Process for preparing a degradable capsule for lowering blood lipids

Abstract

The application discloses a kind of degradable capsules preparation method for lowering blood lipid, belong to biomaterial technical field.It includes the following steps: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate are separately packed into different raw material tanks;Polylactic acid particles are melted to 70-80 DEG C, methyl gallate is added, and is constantly stirred and heated to 85-90 DEG C, after 2-4 hours of processing, 65 DEG C constant temperature water bath is kept for 30-60 minutes under nitrogen protection;Gelatin and cinnamamide are added in constant temperature water bath, and are heated to 90-95 DEG C, after 5-6 hours of sufficient reaction, 0.006 times of potassium persulfate powder of gelatin quality is added, and is stirred uniformly, and continue to react for 25-35 minutes;The solution after the above reaction is added, amylopectin is fully stirred and mixed, 0.5 times of cysteine of amylopectin quality is added at 75 DEG C, and is fully mixed, and freeze-drying is obtained after low-temperature freeze-drying.The prepared capsule has high encapsulation efficiency and large drug loading, and the drug efficacy of unit capsule is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological materials, and particularly relates to a preparation method of a degradable capsule for reducing blood fat. BACKGROUND

[0002] Hyperlipidemia refers to abnormal increase of one or more lipid components in blood, which is quite common in clinical practice. It can be caused by genetic and environmental factors, induced by diabetes, obesity, pancreatitis, and diseases of liver, gallbladder and kidney, and especially improper diet. Regardless of the cause, hyperlipidemia can develop into atherosclerosis. At present, it is well known that the research on nanomedicine is a new and promising direction in the research on medicine, and the medicine is mainly loaded into nanomedicine carriers by encapsulation and adsorption. Nanotechnology has been used for medicine research for many years abroad, and the particle size range is wide, mostly in the range of 100-1000 nm, which is called nanoparticle (nanosphere and nanocapsule), and the larger one is called microcapsule or microsphere. Since the particle size of nanomedicine is smaller than the diameter of capillary (6-8 μm), it can easily enter various tissues and organs of the human body for controlled release, greatly improving the bioavailability of the medicine. It also has many advantages that conventional medicines do not have: slow-release medicine, changing the half-life of the medicine in the body, prolonging the action time of the medicine; as a "biological missile", the medicine can be made into a guided medicine to achieve the purpose of targeted drug delivery to specific organs; under the premise of ensuring the drug effect, the drug use amount is reduced, and the toxic and side effects are reduced or eliminated; the stability of the medicine is improved, which is beneficial to storage; the membrane transport mechanism is changed, the permeability of the medicine to biological membranes is increased, which is beneficial to transdermal absorption of the medicine and exertion of the medicine effect in cells; the solubility of the medicine is increased.

[0003] However, the preparation of nanocapsules is not conducive to carrying large-molecule anti-hyperlipidemic drugs, and it is urgent to research a micron-sized biodegradable capsule to improve the drug carrying capacity and controlled release rate of anti-hyperlipidemic drugs. SUMMARY

[0004] 1. Problems to be solved

[0005] In view of the problems existing in the prior art, the present application provides a preparation method of a degradable capsule for reducing blood fat. The prepared capsule has high encapsulation efficiency, large contact area ratio between the medicine in the medicine preparation and the packaging material, which is beneficial to the close adhesion of the medicine to the side surface of the capsule, long medicine stability and storage period, large drug loading capacity, reduced number of capsules used, and improved medicine curative effect of unit capsule.

[0006] 2. Technical scheme

[0007] A preparation method of a degradable capsule for reducing blood fat, comprising the following steps:

[0008] (1) Preparation of raw materials: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate, and are packed into different raw material tanks for standby;

[0009] (2) The polylactic acid particles are melted to 70-80℃, methyl gallate is added, and the temperature is raised to 85-90℃ under constant stirring, and then treated for 2-4h, and then placed in a 65℃ constant temperature water bath for 30-60min under nitrogen protection;

[0010] (3) In the constant temperature water bath, gelatin and cinnamamide are added, and the temperature is raised to 90-95℃, and then reacted for 5-6h, and then 0.006 times the mass of gelatin potassium persulfate powder is added, and stirred uniformly, and then reacted for 25-35min;

[0011] (4) The solution after the above reaction is added to amylopectin, and then stirred uniformly, and then 0.5 times the mass of amylopectin cysteine is added at 75℃, and then stirred uniformly, and then low-temperature freeze-dried to obtain a freeze-dried powder of the degradable capsule.

[0012] The above-mentioned degradable capsule preparation method for lowering blood lipids,

[0013] The raw materials in step (1) are as follows in terms of weight parts:

[0014]

[0015] The above-mentioned degradable capsule preparation method for lowering blood lipids,

[0016] The raw materials in step (1) are as follows in terms of weight parts:

[0017]

[0018] The above-mentioned degradable capsule preparation method for lowering blood lipids,

[0019] The raw materials in step (1) are as follows in terms of weight parts:

[0020]

[0021] The above-mentioned degradable capsule preparation method for lowering blood lipids,

[0022] The dialysis treatment is performed before low-temperature freeze-drying in step (4);

[0023] The dialysis treatment is performed before low-temperature freeze-drying in step (4);

[0024] The solution after being stirred uniformly is filtered using a dialysis membrane with a molecular weight of 500-1000Da, and the retained liquid in the recovery bag is recovered;

[0025] The dialysis membrane is pretreated by heating to 100℃ in 100mM sodium hydroxide solution and washed clean.

