WO2014108076A1

WO2014108076A1 - Gel composition of insoluble drug and preparation method therefor

Info

Publication number: WO2014108076A1
Application number: PCT/CN2014/070369
Authority: WO
Inventors: 张强; 代文兵; 林志强; 王学清
Original assignee: 北京大学
Priority date: 2013-01-10
Filing date: 2014-01-09
Publication date: 2014-07-17
Also published as: CN103054794A; CN103054794B

Abstract

A gel composition of insoluble drug comprises drug nanocrystal of insoluble drug, stabilizer, thermo-sensitive material and solvent. The gel composition of insoluble drug could increase the drug loading of the insoluble drug, avoid the deposition of the drug during long term storage, improve the needle passability of injection, and improve the uniformity of the drug and the release.

Description

Insoluble drug gel composition and preparation method thereof

Technical field

The present application relates to a poorly soluble pharmaceutical gel composition and a process for the preparation thereof, which belong to the field of pharmaceutical preparations.

Background technique

In the field of pharmacy, nanocrystal refers to drug solid particles with nanometer scale, also known as nanocrystals or nanocrystals. If the drug nanocrystals are dispersed in a suitable liquid medium, a nanosuspension can be formed. Generally, the nanometer-sized drug particles can be dispersed in water by the stabilization of the surfactant or the polymer material, thereby forming a relatively stable colloidal dispersion system. In recent years, a series of oral nano-drugs have been developed at home and abroad for the problem of low oral bioavailability of poorly soluble drugs. These poorly soluble drugs have been prepared into nanocrystalline drugs through special techniques. Studies have shown that this can significantly improve the poor solubility. Oral absorption of the drug, while the preparation of the nanocrystal can avoid the use of a large number of additional components, thereby reducing the toxic side effects on the patient. In addition to oral administration, if nanocrystals are used for injection or topical administration (such as the eyes, nasal cavity, etc.), it can solve the problem that poorly soluble drugs cannot be made into liquid preparations due to poor solubility, and it is possible to produce local sustained release. The effect, thereby prolonging the duration of action of the drug.

For nanocrystals, the saturation solubility is affected by the particle size, the solubility of small particles is large, and the solubility of large particles is small. As a result, small particles gradually dissolve and large particles gradually become larger. This phenomenon is called austenitic ripening. (Ostwald ripening ). In addition to crystal growth, drug nanocrystals may also have problems such as sedimentation and agglomeration during their preparation, storage, and transportation. Therefore, how to improve the stability of drug nanocrystals is also a difficult problem to be solved by pharmacy.

Temperature-sensitive gels are a class of gel systems prepared from temperature-sensitive, intelligent polymers that undergo a phase transition with temperature to form a non-chemically crosslinked gel. Generally, under storage conditions, the liquid state is exhibited because the ambient temperature is lower than the lowest critical phase transition temperature (LCST) of the gel, and the semi-solid gel state is exhibited when the temperature of the drug site is higher than the LCST. When the injection enters the human body, a phase transition can be rapidly formed at the injection site to form a semi-solid gel, thereby prolonging the residence time of the drug at the site of administration after local administration, and achieving a good sustained release effect. Therefore temperature Sensitive gels are attractive as topical formulations, including topical administration to tumors (such as intratumoral or peritumoral injections) and ocular administration. For the medicinal temperature-sensitive gel materials that have been marketed, the sustained release effect after local injection (such as intramuscular injection) is within 10 days, and the current polymer microsphere technology can achieve a sustained release effect of more than one month. However, gelling agents have more advantages than polymer microsphere preparations in terms of preparation, quality control and cost. Therefore, it would be of great practical significance to prepare a temperature-sensitive gelling agent with a sustained release of more than one month.

Since the gel is mostly hydrophilic, for the poorly soluble drug, when the temperature sensitive gel is prepared, the drug loading amount is insufficient, or some drugs are present in the gel in a suspended form, the drug dispersion is uneven, and the release rate is high. It is not easy to control, thus affecting the exertion of the drug effect. Although surfactants can be added to increase the drug loading, but the amount of the drug is large, a large number of surfactants bring new problems such as toxic side effects, and surfactants cannot solve or even aggravate the existing medicinal temperature-sensitive coagulation. The problem of releasing the drug faster.

Chinese Patent Publication No. CN102579323 discloses a paclitaxel plastid gel which is formed by uniformly mixing an alcoholic substance of paclitaxel and a hydrophilic gel, and is mainly used for transdermal administration of a drug, preferably It promotes the percutaneous absorption of the drug and can reduce the irritating effect of the preparation on the skin. The patent publication CN101336891 discloses an anticancer sustained release gel injection and a preparation method thereof, which are prepared by mixing a solution of an anticancer drug or an anticancer drug directly with an aqueous solution of an amphiphilic copolymer. Patent Publication No. CN101342142 discloses a gel injection for a taxane anticancer drug and a preparation method thereof, which are characterized in that a taxane anticancer drug is firstly solubilized with a surfactant and then reacted with a temperature sensitive copolymer. Prepared by mixing.

For poorly soluble drugs, problems such as incomplete drug release or toxicity of surfactants still exist in the prior art. In the prior art, the release of the drug in the animal body is relatively fast, and the sustained release drug lasts for about one week.

In summary, there is currently no stable local drug delivery system for poorly soluble drugs prepared from medicinal temperature sensitive materials and sustained release drugs for more than one month. Summary of the invention

The purpose of the present application is to provide a poorly soluble pharmaceutical gel composition to overcome the technical problems of poor physical stability of the drug nanocrystal, low drug loading of the general temperature sensitive gel, and short drug release time. The purpose of long-term treatment after administration.

Specifically, the present application provides a poorly soluble pharmaceutical gel composition comprising: a drug nanocrystal of a poorly soluble drug, a stabilizer, a temperature sensitive material, and a vehicle.

