Stable nitroimidazole ophthalmic pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a preparation method and application of a stable nitroimidazole ophthalmic pharmaceutical composition. Specifically, the invention relates to an ophthalmic pharmaceutical composition, which comprises a nitroimidazole drug, a solubilizer, a stabilizer, a thickener, an osmotic pressure regulator and a pH regulator, and the stabilizer comprises a block polymer. The invention also relates to a preparation method of the ophthalmic pharmaceutical composition and application of the ophthalmic pharmaceutical composition in prevention / treatment of demodex blepharitis and meibomian gland dysfunction.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a stable nitroimidazole ophthalmic drug composition, its preparation method, and its application. Background Technology

[0002] Demodex mites are small parasitic mites widely distributed in nature. Ocular Demodex mites include *Demodex folliculorum* and *Demodex brevis*, which reside in the eyelash follicles, sebaceous glands, and meibomian glands, respectively, often causing symptoms such as blepharitis and meibomian gland dysfunction. Demodex blepharitis is an inflammation of the eyelid margin caused by *Demodex folliculorum* and *Demodex brevis*. Demodex mites cause inflammation through direct damage, immune responses, and secondary microbial infections. The detection rate of Demodex mites in patients with blepharitis ranges from 23.8% to 90.0%. A single-center study in India showed a 78.7% detection rate of Demodex mites in 150 patients with blepharitis, with a detection rate of 90% in anterior blepharitis, 60% in posterior blepharitis, and 90% in mixed blepharitis. A single-center study in Huainan, my country, showed a 26.76% detection rate of Demodex mites in 400 patients with blepharitis. Demodex blepharitis can occur in people of all ages, but epidemiological data on its incidence in different age groups are still lacking. Although the detection rate of Demodex blepharitis varies among different studies, most studies agree that the detection rate of both Demodex brevis and Demodex folliculorum on the eyelid margin increases with age. No significant difference in the detection rate of Demodex blepharitis has been found between male and female patients.

[0003] Currently, treatment for Demodex blepharitis and meibomian gland dysfunction primarily involves local deworming, with a course of treatment typically lasting 2-3 months to prevent recurrence. There are three main treatment methods: local physical therapy (eyelid cleaning, warm compresses and massage, and intense pulsed light), local drug therapy (deworming medications: 2% metronidazole eye ointment or gel, tea tree oil wipes or 5% tea tree oil eye ointment; local anti-inflammatory medications: corticosteroid eye ointment, low-concentration corticosteroid eye drops, nonsteroidal anti-inflammatory drugs, artificial tears), and systemic drug therapy (which may combine oral doxycycline to suppress the inflammatory response, ivermectin, and metronidazole).

[0004] Nitroimidazole compounds, as a class of antibacterial drugs, have good killing effects on anaerobic bacteria and Demodex mites. Demodex blepharitis is a chronic inflammation caused by Demodex mites parasitizing the eyelash follicles or meibomian glands. Nitroimidazole drugs reduce the irritation and damage to ocular tissues by inhibiting the metabolic activity of Demodex mites. Clinically, 2% metronidazole eye ointment or gel is commonly used, applied daily to the eyelid margin and eyelash roots. Studies have shown that metronidazole combined with other drugs (such as 4-terpineol) can significantly improve the mite-killing effect and improve tear film stability. In addition, metronidazole can also be used in combination with ivermectin, achieving a Demodex mite eradication rate of up to 96.6% after local application, with no obvious adverse reactions. Meanwhile, metronidazole is often used as a local antibacterial and acaricidal drug. By killing Demodex mites, it reduces their stimulation of the meibomian glands, thereby improving the secretory function of the meibomian glands. Furthermore, metronidazole also has a certain anti-inflammatory effect, which can reduce the inflammatory response around the meibomian glands.

[0005] However, metronidazole is a hydrophobic drug with an alcoholic hydroxyl group in its chemical structure. Under neutral or alkaline conditions, the hydrogen ions in this hydroxyl group readily dissociate. Furthermore, metronidazole belongs to the nitroimidazole class of compounds, and its chemical structure contains an aromatic ring, which may lead to degradation under light and oxidation. Currently, metronidazole is typically formulated as an ointment or gel, and cannot be prepared as eye drops. This results in the common drawbacks of traditional ophthalmic formulations: short residence time in the eye, poor stability, susceptibility to tear film affecting bioavailability, long treatment cycles, and significant economic costs, placing a burden on patients. Therefore, it is essential to develop a stable metronidazole ophthalmic drug composition that overcomes the shortcomings of traditional formulations. Summary of the Invention

[0006] To address the shortcomings of traditional nitroimidazole formulations in the prior art, such as poor stability due to poor solubility and easy degradation of nitroimidazole compounds, as well as the short residence time, low bioavailability, and long dosing cycle of nitroimidazole drugs, this invention selects block polymers as stabilizers and cyclodextrin pharmaceutical excipients as solubilizers to prepare a stable nitroimidazole ophthalmic drug composition.

[0007] The block polymer selected in this invention is composed of hydrophilic and hydrophobic polymer fragments, and forms a core-shell structure with a hydrophobic core and a hydrophilic shell through hydrophilic-hydrophobic interactions.

[0008] On the one hand, the core-shell structure with a hydrophobic core and a hydrophilic shell encapsulates the active ingredient (nitroimidazole compounds), preventing it from dissociating or degrading due to environmental influences, thus improving the stability of the active ingredient in aqueous solution. Furthermore, the sustained-release properties of the hydrophilic and hydrophobic structure allow for the continuous and effective release of the active ingredient. On the other hand, thermosensitive polymers can undergo phase transitions at specific temperatures. Some embodiments of this invention employ thermosensitive polymers. The pharmaceutical composition is typically liquid under environmental conditions, but after application to the eye (32–33°C), it transforms from a liquid to a gel state under the action of the thermosensitive polymer, exhibiting a certain degree of viscosity and prolonging its residence time in the eye.

[0009] Therefore, this application provides the following invention:

[0010] In one aspect, this application provides an ophthalmic pharmaceutical composition comprising, by weight, the following components:

[0011]

[0012] Solvent;

[0013] The nitroimidazole compounds include one or more of metronidazole, tinidazole, ornidazole, and morphinidazole;

[0014] The solubilizer includes one or more of hydroxypropyl-β-cyclodextrin, sulfonyl-β-cyclodextrin, β-cyclodextrin, sodium sulfonyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and γ-cyclodextrin.