[0026] The preparation method of the blood lipid-lowering degradable capsule,

[0027] The temperature of the low-temperature freeze-drying is -55℃.

[0028] The pressure of the low-temperature freeze-drying is 1Pa.

[0029] The time of the low-temperature freeze-drying is 24h-36h.

[0030] The preparation method of the blood lipid-lowering degradable capsule,

[0031] The preparation method of the polylactic acid particles is as follows:

[0032] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus;

[0033] The pre-polycondensation product is obtained by pre-polycondensation of lactic acid at a temperature of 150℃, a vacuum degree of 0.5KPa, in the presence of tin catalyst, for 6-10h;

[0034] The polylactic acid is obtained by solid-phase polymerization of the pre-polycondensation product at a temperature of 135℃, a pressure of 0.1KPa, for 8-48h.

[0035] The preparation method of the blood lipid-lowering degradable capsule,

[0036] The process method of the fermentation of Lactobacillus rhamnosus is as follows:

[0037] Before inoculation, the Lactobacillus rhamnosus is seed cultured to obtain seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include: rotation speed of 100-180r·min -1 ; temperature of 37-40℃; time of 12-24h, and OD600 value of more than 5; molecular distillation, and the product is obtained.

[0038] The preparation method of the blood lipid-lowering degradable capsule,

[0039] The process method of the molecular distillation is as follows:

[0040] The bacteria are filtered out to obtain calcium lactate, and the calcium lactate is acid hydrolyzed with sulfuric acid to obtain lactic acid and calcium sulfate. The calcium sulfate is filtered out, and the clear liquid is crude lactic acid, which is crystallized at 4℃ to obtain lactic acid.

[0041] The preparation method of the blood lipid-lowering degradable capsule,

[0042] The tin catalyst is stannous acetate.

[0043] 3. Advantages

[0044] Compared with the prior art, the advantages of the present application are:

[0045] The capsule prepared in the present application has high encapsulation efficiency, a large contact area ratio between the drug in the pharmaceutical preparation and the packaging material, which is beneficial to the close adhesion of the drug to the side of the capsule, long drug stability and storage period, large drug loading, reduced number of capsules used, and improved drug efficacy per capsule. In addition, compared with traditional gelatin capsules, polylactic acid particles, amylopectin, cinnamamide and methyl gallate components are introduced, which are all degradable and have little environmental pollution, do not produce toxic substances during production and are degraded by gastric juice, and can also promote the formation of a three-dimensional network structure inside the capsule to enhance the strength of the capsule. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 DLS particle size diagram of the capsule particles prepared in Example 5 of the present application;

[0047] Figure 2 Scanning electron microscope diagram of the capsule particles prepared in Example 5 of the present application. DETAILED DESCRIPTION

[0048] The present application will be further described below in conjunction with specific examples.

[0049] Example 1

[0050] The preparation method of the degradable capsule for lowering blood lipids comprises the following steps:

[0051] (1) Prepare raw materials: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate, and divide them into different raw material tanks for standby use;

[0052] (2) Melt the polylactic acid particles to 70℃, add methyl gallate, continuously stir and warm to 85℃, and after 2h of treatment, keep the temperature at 65℃ in a nitrogen-protected water bath for 30min;

[0053] (3) Add gelatin and cinnamamide in a constant temperature water bath pot, warm to 90℃, and after 5h of sufficient reaction, add 0.006 times the mass of potassium persulfate powder to the gelatin, stir uniformly, and continue to react for 25min;

[0054] (4) Add amylopectin to the above-mentioned reaction solution, stir well, add 0.5 times the mass of cysteine to the amylopectin at 75℃, mix well, and then freeze-dry at low temperature to obtain the freeze-dried powder of the degradable capsule.

[0055] The method for preparing the degradable capsule for lowering blood fat,

[0056] The raw material in step (1) is as follows in terms of weight parts:

[0057]

[0058] The method for preparing the degradable capsule for lowering blood fat,

[0059] The dialysis treatment is performed before the low-temperature freeze drying in step (4);

[0060] The dialysis treatment is performed as follows:

[0061] The solution after being fully mixed is filtered by using a dialysis membrane with a molecular weight of 500 Da, and the retained solution in the bag is recovered;

[0062] The dialysis membrane is previously treated by using a 100 mM sodium hydroxide solution and heated to 100 ℃, and then cleaned.

[0063] The method for preparing the degradable capsule for lowering blood fat,

[0064] The temperature of the low-temperature freeze drying is -55 ℃;

[0065] The pressure of the low-temperature freeze drying is 1 Pa;

[0066] The time of the low-temperature freeze drying is 24 h.

[0067] The method for preparing the degradable capsule for lowering blood fat,

[0068] The method for preparing the polylactic acid particles is as follows:

[0069] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus;

[0070] The lactic acid is used as a raw material, and pre-polycondensation is performed at a temperature of 150 ℃ and a vacuum degree of 0.5 KPa in the presence of a tin catalyst for 6 h to obtain a pre-polycondensation product;

[0071] The pre-polycondensation product is subjected to solid-phase polymerization at a temperature of 135 ℃ and a pressure of 0.1 KPa for 8 h to obtain polylactic acid.

