil phase, 40-80 parts of emulsifier, 10-50 parts of co-emulsifier, and 200-650 parts of matrix.

[0006] As a further explanation of the present invention: the valerian volatile oil is the volatile oil extracted from valerian using supercritical carbon dioxide extraction or steam distillation; the valerian extract powder is a dry extract prepared by extracting the residue after volatile oil extraction with 70-95% v / v ethanol using percolation or heating reflux.

[0007] As a further explanation of the present invention: preferably, the oil phase is any one or more of oleic acid, ethyl oleate, caprylic triglyceride, caprylic triglyceride, medium-chain triglyceride, and isopropyl myristate.

[0008] Preferably, the emulsifier is any one or more of the following: polyoxyethylene hydrogenated castor oil, polyoxyethylene ether-35-castor oil, polyoxyethylene ether-40-castor oil, polyethylene glycol glycerol amylopectin, polyethylene glycol-8-glyceryl caprylate, polyethylene glycol-8-glyceryl caprylate, polyethylene glycol 15-hydroxystearate, lecithin, Tween 85, and Tween 80.

[0009] Preferably, the co-emulsifier is any one or more of anhydrous ethanol, 1,2-propanediol, diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400.

[0010] Preferably, the matrix is ​​any one or more of PEG6000, PEG4000, and PEG1500. More preferably, the mass ratio of PEG6000, PEG4000, and PEG1500 in the matrix is ​​3:4:5, and the matrix further contains 1% sodium carboxymethyl starch by mass of the total mass of the mixed matrix.

[0011] In another aspect, the present invention provides a method for preparing the aforementioned valerian self-microemulsion droplets, comprising the following steps: S1. Mix the emulsifier and co-emulsifier evenly, add the oil phase and valerian volatile oil and mix well, then add valerian extract powder and stir evenly to obtain valerian volatile oil microemulsion; S2. Heat the matrix to a molten state, add the valerian volatile oil microemulsion obtained in step S1, stir evenly, and obtain the drug-containing matrix; S3. Heat the drug-containing matrix obtained in step S2 to 89-90°C and keep it at that temperature. Then, drop it into dimethyl silicone oil at a height of 7.9-8.6 cm. Collect the solid droplets that have condensed and formed to obtain the valerian microemulsion droplets.

[0012] Preferably, in step S1, the emulsifier and co-emulsifier are weighed and mixed under the action of a magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed under the action of a magnetic stirrer at 37°C; then valerian extract powder is added and stirred at 1000 rpm for 5 minutes under the constant temperature of 37°C to obtain a yellow, clear and transparent valerian microemulsion.

[0013] As a further explanation of the present invention: Preferably, in step S3, the added drug-containing matrix is ​​dripped into dimethyl silicone oil at a height of 7.9 to 8.6 cm at a rate of 20 drops / min.

[0014] As a further explanation of the present invention, preferably, the valerian volatile oil is prepared by the following steps: Valerian herbal powder was extracted using supercritical carbon dioxide extraction technology at an extraction temperature of 50–70℃, an extraction pressure of 25–40 MPa, and an extraction time of 2–4 h. The supercritical CO2 fluid flow rate was controlled at 10–20 L / h. The extraction vessel was depressurized. The desorption temperature was 30–40℃ and the desorption pressure was 3–6 MPa to obtain valerian volatile oil. Alternatively, fresh valerian rhizomes and roots can be used, washed to remove dirt, drained, and chopped into 1-5cm long pieces before direct steam distillation using a double-boiler pressurized steam distillation method. The initial steam pressure during distillation is 0.08-0.12 mPa / cm². 2 During the distillation process, the steam pressure was 0.02-0.06 mPa / cm. 2 The steam pressure in the later stage of distillation is 0.08-0.10 mPa / cm. 2 The valerian volatile oil was isolated after a duration of 1.5-2.5 hours.

[0015] As a further explanation of the present invention, preferably, the valerian extract powder is prepared by the following steps: After extracting the volatile oil of valerian using supercritical carbon dioxide extraction or steam distillation, the residue is pre-dried: sun-dried, oven-dried, or vacuum-dried, placed in a percolation tank and compacted. It is then soaked in 70-95% v / v ethanol (1.5 times the amount of fresh valerian) for 8-12 hours before percolation begins. The percolate is filtered, the ethanol is recovered, concentrated, and dried to obtain valerian dry extract. The extract is then ground and sieved to obtain valerian extract powder. Beneficial effects of the present invention

[0016] 1) This invention extracts the volatile oil and alcohol-soluble components of valerian. The volatile oil itself possesses potential oil-phase properties. Combined with oil esters, emulsifiers, co-emulsifiers, and valerian alcohol extract powder, a self-microemulsion is prepared, increasing drug solubility, promoting drug absorption, and improving bioavailability. This self-microemulsion is then solidified into pellets, resulting in valerian self-microemulsion pellets with high drug solubility, bioavailability, and good stability. By controlling the mass ratio of the matrix to the valerian self-microemulsion, the heating temperature of the drug-containing matrix, and the dropping distance, the pellet formation rate can reach over 90%.