[0015] The stabilizer comprises one or more of the following block polymers: polyethylene glycol-polylactic acid (PEG-b-PLA), polyethylene glycol-polycaprolactone (PEG-b-PCL), polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), polyethylene glycol-polyglycolic acid (PEG-b-PGA), polyethylene glycol-polyacrylic acid (PEG-b-PAA), polyethylene glycol-polyvinyl alcohol (PEG-b-PVA), polyethylene glycol-polycarbonate (PEG-b-PC), and polyethylene glycol-b-poly(N-isocyanate). Poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM), poly(2-methyl-2-oxetanebutyl methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO), polyethylene glycol Poly(lactic acid)-poly(ethylene glycol) (PEG-b-PLA-b-PEG), polyethylene glycol-polycaprolactone-poly(ethylene glycol) (PEG-b-PCL-b-PEG), polyethylene glycol-polymethyl methacrylate-poly(ethylene glycol) (PEG-b-PMMA-b-PEG), polyethylene glycol-polyglycolic acid-poly(ethylene glycol) (PEG-b-PGA-b-PEG), polyethylene glycol-polyacrylic acid-poly(ethylene glycol) (PEG-b-PAA-b-PEG), polyethylene glycol-polyvinyl alcohol-poly(ethylene glycol) (PEG-b-PVA) -b-PEG), polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), polymethoxyethylene glycol ester-b-poly(N-isopropylacrylamide-co-polyethylene glycol methacrylate) (PMAPOSSn-bP(NIPAMp-co-OEGMAq)), poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA).

[0016] In some embodiments, the stabilizer comprises:

[0017] (1) One or more of the following: polyethylene glycol-polylactic acid (PEG-b-PLA), polyethylene glycol-polycaprolactone (PEG-b-PCL), polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), polyethylene glycol-polyglycolic acid (PEG-b-PGA), polyethylene glycol-polyacrylic acid (PEG-b-PAA), and polyethylene glycol-polyvinyl alcohol (PEG-b-PVA);

[0018] (2) One or more of polyethylene glycol-polycarbonate (PEG-b-PC), polyethylene glycol-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM), and poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM);

[0019] (3) One or more of the following: poly(2-methyl-2-oxetanebutyl methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-b-PPO-b-PEO), and polyethylene glycol-polylactic acid-polyethylene glycol (PEG-b-PLA-b-PEG);

[0020] (4) One or more of the following: polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-b-PCL-b-PEG), polyethylene glycol-polymethyl methacrylate-polyethylene glycol (PEG-b-PMMA-b-PEG), polyethylene glycol-polyglycolic acid-polyethylene glycol (PEG-b-PGA-b-PEG), and polyethylene glycol-polyacrylic acid-polyethylene glycol (PEG-b-PAA-b-PEG); and / or

[0021] (5) One or more of the following: polyethylene glycol-polyvinyl alcohol-polyethylene glycol (PEG-b-PVA-b-PEG), polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), polymethoxyethylene glycol ester-b-poly(N-isopropylacrylamide-co-polyethylene glycol methacrylate) (PMAPOSSn-bP(NIPAMp-co-OEGMAq)), and poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA).

[0022] In some embodiments, the stabilizer comprises:

[0023] (1) One of polyethylene glycol-polylactic acid (PEG-b-PLA), polyethylene glycol-polycaprolactone (PEG-b-PCL), polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), polyethylene glycol-polyglycolic acid (PEG-b-PGA), polyethylene glycol-polyacrylic acid (PEG-b-PAA), and polyethylene glycol-polyvinyl alcohol (PEG-b-PVA);

[0024] (2) One of polyethylene glycol-polycarbonate (PEG-b-PC), polyethylene glycol-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM), and poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM);

[0025] (3) One of the following: poly(2-methyl-2-oxetanebutyl methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-b-PPO-b-PEO), and polyethylene glycol-polylactic acid-polyethylene glycol (PEG-b-PLA-b-PEG);

[0026] (4) One of the following: polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-b-PCL-b-PEG), polyethylene glycol-polymethyl methacrylate-polyethylene glycol (PEG-b-PMMA-b-PEG), polyethylene glycol-polyglycolic acid-polyethylene glycol (PEG-b-PGA-b-PEG), and polyethylene glycol-polyacrylic acid-polyethylene glycol (PEG-b-PAA-b-PEG); and / or

[0027] (5) One of the following: polyethylene glycol-polyvinyl alcohol-polyethylene glycol (PEG-b-PVA-b-PEG), polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), polymethoxyethylene glycol ester-b-poly(N-isopropylacrylamide-co-polyethylene glycol methacrylate) (PMAPOSSn-bP(NIPAMp-co-OEGMAq)), and poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA).

[0028] In some embodiments, the stabilizer is selected from:

[0029] (1) PEG-b-PLA, PCL-b-PNIPAM and PEG-b-PAA-b-PEG;

[0030] (2) PEG-b-PCL, PEG-b-PNIPAM, PMOP-b-PNIPAM, PEG-b-PGA-b-PEG and PEG-PVA-PEG;

[0031] (3) PEG-b-PMMA, PEG-b-PC, PMMA-b-PNIPAM, PEG-b-PMMA-b-PEG and PEG-PC-PEG;

[0032] (4) PEG-b-PGA, PEG-b-PVA, PEO-b-PPO-b-PEO, PEG-b-PCL-b-PEG and PMAPOSSn-bP (NIPAMp-co-OEGMAq);

[0033] (5) PEG-b-PAA, PEG-b-PLA-b-PEG and PHEMA-b-PNIPAM-b-PHEMA;

[0034] (6) PEG-b-PVA;

[0035] (7) PEG-b-PNIPAM;

[0036] (8) PEG-b-PVA-b-PEG; or

[0037] (9)PHEMA-b-PNIPAM-b-PHEMA.

[0038] In some embodiments, the stabilizer has one or more of the following characteristics:

[0039] (1) The stabilizer includes polyethylene glycol-polylactic acid (PEG-b-PLA), wherein the mass ratio of polyethylene glycol segments to polylactic acid segments is 0.5:(0.1-15), for example 0.5:(0.1-0.3), 0.5:(0.3-0.5), 0.5:(0.5-0.75), 0.5:(0.75-1), 0.5:(1-5), 0.5:(5-10) or 0.5:(10-15);

[0040] (2) The stabilizer includes polyethylene glycol-polycaprolactone (PEG-b-PCL), wherein the mass ratio of polyethylene glycol segments to polycaprolactone segments is 0.5:(0.8-35), for example 0.5:(0.8-1), 0.5:(1-1.5), 0.5:(1.5-2), 0.5:(2-5), 0.5:(5-10), 0.5:(10-15), 0.5:(15-20), 0.5:(20-25), 0.5:(25-30) or 0.5:(30-35);

[0041] (3) The stabilizer includes polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), wherein the mass ratio of polyethylene glycol segments to polymethyl methacrylate segments is 0.5:(1-20), for example 0.5:(0.1-0.3), 0.5:(0.3-0.5), 0.5:(0.5-0.75), 0.5:(0.75-1), 0.5:(1-5), 0.5:(5-10), 0.5:(10-15) or 0.5:(15-20);

