CN108498455B

CN108498455B - Oily water-soluble medicine nanocrystal and preparation method thereof

Info

Publication number: CN108498455B
Application number: CN201810367219.3A
Authority: CN
Inventors: 李迎; 郑爱萍; 高翔; 张慧; 喻芳邻; 高静; 杨茜
Original assignee: Institute of Pharmacology and Toxicology of AMMS
Current assignee: Institute of Pharmacology and Toxicology of AMMS
Priority date: 2018-04-23
Filing date: 2018-04-23
Publication date: 2020-12-04
Anticipated expiration: 2038-04-23
Also published as: CN108498455A

Abstract

The invention provides an oily water-soluble drug nanocrystal, belonging to the technical field of water-soluble drug preparation; the oily water-soluble medicine nanocrystal comprises the following components in percentage by weight: 1-50% of active drug, 0.1-20% of stabilizer and the balance of oily matrix; the active drug is a BCSIII drug or a BDDCSIII drug; the water-soluble medicine nanocrystal is obtained by uniformly mixing the oily matrix, the stabilizer and the active medicine to prepare the nanocrystal, and the permeability of the water-soluble medicine nanocrystal in the body is improved, so that the bioavailability is improved.

Description

Oily water-soluble medicine nanocrystal and preparation method thereof

Technical Field

The invention belongs to the technical field of water-soluble medicine preparation, and particularly relates to an oily water-soluble medicine nanocrystal and a preparation method thereof.

Background

Oral administration has the advantages of good patient compliance and safe and convenient administration, and is still the best administration mode clinically recommended at present. Thus, oral bioavailability (oral) of a drug is an important attribute of lead compound optimization in drug discovery. The degree of absorption is closely related to bioavailability after oral administration of a drug, and the degree of absorption is directly related to the solubility, permeability and intestinal metabolic stability of the drug under the pH conditions of the gastrointestinal tract.

The importance of drug solubility and permeability can also be reflected by the Biopharmaceutical Classification System (BCS). In the BCS classification system, BCSIII drugs refer to drugs that have good solubility and low permeability. Among them, compounds having good solubility and low metabolic rate can be further classified as BDDCSIII according to the Biopharmaceutical Drug Distribution Classification System (BDDCS). In recent years, studies have found that lipophilic drugs are more susceptible to problems of toxicity and drug interaction, and therefore more and more bddcsiiii candidate compounds enter the new drug discovery phase. While this shift reduces drug toxicity in vivo and increases efficacy on biological targets, it causes problems with oral delivery. Because the biological membrane is a phospholipid bilayer structure, the intestinal membrane permeability of compounds with stronger hydrophilicity generally has a certain problem, and the lower intestinal membrane permeability causes the Foral to be lower. However, studies of intestinal permeability are much more complex than solubility, the main reasons including: firstly, The commonly measured effective permeation of The jejunum (Peff) is not representative of all intestinal tracts; ② the metabolism of CYP enzymes and flora in the intestinal tract brings complexity to the determination of the penetration of the drug prototypes. Thus, there is currently much less research on improving the permeability of BCSIII class of drugs than improving the solubility of BCSIII class of drugs. Research suggests that effective permeation (Peff) of drugs through The intestinal tract is a comprehensive result of multiple parallel transmission processes such as passive diffusion, active transport of endocytosis, efflux and cell bypass. Thus, with respect to the mechanism of intestinal permeation, current approaches to addressing the permeability of bcsiiii class of drugs include mainly: firstly, a transmembrane absorption enhancer (promoting the drug to transport across cell membranes and cell bypasses) is added; improving the liposolubility of the medicine (preparing a prodrug); thirdly, the metabolism and efflux transport of the intestinal wall of the drug are inhibited (enzyme and efflux transporter inhibitor are added); fourthly, a particle drug delivery system (liposome, nano-particle, microemulsion, self-microemulsion); fifthly, the retention time of the medicine in the gastrointestinal tract (biological adhesive preparation, gastric floating tablet) is increased. Although these methods solve the problem of some BCSIII drugs, oral, for some BDDCSIII drugs with extremely high water solubility, one of the methods is simply applied, and the purposes of improving the permeability and increasing oral are difficult to achieve.