[0017] 2) This invention organically combines liquid self-microemulsion and pellet technology, transforming liquid self-microemulsion into solid pellet self-microemulsion, thus overcoming the dosage form limitations of liquid self-microemulsion and fulfilling the requirements for solidification. Using PEG6000, PEG4000, PEG1500, and sodium carboxymethyl starch as a mixed matrix, the invention found that when PEG6000 is used alone as a matrix, the molten matrix is ​​neither dispersed nor flowable; when PEG4000 is used alone, pellet formation is difficult; and when PEG1500 is used alone, the pellet shape is good but the hardness is poor, making it deformable by hand. This invention, using PEG6000, PEG4000, and PEG1500 as a mixed matrix, easily yields pellets with a round shape and moderate hardness. The addition of the antioxidant ascorbate palmitate and the disintegrant sodium carboxymethyl starch to the pellet matrix prevents pellet aging and reduces dissolution, thereby increasing drug stability. Detailed Implementation

[0018] The present invention will be further illustrated with specific examples. These examples are for illustrative purposes only and do not limit the scope of the invention. Unless otherwise specified, experimental conditions not explicitly stated in the examples are generally performed under conventional conditions or as recommended by the reagent company. The reagents and consumables used in the following examples are commercially available unless otherwise specified. The following examples further illustrate the invention but do not constitute a limitation thereof. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0019] Example 1. Preparation of Valerian volatile oil and Valerian extract powder 1) Fresh valerian rhizomes and roots are used. After washing away the dirt and draining, they are chopped into 1-5cm long pieces and then distilled using a water-double-barrel pressurized direct steam distillation method. The initial steam pressure is 0.08-0.12mPa / cm². 2 During the distillation process, the steam pressure was 0.02-0.06 mPa / cm. 2 The steam pressure in the later stage of distillation is 0.08-0.10 mPa / cm. 2The process lasts for 1.5-2.5 hours, during which volatile oil and dregs are separated, with a volatile oil yield of 1.2-1.5%. The valerian volatile oil is a pale yellow, clear liquid with a fragrant odor and a slightly pungent taste. It has a relative density of 0.94-0.96, a refractive index of 1.48-1.49, a heavy metal content of no more than 10 parts per million, and a bornyl acetate content of ≥27%.

[0020] 2) Pre-drying of the dregs: Sun-dry, oven-dry, or vacuum-dry, place in a percolation tank and compact, soak in 70-95% v / v ethanol (1.5 times the amount of fresh medicinal material) for 8-12 hours, then begin percolation. Filter the percolate, recover the ethanol, concentrate and dry to obtain valerian dry extract, grind and sieve to obtain valerian extract powder; the valerian extract powder is a brownish-brown powder with a moisture content of <5%, valerian terpene lactone A content ≥1.3%, and total terpene lactone content ≥8.0%.

[0021] Existing medicinal valerian preparations mainly include valerian powder, valerian extract, valerian tincture, and compound preparations. All are made from dried valerian as raw material, directly powdered or powdered and then extracted with low-to-medium concentration ethanol (60% or less). Preparations produced using existing techniques have extremely low valerian volatile oil content and low terpene lactone content. According to literature reports, the volatile oil content of valerian can decrease by 50% after six months of storage. Our observations show that the volatile oil content of fresh valerian from a certain region was 1.8%, but after two years of storage in a cool, shady indoor environment at high altitudes, the volatile oil content plummeted to 0.5%. Powdering the herb further significantly reduces the oil content. Secondly, valerian volatile oil is insoluble in low-to-medium concentration ethanol, and valerian terpene lactones are also poorly soluble in low-to-medium concentration ethanol. Therefore, valerian preparations made from dried valerian using low-to-medium concentration ethanol (60% or less) have extremely low valerian volatile oil and very low terpene lactone content. This invention uses the roots and rhizomes of fresh valerian. After rinsing the herbs to remove mud and sand, draining them, and chopping them into small pieces (about 1-5 cm long), the volatile oil is prepared by direct steam distillation under pressure in a water-split manner. During the distillation process, the water in the distillation tank is drained every 1 / 2 hour or so, which saves time and labor and yields a high oil yield.

