CN109700816B - Phosphatidylserine enteric coating preparation and preparation method thereof - Google Patents

Abstract

The invention provides a phosphatidylserine enteric coating preparation and a preparation method thereof, wherein the phosphatidylserine enteric coating preparation consists of a core and a coating layer; wherein the core comprises the following raw material components in parts by weight: 45-95 parts of phosphatidylserine, 0.1-1 part of antioxidant, 4-12 parts of disintegrating agent, 0.5-10 parts of adsorbent, 0.5-3 parts of lubricant and 0-20 parts of bonding filler. The phosphatidylserine enteric coating preparation can be dissolved in the intestinal tract at a fixed point, avoids the damage of enzymes and gastric acid in the stomach to the phosphatidylserine, and can be released and absorbed in the intestinal tract continuously at a higher concentration; meanwhile, the preparation method takes the active substance phosphatidyl serine which plays a role in medicine as a core to carry out coating, so that the activity of the active substance phosphatidyl serine is not lost.

Description

Phosphatidylserine enteric coating preparation and preparation method thereof

technical field

The present invention relates to a phosphatidylserine preparation and a preparation method thereof, in particular to a phosphatidylserine enteric coating preparation and a preparation method thereof.

Background technique

Phosphatidylserine (PS), a phospholipid nutrient, is active in cell membranes and is the major acidic phospholipid component in brain cell membranes. PS plays a key role in many membrane-related neuronal processes. The primary purpose of PS is to help maintain proper membrane fluidity, a property closely related to most membrane functions. PS has been the subject of many human clinical trials related to memory loss, mood, cognitive behavior and learning ability. Numerous studies have shown that PS may help subjects with age-related memory impairment. Additionally, PS may even contribute to cognitive optimization in subjects without cognitive impairment.

Dietary PS is efficiently and rapidly absorbed into the bloodstream in the intestine and readily crosses the blood-brain barrier to the nerve cells in the brain. PS can be extracted from bovine brain, plants, or PS can be produced from soybean phospholipids using biocatalytic techniques. The head groups of phospholipids can be easily modified by transphosphatidylation reactions using phospholipase Ds (PLDs). Thus, phosphatidylserine can be catalyzed by PLD from phosphatidylcholine or any other phospholipid mixture with serine.

Phosphatidylserine (PS), as the raw material of medicines and health products, has been widely used in various types of brain food and nutritional products. However, the phosphatidylserine monomer in the prior art is prepared as a medicine or health care product as a raw material, and the phosphatidylserine is easily oxidized and hygroscopic during storage, and the phosphatidylserine is easily destroyed by intragastric enzymes and gastric acid during taking.

SUMMARY OF THE INVENTION

Purpose of the invention: The first purpose of the present invention is to provide a phosphatidylserine enteric-coated preparation for sustained release and absorption of phosphatidylserine at a higher concentration in the intestinal tract; the second purpose of the present invention is to provide a preparation method of this preparation .

Technical scheme: The present invention provides a phosphatidylserine enteric coating preparation, which consists of a core and a coating layer; wherein the core comprises the following raw material components by weight: 45-95 parts of phosphatidylserine, 0.1-1 part of antioxidant , 4-12 parts of disintegrant, 0.5-10 parts of adsorbent, 0.5-3 parts of lubricant and 0-20 parts of adhesive filler.

Further, the mass percentage of the coating is 10-30%. When the mass ratio of coating accounts for 10-30% of the total preparation, the release amount in acid for 2 hours reaches a minimum of 3.0% of the declared amount, and the release amount in buffer solution reaches a maximum of 97.5%, which meets the requirements of the Pharmacopoeia.

Preferably, the antioxidant is one of butylated hydroxyanisole, dibutylated hydroxytoluene, propyl gallate, tert-butyl hydroquinone, tocopherol and sodium erythorbate.

