Codonopsis pilosula and dendrobium extract soft capsule and preparation method thereof

Abstract

The invention provides a codonopsis pilosula and dendrobe extract soft capsule and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the codonopsis pilosula and dendrobe extract soft capsule comprises a content and a capsule skin coating the content; the content is prepared from the following raw materials: a codonopsis pilosula and dendrobe extract, a dispersion medium, a suspending aid and a wetting agent; the dispersion medium comprises PEG-400, and the suspending aid comprises xanthan gum; the capsule skin is prepared from the following raw materials: gelatin, water, a plasticizer and a disintegrating agent. Hydrophilic groups are introduced through chemical modification, a network structure is opened, a physical plasticizing flexible chain is inserted, the crosslinking density is further reduced, dynamic balance of a network is optimized through moisture regulation and control, and the elasticity index of the capsule skin is increased and the disintegration time is shortened through a synergistic effect. The prepared codonopsis pilosula and dendrobe extract soft capsule is good in content stability, high in capsule skin elasticity index and short in disintegration time.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a soft capsule of Codonopsis pilosula and Dendrobium nobile extract and a preparation method thereof. Background Art

[0002] Codonopsis pilosula and Dendrobium nobile are two natural medicinal materials with extremely high medicinal values. Research shows that Codonopsis pilosula has the functions of strengthening the spleen and benefiting the lung, nourishing blood and promoting the production of body fluid, and can regulate the spleen and stomach and enhance the transportation and transformation function of the spleen. Dendrobium nobile is sweet and cold, and can play the effects of benefiting the stomach and promoting fluid production, nourishing yin and clearing heat for the symptoms of accumulated heat in the stomach yin and dry mouth and damaged body fluid. The combination of Codonopsis pilosula for tonifying qi and strengthening the spleen and Dendrobium nobile for nourishing yin and clearing heat with a ratio of 6:4 can take both the root cause and symptoms into consideration, with the root cause as the main focus, and regulate the function of the spleen.

[0003] Traditional Chinese medicines and their extracts often have special odors, which are unacceptable to many people. Mixing traditional Chinese medicines with excipients in a certain proportion to form a suspension as the content of the soft capsule, and then wrapping it with a soft capsule material to make a soft capsule can cleverly solve the above problems. Due to its unique administration method, it can cover up the bad smell of the drug and block the contact between air and the active ingredient, and is widely used in the pharmaceutical and health product industries. At present, soft capsule preparations have a large development space abroad and good market prospects. The research on the production process of soft capsules in China started relatively late, but with the introduction of advanced technologies and equipment and the research on new equipment technologies, the research level of the soft capsule preparation process in China has been greatly improved, and the production scope of soft capsules has gradually developed towards traditional Chinese medicine preparations. By the 1990s, traditional Chinese medicine soft capsules such as Huoxiang Zhengqi Soft Capsule, Xuesaitong Soft Capsule, Maren Soft Capsule, and Compound Danshen Soft Capsule were developed in China, and the unique therapeutic effects of traditional Chinese medicine have been unanimously recognized. The characteristics such as the stability and redispersibility of the content in the soft capsule, the elastic index and disintegration time of the capsule shell are of great significance for the quality, efficacy and safety of the drug. The viscosity of traditional Chinese medicine extracts is relatively large, and an appropriate amount of suspending agent and wetting agent need to be added to improve the uniformity and fluidity of the content. However, there are differences in the density and viscosity between traditional Chinese medicine extracts and excipients (such as vegetable oil, PEG400, etc.), resulting in easy stratification of the content during standing. Therefore, it is particularly important to select appropriate suspending agents and wetting agents according to the characteristics of traditional Chinese medicine extracts to improve the uniformity and fluidity of the content. The elastic index of the capsule shell of some soft capsules is relatively low, and it is easy to rupture during storage and use. If the soft capsule disintegrates slowly, it will affect the release and absorption of the drug. Therefore, the formulation optimization of the capsule shell is also particularly important.

[0004] Therefore, it is of great significance to develop a suitable soft capsule of Codonopsis pilosula and Dendrobium nobile extract and its preparation process. Summary of the Invention

[0005] In view of the technical problems existing in the background art, the present invention provides a soft capsule of Codonopsis pilosula and Dendrobium nobile extract and a preparation method thereof, aiming to solve the technical problems of poor stability of the content of existing soft capsules and easy breakage of the capsule skin.

