WO2003037359A1 - Nanoparticle of insoluble medicinal components and method to produce thereof - Google Patents

Abstract

The invention discloses a nanoparticle of insoluble medicinal components and method to produce them.

Description

 Nanoparticles of poorly soluble drugs and preparation method thereof

 The invention relates to nanoparticles of poorly soluble drugs and a preparation method thereof.

Background technique

 According to the different parts of the drug, it can be divided into local effect and absorption effect. Absorptive effect is also called systemic effect, which refers to the effect played by drugs that are absorbed into the blood and distributed to various parts of the body. Most drugs have absorption effects. The indicators for evaluating drug absorption are mainly the rate and procedure of absorption, or bioavailability. In addition to factors affecting transmembrane transport,

#> Variable factors affect drug absorption. (1) The solubility of the drug. The absorption of a drug depends on its solubility. The drug is absorbed more quickly when administered as an aqueous solution than as an oil solution, suspension or solid, because its absorption site mixes more quickly with the water phase. The rate of dissolution of a drug administered in solid form may be a limiting factor for absorption. (2) Drug concentration. The concentration of the drug at the absorption site can affect its own absorption rate. In the same administration site, high concentration drugs can be absorbed faster than low concentration drug solutions. (3) Local blood flow. Blood circulation at the absorption site also affects the absorption of the drug. (4) Absorption surface area. The surface area absorbed by a drug is a more important factor in determining the rate of absorption. As mentioned above, the bioavailability of poorly soluble drugs is not high. In order to provide the bioavailability of poorly soluble drugs to a large extent, it is very important to prepare the hardly soluble drugs or the hardly soluble effective components of the drugs into nanoparticles. Effective measures. Brief description of the invention

 The purpose of the present invention is to improve or increase the (water) solubility of poorly soluble drugs (traditional Chinese medicines and synthetic drugs), thereby improving or increasing the bioavailability of poorly soluble drugs and their medicinal effects.

The present inventors have found through research that by converting a poorly soluble drug into nano-sized particles having a particle size of 1-100 nm, the (water) solubility of the poorly soluble drug can be effectively improved or improved. The bioavailability of the insoluble matter and its medicinal effect are improved.

 Therefore, the first aspect of the present invention relates to nano-sized particles of poorly soluble drugs, and the nano-sized particles have a particle diameter of 1-100 nm.

 Another aspect of the present invention relates to a method for preparing nano-sized particles of poorly soluble drugs, which includes:

 (a) selecting one or more solvents to make a drug (traditional Chinese medicine or synthetic medicine) that is hardly soluble in water into a solution or a saturated solution,

 (b) adding the solution obtained in (a) slowly (or spraying) to an aqueous solution containing a surfactant under the condition of the interaction of stirring and ultrasonic vibration, to form an aqueous suspension of drug nanoparticles, if necessary Remove water solvents to form an aqueous suspension of drug nanoparticles.

 (c) If necessary, a method of salting out can be used to filter out a large amount of water, and then spray drying, vacuum drying, or low temperature vacuum drying are separately selected to prepare fine powders of nano-scale insoluble drugs. Detailed description of the invention

 The present invention relates to nano-sized particles of poorly soluble drugs, wherein the particle size of the nano-sized particles is 1-100 nm.

 According to the present invention, the term poorly soluble drug: refers to a drug whose solubility in water at room or ambient temperature is less than 1%.

According to the present invention, the term "poorly soluble drug" refers to a Chinese medicine or a synthetically obtained drug at room temperature. The traditional Chinese medicine can be a single plant or animal or their parts or extracts or a combination of two or more plants or animals or their parts or extracts, such as the resin extract of dracaena, propolis, salvia, blood Exhaustion, myrrh, frankincense, heliotrope and hematoxylin, propolis and blood exhaustion, etc. Examples of synthetic drugs include: vitamin A, vitamin A, D, vitamin E, "CLA", spiramycin, earth Mycin, erythromycin, Dexamethasone, captopril, benoxime, anti-inflammatory disease, testosterone, fembitol, etc.

