CN107233298B - Yeast cell wall particle preparation for promoting oral absorption of protein polypeptide medicine - Google Patents
Yeast cell wall particle preparation for promoting oral absorption of protein polypeptide medicine Download PDFInfo
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- CN107233298B CN107233298B CN201610185695.4A CN201610185695A CN107233298B CN 107233298 B CN107233298 B CN 107233298B CN 201610185695 A CN201610185695 A CN 201610185695A CN 107233298 B CN107233298 B CN 107233298B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
- A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a yeast cell wall particle preparation for promoting oral absorption of a protein polypeptide medicament. The invention entraps the protein or polypeptide drug in the yeast cell wall particles, further increases the stability of the protein or polypeptide drug in the gastrointestinal tract through internal gelation, and ensures that the protein or polypeptide drug is not degraded by rapid leakage in the gastrointestinal tract. The yeast cell wall particle can specifically target M cells of the Peltier's knot in the intestinal tract, and the oral bioavailability of a protein polypeptide medicament is improved by transferring the M cells into lymphatic circulation.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a yeast cell wall particle preparation capable of promoting oral absorption of protein or polypeptide and a preparation method thereof.
Background
In recent years, more and more protein polypeptide drugs enter clinical experiments or clinical treatment stages, and the main administration mode is injection route, but practice shows that most of protein and polypeptide drugs have short in vivo biological half-life, need frequent administration, and have extremely poor patient compliance; therefore, the development of protein polypeptide preparations by non-injection routes becomes a hot spot of research in the pharmaceutical field at present, and is also a subject of important breakthrough in the related field. Clinical practice shows that oral administration is the most convenient and safe clinical administration route, but protein and polypeptide medicines have the following problems, so that the oral bioavailability is low, and a better treatment effect cannot be achieved: 1. the gastric juice is unstable and is easily and rapidly degraded by pepsin; 2. can be degraded by protease in intestinal tract; 3. protein and polypeptide drugs have strong hydrophilicity and poor cell membrane permeability; 4. the large molecular weight of the protein is one of the reasons for poor membrane permeability. The research for improving the oral absorption of protein polypeptide drugs is very extensive at present, and mainly comprises the following methods: 1. the bioavailability can be improved to a certain extent by adopting permeation promotion and a protease inhibitor, but the development prospect is unpredictable because of serious toxicity; 2. adopting transferrin (Tf), cell-penetrating peptide TAT and the like to modify and improve the permeability of cells; 3. the improvement of the oral bioavailability of insulin by adopting a particle drug delivery system is the most popular aspect of the current research, the particle drug delivery system can protect a medicament from being degraded by enzyme to a certain degree and can improve the transmembrane capability of the medicament, and the current methods mainly comprise nanoparticles, liposome, microemulsion, multiple emulsion and the like; however, current microparticle delivery systems still do not significantly improve their bioavailability, primarily because the particles are unable to transport the drug across the intestinal cell membrane in large quantities.
Research shows that a special structure, namely Peyer's Patch, exists in the intestinal tract, and the Peyer's Patch can phagocytose larger particles and transport the particles to lymphatic circulation so as to enter the systemic circulation to exert the curative effect of the medicine; and the yeast cell wall particles are rich in beta-glucan and can be specifically targeted to M cells, so that the transport effect of the yeast cell wall particles is increased. Based on the basis of the prior art and the advantage that yeast cell walls are cheap and easy to obtain, the yeast cell wall particle preparation can be prepared by directly using baker's yeast, has better safety and is suitable for being used as a material of a drug delivery system, the inventor of the application aims to provide the yeast cell wall particle preparation for promoting oral absorption of protein polypeptide drugs, and the bioavailability in vivo is increased by increasing the targeting effect of M cells by virtue of the characteristics that the yeast cell walls have larger cavities and have higher drug loading capacity.
Disclosure of Invention
The invention aims to provide a yeast cell wall particle preparation for promoting oral absorption of protein polypeptide medicines, and the oral bioavailability of the yeast cell wall particle is improved by carrying protein or polypeptide through the yeast cell wall particle. The preparation has the advantages of high bioavailability, long-term effect maintenance, convenient use and good reproducibility.
