Stable levocetirizine hydrochloride eye drop composition and preparation method thereof

Abstract

The invention discloses a stable levocetirizine hydrochloride eye drop composition and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The composition is prepared from levocetirizine hydrochloride, glycerol, polyethylene glycol 400, polysorbate 80, edetate disodium, benzalkonium chloride, hydroxypropyl methylcellulose, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid and water. The composition is simple in preparation method, the pH value and osmotic pressure molar concentration of the composition are similar to those of tears, and the composition is free of irritation, good in medication comfort and good in stability during storage.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to an eye drop composition containing levocetirizine hydrochloride and a preparation method thereof. Background Art

[0002] Allergic conjunctivitis, also known as allergic conjunctivitis, is a hypersensitivity reaction of the conjunctiva to external allergens. The most common symptom of allergic conjunctivitis is itchy eyes, which can occur in almost all patients with allergic conjunctivitis, among which spring keratoconjunctivitis is usually the most obvious.

[0003] Levocetirizine hydrochloride belongs to the third generation of antihistamine drugs. It is the R configuration isomer obtained from cetirizine hydrochloride by chiral separation. Its CAS number is 130018-87-0. Its chemical name is R-(-)2-[2-[4-[4-(chlorophenyl)benzyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride. Its molecular formula is C 21 H 27 Cl3N2O3, chemical structure is shown below.

[0004]

[0005] The affinity of levocetirizine hydrochloride to histamine H1 receptor is about 2 times higher than that of cetirizine hydrochloride and about 30 times higher than that of dextrocetirizine hydrochloride. Compared with cetirizine hydrochloride, levocetirizine hydrochloride requires less dosage, has a faster onset of action, and has fewer side effects.

[0006] Levocetirizine hydrochloride is used to relieve allergic symptoms of allergic diseases. It is clinically used to treat allergic rhinitis, urticaria, angioedema and other skin and mucous membrane allergic diseases. It is also used to relieve allergic symptoms during colds.

[0007] So far, no levocetirizine hydrochloride eye drops have been registered or marketed.

[0008] Cetirizine hydrochloride eye drops were developed by Eyevance Pharmaceuticals Llc in the United States. The specification is 0.24% and the trade name is It was approved for marketing in the United States by the FDA on May 30, 2017, with the indication being "for the treatment of ocular itching associated with allergic conjunctivitis." However, cetirizine hydrochloride eye drops contain dextrocetirizine hydrochloride, which is the main ingredient causing side effects.

[0009] Currently, newer levocetirizine hydrochloride eye drops need to be developed. Summary of the invention

[0010] In order to solve the persistent imbalance between supply and demand, the inventors have conducted in-depth research and experiments, and provided an eye drop composition containing levocetirizine hydrochloride and a preparation method thereof, aiming at the problems of high drug concentration, slow onset of effect and many side effects of the currently marketed cetirizine hydrochloride eye drops.

[0011] The levocetirizine hydrochloride eye drops provided by the present invention are mainly used to treat eye itching associated with allergic conjunctivitis. However, in addition to causing eye itching, allergic conjunctivitis is usually accompanied by irritation symptoms and dryness symptoms such as dry eyes, foreign body sensation, and eye fatigue.

[0012] Glycerin, also known as propylene glycol, is a colorless, odorless, non-toxic viscous liquid. It is often used in medicines as an osmotic pressure regulator, thickener, and moisturizer. It can relieve irritation and dryness symptoms such as dry eyes, foreign body sensation, and eye fatigue. It can also relieve irritation caused by long-term use of preservatives.

[0013] However, the inventors have found that when glycerol is added to the levocetirizine hydrochloride eye drop composition, an esterification reaction will occur during a high temperature test to produce larger impurities such as glycerol-cetirizine, glycerol-dicetirizine or glycerol-tricetirizine, and the related substances do not meet the limit requirements and have poor stability.

[0014] The inventors unexpectedly discovered during the screening of auxiliary materials that using an appropriate amount of sodium dihydrogen phosphate as a buffering agent can significantly reduce the impurities generated by the esterification reaction of glycerol and levocetirizine hydrochloride while ensuring that the composition has a strong buffering capacity, a relatively stable pH value, and better medication comfort, thereby achieving better stability.