Wherein, butylated hydroxyanisole is relatively stable to heat, and is not easily destroyed under weak alkaline conditions, so it is a good antioxidant;

Dibutylhydroxytoluene is a fat-soluble antioxidant, and its application in food is basically the same as that of BHA, but its antioxidant capacity is not as good as BHA;

As a fat-soluble antioxidant, propyl gallate can be used in food, but its stability is poor, it is not resistant to high temperature, and it is not suitable for baking;

The antioxidant effect of tert-butyl hydroquinone is 5 to 7 times stronger than that of BHA, BHT and PG. It is suitable for animal and vegetable fats and fatty foods, especially for vegetable oils. It is the first choice for salad oil, blending oil and high cooking oil. Antioxidant, and can effectively delay the oxidation of oil, improve the stability of food, and significantly prolong the shelf life of oil and fat-rich food;

Tocopherol is a natural oil-soluble antioxidant that is currently mass produced. It has a wide range of applications in whole milk powder, cream or margarine, meat products, processed aquatic products, dehydrated vegetables, fruit juice drinks, frozen foods and convenience foods;

Sodium erythorbate is an important antioxidant and preservative in the food industry. It can maintain the color, natural flavor and shelf life of food without any toxic and side effects. In the food industry, it is mainly used in meat products, fruits, vegetables, canned food, jams , beer, soft drinks, fruit tea, juice, wine, etc.

Preferably, the disintegrant is one of croscarmellose sodium, sodium starch glycolate, crospovidone, and low-substituted hydroxypropyl cellulose; the adsorbent is silicon dioxide and /or magnesium aluminum silicate; the lubricant is one of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, glyceryl palmitate stearate The adhesive filler is one of microcrystalline cellulose, mannitol, and anhydrous calcium hydrogen phosphate.

Preferably, the coating consists of triethyl citrate, glycerol monostearate, polysorbate 80 and a copolymer of methacrylic acid-ethyl acrylate.

Among them, triethyl citrate has strong dissolving ability and good compatibility with many resins. Products plasticized with it have good oil resistance, light resistance and mildew resistance, and are respectable for digestive tract, respiratory tract and skin, etc. The route is absorbed by the body;

The glycerol monostearate can form a stable hydrated dispersion in water, has good surface activity, can play the roles of emulsifying, foaming, dispersing, defoaming, anti-starch aging, etc., and is the most widely used in food and cosmetics. an emulsifier;

The polysorbate 80 improves hydrophobicity and allows the coating to maintain suitable hardness and appearance.

Preferably, the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer of ethyl methacrylate acrylate, which is a commonly used aqueous coating material.

Preferably, the mass ratio of the copolymer of triethyl citrate, glycerol monostearate, polysorbate 80 and methacrylic acid-ethyl acrylate is 1:1:1:1.

The present invention also provides a preparation method of a phosphatidylserine enteric coating preparation, comprising the following steps:

(1) phosphatidylserine, antioxidant, disintegrant, adsorbent, lubricant and adhesive filler are mixed by weight to obtain a mixture;

(2) dry granulating the mixture to obtain mixture particles;

(3) the copolymer of triethyl citrate, glyceryl monostearate, polysorbate 80 and methacrylic acid-ethyl acrylate is dispersed in water and mixed and stirred to obtain a coating dispersion; the coating is dispersed Coating after body filtration;

(4) heating and drying after the coating is completed to obtain the phosphatidylserine enteric coating preparation.

Preferably, the dry granulation in step (2) is to obtain dry extract powder through spray drying, press into thin slices with a dry extrusion granulator, and then pulverize into granules.

Preferably, when the coating temperature in step (3) is 50-55°C, and the coating temperature is 50-55°C, the quality of the phosphatidylserine enteric coating preparation is excellent, and the release amount of phosphatidylserine is low; and When the coating temperature is lower than 50°C or higher than 55°C, the quality of the phosphatidylserine enteric coating preparation is poor; the release amount of phosphatidylserine is high.

Preferably, the mixing and stirring in step (3) is shear mixing with a high shear homogenizer for 30 minutes, and the filtration is 60 mesh sieves.

Preferably, the mass ratio of the copolymer of triethyl citrate, glyceryl monostearate, polysorbate 80 and methacrylic acid-ethyl acrylate described in step (3) is 1:1:1:1 .

Preferably, the weight part of the water in step (3) is the sum of the weight parts of triethyl citrate, glycerol monostearate, polysorbate 80 and methacrylic acid-ethyl acrylate copolymer.