[0022] Example 2. Preparation of Valerian Volatile Oil and Valerian Extract Powder Valerian herbal powder was extracted using supercritical carbon dioxide extraction at a temperature of 50–70℃, an extraction pressure of 25–40 MPa, and an extraction time of 2–4 h, with the supercritical CO2 flow rate controlled at 10–20 L / h. The extraction vessel was then depressurized. The desorption temperature was 30–40℃, and the desorption pressure was 3–6 MPa, yielding valerian volatile oil with a yield of 1.8–2.3%. The valerian volatile oil is a pale yellow, clear liquid with a fragrant odor and a slightly pungent taste. It has a relative density of 0.95–0.97, a refractive index of 1.48–1.50, a heavy metal content not exceeding 10 parts per million, and a bornyl acetate content ≥30%.

[0023] The dregs are pre-dried: sun-dried, oven-dried, or vacuum-dried, placed in a percolation tank and compacted. They are then soaked in 70-95% v / v ethanol (1.5 times the amount of fresh medicinal material) for 8-12 hours before percolation begins. The percolate is filtered, the ethanol is recovered, concentrated, and dried to obtain valerian dry extract. This extract is then ground and sieved to obtain valerian extract powder. The valerian extract powder is a brownish-brown powder with a moisture content <5%, valerian terpene lactone A content ≥ 1.5%, and total terpene lactone content ≥ 10.0%.

[0024] Example 3. Formulation screening of valerian self-microemulsion solution Prescription 1. A valerian self-microemulsion droplet, made from the following components in parts by weight: 20 parts valerian volatile oil, 8 parts valerian extract powder, 10 parts oil phase, 40 parts emulsifier, and 10 parts co-emulsifier.

[0025] The oil phase consists of oleic acid and ethyl oleate in a weight ratio of 1:1; the emulsifier is polyoxyethylene hydrogenated castor oil; and the co-emulsifier is polyethylene glycol 400. The emulsifier and co-emulsifier are weighed and mixed thoroughly using a magnetic stirrer at 37°C. The oil phase and valerian volatile oil are added and mixed thoroughly using a magnetic stirrer at 37°C. Valerian extract powder is then added, and the mixture is stirred at 1000 rpm for 5 minutes at a constant temperature of 37°C to obtain a clear, transparent, yellow valerian microemulsion.

[0026] Prescription 2. A valerian self-microemulsion droplet, made from the following components in parts by weight: 40 parts valerian volatile oil, 10 parts valerian extract powder, 30 parts oil phase, 80 parts emulsifier, and 50 parts co-emulsifier.

[0027] The oil phase is isopropyl myristate; the emulsifier is polyoxyethylene ether-35-castor oil; the co-emulsifier is anhydrous ethanol and 1,2-propanediol in a weight ratio of 1:1; the emulsifier and co-emulsifier are weighed and mixed under the action of a magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed under the action of a magnetic stirrer at 37°C; then valerian extract powder is added and stirred at 1000 rpm for 5 minutes under the condition of constant temperature at 37°C to obtain a yellow, clear and transparent valerian microemulsion.

[0028] Prescription 3. A valerian self-microemulsion droplet, made from the following components in parts by weight: 30 parts valerian volatile oil, 9 parts valerian extract powder, 20 parts oil phase, 60 parts emulsifier, and 30 parts co-emulsifier.

[0029] The oil phase is caprylic / capric triglyceride; the emulsifier is polyoxyethylene ether-40-castor oil; the co-emulsifier is diethylene glycol monoethyl ether; the emulsifier and co-emulsifier are weighed and mixed under the action of a magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed under the action of a magnetic stirrer at 37°C; then valerian extract powder is added and stirred at 1000 rpm for 5 minutes under the constant temperature of 37°C to obtain a yellow, clear and transparent valerian microemulsion.

[0030] Prescription 4. A valerian self-microemulsion droplet, made from the following components in parts by weight: 30 parts valerian volatile oil, 9 parts valerian extract powder, 20 parts oil phase, 60 parts emulsifier, and 30 parts co-emulsifier.