[0072] The method for preparing the degradable capsule for lowering blood fat,

[0073] The process for fermentation of Lactobacillus rhamnosus is as follows:

[0074] Before inoculating Lactobacillus rhamnosus, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid medium. -1 ; the temperature is 37℃; the time is 12h, the OD600 value reaches 6; molecular distillation, and the seed liquid is obtained.

[0075] The above-mentioned preparation method of the degradable capsule for lowering blood fat,

[0076] The process method of the above-mentioned molecular distillation is as follows:

[0077] The bacterial bodies are filtered out to obtain calcium lactate, lactic acid and calcium sulfate are obtained by acidolysis with sulfuric acid, calcium sulfate is filtered out, the clear liquid is crude lactic acid, and lactic acid is obtained by crystallization at 4℃.

[0078] The above-mentioned preparation method of the degradable capsule for lowering blood fat,

[0079] The tin catalyst is stannous acetate.

[0080] Example 2

[0081] The preparation method of the degradable capsule for lowering blood fat comprises the following steps:

[0082] (1) Prepare raw materials: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate, and pack them into different raw material tanks for standby;

[0083] (2) Melt the polylactic acid particles to 80℃, add methyl gallate, continuously stir and warm to 90℃, and then treat for 4h, and then keep the temperature at 65℃ in a nitrogen protection water bath for 60min;

[0084] (3) Add gelatin and cinnamamide in the constant temperature water bath, warm to 95℃, and fully react for 6h, then add 0.006 times of potassium persulfate powder of the mass of gelatin, stir uniformly, and continue to react for 35min;

[0085] (4) Add amylopectin to the above-mentioned solution after reaction, fully stir and mix, add 0.5 times of cysteine of the mass of amylopectin at 75℃, fully mix, and then freeze-dry at low temperature to obtain the freeze-dried powder of the degradable capsule.

[0086] The above-mentioned preparation method of the degradable capsule for lowering blood fat,

[0087] The raw materials in step (1) are as follows in terms of weight parts:

[0088]

[0089] The above-mentioned preparation method of the degradable capsule for lowering blood fat,

[0090] Step (4) is dialysis treatment before low temperature freeze drying;

[0091] The dialysis treatment is as follows:

[0092] The well-mixed solution is filtered using a 1000 Da dialysis membrane, and the retained liquid in the bag is recovered.

[0093] The dialysis membrane is previously treated with 100 mM sodium hydroxide solution heated to 100°C and cleaned.

[0094] The above-mentioned method for preparing a blood lipid-lowering degradable capsule,

[0095] The temperature of the low temperature freeze drying is -55°C;

[0096] The pressure of the low temperature freeze drying is 1 Pa;

[0097] The time of the low temperature freeze drying is 36 h.

[0098] The above-mentioned method for preparing a blood lipid-lowering degradable capsule,

[0099] The method for preparing the polylactic acid particles is as follows:

[0100] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus;

[0101] Using lactic acid as a raw material, pre-polycondensation is carried out at a temperature of 150°C, a vacuum degree of 0.5 KPa, in the presence of a tin catalyst, for 10 h, to obtain a pre-polycondensation product.

[0102] The pre-polycondensation product is subjected to solid-phase polymerization at a temperature of 135°C and a pressure of 0.1 KPa for 48 h to obtain polylactic acid.

[0103] The above-mentioned method for preparing a blood lipid-lowering degradable capsule,

[0104] The process method for fermentation of Lactobacillus rhamnosus is as follows:

[0105] Before inoculation of Lactobacillus rhamnosus, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include: rotation speed of 180 r·min -1 ; temperature of 40°C; time of 24 h, OD600 value of 6; molecular distillation, and the product is obtained.

[0106] The above-mentioned method for preparing a blood lipid-lowering degradable capsule,

[0107] The process method for molecular distillation is as follows:

[0108] The bacteria are filtered out to obtain calcium lactate, which is acidized with sulfuric acid to obtain lactic acid and calcium sulfate. The calcium sulfate is filtered out, and the clear solution is crude lactic acid, which is crystallized at 4°C to obtain lactic acid.

[0109] The preparation method of the hypolipidemic degradable capsule,

[0110] The tin catalyst is stannous acetate.

[0111] Example 3

[0112] The preparation method of the hypolipidemic degradable capsule,

[0113] (1) Prepare raw materials: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate, and pack them into different raw material tanks for standby;

[0114] (2) Melt the polylactic acid particles to 70°C, add methyl gallate, continuously stir and heat to 85°C, and treat for 2h, then keep the temperature at 65°C in a nitrogen atmosphere water bath for 30min;

[0115] (3) Add gelatin and cinnamamide in the constant temperature water bath, heat to 90°C, and react for 5h, then add 0.006 times the mass of gelatin of potassium persulfate powder, stir uniformly, and continue to react for 25min;

[0116] (4) Add amylopectin to the above-mentioned reaction solution, stir well, add 0.5 times the mass of amylopectin of cysteine at 75°C, mix well, and then freeze-dry at low temperature to obtain the freeze-dried powder of the degradable capsule.