Nano-drugs gradually become a hot spot in the research and development of preparations, and many research reports on nano-carrier preparations such as micelles, liposomes, nanocapsules, nanoparticles, dendritic copolymers and the like exist. These carrier systems can carry drugs by means of entrapment, binding, electrostatic attraction and the like, but most of these carrier nano-preparations have the problems of low encapsulation efficiency, instability, leakage and carrier material toxicity. The nano-crystal drug is prepared by nano-crystallizing the drug per se, so that the nano-crystal drug has the advantages that: the preparation has no limitation of encapsulation rate, only contains a small amount of stabilizing agent and emulsifying agent, and the main drug can reach more than 90 percent, so that the drug with the therapeutic dose of more than 500mg can also be prepared into the nanocrystalline; secondly, the formulation is diversified: the nanocrystalline can be further prepared into tablets, capsules or injection and other dosage forms through drying; the nanometer particle size is controllable; the preparation method is simple and easy to convert into clinical application: the high pressure or media milling method is hardly affected by the properties of the drug itself. Currently 8 varieties of FDA in the united states are approved for marketing. However, in the existing nanocrystalline in the prior art, water is used as a dispersion medium, which is mainly used for improving the solubility of insoluble drugs, and the nanocrystalline technology for solving the permeability of water-soluble drugs has not been reported in documents.

Disclosure of Invention

In view of the above, the present invention is directed to provide an oily water-soluble drug nanocrystal for improving the permeability of a water-soluble drug and further improving the bioavailability thereof, and a preparation method thereof.

In order to achieve the above object, the present invention provides the following technical solutions: an oily water-soluble medicine nanocrystal comprises the following components in percentage by weight: 1-50% of active drug, 1-10% of stabilizer and the balance of oily matrix; the active drug is a BCSIII drug or a BDDCSIII drug; the active drug is present in the form of nanocrystals.

Preferably, the oily matrix is one or more of medium chain triglyceride, polyglycerol oleate, capric acid, caprylic acid, oleic acid, linoleic acid and vegetable fatty oil.

Preferably, the vegetable fatty oil comprises one or more of cottonseed oil, corn oil, tea oil and castor oil.

Preferably, the stabilizer is one or more of polyglycerol oleate, propylene glycol monocaprylate, tricaprylin, glycerol monolinoleate, sorbitan fatty acid, polysorbate, sorbitan fatty acid ester, polyoxyethylene fatty acid ester/ether, polyoxyethylene polyoxypropylene copolymer, casein, phospholipid, cholesterol, glycerol monostearate, cetyl alcohol, stearic acid, oleic acid, sodium oleate, cholic acid, deoxycholic acid and deoxycholic acid sodium salt.

Preferably, the average particle size of the oily water-soluble drug nanocrystal is 100-1000 nm.

The invention provides a preparation method of oily water-soluble medicine nanocrystalline, which comprises the following steps:

1) uniformly mixing a stabilizer and an oily matrix to obtain an oil phase liquid;

2) and injecting the active drug aqueous solution into the oil phase liquid under the stirring condition of 500-1500 rpm.

3) Stirring and mixing for 0.5-12 h to obtain the oily water-soluble medicine nanocrystal.

Preferably, the step 2) is followed by further ultrasonic treatment of the oily water-soluble drug nanocrystals.

Preferably, the power of ultrasonic treatment is 20-300W, and the time of ultrasonic treatment is 1-60 min.

The invention provides another preparation method of the oily water-soluble medicine nanocrystal, which comprises the following steps:

mixing an active drug, a stabilizer and an oily matrix, and then shearing at a high speed to obtain a pre-dispersion solution, wherein the high-speed shearing speed is 18000-30000 rpm;

homogenizing the pre-dispersion solution under high pressure to obtain oily water-soluble medicine nanocrystals; the pressure of the high-pressure homogenizing is 200-1200 bar.

and replacing the high-pressure homogenization with wet grinding, adding zirconia beads with the diameter of 0.1-0.5 mm into a wet grinder for wet grinding to obtain the oily water-soluble drug nanocrystals, wherein the grinding speed is 1500-5000 rpm.