[0042] (4) The stabilizer includes polyethylene glycol-polyglycolic acid (PEG-b-PGA), wherein the mass ratio of polyethylene glycol segments to polyglycolic acid segments is 0.5:(0.5-18), for example 0.5:(0.1-0.3), 0.5:(0.3-0.5), 0.5:(0.5-0.75), 0.5:(0.75-1), 0.5:(1-3), 0.5:(3-6), 0.5:(6-12) or 0.5:(12-18);

[0043] (5) The stabilizer includes polyethylene glycol-polyacrylic acid (PEG-b-PAA), wherein the mass ratio of polyethylene glycol segments to polyacrylic acid segments is 0.5:(0.5-30), for example 0.5:(0.5-1), 0.5:(1-5), 0.5:(5-10), 0.5:(10-15), 0.5:(15-20), 0.5:(20-25), 0.5:(25-30);

[0044] (6) The stabilizer includes polyethylene glycol-polyvinyl alcohol (PEG-b-PVA), wherein the mass ratio of polyethylene glycol segments to polyvinyl alcohol segments is 0.5:(0.5-38), for example 0.5:(0.5-1), 0.5:(1-5), 0.5:(5-10), 0.5:(10-15), 0.5:(15-20), 0.5:(20-25), 0.5:(25-30) or 0.5:(0.5-38);

[0045] (7) The stabilizer includes polyethylene glycol-polycarbonate (PEG-b-PC), wherein the mass ratio of polyethylene glycol segments to polycarbonate segments is 0.5:(0.2-18), for example 0.5:(0.2-0.6), 0.5:(0.6-1), 0.5:(1-2), 0.5:(2-4), 0.5:(4-8), 0.5:(8-12), 0.5:(12-16), or 0.5:(16-18);

[0046] (8) The stabilizer comprises polyethylene glycol-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM), wherein the mass ratio of polyethylene glycol segments to poly(N-isopropylacrylamide) segments is (0.1–20):5, for example (0.1–1):5, (1–2):5, (2–3.3):5, (3.3–5):5.

[0047] 5, (5-10): 5, (10-15): 5 or (15-20): 5;

[0048] (9) The stabilizer comprises poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM), wherein the mass ratio of the poly(ε-caprolactone) segment to the poly(N-isopropylacrylamide) segment is (0.2–40):5, for example (0.2–1):5, (1–2):5, (2–5):5, (5–8.3):5, (8.3–10):5, (10–15):5, (15–20):5, (20–25):5.

[0049] 5, (25-30): 5, (30-35): 5 or (35-40): 5;

[0050] (10) The stabilizer comprises poly(2-methyl-2-oxetanebutyric methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), wherein the mass ratio of the poly(2-methyl-2-oxetanebutyric methacrylate) segment to the poly(N-isopropylacrylamide) segment is (0.1–30):5, for example (0.1–0.5):5, (0.5–1):5, (1–5):5, (5–7):5.

[0051] 5, (7-10): 5, (10-15): 5, (15-20): 5, (20-25): 5 or (25-30): 5;

[0052] (11) The stabilizer comprises poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), wherein the mass ratio of poly(methyl methacrylate) segments to poly(N-isopropylacrylamide) segments is (0.2–18):5, for example (0.2–1):5, (1–2):

[0053] 5, (2-5): 5, (5-8.3): 5, (8.3-10): 5, (10-15): 5 or (15-18): 5;

[0054] (12) The stabilizer comprises polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO), wherein the mass ratio of polyethylene oxide segments, polypropylene oxide segments, and polyethylene oxide segments is 0.2:

[0055] (0.6~10):(0.2~0.8), for example 0.2:(0.6~1):(0.2~0.4), 0.2:(0.6~1):(0.4~0.8), 0.2:(1~2):(0.2~0.5), 0.2:(2~4):(0.2~0.8), 0.2:(4~6):(0.3~0.5), 0.2:(6~10):(0.4~0.6), 0.2:(0.8~2):(0.4~0.6), 0.2:(5~7):(0.4~0.7), 0.2:(9~10):(0.6~0.8) or 0.2:(0.6~1):(0.6~0.8);

[0056] (13) The stabilizer includes polyethylene glycol-polylactic acid-polyethylene glycol (PEG-b-PLA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polylactic acid segments and polyethylene glycol segments is 0.5:(0.1~20):(0.5~10), for example 0.5:(0.1~0.5):(0.5~1), 0.5:(0.1~1):(0.5~1), 0.5:(1~3):(0.5~1), 0.5:(3~5):(1~5), 0.5:(5~10):(5~7), 0.5:(10~15):(5~10) or 0.5:(15~20):(8~10);

[0057] (14) The stabilizer includes polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-b-PCL-b-PEG), wherein the mass ratio of polyethylene glycol segments, polycaprolactone segments and polyethylene glycol segments is 0.5:(0.2-20):(0.5-10), for example 0.5:(0.2-1):(0.5-1), 0.5:(1-2):(1-2), 0.5:(2-5):(0.5-1), 0.5:(5-10):(2-4), 0.5:(5-10):(4-5), 0.5:(10-20):(5-7) or 0.5:(10-20):(7-10);

[0058] (15) The stabilizer comprises polyethylene glycol-polymethyl methacrylate-polyethylene glycol (PEG-b-PMMA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polymethyl methacrylate segments and polyethylene glycol segments is 0.5:(0.5-28):(0.5-10), for example 0.5:(0.5-1.5):(0.5-1), 0.5:(1.5-3):(0.5-1.5), 0.5:(3-7):(1.5-5), 0.5:(7-10):(0.5-5), 0.5:(10-15):(5-10), 0.5:(15-20):(5-10), 0.5:(15-28):(5-10) or 0.5:(15-20):(1-5);

[0059] (16) The stabilizer includes polyethylene glycol-polyglycolic acid-polyethylene glycol (PEG-b-PGA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polyglycolic acid segments and polyethylene glycol segments is 0.5:(0.1-20):(0.5-10), for example 0.5:(0.1-1):(0.5-1), 0.5:(1-2):(0.5-5), 0.5:(2-2.75):(0.5-1), 0.5:(2.75-3):(0.5-1.5), 0.5:(3-5):(5-10), 0.5:(5-10):(5-10), 0.5:(10-15):(1-10) or 0.5:(15-20):(2-5);

[0060] (17) The stabilizer comprises polyethylene glycol-polyacrylic acid-polyethylene glycol (PEG-b-PAA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polyacrylic acid segments and polyethylene glycol segments is 0.5:(0.1-18):(0.5-10), for example 0.5:(0.1-1):(0.5-1), 0.5:(1-2):(0.5-1), 0.5:(2-6):(1-3), 0.5:(2-6):(3-6), 0.5:(3-8):(6-10), 0.5:(4-10):(5-10), 0.5:(10-15):(5-10) or 0.5:(15-18):(5-6);