Based on the prior art, the protein polypeptide drug is unstable in the gastrointestinal tract, is easily degraded by various proteases in the gastrointestinal tract, has poor transmembrane capacity, and causes extremely low bioavailability, the yeast cell wall particles can be directly targeted to M cells of the Peltier knot, the M cells have strong capacity of transporting particles, and the drug is wrapped in the yeast cell wall particles and can avoid the damage of the proteases in the gastrointestinal tract, so that the stability of the drug in the gastrointestinal tract can be improved; however, if the protein or polypeptide drug is directly entrapped in the yeast cell wall particles, the protein or polypeptide drug is easy to leak from cell wall pore canals in the gastrointestinal tract, the protein or polypeptide drug can be kept in the yeast cell wall particles by performing gelation on the protein or polypeptide drug in the yeast cell wall particles, so that the yeast cell wall particles are transported in a large amount by M cells, the concentration of the protein polypeptide in the systemic circulation is increased, and the oral bioavailability of the protein polypeptide drug is further increased.
The invention provides the following technical scheme to solve the problems in the prior art:
the invention relates to a yeast cell wall particle preparation for promoting oral absorption of protein and polypeptide medicines, which is characterized by consisting of protein or polypeptide medicines, medicine auxiliary materials and yeast cell wall particles, wherein the protein or polypeptide medicines or the protein or polypeptide medicines and the auxiliary materials are wrapped in yeast cell walls together to realize internal gelation at a certain temperature.
In the invention, the yeast cell wall particles are prepared by baker's yeast.
In the invention, the auxiliary material is selected from poloxamer, sodium alginate or chitosan.
In the present invention, the poloxamer is poloxamer 407 or 188, or a mixture of both.
In the invention, the concentration of the poloxamer 407 is 10-50%, the concentration of the poloxamer 188 is 10-50%, and the proportion of the poloxamer 407 to the poloxamer 188 is 5: 1-4.
In the invention, the sodium alginate is matched with calcium ions or chitosan for use, wherein the ratio of the sodium alginate to the calcium ions is 1:0.1-5, and the ratio of the sodium alginate to the chitosan is 1: 0.1-5.
In the invention, the protein or polypeptide medicament is an aqueous solution thereof, the pH is 1.0-8.0, and the concentration is 0.1-10 mg/mL.
The yeast cell wall particle preparation containing the protein or polypeptide medicament is prepared by a two-step method, and comprises the steps of firstly preparing an aqueous solution of the protein or polypeptide, then dispersing yeast cell wall powder in the solution, enabling the protein or polypeptide to diffuse into the interior of the yeast cell wall, finally adjusting the pH to be close to the isoelectric point of the protein or polypeptide, precipitating the protein or polypeptide, centrifuging, washing, adding an auxiliary material solution, and carrying out internal gelation.
In the preparation method, when the auxiliary material is sodium alginate, calcium ions or chitosan are added to crosslink the internal sodium alginate after the external phase protein or polypeptide and the auxiliary material are removed; when poloxamer is used as the auxiliary material, the auxiliary material is in a solution state by low-temperature operation, and after the outer-phase protein or polypeptide and the auxiliary material are removed, the temperature is raised to gelatinize the inner part of the auxiliary material.
In one embodiment of the present invention, insulin-loaded, internally-gelled yeast cell wall microparticles are first prepared using insulin as a model drug and further evaluated in vitro and in vivo.
The yeast cell wall particles comprise insulin, auxiliary materials and yeast cell wall particles, wherein the active ingredient insulin is encapsulated in the yeast cell wall, and the auxiliary materials are gellable materials;
the concentration of the insulin is preferably 0.1-100 mg/mL;
the yeast cell wall particles are prepared from baker's yeast, and the baker's yeast is subjected to acid-base treatment and drying to obtain the yeast cell wall particles.
The gelling material comprises one or more of poloxamer 188, 407 and sodium alginate.
In the invention, the insulin-carrying yeast cell wall particles are prepared by the following method:
weighing a certain amount of yeast cell wall powder, dispersing in an insulin solution, mixing uniformly by vortex, adjusting the pH to 2 by using 1M hydrochloric acid, then magnetically stirring for 2h at the temperature of 4 ℃ and at the speed of 200rpm, adjusting the pH to 5.6 (near the isoelectric point of insulin) by using 1M sodium hydroxide, precipitating a large amount of insulin, and depositing the insulin incubated in the inner cavity and pore canal of the yeast cell wall in the cavity canals; repeating the above operation for 3 times, and increasing the amount of insulin deposited in the yeast cell wall by repeatedly adjusting pH to improve drug loading; centrifuging at 2000g for 10min, discarding the supernatant, adding gelating material solution with specific concentration and pH of 7.0, and incubating at room temperature for 4 h; finally, centrifuging for 10min at 2000g, collecting precipitate, changing conditions to realize internal gelation, and washing off residual adjuvant solution and insulin on filter paper with hot water.
