CN112245399B - Dihydromyricetin gastric floating pill and preparation method thereof - Google Patents

Dihydromyricetin gastric floating pill and preparation method thereof Download PDF

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CN112245399B
CN112245399B CN202011182815.8A CN202011182815A CN112245399B CN 112245399 B CN112245399 B CN 112245399B CN 202011182815 A CN202011182815 A CN 202011182815A CN 112245399 B CN112245399 B CN 112245399B
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dihydromyricetin
pill
floating
parts
gastric
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CN112245399A (en
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刘浩
甘晨云
张锐锐
王斯娇
屈坤燕
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Southwest Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a dihydromyricetin floating pill and a preparation method thereof. Aiming at the problems of poor solubility, low encapsulation rate, easy drug leakage and low drug stability of the dihydromyricetin preparation in the prior art. The invention provides a dihydromyricetin gastric floating pill, which comprises the following components: dihydromyricetin; 13-17 parts of hydrophilic gel. The invention also provides a preparation method of the dihydromyricetin gastric floating pill and application of the dihydromyricetin gastric floating pill in preparation of medicaments. The dihydromyricetin gastric floating pill provided by the invention is suitable for administration of dihydromyricetin, can improve the conditions of high-dose and high-frequency administration of dihydromyricetin, and only needs once-a-day administration.

Description

Dihydromyricetin gastric floating pill and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a dihydromyricetin floating pill and a preparation method thereof.
Background
The floating preparation in stomach is based on fluid dynamic balance controlled release system, is prepared from medicine, one or more hydrophilic gel matrix materials and other auxiliary materials, and can be in capsule, tablet or other forms. Tossunian and Sheth originally described in detail the intragastric floating sustained release formulations and were referred to as "bioavailable formulations". In the beginning of the 20 th century 80 years, hofmann-La Roche first introduced two floating preparations of Valrelease and ValiumCR, and then new HBS products were continuously introduced into the market. In recent decades, scientists have successively proved that the slow-release preparation floating in the stomach prolongs the retention time of the drug in the body and reduces the fluctuation of the blood concentration, so that the slow-release preparation floating in the stomach is further widely researched and is mainly applied to novel preparations of drugs with unstable properties and other dosage forms which can not play a good role. After the medicament is orally taken, the medicament is in contact with gastric juice to generate hydration, a layer of gel barrier is formed on the surface of the preparation to enable the volume of the preparation to expand, the preparation floats on the gastric juice due to the density of the preparation being smaller than that of gastric contents, a part of the medicament is diffused and released through a gel layer after a certain time, and the other part of the medicament is dissolved out along with the corrosion of the gel, so that the aim of controlling the release of the medicament is fulfilled.
Dihydromyricetin (DHM), also known as Dihydromyricetin and ampelopsin, is a flavonol compound extracted from Chinese medicinal herb ampelopsis grossedentata widely distributed in south and China. In previous researches, dihydromyricetin has the effects of protecting liver, resisting oxidation, protecting heart, resisting inflammation, reducing blood sugar and the like, so that the natural product has great drug development potential. It has been reported that dihydromyricetin can obviously inhibit the release of inflammatory factors such as IL-1 beta, IL-6 and TNF-alpha, etc. The anti-inflammatory effect of dihydromyricetin is determined by experiments of foot swelling, auricle swelling, permeability of abdominal capillary and the like of Sorana [ Sorana, 2002], zhong Zhengxian [ Zhong Zhengxian, 2004] and the like. Hou Xiaolong also demonstrates the effect of dihydromyricetin in inhibiting inflammatory responses. Therefore, dihydromyricetin is a potential anti-inflammatory drug. But their poor water solubility and stability have led to less research on their formulations in the clinic.