[0061] (18) The stabilizer comprises polyethylene glycol-polyvinyl alcohol-polyethylene glycol (PEG-b-PVA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polyvinyl alcohol segments and polyethylene glycol segments is 0.5:(0.5-15):(0.5-10), for example 0.5:(0.5-1.5):(0.5-1), 0.5:(0.5-1.5):(0.5-1.5), 0.5:(1.5-3):(0.5-2), 0.5:(3-5):(2-5), 0.5:(5-10):(5-10), 0.5:(7-9):(2-5) or 0.5:(6-8):(7-10);

[0062] (19) The stabilizer comprises polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), wherein the mass ratio of polyethylene glycol segments, polycarbonate segments and polyethylene glycol segments is 0.5:(0.1-15):(0.5-10), for example 0.5:(0.1-1):(0.5-1), 0.5:(1-2):(0.5-1.5), 0.5:(2-2.5):(0.5-1), 0.5:(2.5-5):(1-5), 0.5:(5-8):(5-8), 0.5:(8-10):(5-7) or 0.5:(10-15):(8-10);

[0063] (20) The stabilizer comprises poly(N-isopropylacrylamide-co-poly ...

[0064] (21) The stabilizer comprises poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA), wherein the mass ratio of poly(2-hydroxyethyl methacrylate) segment, poly(N-isopropylacrylamide) segment and poly(2-hydroxyethyl methacrylate) segment is (2-8):15:(3-20), for example (2-8):15:(3-8), (2-8):15:(8-20), (4-8):15:(4-8), (6-8):15:(12-20), (7-8):15:(8-10), (5-8):15:(10-15) or (5-8):15:(15-20).

[0065] In some embodiments, the stabilizer comprises a block polymer having a molecular weight (e.g., number average molecular weight) of 4-40 kDa, such as 4-5 kDa, 5-8 kDa, 8-10 kDa, 10-12 kDa, 12-15 kDa, 15-18 kDa, 18-20 kDa, 20-25 kDa, 25-28 kDa, 28-30 kDa, 30-35 kDa, or 35-40 kDa.

[0066] In some embodiments, the nitroimidazole compound or its pharmaceutically acceptable salt includes one or a mixture of metronidazole, metronidazole disodium phosphate, and metronidazole hydrochloride.

[0067] In some embodiments, the ophthalmic pharmaceutical composition contains 0.1–0.3 parts by weight, 0.3–0.5 parts by weight, 0.5–1 part by weight, 1–2 parts by weight, 2–4 parts by weight, 4–5 parts by weight, 5–6 parts by weight, 6–8 parts by weight, 8–10 parts by weight, 10–15 parts by weight, or 15–20 parts by weight. In some embodiments, the ophthalmic pharmaceutical composition contains 0.3–10 parts by weight of the nitroimidazole compound or its pharmaceutically acceptable salt.

[0068] In some embodiments, the solubilizer in the ophthalmic pharmaceutical composition is 5-8 parts by weight, 8-10 parts, 10-12 parts, 12-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-70 parts, or 70-80 parts. In some embodiments, the solubilizer in the ophthalmic pharmaceutical composition is 10-60 parts by weight.

[0069] In some embodiments, the stabilizer in the ophthalmic pharmaceutical composition is present in parts by weight of 50-75, 75-90, 90-100, 100-120, 120-150, 150-180, or 180-200. In some embodiments, the stabilizer in the ophthalmic pharmaceutical composition is present in parts by weight of 50-150.

[0070] In some embodiments, the thickener in the ophthalmic pharmaceutical composition is 0.5 to 1 part, 1 to 2 parts, 2 to 4 parts, 4 to 5 parts, 5 to 6 parts, 6 to 8 parts, or 8 to 10 parts by weight.

[0071] In some embodiments, the osmotic pressure regulator in the ophthalmic pharmaceutical composition is present in weight parts of 0.05–0.1 parts, 0.1–0.2 parts, 0.2–0.5 parts, 0.5–1 part, 1–1.2 parts, 1.2–1.6 parts, 1.6–1.8 parts, or 1.8–2 parts.

[0072] In some embodiments, the pH regulator in the ophthalmic pharmaceutical composition is present in weight parts of 0.2–0.3, 0.3–0.5, 0.5–0.7, 0.7–0.8, or 0.8–1.

[0073] In some embodiments, the thickener in the ophthalmic pharmaceutical composition includes one or more of hydroxypropyl methylcellulose, povidone, sodium hyaluronate, and glycerin.

[0074] In some embodiments, the ophthalmic pharmaceutical composition includes one or more of sodium chloride, potassium chloride, borax, boric acid, sodium sulfate, potassium sulfate, sodium nitrate, sodium acetate, mannitol, propylene glycol, and glucose.

[0075] In some embodiments, the pH adjuster in the ophthalmic pharmaceutical composition includes one or more of dilute hydrochloric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, citric acid, and sodium citrate.

[0076] In some embodiments, the solvent in the ophthalmic pharmaceutical composition is water for injection.

[0077] In some embodiments, the pH value of the ophthalmic pharmaceutical composition is 4.5 to 6.5, for example 5.0 to 6.0.

[0078] In one aspect, this application provides two methods for preparing the above-described ophthalmic pharmaceutical compositions.

[0079] Method 1 includes: after complete dissolution, adding stabilizer, thickener and osmotic pressure regulator, adjusting the pH of the solution to 5.0-6.0 with pH regulator, adding solvent to the full volume, filtering for sterilization, and obtaining a homogeneous solution.

[0080] Method 2 includes: preparing nitroimidazole compounds or their pharmaceutically acceptable salts, solubilizers and stabilizers into lyophilized powders using freeze-drying technology, then adding them to an isotonic buffer solution containing thickeners and osmotic pressure regulators, adjusting the pH of the solution to 5.0-6.0 with a pH adjuster, adding solvent to the total volume, filtering for sterilization, and obtaining a homogeneous solution.

[0081] In one aspect, this application provides the use of the above-described ophthalmic pharmaceutical composition in the preparation of pharmaceutical formulations for inhibiting the growth of ocular mites, or for the prevention / treatment of Demodex blepharitis and meibomian gland dysfunction.

[0082] The pharmaceutical composition used in this invention is a deworming drug that can be used to treat Demodex blepharitis and meibomian gland dysfunction. The dosage and administration method is as follows: for external use, 2-3 drops / time, 1-2 times / week, for continuous use for 6-12 months.

[0083] Beneficial effects

[0084] Compared with the prior art, the present invention achieves the following technical effects:

[0085] 1. The ophthalmic pharmaceutical composition of the present invention optimizes the dosage form of nitroimidazole ophthalmic preparations in the prior art; wherein, the use of block polymers improves the stability of nitroimidazole compounds under conditions such as light, redox, neutral or alkaline aqueous solutions, prolongs the shelf life of the drug, and improves the safety of topical eye drops; the sustained-release property of the hydrophilic-hydrophobic structure can continuously and effectively release nitroimidazole compounds, reduce the dosage concentration and frequency of administration, and improve patient compliance; prolonging the residence time of the drug in the eye and improving bioavailability.