[0006] In the first aspect, the present invention provides a soft capsule of Codonopsis pilosula and Dendrobium nobile extract, which includes a content and a capsule skin covering the content; the preparation raw materials of the content include Codonopsis pilosula and Dendrobium nobile extract, a dispersion medium, a suspending agent, and a wetting agent; the dispersion medium includes PEG-400, and the suspending agent includes xanthan gum; the preparation raw materials of the capsule skin include gelatin, water, a plasticizer, and a disintegrant.

[0007] Preferably, the wetting agent includes soybean phospholipid.

[0008] Preferably, the mass ratio of Codonopsis pilosula and Dendrobium nobile extract, the dispersion medium, the suspending agent, and the wetting agent is 1:(2-4):0.015-0.025:0.003-0.005.

[0009] Preferably, the mass ratio of Codonopsis pilosula and Dendrobium nobile extract, the dispersion medium, the suspending agent, and the wetting agent is 1:2:0.025:0.004; Or, the mass ratio of Codonopsis pilosula and Dendrobium nobile extract, the dispersion medium, the suspending agent, and the wetting agent is 1:3:0.015:0.005.

[0010] Preferably, the plasticizer includes succinic anhydride, and the disintegrant includes PEG-400.

[0011] Preferably, the mass ratio of gelatin, water, the plasticizer, and the disintegrant is 1:1-5:0.03-0.04:0.025-0.05 Preferably, the mass ratio of gelatin, water, the plasticizer, and the disintegrant is 1:5:0.04:0.05.

[0012] In the second aspect, the present invention provides a preparation method of a soft capsule of Codonopsis pilosula and Dendrobium nobile extract, which includes the following steps: Weigh Codonopsis pilosula and Dendrobium nobile and mix them, extract them by water bath, centrifuge, and distill under reduced pressure to obtain a concentrated solution, filter after alcohol precipitation to obtain a polysaccharide precipitate, wash and dry it to obtain Codonopsis pilosula and Dendrobium nobile extract; Mix the Codonopsis pilosula and Dendrobium nobile extract with the dispersion medium, the suspending agent, and the wetting agent, then melt them, and homogenize them after mixing with water to obtain the content; Soak the gelatin in water, heat and stir to dissolve it, then add the plasticizer and the disintegrant and stir to dissolve them, and obtain the capsule skin after cooling and shaping; Press the content and the capsule skin into pills and shape them to obtain a soft capsule of Codonopsis pilosula and Dendrobium nobile extract.

[0013] Preferably, the mass ratio of Codonopsis pilosula and Dendrobium nobile is 6:4.

[0014] Preferably, the temperature for water bath extraction is 80 - 85°C, and the time for water bath extraction is 2 - 3 h.

[0015] Preferably, the temperature for vacuum distillation is 50 - 65°C. Preferably, the melting temperature is 70 - 75°C.

[0016] The principle of the technical solution of the present invention is as follows: PEG - 400 provides the dispersion power, xanthan gum constructs the mechanical barrier, and soybean phospholipid optimizes the interfacial properties. The three form a "dispersion - fixation - wetting" synergistic system. The fluidity of PEG - 400, the viscoelasticity of xanthan gum, and the interfacial activity of phospholipids jointly regulate the rheological properties of the content, making it have both processing applicability (such as homogenization, filling) and storage stability.

[0017] Gelatin is a partial hydrolysis product of collagen, and a three - dimensional network structure is formed by the cross - linking of polypeptide chains through hydrogen bonds and hydrophobic interactions, endowing the capsule skin with basic elasticity and film - forming properties. Succinic anhydride (anhydride group) reacts with the amino group (-NH2) in the gelatin molecule to undergo an acylation reaction. The acylation reaction reduces the number of hydrogen bonds between gelatin molecules, weakens the rigid network, and improves elasticity. The introduction of succinic anhydride introduces a carboxylic acid group (-COOH), increasing the hydrophilicity of gelatin, promoting the penetration of water molecules, and accelerating disintegration. The flexible long chain of PEG (polyethylene glycol) inserts into the gelatin network, filling the pores and reducing the friction between peptide chains. The lubricating effect of PEG makes the gelatin network more easily deformed and quickly restored under external force. The hydrophilicity of PEG accelerates the diffusion of water into the capsule skin, and cooperates with the carboxylic acid group to shorten the disintegration time.