The gelling material is selected from one or more of poloxamer 407, 188 and sodium alginate, wherein poloxamer 407 is preferred.
FIG. 1 shows the particle size and potential of insulin-loaded, internally gelatinized yeast cell wall microparticles (hereinafter referred to as P-INS-GMs) obtained by the present invention, as measured by Malvern scanning electron microscopy.
The results of in vitro stability and in vivo blood sugar reduction experiments show that the yeast cell wall particles are used for encapsulating insulin and performing internal gelation on the insulin, so that the stability of the insulin in the gastrointestinal tract is improved, and the oral bioavailability of the insulin is increased by targeting M cells.
Drawings
Fig. 1 shows: scanning electron micrographs of blank yeast cell wall microparticle (GMs) (A) and its cross section (B), insulin-gelling yeast cell wall microparticle (P-INS-GMs) (C) and cross section (D); blank GMs and P-INS-GMs particle size plot (E).
FIG. 2 shows the release of gelatinized (INS-GMs) and gelatinized (P-INS-GMs) yeast cell wall particles in enzyme-free SGF (A) and SIF (B),
the degradation curves of insulin in enzyme-containing sgf (c) and sif (d) are shown.
Fig. 3 is a graph of the hypoglycemic curves (n-4) in normal rats (a) and diabetic rats (B) for different oral insulin formulations, showing the dose-dependent area on the hypoglycemic curves in normal rats and diabetic rats (C).
Detailed Description
Example 1
Preparing yeast cell wall particle powder: 100g of baker's yeast is taken, added with 1LNaOH (1M) solution, incubated for 1h in a constant temperature water bath kettle at 80 ℃, and stirred slowly at 50 rpm. Centrifuging for 10min at 2000g, collecting precipitate, dispersing the precipitate in 1L of pure water again, adjusting the pH to about 4.5 by using 2M hydrochloric acid, incubating for 1h in a constant-temperature water bath kettle at 55 ℃ under slow stirring at 50rpm, centrifuging for 10min at 2000g again, collecting precipitate, sequentially washing with 1L of pure water, washing with 200mL of isopropanol for four times, washing with 200mL of acetone for two times, collecting precipitate, drying in vacuum, and weighing to calculate the yield;
insulin entrapment: weighing 1g of prepared yeast cell particle hair (GMs) powder, dispersing in 5mL of Insulin (INS) solution (10mg/mL), mixing uniformly by vortex, adjusting the pH to 2 by using 1M hydrochloric acid, then magnetically stirring at 200rpm at 4 ℃ for 2h, adjusting the pH to 5.6 (around the isoelectric point of INS) by using 1M sodium hydroxide, and precipitating a large amount of INS so that the INS incubated in the GMs inner cavity and the pore channel is deposited inside the cavities; repeating the above operation 3 times to increase the amount of INS deposited inside GMs by repeatedly adjusting the pH, thereby increasing the drug loading; centrifuging at 2000g for 10min, discarding the INS in the supernatant, adding poloxamer solution with specific concentration and pH of 7.0, incubating at room temperature for 4h, centrifuging at 2000g for 10min, collecting precipitate, heating to above Tgel to make the poloxamer in GMs form gel state, and washing residual poloxamer and INS on filter paper with hot water;
the prepared insulin-loaded yeast cell wall microparticles (hereinafter referred to as P-INS-GMs) having internally gelled cells were taken, the particle size and potential thereof were measured in Malvern, and the morphology thereof was observed by a scanning electron microscope, as shown in FIG. 1.
EXAMPLE 2 in vitro Release and anti-enzymatic degradation experiments of insulin-loaded, Internally gelatinized Yeast cell wall microparticles
In vitro release experiments: preparing 10mL of enzyme-free artificial gastric juice or artificial intestinal juice, preheating to 37 ℃ in a constant-temperature water bath oscillator, taking a proper amount of freeze-dried insulin yeast cell wall particles (P-INS-GMs), adding the freeze-dried insulin yeast cell wall particles into the enzyme-free artificial gastric juice or artificial intestinal juice, sampling 200 mu l of the enzyme-free artificial gastric juice or artificial intestinal juice at 0.25, 0.5, 0.75, 1, 1.5 and 2h, supplementing the equivalent amount of the preheated enzyme-free artificial gastric juice or artificial intestinal juice, centrifuging 8000g of the sample, then injecting the sample through a 0.25 mu m filter membrane, and calculating the released INS content, wherein the release curve is shown in figure 2;
enzyme degradation resistance experiment: preparing 10mL of artificial gastric juice or artificial intestinal juice, preheating to 37 ℃ in a constant-temperature water bath oscillator, taking a proper amount of freeze-dried P-INS-GMs, adding the freeze-dried P-INS-GMs into the artificial gastric juice (SGF) or the artificial intestinal juice (SIF), and taking samples with the sampling time points of 0.5, 1, 2h (SGF) and 0.5, 1, 4h (SIF), and the rest operations are the same as the previous operations, centrifuging 8000g of the taken sample, discarding the supernatant, washing once with pure water and centrifuging, taking the precipitate, digesting for 30min with beta-glucanase, centrifuging to take the supernatant after swirling 8000g, diluting to a proper concentration, feeding through a 0.25 mu m filter membrane, and calculating the residual INS content, wherein the stability result is shown in figure 2.