[0015] The inventors conducted influencing factor tests (high temperature 60°C), accelerated tests (temperature 40°C ± 2°C, relative humidity 25% ± 5%) and long-term tests (temperature 25°C ± 2°C, relative humidity 40% ± 5%) on the composition in accordance with the provisions of the 2020 edition of the Chinese Pharmacopoeia, Part IV General Rules 9001, Stability Test Guidelines for Raw Materials and Preparations. The results showed that the pH value and osmotic pressure molar concentration of the composition were similar to those of tears, and the medication was comfortable; the buffering capacity was strong, the impurities were few, and the stability was good.

[0016] Based on the above findings, the present inventors provide the following invention.

[0017] In the first aspect, the present invention provides a levocetirizine hydrochloride eye drop composition, specifically, comprising levocetirizine hydrochloride, glycerol, polyethylene glycol 400, polysorbate 80, disodium edetate, benzalkonium chloride, hypromellose, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, and water. Among them, levocetirizine hydrochloride is an active ingredient, glycerol is an osmotic pressure regulator, polyethylene glycol 400 is a lubricant, polysorbate 80 is a surfactant, disodium edetate is an antioxidant, benzalkonium chloride is a preservative, hypromellose is a thickener, sodium dihydrogen phosphate is a buffer, sodium hydroxide and hydrochloric acid are pH regulators, and water is a solvent.

[0018] In certain embodiments, the composition consists of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hydroxypropyl methylcellulose, 0.05% to 0.4% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder water.

[0019] In certain embodiments, the amount of sodium dihydrogen phosphate in the composition is 0.05%, 0.1%, 0.2%, 0.3% or 0.4%.

[0020] In certain embodiments, the composition consists of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.05% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder water.

[0021] In certain embodiments, the composition consists of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.1% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder water.

[0022] In certain embodiments, the composition consists of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.2% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder water.

[0023] In certain embodiments, the composition consists of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.3% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder water.

[0024] In certain embodiments, the composition consists of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.4% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder water.

[0025] In certain embodiments, the buffer further comprises disodium hydrogen phosphate, sodium phosphate, borax, sodium citrate, sodium acetate.

[0026] In certain embodiments, the pH adjuster further comprises boric acid, citric acid, or acetic acid.

[0027] In certain embodiments, the pH value of the composition is 6.4 to 7.6, preferably 6.6 to 7.4, more preferably 6.8 to 7.3, and even more preferably 7.0 to 7.2.

[0028] In a second aspect, the present invention also provides a method for preparing levocetirizine hydrochloride eye drops, comprising the following steps:

[0029] (1) dissolving hydroxypropyl methylcellulose in the first part of water;

[0030] (2) dissolving glycerol, polyethylene glycol 400, polysorbate 80, edetate disodium, benzalkonium chloride, and sodium dihydrogen phosphate in the second portion of water;

[0031] (3) dissolving levocetirizine hydrochloride in the product obtained in (2), and adjusting the pH value to 7.0 to 7.2 with sodium hydroxide and hydrochloric acid;

[0032] (4) adding the product obtained in (1) to the product obtained in (3);

[0033] (5) Replenish water to full volume.

[0034] The levocetirizine hydrochloride eye drops provided by the invention are used for treating eye itching associated with allergic conjunctivitis. The composition is used for eye drops, one drop at a time, twice a day.

[0035] In the present invention, unless otherwise specified, the term "%" refers to w / v%, i.e. weight / volume percentage. For example, 0.12% levocetirizine hydrochloride means that the content of levocetirizine hydrochloride in the composition is 0.12 g / 100 ml, or 1.2 mg / ml, or 1.2 g / L.

[0036] Beneficial effects achieved by the present invention:

[0037] (1) It solves the problems of high drug concentration, slow onset of effect and many side effects of the cetirizine hydrochloride eye drops that are already on the market;

[0038] (2) It solves the irritation and dryness symptoms of allergic conjunctivitis, such as dry eyes, foreign body sensation, and eye fatigue;

[0039] (3) The medication is comfortable and stable. DETAILED DESCRIPTION

[0040] 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 to be regarded as limiting the scope of the present invention. However, the following examples all fall within the scope of the present invention.

[0041] Although many materials and operating methods used in the following examples are well known in the art, the present invention is still described in as much detail as possible. It is clear to those skilled in the art that the materials and operating methods used in the following examples are well known in the art unless otherwise specified.