 The present invention further relates to a method for preparing nano-sized particles of a poorly soluble drug, including: (a) selecting one or more solvents to make a poorly soluble drug (traditional Chinese medicine or synthetic drug) into a solution or a saturated solution, ( b) Add the solution obtained in (a) slowly (or spray) to the aqueous solution containing the surfactant under the condition of stirring and ultrasonic vibration together to form an aqueous suspension of drug nanoparticles, if necessary, Remove the non-aqueous solvent to form an aqueous suspension of the drug nanoparticles. (C) If necessary, salting out can be used to filter out a large amount of water, and then spray drying, vacuum drying, or low temperature vacuum drying are used to prepare the nanoparticles. Fine powder of grade insoluble drug.

 According to the present invention, the solvent used in the method of the present invention may be selected from alcohols, esters, ketones, liquid acids or bases, or other solvents. The alcohols are selected from monohydric or polyhydric alcohols, such as ethanol, propanol, butanol, ethylene glycol, propylene glycol, glycerol, and the like; examples of the esters include ethyl lactate, butyl lactate, ethyl acetate, and butyl acetate , Y-butyrolactone, etc .; Examples of ketones are acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methylpentanone, etc .; Examples of acids or bases are acetic acid, hydrochloric acid, sodium hydroxide, etc .; Other solvents Examples include pyridine and tetrahydrofuran.

 Not often used due to toxicity, such as dimethylbenzyl, alcohol ethers, chlorinated hydrocarbon solvents and terpenes.

According to the invention, the surfactants used in the method of the invention are one or more surfactants and co-surfactants. Select appropriate surfactants and co-surfactants according to the active ingredients and structure of the drug. Since the selected surfactants will form a protective layer on the surface of the drug nano-particles made, the selected surfactant must be Poisonous and edible. Available surfactants and co-surfactants are: Anionic surfactants, such as sodium dodecyl sulfate, sodium dodecyl benzyl sulfonate, etc .; non-ionic surfactants, such as octadecyl Polyoxyethylene, fatty acid sorbitan polyoxyethylene and polysorbate, etc .; amphoteric surfactants, such as amine carboxylates and quaternary ammonium salt carboxylates; etc .; cationic surfactants, such as cetyl Trimethylammonium bromide, etc .; help surface activity Sexual agents, such as alcohols of medium carbon chain length, such as dodecanol, cetyl alcohol, and the like. A preferred surfactant is a mixed surfactant including a surfactant and a co-surfactant.

Ultrasonic vibration refers to: Ultrasonic vibration with a frequency of 40K¾- 60KH _Z.

 According to the present invention, the removal of the non-aqueous solvent may be selected from the method of distillation, vacuum distillation, or freezing.

 The following examples are further specific descriptions of the present invention, but they are not meant to limit the present invention in any way.

Example 1 Preparation of Nanoscale Blood Depletion

 Blood exhaustion is a pure natural extract extracted from the resin of the rare plant dracaena. It has significant effects of activating blood circulation, removing blood stasis, swelling and pain relief, astringent and hemostatic, softening and firming, and muscle healing sores.

 Weigh 3 g of blood exhaustion and dissolve it in 30 ml of absolute ethanol to prepare a 10% (w / v) blood exhaustion ethanol solution. Weigh 0.3g of sodium lauryl sulfate (or anionic surfactants such as sodium dodecylbenzylsulfonate) and dissolve it in 600ml of distilled water. Stirring can be used to accelerate the dissolution of the surfactant. Surfactants can also be added to the ethanol solution. In order to further reduce the surface tension, co-surfactants are added, such as dodecanol or cetyl alcohol. The amount of co-surfactant is 100% of the amount of surfactant; it is composed of mixed surfactant. Under the combined action of stirring and ultrasonic vibration, 30 liters of blood-exhausted ethanol solution was added dropwise to 600 liters of surfactant-dissolved aqueous solution, and the drop rate was 1-2 drops per second to form a nano-blooded water suspension . As determined by the "State Key Laboratory of Advanced Materials Composite Technology" using the Malta Instruments ZataPals laser particle size analyzer, the particle size distribution of the nanometer blood exhausted microparticles ranges from 8.1 to 35.4 nm, and the average particle size is 17 nm; As determined by the Testing Center of Wuhan University using Japan Electronics GEM-100cxc transmission electron microscope, the nanometer blood draught particles became spherical and the particle size was less than 50nm.