The invention has the beneficial effects that: the oily water-soluble medicine nanocrystal is obtained by uniformly mixing an oily matrix, a stabilizer and an active medicine to prepare the nanocrystal, wherein the water-soluble active medicine is suspended in the oily matrix in a nanocrystal form; after the nano-crystal of the oily water-soluble medicine is administrated, part of the medicine can directly enter blood circulation through intestinal wall cells, and part of the medicine forms chylomicron particles under the action of gastrointestinal digestive juice and bile, so that the penetration and absorption of the medicine are facilitated, and the bioavailability is improved. The rat lymph detection result of the embodiment of the invention shows that peramivir is not detected in the peramivir water solution lymph, while the accumulated transport amount of the oily peramivir nanocrystal lymph is 1.0 +/-0.4 mug, which proves that the drug can be transported through lymph and the drug effect is further increased.

According to the oily water-soluble medicine nanocrystal provided by the invention, as the active medicine is suspended in the oily matrix in the form of nanocrystal, the density of the oily matrix is low, the oily matrix can be further concentrated easily in a centrifugal mode and other modes, the oily water-soluble medicine nanocrystal with high concentration and stability can be effectively prepared, and the concentrated water-soluble medicine nanocrystal can be prepared into oral liquid or filled into capsules.

After the water-soluble medicine nanocrystalline is administrated, part of the water-soluble medicine nanocrystalline can directly enter blood circulation through intestinal wall cells, and part of the water-soluble medicine nanocrystalline forms chylomicron particles under the action of gastrointestinal digestive juice and bile, so that the absorption of the medicine is facilitated. Therefore, the bioavailability of the water-soluble medicine nano-crystal is greatly improved.

The embodiment of the invention partially describes oily nanocrystals prepared from peramivir (BCSIII drugs) and hydroxysafflor yellow A (BDDCSIII drugs). The peramivir oily nanocrystal is a short needle-shaped nanocrystal with the average particle size of 300nm, and is stable after being placed at room temperature for 1 month for a long time. The results of in vivo drug-induced research show that the bioavailability of the peramivir oily nanocrystal can be improved to 30% (the bioavailability of the original aqueous solution is 5%). Lymph intubation experiments show that the peramivir aqueous solution of the control group cannot be detected in lymph liquid, and the peramivir oily nanocrystal has higher absorption in lymph, and the cumulative absorption for 24 hours reaches 1.02 +/-0.4 mu g. The hydroxysafflor yellow A oily nanocrystal is a blocky crystal, the particle size is about 220nm, the bioavailability is improved by 10.8 times compared with that of a contrast group hydroxysafflor yellow A aqueous solution, and the Cmax is improved by 18.1 times.

Drawings

FIG. 1 is a transmission electron microscope image of peramivir oily nanocrystals;

fig. 2 is a graph of drug-time curves (n ═ 6) for rats given intravenously, orally, and 30mg/kg of peramivir oily nanocrystals;

fig. 3 is a lymph transport volume curve after oral administration of an aqueous peramivir solution and 30mg/kg of an oily nanocrystal (n-3);

fig. 4 is a graph of drug-time (n ═ 3) for rats orally administered varying amounts of peramivir oily nanocrystals in oily matrix 30 mg/kg;

FIG. 5 is a transmission electron microscope image of hydroxysafflor yellow A oily nanocrystal;

fig. 6 is a graph showing drug-time curves of rats orally administered with an aqueous solution of hydroxysafflor yellow a and 1mg/kg of hydroxysafflor yellow a oily nanocrystal (n ═ 6).

Detailed Description

The invention provides an oily water-soluble medicine nanocrystal which comprises the following components in percentage by weight: 1-50% of active drug, 1-10% of stabilizer and the balance of oily matrix; the active drug is a BCSIII drug or a BDDCSIII drug; the active drug is suspended in the oily matrix in the form of nanocrystals.

