A hydroxymethazine hydrochloride eye drop composition and its preparation method

Abstract

This invention discloses an oxymetazoline hydrochloride eye drop composition and its preparation method, belonging to the field of pharmaceutical preparations. The composition comprises oxymetazoline hydrochloride, sodium chloride, sodium acetate, sodium citrate, hydroxypropyl methylcellulose, hydrochloric acid, and water. The preparation method is simple, and the composition can be filtered and sterilized using a 0.22 μm pore size filter, allowing for stable storage for 48 months.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a composition containing oxymetazoline hydrochloride eye drops and its preparation method. Background Technology

[0002] Ptosis, or drooping eyelid, is a common clinical condition caused by structural abnormalities (muscles or aponeurosis) or neurological problems leading to downward displacement of the upper eyelid. It can be classified as congenital or acquired, and is generally treated surgically.

[0003] Oxymetazoline hydrochloride is an imidazoline derivative with sympathomimetic activity. It is an α-adrenergic receptor agonist and is commonly used as a vasoconstrictor in eye drops and nasal sprays. The chemical name of oxymetazoline hydrochloride is 6-tert-butyl-3-[(4,5-dihydro-1-yl) ... H [-imidazol-2-yl)methyl]-2,4-dimethylphenol hydrochloride, with the chemical formula C1 16 H 24 N2O·HCl, with a molecular weight of 296.84 and CAS number 2315-02-8.

[0004] Rvl Pharmaceuticals Inc.'s oxymetazoline hydrochloride eye drops were launched in the United States on July 8, 2020, under the brand name Upneeq. ® The specification is 0.1% (0.3ml: 0.3mg), and the indication is for the treatment of acquired ptosis in adults.

[0005] ZL202010249167.7 disclosed Upneeq ® The composition has a shelf life of 30 months. Summary of the Invention

[0006] Through in-depth research and experimentation, the inventors have provided an eye drop composition containing oxymetazoline hydrochloride and its preparation method.

[0007] Upneeq ® It uses a balanced salt solution as an excipient to achieve a pH value and osmolar concentration close to that of artificial tears.

[0008] The inventors of Upneeq ® When conducting compatibility tests on the four osmotic pressure regulators (sodium chloride, potassium chloride, calcium chloride, and magnesium chloride) in the composition, it was unexpectedly found that using only sodium chloride as an osmotic pressure regulator not only ensured that the product's osmotic molar concentration was close to that of artificial tears, but also... ® Approaching, and of quality with Upneeq ®In addition to consistency, it also improves the stability of the product, which can be stably stored for 48 months under long-term test conditions (temperature 25℃±2℃, relative humidity 40%±5%).

[0009] In accordance with the guidelines for stability testing of active pharmaceutical ingredients and preparations in General Chapter 9001 of the 2025 edition of the Chinese Pharmacopoeia, the inventors conducted influencing factor tests (high temperature 60℃, 30 days), accelerated tests (temperature 40℃±2℃, relative humidity not exceeding 25%RH, 6 months), and long-term tests (temperature 25℃±2℃, relative humidity 40%±5%, 48 months) on the composition. The results showed that the composition's appearance, pH value, osmolality, viscosity, related substances, insoluble particles, visible foreign matter, fill volume, sterility, and content all met the quality standard requirements.

[0010] Based on the above findings, the inventors provide the following invention.

[0011] In a first aspect, the inventors provide an oxymetazoline hydrochloride eye drop composition, specifically comprising oxymetazoline hydrochloride, sodium chloride, sodium acetate, sodium citrate, hydroxypropyl methylcellulose, hydrochloric acid, and water. Oxymetazoline hydrochloride is the active ingredient, sodium chloride is an osmotic pressure regulator, sodium acetate and sodium citrate are buffers, hydroxypropyl methylcellulose is a thickener, hydrochloric acid is a pH adjuster, and water is a solvent.

[0012] In some embodiments, the composition comprises 0.1% oxymetazoline hydrochloride, 0.74% sodium chloride, 0.39% sodium acetate, 0.17% sodium citrate, 0.5% hydroxypropyl methylcellulose, a suitable amount of hydrochloric acid, and the balance being water.

[0013] In some embodiments, the osmotic pressure regulator is potassium chloride. Specifically, the composition consists of 0.1% oxymetazoline hydrochloride, 0.94% potassium chloride, 0.39% sodium acetate, 0.17% sodium citrate, 0.5% hydroxypropyl methylcellulose, a suitable amount of hydrochloric acid, and the balance being water.

[0014] In some embodiments, the osmotic pressure regulator is calcium chloride. Specifically, the composition consists of 0.1% oxymetazoline hydrochloride, 1.24% calcium chloride, 0.39% sodium acetate, 0.17% sodium citrate, 0.5% hydroxypropyl methylcellulose, a suitable amount of hydrochloric acid, and the balance being water.

[0015] In some embodiments, the osmotic pressure regulator is magnesium chloride. Specifically, the composition consists of 0.1% oxymetazoline hydrochloride, 1.72% magnesium chloride, 0.39% sodium acetate, 0.17% sodium citrate, 0.5% hydroxypropyl methylcellulose, a suitable amount of hydrochloric acid, and the balance being water.