[0031] The oil phase consists of ethyl oleate and isopropyl myristate in a weight ratio of 1:1; the emulsifier is polyethylene glycol 15-hydroxystearate; the co-emulsifier consists of 1,2-propanediol and polyethylene glycol 200 in a weight ratio of 1:3; the emulsifier and co-emulsifier are weighed and mixed under the action of a magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed under the action of a magnetic stirrer at 37°C; then valerian extract powder is added, and the mixture is stirred at 1000 rpm for 5 minutes under the constant temperature of 37°C to obtain a yellow, clear and transparent valerian microemulsion.

[0032] Prescription 5. A valerian self-microemulsion droplet, made from the following components in parts by weight: 20 parts valerian volatile oil, 8 parts valerian extract powder, 10 parts oil phase, 40 parts emulsifier, and 10 parts co-emulsifier.

[0033] The oil phase is a mixture of ethyl oleate, oleic acid, and isopropyl myristate in a mass ratio of 4:4:2; the emulsifier is castor oil polyoxyethylene ether-40 and lecithin in a mass ratio of 1:1; the co-emulsifier is anhydrous ethanol and polyethylene glycol 400 in a mass ratio of 6:4. The emulsifier and co-emulsifier are weighed and mixed thoroughly using a magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed thoroughly using a magnetic stirrer at 37°C; then valerian extract powder is added, and the mixture is stirred at 1000 rpm for 5 minutes at a constant temperature of 37°C to obtain a clear, transparent yellow valerian microemulsion.

[0034] Prescription 6. A valerian self-microemulsion droplet, made from the following components in parts by weight: 40 parts valerian volatile oil, 10 parts valerian extract powder, 30 parts oil phase, 80 parts emulsifier, and 50 parts co-emulsifier.

[0035] The oil phase consists of ethyl oleate, medium-chain triglycerides, and isopropyl myristate in a mass ratio of 1:2:2; the emulsifier consists of polyethylene glycol-8-glyceryl caprylate and Tween 80 in a mass ratio of 3:1; the co-emulsifier consists of 1,2-propanediol and polyethylene glycol 300 in a mass ratio of 3:1. The emulsifier and co-emulsifier are weighed and mixed under a constant temperature magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed under a constant temperature magnetic stirrer at 37°C; then valerian extract powder is added, and the mixture is stirred at 1000 rpm for 5 minutes under a constant temperature of 37°C to obtain a clear, transparent yellow valerian microemulsion.

[0036] The above formulation experiments can prepare a clear, transparent, milky solution of valerian microemulsion droplets with a viscosity close to that of water. The prepared microemulsion droplet solution has good stability and shows no turbidity, precipitation, or discoloration after standing overnight. Electron microscopy observation shows that the droplets are regularly spherical, with a particle size below 200 nm, and no adhesion; the particle size distribution is between 25 and 40 nm, with uniform particle size and concentrated distribution.

[0037] The self-microemulsification rate can be measured visually by observing the time it takes for the self-microemulsion to disperse uniformly into a microemulsion. In this study, a valerian self-microemulsification droplet solution prepared according to the above experimental formula was mixed with 20 times its volume of water in a 37°C water bath under gentle magnetic stirring to form a microemulsion. The time for uniform dispersion and microemulsification was observed and recorded. The results showed that self-emulsification could be achieved within 1 minute.

[0038] Example 4. Study on Valerian Self-Microemulsion Droplets The matrix of the following formulation was heated to a molten state, and the valerian volatile oil self-microemulsion of formulation 4 in Example 3 was added and stirred evenly to obtain a drug-containing matrix. The drug-containing matrix was heated to 89-90°C and kept at this temperature. It was then dropped into dimethyl silicone oil at a rate of 20 drops / min and a height of 7.9-8.6 cm. The solid pellets that had cooled and solidified were collected to obtain the valerian self-microemulsion pellets. The pellet shape and hardness of the valerian self-microemulsion pellets were tested. The hardness (hand-pressed), roundness, and other factors of the pellets were used as indicators, and the mass ratio of matrix to valerian self-microemulsion was 5-3:1. The test results are shown in Table 1.

[0039] Matrix formulation 1: PEG6000; Matrix formulation 2: PEG4000; Matrix formulation 3: PEG1500; Matrix formulation 4: The mass ratio of PEG4000 to PEG1500 is 1:1; Matrix formulation 5: The mass ratio of PEG4000 to PEG6000 is 1:1; Matrix formulation 6: The mass ratio of PEG6000, PEG4000 and PEG1500 is 1:1:1; Matrix formulation 7: The mass ratio of PEG6000, PEG4000 and PEG1500 is 1:2:1; Matrix formulation 8: The mass ratio of PEG6000, PEG4000 and PEG1500 is 1:1:2; Matrix formulation 9: The mass ratio of PEG6000, PEG4000 and PEG1500 is 3:4:5; Matrix formulation 10: PEG6000, PEG4000 and PEG1500 in a mass ratio of 3:4:5, and also contains sodium carboxymethyl starch at 1% of the total mass of the mixed matrix.