In the invention, the mass percentage of the active drug in the oily water-soluble drug nanocrystal is 1-50%, preferably 10-45%. The water-soluble active drug is a BCSIII drug with good solubility and low permeability or a BDDCSIII drug with good solubility and low metabolic rate in a BCS classification system; although the active drug in the invention has good solubility, the active drug nanocrystals of the class usually use water as a dispersion medium, and have low permeability and low bioavailability, such as peramivir and hydroxysafflor yellow A.

In the invention, the mass percentage of the stabilizer in the oily water-soluble medicine nanocrystal is 0.1-10%, preferably 0.1-8%. In the present invention, the stabilizer may be a conventional pharmaceutical stabilizer in the art, and is preferably an emulsifier or a surfactant. The stabilizer in the invention is specifically one or more of polyglycerol oleate, propylene glycol monocaprylate, tricaprylin, glycerol monolinoleate, sorbitan fatty acid, polysorbate, sorbitan fatty acid ester, polyoxyethylene fatty acid ester/ether, polyoxyethylene polyoxypropylene copolymer, casein, phospholipid, cholesterol, glycerol monostearate, cetyl alcohol, stearic acid, oleic acid, sodium oleate, cholic acid, deoxycholic acid and deoxycholic acid sodium salt. In the present invention, the stabilizer functions as a suspending agent, preventing aggregation. Span 80 used in the examples is a stabilizer.

The oily water-soluble medicine nanocrystal provided by the invention comprises the balance of an oily substrate, wherein the oily substrate is a non-toxic oily substance which is conventional in the field, and is preferably one or more of medium chain triglyceride (WL1349), polyglycerol oleate, capric acid, caprylic acid, oleic acid, linoleic acid and vegetable fatty oil. In the present invention, the vegetable fatty oil preferably includes one or more of cottonseed oil, corn oil, tea oil and castor oil. In the invention, the active drug exists in the oily matrix in the form of nanoparticles, and the oily matrix as a matrix does not influence the absorption of the drug, but can promote the permeation of the drug and improve the bioavailability by 5-20 times. Meanwhile, as the active drug is suspended in the oily matrix in the form of nanocrystal, the oily matrix has low density, is easy to be further concentrated by centrifugation and the like, the dosage of the auxiliary materials can be greatly reduced, and the delivery of large-dose drug is facilitated.

The invention provides a preparation method of oily water-soluble medicine nanocrystalline, which comprises the following steps: 1) uniformly mixing a stabilizer and an oily matrix to obtain an oil phase liquid; 2) and under the stirring condition of 500-1500 rpm, injecting the active drug aqueous solution into the oil phase liquid, and stirring and mixing for 0.5-12 h to obtain the oily water-soluble drug nanocrystal. In the invention, the stabilizer is uniformly mixed with the oily matrix to obtain the oil phase liquid. In the invention, the stabilizer and the oily matrix are preferably uniformly mixed by adopting a stirring mode. In the invention, the rotating speed of the stirring is preferably 500-1500 rpm, more preferably 1000-1200 rpm; the stirring time is preferably 1-60 min, and more preferably 10-50 min; the stirring temperature is not particularly limited, and the stirring temperature can be normal room temperature, and is 23-28 ℃ in the specific implementation process of the invention. In the present invention, the stirring tool used for the stirring is a stirring tool conventional in the art, and preferably a magnetic stirrer or a mechanical stirrer.

After the oil phase liquid is obtained, the active drug aqueous solution is injected into the oil phase liquid under the stirring condition of 500-1500 rpm. In the invention, the active drug water solution is preferably a saturated solution obtained by dissolving an active drug in water at 30-100 ℃; the preferable dissolving temperature is 37-99 ℃. The temperature of the aqueous solution of the active drug after dissolution is not limited, and the temperature during dissolution does not need to be maintained.

After the active drug aqueous solution is obtained, injecting the active drug aqueous solution into oil phase liquid under the condition of stirring to obtain emulsion; the rotation speed of the stirring is preferably 800-1300 rpm, more preferably 900-1100 rpm.