The salting-out method was used to filter off the water in the nano-blood-dried aqueous suspension, and then the adsorbed water was removed by a low-temperature vacuum drying method to obtain nano-blood-dried fine powder. Use NaCl salt with a concentration of 2%. Example 2 Dissolution performance of nanometer blood exhaustion:

 The Shimadzu 240 UV spectrophotometer was used to semi-quantitatively measure the dissolution of commercially available blood dried capsules (with a particle size of 250 μm) and the nano blood dried prepared in Example 1. The test results showed that the nano blood dried in pure water The dissolution amount is more than 200 times higher than that of the commercially available blood exhausted capsules.

 Using a conductivity meter to measure the dissolution rate of nano-dried blood and commercially available blood-dried gelatin capsules in pure water, the test results show that as the particle size of blood-dried particles decreases, the dissolution speed increases, and the final dissolution volume also increases. Example 3 Comparison of the biological activity of the nano-drainage prepared in Example 1 with the known commercially available blood-dried capsules

 Experimental Study on Prevention of Thrombosis

 Effects of different particle sizes of blood exhaustion on thrombosis in rats

 experiment material

 Animals: Wistar rats, male and female, weighing 200-300g.

 Equipment: surgical instruments, silk threads, polyethylene tubes, arterial clips.

 Test sample

 Number: 1: Concentration of commercially available blood-dried gelatin capsules 0.5%, particle size 125 μ ιη,

 No. 2: Commercially available blood-dried gelatin capsules have a concentration of 4.5% and a particle size of 125 μm,

 No. 3: Example of nanometer blood exhaustion in the present application Concentration 0.5%, particle size (30-80) μ m,

 12500u / ml heparin injection, 3g / dl sodium pentobarbital.

 Note: 1 μm 2 lOOOnm

 experiment method:

Eighteen Wistar rats were randomly divided into three groups according to body weight and sex, with six in each group. 30ml / k _{g of} test samples 1 to 3 were administered by gavage for 7 consecutive days. Take rats, weigh them, abdominal cavity 0.05 mg / kg of barbiturate was injected to separate the right common carotid artery and the left vein. In the middle of the three sections of polyethylene, a 5 cm long surgical wire was placed. Heparin saline solution (50u / ml) was filled into the polyethylene lumen. When one end of the tube was inserted into the left external jugular vein, 50u / kg of heparin was injected from a polyethylene tube, and the tube wall was clamped. Insert one end of the tube into the right common carotid artery. The blood flow is released, and the blood flows from the right artery through the polyethylene tube to the left external jugular vein. After opening the blood flow for 15 minutes, the blood flow was interrupted, and the silk thread was quickly taken out and weighed. The total weight minus the silk weight was the wet thrombus weight. The experimental results are shown in Table 1.

 Effects of different diameters of blood exhaustion on thrombus formation (X: ¾)

Fibrinolysis

 Effects of different size hemorrhage on fibrinolytic activity in rats

 The test materials, test animals, and test samples were the same as described in the above-mentioned experiment for preventing thrombosis.

 Test equipment: water bath, timer.

 experiment method

 Whole blood clot dissolution test

A whole blood clot was used as a sample, and the time of total dissolution was observed as an indicator of fibrinolytic activity. Forty rats, half male and half female, were randomly divided into 4 groups according to body weight and gender. The grouping, dosage, time and route were the same as those in the thrombosis prevention experiment. Thirty minutes after the last administration, each animal took 1 ml of blood, placed in separate test tubes, placed a cork, and placed it in a 37 ° C water bath. It was timed when it solidified, and the time required for complete dissolution was observed. The results are shown in Table 2. Table 2 Effect of blood particles of different particle sizes on the dissolution time of whole blood clots

 Whole plasma clot dissolution test

 Thrombin was added to the citrated plasma to coagulate it, and the clot was checked for dissolution. Forty rats, half male and half female, were randomly divided into 4 groups. The administration is the same as in the thrombosis prevention experiment. After the last administration for 30 minutes, 1 ml of blood was taken from each animal, 0.2 ml of 3.8% sodium arsenate sodium solution was added, mixed, and centrifuged at 3000 rpm for 10 minutes. Separation of plasma. Remove 0.5ml of plasma, place it in a small test tube, and add 0.1ml of thrombin (equivalent to 10 units) to coagulate. Observe the dissolution every one hour until the clot is completely dissolved, and record the time.