[0117] The preparation method of the hypolipidemic degradable capsule,

[0118] The raw materials in step (1) are as follows in weight parts:

[0119]

[0120] The preparation method of the hypolipidemic degradable capsule,

[0121] The dialysis treatment is performed before low-temperature freeze-drying in step (4);

[0122] The dialysis treatment is performed before low-temperature freeze-drying in step (4);

[0123] The well-mixed solution is filtered using a dialysis membrane with a molecular weight cut-off of 500Da, and the retained liquid in the recovery bag is recovered.

[0124] The dialysis membrane is previously treated with 100mM sodium hydroxide solution by heating to 100°C and cleaned thoroughly.

[0125] The preparation method of the degradable capsule for lowering blood fat,

[0126] The temperature of the low-temperature freeze drying is -55℃.

[0127] The pressure of the low-temperature freeze drying is 1 Pa.

[0128] The time of the low-temperature freeze drying is 24 h.

[0129] The preparation method of the degradable capsule for lowering blood fat,

[0130] The preparation method of the polylactic acid particles is as follows:

[0131] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus.

[0132] The pre-polycondensation product is obtained by pre-polycondensation of lactic acid at a temperature of 150℃, a vacuum degree of 0.5 KPa, in the presence of a tin catalyst, for 6 h.

[0133] The polylactic acid is obtained by solid-phase polymerization of the pre-polycondensation product at a temperature of 135℃, a pressure of 0.1 KPa, for 8 h.

[0134] The preparation method of the degradable capsule for lowering blood fat,

[0135] The process method of fermentation of Lactobacillus rhamnosus is as follows:

[0136] Before inoculation of Lactobacillus rhamnosus, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include: a rotation speed of 100 r·min -1 -1; a temperature of 37℃; a time of 24 h, and an OD600 value of 6.

[0137] The preparation method of the degradable capsule for lowering blood fat,

[0138] The process method of molecular distillation is as follows:

[0139] The bacterial cells are filtered out to obtain calcium lactate, and lactic acid and calcium sulfate are obtained by acidolysis of the calcium lactate with sulfuric acid. The calcium sulfate is filtered out, and the clear liquid is crude lactic acid, which is crystallized at 4℃ to obtain lactic acid.

[0140] The preparation method of the degradable capsule for lowering blood fat,

[0141] The tin catalyst is stannous acetate.

[0142] Example 4

[0143] The preparation method of the degradable capsule for lowering blood fat, comprising the following steps:

[0144] (1) Preparation of raw materials: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate, and then stored in different raw material tanks for standby;

[0145] (2) The polylactic acid particles were melted to 80℃, and methyl gallate was added. Stir constantly and heat to 90℃, and then treat for 4h. Then, under the protection of nitrogen, keep the temperature at 65℃ in a water bath for 60min;

[0146] (3) In the constant temperature water bath, add gelatin and cinnamamide, and heat to 95℃. After fully reacting for 6h, add 0.006 times the mass of gelatin of potassium persulfate powder, stir uniformly, and continue to react for 35min;

[0147] (4) After the above reaction, add amylopectin, fully stir and mix, and then add 0.5 times the mass of amylopectin of cysteine at 75℃. After fully mixing, freeze-dry at low temperature to obtain the freeze-dried powder of the degradable capsule.

[0148] The preparation method of the degradable capsule for lowering blood fat,

[0149] The raw materials in step (1) are as follows in terms of weight parts:

[0150]

[0151] The preparation method of the degradable capsule for lowering blood fat,

[0152] The dialysis treatment is performed before the low-temperature freeze-drying in step (4);

[0153] The dialysis treatment is performed as follows:

[0154] The fully mixed solution is filtered using a dialysis membrane with a molecular weight of 1000Da, and the retained liquid in the recovery bag is recovered.

[0155] The dialysis membrane is previously treated with 100mM sodium hydroxide solution heated to 100℃ and cleaned.

[0156] The preparation method of the degradable capsule for lowering blood fat,

[0157] The temperature of the low-temperature freeze-drying is -55℃;

[0158] The pressure of the low-temperature freeze-drying is 1Pa;

[0159] The time of the low-temperature freeze-drying is 36h.

[0160] The preparation method of the degradable capsule for lowering blood fat,

[0161] The preparation method of the polylactic acid particles is as follows:

[0162] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus;

[0163] The pre-polycondensation product is obtained by pre-polycondensation of lactic acid at a temperature of 150 DEG C, a vacuum degree of 0.5 KPa, in the presence of a tin catalyst, for 10 h;

[0164] The polylactic acid is obtained by solid-phase polymerization of the pre-polycondensation product at a temperature of 135 DEG C, a pressure of 0.1 KPa, for 48 h.

[0165] The preparation method of the hypolipidemic degradable capsule,

[0166] The fermentation process of Lactobacillus rhamnosus is as follows:

[0167] Before inoculation, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include: a rotation speed of 180 r·min -1 -1; a temperature of 40 DEG C; a time of 24 h, and an OD600 value of 6.

[0168] The preparation method of the hypolipidemic degradable capsule,

[0169] The process of molecular distillation is as follows:

[0170] The bacteria are filtered out to obtain calcium lactate, which is acid hydrolyzed with sulfuric acid to obtain lactic acid and calcium sulfate. The calcium sulfate is filtered out, and the clear liquid is crude lactic acid, which is crystallized at 4 DEG C to obtain lactic acid.