In the present invention, it is preferable to perform ultrasonic treatment after obtaining the emulsion. In the invention, the power of ultrasonic treatment is preferably 20-300W, and more preferably 50-250W; the time of ultrasonic treatment is preferably 1-60 min, and more preferably 10-50 min.

The emulsion is stirred after being subjected to ultrasonic treatment, and the stirring time is preferably 0.5-12 h, and more preferably 4-10 h. In the stirring process, water in the active medicine aqueous solution is separated out along with stirring to obtain the oily water-soluble medicine nanocrystal.

In the invention, the preparation method of the oily water-soluble drug nanocrystal can also adopt a second scheme, and specifically comprises the following steps: 1A) mixing an active drug, a stabilizer and an oily matrix, and shearing at a high speed to obtain a pre-dispersion solution, wherein the high-speed shearing rate is 18000-30000 rpm; 2A) and (3) homogenizing the pre-dispersion solution at high pressure to obtain the oily water-soluble medicine nanocrystal, wherein the pressure of the high-pressure homogenization is 200-1200 bar, and the preferable pressure is 500-1200 bar.

In the invention, the active drug, the stabilizing agent and the oily matrix are mixed and sheared at high speed to obtain a pre-dispersion solution. The volume ratio of the total mass of the oily matrix and the stabilizing agent to the active medicine aqueous solution is preferably (5-20): 1, more preferably (10-15): 1. In the invention, the high-speed shearing rotating speed is preferably 18000-30000 rpm, more preferably 19000-25000 rpm; the high-speed shearing time is preferably 1-10 min, and more preferably 4-8 min. In the invention, the high-speed shearing is preferably carried out by adopting a high-speed shearing machine; the high-speed shearing action of the invention is to fully disperse the active drug in the oily matrix to obtain the micron-sized pre-dispersion liquid.

After the pre-dispersion solution is obtained, the pre-dispersion solution is homogenized under high pressure to obtain the oily water-soluble medicine nanocrystal. In the invention, the high-pressure homogenization is preferably carried out by using a high-pressure homogenizer; the procedure of the high-pressure homogenization is preferably as follows: circulating for 2-10 times under the pressure of 200, 400, 600, 800, 1000 and 1100bar in sequence, and then circulating for 2-50 times under the pressure of 1200 bar; the time and the cycle number of the high-pressure homogenization are determined according to the granularity of the pre-dispersion liquid in the high-pressure homogenization process, and the process is finished when the average granularity of the pre-dispersion liquid is 100-1000 nm. After the high-pressure homogenization is finished, the oily water-soluble medicine nano-crystal is obtained.

In the present invention, the high pressure homogenization may be replaced with wet milling. In the present invention, the wet milling is preferably performed using a wet mill filled with zirconia beads; the diameter of the zirconia beads is preferably 0.1mm to 0.5mm, and the volume of the zirconia beads is preferably 20 mL to 100 mL. The wet grinding is specifically grinding at 1 to 3 rotation speeds optionally from 1500 to 5000rpm, and each rotation speed is used for grinding for 1 to 3 hours; in the practice of the invention, the rotation speed is preferably 3000, 4000, 5000 rpm. According to the invention, the oily water-soluble medicine nanocrystalline is obtained after the wet grinding is finished.

After the oily water-soluble drug nanocrystal is obtained, the method preferably further comprises the following steps: centrifuging the oily water-soluble nano crystals, collecting oily water-soluble medicine nano crystals with the volume of 5-80% of the total volume from the lower layer, and performing secondary ultrasonic suspension to prepare medicines with different dosage forms; the dosage form of the invention is preferably a soft capsule preparation or an oral liquid preparation. In the invention, the rotation speed of the centrifugation is preferably 500-5000 rpm; more preferably 1000-3000 rpm, and the centrifugation time is preferably 1-60 min, more preferably 5-40 min. In the present invention, it is preferable that 10 to 70%, more preferably 20 to 60% of the total volume is collected from the lower layer after the centrifugation. In the invention, the secondary ultrasonic treatment power is preferably 20-300W, and more preferably 50-250W; the time of the secondary ultrasonic treatment is preferably 1-60 min, and more preferably 5-40 min.

