CN112370425A - Chlorophyll oral self-microemulsion preparation - Google Patents
Chlorophyll oral self-microemulsion preparation Download PDFInfo
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Abstract
The invention discloses a chlorophyll oral self-microemulsion preparation with stable physicochemical property and high bioavailability. The preparation comprises the following components per 100 mL: oil phase: 20-50 g; 20-80g of emulsifier, 10-50g of co-emulsifier and chlorophyll. The self-microemulsion preparation can spontaneously form O/W type microemulsion in stomach after oral administration, the microemulsion is green and clear liquid, and the particle size is less than 100nm, so that the microemulsion preparation is favorable for wide distribution and rapid absorption of the microemulsion preparation in the whole gastrointestinal tract, and the oral bioavailability of the medicament is further improved. The oral chlorophyll self-microemulsion preparation can effectively improve the solubility of chlorophyll in water, increase the stability of the medicine and improve the oral bioavailability of the medicine, and has simple preparation method and low cost. The chlorophyll oral self-microemulsion preparation obtained by the invention can be applied to oral solid dosage forms such as soft capsules, hard capsules or enteric capsules.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a chlorophyll oral self-microemulsion preparation and a preparation method thereof.
Background
Chlorophyll (chlorophyllil) is an important substance for photosynthesis in higher plants and is widely present in leaves of green plants. Higher plants contain chlorophyll a and chlorophyll b mainly. Chlorophyll is mainly composed of two parts, the core part is a porphyrin ring, a light absorption functional group, and the other part is a long aliphatic hydrocarbon side chain (the side chain of chlorophyll a is methyl, the side chain of chlorophyll b is aldehyde, and the former is the main component in green leaves). Chlorophyll is dark green or dark green oily or pasty, insoluble in water, slightly soluble in alcohol, and easily soluble in organic solvents such as acetone and diethyl ether and oils. Chlorophyll has mainly the following pharmacological activities: (1) antioxidant function, which inhibits the damage of oxygen free radicals to cell membranes by activating the metabolic function of cells; (2) protecting liver; (3) regulating blood sugar; (4) anemia resistance, hematopoietic function promotion; (5) detoxification, anti-allergy, anti-complement; (6) dilating blood vessels and improving microcirculation; (7) deodorizing, promoting granulation and wound healing; (8) has anticancer effect. Chlorophyll is unstable and can be decomposed by light, heat, acid, oxygen, oxidizing agents, etc. In order to increase the light, heat, acid stability and solubility of chlorophyll, the magnesium ion in the chlorophyll molecule is usually substituted by copper, iron, cobalt or the like ions to form a chlorophyll derivative, and at present, sodium copper, sodium magnesium, sodium potassium, sodium copper potassium, sodium iron, potassium copper, sodium zinc, and the like are commercially available. The sodium copper chlorophyllin capsule is approved by the international health organization for food, is edible natural pigment approved and allowed to be used in China, and can be used for acute and chronic hepatitis and leukopenia in medical treatment. Most of chlorophyll derivatives are heavy metal complexes, which have high toxicity and the content of the chlorophyll should be strictly controlled. The chlorophyll is a natural product, has no toxic or side effect, is safe and reliable to eat for a long time, and the FAO/WHO does not stipulate the daily allowable intake of the chlorophyll. However, chlorophyll has the problems of poor water solubility, poor stability, low oral bioavailability and the like, so that the development and application of chlorophyll are limited.
Self-microemulsifying drug delivery systems (SMEDDS) are stable, uniform, transparent, thermodynamically stable dispersions formed from a drug, an oil phase, an emulsifier, and a co-emulsifier. Under the conditions of ambient temperature and mild stirring or gastrointestinal peristalsis, the drug-loaded microemulsion with the particle size of less than 100nm can be spontaneously formed when meeting water due to the action of the surfactant. The formed O/W type microemulsion has hydrophilicity and lower surface tension on the surface, so that the drug-loaded emulsion droplets can pass through a hydration layer of a gastrointestinal wall more easily, and the drugs in the emulsion droplets can be directly contacted with epithelial cells of the gastrointestinal tract to increase drug absorption. In addition, SMEDDS can promote absorption of macromolecular drugs in vivo through lymphatic absorption, overcome first-pass effect, and improve bioavailability.