[0171] The preparation method of the hypolipidemic degradable capsule,

[0172] The tin catalyst is stannous acetate.

[0173] Example 5

[0174] The preparation method of the hypolipidemic degradable capsule,

[0175] (1) Prepare raw materials: gelatin, amylopectin, polylactic acid particles, cinnamoyl amide and methyl gallate, and pack them into different raw material tanks for standby;

[0176] (2) Melt the polylactic acid particles to 75 DEG C, add methyl gallate, continuously stir and heat to 88 DEG C, and treat for 3 h, then keep the temperature at 65 DEG C in a nitrogen protection water bath for 50 min;

[0177] (3) In a constant temperature water bath, add gelatin and cinnamylamide, and heat to 95℃, and after 6h of sufficient reaction, add 0.006 times the mass of the gelatin of potassium persulfate powder, and stir uniformly, and continue to react for 25min;

[0178] (4) After the above reaction, add amylopectin to the solution, and stir uniformly, and at 75℃, add 0.5 times the mass of the amylopectin of cysteine, and after sufficient mixing, freeze-dry at low temperature, and the freeze-dried powder of the degradable capsule is obtained.

[0179] The preparation method of the degradable capsule for lowering blood lipid,

[0180] The raw materials in step (1) are as follows in parts by weight:

[0181]

[0182] The preparation method of the degradable capsule for lowering blood lipid,

[0183] The dialysis treatment is performed before the low-temperature freeze-drying in step (4);

[0184] The dialysis treatment is performed before the low-temperature freeze-drying in step (4);

[0185] The solution after sufficient mixing is filtered using a dialysis membrane with a molecular weight cut-off of 1000Da, and the retained liquid in the bag is recovered.

[0186] The dialysis membrane is previously treated with 100mM sodium hydroxide solution by heating to 100℃ and cleaned.

[0187] The preparation method of the degradable capsule for lowering blood lipid,

[0188] The temperature of the low-temperature freeze-drying is -55℃;

[0189] The pressure of the low-temperature freeze-drying is 1Pa;

[0190] The time of the low-temperature freeze-drying is 24h.

[0191] The preparation method of the degradable capsule for lowering blood lipid,

[0192] The preparation method of the polylactic acid particles is as follows:

[0193] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus;

[0194] Using lactic acid as the raw material, pre-polymerization is performed at a temperature of 150℃, a vacuum degree of 0.5KPa, in the presence of a tin catalyst, and for 10h, to obtain a pre-polymerization product;

[0195] The pre-polycondensation product is subjected to solid-phase polymerization at a temperature of 135 DEG C and a pressure of 0.1 KPa for 48 h to obtain polylactic acid.

[0196] The preparation method of the biodegradable capsule for lowering blood fat,

[0197] The fermentation process of the Lactobacillus rhamnosus is as follows:

[0198] Before inoculation, the Lactobacillus rhamnosus is subjected to seed culture to obtain a seed liquid, and the seed culture medium is MRS liquid medium. -1 The seed culture conditions include a rotation speed of 180 r·min-1, a temperature of 40 DEG C, and a time of 24 h, and the OD600 value reaches 6.

[0199] The preparation method of the biodegradable capsule for lowering blood fat,

[0200] The molecular distillation process is as follows:

[0201] The bacterial cells are filtered off to obtain calcium lactate, which is acidified with sulfuric acid to obtain lactic acid and calcium sulfate, and the calcium sulfate is filtered off, and the clear liquid is crude lactic acid, which is crystallized at 4 DEG C to obtain lactic acid.

[0202] The preparation method of the biodegradable capsule for lowering blood fat,

[0203] The tin catalyst is stannous acetate.

[0204] Comparative Example 1

[0205] The preparation method of the biodegradable capsule for lowering blood fat,

[0206] (1) Prepare raw materials: gelatin, amylopectin, polylactic acid particles and methyl gallate, and pack them into different raw material tanks for standby;

[0207] (2) Melt the polylactic acid particles to 75 DEG C, add methyl gallate, continuously stir and warm to 88 DEG C, and treat for 3 h, and then keep the temperature at 65 DEG C in a nitrogen protection water bath for 50 min;

[0208] (3) Add gelatin to the constant-temperature water bath pot, warm to 95 DEG C, and fully react for 6 h, then add 0.006 times the mass of gelatin of potassium persulfate powder, stir uniformly, and continue to react for 25 min;

[0209] (4) Add amylopectin to the above-mentioned reaction solution, fully stir and mix, add 0.5 times the mass of amylopectin of cysteine at 75 DEG C, fully mix, and then freeze-dry at low temperature to obtain the freeze-dried powder of the biodegradable capsule.

[0210] The preparation method of the biodegradable capsule for lowering blood fat,

[0211] The raw materials in step (1) are as follows in parts by weight:

[0212]

[0213] The preparation method of the degradable capsule for lowering blood fat,

[0214] The dialysis treatment is performed before the low-temperature freeze drying in step (4).

[0215] The dialysis treatment is performed before the low-temperature freeze drying in step (4).