The soft capsule preparation or the oral liquid preparation in the invention can be prepared by adopting the conventional preparation method in the field.

The following examples are provided to illustrate the oily water-soluble drug nanocrystals and the preparation method thereof in detail, but they should not be construed as limiting the scope of the present invention.

First, two model drugs used in the examples of the present invention are explained as follows:

two model drugs, peramivir and hydroxysafflor yellow a, both of which are typical BCSIII and BDDCSIII drugs, represent two broad classes of drugs, respectively: zwitterionic antiviral drugs and traditional Chinese medicine flavonoid drugs. Wherein, the peramivir is a first-line medicament for clinically treating the severe influenza virus. However, only the peramivir sodium chloride injection (national standard character H20130029) is on the market due to the Foral limitation, and the clinical application of the peramivir sodium chloride injection is greatly limited.

The hydroxysafflor yellow A is the main monomer in the water-soluble components of safflower, and belongs to chalcone glycoside compounds. It has the clinical effects of removing blood stasis, relieving pain, reducing cholesterol, lowering blood pressure, etc. Recent research shows that hydroxysafflor yellow A also has the effects of protecting heart, preventing cerebral anoxia, resisting cerebral thrombosis and resisting cancer. However, the existing domestic hydroxysafflor yellow A only comprises an injection (freeze-dried powder injection), and the key reason is that the hydroxysafflor yellow AForal is less than 1.7 percent; the root of the deep research mainly lies in the extremely strong water solubility and the P-gp efflux function, which is the common problem of low Foral of flavonoid traditional Chinese medicines. Therefore, the project selects two typical high-solubility hypotonic drugs, and has stronger representative significance.

Example 1

The physical and chemical properties and pharmacokinetic characteristics of peramivir are deeply researched by adopting the peramivir as a research object: the dissociation degree and lipophilicity of peramivir are measured by a shake flask method and a potentiometric titration method, and the result shows that the basic pKa is 12.5 and the acidic pKa is 4.2. The drug is typical Zwitterions (Zwitterions), which are ionic under physiological pH conditions; the peramivir logP is-1.4, the lipophilicity is poor, and the solubility in water is high; ② the apparent permeability coefficient (P) of the medicine in a Caco-2 cell permeability model_app) The average is 3.29 +/-0.73 multiplied by 10^-7cm/s, which is a low permeability drug; the efflux ratio (Re) was 0.23 on average, indicating no effect of efflux; two active transporters, namely organic cation transporters (OATs) and organic anion transport peptide (OATP1B), participate in the active absorption process of the drug; ③ after the rat is gavaged with 30mg/kg, the oral is 4.4 percent. Tissue distribution research of mice shows that the content of the kidney is highest and no tissue accumulation phenomenon exists; fifthly, after the rat is statically injected with peramivir, the urine excretion amount is 81.08 percent of the dosage for 72 hours, after the human is subjected to single-dose intravenous drip of 300mg, the urine excretion amount is 82.25 percent of the dosage for 24 hours, and the condition that the medicine is mainly excreted from urine in an original form is fully explained. Combining the above results, it is shown that the drug is typical of BDDCSIII, and the mechanism of Foral's low is: firstly, the ionic state is adopted under the condition of physiological pH, the fat solubility is poor, and the passive diffusion is poor; secondly, active transporters participate in the permeation process, but the permeation amount is very small; ③ the medicine has good stability, and most of the medicine is rapidly eliminated through the kidney in the original form.

1. Research on peramivir oil matrix nanocrystal

1.1 preparation of Peramivir oil matrix nanocrystals

Precisely weighing about 24mg peramivir, and adding 0.3mL of purified water for dissolving (the solubility can be increased by appropriate heating); WL13493.95g and span 80 (sorbitan fatty acid ester) 50 mu L are precisely weighed, and are magnetically stirred for 5min at 1000rpm to be uniformly mixed to obtain an oil phase. The aqueous drug solution was injected into the oil at a rate of 15mL/min at 1500rpm to form a W/O emulsion. Performing ultrasonic treatment at 60W for 10min, and magnetically stirring (500rpm) for 12h until the nanocrystals are fully solidified. 6mg/mL peramivir oil matrix nanocrystal is obtained.