In some embodiments, the poorly soluble drug may be selected from the group consisting of paclitaxel, docetaxel, camptothecin, 9-hydroxycamptothecin, 10-hydroxycamptothecin, itraconazole, teniposide, backing Botulin, cyclosporine A, doxorubicin, capecitabine, oxaliplatin, irinotecan, gemcitabine, temozolomide, imatinib, vinorelbine, letrozole, vinblastine, vincristine, Vindesine, Vinpocetine, Deinhibitor, Silybin, Artemisinin, Dihydroartemisinin, Sirolimus, Nitrendipine, Nicardipine, Nimodipine, Breviscapine , ferulic acid, acetaminophen, vitamin A, tamoxifen, valproic acid, tacrolimus, fenofibrate, amphotericin B, ketoconazole, domperidone, sulpiride, azithromycin , miconazole, brimonidine, latanoprost, erythromycin, roxithromycin, rifamin, diclofenac, felodipine, ibuprofen, indomethacin, nifedipine, terfena Ding, theophylline, ketoprofen, furosemide, spironolactone, dipyrimidine One or more of Mo, piroxicam, guanlorol, dexamethasone, fluorometholone, phenbutanol, cortisone acetate, hydrocortisone acetate, budesonide, and fluticapine propionate Kind. Preferably, the poorly soluble drug may be selected from one or both of paclitaxel and docetaxel.

In some embodiments, the stabilizer may be selected from the group consisting of Tween-80, sodium lauryl carbonate (SDS), polyoxyethylene hydrogenated castor oil, omega ester, polyethylene glycol, poloxamer, hydroxypropyl hydrazine Cellulose (HPMC), povidone, polyethylene glycol vitamin E succinic acid (TPGS), cholic acid, sodium cholate, sulfhydryl cellulose (MC), hydroxypropyl cellulose (HPC) or polyvinyl alcohol (PVA) One or more of them. Preferably, the stabilizer may be selected from one or more of poloxamer, polyethylene glycol vitamin E succinic acid or sodium lauryl sulfate.

In some embodiments, the temperature sensitive material may be selected from the group consisting of poloxamer, polylactic acid-polyethylene glycol-polylactic acid, polyglycolide lactide-polyethylene glycol-polyglycolide lactide. , polyethylene glycol-polylactic acid-polyethylene glycol, polyethylene glycol-polyglycolide lactide-polyethylene glycol, polycaprolactone-polyethylene glycol-polycaprolactone or chitosan One or more of them. Preferably, the temperature sensitive material may be a poloxamer.

In some embodiments, the vehicle may be selected from one or more of water, physiological saline, 5% dextrose solution, glycerol, polyethylene glycol, propylene glycol, ethanol. Preferably, the solvent may be water, and preferably, the solvent may be purified water, and more preferably, the solvent may be a note. Shoot water.

In some embodiments, the poloxamer may be one or both of poloxamer 407 (trade name: Pluronic F127) and poloxamer 188 (trade name: Pluronic F68).

Polymers such as polyethylene glycol, polylactic acid, polyglycolide lactide, polycaprolactone and the like as stabilizers or temperature sensitive materials in the present application may include different molecular weights. As will be appreciated by those skilled in the art, the molecular weight of the polymers will not significantly alter their role in the present invention, with most of the polymers used in this application being commercially available.

In some embodiments, in the poorly soluble pharmaceutical gel composition, the weight ratio of the stabilizer to the poorly soluble drug may be from 1:20 to 50:1, preferably from 1:5 to 5:1.

In some embodiments, the sum of the weight of the stabilizer and the poorly soluble drug may range from 0.001% to 20%, preferably from 0.05% to 5%, based on the total weight of the entire poorly soluble pharmaceutical gel composition.

In still other embodiments, the sum of the weight of the stabilizer and the poorly soluble drug may be from 0.008% to 10%, preferably from 0.04% to 3% of the total weight of the entire poorly soluble pharmaceutical gel composition. %.

In some embodiments, in the poorly soluble pharmaceutical gel composition, the weight ratio of the temperature sensitive material to the solvent may be 1:10 to 1.5:1, preferably 1:5-3. : 5.

In some embodiments, the particle size of the drug nanocrystal of the poorly soluble drug may range from 20 to 600 nm, preferably from 100 to 300 nm. It should be noted that the particle size described herein is the average particle size measured by a commercially available laser particle size analyzer, rather than the long or short diameter of the drug nanocrystals observed under electron microscopy.

In a further aspect, the present application also provides a method of preparing the above poorly soluble pharmaceutical gel composition, the method comprising the steps of:

a. adding the poorly soluble drug and the stabilizer to the organic solvent, after completely dissolving, preferably completely solubilizing by sonication, removing the organic solvent, preferably removing the organic solvent by nitrogen blowing or rotary evaporation under reduced pressure, and then using the solvent Hydrating, vortexing, followed by stirring or sonication, preferably by water bath ultrasonic method, probe ultrasonic method, high pressure homogenization method, high speed tissue dispersion method or high speed stirring method to obtain a suspension of drug nanocrystals A; b. adding the temperature sensitive material to A, stirring under a water bath, and obtaining the poorly soluble pharmaceutical gel composition after the temperature sensitive material is completely dissolved;

Or

The method can include the following steps:

a. adding the poorly soluble drug and the stabilizer to the organic solvent, after completely dissolving, preferably completely solubilizing by sonication, removing the organic solvent, preferably removing the organic solvent by nitrogen blowing or rotary evaporation under reduced pressure, and then using the solvent Hydration, vortex, followed by stirring or sonication, preferably by water bath ultrasonic method, probe ultrasonic method, high pressure homogenization method, high speed tissue dispersion method or high speed stirring method to obtain a suspension of drug nanocrystals A;

b. The temperature sensitive material is added to the solvent, stirred under a water bath, and after the temperature sensitive material is completely dissolved, a blank gel B is obtained;

c A and B were uniformly mixed under a water bath to obtain the poorly soluble pharmaceutical gel composition. In some embodiments, the organic solvent may be selected from one or more of the group consisting of dichloromethane, chloroform, anhydrous ethanol, decyl alcohol, acetonitrile, propylene glycol, ethyl acetate, and petroleum ether.