[0040] Table 1 Results of hardness (by hand) and sphericity of valerian self-microemulsion droplets. Group Pill roundness hardness Prescription 1 -- -- Prescription 2 Over 90% of the material sticks together, trails, and has an uneven surface. The dripping method is difficult to form and will break completely. Prescription 3 The pellets are not perfectly round; more than 50% are stuck together or have a trailing shape. More than 80% cracked and severely deformed. Prescription 4 Less than 50% adhesion, partial trailing 60% fractured, with numerous deep cracks and deformation. Prescription 5 The pellet shape is relatively good, with less than 50% adhesion and some trailing. 20% fractured, some deep cracks, or deformed. Prescription 6 No adhesion, no trailing, smooth surface Minor cracks, minor deformation Prescription 7 No adhesion, no trailing, smooth surface Minor cracks, minor deformation Prescription 8 No adhesion, no trailing, smooth surface No cracks, no deformation Prescription 9 No adhesion, no trailing, smooth surface No cracks, no deformation Prescription 10 No adhesion, no trailing, smooth surface No cracks, no deformation Experimental studies have found that when PEG6000 is used alone as a matrix, the molten matrix does not disperse or flow, making it impossible to form droplets; when PEG4000 is used alone as a matrix, it is difficult to form droplets, resulting in non-spherical droplets; when PEG1500 is used alone as a matrix, the droplets have a better shape but poor hardness and are easily deformed by hand. This invention uses a mixture of PEG6000, PEG4000, and PEG1500 as a matrix to easily obtain droplets with a spherical shape, moderate hardness, smooth surface, and uniform size. The addition of sodium carboxymethyl starch as a disintegrant to the droplet matrix prevents droplet aging and reduces solubility, increasing drug stability. This invention prepares valerian into a self-microemulsion, increasing drug solubility, promoting drug absorption, and improving bioavailability; then, the valerian self-microemulsion is solidified into droplets, resulting in valerian self-microemulsion droplets with high drug solubility, bioavailability, and good stability.

[0041] Example 6. Accelerated Stability Comparison Experiment The valerian extract capsules prepared by conventional methods (produced by Wuhan United Pharmaceutical Co., Ltd.) showed a decrease in the content of the active ingredients bornyl acetate and valeride lactone A by 1.23% and 0.95%, respectively, after high-low temperature cycling (10 days at 60℃ and 10 days at 40℃). After 5 and 10 days of light exposure, the contents of the active ingredients bornyl acetate and valeride lactone A decreased by 4.63% and 3.58%, and 5.28% and 4.62%, respectively. The formulation is relatively stable to heat but unstable to light and needs to be stored away from light. In contrast, the valerian self-microemulsion droplets prepared in this example, after high-low temperature cycling under the same conditions, showed a decrease in the content of the active ingredients bornyl acetate and valeride lactone A by 0.35% and 0.22%, respectively. After 5 and 10 days of light exposure, the contents of the active ingredients bornyl acetate and valeride lactone A decreased by 1.23% and 0.95%, and 1.63% and 1.45%, respectively. Therefore, the volatile oil solid self-emulsified tablets prepared in this embodiment are stable to heat and light. Experiments show that solid self-emulsified formulations prepared using self-microemulsification and pelleting techniques can significantly improve the stability of the formulation. Furthermore, formulating the liquid dosage form self-emulsified drug delivery system into pellets can greatly improve the formability of the solid dosage form preparation process, reduce the impact of volatile oil on particle compression, and prevent the migration and volatilization of volatile oil in capsules during storage, thus preventing a decrease in content.

[0042] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of them. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention. Although the above description is in conjunction with specific embodiments of the present invention, it is not intended to limit the protection scope of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art without creative effort based on the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A valerian microemulsion droplet, characterized in that... It is made from the following components in parts by weight: 20-40 parts valerian volatile oil, 8-10 parts valerian extract powder, 10-30 parts oil phase, 40-80 parts emulsifier, 10-50 parts co-emulsifier, and 200-650 parts matrix.