[0016] In some embodiments, the osmotic pressure regulator is sodium chloride, potassium chloride, calcium chloride, or magnesium chloride. Specifically, the composition consists of 0.1% oxymetazoline hydrochloride, 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calcium chloride, 0.03% magnesium chloride, 0.39% sodium acetate, 0.17% sodium citrate, 0.5% hydroxypropyl methylcellulose, a suitable amount of hydrochloric acid, and the balance being water.

[0017] Secondly, the present invention also provides a method for preparing an oxymetazoline hydrochloride eye drop composition, comprising the following steps: (1) Dissolve hydroxypropyl methylcellulose in the first portion of water; (2) Dissolve oxymetazoline hydrochloride, sodium chloride, sodium acetate, and sodium citrate in the second part of the water; (3) Mix the product obtained in (1) with the product obtained in (2) and adjust the pH value to 6.3~6.5 with hydrochloric acid; (4) Add water to full volume; (5) Filter with a 0.22μm pore size filter.

[0018] The oxymetazoline hydrochloride eye drop composition provided by this invention is used to treat acquired ptosis in adults.

[0019] In this invention, unless otherwise specified, the term "%" refers to w / v%, that is, weight / volume percentage. For example, 0.1% oxymetazoline hydrochloride means that the content of oxymetazoline hydrochloride in the composition is 0.1g / 100ml, or 1mg / ml, or 1g / L.

[0020] The beneficial effects achieved by this invention are as follows: (1) The composition provided by the present invention uses only sodium chloride as an osmotic pressure regulator, and its mass is similar to that of Upneeq. ® Consistent; (2) The composition provided by the present invention has few impurities and good stability. It can be stably stored for 48 months under long-term test conditions (temperature 25℃±2℃, relative humidity 40%±5%). Detailed Implementation

[0021] The embodiments of the present invention will be described in detail below with reference to examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention, but all of the following examples fall within the scope of the present invention.

[0022] While many of the materials and methods of operation used in the following embodiments are well known in the art, the present invention is still described in as much detail as possible herein. It will be apparent to those skilled in the art that, unless otherwise stated, the materials and methods of operation used in the following embodiments are well known in the art.

[0023] In the embodiments or comparative examples of the present invention, when describing the dosage, "%" refers to w / v%, that is, weight / volume percentage. For example, 0.1% oxymetazoline hydrochloride means that the content of oxymetazoline hydrochloride in the composition is 0.1g / 100ml, or 1mg / ml, or 1g / L. Implementation

[0024] Prepare samples of different osmotic pressure regulators according to the table below.

[0025]

[0026] Example 5 is the Upneeq disclosed in ZL202010249167.7. ® The composition.

[0027] Preparation methods of Examples 1 to 5: (1) Dissolve hydroxypropyl methylcellulose in the first portion of water; (2) Dissolve oxymetazoline hydrochloride, sodium chloride (or potassium chloride, or calcium chloride, or magnesium chloride, or sodium chloride, potassium chloride, calcium chloride, magnesium chloride), sodium acetate, and sodium citrate in the second part of the water; (3) Mix the product obtained in (1) with the product obtained in (2) and adjust the pH value to 6.3~6.5 with hydrochloric acid; (4) Add water to full volume; (5) Filter with a 0.22μm pore size filter.

[0028] Quality characteristic comparison test Examples 1 to 5 were tested. The properties were determined by visual inspection. The pH value was determined according to General Chapter 0631 of Part IV of the Chinese Pharmacopoeia 2025 Edition. The osmolality was determined according to General Chapter 0632 of Part IV of the Chinese Pharmacopoeia 2025 Edition. The viscosity was determined according to Method I of General Chapter 0633 of Part IV of the Chinese Pharmacopoeia 2025 Edition. The related substances and content were determined according to the related substances determination method of oxymetazoline hydrochloride in European Pharmacopoeia 11.0. The test results are shown in Table 2.

[0029]

[0030] The results of the quality characteristic comparison test show that: (1) The properties, pH value, osmolar concentration, viscosity, related substances and content of Examples 1 to 5 all meet the quality standard limit requirements; (2) That is, using 0.74% sodium chloride, or 0.94% potassium chloride, or 1.24% calcium chloride, or 1.72% magnesium chloride as osmotic pressure regulators, the quality is the same as Upneeq ®The osmotic pressure regulators are consistent with those using 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calcium chloride, and 0.03% magnesium chloride.

[0031] Stability test Influencing factor tests were conducted on Examples 1 to 5 (high temperature 60℃), and the test results are shown in Table 3.

[0032]

[0033] The results of the influencing factor experiment (high temperature 60℃) show that: (1) The pH value, osmolar concentration, viscosity and content of Examples 1 to 5 all meet the quality standard limit requirements; (2) The properties, related substances, and content of Example 1 are significantly better than those of Examples 2 to 5; after being placed at a high temperature of 60°C for 30 days, the properties and related substances of Examples 2 to 5 no longer meet the quality standard limits. (3) That is, using 0.74% sodium chloride as an osmotic pressure regulator, the stability under high temperature (60°C) is better than using 0.94% potassium chloride, or 1.24% calcium chloride, or 1.72% magnesium chloride, or Upneeq. ® 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calcium chloride, and 0.03% magnesium chloride are used as osmotic pressure regulators.