 Grouping: No. 0: saline.

 No. 1: Commercially available blood dried capsules 0.5%, particle size 125 μm, No. 2: Commercially available blood dried capsules, 4.5%, particle size 125 μm,

 No. 3: Nano blood dysfunction 0.5%, particle size (30-80) nm, Table 3 Effect of blood drench with different particle size on dissolution time of whole blood paddle clot (X: iS)

 Group Number of animals (only) Total plasma clot dissolution time (hours)

0 physiological saline 10 74.0¾0.0

 1 Concentration of blood exhausted gelatin 0.5% 10 72.0¾5.0

 2 Concentration of blood exhausted gelatin 4.5% 10 48.0 ^ 8.0

 3nm blood exhaustion concentration 0.5% 10 9.0.0

 Determination of Euglobulin Dissolution Time (ELT)

Dilute platelet-free plasma, adjust pH to 4.5 with acetic acid, isolate euglobulin, It was redissolved in isotonic saline, and then calcium was added to coagulate the euglobulin. Observe the clot dissolution time again.

 Animals and group medication were the same as before. Thirty minutes after the last dose, 9 parts of whole blood and 1 part of 3.8% sodium citrate solution were mixed and immediately centrifuged at 3000 rpm for 10 minutes to separate platelet-free plasma. Take 0.5 ml of plasma, add 9 ml of distilled water, and then add 0.1 ml of 1% acetic acid solution to make the pH to 4.5. After mixing thoroughly, place the mixture in a 4 ° C water tank for 10 minutes. Euglobulin was precipitated by weak acid, and then centrifuged at 3000 rpm for 5 minutes. Discard the supernatant, place the sediment tube on the filter paper, and aspirate the excess liquid. Add 0.5 ml of boric acid buffer (PH9) to the precipitation tube and stir with a glass rod for about 1 minute. After placing the test tube in a 37 ° C water bath for 2 minutes, add 0.5 ml of a 1M / 40 calcium chloride solution and wait for it to solidify. Observe every 10 minutes until the clot is completely dissolved, and record the time required for its dissolution. The results are shown in Table 4.

 Effect of blood particles with different particle sizes on dissolution time of Euglobulin (X) Group Number of animals (only) Dissolution time of Euglobulin (hours)

0 physiological saline 10 580. 0 ± 100. 0

 1 Concentration of blood exhausted capsules 0. 5% 10 450. 0 0

 2 Concentration of blood exhausted capsules 4.5% 10 250. 0 ¾0. 0

 3 Nanometer blood exhaustion concentration 0.5% 10 70. 0 ¾0. 0 Example 4 Preparation of nanometer propolis

A large number of studies at home and abroad have confirmed that propolis has numerous medical health care functions. The main active ingredients of propolis are flavonoids, terpenes, aldehydes, ketones, esters and organic acid compounds. Propolis is a natural antibiotic with special biological effects. Its main function is to have a broad-spectrum antibacterial and anti-inflammatory effect, enhance the body's immune capacity, precious natural antioxidants, "sweepers" of blood vessels and "protector" of microcirculation. Therefore, propolis, like royal jelly, is a very precious bee product. The main effective components in propolis are flavonoids and terpenoids, which are difficult to dissolve in water, but soluble in alcohol. In the present invention, ethanol is used as a solvent to prepare nano-propolis particles or aqueous suspensions.

 Preparation of nano propolis water suspension:

 Take a portion of propolis alcohol extract, add 0.55% anionic surfactant (sodium dodecyl sulfate), add 0.15% non-ionic surfactant (polysorbate), add 0.55% Co-surfactant (hexadecanol), after being dissolved by stirring, is slowly added to 20 times pure water under the combined action of stirring and ultrasonic vibration, and the dropping acceleration is 1-2 drops per second, which becomes nano-propolis suspension liquid.

 The "State Key Laboratory of Advanced Materials Composite Technology" was measured by the Maltese Instruments ZataPalS laser particle size analyzer, and its particle size distribution range was 10.9nm-51.3nm, with an average particle size of 23.7nm.

 The Shimadzu 240 UV spectrophotometer was used to semi-quantitatively determine the content of effective components in the propolis and nano-propolis aqueous suspensions. The test results showed that the dissolution of nano-propolis in water increased by nearly 500 times.