[0042] In the embodiments or comparative examples of the present invention, when describing the dosage, "%" refers to w / v%, i.e., weight / volume percentage. For example, 0.12% levocetirizine hydrochloride means that the content of levocetirizine hydrochloride in the composition is 0.12 g / 100 ml, or 1.2 mg / ml, or 1.2 g / L.

[0043] Implementation

[0044] Example 1 to Example 6: Prescriptions with different dosages of sodium dihydrogen phosphate

[0045]

[0046] The preparation methods of Examples 1 to 6:

[0047] (1) dissolving hydroxypropyl methylcellulose in the first part of water;

[0048] (2) dissolving glycerol, polyethylene glycol 400, polysorbate 80, edetate disodium, benzalkonium chloride, and sodium dihydrogen phosphate in the second portion of water;

[0049] (3) dissolving levocetirizine hydrochloride in the product obtained in (2), and adjusting the pH value to 7.0 to 7.2 with sodium hydroxide and hydrochloric acid;

[0050] (4) adding the product obtained in (1) to the product obtained in (3);

[0051] (5) Replenish water to full volume.

[0052] Quality characteristic comparison test

[0053] Examples 1 to 6 were taken for inspection, wherein the pH value determination method was the general rule 0631 of Part IV of the 2020 edition of the "Chinese Pharmacopoeia", the osmotic pressure molar concentration determination method was the general rule 0632 of Part IV of the 2020 edition of the "Chinese Pharmacopoeia", and the related substances and content determination method were the related substance determination method of levocetirizine hydrochloride in the 11.0 edition of the "European Pharmacopoeia". The test results are shown in Table 1.

[0054] Table 1 Test results of Examples 1 to 6

[0055]

[0056] The test results show that:

[0057] (1) All the results of Examples 1 to 5 meet the limit requirements;

[0058] (2) As the amount of sodium dihydrogen phosphate increases, the osmotic pressure molar concentration increases. When the amount of sodium dihydrogen phosphate is 0.5%, the osmotic pressure molar concentration does not meet the limit requirement;

[0059] (3) That is, 0.05% to 0.4% sodium dihydrogen phosphate is used as a buffer, the product quality meets the requirements, the pH value and osmotic pressure molar concentration are similar to those of tears, and the medication is comfortable.

[0060] Comparative Examples 1 to 6: Different Buffer Prescriptions

[0061]

[0062]

[0063] Preparation methods of Comparative Examples 1 to 6:

[0064] (1) dissolving hydroxypropyl methylcellulose in the first part of water;

[0065] (2) dissolving glycerol, polyethylene glycol 400, polysorbate 80, disodium edetate, benzalkonium chloride, and buffer (if any) in the second portion of water;

[0066] (3) dissolving levocetirizine hydrochloride in the product obtained in (2), and adjusting the pH value to 7.0 to 7.2 with a corresponding pH adjuster;

[0067] (4) adding the product obtained in (1) to the product obtained in (3);

[0068] (5) Replenish water to full volume.

[0069] Stability test

[0070] Take Example 1 to Example 5 and Comparative Example 1 to Comparative Example 6 for the influencing factor test (high temperature 60°C), and the test results are shown in

[0071] Table 2~Table 3.

[0072]

[0073]

[0074] The test results show that:

[0075] (1) In Examples 1 to 5, where sodium dihydrogen phosphate was used as a buffer, the test results all met the limit requirements; as the amount of sodium dihydrogen phosphate increased, the buffering capacity gradually increased and the pH stability was better;

[0076] (2) Comparative Example 1 without adding buffer, and Comparative Examples 2 to 5 using different buffers, the properties and contents all meet the limit requirements;

[0077] (3) Comparative Example 1 without adding a buffer, Comparative Example 4 using borax as a buffer, and Comparative Example 6 using sodium acetate as a buffer had weak buffering capacity. After being placed at a high temperature of 60° C. for 30 days, the pH value no longer met the limit requirements, and the stability was poor;

[0078] (4) Comparative Example 1 without adding a buffer, Comparative Example 2 using disodium hydrogen phosphate as a buffer, Comparative Example 3 using sodium phosphate as a buffer, and Comparative Example 5 using sodium citrate as a buffer all showed large amounts of glycerol-cetirizine esterified impurities, glycerol-dicetirizine esterified impurities, or glycerol-tricetirizine esterified impurities, and the osmotic pressure molar concentration and content showed a significant downward trend, indicating poor stability;

[0079] (5) In comparative example 4 using borax as a buffer, a large unknown impurity appeared, and the osmotic pressure molar concentration and content showed a significant downward trend, and the stability was poor;

[0080] (6) That is, using 0.05% to 0.4% sodium dihydrogen phosphate as a buffer and placing it at a high temperature of 60°C for 30 days, the test results of each item all meet the limit requirements and have good stability.