Disclosure of Invention
The invention aims to provide an oral chlorophyll self-microemulsion preparation and a preparation method thereof, which can obviously improve the solubility of chlorophyll in water and the oral bioavailability thereof, have simple preparation process and low cost, can realize industrial large-scale production and have obvious economic benefit. The chlorophyll oral self-microemulsion preparation obtained by the invention can also be applied to oral solid dosage forms such as soft capsules, hard capsules or enteric capsules.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the oral chlorophyll self-microemulsion preparation is a liquid self-microemulsion preparation and consists of chlorophyll, an oil phase, an emulsifier and an auxiliary emulsifier.
The oil phase is one or two of polyethylene glycol oleate, caprylic capric triglyceride and propylene glycol monolaurate;
the emulsifier is one or two of tween 80 and polyoxyethylene hydrogenated castor oil-40;
the coemulsifier is one or two of diethylene glycol monoethyl ether and polyethylene glycol-400.
The liquid self-microemulsion preparation comprises 1-10% of chlorophyll, 19-40% of an oil phase, 20-70% of an emulsifier and 10-30% of a co-emulsifier by weight percentage, wherein the sum of the weight percentages of the auxiliary materials is 100%.
The preparation method of the chlorophyll oral self-microemulsion preparation comprises the following steps:
(1) weighing the oil phase, the emulsifier and the co-emulsifier according to the proportion of the components, and uniformly stirring at 60 ℃ to obtain blank self-microemulsion;
(2) adding chlorophyll into the mixture formed in the step (1), and uniformly stirring at 60 ℃ until the chlorophyll is completely dissolved, thereby obtaining the oral chlorophyll self-microemulsion preparation.
The invention also provides an oral chlorophyll self-microemulsion capsule which is prepared by filling the chlorophyll self-microemulsion into soft capsules.
Due to the adoption of the technology, the method has the following beneficial effects:
(1) the chlorophyll oral self-microemulsion preparation has good stability, and the medicine content in the preparation is still kept above 98 percent after being stored for six months under the refrigeration condition of 4 ℃;
(2) the solubility of chlorophyll in water is improved by nearly 40 times, and the water solubility of chlorophyll is greatly improved;
(3) the chlorophyll oral self-microemulsion forms a particle size smaller than 100nm after the chlorophyll oral self-microemulsion spontaneously emulsifies in the gastrointestinal tract, which is beneficial to improving the oral bioavailability of the chlorophyll oral self-microemulsion;
(4) each component in the formula has good safety, no stimulation to organisms and no toxicity, and can be widely used in the fields of foods and health care products;
(5) the preparation method has simple and controllable process and low cost.
(6) The chlorophyll oral self-microemulsion preparation obtained by the invention can also be applied to oral solid dosage forms such as soft capsules, hard capsules or enteric capsules.
Drawings
Fig. 1 is a graph showing a distribution of particle sizes of the chlorophyll oral self-microemulsion preparation in example 7.
Fig. 2 is a graph showing a potential distribution of the chlorophyll oral self-microemulsion preparation in example 7.
Fig. 3 is a transmission electron micrograph of the emulsified oral chlorophyll self-microemulsion preparation of example 7.
Fig. 4 is a dispersion curve of the chlorophyll oral self-microemulsion preparation in different dissolution media in the embodiment 9.
Fig. 5 is a graph showing the values of the absorption rate constant (Ka) and the apparent absorption coefficient (Papp) of the chlorophyll oral self-microemulsion preparation in the rat intestinal circulation in vivo in example 10.