At present, the preparation formulations for researching the dihydromyricetin mainly comprise 3 preparation formulations; (1) liposome: the dihydromyricetin is encapsulated in the lipid bilayer to form the micro-vesicular body. (2) Inclusion compound: the dihydromyricetin enters the inclusion material molecules to form cavities by virtue of intermolecular force, so as to form a 1: 1 molecular complex with the inclusion material. (3) Nano-micelle: is a thermodynamically stable system formed spontaneously when the concentration of the polymer carrier exceeds the Critical Micelle (CMC) concentration, and the dihydromyricetin is encapsulated by the hydrophobic inner core. The three drug forms all adopt the hydrophobic inner core to wrap the dihydromyricetin, so that the problem of poor water solubility of the dihydromyricetin is solved to a certain extent, and the dihydromyricetin is prevented from being damaged due to the influence of external environmental factors, thereby improving the stability of the dihydromyricetin.
Disadvantages of these formulations include: 1) The solubilization effect is not good, the mass concentration of the dihydromyricetin in most preparation solutions is only 1-10 mg/mL, and needs to be further improved. 2) The entrapment rate is too low, wherein the entrapment rate of the liposome is mainly 58.1-75.5% (world science and technology-traditional Chinese medicine modernization, 2014,16 (6): 1427-1433; chinese traditional medicine J2008,33 (1): 27-30; in modern application pharmacy 2013,30 (2): 158-163) in China, the volume of a hydration medium is a key factor influencing the encapsulation efficiency and the particle size of the nano-micelle in the preparation process of the nano-micelle, and the larger the volume of the hydration medium is, the more easily the medicine leaks, so that the encapsulation efficiency of the nano-micelle is reduced (J Controlled Release,2000,63 (3): 235-259), which is far lower than the requirement of Chinese pharmacopoeia. 3) These dosage forms did not have a significant increase in drug stability, and the greater the time of storage, the higher the drug release rate. 4) In addition to the above problems, side effects of dihydromyricetin itself should be considered. Based on the above reasons of poor solubilization, encapsulation efficiency and stability, dihydromyricetin needs to be administered at high dose and high frequency to achieve therapeutic effect, so that it is treated as a poison although its medicinal effect is significant.
Disclosure of Invention
Aiming at the problems of poor solubility, low encapsulation rate, easy drug leakage, low drug stability and high dosage and high frequency administration requirement of dihydromyricetin preparations in the prior art. The invention provides a dihydromyricetin gastric floating pill and a preparation method thereof, and aims to provide a dihydromyricetin gastric floating pill which comprises the following steps: improves the encapsulation rate and stability of the dihydromyricetin preparation, overcomes the problems of poor solubility of the medicament and high dosage and high frequency administration requirement by a sustained-release medicament mode, improves the bioavailability of the medicament, simplifies the preparation process and realizes batch production.
A dihydromyricetin gastric floating pill comprises the following components in parts by weight:
20 parts of dihydromyricetin;
13-17 parts of hydrophilic gel.
Preferably, the hydrophilic gel is selected from at least one of hyaluronic acid or Hydroxypropylmethylcellulose (HPMC).
Preferably, the raw materials further comprise: 9-11 parts of an amphiphilic material; preferably, the amphiphilic material is selected from at least one of 1-hexadecanol or Ethylcellulose (EC).
Preferably, the raw materials further comprise: 7-9 parts of a water absorbent; preferably, the water absorbent is at least one selected from PVP, starch, dextran or ethylene glycol polyoxyethylene ether; the PVP is further preferably PVP-K30.
Preferably, the raw materials further comprise: 5-7 parts of an effervescent agent; preferably, the effervescent agent is selected from sodium bicarbonate, potassium bicarbonate, a mixture of sodium bicarbonate and citric acid or a mixture of potassium bicarbonate and citric acid.
Preferably, the composition is prepared from the following components in parts by weight:
20 parts of dihydromyricetin;
9-11 parts of 1-hexadecanol;
13-17 parts of hyaluronic acid;
7-9 parts of PVP;
5-7 parts of sodium bicarbonate.
