CN110694072A - Maillard reaction product capable of promoting absorption of oral medicine and preparation method thereof - Google Patents
Maillard reaction product capable of promoting absorption of oral medicine and preparation method thereof Download PDFInfo
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- CN110694072A CN110694072A CN201910341725.XA CN201910341725A CN110694072A CN 110694072 A CN110694072 A CN 110694072A CN 201910341725 A CN201910341725 A CN 201910341725A CN 110694072 A CN110694072 A CN 110694072A
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- A—HUMAN NECESSITIES
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
The invention discloses a Maillard reaction product capable of promoting absorption of oral drugs and a preparation method thereof. The Maillard reaction product is prepared by the following raw materials of fructose, glucose, maltose, glycine, histidine, arginine, aminobutyric acid, threonine, alanine, proline, tyrosine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan and lysine in parts by weight, adding the raw materials into a mixer, mixing for 8-10 minutes to form a mixture, and heating at 80-220 ℃ for 4-40 minutes. The Maillard reaction product prepared by the method can be used as an oral medicine absorption enhancer to improve the oral absorption rate of medicines with large polarity, poor fat solubility and large molecular weight or medicines mainly absorbed by a cell bypass way, and has wide application prospect in the field of oral administration.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a Maillard reaction product capable of promoting absorption of oral medicines and a preparation method thereof.
Background
Oral administration is always the most commonly used administration mode of pharmacotherapy because of its characteristics of convenient administration, safety, effectiveness, low production cost, etc. Oral drugs need to be absorbed by gastrointestinal mucosa, and for some drugs with large polarity, poor lipid solubility and large molecular weight, the oral application is limited because the drugs are difficult to pass through biological membranes and absorbed by gastrointestinal tract to cause poor bioavailability. In order to improve the oral bioavailability of a drug, in addition to changing the physicochemical properties of the drug to improve its membrane permeability or to improve its dissolution characteristics, another approach is to improve the membrane characteristics to improve the membrane permeability of the drug.
Research reports that an absorption enhancer can improve the absorption of a drug in the gastrointestinal tract so as to improve the oral bioavailability of the drug, and many natural or synthetic auxiliary materials with different physicochemical properties are currently common absorption enhancers, comprise various surfactants, bioadhesive polymers, chelating agents, amino acid derivatives, cyclodextrin and the like, have nonspecific mechanisms, generally relate to a transcellular channel and a cell bypass pathway, and can also increase the permeability of the drug by influencing the integrity of cell tight connection and (or) the function of an efflux system so as to influence the bioavailability of the drug. However, these absorption enhancers have some adverse reactions to human bodies, and thus, low-toxicity and high-efficiency oral absorption enhancers have become hot spots in research.
The Maillard Reaction is a nonenzymatic browning Reaction that occurs between reducing sugars and compounds containing free amino groups, such as amino acids, polypeptides, and proteins, and the Products thereof are called Maillard Reaction Products (hereinafter abbreviated as MRPs). The species of reaction which can generate Maillard reaction are various, the obtained products are also various, and correspondingly, the Maillard reaction also has various properties and biological activities. Researches show that melanoidins generated by the Maillard reaction show remarkable pharmacological activities such as oxidation resistance and antibiosis and metal ion complexing characteristics, and a cell tight connection structure contains specific protein and divalent metal ions, so that MRPs can influence the integrity of cell tight connection by complexing with the divalent metal ions on the cell tight connection, and the permeability of intestinal cells to medicaments is improved.
Although MRPs have potential broad uses, their use as oral pro-absorptives for pharmaceuticals has not been reported.
Disclosure of Invention
The invention aims to provide a preparation method of MRPs.
The invention also aims to provide the application of the MRPs as an oral drug absorption enhancer, so as to improve the membrane permeability of drugs with large polarity, poor lipid solubility and large molecular weight or drugs mainly absorbed by a cell bypass pathway, promote the absorption of the drugs and increase the bioavailability of the drugs.
The purpose of the invention is realized by the following technical scheme.
A method for preparing MRPs comprises the following steps:
(1) respectively taking fructose, glucose, maltose, glycine, histidine, arginine, aminobutyric acid, threonine, alanine, proline, tyrosine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan and lysine as raw materials in certain parts by weight, adding a mixer, and mixing for 8-10 minutes to obtain a mixture;
(2) and (2) uniformly spreading the mixture obtained in the step (1) on a glass plate, continuously heating at a certain temperature and for a certain time, and carrying out Maillard reaction to obtain MRPs.