Detailed Description
In order to make the present invention easier to understand, the technical solutions of the present invention are further described below with reference to the specific embodiments, but the present invention is not limited thereto.
Example 1 Effect of the types of oil, emulsifier, and co-emulsifier on the drug loading of chlorophyll oral self-microemulsion formulations
In the research process, the invention discovers that the types of the oil phase, the emulsifier and the co-emulsifier have great influence on the drug loading rate of the chlorophyll oral self-microemulsion preparation. Therefore, this study compared the equilibrium solubility of chlorophyll in different oil phases, emulsifiers, co-emulsifiers. The results are shown in Table 1.
Table 1 solubility of chlorophyll in different oil phases, emulsifiers, co-emulsifiers (37 ℃, n ═ 3)
As can be seen from the solubility results in table 1, the solubility of chlorophyll in polyethylene glycol oleate, propylene glycol monolaurate, medium chain triglycerides, caprylic capric triglyceride, propylene glycol monocaprylate is significantly higher than the other oil phases; for the emulsifier, the solubility of chlorophyll in kolliphor RH40 is the largest, and because the safety of Tween 80 is higher than that of Tween 20, the emulsifier is selected from one or two of kolliphor RH40 and Tween 80; the solubility of Transcutol HP, ethanol and PEG-400 in the co-emulsifier is stronger to chlorophyll, but the ethanol has certain irritation and toxicity, so the co-emulsifier selects one or two of Transcutol HP and PEG-400.
Example 2 Effect of compatibility experiment on quality of chlorophyll oral self-microemulsion preparation
The screened oil phase, emulsifier and co-emulsifier are subjected to compatibility test, kolliphor RH40 is taken as the emulsifier, and Transcutol HP is taken as the co-emulsifier. Mixing the oil phase, the emulsifier and the co-emulsifier uniformly according to a certain proportion, then adding 100 times of purified water by volume, stirring and emulsifying, and observing the emulsification result. The emulsification condition is divided into four grades of ABCD by taking a visual method and the particle size after emulsification as standards. A: clear and blue opalescence, particle size less than 100nm, B: slightly cloudy and with blue opalescence, particle size greater than 100nm, C: is milk-white liquid with the particle size larger than 300nm, D: a uniform system can not be formed all the time, and oil drops float on the liquid surface. The final emulsification results are shown in table 2.
Table 2 emulsification results for different oils, emulsifiers and co-emulsifiers (n ═ 3)
From the emulsification results in table 2, it can be seen that propylene glycol monolaurate and medium chain triglyceride can form a microemulsion with blue opalescence when used as oil phase, but the particle size is larger, and oleic acid macrogol glyceride and caprylic capric triglyceride can form a microemulsion with clear particle size below 100nm and light blue opalescence when used as oil phase, but the self-microemulsion formed by oleic acid macrogol glyceride has smaller particle size and higher solubility of chlorophyll, so that the oil phase is selected from one or two of oleic acid macrogol glyceride, caprylic capric triglyceride and propylene glycol monolaurate.
Embodiment 3
Prescription:
the preparation process comprises the following steps:
a: weighing the formula amount of the polyethylene glycol glyceryl oleate, the Tween 80 and the Transcutol HP, and uniformly stirring at 60 ℃ to form a blank liquid self-microemulsion preparation for later use;
b: adding the chlorophyll with the prescription amount into the hollow white liquid self-microemulsion a, and fully stirring at 60 ℃ until the chlorophyll is completely dissolved to obtain the chlorophyll oral self-microemulsion preparation.
Example 4
Prescription:
the preparation process comprises the following steps:
a: weighing the propylene glycol monolaurate, kolliphor RH40 and PEG400 according to the prescription amount, and uniformly stirring at 60 ℃ to form a blank liquid self-microemulsion preparation for later use;
b: adding the chlorophyll with the prescription amount into the hollow white liquid self-microemulsion a, and fully stirring at 60 ℃ until the chlorophyll is completely dissolved to obtain the chlorophyll oral self-microemulsion preparation.