 Propolis made into nano-propolis aqueous suspension can significantly increase the dissolution of the effective components of propolis in water, thereby greatly improving the bioavailability of propolis. Example 5 Preparation of Nano Salvia

 Salvia is the root of Salvia miltiorrhiza. Its main function is to promote blood circulation and remove blood stasis.

 The active ingredients in Salvia miltiorrhiza are confirmed in two parts, that is, fat-soluble ingredients include tanshinone and cryptotanshinone (diterpene quinones), and the other part is water-soluble, mainly phenolic ingredients (phenolic acids, etc.), glycosides, and amino acids. . Therefore, the present invention uses two methods, water extraction and alcohol extraction, to extract water-soluble and alcohol-soluble effective components from Salvia miltiorrhiza.

 The object of the present invention is achieved by the following technical solutions:

Salvia miltiorrhiza was sliced and pulverized by a pulverizer. 10g of crushed dan is added to 100ml of distilled water, Cook at 80-90 ° C for 1-2 hours, and filter to obtain Danshen decoction. Add 100ml of absolute ethanol to the filter residue of Danshen decoction, heat and reflux at 65-75 ° C for 0.5 to 1 hour, filter to obtain the filtrate, and concentrate the filtrate through tilling until a small amount of precipitate appears in the filtrate. filtrate. Lg。 Danshen decoction was diluted with distilled water to the design concentration, per liter of filtrate containing Danshen crude medicine 0. lg. Add 0.3% surface active material, sodium lauryl sulfate, and disperse by ultrasonic vibration. Under the conditions of stirring and ultrasonic vibration, the alcohol filtrate was added dropwise to the salvia miltiorrhizae decoction containing surfactant, and the dropping rate was 1-2 drops per second. After the dropwise addition, a suspension of Salvia miltiorrhiza nanoparticles was prepared. As measured by a transmission electron microscope, most of the particles had a particle size of less than 100 nm. If it is necessary to prepare the salvia miltiorrhiza nanopowder, the salvia miltiorrhiza nano suspension can be salted out and the precipitate can be dried at low temperature to obtain the salvia miltiorrhiza nanopowder.

 The nano-suspension of Salvia miltiorrhiza prepared by using the present invention is measured by ultraviolet spectroscopy, and the dissolution concentration thereof is about 28 times higher than that of Salvia miltiorrhiza injection.

 The invention can be used for the preparation of nano-powders of all components of traditional Chinese medicine containing both water-soluble and alcohol-soluble effective components. Using the above technical solution of the present invention, a plurality of single-component nanoparticles such as astragalus, Bupleurum, Banlangen, Gastrodia, Houttuynia cordata, Panax notoginseng and Eucommia ulmoides have been prepared. Example 6 Preparation of Compound Nano Blood Drain

 Compound blood exhaust consists of blood exhaust, myrrh, frankincense, hellebore, and hematoxylin.

 Weigh 3g of blood exhaustion and dissolve in 30ml of absolute ethanol; weigh 2g of myrrh and dissolve in 20ml of absolute ethanol; weigh 2g of mastic and dissolve in 20ml of absolute ethanol. Filter separately to obtain the filtrate. Hematoxylin and Sorbaria are soaked in absolute ethanol for 15 days, filtered separately, and the filtrate is taken.

Five kinds of filtrates were measured and mixed according to the following volume ratios, and then subjected to ultrasonic vibration for 10 minutes. Blood exhaustion: Myrrh: Frankincense: Hematoxylin: Hemophilia = 20: 10: 10: 10: 10 (ml). Weigh 0.2g of sodium dodecylbenzenesulfonate, dissolve in 600ml of distilled water, and stir It can accelerate the dissolution of surfactants. Under agitation, slowly add 30ml of alcohol solution and alcohol extract to the mixture (acceleration rate is 1-2 drops per second) or spray to add Sex agent in water. If necessary, ultrasonic vibration dispersion measures can be added. This example was completed at room temperature and determined by the Testing Center of Wuhan University using Japan Electronics GEM-100cxc transmission electron microscope. The particle size distribution of the compound Chinese medicine particles was in the range of 10-100nm and the average particle size was 80nm. Example 7 Preparation of Compound Nano Blood Dried Propolis

 Propolis is a resin collected by bees from the tree buds and bark of plants. It is mixed with honey bee tongue glands, wax glands and other glandular secretions. Propolis has the functions of sterilizing and anti-inflammatory, purifying blood, eliminating toxins and enhancing immunity.