[0086] 2. The block polymer raw materials used in this invention are inexpensive, the preparation process of the formulation is relatively simple, the preparation cost is low, it is easy to carry out industrial production, and it is conducive to large-scale promotion and application, thus promoting technological innovation. Attached Figure Description

[0087] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0088] Figure 1 The degradation trend of metronidazole in Comparative Example 1 solution as pH value increased;

[0089] Figure 2 The eutectic point of the eye drops obtained in Example 10 of this invention;

[0090] Figure 3 The freeze-drying curve of the eye drops obtained in Example 10 of this invention;

[0091] Figure 4 The figures show the average tear concentration-time distribution curves after the tears were instilled into the rabbit conjunctiva in Examples 1, 10, and 1 of this invention. Detailed Implementation

[0092] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention. The present invention takes a 0.05% concentration of metronidazole as an example to further explain the present invention.

[0093] Table 1 lists information on the amphiphilic block polymers used in the following embodiments.

[0094]

[0095]

[0096] Methods for testing polymer molecular weight:

[0097] The molecular weight of the above block polymers was determined by gel permeation chromatography (GPC).

[0098] Chromatographic conditions: The detector was a differential refractive index detector, the eluent was tetrahydrofuran (THF) with a purity greater than 99.5%, the column was a Plgel 5μm MIXED-C column, the flow rate was 1.0 mL / min, and the injection volume was 20 μL.

[0099] Standard sample: Polystyrene (PS) standard sample.

[0100] Plotting the standard curve: Prepare 5-6 standard samples with different molecular weights, dissolve them in THF to obtain solutions with concentrations of 5-10 mg / mL, filter them through a 0.22 μm organic phase filter membrane, and transfer them to sample vials.

[0101] After the system has reached equilibrium, standard solutions are injected sequentially in ascending order of molecular weight, and chromatograms are recorded. Linear fitting is performed with the logarithmic molecular weight of the standard (Log M) as the ordinate and the eluent volume (V) as the abscissa.

[0102] Determination of sample solution: Take the sample to be tested, weigh it accurately, put it in a 10 mL volumetric flask, add THF to dissolve it, make up to volume, filter it through a 0.22 μm organic phase filter membrane, and then inject it for analysis. Record the chromatogram and obtain the evaluation elution volume (V) of the main peak. Substitute V into the above standard curve to calculate the molecular weight (M) of the sample.

[0103] Polymer source or preparation method:

[0104] PEG-PLA, PEG-PCL, PEG-PMMA, PEG-PGA, PEG-PC, and PEG-b-PNIPAM were all purchased from Sigma; PEG-PAA, PEG-PVA, PCL-b-PNIPAM, PMOP-b-PNIPAM, PMMA-b-PNIPAM, PEG-PLA-PEG, and PEG-PCL-PEG were all purchased from Qiyue Biotechnology Co., Ltd.

[0105] PEG-PMMA-PEG, PEG-PGA-PEG, PEG-PAA-PEG, PEG-PVA-PEG, PEG-PC-PEG, PMAPOSSn-bP(NIPAMp-co-OEGMAq) and PHEMA-b-PNIPAM-b-PHEMA were all purchased from RAFT Laboratories;

[0106] PEO-PPO-PEO was purchased from BASF.

[0107] Formula composition: 5 parts metronidazole, 10 parts hydroxypropyl-β-cyclodextrin (solvent), 100 parts stabilizer (shown in Tables 2 and 3), 1 part hydroxypropyl cellulose (thickener), 0.5 parts borax (osmotic pressure regulator) and 0.4 parts citric acid (pH regulator).

[0108] Preparation process 1: First, metronidazole is dissolved in an aqueous solution for injection containing a solubilizer. After complete dissolution, stabilizer, thickener and osmotic pressure regulator are added, and the pH of the solution is adjusted to 5.0-6.0 with a pH regulator. Water for injection is added to the total volume, filtered to remove bacteria, and a homogeneous solution is obtained for ocular administration.

[0109] The distribution of stabilizers in metronidazole ophthalmic drug compositions is shown in Table 2, in mg.

[0110] Table 2

[0111]

[0112]

[0113] Stability assessments were performed on Example 1 and Comparative Example 1; the stability trend of Comparative Example 1 under different pH conditions is shown in the figure. Figure 1 .

[0114] Method for determining the content of metronidazole eye drops: The determination shall be performed by high performance liquid chromatography (HPLC), using octadecylsilane-bonded silica gel as the packing material and methanol-water (20:80) as the mobile phase; the detection wavelength is 320 nm. The theoretical plate number, calculated based on the metronidazole peak, shall not be less than 2000. Accurately measure an appropriate amount of the product, quantitatively dilute it with the mobile phase to prepare a solution containing approximately 0.25 mg of metronidazole per ml, shake well, and use this as the test solution. Accurately measure 10 μl and inject it into the HPLC system, recording the chromatogram. Separately, accurately weigh an appropriate amount of metronidazole reference standard, dissolve it in the mobile phase, and quantitatively dilute it to prepare a solution containing approximately 0.25 mg of metronidazole per ml, and determine it using the same method. The result is calculated based on the peak area using the external standard method.

[0115] Method for detecting related substances in metronidazole eye drops: The determination is performed by high-performance liquid chromatography (HPLC), using octadecylsilane-bonded silica gel as the stationary phase and methanol-1.36 g / L potassium dihydrogen phosphate solution (14:86) as the mobile phase; the detection wavelength is 315 nm; the flow rate is 1.0 mL / min; and the injection volume is 30 μL. Take 10 mL of this product as the test solution; accurately measure 1.0 mL into a 100 mL volumetric flask, dilute to volume with the mobile phase, and use as the control solution. Accurately measure both the test solution and the control solution, inject them into the HPLC system, and record the chromatograms at three times the retention time of the main peak.

[0116] 1. Experiment on influencing factors

[0117] Take the prepared sample solutions of Example 1 and Comparative Example 1, place them in colorless, transparent, sealed ampoules, and place them under temperature of 60°C and light (4500Lx±500Lx) respectively. Samples were taken on the 5th and 10th days respectively for inspection. The results were compared with the sample on day 0. The test results are shown in Table 3.

[0118] Table 3. Results of experiments on factors affecting metronidazole eye drops.

[0119]

[0120]

[0121] 2. Accelerated testing

[0122] Metronidazole eye drops from Example 1 and Comparative Example 1 were packaged in commercially available brown eye drop bottles and placed at a temperature of 40℃±2℃ and RH of 75%±5% for 6 months. Samples were taken and tested at 1, 2, 3 and 6 months respectively. The results were compared with the sample on day 0. The test results are shown in Table 4.