Example 5
Prescription:
the preparation process comprises the following steps:
a: weighing the prescription amount of the polyethylene glycol glyceryl oleate, the kolliphor RH40 and the Transcutol HP, and uniformly stirring at 60 ℃ to form a blank liquid self-microemulsion preparation for later use;
b: adding the chlorophyll with the prescription amount into the hollow white liquid self-microemulsion a, and fully stirring at 60 ℃ until the chlorophyll is completely dissolved to obtain the chlorophyll oral self-microemulsion preparation.
Example 6
Prescription:
the preparation process comprises the following steps:
a: weighing the prescription amount of the polyethylene glycol glyceryl oleate, the kolliphor RH40 and the Transcutol HP, and uniformly stirring at 60 ℃ to form a blank liquid self-microemulsion preparation for later use;
b: adding the chlorophyll with the prescription amount into the hollow white liquid self-microemulsion a, and fully stirring at 60 ℃ until the chlorophyll is completely dissolved to obtain a chlorophyll oral self-microemulsion preparation for later use;
c: and filling the obtained chlorophyll oral liquid self-microemulsion preparation into a soft capsule to obtain the chlorophyll oral self-microemulsion capsule.
Example 7 particle diameter, PDI, zeta potential and microemulsion appearance morphology observations
Taking example 5 as an example, the blank self-microemulsion is a clear, transparent and colorless viscous liquid; after being emulsified by water, the microemulsion is clear and transparent, has bluish opalescence and good fluidity. The chlorophyll oral self-microemulsion preparation is a green viscous liquid, and is a clear, transparent and green liquid after being emulsified by water.
And observing the form of the emulsified microemulsion by adopting a transmission electron microscope. The results are shown in FIG. 3, which shows that spherical emulsion droplets of a relatively uniform size can be formed. And (3) measuring the particle size, PDI (PDI) and zeta potential of the chlorophyll self-microemulsion by adopting a Brookhei particle size analyzer. As shown in figure 1 and figure 2, the self-microemulsion has the particle size of 22.82 +/-1.29 nm, narrow distribution, zeta potential of-24.21 +/-3.45 and good physical stability, and meets the requirement of an oral self-microemulsion preparation.
Example 8 preliminary stability study
Placing the chlorophyll oral self-microemulsion preparation in a vial with penicillin, sealing, refrigerating at 4 deg.C, standing for 6 months, sampling at the end of 0, 1, 2, 3, 6 months, and examining the stability of the sample, the results are shown in Table 3.
Table 3 preliminary stability test results (n ═ 3)
As can be seen from Table 3, the appearance, particle size and content of the oral chlorophyll self-microemulsion preparation after being placed at 4 ℃ for six months have no obvious change compared with 0 month, indicating that the stability of chlorophyll is good.
EXAMPLE 9 in vitro Dispersion test
The in vitro dispersion test of chlorophyll oral self-microemulsion is determined by using Chinese pharmacopoeia dissolution instrument I (basket method). The dispersion medium used was 500mL of water and 0.1M HCl, respectively, and the results are shown in FIG. 4, with a constant temperature of 37 ℃ and a rotation speed of 100 rpm. As can be seen from the figure, more than 97% of the chlorophyll oral self-microemulsion dispersed in pure water within 45 minutes formed a microemulsion, while 90% of the chlorophyll oral self-microemulsion dispersed in pH 1.2 HCl within 30 minutes. In the pH 6.8 PBS medium, the early dispersion rate was slow, but complete dispersion was achieved within 90 minutes.