Preferably, the reaction system in the step (1) comprises the following components in parts by weight:
20-40 parts of fructose
20-40 parts of glucose
20-35 parts of maltose
0.2-0.4 part of glycine
Histidine 0.1-0.3 part
0.5-1.5 parts of arginine
0.2-0.4 part of aminobutyric acid
0.2-0.5 parts of threonine
0.5-1.5 parts of alanine
1-3 parts of proline
0.5 to 1.5 portions of tyrosine
0.5-1.5 parts of valine
0.01-0.1 part of methionine
Isoleucine 0.2-1 part
0.5-2 parts of leucine
0.5-2 parts of phenylalanine
0.5-2 parts of tryptophan
0.2-1 part of lysine.
Preferably, the temperature of the Maillard reaction in the step (2) is 80-220 ℃, and the reaction time is 4-40 min.
Preferably, the thickness of the tiled mixture in the step (2) is 0.5-2 cm.
The MRPs are used as oral absorption promoters for drugs with high polarity, poor lipid solubility and high molecular weight or drugs mainly absorbed by a cell bypass pathway.
The MRPs can be used for preparing oral tablets, capsules, granules, powder, films, pills, oral liquid, suspensions, emulsions, microspheres, liposomes, nanoparticles and other preparations.
The invention has the beneficial effects that: the MRPs is prepared by taking amino acid and reducing sugar as reactants, the conditions are controllable, and the method is simple. The prepared MRPs can be used as oral absorption enhancer of medicine, can safely and effectively improve the oral bioavailability of the medicine, and has definite effect.
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FIG. 1: examples the effect of MRPs on the expression of Claudin-1, ZO-1, in rat duodenal tissue.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but the scope of the present invention is not limited thereto.
Example 1: rat in vivo single-direction intestinal perfusion method is used for researching the influence of the prepared MRPs on the absorption of phenol red in small intestine.
Phenol red may represent a hydrophilic drug that is predominantly absorbed by the alternative pathway. These drugs have very low bioavailability under normal physiological conditions and are essentially poorly absorbed. Rat in-vivo unidirectional intestinal perfusion method is adopted to research absorption rate constant (K) of MRPs (total reflection fractions) on phenol red permeable membrane absorptiona) And apparent permeability coefficient (P)app) The influence of (c).
(1) Preparation of MRPs:
weighing 19.85 g of fructose, 37.58 g of glucose, 32.11 g of maltose, 0.32 g of glycine, 0.26 g of histidine, 0.95 g of arginine, 0.32 g of aminobutyric acid, 0.39 g of threonine, 0.97 g of alanine, 2.38g of proline, 0.82 g of tyrosine, 0.94 g of valine, 0.06 g of methionine, 0.58 g of isoleucine, 1.06 g of leucine, 0.78 g of phenylalanine, 0.11 g of tryptophan and 0.52 g of lysine according to parts by weight, adding into a mixer, and mixing for 8 minutes to obtain a mixture;
and uniformly spreading the mixture on a glass plate with the thickness of about 1 cm, then placing the glass plate in an oven with the temperature of 180 ℃, heating for 20 min, and carrying out Maillard reaction to obtain MRPs.
(2) Preparation of perfusion liquid:
phenol red-containing K-R perfusate: precisely weighing 0.1g of phenol red, placing the phenol red into a 50mL measuring flask, and performing constant volume by using K-R solution to obtain 2mg/mL of phenol red mother solution. And (3) putting 1.0mL of mother liquor into a 100mL measuring flask, diluting the K-R solution and diluting to constant volume to obtain the K-R perfusion solution with the phenol red concentration of 20 mu g/mL.
K-R perfusate containing phenol red and MRPs:
respectively placing 2.5 g of MRPs obtained by the reaction and 1.0mL of phenol red mother liquor of 2mg/mL into the same 100mL measuring flask, diluting with K-R solution and fixing the volume to obtain the K-R perfusion solution containing phenol red and MRPs with the phenol red concentration of 20 mu g/mL.
(3) The method for measuring the content of phenol red comprises the following steps:
high performance liquid chromatography condition C18 chromatographic column (4.6 mm. times.250 mm, 5 μm), flow rate of 1.0mL/min, detection wavelength of 230 nm, column temperature of 30 deg.C, sample injection amount of 20 μ L, mobile phase of 0.1% phosphoric acid (A) -acetonitrile (B) (65: 35), isocratic elution.