Preferably, the temperature of heating and drying in step (4) is 60-70°C, and when the drying temperature after coating is 60-70°C, the quality of the phosphatidylserine enteric coating preparation is excellent; the release amount of phosphatidylserine is low; However, when the drying temperature is lower than 60°C or higher than 70°C, the quality of the phosphatidylserine enteric coating preparation is poor; the release amount of phosphatidylserine is high.

Further, the drying time of step (4) is 20-30 minutes.

Beneficial effects: compared with the prior art, the present invention has the following advantages: the phosphatidylserine enteric coating preparation can be dissolved in the intestinal tract at a fixed point, avoid the destruction of the phosphatidylserine by the enzymes in the stomach and gastric acid, and can be dissolved in the intestinal tract with High concentration sustained release and absorption; at the same time, the preparation method uses phosphatidylserine as the core to coat the active substance that exerts medicinal effect, which will not cause its loss of activity.

Detailed ways

Specific embodiments of the present invention will be described in detail below.

Example 1

Step 1: Mix 450 g of phosphatidylserine, 1 g of butylated hydroxyanisole, 40 g of croscarmellose sodium, 5 g of silicon dioxide, and 5 g of magnesium stearate to obtain a mixture;

Step 2: the mixture is spray-dried to obtain dry extract powder, which is pressed into flakes with a dry extrusion granulator, and then pulverized into particles to obtain mixture particles.

Step 3: Disperse 110 g of triethyl citrate, 110 g of glycerol monostearate, 110 g of polysorbate 80 and 110 g of a 1:1 copolymer of methacrylic acid-ethyl acrylate in 440 g of water. The mixer was sheared and mixed for 30 minutes to obtain a coating dispersion; the coating dispersion was filtered through a 60-mesh sieve and then subjected to fluid bed coating;

Step 4: heating and drying after the coating is completed, the drying temperature is 60°C, and the drying time is 20 minutes; the phosphatidylserine enteric coating preparation is obtained.

The above-mentioned fluidized bed coating adopts GLATT mini coating machine, and the coating process is controlled according to the following parameters.

equipment GLATT Mini Coater Loading volume 500g coating temperature 50℃ Outlet air temperature 30℃ Inlet air flow 1.1m³/min Spray feed rate 4.5-5.0g/min Atomizing air pressure 100kpa Nozzle diameter 0.8mm

Example 2

Step 1: Mix 95 g of phosphatidylserine, 1 g of dibutylhydroxytoluene, 12 g of sodium starch glycolate, 10 g of magnesium aluminum silicate, 3 g of calcium stearate and 20 g of microcrystalline cellulose to obtain a mixture;

Step 2: the mixture is spray-dried to obtain dry extract powder, which is pressed into flakes with a dry extrusion granulator, and then pulverized into particles to obtain mixture particles.

Step 3: Disperse 40 g of triethyl citrate, 40 g of glycerol monostearate, 40 g of polysorbate 80 and 40 g of 1:1 copolymer of methacrylic acid-ethyl acrylate in 160 g of water, respectively, after high shearing Shear and mix with a shear homogenizer for 30 minutes to obtain a coating dispersion; filter the coating dispersion through a 60-mesh sieve and perform fluid bed coating;

Step 4: heating and drying after the coating is completed, the drying temperature is 70°C, and the drying time is 30 minutes; the phosphatidylserine enteric coating preparation is obtained.

The above-mentioned fluidized bed coating adopts GLATT mini coating machine, and the coating process is controlled according to the following parameters.

equipment GLATT Mini Coater Loading volume 140g coating temperature 55℃ Outlet air temperature 30℃ Inlet air flow 1.1m³/min Spray feed rate 4.5-5.0g/min Atomizing air pressure 100kpa Nozzle diameter 0.8mm

Example 3

Step 1: 500 g of phosphatidylserine, 0.7 g of propyl gallate, 10 g of crospovidone, 5 g of a 1:1 mixture of silica and aluminum magnesium silicate, 2.5 g of sodium stearoyl fumarate and mannitol 10g was mixed to obtain a mixture;

Step 2: the mixture is spray-dried to obtain dry extract powder, which is pressed into flakes with a dry extrusion granulator, and then pulverized into particles to obtain mixture particles.