Preferably, the floating pellets are spherical pellets with a diameter of 3-8 mm; and/or the density of the floating pellets is less than 1g/cm 3 。
The invention also provides a preparation method of the dihydromyricetin floating pill, which comprises the following steps:
(1) Grinding and mixing the components;
(2) Adding water into the ground material, and continuously grinding to prepare a pasty mixture;
(3) Preparing the pasty mixture into pre-pills;
(4) And (4) drying the pre-pill obtained in the step (3) to prepare the dihydromyricetin floating pill.
Preferably, the drying method in the step (4) is freeze drying for 12-36 hours or low-temperature vacuum drying for 12-48 hours.
The invention also provides application of the dihydromyricetin gastric floating pill in preparation of medicaments.
The floating pill is prepared by the specific proportion of dihydromyricetin and hydrophilic gel. The floating pill can float on the content of stomach in human stomach, and can release dihydromyricetin slowly. The technical scheme solves the problems of poor solubility and low encapsulation rate of the dihydromyricetin preparation in the prior art, so that the dihydromyricetin does not need high-dose and high-frequency administration when used for treating patients, the bioavailability of the dihydromyricetin is improved, and the compliance of the patients is also improved.
In a preferred embodiment of the present invention, hyaluronic acid is hyaluronic acid (Hyaluronan), a disaccharide unit consisting of D-glucuronic acid and N-acetylglucosamine, also known as uronic acid. In the literature on formulations of gastric floating tablets or floating pellets, hyaluronic acid is rarely used as a hydrophilic sol. In the application, hyaluronic acid is used as a filler and hydrophilic sol to prepare the dihydromyricetin gastric floating pill. Hyaluronic acid has a special water retention effect, is a substance which is found to have the best moisture retention in nature at present, is called as an ideal natural moisture retention factor, has the characteristic of swelling volume after moisture retention, and is suitable for preparing floating pills due to the biostability, difficult transfer and water insolubility of the hyaluronic acid. In addition, no report is provided for the toxic effect or other side effects of hyaluronic acid, most of hyaluronic acid is artificially synthesized at present, the problems of allergy, infection and the like are eliminated, the hyaluronic acid has high safety, and the hyaluronic acid is a good choice for tissue fillers in pharmaceutical preparations. Hyaluronic acid may form a gel again when hydrated by water in the stomach contents. The gel formed around the pill can slow down the diffusion of the dihydromyricetin and realize the effect of slowly releasing the medicament, which is beneficial to realizing the sustained release of the medicament, thereby overcoming the problems of poor medicament solubility and low medicament bioavailability in other dihydromyricetin preparations.
In addition, in the preferable scheme of the application, the pill can further achieve the optimal floating capacity and drug release rate by adjusting the contents of the amphiphilic material, the water absorbing agent and the effervescent agent in the formula.
The amphiphilic material is selected from 1-hexadecanol or ethyl cellulose, and has the effect of wrapping dihydromyricetin through hydrophobic interaction, so that the content of the dihydromyricetin in the gastric floating pill is increased, and the encapsulation efficiency is increased. The medicine is in a hydrophobic environment, so that the influence of the pH value of the solution and a water-soluble substance on the medicine is greatly reduced, the interference of adverse factors in the external environment on the activity of the dihydromyricetin is reduced, the stability of the medicine is improved, the medicine is not easy to leak even if the pill is stored for a long time, and the pill is kept in a certain activity all the time. In addition, the 1-hexadecanol as a hydrophobic polymer can be used as a bleaching aid and a hydrophobic gel skeleton of the floating pill and also plays a certain role in adhesion. In addition, 1-hexadecanol can help to improve the pill's resistance to immortal forces (e.g., water shear).
The water absorbent is hydrophilic polymer, and can promote dissolution of the medicine after hydration, and increase erosion of the pill. Therefore, the release of the medicine can be adjusted by adjusting the using amount of the water absorbent, and the release rate of the medicine can be improved by increasing the using amount of the water absorbent.