Example 10 circulation of rats in the body intestine
3 rats fasted with free water before the experiment were taken, 25% urethane solution (7mL/kg) was injected into the abdominal cavity during the experiment, and the dorsal position was fixed on an operating table after anesthesia. Cutting the middle lower part of the abdominal cavity for about 3-4 cm along the abdominal midline according to the following intestinal segment intervals: the duodenum section starts 1cm away from the pylorus, the jejunum section starts 15cm away from the pylorus, the ileum section starts 20cm away from the ascending part of the caecum, the colon section starts from the rear section of the caecum, each section is about 10cm, the two ends are intubated and tied, the content is flushed by physiological saline at 37 ℃, and then the physiological saline is discharged by air. The abdomen is covered with absorbent cotton soaked with normal saline for moisture preservation, and is kept warm under an infrared lamp, and a reflux device is installed. Taking 50mL of chlorophyll oral self-microemulsion intestinal perfusion liquid preheated to 37 ℃, circulating for 30min at the flow rate of 1.0mL/min, adjusting the flow rate to 0.2mL/min, starting timing, sampling at 15 min, 30min, 45 min, 60 min, 75 min, 90min and 120min, and weighing. Finally, the rats were sacrificed, sections of the intestine were cut off, the length (L) and the section radius (r) were measured, and the chlorophyll content in the samples was measured. The absorption rate constant (Ka) and apparent absorption coefficient (Papp) of the drug were calculated according to the following formulas. The results are shown in FIG. 5. According to perfusion results, the chlorophyll oral self-microemulsion preparation is absorbed in four intestinal sections, and duodenum is larger than jejunum and larger than ileum, so that the duodenum is rich in small intestinal villi and capillary vessels, and the absorption of the medicine is promoted.
Claims (6)
1. An oral chlorophyll self-microemulsion preparation is characterized by comprising the following components in percentage by mass:
2. the oral chlorophyll self-microemulsion formulation according to claim 1, wherein: the oil phase is one or the combination of two of oleic acid polyethylene glycol glyceride, caprylic capric triglyceride and propylene glycol monolaurate.
3. The oral chlorophyll self-microemulsion formulation according to claim 1, wherein: the emulsifier is one or the combination of two of Tween 80 and polyoxyethylene hydrogenated castor oil 40(Kolliphor RH 40).
4. The oral chlorophyll self-microemulsion formulation according to claim 1, wherein: the coemulsifier is one or the combination of two of diethylene glycol monoethyl ether (Transcutol HP) and polyethylene glycol-400 (PEG-400).
5. The oral chlorophyll self-microemulsion preparation according to claim 1, wherein the oral chlorophyll self-microemulsion preparation can be filled in soft capsules to prepare the oral chlorophyll self-microemulsion capsule.
6. The oral chlorophyll self-microemulsion preparation according to claim 1, wherein the preparation method comprises the following steps:
(1) preparing the following components in percentage by mass: 1-10% of chlorophyll, 19% -40% of oil phase, 20% -70% of emulsifier and 10% -30% of co-emulsifier;
(2) stirring and uniformly mixing the oil phase, the emulsifier and the co-emulsifier at 60 ℃ to obtain blank self-microemulsion;
(3) and (3) adding chlorophyll into the blank self-microemulsion formed in the step (2), and stirring at 60 ℃ until the chlorophyll is completely dissolved, thus obtaining the chlorophyll oral self-microemulsion preparation.
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| CN202011366695.7A CN112370425A (en) | 2020-11-27 | 2020-11-27 | Chlorophyll oral self-microemulsion preparation |
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| CN202011366695.7A Pending CN112370425A (en) | 2020-11-27 | 2020-11-27 | Chlorophyll oral self-microemulsion preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115192525A (en) * | 2021-04-29 | 2022-10-18 | 湖南慧泽生物医药科技有限公司 | Self-microemulsion composition of sirolimus and preparation method thereof |
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Non-Patent Citations (1)
| Title |
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| WENLI LIU等: "Preparation and evaluation of self-microemulsifying drug delivery system of baicalein", 《FITOTERAPIA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115192525A (en) * | 2021-04-29 | 2022-10-18 | 湖南慧泽生物医药科技有限公司 | Self-microemulsion composition of sirolimus and preparation method thereof |
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