[0018] The beneficial effects of the present invention: The present invention provides a soft capsule of Codonopsis pilosula and Dendrobium officinale extract. By regulating the types and dosages of Codonopsis pilosula and Dendrobium officinale extract, dispersion medium, suspending agent, and wetting agent, the formula of the content is optimized. Through the fluidity of PEG - 400, the viscoelasticity of xanthan gum, and the interfacial activity of phospholipids, the rheological properties of the content are jointly regulated, making it have both processing applicability (such as homogenization, filling) and storage stability.

[0019] The present invention optimizes the formula of the capsule skin by regulating the types and dosages of gelatin, water, plasticizer, and disintegrant. Through chemical modification (succinic anhydride) to introduce hydrophilic groups, open the network structure, and physically plasticize (PEG) the flexible chain to insert, further reducing the cross - linking density, and optimizing the network dynamic balance through water regulation, the elastic index of the capsule skin is enhanced and the disintegration time is shortened by the synergistic effect of the compound system that improves the deformation recovery ability.

[0020] The soft capsule of Codonopsis pilosula and Dendrobium officinale extract prepared by the present invention has good stability of the content, high elastic index of the capsule skin, and short disintegration time. Specific embodiments

[0021] The embodiments of the technical solution of the present invention will be described in detail below. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, so they are only used as examples and cannot be used to limit the protection scope of the present invention.

[0022] For those not specifying specific techniques or conditions in the embodiments, follow the techniques or conditions described in the literature in this field or according to the product instructions. For reagents or instruments not indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase or commonly used in this field.

[0023] Experiment 1 Content Formulation Design and Verification The contents of the Codonopsis pilosula and Dendrobium officinale extract soft capsules were prepared according to the formulations in Table 1 for each of the examples and comparative examples. The preparation method of the soft capsule contents in the following examples of the present invention is as follows: S1. Weigh the powders of Codonopsis pilosula and Dendrobium officinale, mix them according to the mass ratio of Codonopsis pilosula to Dendrobium officinale of 6:4, and extract them in a water bath at 85°C for 3 h. After water extraction, the leaching solution is obtained. After centrifugation with a centrifuge, the supernatant is taken and subjected to reduced pressure distillation at 60°C with a rotary evaporator, concentrated to one-seventh of the original volume, and a concentrated solution is obtained. Four times the volume of absolute ethanol is added, and it is left to stand at room temperature for 24 h, then filtered by suction to obtain a polysaccharide precipitate. The polysaccharide precipitate is washed twice with absolute ethanol, placed in an oven and dried at 40°C for 8 h to collect the dried product, which is ground into a dry powder to obtain the Codonopsis pilosula and Dendrobium officinale extract powder; S2. Take 1 g of the powder and put it into a beaker, add the formulated amount of dispersion medium and suspending agent, mix and heat to melt at 75°C, then add an appropriate amount of distilled water to make the total volume 10 mL, and homogenize twice with a homogenizer for one minute each time to obtain the soft capsule contents.

[0024] The stability and redispersibility of the prepared soft capsule contents were measured, and the test results are shown in Table 1. The specific test methods are as follows: (1) Determination of sedimentation volume ratio (F) Taking the sedimentation volume ratio F as the determination standard for the stability of the contents, the value of F is between 0 and 1, and the closer F is to 1, the better its stability.

[0025] Transfer the homogenized contents to a stoppered graduated cylinder, cover the bottle stopper, record the initial height H0 of the contents, let it stand for one week, record the height H1 of the sediment in the stoppered graduated cylinder, and calculate the sedimentation volume ratio F (F = H1 / H0).

[0026] (2) Determination of redispersibility (R) The redispersibility of the contents standing for one week was measured. Turning the stoppered graduated cylinder 180° and then turning it back is recorded as one time, and the number of turns required to return to the initial suspension state is measured. When the number of turns is 1 time, the redispersibility is good, marked as ++; when the number of turns is 2 times, the redispersibility is average, marked as +.