Those skilled in the art will appreciate that although in the present application, a poorly soluble drug is prepared as a suspension of a drug nanocrystal by the above method, the preparation of the drug nanocrystal (or a suspension thereof) can also be accomplished by the skill or person. Preparation of drug nanocrystals by well-known Top-down methods or Bottom-up methods, such as wet milling, co-evaporation or anti-solvent methods [Chavhan SS, Petkar KC, Sawant KK. Nanosuspensions in drug delivery: recent advances, patent scenarios , and commercialization aspects. Crit Rev Ther Drug Carrier Syst. 2011;28(5):447-88.].

It will also be understood by those skilled in the art that in the preparation process, after the organic solvent is removed, the residual organic solvent can be further removed by conventional operations such as vacuum drying.

At the same time, as will also be understood by those skilled in the art, other pharmaceutical excipients such as pH adjusters, bacteriostatic agents, antioxidants, osmotic pressure regulators, and the like may be further added to the compositions of the present application as needed. Additives, etc. The additives described herein include lactose, glucose, glycerin, MC, HPMC, PVA, and sodium alginate. These additives can be used to adjust the gelation temperature and viscosity of the gel. Degree, bioadhesiveness, release rate, etc., it should be noted that the above additives such as MC, PVA, HPMC, etc. can also function as stabilizers.

In still another aspect, the present application further provides the above-mentioned poorly soluble pharmaceutical gel composition in intratumoral injection, peritumoral injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, interventional treatment, postoperative administration, ocular medication or nasal medication. Application in .

The poorly soluble pharmaceutical gel composition of the present application has the following advantages over the prior art:

1. The amount of stabilizer used in the present application is extremely small. For example, in the present application, the sum of the weight of the stabilizer and the poorly soluble drug is only 0.008%-10% of the total weight of the entire poorly soluble pharmaceutical gel composition. It eliminates hidden dangers such as allergies caused by solubilized surfactants in commercially available poorly soluble drug injections, and improves the safety of drugs.

2. The physical stability of the drug nanocrystals in the poorly soluble pharmaceutical gel composition provided by the present application is significantly improved compared to the single drug nanocrystal composition, especially the long-term storage stability is remarkably improved.

3. Compared with the temperature-sensitive gel composed of the poorly soluble drug solution (the drug is in a solution state) and the temperature sensitive material, the poorly soluble drug gel composition provided by the present application can significantly delay the drug release time, thereby prolonging the action time of the drug and improving treatment effect.

4. Compared with a single temperature-sensitive gel composed of a poorly soluble drug suspension and a temperature sensitive material, the poorly soluble pharmaceutical gel composition provided by the present application can increase the drug loading of the poorly soluble drug and avoid the occurrence of long-term storage. Problems such as drug deposition improve the needle-forming properties of the injection, and improve the uniformity of drug distribution and release. DRAWINGS

The drawings are intended to provide a further understanding of the present invention, and are intended to be a part of the present invention, and the description of the present invention and the description thereof are not intended to limit the invention. In the drawing:

1 is a particle size distribution diagram (A, C) and a transmission electron micrograph (B, D) of paclitaxel nanocrystals in a paclitaxel nanocrystal and a paclitaxel nanocrystal gel composition in a paclitaxel nanocrystal suspension of Example 1. 2 is an in vitro release profile of the paclitaxel nanocrystalline gel composition of Example 1; FIG. 3 is a comparison of the paclitaxel nanocrystals in the paclitaxel nanocrystal suspension of Example 1 and the paclitaxel nanocrystals in the paclitaxel nanocrystalline gel composition. a particle size change diagram with an extended time;

Fig. 4 Tumor volume-time change pattern of BALB/c mice bearing 4T1 tumors in each administration group after intratumoral administration;

Fig. 5 is a graph showing changes in body weight of BALB/c mice bearing 4T1 tumors in each administration group after intratumoral administration;

Fig. 6 Tumor volume-time change pattern of MCF-7 tumor-bearing mice in each administration group after intratumoral administration;

Fig. 7 Changes in body weight of mice bearing MCF-7 tumors in each administration group after intratumoral administration. Preferred embodiment of the invention

The embodiments of the present application are described below by way of examples, and those skilled in the art should understand that the specific embodiments are merely illustrative of the embodiments of the invention. Improvements to the technical solutions of the present application are apparent from the teachings of the present application, and are within the scope of the present disclosure.

Example 1 Preparation of Paclitaxel Nanocrystalline Gel Composition

1. Weigh 32 mg of paclitaxel and 160 mg of pluronic F127, respectively, and add them to 4 ml of chloroform, soon them completely, dissolve chloroform by nitrogen at a constant flow rate, and place

The dried chloroform was removed by drying in a vacuum oven at 25 ° C for 12 hours to obtain a dried paclitaxel and a Plenix F127 film. 8 ml of purified water was added to the above dried paclitaxel and Pluronic F127 film, and rotary evaporation was continued in a RE52CS-1 rotary evaporator, hydrated for 40 min, and vortexed in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). After spinning for 10 min, the vortex speed was 2400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a uniform transparent paclitaxel nanocrystal suspension.

2. Weigh 2g of Pluronic F127, directly into the suspension of paclitaxel nanocrystals, and stir magnetically for 6h in a water bath to completely dissolve the Pluronic F127 to obtain a transparent, liquid form. Paclitaxel nanocrystalline gel composition.

Wherein, the particle size of the drug solid particles in the suspension of paclitaxel nanocrystals and the finally obtained paclitaxel nanocrystalline gel composition was measured, and a transmission electron micrograph was taken, as follows: Prepared in Example 1 The paclitaxel nanocrystal suspension and the paclitaxel nanocrystalline gel composition were diluted 10 times and 100 times with purified water, respectively, and the particles at 25 ° C were measured using a Malvern laser particle size analyzer (Zetasizer 3000HS, Malvem, UK). Path (results shown in A and C in Figure 1).

The paclitaxel nanocrystal suspension was diluted 10 times with purified water, and the paclitaxel nanocrystal gel composition was diluted 100 times with purified water, and its structure was observed by a transmission electron microscope (JEM-200X, JEOL, Japan) (results as shown in Fig. 1) B and D)). The specific operation is as follows: After the diluted sample is kept at room temperature (20 °C) for 30 min, it is added dropwise to the copper mesh of the carbon coated film, and after the water is volatilized, it is directly added to the JEM-200X transmission electron microscope to observe the acceleration voltage. 80kv.