[0123] Table 4 Results of accelerated test of metronidazole eye drops

[0124]

[0125] 3. Long-term testing

[0126] The metronidazole eye drops prepared in Example 1 and Comparative Example 1 were packaged in commercially available brown eye drop bottles and stored at a temperature of 25℃±2℃ and RH of 60%±10%. Samples were taken and tested at the 3rd and 6th months. The results were compared with the sample taken at day 0. The test results are shown in Table 5.

[0127] Table 5. Results of long-term trials of metronidazole eye drops

[0128]

[0129] Preparation process 2: Based on preparation process 1, metronidazole, solubilizer and stabilizer are prepared into lyophilized powder by freeze drying technology (freeze drying time is 24 hours), and then added to isotonic buffer containing thickener and osmotic pressure regulator. The pH of the solution is adjusted to 5.0 to 6.0 with pH regulator, and water for injection is added to the total volume. The solution is filtered to remove bacteria and a homogeneous solution is obtained for ocular administration.

[0130] Isotonic buffer: 1 part hydroxypropyl cellulose (thickener), 0.5 parts borax (osmotic pressure regulator) and water for injection.

[0131] The comparative example uses a conventional preparation process and is not freeze-dried.

[0132] The distribution of stabilizers in metronidazole ophthalmic drug compositions is shown in Table 6, in mg.

[0133] Table 6

[0134]

[0135]

[0136] The pH value of the test solutions in Examples 6-10 was measured before lyophilization and the stability was evaluated after lyophilization.

[0137] (1) Determination of pH value of samples before freeze-drying in Examples 6-10

[0138] The pH values ​​of the sample solutions (volume 1 mL) in Examples 6-10 before lyophilization were measured using a pH meter. The pH values ​​of the sample solutions before lyophilization were almost identical, as detailed in Table 7.

[0139] Table 7

[0140]

[0141] (2) Stability of the freeze-dried sample of Example 10 and Comparative Example 2 under influencing factors

[0142] Take the sample solutions of Example 10 and Comparative Example 2, place them in colorless, transparent, sealed ampoules, and place them under the conditions of temperature 60°C and light (4500Lx±500Lx), respectively. Samples were taken and tested on the 5th and 10th days, respectively. The results were compared with the sample on day 0. The test results are shown in Table 8.

[0143] Table 8. Results of Experiments on Factors Affecting Metronidazole Lyophilized Eye Drops

[0144]

[0145]

[0146] Therefore, the freeze-dried sample of Example 10 was used as the test sample to plot the freeze-drying minimum eutectic point and freeze-drying curve.

[0147] (3) Determination of the lowest eutectic point

[0148] Detection method: The metronidazole solution before lyophilization was placed in a freezer at -20℃. The temperature of the solution was measured using a Beckman thermometer, and recorded every 1 minute. The plateau period of the temperature-time curve was the eutectic point. The results showed that the eutectic point of the lyophilized metronidazole sample was approximately -1℃. See details... Figure 2 .

[0149] (4) Determination of freeze-drying curve

[0150] Freeze-drying process: The metronidazole solution before freeze-drying was first pre-frozen at -80℃ for 8 hours, then frozen under reduced pressure at -35℃ for 2 hours, followed by sublimation drying at -25℃ for 12 hours, and then heated to 20℃ for desorption drying for 2 hours. Data were recorded and a freeze-drying curve was plotted. See details. Figure 3 .

[0151] The results of the determination of the lowest eutectic point and the freeze-drying curve indicate that it is feasible to prepare metronidazole freeze-dried eye drops using the above freeze-drying process.

[0152] Furthermore, Examples 1 and 10 were selected for rabbit eye irritation and intraocular elimination dynamics characterization:

[0153] Rabbit eye irritation

[0154] Four healthy rabbits were used. Before administration, the cornea, iris, and conjunctiva of each rabbit were observed and recorded. Rabbits with lesions or inflammation were excluded. During the experiment, the left eye of the rabbit was instilled with the drug from Example 1 as the test group, and the right eye was instilled with physiological saline as the control group. For the single-dose eye irritation test, the eyes were examined at 1, 2, 4, 24, 48, and 72 hours after the first administration. For the multiple-dose eye irritation test, the drug was administered 3-4 times a day for 5 consecutive days, and the eyes were examined before each administration and at 1, 2, 4, 24, 48, and 72 hours after the last administration. The degree of irritation in the test group was determined according to the "Draize Eye Irritation Test Scoring Criteria". The results showed that after single and multiple administrations, no abnormal changes were observed in the cornea, iris, and conjunctiva by naked eye, and the overall irritation score was 0, indicating that the metronidazole ophthalmic drug composition was non-irritating to the rabbit eyes, had good safety, and met the requirements for ophthalmic medication (see Table 9 for details).

[0155] Table 9

[0156]

[0157] Intraocular elimination dynamics characterization

[0158] Test method:

[0159] Healthy rabbits were randomly divided into three groups: Example 1, Example 10, and Comparative Example 1. 50 μL of the drug solution was injected into each eye using a pipette, and the drug was administered to both eyes. Tears were collected at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 420 min after drug administration and stored frozen at -20°C.

[0160] Chromatographic and mass spectrometry conditions:

[0161] Chromatographic conditions: Mobile phase: acetonitrile-methanol-30 mmol·L⁻¹ -1 Ammonium acetate aqueous solution (65:15:20), flow rate 1.0 mL·min⁻¹, split ratio 1:3, column temperature room temperature;

[0162] Column: C 18 Chromatographic column (4.6×250mm, 5μm)

[0163] Mass spectrometry conditions: Ion source: electrospray ionization source (ESI source); Detection mode: positive ion detection; Scanning mode: MRM; Capillary voltage: 3.0KV; Cone voltage: 50V.

[0164] The results showed that single-dose administration in Examples 1 and 10 significantly improved bioavailability and intraocular retention time. Detailed results can be found in [link to relevant documentation]. Figure 4 .

[0165] In summary, this invention discloses a stable metronidazole ophthalmic pharmaceutical composition. During the preparation process, the metronidazole ophthalmic pharmaceutical composition of this invention utilizes freeze-drying technology combined with the functional properties of a temperature-sensitive polymer block copolymer, significantly improving the stability of metronidazole, delaying the drug's residence time on the ocular surface, and increasing the drug's accumulation concentration in the eye, thus providing a more effective novel pharmaceutical formulation for Demodex blepharitis and meibomian gland dysfunction.