(4) In vivo intestinal absorption experiment of rats:
the rat is fasted for 18 hours without water supply, the rat is fixed on an operating table after chloral hydrate anesthesia, the abdomen is cut open by 3-4 cm along the midline of the abdomen, an experimental intestine section is found, 10cm is taken, a small opening is cut at two ends of the taken intestine section, a plastic pipe is inserted, and the operation is fixed by silk threads. Flushing intestinal contents with physiological saline, connecting injection pump at small opening of upper end of intestine, perfusing medicinal liquid at flow rate of 0.23mL/min, absorbing for about 30min, timing, collecting with small vial of known quality at outlet every 15min for 1 time as 1 sampling point, replacing with the next small vial of known quality, collecting for 6 times, calculating mass balance of small vials before and after collection, and measuring phenol red concentration in the collected liquid by HPLC method. After the experiment, the rats were sacrificed, rinsed with physiological saline, and the perfused intestinal segment was cut off, and its length and inner diameter were measured. Calculating the absorption rate constant (K) of phenol red in 2 perfusion liquidsa) And apparent permeability coefficient (P)app) The results are shown in Table 1.
TABLE 1 rat in vivo one-way intestinal perfusion method for studying K of MRPs to phenol redaAnd PappInfluence of (x ± s, n = 5)
| Perfusion liquid | Ka/（× 10-5s-1） | Papp/（× 10-6cm·s-1） |
| Phenol red-containing |
1. 21 ± 0.67 | 1. 27 ± 0. 62 |
| K-R perfusion fluid containing phenol red and MRPs | 2. 63 ± 0.91* | 3. 01 ± 0. 99* |
Note: p <0.05 compared to K-R perfusate containing phenol red.
The results show that MRPs prepared as described above increase the rate constant of absorption and apparent permeability coefficient of phenol red, and that MRPs affect the paracellular pathway of absorption in the small intestine.
Example 2: effect of MRPs on the expression of Claudin-1, ZO-1, in rat duodenal tissue.
Tight junction protein in intestinal epithelial cells is a barrier for maintaining intestinal permeability, can limit the passage of macromolecules and microorganisms, and can regulate the passive transport of ions and macromolecular substances across a cell bypass, thereby influencing the intestinal absorption rate of ionic drugs, hydrophilic small molecular drugs and macromolecular drugs. Western blot was used to study the effect of MRPs on the expression of zonulin ZO-1 and Claudin-1 in rat duodenal tissues.
(1) Preparation of MRPs:
weighing 19.85 g of fructose, 37.58 g of glucose, 32.11 g of maltose, 0.32 g of glycine, 0.26 g of histidine, 0.95 g of arginine, 0.32 g of aminobutyric acid, 0.39 g of threonine, 0.97 g of alanine, 2.38g of proline, 0.82 g of tyrosine, 0.94 g of valine, 0.06 g of methionine, 0.58 g of isoleucine, 1.06 g of leucine, 0.78 g of phenylalanine, 0.11 g of tryptophan and 0.52 g of lysine according to parts by weight, adding into a mixer, and mixing for 8 minutes to obtain a mixture;
and uniformly spreading the mixture on a glass plate with the thickness of about 1 cm, then placing the glass plate in an oven with the temperature of 180 ℃, heating for 20 min, and carrying out Maillard reaction to obtain MRPs.
(2) Grouping administration of rats:
12 SD rats weighing 200 + -20 g were divided into 2 groups of 6 rats each, and the male and female rats were blank and MRPs. 2 mL of physiological saline is perfused into rats in a blank group every day, MRPs in the MRPs group are perfused into MRPs solution with the gastric concentration of 75mg/mL according to the weight of 750mg/kg body weight every day, the solution is perfused once a day for 14 days continuously and fed with feed for normal feeding, after the drug administration on the 14 th day, the solution is fasted for 12 hours, the head is cut off and killed, the rats are cut along the abdominal median line, the duodenum part is taken out quickly and placed into a self-sealing bag, and the rat is stored in a refrigerator at the temperature of-80 ℃.
(3) Western blot experiment:
the duodenal tissue is taken, cracked by lysate and ground, and the total protein is extracted. The BCA method is used for protein quantification, total protein is separated through SDS-PAGE electrophoresis, the total protein is transferred onto a PVDF membrane through electrotransfer, after 5 percent skim milk is sealed for 1h, an anti-ZO-1 antibody (1: 1000), an anti-Claudin-1 antibody (1: 500) and an anti-beta-actin antibody (1: 2000) are incubated overnight at 4 ℃. After TBST membrane washing, adding HRP-labeled goat anti-rabbit secondary antibody (1: 1000), incubating for 1h at room temperature, developing with ECL luminescent solution and full-function developing instrument. The bands were analyzed using ImageJ software.