The bicarbonate in the effervescent agent acts as carbon dioxide generated by the reaction with gastric acid, and the carbon dioxide is retained in the gel formed by hyaluronic acid, which is beneficial to prolonging the floating time.
In addition, the floating rate of the dihydromyricetin gastric floating pill can be improved by adjusting the dosage of the water absorption agent and the effervescent agent.
The dihydromyricetin gastric floating pill provided by the invention has the advantages of fewer preparation steps, fewer preparation conditions in the process compared with other preparations, easiness in reaching and simple process. The pill can be subjected to batch processing by extrusion molding and freeze drying, and is beneficial to the enlargement of the yield. If large-scale preparation is required, a mixer can be used to meet the requirements of the future pharmaceutical market.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a flow chart showing a method for preparing a dihydromyricetin gastric floating pill of the present invention;
FIG. 2 is a graph showing the floating rate of dihydromyricetin gastric-floating pellets prepared in example 7 of the present invention;
FIG. 3 is a graph of the percent swelling of dihydromyricetin gastric-floating pills prepared in example 7 of the present invention as a function of time;
FIG. 4 is a graph showing the average degree of erosion of dihydromyricetin gastric-floating pills prepared in example 7 of the present invention as a function of time;
FIG. 5 is the drug release profile of dihydromyricetin gastric-floating pill prepared in example 7 of the present invention;
fig. 6 shows the concentration fluctuation of the drug in plasma of animals after the animals respectively use the dihydromyricetin gastric floating pill and the dihydromyricetin powder prepared in example 7 of the present invention.
Detailed Description
The technical solution of the present application is further described below by specific examples.
The experimental equipment and materials used in the following examples are as follows:
(1) Experimental equipment: marble mortar, HK-93C high Performance pill machine (Xulang mechanical Equipment, china), RT612-AT dissolution System (Raytor instruments, china), 1260Infinity high Performance liquid chromatography System (Agilent technologies, USA), vacuum drying oven, vernier calipers (Delhi group, china), YPD-300D sclerometer (Shanghai yellow sea pharmaceutical instruments, ltd.), liquid chromatography-2030 high Performance liquid chromatography System (Shimadzu, japan).
(2) Experimental materials: dihydromyricetin (purity > 98%), sodium bicarbonate, 1-hexadecanol, hyaluronic acid were provided by Shanghai Aladdin Biotechnology Ltd, china. PVP-K30 is supplied by sigma aldrich, usa. Purified water, hydrogen chloride (PH 1.2), new zealand rabbits (2.1 ± 0.1 kg, male) were supplied by the laboratory animals center of southwest medical university (luzhou city).
The preparation of examples 1-10 is as follows:
the method comprises the following steps: adding dihydromyricetin, 1-hexadecanol, hyaluronic acid, PVP-K30 and sodium bicarbonate into marble mortar.
Step two: purified water is added and thoroughly ground to form a paste-like mixture.
Step three: transferring the paste mixture to HK-93C high performance pellet mill to obtain spherical pre-pellets with diameter of about 3-8 mm.
Step four: the spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 1
(1) 200mg of dihydromyricetin, 90mg of 1-hexadecanol, 130mg of hyaluronic acid, 3070mg of PVP-K and 50mg of sodium bicarbonate are added into a marble mortar.
(2) Purified water 225. Mu.l was added and thoroughly ground to form a paste-like mixture.
(3) Transferring the paste mixture to HK-93C high performance pellet mill to obtain spherical pre-pellets with diameter of about 3-8 mm.
(4) And freeze-drying the spherical prepellets for 12 to 36 hours to obtain the final product.
Example 2
(1) Adding dihydromyricetin 200mg, 1-hexadecanol 90mg, hyaluronic acid 140mg, PVP-K3080mg and sodium bicarbonate 50mg into marble mortar.
(2) Purified water 263 μ l was added and thoroughly ground to form a paste mixture.