[0166] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An ophthalmic pharmaceutical composition, comprising, by weight, the following components: The nitroimidazole compounds include one or more of metronidazole, tinidazole, ornidazole, and morphinidazole; The solubilizer includes one or more of hydroxypropyl-β-cyclodextrin, sulfonyl-β-cyclodextrin, β-cyclodextrin, sodium sulfonyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and γ-cyclodextrin. The stabilizer comprises one or more of the following block polymers: polyethylene glycol-polylactic acid (PEG-b-PLA), polyethylene glycol-polycaprolactone (PEG-b-PCL), polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), polyethylene glycol-polyglycolic acid (PEG-b-PGA), polyethylene glycol-polyacrylic acid (PEG-b-PAA), polyethylene glycol-polyvinyl alcohol (PEG-b-PVA), polyethylene glycol-polycarbonate (PEG-b-PC), and polyethylene glycol-b-poly(N-isocyanate). Poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM), poly(2-methyl-2-oxetanebutyl methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO), polyethylene glycol Poly(lactic acid)-poly(ethylene glycol) (PEG-b-PLA-b-PEG), polyethylene glycol-polycaprolactone-poly(ethylene glycol) (PEG-b-PCL-b-PEG), polyethylene glycol-polymethyl methacrylate-poly(ethylene glycol) (PEG-b-PMMA-b-PEG), polyethylene glycol-polyglycolic acid-poly(ethylene glycol) (PEG-b-PGA-b-PEG), polyethylene glycol-polyacrylic acid-poly(ethylene glycol) (PEG-b-PAA-b-PEG), polyethylene glycol-polyvinyl alcohol-poly(ethylene glycol) (PEG-b-PVA) -b-PEG), polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), polymethoxyethylene glycol ester-b-poly(N-isopropylacrylamide-co-polyethylene glycol methacrylate) (PMAPOSSn-bP(NIPAMp-co-OEGMAq)), poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA).

2. The ophthalmic pharmaceutical composition according to claim 1, wherein, The stabilizer includes: (1) One or more of the following: polyethylene glycol-polylactic acid (PEG-b-PLA), polyethylene glycol-polycaprolactone (PEG-b-PCL), polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), polyethylene glycol-polyglycolic acid (PEG-b-PGA), polyethylene glycol-polyacrylic acid (PEG-b-PAA), and polyethylene glycol-polyvinyl alcohol (PEG-b-PVA); (2) One or more of polyethylene glycol-polycarbonate (PEG-b-PC), polyethylene glycol-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM), and poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM); (3) One or more of the following: poly(2-methyl-2-oxetanebutyl methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-b-PPO-b-PEO), and polyethylene glycol-polylactic acid-polyethylene glycol (PEG-b-PLA-b-PEG); (4) One or more of the following: polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-b-PCL-b-PEG), polyethylene glycol-polymethyl methacrylate-polyethylene glycol (PEG-b-PMMA-b-PEG), polyethylene glycol-polyglycolic acid-polyethylene glycol (PEG-b-PGA-b-PEG), and polyethylene glycol-polyacrylic acid-polyethylene glycol (PEG-b-PAA-b-PEG); and / or (5) One or more of the following: polyethylene glycol-polyvinyl alcohol-polyethylene glycol (PEG-b-PVA-b-PEG), polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), polymethoxyethylene glycol ester-b-poly(N-isopropylacrylamide-co-polyethylene glycol methacrylate) (PMAPOSSn-bP(NIPAMp-co-OEGMAq)), and poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA).

3. The ophthalmic pharmaceutical composition according to claim 1 or 2, wherein, The stabilizer includes: (1) One of polyethylene glycol-polylactic acid (PEG-b-PLA), polyethylene glycol-polycaprolactone (PEG-b-PCL), polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), polyethylene glycol-polyglycolic acid (PEG-b-PGA), polyethylene glycol-polyacrylic acid (PEG-b-PAA), and polyethylene glycol-polyvinyl alcohol (PEG-b-PVA); (2) One of polyethylene glycol-polycarbonate (PEG-b-PC), polyethylene glycol-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM), and poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM); (3) One of the following: poly(2-methyl-2-oxetanebutyl methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-b-PPO-b-PEO), and polyethylene glycol-polylactic acid-polyethylene glycol (PEG-b-PLA-b-PEG); (4) One of the following: polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-b-PCL-b-PEG), polyethylene glycol-polymethyl methacrylate-polyethylene glycol (PEG-b-PMMA-b-PEG), polyethylene glycol-polyglycolic acid-polyethylene glycol (PEG-b-PGA-b-PEG), and polyethylene glycol-polyacrylic acid-polyethylene glycol (PEG-b-PAA-b-PEG); and / or (5) One of the following: polyethylene glycol-polyvinyl alcohol-polyethylene glycol (PEG-b-PVA-b-PEG), polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), polymethoxyethylene glycol ester-b-poly(N-isopropylacrylamide-co-polyethylene glycol methacrylate) (PMAPOSSn-bP(NIPAMp-co-OEGMAq)), and poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA).

4. The ophthalmic pharmaceutical composition according to any one of claims 1-3, wherein, The stabilizer is selected from: (1) PEG-b-PLA, PCL-b-PNIPAM and PEG-b-PAA-b-PEG; (2) PEG-b-PCL, PEG-b-PNIPAM, PMOP-b-PNIPAM, PEG-b-PGA-b-PEG and PEG-PVA-PEG; (3) PEG-b-PMMA, PEG-b-PC, PMMA-b-PNIPAM, PEG-b-PMMA-b-PEG and PEG-PC-PEG; (4) PEG-b-PGA, PEG-b-PVA, PEO-b-PPO-b-PEO, PEG-b-PCL-b-PEG and PMAPOSSn-bP (NIPAMp-co-OEGMAq); (5) PEG-b-PAA, PEG-b-PLA-b-PEG and PHEMA-b-PNIPAM-b-PHEMA; (6) PEG-b-PVA; (7) PEG-b-PNIPAM; (8) PEG-b-PVA-b-PEG; or (9)PHEMA-b-PNIPAM-b-PHEMA.