(4) The experimental results are as follows:
taking beta-actin as an internal reference, a ZO-1 protein band appears at about 210kDa, and a Claudin-1 protein band appears at about 65kDa, and the result is shown in figure 1. Gray scale analysis of each band revealed that compared with the blank group, both of the tight junction proteins ZO-1 and Claudin-1 were significantly reduced in the MRPs group (p < 0.05). Thus, MRPs can reduce the contents of ZO-1 and Claudin-1 which are tight junction proteins, thereby influencing the intestinal permeability.
The above-described embodiments are intended to illustrate rather than to limit the invention, and any modifications and variations of the present invention are within the spirit of the invention and the scope of the appended claims.
Claims (7)
1. A maillard reaction product for promoting absorption of an orally administered drug, the preparation method comprising the steps of:
(1) respectively taking fructose, glucose, maltose, glycine, histidine, arginine, aminobutyric acid, threonine, alanine, proline, tyrosine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan and lysine as raw materials in certain parts by weight, adding a mixer, and mixing for 8-10 minutes to obtain a mixture;
(2) and (2) uniformly spreading the mixture obtained in the step (1) on a glass plate, continuously heating at a certain temperature and for a certain time, and carrying out Maillard reaction to obtain a Maillard reaction product.
2. The preparation method according to claim 1, wherein the reaction system in the step (1) comprises the following components in parts by weight:
20-40 parts of fructose
20-40 parts of glucose
20-35 parts of maltose
0.2-0.4 part of glycine
Histidine 0.1-0.3 part
0.5-1.5 parts of arginine
0.2-0.4 part of aminobutyric acid
0.2-0.5 parts of threonine
0.5-1.5 parts of alanine
1-3 parts of proline
0.5 to 1.5 portions of tyrosine
0.5-1.5 parts of valine
0.01-0.1 part of methionine
Isoleucine 0.2-1 part
0.5-2 parts of leucine
0.5-2 parts of phenylalanine
0.5-2 parts of tryptophan
0.2-1 part of lysine.
3. The preparation method according to claim 1, wherein the temperature of the Maillard reaction in the step (2) is 80-220 ℃ and the reaction time is 4-40 min.
4. The method according to claim 1, wherein the mixture of step (2) is spread to a thickness of 0.5 to 2 cm.
5. Use of the maillard reaction product of claim 1 as a pharmaceutical oral absorption enhancer.
6. The use according to claim 5, wherein the Maillard reaction product can be used as an oral absorption enhancer for drugs with high polarity, poor lipid solubility and high molecular weight or drugs mainly absorbed by the cell bypass pathway.
7. Use according to claims 5 and 6, characterized in that the Maillard reaction product can be used in oral tablets, capsules, granules, powders, films, pills, oral liquids, suspensions, emulsions, microspheres, liposomes, nanoparticles and the like.
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Citations (4)
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| CN101176571A (en) * | 2007-11-02 | 2008-05-14 | 云南瑞升烟草技术（集团）有限公司 | Perfume additive for tobacco and preparation method thereof |
| CN105859591A (en) * | 2016-04-22 | 2016-08-17 | 福州美瑞蒂恩生物科技有限公司 | Maillard reaction product with functions of reducing blood glucose and blood pressure |
| CN109161440A (en) * | 2018-08-29 | 2019-01-08 | 上海烟草集团有限责任公司 | A kind of maillard reaction product and its preparation method and application |
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- 2019-04-26 CN CN201910341725.XA patent/CN110694072A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011392A (en) * | 2007-01-31 | 2007-08-08 | 中国人民解放军军事医学科学院卫生学环境医学研究所 | Amino acid composition for enhancing traumatic organism growth factor expression and oxidation resistance function |
| CN101176571A (en) * | 2007-11-02 | 2008-05-14 | 云南瑞升烟草技术（集团）有限公司 | Perfume additive for tobacco and preparation method thereof |
| CN105859591A (en) * | 2016-04-22 | 2016-08-17 | 福州美瑞蒂恩生物科技有限公司 | Maillard reaction product with functions of reducing blood glucose and blood pressure |
| CN109161440A (en) * | 2018-08-29 | 2019-01-08 | 上海烟草集团有限责任公司 | A kind of maillard reaction product and its preparation method and application |
Non-Patent Citations (2)
| Title |
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| 吴璐等: ""从药性物质的角度研究麦芽"炒香"过程中氨基酸的含量变化规律"", 《中华中医药学刊》 * |
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