The results of the laser particle size analyzer showed that the nanocrystal particle diameter in the suspension of paclitaxel nanocrystals was 120 nm, and the drug solid particle diameter of the paclitaxel nanocrystal gel composition was 156 nm. The results of transmission electron microscopy showed that the nanocrystals in the paclitaxel suspension were short rod-like structures with a particle size of 100-200 nm. After loading the Pluronic F127 gel, they still existed in the form of nanocrystalline short rods with a particle size of 100- Between 200nm. The results observed by transmission electron microscopy were consistent with those obtained by laser particle size analyzer.

According to the above method, the particle size of the drug solid particles in the suspension of the poorly soluble drug nanocrystals prepared in the other examples and the poorly soluble drug nanocrystal gel composition was measured by a Malvern laser particle size analyzer, and the results showed All drug nanocrystals have a particle size of less than 600 nm and most of the particle size is between 100 and 300 Å.

Example 2 Preparation of Docetaxel Nanocrystalline Gel Composition

1. Weighed 32 mg of docetaxel and 160 mg of polyethylene glycol vitamin E succinic acid (TPGS), respectively, and added them to 3 ml of dichloromethane, sonicated to completely dissolve them, in the form of RE52CS-1 rotary evaporation. The mixture was evaporated to dryness under reduced pressure to remove dichloromethane and dried in a vacuum oven at 25 ° C for 12 h to remove residual dichloromethane to obtain a dried docetaxel and TPGS film. 7.5 ml of purified water was added to the above dried docetaxel and TPGS film, and rotary evaporation was continued in a RE52CS-1 rotary evaporator, hydrated for 40 min, and mixed in WH-861 vortex. The instrument (Taicang Science and Education Equipment Factory) vortex lOmin, the vortex speed is 2400 rpm, and then, in the KQ-100DE ultrasonic cleaner, ultrasonic lOmin at 100W, to obtain uniform, transparent docetaxel nano Crystal suspension.

2. Weigh the polycaprolactone ₁₅₀₀ -polyethylene glycol ₁₅₀₀ -polycaprolactone ₁₅₀₀ 2.58 directly into the suspension of the above docetaxel nanocrystals, magnetically stir for 6 hours under water bath, so that the temperature sensitive material is completely dissolved. A liquid, transparent docetaxel nanocrystalline gel composition was obtained.

Example 3 Preparation of Docetaxel Paclitaxel Nanocrystalline Gel Composition

1. Weigh 16 mg of docetaxel and 160 mg of Tween, respectively, and add them to 5 ml of absolute ethanol, sonicate them completely, and dry the anhydrous ethanol by nitrogen at a constant flow rate. It was dried in a vacuum oven at 25 ° C for 12 h to remove residual absolute ethanol to obtain a film of dried docetaxel and Tween 80. 5 ml of purified water was added to the above dried docetaxel and Tween 80 film, and rotary evaporated in a RE52CS-1 rotary evaporator, hydrated for 40 min, in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). The middle vortex was 10 min, the vortex speed was 2400 rpm, and then, in a KQ-100DE ultrasonic cleaner, ultrasonic at 100 W for 10 min to obtain a uniform, transparent docetaxel nanocrystal suspension.

2. Weigh 16 mg of paclitaxel and 160 mg of pluronic F127, add the drug and stabilizer to 4 ml of absolute ethanol, dissolve it completely by sonication, and dry the organic solvent by nitrogen at a constant flow rate. Drying at 25 ° C for 12 h under vacuum to remove residual organic solvent gave a film of dried paclitaxel and pluronic F127. 5 ml of purified water was added to the above dried paclitaxel and pluronic F127 membrane, and rotated in a RE52CS-1 rotary evaporator, hydrated for 40 min, and vortexed in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). After spinning for 10 min, the vortex speed was 2400 rpm, and then ultrasonication at 100 W for 15 min in a KQ-50DE ultrasonic cleaner to obtain a uniform, transparent paclitaxel nanocrystal suspension.

3. After mixing the above docetaxel nanocrystal suspension and paclitaxel nanocrystal suspension, weigh 2g of Pluronic F127 and lg of Pluronic F68, and directly add to the suspension of the above nanocrystals. After magnetic stirring in a water bath until the Pluronic F127 and the Pluronic F68 were completely dissolved, a liquid, transparent docetaxel paclitaxel nanocrystalline gel composition was obtained.

Example 4 Preparation of Camptothecin Nanocrystalline Gel Composition 1. Weigh 6 mg of camptothecin and 12 mg of stabilizer polyethylene glycol vitamin E succinic acid (TPGS), add them to 8 ml of absolute ethanol, dissolve them completely for 1 min, and pass nitrogen at a constant flow rate. The ethanol was blown off and dried in a vacuum oven at 25 ° C for 12 hours to remove residual ethanol to obtain a film of dried camptothecin and TPGS. 1.5 ml of purified water was added to the above dried camptothecin and TPGS film, and rotated in a RE52CS-1 rotary evaporator, hydrated for 20 min, and vortexed in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). After spinning for 10 min, the vortex speed was 2400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a liquid, transparent camptothecin nanocrystal suspension.

2. Preparation of blank gel Weigh 2.5g of polyglycolide lactide ₂₅₍₎₍₎ -polyethylene glycol 5000-polyglycolide lactide ₂₅ QQ directly into 6ml purified water, water bath magnetic After stirring for 12 h, a blank gel was obtained.

3. Mix the prepared camptothecin nanocrystal suspension in step 1 with the blank gel prepared in step 2, and stir the magnetic bath uniformly to obtain the camptothecin nanocrystalline gel composition.

Example 5 Preparation of Itraconazole Nanocrystalline Gel Composition

1. Weigh itraconazole 6mg, TPGS 12mg and 12 mg of polyvinyl alcohol, and added to a mixed solvent of chloroform and Yue 5ml l _5m l of alcohol, the ultrasound 5min completely dissolved, the organic solvent removed by rotary evaporation, and placed The dried itraconazole and TPGS, polyvinyl alcohol film were dried in a vacuum oven at 25 ° C for 12 h. 1.5 ml of 5% glucose was added to the above dried itraconazole and TPGS, polyvinyl alcohol film, and rotary evaporation was continued in a RE52CS-1 rotary evaporator, hydrated for 40 min, in a WH-861 vortex mixer. (Taicang Science and Education Equipment Factory) The vortex was 10 min, the vortex speed was 2400 rpm, and then it was ultrasonicated at 100 W for 10 min in a KQ-100DE ultrasonic cleaner to obtain a uniform transparent Itrakang. A suspension of azole nanocrystals.