Example 3 oral hypoglycemic experiments with insulin-loaded, internally gelled yeast cell wall microparticles
Normal rats and diabetic rats were randomly divided into 6 groups of 4 rats, each group was fasted for 12h before the experiment and allowed free access to water, 6 groups of formulations were P-INS-GMs (10, 30 and 50IU/kg, respectively, measured in insulin), uncured yeast cell wall microparticles INS-GMs (30IU/kg), blank yeast cell wall microparticles gelled with internal poloxamer P-GMs and INS solution group (2IU/kg), respectively, wherein the remaining formulation groups were intragastrically administered except for the INS solution group which was administered by subcutaneous injection;
taking blood from tail vein of rat at characteristic time point after administration, dropping one drop in the sensing region of glucometer test paper to determine instant blood sugar value, measuring 3 times at each time point and taking average value, and drawing the determined blood sugar value into blood sugar-time curve; the results show that the blood glucose-time curves in normal rats and diabetic rats are shown in FIG. 3.
Claims (3)
1. A yeast cell wall particle preparation for promoting oral absorption of protein and polypeptide medicines is characterized by consisting of protein or polypeptide medicines, medicine auxiliary materials and yeast cell wall particles, wherein the protein or polypeptide medicines or the protein or polypeptide medicines and the auxiliary materials are wrapped in yeast cell walls together to realize internal gelation at a certain temperature;
the yeast cell wall particles are prepared by baker's yeast; the auxiliary material is selected from poloxamer, sodium alginate or chitosan; the protein or polypeptide medicine is water solution, the pH is 1.0-8.0, and the concentration is 0.1-10 mg/mL; the poloxamer is poloxamer 407 or 188 or a mixture of the poloxamer 407 and the 188, wherein the concentration of the poloxamer 407 is 10-50%, the concentration of the poloxamer 188 is 10-50%, and the ratio of the poloxamer 407 to the poloxamer 188 is 5: 1-4; the sodium alginate is matched with calcium ions or chitosan for use, wherein the ratio of the sodium alginate to the calcium ions is 1:0.1-5, and the ratio of the sodium alginate to the chitosan is 1: 0.1-5;
the yeast cell wall particle preparation containing the protein or polypeptide medicine is prepared by a two-step method, and comprises the steps of firstly preparing an aqueous solution of the protein or polypeptide, then dispersing yeast cell wall powder in the solution, enabling the protein or polypeptide to diffuse into the interior of the yeast cell wall, finally adjusting the pH to be close to the isoelectric point of the protein or polypeptide, precipitating the protein or polypeptide, centrifuging, washing, adding an auxiliary material solution, and carrying out internal gelation.
2. The yeast cell wall particle preparation for promoting oral absorption of protein and polypeptide drugs according to claim 1, wherein in the preparation method, when sodium alginate is used as an auxiliary material, calcium ions or chitosan is added to crosslink the internal sodium alginate after removing the external phase protein or polypeptide and the auxiliary material.
3. The yeast cell wall particle preparation for promoting oral absorption of protein and polypeptide drugs according to claim 1, wherein in the preparation method, when poloxamer is used as the auxiliary material, the preparation is performed in a low temperature state, and after the removal of the external phase protein or polypeptide and the auxiliary material, the preparation is performed in a high temperature state to gel the interior thereof.
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| CN111569082B (en) * | 2020-06-11 | 2021-12-24 | 四川大学 | Oral delivery system for protein-loaded polypeptide drug exosomes |
| CN114470228B (en) * | 2021-12-08 | 2023-06-27 | 深圳先进技术研究院 | Blood coagulation medicine-carrying yeast immune micro-nano biological robot and preparation and application thereof |
| CN115212184A (en) * | 2022-08-23 | 2022-10-21 | 怀化学院 | Perilla seed oil nano-particles and preparation method and application thereof |
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