5. The ophthalmic pharmaceutical composition according to any one of claims 1-4, wherein, The stabilizer has one or more of the following characteristics: (1) The stabilizer includes polyethylene glycol-polylactic acid (PEG-b-PLA), wherein the mass ratio of polyethylene glycol segments to polylactic acid segments is 0.5:(0.1-15); (2) The stabilizer includes polyethylene glycol-polycaprolactone (PEG-b-PCL), wherein the mass ratio of polyethylene glycol segments to polycaprolactone segments is 0.5:(0.8-35); (3) The stabilizer includes polyethylene glycol-polymethyl methacrylate (PEG-b-PMMA), wherein the mass ratio of polyethylene glycol segments to polymethyl methacrylate segments is 0.5:(1-20); (4) The stabilizer includes polyethylene glycol-polyglycolic acid (PEG-b-PGA), wherein the mass ratio of polyethylene glycol segments to polyglycolic acid segments is 0.5:(0.5~18); (5) The stabilizer includes polyethylene glycol-polyacrylic acid (PEG-b-PAA), wherein the mass ratio of polyethylene glycol segments to polyacrylic acid segments is 0.5:(0.5~30); (6) The stabilizer includes polyethylene glycol-polyvinyl alcohol (PEG-b-PVA), wherein the mass ratio of polyethylene glycol segments to polyvinyl alcohol segments is 0.5:(0.5~38); (7) The stabilizer includes polyethylene glycol-polycarbonate (PEG-b-PC), wherein the mass ratio of polyethylene glycol segments to polycarbonate segments is 0.5:(0.2-18); (8) The stabilizer includes polyethylene glycol-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM), wherein the mass ratio of polyethylene glycol segments to poly(N-isopropylacrylamide) segments is (0.1-20):5; (9) The stabilizer comprises poly(ε-caprolactone)-b-poly(N-isopropylacrylamide) (PCL-b-PNIPAM), wherein the mass ratio of poly(ε-caprolactone) segment to poly(N-isopropylacrylamide) segment is (0.2-40):5; (10) The stabilizer comprises poly(2-methyl-2-oxetanebutyric methacrylate)-b-poly(N-isopropylacrylamide) (PMOP-b-PNIPAM), wherein the mass ratio of poly(2-methyl-2-oxetanebutyric methacrylate) segment to poly(N-isopropylacrylamide) segment is (0.1-30):5; (11) The stabilizer comprises poly(methyl methacrylate)-b-poly(N-isopropylacrylamide) (PMMA-b-PNIPAM), wherein the mass ratio of poly(methyl methacrylate) segments to poly(N-isopropylacrylamide) segments is (0.2-18):5; (12) The stabilizer includes polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO), wherein the mass ratio of polyoxyethylene segments, polyoxypropylene segments and polyoxyethylene segments is 0.2:(0.6-10):(0.2-0.8); (13) The stabilizer includes polyethylene glycol-polylactic acid-polyethylene glycol (PEG-b-PLA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polylactic acid segments and polyethylene glycol segments is 0.5:(0.1~20):(0.5~10); (14) The stabilizer includes polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-b-PCL-b-PEG), wherein the mass ratio of polyethylene glycol segments, polycaprolactone segments and polyethylene glycol segments is 0.5:(0.2~20):(0.5~10); (15) The stabilizer includes polyethylene glycol-polymethyl methacrylate-polyethylene glycol (PEG-b-PMMA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polymethyl methacrylate segments and polyethylene glycol segments is 0.5:(0.5~28):(0.5~10); (16) The stabilizer includes polyethylene glycol-polyglycolic acid-polyethylene glycol (PEG-b-PGA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polyglycolic acid segments and polyethylene glycol segments is 0.5:(0.1~20):(0.5~10); (17) The stabilizer includes polyethylene glycol-polyacrylic acid-polyethylene glycol (PEG-b-PAA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polyacrylic acid segments and polyethylene glycol segments is 0.5:(0.1~18):(0.5~10); (18) The stabilizer includes polyethylene glycol-polyvinyl alcohol-polyethylene glycol (PEG-b-PVA-b-PEG), wherein the mass ratio of polyethylene glycol segments, polyvinyl alcohol segments and polyethylene glycol segments is 0.5:(0.5~15):(0.5~10); (19) The stabilizer includes polyethylene glycol-polycarbonate-polyethylene glycol (PEG-b-PC-b-PEG), wherein the mass ratio of polyethylene glycol segments, polycarbonate segments and polyethylene glycol segments is 0.5:(0.1-15):(0.5-10); (20) The stabilizer comprises poly(N-isopropylacrylamide-co-poly ... (21) The stabilizer comprises poly(2-hydroxyethyl methacrylate)-b-poly(N-isopropylacrylamide)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-PNIPAM-b-PHEMA), wherein the mass ratio of poly(2-hydroxyethyl methacrylate) segment, poly(N-isopropylacrylamide) segment and poly(2-hydroxyethyl methacrylate) segment is (2-8):15:(3-20).

6. The ophthalmic pharmaceutical composition according to any one of claims 1-4, wherein, The stabilizer comprises a block polymer having a molecular weight of 4-40 kDa.

7. The ophthalmic pharmaceutical composition according to any one of claims 1-6, wherein, The nitroimidazole compounds or their pharmaceutically acceptable salts include one or a mixture of metronidazole, metronidazole disodium phosphate, and metronidazole hydrochloride.

8. The ophthalmic pharmaceutical composition according to any one of claims 1-7, having one or more of the following characteristics: (1) The weight parts of the nitroimidazole compound or its pharmaceutically acceptable salt are 0.3 to 10 parts; (2) The solubilizer is 10 to 60 parts by weight; (3) The stabilizer is 50 to 150 parts by weight.

9. The ophthalmic pharmaceutical composition according to any one of claims 1-8, having one or more of the following characteristics: (1) The thickener includes one or more of hydroxypropyl methylcellulose, povidone, sodium hyaluronate, and glycerin; (2) The osmotic pressure regulator includes one or more of sodium chloride, potassium chloride, borax, boric acid, sodium sulfate, potassium sulfate, sodium nitrate, sodium acetate, mannitol, propylene glycol, and glucose; (3) The pH adjuster includes one or more of dilute hydrochloric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, citric acid, and sodium citrate; (4) The solvent is water for injection.

10. The ophthalmic pharmaceutical composition according to any one of claims 1-9, wherein the pH value of the ophthalmic pharmaceutical composition is 4.5-6.5, preferably 5.0-6.

0.

11. A method for preparing an ophthalmic pharmaceutical composition according to any one of claims 1-10, the method comprising: Nitroimidazole compounds or their pharmaceutically acceptable salts are dissolved in a solution containing a solubilizer. After complete dissolution, stabilizers, thickeners, and osmotic pressure regulators are added, and the pH of the solution is adjusted to 5.0–6.0 with a pH adjuster. The solvent is then added to the total volume, and the solution is filtered to remove bacteria, resulting in a homogeneous solution.

12. A method for preparing an ophthalmic pharmaceutical composition according to any one of claims 1-10, the method comprising: Nitroimidazole compounds or their pharmaceutically acceptable salts, solubilizers, and stabilizers are prepared into lyophilized powders using freeze-drying technology. These powders are then added to an isotonic buffer solution containing a thickener and an osmotic pressure regulator. The pH of the solution is adjusted to 5.0–6.0 using a pH adjuster. Solvent is added to the final volume, and the solution is filtered to remove bacteria, resulting in a homogeneous solution.

13. Use of the ophthalmic pharmaceutical composition according to any one of claims 1-10 in the preparation of a pharmaceutical formulation for inhibiting the growth of ocular mites, or for the prevention / treatment of Demodex blepharitis and meibomian gland dysfunction.

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