2. Weigh 2.5 g of Pluronic F127 and 0.5 g of Pluronic F68 into 6 ml of 5% glucose and stir in a water bath for 12 h to obtain a blank gel.

3. Mix the prepared suspension of itraconazole nanocrystals prepared in step 1 with the blank gel prepared in step 2, and stir evenly in a water bath to obtain an itraconazole nanocrystalline gel composition.

Example 6 Preparation of Dexamethasone Nanocrystalline Gel Composition

1. Weigh dexamethasone 5mg and stabilizer Pluron F127 20mg, respectively, and add them Into 4 ml of absolute ethanol, ultrasonically dissolved completely, and the organic solvent was evaporated by nitrogen at a constant flow rate, and dried in a vacuum oven at 25 ° C for 12 h to remove residual organic solvent to obtain a dry Thin film of dexamethasone and pluronic F127. 5 ml of purified water was added to the above-mentioned dried dexamethasone and Pluronic F127 membranes, and rotary evaporated in a RE52CS-1 rotary evaporator, hydrated for 40 min, in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). The middle vortex was 10 min, the vortex speed was 2400 rpm, and then the ultrasonic suspension was immersed in a KQ-100DE ultrasonic cleaner at 100 W for 15 min to obtain a suspension of dexamethasone nanocrystals.

2. Weigh 1.5g of the temperature sensitive material Pluronic F127, directly into the suspension of the above dexamethasone nanocrystals, magnetically stirred in a water bath until the Pluronic F127 is completely dissolved, and the dexamethasone nanocrystalline gel composition is obtained. .

Example 7 Preparation of Hydrocortisone Acetate Nanocrystalline Gel Composition

1. Weigh 15 mg of hydrocortisone acetate and 30 mg of the stabilizer Pluronic F127, add them to 2 ml of absolute ethanol, dissolve them completely by sonication, and dry the organic solvent by nitrogen at a constant flow rate. And dried in a vacuum oven at 25 ° C for 12 h to remove residual organic solvent to obtain a dried film of hydrocortisone acetate and pluronic F127. 3 ml of purified water was added to the above dried hydrocortisone acetate and Pluronic F127 membranes, and rotary evaporated in a RE52CS-1 rotary evaporator, hydrated for 40 min, in a WH-861 vortex mixer (Taicang Science and Education). The equipment factory was vortexed for 10 min, and the vortex speed was 2,400 rpm. Then, it was ultrasonicated at 100 W for 10 min in a KQ-100DE ultrasonic cleaner to obtain a suspension of cortisone acetate nanocrystals.

2. Weigh 0.8g of the temperature sensitive material Pluronic F127, directly into the above suspension of hydrocortisone acetate nanocrystals, magnetically stirred in a water bath until the Pluronic F127 is completely dissolved, and the hydrocortisone acetate nanocrystals are obtained. Gel composition.

Example 8 Preparation of Fluticasine Propionate Nanocrystalline Gel Composition

1. Weigh 6 mg of fluticasone propionate and 6 mg of pluronic F 127, respectively, and add them to

In 5 ml of absolute ethanol, the solution was completely dissolved by ultrasonication, and the organic solvent was evaporated by nitrogen at a constant flow rate, and dried in a vacuum oven at 25 ° C for 12 hours to remove residual organic solvent to obtain a dried C. A film of acid fluocene ^^ and pluronic F127. 12 ml of purified water was added to the above-mentioned dry film of fluticasone propionate and pluronic F127, and relayed in a RE52CS-1 rotary evaporator Continued rotary evaporation, hydration for 40 min, vortex lO min in the WH-861 vortex mixer (Taicang Science and Education Equipment Factory), the vortex speed is 2400 rpm, and then in the KQ-100DE ultrasonic cleaner at 100 Ultrasonic for 10 min at W power gave a suspension of fluticasone propionate nanocrystals.

2. Weigh 3g of Pluronic F127 and directly add it to the above suspension of fluticasone propionate nanocrystals. After magnetic stirring in a water bath until the Pluronic F127 is completely dissolved, the fluticasone propionate nanocrystals are obtained. Gum composition.

Example 9 Preparation of Paclitaxel Nanocrystalline Gel Composition

1. Weigh 20 mg of paclitaxel and prepare a solution of 2 mg/ml with dimethyl sulfoxide; weigh 10 mg of Plenic F127 and prepare a solution of 0.25 mg/ml with purified water. 0.5 ml of paclitaxel solution was injected into 10 ml of 0.25 mg/ml Pluronic F127 solution, and the probe was sonicated for 3 minutes (Ningbo Xinzhi JY92-2D) at 400 W, and then filtered through a polycarbonate membrane with a pore size of 50 nm. After repeatedly washing with purified water, the filtrate was resuspended in 10 ml of purified water to obtain a suspension of paclitaxel nanocrystals in a uniform transparent state.

2. Weigh 2g of Pluronic F127 and directly add it to the suspension of paclitaxel nanocrystals. The water bath is magnetically stirred until the Pluronic F127 is completely dissolved to obtain a transparent, liquid paclitaxel nanocrystalline gel composition.

Example 10 Preparation of Fenofibrate Nanocrystalline Gel Composition

1. Weigh 20 mg of fenofibrate and prepare a solution of 2 mg/ml with ethanol; weigh 10 mg of povidone and prepare a solution of 0.1 mg/ml with purified water. Take 0.5ml of fenofibrate solution, inject it into 10ml of O.lmg/ml povidone solution, ultrasonically probe for 3 minutes at 400W (Ningbo Xinzhi JY92-2D), and then use polycarbonate with pore size of 50nm. The membrane was filtered, washed repeatedly with purified water, and the filtrate was resuspended in 10 ml of purified water to obtain a suspension of fenofibrate nanocrystals in a uniform transparent state.