2. The valerian self-microemulsion droplets according to claim 1, characterized in that: The valerian volatile oil is extracted using supercritical carbon dioxide extraction or steam distillation; the valerian extract powder is a dry extract prepared by extracting the residue after volatile oil extraction with 70-95% v / v ethanol using percolation or reflux extraction.

3. The valerian self-microemulsion droplet according to claim 1, characterized in that: The oil phase is any one or more of oleic acid, ethyl oleate, caprylic triglyceride, caprylic triglyceride, medium-chain triglycerides, and isopropyl myristate; the emulsifier is any one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene ether-35-castor oil, polyoxyethylene ether-40-castor oil, polyethylene glycol glyceryl amylopectin, polyethylene glycol-8-glyceryl caprylate, polyethylene glycol-8-glyceryl caprylate, polyethylene glycol 15-hydroxystearate, lecithin, Tween 85, and Tween 80; the co-emulsifier is any one or more of anhydrous ethanol, 1,2-propanediol, diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400; and the matrix is ​​any one or more of PEG6000, PEG4000, and PEG1500.

4. The valerian self-microemulsion droplets according to claim 1, characterized in that: The matrix contains PEG6000, PEG4000 and PEG1500 in a mass ratio of 3:4:5, and also contains sodium carboxymethyl starch at a mass of 1% of the total mass of the mixed matrix.

5. The method for preparing valerian self-microemulsion droplets according to any one of claims 1-4, characterized in that, Includes the following steps: S1. Mix the emulsifier and co-emulsifier evenly, add the oil phase and valerian volatile oil and mix well, then add valerian extract powder and stir evenly to obtain valerian volatile oil microemulsion; S2. Heat the matrix to a molten state, add the valerian volatile oil microemulsion obtained in step S1, stir evenly, and obtain the drug-containing matrix; S3. Heat the drug-containing matrix obtained in step S2 to 89-90°C and keep it at that temperature. Then, drop it into dimethyl silicone oil at a height of 7.9-8.6 cm. Collect the solid droplets that have condensed and formed to obtain the valerian microemulsion droplets.

6. The method for preparing valerian self-microemulsion droplets according to claim 5, characterized in that: In step S1, the emulsifier and co-emulsifier are weighed and mixed under the action of a magnetic stirrer at 37°C; the oil phase and valerian volatile oil are added and mixed under the action of a magnetic stirrer at 37°C; then valerian extract powder is added and stirred at 1000 rpm for 5 minutes under the constant temperature of 37°C to obtain a yellow, clear and transparent valerian microemulsion.

7. The method for preparing valerian self-microemulsion droplets according to claim 5, characterized in that: In step S3, the added drug-containing matrix is ​​dripped into dimethyl silicone oil at a height of 7.9–8.6 cm at a rate of 20 drops / min.

8. The method for preparing valerian self-microemulsion droplets according to claim 5, characterized in that, The valerian volatile oil is prepared by the following steps: taking coarse powder of valerian herb, using supercritical carbon dioxide extraction technology, extraction temperature 50-70℃, extraction pressure 25-40MPa, extraction time 2-4h, controlling the supercritical CO2 fluid flow rate to 10-20L / h; depressurizing the extraction vessel; desorption temperature 30-40℃, desorption pressure 3-6MPa, to obtain valerian volatile oil.

9. The method for preparing valerian self-microemulsion droplets according to claim 5, characterized in that, The valerian volatile oil is prepared using the following steps: Fresh valerian rhizomes and roots are washed to remove dirt, drained, and chopped into 1-5 cm long pieces. The mixture is then distilled using a water-jacketed pressurized direct steam distillation method. The initial steam pressure during distillation is 0.08-0.12 mPa / cm². 2 During the distillation process, the steam pressure was 0.02-0.06 mPa / cm. 2 The steam pressure in the later stage of distillation is 0.08-0.10 mPa / cm. 2 The valerian volatile oil was isolated after a duration of 1.5-2.5 hours.

10. The method for preparing valerian self-microemulsion droplets according to claim 5, characterized in that, The valerian extract powder is prepared by the following steps: the residue after extracting the volatile oil of valerian by supercritical carbon dioxide extraction or steam distillation is pre-dried: sun-dried, oven-dried or vacuum-dried, placed in a percolation tank and compacted, soaked in 70-95% v / v ethanol (1.5 times the amount of fresh medicinal material) for 8-12 hours and then percolated. The percolate is filtered and the ethanol is recovered, then concentrated and dried to obtain dry valerian extract, which is then ground and sieved to obtain valerian extract powder.