(3) Transferring the paste mixture to HK-93C high performance pellet mill to obtain spherical pre-pellets with diameter of about 3-8 mm.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 3
(1) Adding dihydromyricetin 200mg, 1-hexadecanol 90mg, hyaluronic acid 150mg, PVP-K3090mg, and sodium bicarbonate 50mg into marble mortar.
(2) Purified water 263 μ l was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to make spherical pre-pellets approximately 3-8mm in diameter.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 4
(1) 200mg of dihydromyricetin, 100mg of 1-hexadecanol, 150mg of hyaluronic acid, PVP-K3090mg and 60mg of sodium bicarbonate are added into a marble mortar.
(2) Purified water, 263 μ l, was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to form spherical pre-pellets of about 3-8mm diameter.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 5
(1) 200mg of dihydromyricetin, 100mg of 1-hexadecanol, 160mg of hyaluronic acid, 3090mg of PVP-K and 60mg of sodium bicarbonate are added into a marble mortar.
(2) Purified water, 263 μ l, was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to form spherical pre-pellets of about 3-8mm diameter.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 6
(1) 200mg of dihydromyricetin, 100mg of 1-hexadecanol, 170mg of hyaluronic acid, 3090mg of PVP-K and 70mg of sodium bicarbonate are added into a marble mortar.
(2) Purified water 263 μ l was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to make spherical pre-pellets of about 3-8mm diameter.
(4) And (3) carrying out low-temperature vacuum drying on the spherical prepellets for 12-48 hours to obtain a final product.
Example 7
(1) Adding dihydromyricetin 200mg, 1-hexadecanol 100mg, hyaluronic acid 150mg, PVP-K3080mg, and sodium bicarbonate 70mg into marble mortar.
(2) Purified water 263 μ l was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to make spherical pre-pellets of about 3-8mm diameter.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 8
(1) Adding dihydromyricetin 200mg, 1-hexadecanol 110mg, hyaluronic acid 150mg, PVP-K3080mg, and sodium bicarbonate 70mg into marble mortar.
(2) Purified water 263 μ l was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to form spherical pre-pellets of about 3-8mm diameter.
(4) And (3) carrying out low-temperature vacuum drying on the spherical prepellets for 12-48 hours to obtain a final product.
Example 9
(1) 200mg of dihydromyricetin, 100mg of 1-hexadecanol, 160mg of hyaluronic acid, 3090mg of PVP-K and 70mg of sodium bicarbonate are added into a marble mortar.
(2) Purified water, 263 μ l, was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to form spherical pre-pellets of about 3-8mm diameter.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
Example 10
(1) Adding dihydromyricetin 200mg, 1-hexadecanol 110mg, hyaluronic acid 170mg, PVP-K3090mg and sodium bicarbonate 70mg into marble mortar.
(2) Purified water 263 μ l was added and thoroughly ground to form a paste mixture.
(3) The mixture was transferred to a HK-93C high performance pellet mill to form spherical pre-pellets of about 3-8mm diameter.
(4) The spherical prepellets were freeze-dried for 12-36 hours to obtain the final product.
The beneficial effects of the invention are illustrated by way of experimental examples below:
experimental example: quality control of dihydromyricetin gastric floating pill
To illustrate the effect of the present application, the quality evaluation was performed on the samples of examples as follows:
the quality evaluation content includes weight, particle size and hardness, drug content, water content, floating capacity, swelling and erosion, drug release, biological effect. The specific method and results are as follows:
(1) The weight, particle size, density and hardness of the samples were measured using a balance, vernier caliper (Delhi group, china), YPD-300D durometer (Shanghai yellow sea pharmaceutical instruments, inc.), each in triplicate.
(2) The high performance liquid chromatography is adopted to determine the content of the medicine: ten randomly selected samples were weighed together and ground in a marble mortar, 50mg of the ground fine powder was dissolved in 100ml of 0.1n Hydrogen Chloride (HCL), and the extract was filtered through a 0.45 μm cellulose acetate membrane and then the drug content was measured using 1260Infinity hplc system (agilent technologies, usa).
