A drug nanocrystalline formulation and its preparation method

Abstract

This invention belongs to the field of pharmaceutical formulations and relates to a drug nanocrystal using a low-molecular-weight weak acid salt as a stabilizer and its preparation method. This invention uses a low-molecular-weight weak acid salt as a stabilizer for nanoscale drug crystal particles, resulting in a simple formulation and good safety profile. The preparation method described in this invention is based on media grinding and can be further freeze-dried to obtain a lyophilized product that can be reconstituted to the nanoscale, facilitating large-scale preparation and long-term storage. The formulation described in this invention can be administered via mucosal routes such as intravenous injection, local injection, oral administration, vaginal administration, intranasal administration, oral administration, rectal administration, and intraocular administration, as well as inhalation administration, intravesical instillation, or surgical margin administration.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a pharmaceutical nanocrystalline preparation using low molecular weight weak acid salt as a stabilizer and its preparation method. Background Technology

[0002] Drug nanocrystals refer to drug crystalline particles at the nanoscale (1-1000 nm), possessing the advantages of high drug loading and high dispersibility, and have been developed for the preparation of various poorly soluble drug formulations. To maintain the stability of nanocrystals and prevent their growth and aggregation, most reported drug nanocrystals use surfactants and hydrophilic polymers as stabilizers, such as povidone, Tween, poloxamer, and hydroxypropyl methylcellulose. However, these substances pose safety concerns when used as pharmaceutical excipients (especially in injections), hindering the clinical application of drug nanocrystals. Finding safer drug nanocrystal formulations is a significant challenge for researchers in this field. Summary of the Invention

[0003] This invention aims to provide a drug nanocrystal formulation using low-molecular-weight weak acid salts as stabilizers and its preparation method. This invention discovers that mixing a low-molecular-weight weak acid salt solution with a drug substance (at the micron level or even larger) and then pulverizing it using a media grinder can yield drug nanocrystals with good stability. The mechanism may be that the ions formed after the ionization of the weak acid salt strengthen the electric double layer of the drug crystal particles, thereby improving the stability of the drug nanocrystals. The weak acid salts selected in this invention are all common injectable buffer salt components, avoiding the use of surfactants and hydrophilic polymers, thus improving the practicality of the formulation.

[0004] The preparation method described in this invention is based on media grinding, in which the active pharmaceutical ingredient and an aqueous solution of a low-molecular-weight weak acid salt are placed together in a grinding cup and ground to obtain nanoscale drug crystals. The obtained nanocrystals can be further freeze-dried to obtain a lyophilized product that can be resoluble to the nanoscale.

[0005] The formulation described in this invention can be administered via mucosal routes such as intravenous injection, local injection, oral administration, vaginal administration, nasal administration, oral administration, rectal administration, and intraocular administration. It can also be used for inhalation administration, intravesical instillation, or administration to surgical margins.

[0006] This invention provides a pharmaceutical nanocrystal formulation comprising pharmaceutical crystalline particles and a stabilizer, wherein the stabilizer is a low molecular weight weak acid salt, particularly selected from sodium bicarbonate, sodium citrate, sodium lactate, or sodium tartrate.

[0007] The drugs described in this invention are selected from paclitaxel, docetaxel, borneol, asarone, gossypol acetate, tetrandrine, indirubin, triptolide, ursolic acid, felofibrate, methylphenidate, mycophenolate mofetil, naproxen, nevirapine, nifedipine, triamcinolone, olanzapine, omeprazole, oxapazol, phenacetin, phenytoin sodium, etc., metronidazole, trimethoprim, rifampin, carbamazepine, ibuprofen, indomethacin, clopidogrel, loratadine, glibenclamide, furosemide, spironolactone, mifepristone, acetazolamide, haloperidol, cefuroxime axetil, hydrochlorothiazide, clarithromycin, carbazide, camptothecin, 9-hydroxycamptothecin, 9-nitrocamptothecin, 9-amino Camptothecin, doxorubicin, daunorubicin, arubicin, epirubicin, idarubicin, pentorubicin, mitoxantrone, imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, nilotinib, lapatinib, pazopanib, icotinib, vandetanib, vemurafenib, crizotinib, axitinib, besutinib, cabozantinib, ponatinib, regorafenib, ladotinib, dabrafenib, trametinib, afatinib, ibrutinib, ceritinib, alectinib, apatinib, nintedanib, lenvatinib, osimertinib, oximertinib, vinblastine, vincristine, vinorelbine, vindesine, everolimus, zotamolimus, or borneol.

[0008] The mass ratio of drug crystal particles to stabilizer in this invention is 1:5 to 2:1, and the formulation further includes a freeze-drying protectant.

[0009] The formulation provided by the present invention has a mass ratio of drug: stabilizer: freeze-drying protectant of 1:(0.5-3):(1-2).

[0010] The present invention also provides a method for preparing a drug nanocrystal preparation, comprising: (1) suspension preparation: placing the active pharmaceutical ingredient, stabilizer solution and grinding beads in a grinding cup and grinding them with a planetary ball mill; (2) freeze drying: adding a freeze drying protectant to the grinding liquid and obtaining a freeze-dried product by freeze drying treatment.

[0011] The grinding beads are selected from 0.1mm, 0.2-0.3mm and 1mm in size, and the grinding bead material is selected from zirconium dioxide or agate; the grinding speed is 200-800rpm and the grinding time is 0.5-10h.