[0034] Accelerated tests were conducted on Examples 1 to 5 (temperature 40℃±2℃, relative humidity not exceeding 25%RH), and the test results are shown in Table 4.

[0035]

[0036] Accelerated test results show that: (1) The pH value, osmolar concentration, viscosity and content of Examples 1 to 5 all meet the quality standard limit requirements; (2) The properties, related substances, and content of Example 1 are significantly better than those of Examples 2 to 5; after being placed under accelerated test conditions for 6 months, the properties and related substances of Examples 2 to 5 no longer meet the quality standard limits. (3) That is, using 0.74% sodium chloride as an osmotic pressure regulator accelerates the stability under test conditions better than using 0.94% potassium chloride, or 1.24% calcium chloride, or 1.72% magnesium chloride, or Upneeq ® 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calcium chloride, and 0.03% magnesium chloride are used as osmotic pressure regulators.

[0037] Take Example 1 (pilot batch sample) and Example 5 (Upneeq)® The commercially available product underwent a long-term test (temperature 25℃±2℃, relative humidity 40%±5%). The test methods for insoluble particulate matter were as follows: General Chapter 0903 of the 2025 edition of the Chinese Pharmacopoeia, Part IV; visible foreign matter: General Chapter 0904 of the 2025 edition of the Chinese Pharmacopoeia, Part IV; fill volume: General Chapter 0942 of the 2025 edition of the Chinese Pharmacopoeia, Part IV; and sterility: General Chapter 1101 of the 2025 edition of the Chinese Pharmacopoeia, Part IV. The test results are shown in Table 5.

[0038]

[0039] Long-term test results show that: (1) Example 1 (pilot batch sample) was placed under long-term test conditions for 48 months. Its properties, pH value, osmolar concentration, viscosity, related substances, insoluble particles, visible foreign matter, fill volume, sterility and content all met the quality standard limit requirements. (2) Example 5 (Upneeq) ® (Commercially available products) After being stored under long-term testing conditions for 24 months, the properties, pH value, osmolality, viscosity, related substances, and content all meet the quality standard limits; after being stored for 36 months, the properties and related substances no longer meet the quality standard limits. (3) That is, using 0.74% sodium chloride as an osmotic pressure regulator, it can be stably stored for 48 months under long-term test conditions (temperature 25℃±2℃, relative humidity 40%±5%), and its stability is better than Upneeq. ® 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calcium chloride, and 0.03% magnesium chloride are used as osmotic pressure regulators.

[0040] Stimulation test An irritation test was conducted on the sample from Example 1 (pilot batch) to observe whether the instillation of oxymetazoline hydrochloride eye drops into rabbits had an eye irritant effect, and compared with Example 5 (Upneeq). ® By comparing it with commercially available products, relevant data can be provided to evaluate its safety.

[0041] Evaluation method: Six male Japanese white rabbits were selected, and a self-comparison method was used, with left and right sides of the same animal being compared. Oxymetazoline hydrochloride eye drops (pilot batch sample or Upneeq) were instilled into the left eye of the animals. ® (Commercially available product). Instill 0.9% sodium chloride injection into the right eye. One drop each time, once daily for 28 consecutive days. Examine the eye before the first dose each day, and at 1 hour, 2 hours, 4 hours, 24 hours, 48 ​​hours, and 72 hours after the last dose on the last day.

[0042]

[0043]

[0044]

[0045] The irritation test results showed that, under the conditions of this test, the use of oxymetazoline hydrochloride eye drops (pilot batch sample or Upneeq) was not recommended. ® (Commercially available product) was administered to rabbits via eye drops for 28 consecutive days, once daily, one drop each time, and no eye irritation was observed.

[0046] Although specific embodiments of the invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and all such changes are within the scope of protection of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

1. A composition of oxymetazoline hydrochloride eye drops, comprising 0.1% oxymetazoline hydrochloride, 0.74% sodium chloride, 0.39% sodium acetate, 0.17% sodium citrate, 0.5% hydroxypropyl methylcellulose, appropriate amount of hydrochloric acid, and balance water.

2. The eye drop composition according to claim 1, the preparation method comprising the following steps: (1) Dissolve hydroxypropyl methylcellulose in the first portion of water; (2) Dissolve oxymetazoline hydrochloride, sodium chloride, sodium acetate, and sodium citrate in the second part of the water; (3) Mix the product obtained in (1) with the product obtained in (2) and adjust the pH value to 6.3~6.5 with hydrochloric acid; (4) Add water to full volume; (5) Filter with a 0.22μm pore size filter.

3. The eye drop composition according to any one of claims 1 to 2 can be stably stored for 48 months under long-term test conditions (temperature 25℃±2℃, relative humidity 40%±5%).

4. The eye drop composition according to any one of claims 1 to 3, for the treatment of acquired ptosis in adults.

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