(3) The water content of the sample is studied by vacuum drying: twenty samples were randomly selected and ground in a marble mortar, 400mg of the fine powder was placed in a dry weighing bottle, dried with a suitable amount of phosphorus pentoxide as a drying agent, air pressure was maintained at 2.67KPa, dried in a vacuum oven at 50 ℃ until the weight of the powder did not change, and after drying, the percentage weight loss of the powder representing the moisture content was calculated.
The results of the above-described measurement showed that the average weight of the dihydromyricetin gastric-floating pill prepared in example 7 was 46.33 ± 0.95 mg, the drug content percentage reached 33.57%, and the water content was 2.03%, indicating that water was almost completely removed. The density of the pill is 0.65g/cm 3 This is also why the pill floats immediately. The average hardness of the dihydromyricetin gastric floating pill is 19.3 newtons.
(4) The sample floating capacity was studied by stirring: forty tablets were placed in 900ml of a 0.1M hydrogen chloride (HCl) solution and stirred at a temperature of 37.0. + -. 1.0 ℃ at a rate of 100 rpm. At different time points, the number of pills remaining floating was recorded and the floating rate was calculated.
The result shows that the floating rate of the dihydromyricetin gastric floating pill prepared by the method of the invention is kept at 100% in the first 6 hours and exceeds 75% in 18 hours. In contrast, in the case of the dihydromyricetin floating pill prepared in example 7, the floating rate in 24 hours exceeds 80% (as shown in fig. 2), which indicates that the pill does not cause too large fluctuation of the drug concentration in the stomach, so that the toxic effect of dihydromyricetin is reduced, even avoided, and the gastric floating pill makes it possible to complete once-a-day administration of dihydromyricetin.
(5) Measuring the dry weight and the wet weight of the sample to calculate the swelling and corrosion capacities of the sample: randomly selecting ten pills for weighing, and recording the total weight as w 0 ", the pellets were then dissolved in 900ml of hydrogen chloride (HCl) and stirred at 100 rpm, maintaining the temperature at 37.0 + -1.0 deg.C. At a predetermined time point, the pill is removed and the surface moisture of the pill is dried with filter paper, at which point the pill is weighed and the total weight (i.e., wet weight) is marked as "w1". The pellets were then placed in a dry weighing bottle and dried in a vacuum oven at 50 c with the appropriate amount of phosphorus pentoxide as the desiccant, with air pressure maintained at 2.67KPa, until the weight of the powder did not change, at which point the pellets were weighed again and the total weight (i.e. dry weight) was marked as "w2". Then according to the formula [28]The percentage of swelling and erosion of the pill at different time points was calculated. Swelling rate = (w 1-w 0)/w 0 × 100%, erosion rate = (w 0-w 2)/w 0 × 100%.
The results show that after hydration, dihydromyricetin gastric-floating pellets rapidly expanded within the first 6 hours, with the percent expansion reaching a maximum at 9 hours (as shown in figure 3); thereafter, the percentage of swelling begins to decrease, mainly due to the increased degree of erosion of the pill. After 24 hours, the average erosion degree of the dihydromyricetin gastric-floating pill exceeds 72% (as shown in fig. 4), and the drug release of the dihydromyricetin gastric-floating pill is almost completed.
(6) Drug release of the samples was determined by the crosslinker method: ten pills were randomly selected and placed in 900ml of 0.1n Hydrogen Chloride (HCL) solution, and the dissolution medium was stirred AT 100 rpm on an RT612-AT dissolution system (Raytor instrument, china) AT 37.0 ± 1.0 ℃. At a predetermined time point, 0.8ml of medium was taken for analysis while the same amount of fresh medium was added, followed by determination of drug concentration by 1260Infinity high performance liquid chromatography system (agilent technologies, usa). The drug release mechanism of dihydromyricetin gastric-floating pellets was studied using Kopcha (drug release amount (Qt) at time t fitted according to the equation Qt/t = A/t1/2+B, where A and B values represent the relative contribution of diffusion and erosion, respectively) and Korsmeyer-Peppas release model (the fraction of drug release at time t (Qt/Q ∞) fitted according to the following equation Qt/Q ∞ = kptn, where kp is the release rate constant and n values represent the drug release mechanism).