[0081] Take Examples 1 to 5 and conduct accelerated tests (temperature 40°C ± 2°C, relative humidity 25% ± 5%) and long-term tests (temperature 25°C ± 2°C, relative humidity 40% ± 5%). The test results are shown in Tables 4 to 5.

[0082]

[0083]

[0084] The test results show that when 0.05% to 0.4% sodium dihydrogen phosphate is used as a buffer, and the test results are placed for 6 months under accelerated test conditions and for 24 months under long-term test conditions, the test results of each item meet the limit requirements and have good stability.

[0085] Irritation test

[0086] Take Examples 1 to 5 to observe whether levocetirizine hydrochloride eye drops are irritating to rabbits after being instilled into their eyes, so as to provide a basis for the evaluation of medication comfort and safety.

[0087] Evaluation method: Three male Japanese white rabbits were selected, and levocetirizine hydrochloride eye drops were instilled into the left eyes of the three animals in the drug administration group, 6 times a day, with an interval of at least 1 hour, for 7 consecutive days. The eyes were examined before the first administration of the day and 1h, 2h, 4h, 24h, 48h, and 72h after the last administration.

[0088] Table 6 Eye irritation response scoring table

[0089]

[0090] Table 7 Eye irritation evaluation standard

[0091]

[0092]

[0093] Table 8 Statistics of irritation test scores

[0094]

[0095] The test results show that Examples 1 to 5 are non-irritating and comfortable to use.

[0096] Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and substitutions may be made to those details based on all the teachings disclosed, and these changes are within the scope of protection of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A stable levocetirizine hydrochloride eye drop composition, consisting of levocetirizine hydrochloride, glycerol, polyethylene glycol 400, polysorbate 80, disodium edetate, benzalkonium chloride, hypromellose, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid and water.

2. The eye drop composition according to claim 1, consisting of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.05% to 0.4% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the remainder of water.

3. The eye drop composition according to claim 2, wherein the amount of sodium dihydrogen phosphate is 0.05%, 0.1%, 0.2%, 0.3% or 0.4%.

4. The eye drop composition according to claim 3, consisting of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.05% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the balance water; or It is composed of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.1% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the balance of water; or It is composed of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hypromellose, 0.2% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the balance of water; or It is composed of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hydroxypropyl methylcellulose, 0.3% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the balance of water; or It is composed of 0.12% levocetirizine hydrochloride, 1.8% glycerol, 1% polyethylene glycol 400, 0.1% polysorbate 80, 0.025% edetate disodium, 0.01% benzalkonium chloride, 0.25% hydroxypropyl methylcellulose, 0.4% sodium dihydrogen phosphate, appropriate amounts of sodium hydroxide and hydrochloric acid, and the balance water.

5. The eye drop composition according to any one of claims 1 to 4, which has a pH value of 6.4 to 7.6, preferably 6.6 to 7.4, more preferably 6.8 to 7.3, and even more preferably 7.0 to 7.

2.

6. A method for preparing the eye drop composition according to any one of claims 1 to 5, comprising the following steps: (1) dissolving hydroxypropyl methylcellulose in the first part of water; (2) dissolving glycerol, polyethylene glycol 400, polysorbate 80, edetate disodium, benzalkonium chloride, and sodium dihydrogen phosphate in the second portion of water; (3) dissolving levocetirizine hydrochloride in the product obtained in (2), and adjusting the pH value to 7.0 to 7.2 with sodium hydroxide and hydrochloric acid; (4) adding the product obtained in (1) to the product obtained in (3); (5) Replenish water to full volume.

7. The eye drop composition according to any one of claims 1 to 6, which is mainly used for treating eye itching associated with allergic conjunctivitis.

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