2. Weigh lg of Pluronic F127, directly into the above suspension of fenofibrate nanocrystals, and magnetically stir for 6 hours in a water bath to obtain a transparent, liquid fenofibrate nanocrystalline gel composition.

Example 11 Preparation of Paclitaxel Nanocrystalline Gel Composition

1. Weigh 50 mg of paclitaxel and 1 mg of SDS, respectively, and add them to 4 ml of chloroform. Ultrasound was completely dissolved, and chloroform was blown off by nitrogen at a constant flow rate, and dried in a vacuum oven at 25 ° C for 12 hours to remove residual chloroform to obtain a dried paclitaxel and a pluronic F127 film. Add 5 ml of purified water to the above dried paclitaxel and SDS film, spin-evaporate in a RE52CS-1 rotary evaporator, hydrate for 40 min, and vortex for 10 min in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). The vortex speed was 2,400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a suspension of paclitaxel nanocrystals in a uniform transparent state.

2. Weigh 3g of Pluronic F127, directly added to the above suspension of paclitaxel nanocrystals, and magnetically stir for 8 hours in a water bath to completely dissolve the pluronic F127 to obtain a transparent, liquid paclitaxel nanocrystalline gel combination. Things.

Example 12 Preparation of Paclitaxel Nanocrystalline Gel Composition

1. Weigh 1 mg of paclitaxel and 50 mg of TPGS, respectively, and add them to 4 ml of chloroform, soon them completely, dissolve chloroform by nitrogen at a constant flow rate, and dry in a vacuum oven at 25 °C. 12h, to remove residual chloroform, to obtain dried paclitaxel and pluronic F127 film. Add 100 ml of purified water to the above dried paclitaxel and TPGS film, spin-evaporate in a RE52CS-1 rotary evaporator, hydrate for 40 min, and vortex for 10 min in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). The vortex speed was 2,400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a suspension of paclitaxel nanocrystals in a uniform transparent state.

2. Weigh 20g of Pluronic F127, directly into the suspension of paclitaxel nanocrystals, and stir it magnetically for 8h in a water bath to completely dissolve Pluronic F127 to obtain a transparent, liquid paclitaxel nanocrystalline gel combination. Things.

Example 13 Preparation of Paclitaxel Nanocrystalline Gel Composition

1. Weigh 50 mg of paclitaxel and 450 mg of pluronic F127, respectively, and add them to 3.5 ml of chloroform and 0.5 ml of petroleum ether, sonicate completely to dissolve, and dry chloroform by nitrogen at a constant flow rate. It was dried in a vacuum oven at 25 ° C for 12 h to remove residual chloroform to obtain a dried paclitaxel and a pluronic F127 film. Add 5 ml of purified water to the above dried paclitaxel and Pluronic F127 membrane, spin-evaporate in a RE52CS-1 rotary evaporator, hydrate for 40 min, and vortex in the WH-861 vortex mixer (Taicang Science and Education Equipment Factory).旋 lOmin, vortex The speed was 2,400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a suspension of paclitaxel nanocrystals in a uniform transparent state.

Example 14 Preparation of Paclitaxel Nanocrystalline Gel Composition

1. Weigh 0.5 mg of paclitaxel and 10 mg of TPGS, respectively, and add them to 4 ml of chloroform, soon them completely, dissolve chloroform by nitrogen at a constant flow rate, and place in a vacuum oven at 25 ° C. After drying for 12 h to remove residual chloroform, dry paclitaxel and pluronic F127 film were obtained. Add 100 ml of purified water to the above dried paclitaxel and TPGS film, spin-evaporate in a RE52CS-1 rotary evaporator, hydrate for 40 min, and vortex for 10 min in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). The vortex speed was 2,400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a suspension of paclitaxel nanocrystals in a uniform transparent state.

Example 15 Preparation of cyclosporin A nanocrystalline gel composition

1. Weigh 6 mg of cyclosporine A and 6 mg of HPMC, respectively, and add them to 5 ml of absolute ethanol, sonicate them completely, and dry the organic solvent by nitrogen at a constant flow rate, and place at 25 °. Drying in a C vacuum oven for 12 h to remove residual organic solvent gave a film of dry cyclosporin A and pluronic F127. 5 ml of purified water was added to the above-mentioned dried cyclosporin A and HPMC films, and rotary evaporated in a RE52CS-1 rotary evaporator to hydrate for 40 min in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). The vortex was 10 min, the vortex speed was 2400 rpm, and then, in a KQ-100DE ultrasonic cleaner, ultrasonic at 100 W for 10 min to obtain a cyclosporin A nanocrystal suspension.

2. Weigh 2.5g of Pluronic F127 and 0.5g of Pluronic F68, directly into the suspension of cyclosporin A nanocrystals, and stir magnetically for 6h under water bath, so that pluronic is completely dissolved. To a clear, liquid cyclosporin A nanocrystalline gel composition.

Example 16 In vitro release of poorly soluble drug nanocrystalline gel compositions

2 ml of the drug nanocrystalline gel composition (NCs-Gel) prepared in Example 1 was weighed and added to a flat bottom vial (2.2 cm in diameter), and preheated to 37 ° C in a water bath to form a semi-solid gel. 8 mL of the release medium (0.9% NaCl solution) preheated to 37 °C was carefully added to the gel surface. The vial was then placed in a 37 ° C gas bath thermostat (ZHWY-100C, Shanghai Zhicheng Analytical Instrument) and shaken at 40 rpm. In the next time, sample at the set time point (2 ml), while replenishing the same volume of fresh release medium (0.9% NaCl solution), and remove the release solution according to HPLC method (high pressure liquid chromatography LC- ΙΟΑΤνρ, Japan) (mobile phase: acetonitrile: water 56:44, flow rate 1 ml/min, column temperature at room temperature) was determined and the total cumulative drug release at each time point was calculated.

The release results are shown in the release graph of Figure 2. As can be seen from Fig. 2, the cumulative release amount of the pharmaceutical nanocrystal gel composition prepared in the present application at 37 ° C for 35 days is less than 80%. Therefore, the pharmaceutical nanogel composition of the present application can significantly delay the release time of the drug, thereby prolonging the action time of the drug and providing a therapeutic effect.