 Take 50 g of blood exhaustion and dissolve it in 400 ml of absolute ethanol; take 10 g of propolis and dissolve it in 100 ml of absolute ethanol, sonicate for 40 minutes, filter the solution and weigh 5 g of insoluble matter after drying. The two solutions were mixed, and after ultrasonic vibration for 10 minutes, there was no precipitation.

 Weigh 0.2 g of sodium dodecyl sulfonate, dissolve it in 600 ml of distilled water, and stir it to accelerate the dissolution of the surfactant. The aqueous solution is heated to start the ultrasonic vibration dispersion system. Under stirring conditions, 30 ml of mixed droplets are added to the aqueous solution containing the surfactant, and the dropping rate is 1-2 drops per second. After the mixed droplets are added, the ultrasonic vibration is turned off. Disperse the system, then turn off the stirring system and store it for a certain period of time to make a compound nano blood exhausted propolis suspension. The particle size of the particles was less than 100nm as determined by the Testing Center of Wuhan University using Japan Electronics GEM-100cxc transmission electron microscope. Example 8 Preparation of Nano Vitamin E

 Vitamin E is a yellow transparent viscous oily liquid, which is insoluble in water and easily soluble in many organic solvents. Used for habitual abortion, muscular dystrophy, and heart disease and hypertension. Can enhance the body's metabolism and prevent aging.

Under the condition of ultrasonic vibration, vitamin E is dissolved in ethanol, and the concentration can be set as required until the saturation concentration. 5%。 Selection of sodium dodecyl sulfate and cetyl alcohol as a surfactant and co-surfactant, the amount of 0.5% by weight of vitamin E. Stirring and ultrasonic vibration Under the action of motion, vitamin E is added to the alcohol solution to make it fully dissolved. Under the combined action of stirring and ultrasonic vibration, a vitamin E alcohol solution containing a surfactant is slowly dropped into purified water, and the amount of purified water is 20 times that of the vitamin E alcohol solution. The dropping rate is 1-2 drops per second. After completion and storage for a certain period of time, an aqueous suspension of vitamin E is obtained. If necessary, the alcohol can be separated and removed from the aqueous solution.

 The vitamin E aqueous suspension prepared in this example was measured by the "National Laboratory for Advanced Materials Composite Technology" using the Maltese Instruments Co., Ltd. ZataPalS laser particle size analyzer, and its particle size distribution range was 12-56. 9nm, average particle size. The diameter is 26.1 nm.

 Vitamin A and vitamin A. D nanoparticles were also prepared using the addicted technical scheme. Example 9 Preparation of Nanometer "CLA"

 "CLA" is a new drug produced in the United States. It is soluble in alcoholic organic solvents but hardly soluble in water. It is reported that taking "CLA" can reduce fat content and promote muscle growth.

 As the solvent, ethanol, propylene glycol, or a mixture thereof can be selected.

 Under the action of ultrasonic vibration and agitation, "CLA" is dissolved in ethanol, and the concentration can be set as required until it is saturated. 5%。 The use of sodium dodecyl sulfate and dodecyl alcohol as a surfactant and co-surfactant, the amount of "CLA" amount of 0.5%. Under the action of stirring and ultrasonic vibration, add "CLA" alcohol solution to make it fully dissolved. Under the combined action of stirring and ultrasonic vibration, the "CLA" alcohol solution containing a surfactant was slowly dropped into purified water, the amount of purified water was 20 times that of the "CLA" alcohol solution, and the drop rate was 1-2 drops per second. After completion of the dropwise addition, an aqueous suspension of "CLA" will be obtained. If necessary, the alcohol can be separated and removed from the aqueous solution.

The "CLA" aqueous suspension prepared in this example was measured by the "State Key Laboratory of Advanced Materials Composite Technology" using the Maltese Instruments Co., Ltd. ZataPalS laser particle size analyzer, and its particle size distribution range was 35. 3-173mm, Lnm。 The average particle size is 78.1 nm. Example 10 Nanospiramycin

 Spiramycin is a multi-component macrolide antibiotic, a white or light yellow crystalline powder, slightly soluble in water, and easily soluble in methanol, ethanol or acetone. It is effective against Gram-positive bacteria and some Gram-negative bacteria such as Streptococcus, Meningococcus, Pertussis, Clostridium.