1.2 particle size of Peramivir oil-based nanocrystal

Taking a certain amount of oil matrix nano-crystal, and adding n-hexane for diluting by 5-10 times. Particle size was determined using a darwinian laser particle sizer MS 2000. The results showed that the average particle size of the nanocrystals was 291.3nm and the PDI was 0.174.

1.3 micro-morphology of Peramivir oil matrix nanocrystals

And repeatedly washing the oil matrix nanocrystals with n-hexane for 6 times, ultrasonically resuspending the n-hexane, and observing the oil matrix nanocrystals by a transmission electron microscope. The result shows that the peramivir is in needle-shaped crystal in oil, and the long diameter is about 200 nm. The results are shown in FIG. 1, with the scale in FIG. 1 being 200 nm.

1.4 in vivo pharmacokinetic study of Peramivir oil-based nanocrystals in rats

The time course of administration of the drug in plasma of male SD rats weighing 200 + -20 g after intravenous administration of an aqueous solution of peramivir, oral administration of an aqueous solution of peramivir, and oral administration of 30mg/kg of peramivir oily nanocrystal are shown in FIG. 2. The pharmacokinetic parameters are shown in table 1.

TABLE 1 rats administered aqueous peramivir solution intravenously, aqueous peramivir solution orally, and peramivir oily nanocrystal orally at 30mg/kg

According to the results, the AUC and Cmax of the rat orally administered aqueous solution and the oily nano crystal are obviously different, the oral administration of the aqueous solution is 4.2 +/-1.4 percent, and the oral administration of the oily nano crystal is 27.5 +/-4.5 percent, which is improved by 6.5 times. Meanwhile, compared with the aqueous solution, the oily nanocrystalline phase has obviously reduced CL and V.

1.5 study on lymph transport amount of Palamivir oil matrix nanocrystal,

Male SD rats, body weight 200 + -20 g, enteroclysm lymphangiocannulation. The lymph transport volume after oral administration of peramivir aqueous solution and oily nanocrystal of 30mg/kg, respectively, is shown in fig. 3. As can be seen from the experimental results, peramivir was not detected in the aqueous peramivir solution lymph, but the cumulative transport amount of the oily nanocrystalline lymph was 1.0 + -0.4. mu.g.

1.6 Effect of oil base dosage on peramivir Foral

Male SD rats, weighing 200 + -20 g, were orally administered with 30mg/kg of aqueous and oily nano-crystalline peramivir solution, respectively. Wherein the dosage of the oily nanocrystalline oil matrix is 1, 3, 5 and 10mL/kg respectively. The time course of the drug in the plasma after the administration is shown in FIG. 4, and the middle graph in FIG. 4 is a partially enlarged view of the main graph.

From the results, rats orally administered peramivir oil-based nanocrystals with different oil-based qualities were 19.6 ± 1.5% for Foral (1mL), 23.1 ± 5.6% for Foral (3mL), 27.5 ± 4.5% for Foral (5mL) and 26.2 ± 1.5% for Foral (10 mL). Except 1mL, the Foral has no obvious difference, and the Foral of each group is obviously improved by 4.7-6.5 times compared with an oral solution.

Example 2

Research on 2-hydroxy safflower yellow A oil-based nanocrystal

2.1 preparation of hydroxysafflor yellow A oil-based nanocrystals

About 10g of hydroxysafflor yellow A was weighed, and 90g of soybean oil, WL134910g and span 801g were added, and the mixture was sheared at 24000rpm in Ultra-TurraxT-25 (high speed disperser) for 10min to uniformly suspend the drug in the oil solution. Pouring the liquid medicine into a grinding cavity (containing 0.3mm of zirconia beads) of a wet grinder (a Wal-Miller nanometer grinder (DYNO-MILLNPM)), and grinding at 3000rpm for 1h respectively to obtain a nanocrystalline suspension with the average particle size of 200-300 nm.