[0027] Table 1

[0028] The test results show that when PEG - 400 is used as the dispersion medium instead of olive oil, the stability of the content is higher; when xanthan gum is used as the suspending agent instead of beeswax and sodium alginate, it can better improve the stability of the content. The results of Comparative Example 4 and Comparative Examples 6 - 9 show that when the dosage of xanthan gum is increased from 1% to 3%, the sedimentation volume ratio of the content first increases and then decreases. When the dosage of xanthan gum is 2%, the sedimentation volume ratio reaches the maximum value of 0.91, and the number of flips in the redispersion experiment also shows an increasing trend. When the dosage of xanthan gum is 1% - 2.5%, the dispersion is good. Too low a dosage of the suspending agent is not conducive to the stability of the content, and too high a dosage is not conducive to the stability and redispersion of the content. The results of Comparative Examples 10 - 14 show that the selection of the dosage of the wetting agent has an important impact on the formulation design of the soft capsule content. Too high or too low a dosage of the wetting agent is not conducive to the stability of the content. When the addition amount of soybean phospholipid is 0.4%, the stability and redispersion of the soft capsule content meet the requirements best. The results of Examples 1 - 9 show that when the mass ratio of Codonopsis pilosula and Dendrobium extract, PEG - 400, xanthan gum, and soybean phospholipid is 1:2:0.025:0.004, the stability of the obtained soft capsule content is the best.

[0029] Experiment 2 Capsule Shell Formulation Design and Verification Glycerol, succinic anhydride, and chitosan were selected as plasticizers, and PEG - 400 was used as a disintegrant to modify gelatin. Each capsule shell sample was prepared according to the formula in Table 2 for the capsule shell of the Codonopsis pilosula and Dendrobium extract soft capsule. The preparation method of the following capsule shell samples of the present invention is as follows: Precisely weigh gelatin: distilled water = 1:5 by proportion (soak gelatin in water for one hour before heating), and stir to dissolve at 80°C. Subsequently, add the plasticizer and 5% of the disintegrant PEG - 400 (referring to the mass of gelatin) to the gelatin solution while stirring (if obvious bubbles appear during the stirring process, a few drops of ethanol can be added). After complete dissolution, pour it into the mold while it is hot and cool it.

[0030] The measurement results of the capsule shell elastic index and disintegration time are shown in Table 2. The specific test method is as follows: Using the capsule shells placed for five days and seven days as samples, test their elastic index and disintegration time respectively. Thus, determine the best choice and dosage of the capsule shell plasticizer and whether its quality meets the regulations.

[0031] (1) Elastic Index Select the capsule shell placed for 5 days as the experimental sample and use the TA - 10 cylindrical probe. At 1.5mm·s -1Perform a compression test on the film at a certain speed, and export the force-time curve in the compression and rebound stages through software; calculate the area under the curve, and the elastic index calculation formula is as follows: Elastic index = work done in the rebound stage (Area2) / work done in the compression stage (Area1) × 100%; the closer the elastic index is to 1, the higher the water content and the more compliant the capsule skin quality is.

[0032] (2)Disintegration time The pharmacopoeia stipulates that the disintegration time of the capsule skin with gelatin as the matrix can be determined in artificial gastric juice.

[0033] Artificial gastric juice: Take 16.4 mL of dilute hydrochloric acid, add about 800 mL of water and 10 g of pepsin, shake well, and then dilute with water to 1000 mL to obtain.

[0034] Cut the capsule skin into capsule pieces with a specification of 2 cm × 2 cm, and let it stand for 7 days for use as a sample.

[0035] First, take 20 mL of artificial gastric juice in a beaker, place it on a water bath at 37 °C and heat it. Then take six portions of the placed samples and put them into the beaker for inspection. All 6 samples should disintegrate within one hour. If one portion cannot completely disintegrate, it indicates non-compliance.

[0036] Table 2 Elastic index and disintegration time of different proportions of different plasticizers

[0037] The test results show that the elastic index of gelatin with 10% chitosan is the highest, but its disintegration time is 58 min, which is relatively long. While the elastic index of gelatin with 4% succinic anhydride is only slightly lower than that of 10% chitosan, but its disintegration time is 43 min. Comparing the two, it is best to choose gelatin with 4% succinic anhydride.

[0038] Experiment 3 Long-term stability test Take the content prepared with the best formula in Example 7 (medicinal powder: PEG-400 = 1:2, xanthan gum dosage 2.5%, soybean phospholipid dosage 0.4%) and the capsule skin material solution prepared with the best capsule skin formula (gelatin: water: succinic anhydride: PEG400 = 1:5:0.04:0.05).