Example 17 Study on Stability of Pharmaceutical Nanocrystalline Gel Composition

The suspension of the drug nanocrystals prepared in Example 1 was stored at 4 ° C and room temperature for 14 days, respectively, and the pharmaceutical nanocrystal gel composition prepared in Example 1 was stored at room temperature for 3 months. The particle size was measured at 0 days, 1 day, 3 days, 7 days, 10 days, 14 days, 1 month, and 3 months, respectively. The particle diameter measuring instrument was a Malvern laser particle size analyzer (Malvem, Zetasizer Nano, UK). The determination method is as follows: firstly, the drug nanocrystal suspension and the drug nanocrystal gel composition are diluted 10 times and 100 times with purified water, and 1.2 ml is added to the sample pool, low-power ultrasound (ultrasound KQ-100DE, Kunshan Ultrasonic Instruments, power 80%) 2-3min, particle size. Repeat the average of 3 times.

The results of particle size measurement are shown in Figure 3. As can be seen from FIG. 3, the particle size of the drug nanocrystals in the drug nanocrystal suspension grows with the increase of the standing time, and the particle size of the drug solid particles in the drug nanocrystal gel composition is almost unchanged. It is thus illustrated that the pharmaceutical nanocrystalline gel composition of the present application can significantly increase the physical stability of the drug nanocrystals in the pharmaceutical nanocrystalline gel composition as compared to a single pharmaceutical nanocrystalline composition. Example 18 Anti-tumor effect of BALB/c's and mice loaded with 4T1 tumor after intratumoral administration of drug nanocrystal gel composition

Female BALB/c mice (18-22g, Beijing Weitong Lihua experimental animals) were inoculated with 106 mouse breast cancer 4T1 cells under the right sac, and administered for 13 days after inoculation. The components were divided into 6 groups, respectively : saline group (Saline), blank gel group (Blank F127-Gel, prepared according to the method described in Example 1, except that the blank gel does not contain paclitaxel), paclitaxel (PTX) nanocrystalline gel composition ( Prepared according to the method of Example 1, NCs-Gel), paclitaxel complex micelle gel (MMG, prepared according to the following literature method: Yang Y, J Control Release, 2009, 135, 175-182), paclitaxel nanocrystals (NCs) (The suspension of paclitaxel nanocrystal prepared according to Example 1, using purified water as a solvent during use), paclitaxel injection (Taolol, Bristol-Myers Squibb, lot number: OM43146), intratumoral administration The dose was 30 mg PTX/kg, 6 rats in each group, single administration. The body weight of the mice was measured every 2 days after administration, and the signs and behaviors of the mice were observed. The length and diameter of each group of tumors were measured using a vernier caliper, and the tumor volume V (V = [length X (width) ² ]/2) was calculated. Draw a tumor volume-time change plot. The animals were sacrificed on the 20th day after the administration, the tumor was exfoliated, the tumor weight was weighed, and the tumor was photographed.

The results are shown in Figures 4 and 5. As can be seen from Fig. 4, Blank F127-Gel has no anti-tumor effect, and NCs-Gel of Example 1 of the present application can significantly reduce the volume of tumor compared with the saline group and other positive control groups, and this The reduction was significantly different from the other positive control groups.

At the same time, as can be seen from Figure 5, the body weight of the Taxol group was significantly reduced 2 days after administration, indicating that Taxol was toxic after administration. The other drug-administered groups had little effect on body weight, indicating that the systemic toxicity caused by in situ injection was small. Moreover, as can be seen from Fig. 5, NCs-Gel, which has the least influence on body weight, indicates that the NCs-Gel of this application has remarkable curative effect and small side effects.

Example 19 Antitumor efficacy of a mouse loaded with MCF-7 tumor after intratumoral administration of a poorly soluble drug nanocrystalline gel composition

Female BALB/c mice (20-22 g, Beijing Weitong Lihua experimental animals) were inoculated with 106 human breast cancer MCF-7 cells under the right iliac crest. After 14 days of inoculation, the drug-administered components were divided into 5 groups. For: saline group (Saline), blank gel group (Blank F127-Gel, prepared according to the method described in Example 1, except that the blank gel does not contain paclitaxel), paclitaxel (PTX) nanocrystals Gel composition (prepared according to the method of Example 1, NCs-Gel), paclitaxel complex micelle gel (MMG, prepared according to the following literature method: Yang Y, J Control Release, 2009, 135, 175-182), Paclitaxel nanocrystals (NCs) (suspension of paclitaxel nanocrystals prepared as in Example 1, using purified water as a vehicle in use), paclitaxel injection (Taxol, Bristol-Myers Squibb, lot number: OM43146), dose For 30 mg PTX/kg, 6 rats in each group, single dose. Tumor body weight was measured every 2 days after administration, and the signs and behaviors of the mice were observed. The length and diameter of each group of tumors were measured using a vernier caliper, and the tumor volume V (V = [length X (width) ² ]/2 ) was calculated and plotted. Tumor volume - time change plot. The animals were sacrificed on the 20th day after the administration, the tumor was exfoliated, the tumor weight was weighed, and the tumor was photographed.

The results are shown in Figures 6 and 7. As can be seen from the figure, the NCs-Gel group is compared with the other groups.

NCs-Gel significantly reduces tumor volume with significant differences. In the Taxol group, the body weight was significantly reduced 2 days after administration, indicating that the Taxol had a certain toxicity after administration. The other drug-administered groups had little effect on body weight, indicating that the systemic toxicity caused by in situ injection was small. Moreover, as can be seen from Fig. 7, the NCs-Gel which has the least influence on the body weight indicates that the NCs-Gel of the present application has a remarkable effect and a small side effect.

In the above experiments, the present invention is merely an exemplary embodiment 1 as an experimental drug, and it is to be noted that other embodiments of the present invention have the same or similar advantageous effects.

The present application includes, but is not limited to, the above embodiments, and any equivalent or partial modifications made by the spirit of the present application are considered to be within the scope of the present application.