The results showed that the mean drug release of dihydromyricetin gastric-floating pills prepared in example 7 was about 50% (to the accuracy of 53.7% ± 3.5%) at 12 hours, and the mean drug release was over 90% (to the accuracy of 93.9% ± 3.1%) at 24 hours (as shown in fig. 5). The slow-release property of the medicine makes the medicine expected to be a one-day administration preparation.
(7) The pharmacokinetic experiments were performed using rabbits: 12 male rabbits (2.1 + -0.1 kg) were randomly divided into two groups of 6 rabbits each. The animals of the experimental group were orally administered with dihydromyricetin intragastric floating pill, and the animals of the control group were orally administered with dihydromyricetin powder (control), with dosage of 115 mg dihydromyricetin/kg body weight. At predetermined time points, 1.5-2mL of blood was collected through the apex of the rabbit and centrifuged (4500 rpm. Times.10 min). After centrifugation, 440 microliters of supernatant was immediately removed. The plasma was then pre-treated and analyzed on a liquid chromatography-2030 high performance liquid chromatography system (Shimadzu, japan). The plasma drug concentrations of each group were then collected for pharmacokinetic analysis to determine the maximum plasma drug concentration (labeled "C max "), to C max Time required (marked " tmax "), area under the plasma concentration-time curve (AUC), mean Retention Time (MRT), and final elimination half-life (labeled" t 1) /2(T-∞) ") and relative bioavailability (labeled" FR ").
According to the rabbit pharmacokinetic experiment (results are shown in fig. 6), the plasma drug concentration of the control group reached a maximum (i.e., maximum concentration) of about 159 μ g/l at 1.5 hours after administration of dihydromyricetin powder. In contrast, experimental groups used myricetin with a longer floating time and slower drug release for gastric floating, t max Longer, 10.33. + -. 0.82 hours (P)<0.001 ); and C thereof max Significantly lower, 86.72 ± 18.92 micrograms/liter. These results indicate that there is less fluctuation in plasma drug concentration after administration of dihydromyricetin gastric-floating pills.
(8) Stability of the test samples: the prepared dihydromyricetin gastric-floating pills are divided into A, B and C, and each group contains 20 pills. The product is stored under vacuum at 25 + -5 deg.C under dry condition for three months (group A), half a year (group B) and one year (group C). Taking out after reaching the time, and measuring the weight, the grain diameter and the hardness, the drug content, the water content, the floating capacity, the swelling and the erosion, the drug release and the biological effect.
The experimental results of the dihydromyricetin gastric-floating pill prepared in example 7 are as follows:
the weight, the content and the water content of the group A of medicines are still unchanged, and the hardness is 19.2 newtons; a 24 hour flotation rate of about 80%; the percent swelling reached a maximum after 9 hours, with an average erosion of about 72% at 24 hours and a 24 hour drug release of about 93%;
the weight, the content and the water content of the medicines in the group B are still unchanged, and the hardness is 19.3 newtons; a 24 hour flotation rate of about 80%; the percent swelling reached a maximum at 9 hours, with an average erosion of about 71% at 24 hours and a 24 hour drug release of 93%;
the weight, the content and the water content of the group C medicines are still unchanged, and the hardness is 19.1 newtons; the floating rate of 24 hours reaches 79 percent; the percent swelling reached a maximum of about 9 hours, at 24 hours, the average degree of erosion was about 70%, and the 24 hour drug release was 92%.