[0216] The solution after being fully mixed is filtered by using a dialysis membrane with a molecular weight of 1000 Da, and the retained solution in the bag is recovered.

[0217] The dialysis membrane is previously treated by using a 100 mM sodium hydroxide solution and heated to 100℃ and then cleaned.

[0218] The preparation method of the degradable capsule for lowering blood fat,

[0219] The temperature of the low-temperature freeze drying is -55℃.

[0220] The pressure of the low-temperature freeze drying is 1 Pa.

[0221] The time of the low-temperature freeze drying is 24 h.

[0222] The preparation method of the degradable capsule for lowering blood fat,

[0223] The preparation method of the polylactic acid particles is as follows:

[0224] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus.

[0225] The pre-polycondensation product is obtained by pre-polycondensation of lactic acid as the raw material at a temperature of 150℃, a vacuum degree of 0.5 KPa, in the presence of a tin catalyst, and for 10 h.

[0226] The polylactic acid is obtained by solid-phase polymerization of the pre-polycondensation product at a temperature of 135℃ and a pressure of 0.1 KPa for 48 h.

[0227] The preparation method of the degradable capsule for lowering blood fat,

[0228] The process method of the fermentation of Lactobacillus rhamnosus is as follows:

[0229] Before inoculation, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include a rotation speed of 180 r·min -1temperature is 40℃, time is 24h, OD600 value reaches 6, molecular distillation, and the product is obtained.

[0230] The preparation method of the degradable capsule for lowering blood fat,

[0231] The process of the molecular distillation is as follows:

[0232] The bacteria are filtered out to obtain calcium lactate, and the calcium lactate is acidized by sulfuric acid to obtain lactic acid and calcium sulfate. The calcium sulfate is filtered out, and the clear liquid is crude lactic acid. The lactic acid is crystallized at 4℃ to obtain lactic acid.

[0233] The preparation method of the degradable capsule for lowering blood fat,

[0234] The tin catalyst is stannous acetate.

[0235] Comparative Example 2

[0236] The preparation method of the degradable capsule for lowering blood fat,

[0237] (1) Prepare raw materials: gelatin, amylopectin, polylactic acid particles, and cinnamamide, and divide them into different raw material tanks for standby;

[0238] (2) Melt the polylactic acid particles to 75℃, and keep the temperature at 65℃ in a nitrogen-protected constant temperature water bath for 50min;

[0239] (3) Add gelatin and cinnamamide to the constant temperature water bath, and heat to 95℃. After fully reacting for 6h, add 0.006 times the mass of gelatin of potassium persulfate powder, stir uniformly, and continue to react for 25min;

[0240] (4) Add amylopectin to the above-mentioned reacted solution, fully stir and mix, add 0.5 times the mass of amylopectin of cysteine at 75℃, fully mix, and then low-temperature freeze-dry to obtain the freeze-dried powder of the degradable capsule.

[0241] The preparation method of the degradable capsule for lowering blood fat,

[0242] The raw materials in step (1) are as follows in terms of weight parts:

[0243]

[0244] The preparation method of the degradable capsule for lowering blood fat,

[0245] The dialysis treatment is performed before the low-temperature freeze-drying in step (4);

[0246] The dialysis treatment is performed before the low-temperature freeze-drying in step (4);

[0247] The solution after being mixed thoroughly is filtered by using a dialysis membrane with a molecular weight cut-off of 1000 Da, and the retained solution in the bag is recovered.

[0248] The dialysis membrane is previously treated by heating to 100 DEG C using a 100 mM sodium hydroxide solution and cleaned.

[0249] The preparation method of the blood lipid-lowering degradable capsule,

[0250] The temperature of the low-temperature freeze-drying is -55 DEG C.

[0251] The pressure of the low-temperature freeze-drying is 1 Pa.

[0252] The time of the low-temperature freeze-drying is 24 h.

[0253] The preparation method of the blood lipid-lowering degradable capsule,

[0254] The preparation method of the polylactic acid particles is as follows:

[0255] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus.

[0256] The pre-polycondensation product is obtained by pre-polycondensation of lactic acid as raw material at a temperature of 150 DEG C, a vacuum degree of 0.5 KPa, in the presence of tin catalyst, for 10 h.

[0257] The polylactic acid is obtained by solid-phase polymerization of the pre-polycondensation product at a temperature of 135 DEG C and a pressure of 0.1 KPa for 48 h.

[0258] The preparation method of the blood lipid-lowering degradable capsule,

[0259] The process method of the fermentation of Lactobacillus rhamnosus is as follows:

[0260] Before inoculation, the Lactobacillus rhamnosus is seed cultured to obtain seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include: rotation speed of 180 r·min -1 -1; temperature of 40 DEG C; time of 24 h, and OD600 value of 6.

[0261] The preparation method of the blood lipid-lowering degradable capsule,

[0262] The process method of the molecular distillation is as follows:

[0263] The bacteria are filtered off to obtain calcium lactate, and the calcium lactate is acid hydrolyzed with sulfuric acid to obtain lactic acid and calcium sulfate. The calcium sulfate is filtered out, and the clear liquid is crude lactic acid, which is crystallized at 4 DEG C to obtain lactic acid.

[0264] The method for preparing the degradable capsule for lowering blood lipid,

[0265] The tin catalyst is stannous acetate.