Industrial applicability

The poorly soluble pharmaceutical gel composition provided by the present application can improve the drug loading amount of the poorly soluble drug, avoid the problem of drug deposition occurring during long-term storage, improve the needle-forming property of the injection, and improve the uniform distribution and release of the drug. Sex, etc., has important practical significance.

Claims

Claim

A poorly soluble pharmaceutical gel composition comprising: a drug nanocrystal of a poorly soluble drug, a stabilizer, a temperature sensitive material, and a solvent.

2. The poorly soluble pharmaceutical gel composition according to claim 1, wherein the poorly soluble drug is selected from the group consisting of paclitaxel, docetaxel, camptothecin, 9-hydroxycamptothecin, 10-hydroxycamptothecin , itraconazole, teniposide, etoposide, cyclosporine A, doxorubicin, capecitabine, oxaliplatin, irinotecan, gemcitabine, temozolomide, imatinib, vinorelbine , letrozole, vinblastine, vincristine, vindesine, vinpocetine, dethioglycoside, silybin, artemisinin, dihydroartemisinin, sirolimus, nitrendipine , nicardipine, nimodipine, breviscapine, ferulic acid, acetaminophen, vitamin A, tamoxifen, valproic acid, tacrolimus, fenofibrate, amphotericin B, Ketoconazole, domperidone, sulpiride, azithromycin, miconazole, brimonidine, latanoprost, erythromycin, roxithromycin, rifamin, diclofenac, felodipine, ibuprofen, Indomethacin, nifedipine, terfenadine, theophylline, ketone Fen, furosemide, spironolactone, dipyridamole, piroxicam, pindolol, dexamethasone, fluorometholone, phenbutanol, cortisone acetate, hydrocortisone acetate, budesonide, propionic acid One or more of fluticasone; preferably, the poorly soluble drug is selected from one or both of paclitaxel and docetaxel.

The poorly soluble pharmaceutical gel composition according to claim 1, wherein the stabilizer is selected from the group consisting of Tween-80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, lecithin, polyethylene glycol , one of poloxamer, hydroxypropyl hydrazine cellulose, povidone, polyethylene glycol vitamin E succinic acid, cholic acid, sodium cholate, decyl cellulose, hydroxypropyl cellulose or polyvinyl alcohol or A plurality of; preferably, the stabilizer is selected from one or more of poloxamer, polyethylene glycol vitamin E succinic acid or sodium lauryl sulfate.

The poorly soluble pharmaceutical gel composition according to claim 1, wherein the temperature sensitive material is selected from the group consisting of poloxamer, polylactic acid-polyethylene glycol-polylactic acid, and polyglycolide lactide- Polyethylene glycol-polyglycolide lactide, polyethylene glycol-polylactic acid-polyethylene glycol, polyethylene glycol-polyglycolide lactide-polyethylene glycol, polycaprolactone-poly One or more of ethylene glycol-polycaprolactone or chitosan; preferably, the temperature sensitive material is poloxamer.

The poorly soluble pharmaceutical gel composition according to claim 1, wherein the solvent is selected from the group consisting of water, physiological saline, 5% glucose solution, glycerin, polyethylene glycol, propylene glycol or ethanol. One or more; preferably, the solvent is water, and more preferably, the solvent is purified water, and more preferably, the solvent is water for injection.

The poorly soluble pharmaceutical gel composition according to claim 4 or 5, wherein the poloxamer is one or both of poloxamer 407 and poloxamer 188.

The poorly soluble pharmaceutical gel composition according to claim 1, wherein in the poorly soluble pharmaceutical gel composition, the weight ratio of the stabilizer to the poorly soluble drug is 1:20-50 :1 , preferably 1:5-5:1.

The poorly soluble pharmaceutical gel composition according to claim 1, wherein, in the poorly soluble pharmaceutical gel composition, the weight ratio of the temperature sensitive material to the solvent is 1:10-1.5: 1 , preferably 1:5-3:5.

9. The poorly soluble pharmaceutical gel composition according to claim 1, wherein a sum of the weight of the stabilizer and the poorly soluble drug is 0.008% to 10% of the total weight of the entire poorly soluble pharmaceutical gel composition. %, preferably from 0.04% to 3%.

The poorly soluble pharmaceutical gel composition according to claim 1, wherein the drug nanocrystal of the poorly soluble drug has a particle diameter in the range of 20 to 600 nm, preferably in the range of 100 to 300 nm.

A method of preparing a poorly soluble pharmaceutical gel composition according to any one of claims 1 to 10, the method comprising the steps of:

a poorly soluble drug and stabilizer added to the organic solvent, after complete dissolution, the organic solvent is removed, and then hydrated with a solvent, vortex, followed by stirring or sonication to obtain a suspension of drug nanocrystals A;

b. adding the temperature sensitive material to A, stirring in a water bath until the temperature sensitive material is completely dissolved, to obtain the poorly soluble pharmaceutical gel composition;

Or

The method includes the following steps:

a poorly soluble drug and stabilizer added to the organic solvent, after complete dissolution, the organic solvent is removed, and then hydrated with a solvent, vortex, followed by stirring or sonication to obtain a suspension of drug nanocrystals A; b. The temperature sensitive material is added to the solvent, stirred in a water bath until the temperature sensitive material is completely dissolved, and a blank gel B is obtained;

c A and B were uniformly mixed under a water bath to obtain the poorly soluble pharmaceutical gel composition.

The method according to claim 11, wherein, in step a, the poorly soluble drug and the stabilizer are completely dissolved in the organic solvent by sonication; the organic component is removed by nitrogen blowing or rotary evaporation under reduced pressure Solvent; treated by a water bath ultrasonic method, a probe ultrasonic method, a high pressure homogenization method, a high speed tissue dispersion method or a high speed stirring method to obtain a suspension A of the drug nanocrystal; wherein the organic solvent is selected from the group consisting of dichloroguanidine One or more of alkane, chloroform, absolute ethanol, decyl alcohol, acetonitrile, propylene glycol, ethyl acetate, petroleum ether.

The poorly soluble pharmaceutical gel composition according to any one of claims 1 to 10, which is intratumor injection, peritumoral injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, interventional treatment, postoperative administration, and eye For administration or nasal administration.