 Weigh 2g of spiramycin and dissolve it in 20ml of absolute ethanol. Weigh 0.3g of sodium dodecyl sulfate and 0.2g of dodecyl alcohol, measure 0.05ml of polysorbate and add it to 300ml of purified water, and stir and sonicate to accelerate dissolution and dispersion. Under the combined action of stirring and ultrasonic vibration, 20 ml of the spiramycin ethanol solution was slowly added dropwise to the aqueous solution containing the mixed surfactant, and the spiramycin aqueous suspension was formed after the addition was completed. The average particle size of spiramycin particles determined by Wuhan University using GEM-100cxc transmission electron microscopy was less than 100nm. Tillering was used to separate and recover the ethanol in the spiramycin aqueous suspension. The present invention also prepares nano-aqueous suspensions of various synthetic drugs such as oxytetracycline, erythromycin, dexamethasone, captopril, benozyl, indomethacin, testosterone, and fembitol.

Claims

Rights request

1. Nano-sized particles of a poorly soluble drug, the particle size of the nano-sized particles is 1-100 nm.

 2. Nanoparticles of a poorly soluble drug according to claim 1, wherein the poorly soluble drug is a traditional Chinese medicine or a synthetically obtained drug.

 3. Nanoparticles of poorly soluble drugs according to claim 1, wherein the traditional Chinese medicine can be a single site or a combination of extracts, such as a resin extract of Dracaena spp., Propolis, salvia, blood exhaustion, myrrh, frankincense , The compound of hellebore and hematoxylin, the compound of propolis and blood exhaustion.

 4. Nanoparticles of a poorly soluble drug according to claim 1, examples of synthetic drugs include: vitamin A, vitamin A, D, vitamin E, "CLA", spiramycin, oxytetracycline, erythromycin, dexamethasone , Captoprin, benoxime, anti-inflammatory, testosterone, fembitol

5. A method for preparing nanoparticles of poorly soluble drugs, comprising:

 (a) selecting one or more solvents to make a drug (traditional Chinese medicine or synthetic medicine) that is hardly soluble in water into a solution or a saturated solution,

 (b) Under the condition of high-speed stirring or stirring and ultrasonic vibration, slowly add (or spray add) the solution obtained in (a) to the aqueous solution containing a surfactant, and complete the dropping and store it for a certain period of time. After that, an aqueous suspension of the drug nanoparticles is formed, and if necessary, an aqueous solvent is removed to form an aqueous suspension of the drug nanoparticles,

 (c) If necessary, a method of salting out can be used to filter out a large amount of water, and then spray drying, vacuum drying, or low temperature vacuum drying are separately selected to prepare fine powders of nano-scale insoluble drugs.

6. The method of claim 5, wherein the solvent used in (a) can be selected from the group consisting of alcohols, esters, ketones, liquid acids or bases, or other solvents, wherein the alcohols are selected from monohydric or polyhydric alcohols, Such as ethanol, propanol, butanol, ethylene glycol, propylene glycol, glycerol, etc .; esters include ethyl lactate, butyl lactate, ethyl acetate, butyl acetate, Y-butyrolactone, etc .; ketones Examples include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and methylpentanone. Examples of the acid or base include acetic acid, hydrochloric acid, and sodium hydroxide. Examples of other solvents include pyridine and tetrahydrofuran.

 7. The method of claim 5, wherein the available surfactants and co-surfactants are: anionic surfactants, such as sodium lauryl sulfate, sodium eicosylbenzenesulfonate, etc .; non-ionic Surfactants, such as octadecyl polyoxyethylene, fatty acid sorbitan polyoxyethylene, and polysorbate; amphoteric surfactants, such as amino acid amine carboxylates and quaternary ammonium salt carboxylates; Cationic surfactants, such as cetyltrimethyl bromide, etc .; co-surfactants, such as alcohols of medium carbon chain length, such as dodecanol, cetyl alcohol, and the like. A preferred surfactant is a mixed surfactant including a surfactant and a co-surfactant. The mixed surfactant may be added to (a) without being added to the water.