[0266] Comparative Example 3

[0267] The method for preparing the degradable capsule for lowering blood lipid comprises the following steps:

[0268] (1) Prepare raw materials: gelatin, polylactic acid particles, cinnamamide and methyl gallate, and store them in different raw material tanks for standby;

[0269] (2) Melt the polylactic acid particles to 75℃, add methyl gallate, continuously stir and heat to 88℃, and treat for 3h, then keep the temperature at 65℃ in a nitrogen-protected water bath for 50min;

[0270] (3) Add gelatin and cinnamamide in the constant-temperature water bath pot, heat to 95℃, and fully react for 6h, then add 0.006 times the mass of gelatin of potassium persulfate powder, stir uniformly, and continue to react for 25min;

[0271] (4) Freeze-dry the solution after the above reaction to obtain the freeze-dried powder of the degradable capsule.

[0272] The method for preparing the degradable capsule for lowering blood lipid,

[0273] The raw materials in step (1) are as follows in terms of weight parts:

[0274]

[0275] The method for preparing the degradable capsule for lowering blood lipid,

[0276] The dialysis treatment is performed before the low-temperature freeze-drying in step (4);

[0277] The dialysis treatment is performed as follows:

[0278] The solution after sufficient mixing is filtered using a dialysis membrane with a molecular weight of 1000Da, and the retained liquid in the recovery bag is recovered.

[0279] The dialysis membrane is previously treated with 100mM sodium hydroxide solution heated to 100℃ and cleaned.

[0280] The method for preparing the degradable capsule for lowering blood lipid,

[0281] The temperature of the low-temperature freeze-drying is -55℃;

[0282] The pressure of the low-temperature freeze-drying is 1Pa;

[0283] The low-temperature freeze-drying time is 24 hours.

[0284] The preparation method of the hypolipidemic degradable capsule,

[0285] The preparation method of the polylactic acid particles is as follows:

[0286] Lactic acid is obtained by fermentation of Lactobacillus rhamnosus;

[0287] The pre-polycondensation product is obtained by pre-polycondensation of lactic acid at a temperature of 150 DEG C, a vacuum degree of 0.5 KPa, in the presence of a tin catalyst, for 10 hours;

[0288] The polylactic acid is obtained by solid-phase polymerization of the pre-polycondensation product at a temperature of 135 DEG C, a pressure of 0.1 KPa, for 48 hours.

[0289] The preparation method of the hypolipidemic degradable capsule,

[0290] The process method of the fermentation of Lactobacillus rhamnosus is as follows:

[0291] Before inoculation, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid medium. The seed culture conditions include: a rotation speed of 180 r·min -1 -1; a temperature of 40 DEG C; a time of 24 hours, and an OD600 value of 6.

[0292] The preparation method of the hypolipidemic degradable capsule,

[0293] The process method of the molecular distillation is as follows:

[0294] The bacteria are filtered out to obtain calcium lactate, which is acid hydrolyzed with sulfuric acid to obtain lactic acid and calcium sulfate, and the calcium sulfate is filtered out. The clear liquid is crude lactic acid, which is crystallized at 4 DEG C to obtain lactic acid.

[0295] The preparation method of the hypolipidemic degradable capsule,

[0296] The tin catalyst is stannous acetate.

[0297] Example 6

[0298] The hypolipidemic degradable capsules prepared in Examples 1-5 and the hypolipidemic degradable capsules prepared in Comparative Examples 1-3 are selected for the following tests.

[0299] The commonly used anti-lipid drug - atorvastatin was used to test the encapsulation efficiency and drug loading capacity, and the method in the following reference (Fu Shuangqing, Du Jie, Jia Xinchao, Liu Huandi, Zhang Honglei, Xu Jianzhong, Zhang Lulu, Li Wei. Comprehensive experimental design of preparation of curcumin biodegradable nanocapsules [J]. Experimental technology and management, 2022, 39(06): 30-33. DOI: 10.16791 / j.cnki.sjg.2022.06.006.) was referred to.

[0300] Example 1: encapsulation efficiency 89.23%, drug loading capacity 78.5mg / g;

[0301] Example 2: encapsulation efficiency 89.58%, drug loading capacity 78.8mg / g;

[0302] Example 3: encapsulation efficiency 89.96%, drug loading capacity 78.9mg / g;

[0303] Example 4: encapsulation efficiency 90.16%, drug loading capacity 79.3mg / g;

[0304] Example 5: encapsulation efficiency 90.24%, drug loading capacity 80.2mg / g;

[0305] Comparative Example 1: encapsulation efficiency 83.57%, drug loading capacity 74.1mg / g;

[0306] Comparative Example 2: encapsulation efficiency 81.22%, drug loading capacity 70.9mg / g;

[0307] Comparative Example 3: encapsulation efficiency 79.48%, drug loading capacity 68.8mg / g;

[0308] In combination with the comparative examples, the capsules prepared in the present application have high encapsulation efficiency, the contact area ratio between the drug in the drug preparation and the packaging material is large, which is beneficial to the close fit of the drug with the side of the capsule, the stability of the drug and the long storage period, and at the same time, the drug loading capacity is large, the number of capsules used is reduced, and the drug efficacy of unit capsule is improved. In addition, compared with traditional gelatin capsules, polylactic acid particles, amylopectin, cinnamamide and methyl gallate components are introduced, which are all biodegradable and have little environmental pollution, and no toxic substances are produced during production and are degraded by gastric juice. It can also promote the formation of a three-dimensional network structure inside the capsule, enhancing the strength of the capsule.