[0012] The freeze-drying protectant of the present invention is selected from one or a combination of several of glucose, sucrose, mannitol, sorbitol, stachyose, arginine, and glycine.

[0013] The preparation method of the present invention further includes reconstituted the lyophilized product, wherein the reconstituted solution is selected from 0.45% to 2% (w / v) sodium chloride aqueous solution, 5% glucose (w / v) aqueous solution, 1% to 5% (w / v) citric acid aqueous solution, 0.1% to 10% (w / v) poloxamer 407 pure aqueous solution, 0.1% to 10% (w / v) poloxamer 188 pure aqueous solution, 0.1% to 5% (w / v) hydroxypropyl methylcellulose pure aqueous solution, or 0.1% to 5% (w / v) hydroxypropyl methylcellulose pure aqueous solution, etc.

[0014] The advantages of this invention are: (1) It uses non-toxic and safe low molecular weight weak acid salt as a stabilizer, avoiding the use of traditional stabilizers such as surfactants or hydrophilic polymers, avoiding the possible solubilizing effect of surfactants and their adverse effects on stability, and avoiding the safety hazards of surfactants or hydrophilic polymer stabilizers; (2) The drug nanocrystals are stored in the form of lyophilized products. Before use, the lyophilized products are reconstituted back to the state of drug nanocrystals with a suitable reconstitution liquid, ensuring the stability of the nanocrystals during storage and the convenience of use. Attached Figure Description

[0015] Figure 1 The particle size distribution of the docetaxel nanocrystal suspension obtained in step 1 of Example 1

[0016] Figure 2 Particle size distribution of the docetaxel nanocrystal suspension obtained by resolution in step 2 of Example 1 Detailed Implementation

[0017] The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0018] Example 1: Preparation of Docetaxel Nanocrystals

[0019] Step 1: Accurately weigh 1.2g of docetaxel raw material and 1.2g of sodium bicarbonate, dissolve in 30mL of pure water, stir thoroughly, transfer to a ball mill cup, add 60mL of zirconia beads (1mm in diameter), and grind using a planetary ball mill for 4 hours at 400rpm with a 5min interval to obtain a docetaxel nanocrystalline suspension with an average particle size of ~167nm.

[0020] Step 2: Add 1.5g of mannitol to the nano-suspension prepared above, pre-freeze at -80℃ for 12h, and then freeze-dry under vacuum at -90℃ for 48h. Docetaxel nanocrystal freeze-dried powder is obtained, which appears as a loose white powder. After reconstitution with 1mL of 2.5% citric acid solution per 100mg of freeze-dried product, docetaxel nanocrystals with an average particle size of ~200nm are obtained. This product can be used for intravenous injection, local injection, and intravesical instillation.

[0021] Example 2: Preparation of Borneol Nanocrystals

[0022] Step 1: Accurately weigh 1.0g of borneol and 1.2g of sodium citrate, dissolve them in 30mL of pure water, stir thoroughly, transfer to a ball mill cup, add 60ml of zirconia beads (1mm in diameter), and grind with a planetary ball mill for 4 hours at 400rpm with a 5min interval to obtain a borneol nanocrystalline suspension.

[0023] Step 2: Add 1.5g of mannitol to the nano-suspension prepared above, pre-freeze at -80℃ for 12h, and then freeze-dry under vacuum at -90℃ for 48h. Docetaxel nanocrystalline freeze-dried powder is obtained, appearing as a loose white powder. After reconstitution with 1mL of 2.5% citric acid solution per 100mg of freeze-dried product, borneol nanocrystalline powder is obtained.

[0024] This product can be used for purposes such as mucosal drug delivery.

Claims

1. A pharmaceutical nanocrystal formulation, characterized in that: The formulation comprises drug crystalline particles and a stabilizer, wherein the drug is docetaxel, and the stabilizer is sodium citrate, and the mass ratio of the drug crystalline particles to the stabilizer is 1:5 to 2:

1. The formulation further includes a freeze-drying protectant, wherein the freeze-drying protectant is mannitol. In the lyophilized product of the preparation, the mass ratio of drug:stabilizer:freeze-drying protectant is 1:(0.5-3):(1-2). The preparation method of the aforementioned drug nanocrystalline formulation includes the following steps: (1) Preparation of suspension: The active pharmaceutical ingredient, stabilizer solution and grinding beads are placed in a grinding cup and ground with a planetary ball mill; (2) Freeze-drying: The freeze-dried product is obtained by adding a freeze-drying protectant to the grinding slurry and then freeze-drying it.

2. The pharmaceutical nanocrystal formulation as described in claim 1, characterized in that: In the preparation method, the size of the grinding beads is selected from 0.1 mm, 0.2-0.3 mm and 1 mm, and the material of the grinding beads is selected from zirconium dioxide or agate.

3. The pharmaceutical nanocrystal formulation as described in claim 1, characterized in that: In the preparation method, the grinding speed is 200-800 rpm and the grinding time is 0.5-10 h.

4. The pharmaceutical nanocrystal formulation as described in claim 1, characterized in that: The preparation method further includes reconstituted lyophilized product, wherein the reconstituted solution is a 1% to 5% (w / v) citric acid aqueous solution.

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