2.2 particle size of hydroxysafflor yellow A oil-based nanocrystals

Taking a certain amount of oil matrix nano-crystal, and adding n-hexane for diluting by 5-10 times. Particle size was determined using a darwinian laser particle sizer MS 2000. The results showed that the average particle size of the nanocrystals was 318.5nm and PDI was 0.133.

2.3 micro-morphology of hydroxysafflor yellow A oil-based nanocrystals

The oil-based nanocrystals were washed repeatedly with n-hexane for 6 times, dried under reduced pressure, and observed by transmission electron microscopy. The results showed that the hydroxysafflor yellow A nanocrystals were bulk crystals with a particle size of about 200-300nm, as shown in FIG. 5, with a scale of 500 nm.

2.4 in vivo pharmacokinetic study of Hydroxysafflower yellow A oil-based nanocrystals in rats

Male SD rats, with a body weight of 200 + -20 g, were orally administered with 1mg/kg of hydroxysafflor yellow A aqueous solution and oily nanocrystal, respectively. The time-course of the drug in plasma after administration is shown in figure 6 below, and the pharmacokinetic parameters are shown in table 2.

Table 2 oral administration of hydroxysafflor yellow a in water and oily nanocrystals at 1mg/kg in rats with major kinetic parameters (n ═ 6)

According to the results, the AUC and Cmax of the rat orally administered aqueous solution and the oily nano-crystal are obviously different, and compared with the aqueous solution, the oily nano-crystal Foral is improved by 10.8 times, and the Cmax is improved by 18.1 times. Meanwhile, compared with the aqueous solution, the oily nanocrystalline phase has obviously reduced CL and V.

The above embodiments show that the oily water-soluble drug nanocrystal provided by the invention solves the problem of low bioavailability of the two drugs peramivir and hydroxysafflor yellow A by improving the drug permeability, not only promotes the development of the oral administration preparation of the two drugs and the clinical application, but also provides a thought for the development of the oral administration preparation of the two drugs.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims

1. The oily water-soluble medicine nanocrystal is characterized by comprising the following components in percentage by weight: 10-45% of active drug, 0.1-8% of stabilizer and the balance of oily matrix; the active drug is peramivir; the active drug exists in the form of nanocrystal; the stabilizer is sorbitan fatty acid ester; the oily base is a medium chain triglyceride.

2. The oily water-soluble drug nanocrystal according to claim 1, wherein the average particle size of the oily water-soluble drug nanocrystal is 100-1000 nm.

3. The method for preparing the oily water-soluble drug nanocrystal, according to claim 1 or 2, comprising the steps of:

1) mixing a stabilizer with an oily matrix to obtain an oil phase liquid;

2) injecting an active drug aqueous solution into the oil phase liquid under the stirring condition of 500-1500 rpm;

3) stirring for 0.5-12 h to obtain the oily water-soluble medicine nanocrystal.

4. The preparation method according to claim 3, wherein the step 2) is further followed by ultrasonic treatment of the oil-based water-soluble drug nanocrystal.

5. The preparation method according to claim 4, wherein the power of the ultrasonic treatment is 20-300W, and the time of the ultrasonic treatment is 1-60 min.

6. A method for preparing the oily water-soluble drug nanocrystal of claim 1 or 2, comprising the steps of:

and (3) carrying out high-pressure homogenization on the pre-dispersion solution to obtain oily water-soluble medicine nanocrystals, wherein the pressure of the high-pressure homogenization is 200-1200 bar.

7. The preparation method of the oily water-soluble medicine nanocrystal, which comprises the following steps: and replacing the high-pressure homogenization with wet grinding, adding zirconia beads with the diameter of 0.1-0.5 mm into a wet grinder, and carrying out wet grinding to obtain the oily water-soluble drug nanocrystals, wherein the grinding speed of the wet grinding is 1500-5000 rpm.