[0309] In addition, the particle size and scanning electron microscope of the capsule particles prepared in Example 5 were tested, as shown in Figure 1 , the particle size is evenly distributed at 0.6um, and the particle size uniformity is good; as shown in Figure 2 , the scanning electron microscope can see that the capsule particles are uniform.

[0310] It will be apparent to those skilled in the art that the application is not limited to the details of the above-exemplified embodiments and that the present application can be implemented in other particular forms without departing from the spirit or essential characteristics of the present application. The presently disclosed embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the application being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

[0311] Furthermore, it should be understood that although the description has been set forth in the context of implementations, the present description is not only directed to each individual implementation, but also to every combination of implementations described herein. The description is thus to be construed as a whole rather than only in its parts, and each implementation can be combined with other implementations in ways that are apparent to those skilled in the art.

Claims

1. A method for preparing a degradable capsule for lowering blood lipids, characterized in that it comprises the following steps: (1) preparing raw materials: gelatin, amylopectin, polylactic acid particles, cinnamamide and methyl gallate, and storing them in different raw material tanks; (2) melting the polylactic acid particles to 70-80°C, adding methyl gallate, stirring constantly and heating to 85-90°C, treating for 2-4 hours, and then placing in a 65°C constant-temperature water bath for 30-60 minutes under nitrogen protection; (3) adding gelatin and cinnamamide to the constant-temperature water bath, heating to 90-95°C, fully reacting for 5-6 hours, adding 0.006 times the amount of potassium persulfate powder based on the amount of gelatin, stirring uniformly, and continuing to react for 25-35 minutes; (4) adding amylopectin to the solution after the above reaction, stirring fully, adding 0.5 times the amount of cysteine based on the amount of amylopectin at 75°C, stirring fully, and then low-temperature freeze-drying to obtain a freeze-dried powder of the degradable capsule; the raw materials in step (1) are as follows, by weight: gelatin 100-150 parts, amylopectin 50-60 parts, polylactic acid particles 40-60 parts, cinnamamide 15-30 parts, and methyl gallate 30-40 parts.

2. The method according to claim 1, characterized in that the raw materials in step (1) are as follows, by weight: gelatin 120-140 parts, amylopectin 55-60 parts, polylactic acid particles 45-55 parts, cinnamamide 18-26 parts, and methyl gallate 30-40 parts.

3. The method according to claim 2, characterized in that the raw materials in step (1) are as follows, by weight: gelatin 130 parts, amylopectin 57 parts, polylactic acid particles 49 parts, cinnamamide 22 parts, and methyl gallate 35 parts.

4. The method according to claim 3, characterized in that the solution is dialyzed before low-temperature freeze-drying in step (4); the dialysis method is as follows: the fully mixed solution is filtered using a dialysis membrane with a molecular weight of 500-1000 Da, and the retained liquid in the recovery bag is recovered; the dialysis membrane is previously heated to 100°C using a 100 mM sodium hydroxide solution and then cleaned.

5. The method according to claim 3, characterized in that the low-temperature freeze-drying is performed at a temperature of -55°C, a pressure of 1 Pa, and for a time of 24-36 hours.

6. The method according to claim 3, characterized in that the polylactic acid particles are prepared as follows: lactic acid is obtained by fermentation of Lactobacillus rhamnosus; the lactic acid is used as a raw material to obtain a pre-polymerization product by pre-polymerization in the presence of a tin catalyst at a temperature of 150°C and a vacuum degree of 0.5 KPa for 6-10 hours. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The pre-polycondensation product is subjected to solid phase polymerization at a temperature of 135 DEG C and a pressure of 0.1 KPa for 8-48 h to obtain polylactic acid.

7. The method of claim 6, wherein the method comprises the following steps: a. preparing a solution of the active ingredient in a solvent; b. preparing a solution of the polymer in a solvent; c. mixing the solutions of step a and step b; d. drying the mixture of step c to obtain the capsule. The fermentation process of the Lactobacillus rhamnosus is as follows: Before inoculating the Lactobacillus rhamnosus, the Lactobacillus rhamnosus is seed cultured to obtain a seed liquid, and the seed culture medium is MRS liquid culture medium; the seed culture conditions include: a rotation speed of 100-180 r·min -1 ; a temperature of 37-40℃; a time of 12-24 h, and an OD600 value of more than 5; molecular rectification, and the seed liquid is obtained.

8. The method of claim 7, wherein the method comprises the following steps: a. preparing a solution of the active ingredient in a solvent; b. preparing a solution of the polymer in a solvent; c. mixing the solutions of step a and step b; d. drying the mixture of step c to obtain the capsule. The molecular distillation process is as follows: The bacteria are filtered out to obtain calcium lactate, which is acidified with sulfuric acid to obtain lactic acid and calcium sulfate. The calcium sulfate is filtered out, and the clear liquid is crude lactic acid, which is crystallized at 4 DEG C to obtain lactic acid.

9. The method of claim 6, wherein the tin catalyst is stannous acetate. ​

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