[0039] Preparation of soft capsules: Pass the capsule skin material solution through a die roller to form two continuous tapes (thickness 1 mm), preliminarily solidify through a cooling roller, control the tape thickness deviation ≤ ±0.05 mm, and the surface is smooth without bubbles; inject the content accurately between the two tapes through a metering pump (filling accuracy ±2%); the die roller applies pressure (0.5 MPa) and heats (50 °C) to make the tapes fuse to form a capsule chamber; the die roller rotates and cuts to form single oval soft capsules; the formed capsules are separated from the die and enter the conveyor belt for drying to obtain soft capsules.

[0040] The soft capsule samples are sub-packed into simulated commercial packages, marked with batches and dates, and stored in a stability test chamber with real-time monitoring of temperature and humidity (recorder accuracy: ±0.5°C / ±3%RH). Samples are taken at preset time points (0, 3, 6, 12, 24 months), and immediately tested or sealed and stored in a desiccator (to prevent moisture absorption) after sampling.

[0041] The test results are as follows: After 24 months of storage, the elasticity index ≥ 70%, the disintegration time is less than 44 minutes, and the moisture content is 12% - 16%. The results indicate that the Codonopsis pilosula and Dendrobium officinale extract soft capsules prepared by the present invention have good long-term stability.

[0042] It should be noted that the present invention is not limited to the above embodiments. The above embodiments are only examples, and embodiments with the same composition and the same function and effect as the technical idea within the scope of the technical solution of the present invention are all included in the technical scope of the present invention. In addition, within the scope of not departing from the gist of the present invention, various modifications that can be conceived by those skilled in the art to the embodiments, and other embodiments constructed by combining some of the constituent elements of the embodiments are also included in the scope of the present invention.

Claims

1. A soft capsule of Codonopsis pilosula and Dendrobium officinale extract, characterized in that: The invention comprises contents and a capsule skin coated on the surface of the contents; the raw materials for preparing the contents comprise a Codonopsis pilosula and Dendrobium officinale extract, a dispersion medium, a suspending agent and a wetting agent; the dispersion medium comprises PEG-400, and the suspending agent comprises xanthan gum; the raw materials for preparing the capsule skin comprise gelatin, water, a plasticizer and a disintegrant.

2. The Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 1, characterized in that: The wetting agent includes soybean lecithin.

3. The soft capsule of Codonopsis pilosula and Dendrobium officinale extract according to claim 1, characterized in that: The mass ratio of the Codonopsis pilosula and Dendrobium officinale extract, the dispersion medium, the suspending agent and the wetting agent is 1:(2-4):(0.015-0.025):(0.003-0.005).

4. The Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 3, characterized in that: The mass ratio of the Codonopsis pilosula and Dendrobium officinale extract, the dispersion medium, the suspending agent, and the wetting agent is 1:2:0.025:0.004; Alternatively, the mass ratio of the Codonopsis pilosula and Dendrobium officinale extract, the dispersion medium, the suspending agent, and the wetting agent is 1:3:0.015:0.

005.

5. The Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 1, characterized in that: The plasticizer includes succinic anhydride, and the disintegrant includes PEG-400.

6. The Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 5, characterized in that: The mass ratio of the gelatin, water, plasticizer and disintegrant is 1:(1-5):(0.03-0.04):(0.025-0.05).

7. The Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 6, characterized in that: The mass ratio of the gelatin, water, plasticizer and disintegrant is 1:5:0.04:0.

05.

8. The method for preparing the soft capsule of Codonopsis pilosula and Dendrobium officinale extract according to any one of claims 1 to 7, characterized in that: The following steps are involved: Mix Codonopsis pilosula and Dendrobium officinale, extract by water bath, centrifuge and distill under reduced pressure to obtain a concentrate, precipitate with alcohol and filter to obtain a polysaccharide precipitate, wash and dry to obtain a Codonopsis pilosula and Dendrobium officinale extract; The Codonopsis pilosula and Dendrobium officinale extract is mixed with a dispersion medium, a suspending agent, and a wetting agent, and then melted, and then mixed with water and homogenized to obtain a content; The gelatin is immersed in water, heated and stirred to dissolve, and then a plasticizer and a disintegrant are added and stirred to dissolve, and the capsule skin is obtained after cooling and forming; The content and the capsule skin are pressed into pills to obtain the Codonopsis pilosula and Dendrobium officinale extract soft capsules.

9. The method for preparing the Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 8, characterized in that: The water bath extraction temperature is 80-90° C., and the water bath extraction time is 2-3 hours.

10. The method for preparing the Codonopsis pilosula and Dendrobium officinale extract soft capsule according to claim 8, characterized in that: The melting temperature is 70-75°C.

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