Step 3: Disperse each of 132.5g triethyl citrate, 132.5g glyceryl monostearate, 132.5g polysorbate 80 and 132.5g 1:1 copolymer of methacrylic acid-ethyl acrylate in 530g water After shearing and mixing with a high-shear homogenizer for 30 minutes, a coating dispersion was obtained; the coating dispersion was filtered through a 60-mesh sieve and then subjected to fluidized bed coating;

Step 4: heating and drying after the coating is completed, the drying temperature is 70°C, and the drying time is 30 minutes; the phosphatidylserine enteric coating preparation is obtained.

The above fluidized bed coating adopts GLATT mini coating machine, and the coating process is controlled according to the following parameters.

equipment GLATT Mini Coater Loading volume 530g coating temperature 55℃ Outlet air temperature 30℃ Inlet air flow 1.1m³/min Spray feed rate 4.5-5.0g/min Atomizing air pressure 100kpa Nozzle diameter 0.8mm

Example 4

Step 1: Mix 80 g of phosphatidylserine, 1 g of tert-butyl hydroquinone, 10 g of low-substituted hydroxypropyl cellulose, 3.5 g of magnesium aluminum silicate, 1 g of glyceryl behenate and 10 g of mannitol to obtain a mixture;

Step 2: The mixture is spray-dried to obtain dry extract powder, which is pressed into flakes with a dry extrusion granulator, and then pulverized into particles to obtain mixture particles.

Step 3: Disperse each of 21.3 g of triethyl citrate, 21.3 g of glycerol monostearate, 21.3 g of polysorbate 80 and 21.3 g of a 1:1 copolymer of methacrylic acid-ethyl acrylate in 85 g of water After shearing and mixing with a high-shear homogenizer for 30 minutes, a coating dispersion was obtained; the coating dispersion was filtered through a 60-mesh sieve and then subjected to fluidized bed coating;

Step 4: heating and drying after the coating is completed, the drying temperature is 65°C, and the drying time is 25 minutes; the phosphatidylserine enteric coating preparation is obtained.

The above-mentioned fluidized bed coating adopts GLATT mini coating machine, and the coating process is controlled according to the following parameters.

equipment GLATT Mini Coater Loading volume 106g coating temperature 55℃ Outlet air temperature 30℃ Inlet air flow 1.1m³/min Spray feed rate 4.5-5.0g/min Atomizing air pressure 100kpa Nozzle diameter 0.8mm

The applicant has found through research that the phosphatidylserine monomer in the prior art is used as a raw material for medicines or health products, and phosphatidylserine is easily oxidized and hygroscopic during storage, and gastric enzymes and gastric acid are easy to phosphatidylserine when taken. problem of destruction. For this reason, it is considered to overcome the problems existing in the prior art by coating, but the existing coating conditions are not tried out, so further research on relevant parameters is required.

Comparative Example 1

Five groups of parallel experiments were designed, and the coating temperatures were designed to be 45, 50, 53, 55, and 60°C, respectively. The remaining raw materials and preparation steps were the same as those in Example 1, and 5 g of granules with different enteric coating ratios were prepared using a disintegration tester. Invasion of PH1.2, USP simulated gastric acid without pepsin for 1 hour, the quality and phosphatidylserine release of phosphatidylserine enteric-coated preparations are shown in Table 1:

Table 1 - Effect of coating temperature on the quality of phosphatidylserine enteric-coated formulations

As can be seen from the above table, in the preparation of phosphatidylserine enteric coating preparation, when the coating temperature is 50-55 ℃,

The quality of the phosphatidylserine enteric-coated preparation is excellent, and the release of phosphatidylserine is low; while when the coating temperature is less than 50°C or greater than 55°C, the quality of the phosphatidylserine enteric-coated preparation is poor; the release of phosphatidylserine high volume.