The indexes show that the dihydromyricetin floating pill provided by the invention has the preservation time within one year, and all properties of the dihydromyricetin floating pill are kept unchanged. Therefore, the medicament leakage rate of the dihydromyricetin floating pill provided by the invention is 0. By contrast, the leakage rate of the dihydromyricetin liposome is relatively high, the leakage rate of the medicine stored at 25 ℃ for 30 days is (13.9 +/-1.3)%, and the leakage rate of the medicine stored at 50 days is (19.4 +/-2.2)%. The stability of the preparation provided by the invention is higher than that of the dihydromyricetin preparation in the prior art.
Through the results of the experimental examples, the dihydromyricetin gastric floating pill provided by the invention has high medicine content and has the characteristic of sustained-release medicine. Therefore, the problems of poor solubility and low encapsulation efficiency of dihydromyricetin in the existing preparation can be overcome, so that the administration of dihydromyricetin is changed from the prior high-frequency high-dose administration to once-a-day administration. After the dihydromyricetin gastric floating pill is administrated, the fluctuation of the plasma drug concentration is small. The toxic and side effects of the medicine on patients are reduced, and the compliance of the patients can be further improved. In addition, the dihydromyricetin gastric floating pill provided by the invention has high stability, and various properties are almost unchanged after the dihydromyricetin gastric floating pill is stored for one year. Therefore, the dihydromyricetin gastric floating pill has good application prospect.

Claims (10)

1. The dihydromyricetin gastric floating pill is characterized by comprising the following raw materials in parts by weight:
20 parts of dihydromyricetin;
13-17 parts of hydrophilic gel;
9-11 parts of an amphiphilic material;
7-9 parts of a water absorbent;
5-7 parts of an effervescent agent;
the hydrophilic gel is selected from hyaluronic acid;
the dihydromyricetin gastric floating pill is prepared by the following steps:
(1) Grinding and mixing the components;
(2) Adding water into the ground material, and continuously grinding to prepare a pasty mixture;
(3) Preparing the pasty mixture into pre-pills;
(4) And (4) drying the pre-pill obtained in the step (3) to prepare the dihydromyricetin floating pill.
2. A dihydromyricetin gastrobuoyant pellet according to claim 1, wherein the amphiphilic material is selected from at least one of 1-hexadecanol or ethylcellulose.
3. A dihydromyricetin gastric floating pill according to claim 1, wherein the water absorbent is selected from at least one of PVP, starch, dextran or polyoxyethylene glycol ether.
4. A dihydromyricetin gastric floating pellet formulation according to claim 3, wherein the PVP is PVP-K30.
5. A dihydromyricetin gastrobuoyant pellet according to claim 1 wherein the effervescent agent is selected from sodium bicarbonate, potassium bicarbonate, a mixture of sodium bicarbonate and citric acid or a mixture of potassium bicarbonate and citric acid.
6. A dihydromyricetin gastrofloating pill according to any one of claims 1 to 5, characterized by being prepared from the following components in parts by weight:
20 parts of dihydromyricetin;
9-11 parts of 1-hexadecanol;
13-17 parts of hyaluronic acid;
7-9 parts of PVP;
5-7 parts of sodium bicarbonate.
7. A dihydromyricetin gastrobuoyant pellet according to claim 1, wherein: the floating pills are spherical pills with the diameter of 3-8 mm;
and/or the density of the floating pellets is less than 1g/cm 3 。
8. A process for the preparation of a dihydromyricetin gastrobuoyant pellet according to any one of claims 1-7, comprising the steps of:
(1) Grinding and mixing the components;
(2) Adding water into the ground material, and continuously grinding to prepare a pasty mixture;
(3) Preparing the pasty mixture into pre-pills;
(4) And (4) drying the pre-pill obtained in the step (3) to prepare the dihydromyricetin floating pill.
9. The method for preparing a dihydromyricetin gastrobuoyant pill according to claim 8, wherein: the drying method in the step (4) is freeze drying for 12-36 hours or low-temperature vacuum drying for 12-48 hours.
10. Use of a dihydromyricetin gastrobuoyant pellet according to any one of claims 1-7 in the manufacture of a medicament.
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