Comparative Example 2

Four groups of parallel experiments were designed, and the drying temperatures after coating were designed to be 55, 60, 65, 70, and 75 °C, respectively. The remaining raw materials and preparation steps were the same as those in Example 1. A disintegration tester was used to put 5g of different enteric coating ratios. The granule formulation invaded at pH 1.2, and the USP simulated gastric acid did not contain pepsin for 1 hour. The quality and phosphatidylserine release of the phosphatidylserine enteric-coated formulation are shown in Table 2:

Table 2 - Effect of drying temperature after coating on the quality of phosphatidylserine enteric-coated formulations

It can be seen from the above table that in the preparation of phosphatidylserine enteric coating preparation, when the drying temperature after coating is 60-70 °C, the quality of phosphatidylserine enteric coating preparation is excellent; the release amount of phosphatidylserine is low; When the temperature is lower than 60°C or higher than 70°C, the quality of phosphatidylserine enteric coating preparation is poor; the release amount of phosphatidylserine is high.

Comparative Example 3

Take phosphatidylserine enteric-coated preparations with different coating ratios for release measurement, and the measurement method refers to the second method in the "Chinese Pharmacopoeia 2010 Edition Part II Appendix X·D Release Determination Method" (for enteric-coated preparations). ). The results of testing the release of phosphatidylserine enteric-coated formulations in acid for 2 hours and in buffer for 20 minutes are shown in the table below. In accordance with the requirements of the Pharmacopoeia, the experimental results are shown in Table 3.

Table 3 - Effect of coating ratio on release of phosphatidylserine enteric-coated formulations

Coating ratio Amount released in acid solution release in buffer 8% 25.6% —— 10% 4.1% 97.5% 18% 3.8% 95.5% 25% 3.4% 93.2% 30% 3.0% 92.8% 33% 3.0% 85.3% 35% 2.9% 81.5%

The above table shows that when the coating mass ratio accounts for 8% of the total preparation, the release of the phosphatidylserine enteric-coated preparation in acid for 2 hours is more than 25% of the labeled amount; and when the coating mass ratio accounts for the total preparation 10 to 30% of the indicated amount, the release amount in acid for 2 hours reaches a minimum of 3.0% of the declared amount, and the release amount in buffer solution reaches a maximum of 97.5%, which meets the requirements of the Pharmacopoeia; 30%, the release in buffer was only 81.5% and 85.3%.

Claims (5)

1. The phosphatidyl serine enteric-coated preparation is characterized by comprising a core and a coating, wherein the coating accounts for 10-30% by mass; the core is prepared from the following raw materials in parts by weight: 45-95 parts of phosphatidylserine, 0.1-1 part of antioxidant, 4-12 parts of disintegrating agent, 0.5-10 parts of adsorbent, 0.5-3 parts of lubricant and 0-20 parts of bonding filler; the coating consists of triethyl citrate, glyceryl monostearate, polysorbate 80 and a methacrylic acid-ethyl acrylate copolymer in a mass ratio of 1:1:1:1, wherein the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer of ethyl methacrylate; the temperature during coating is 50-55 ℃, and the temperature for heating and drying after coating is finished is 60-70 ℃.

2. The enteric coated formulation of phosphatidylserine of claim 1, wherein: the antioxidant is one of butylated hydroxyanisole, dibutyl hydroxy toluene, propyl gallate, tert-butyl hydroquinone, tocopherol and sodium erythorbate.

3. The enteric coated formulation of phosphatidylserine of claim 1, wherein: the disintegrating agent is one of croscarmellose sodium, sodium starch glycolate, crospovidone and low-substituted hydroxypropyl cellulose; the adsorbent is silicon dioxide and/or magnesium aluminum silicate; the lubricant is one of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate and glyceryl palmitostearate; the bonding filler is one of microcrystalline cellulose, mannitol and anhydrous calcium hydrogen phosphate.

4. A method for preparing the enteric coated formulation of phosphatidylserine of claim 1, comprising the steps of:

(1) mixing phosphatidyl serine, an antioxidant, a disintegrating agent, an adsorbent, a lubricant and an adhesive filler according to parts by weight to obtain a mixture;

(2) dry granulating the mixture to obtain mixture granules;

(3) dispersing triethyl citrate, glyceryl monostearate, polysorbate 80 and a copolymer of methacrylic acid and ethyl acrylate in water, mixing and stirring to obtain a coating dispersion, and filtering the coating dispersion to coat;

(4) and heating and drying after coating to obtain the phosphatidylserine enteric coated preparation.

5. The method for preparing a phosphatidylserine enteric coated preparation according to claim 4, wherein: and (4) drying for 20-30 minutes.