Azelastine hydrochloride eye drops

Abstract

The present application relates to an azelastine hydrochloride eye drop, which comprises: azelastine hydrochloride, a gel matrix, a preservative, an isotonicity adjusting agent, a cyclodextrin excipient, and water for injection; the gel matrix is ​​poloxamer 407, poloxamer 188, hydroxypropyl methylcellulose and carboxymethyl chitosan. When preparing the temperature-sensitive eye drops of the present invention, adding a small amount of carboxymethyl chitosan not only helps the formation of the gel, but also can improve the drug stability of the eye drops. The present invention provides a temperature-sensitive eye drop that is easy to use and has good stability for clinical use.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical preparations, and in particular to azelastine hydrochloride eye drops. Background Art

[0002] Azelastine hydrochloride (AH) is a 2,3-phthalazinone derivative with a new structure. It is a potential long-acting antiallergic compound with the characteristics of an H1 receptor blocker. It is mainly used to treat and prevent seasonal allergic conjunctivitis. CAS registration number: 79307-93-0, the chemical name is: (±)-1-(2H)-4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepan-4-yl)-phthalazinone monohydrochloride. Its structural formula is as follows:

[0003]

[0004] After oral administration, azelastine hydrochloride is rapidly absorbed by the body, with an absolute bioavailability of up to 81%. Food has no effect on absorption. The high volume of distribution indicates that the distribution is mainly in peripheral tissues, and the protein binding level is relatively low (80%-90%). After single administration of azelastine hydrochloride, the plasma elimination half-life of chloramphenicol hydrochloride is 20 hours, and the therapeutic active metabolite N-desmethylazelastine is about 45 hours. Excretion is mainly eliminated through feces. The persistent excretion of a small amount of drug in the feces indicates that the drug can undergo enterohepatic circulation. Repeated daily nasal spray application of 0.56 mg of azelastine hydrochloride (equivalent to 1 spray / nostril, 2 times / day), the Cmax steady-state plasma concentration of azelastine hydrochloride in healthy volunteers is about 0.27 ng / ml, and its active metabolite N-desmethylazelastine can be detected at the limit of quantification or below the quantitative level (0.12 ng / ml).

[0005] Studies have shown that azelastine and its physiologically acceptable salt forms exhibit beneficial effects when applied directly to the nasal mucosa and / or the conjunctival sac of the eye in corresponding formulations (see U.S. Pat. No. 5,164,194). Despite its effectiveness, azelastine hydrochloride has a strong bitter taste (see U.S. Pat. No. 5,164,194). Subsequent clinical studies have confirmed that the bitter taste of azelastine hydrochloride is an undesirable component as part of the drug that usually flows downward into the pharynx after intranasal administration, resulting in patient discomfort and undesirable taste experience. Similarly, the fluid formed by the combination of tears secreted by intraocular administration and induced lacrimal glands is drained into the nose through the nasolacrimal duct and eventually flows into the pharynx. This type of postnasal drip caused by ocular administration of a composition containing azelastine hydrochloride may also induce bitterness and uncomfortable taste experience in patients. Ukai et al. (U.S. Pat. No. 6,576,677) discloses the use of polyvinyl pyrrolidone and / or cross-linked polyvinylpyrrolidone in masking the taste of bitter drugs, including azelastine.

[0006] CN104173352A discloses a pharmaceutical composition of azelastine hydrochloride, which is non-aqueous and gel-like, has stable chemical properties, low irritation, and can be used for allergic seasonal rhinitis and allergic perennial rhinitis, and / or can be used to treat other symptoms associated with allergic and non-allergic diseases such as allergic and / or contact dermatitis, etc. CN104173286B discloses a liquid composition of azelastine, which can be packaged in a suitable pharmaceutical form so as to be provided for clinical use in the form of conventional liniment or spray.

[0007] Eye drops are easy to prepare, low-cost, and convenient to use. Patients are not likely to develop compliance, but eye drops have low bioavailability and require long-term and frequent administration. At the same time, the physiological structure of the eye is special. The normal tear volume is about 7μL, and the volume without blinking is about 30μL. Usually, 1 drop of eye drops is about 50-70μL. Most of the liquid medicine overflows from the eye and is lost. In addition, the dilution of the eye fluid by tears affects the effect of medication. The application of in situ gel technology and its new excipients is improving the effect of ocular medication. Thermosensitive in situ gel is liquid at room temperature. After administration, it can be immediately converted into a non-chemically cross-linked semi-solid gel at the medication site, prolonging the drug action time, becoming an important technology to improve drug efficacy.

[0008] Bie Haiyan et al. (China New Drug Journal, 2016, Vol. 25, No. 8, pp. 954-960) reported the preparation of azelastine hydrochloride thermosensitive in-situ gel eye drops by cold dissolution method using poloxamer 407, poloxamer 188 and hydroxypropyl methylcellulose as excipients, and investigated the effect of the dosage ratio of each excipient on the gelation temperature (temperature sensitivity) of the eye drops. The drug release, biocompatibility, stability, etc. of the eye drops have not been investigated too much. CN102283799B discloses an azithromycin gel eye drop, which uses poloxamer 407 as a gel matrix for regulating the gel temperature. At present, there is no thermosensitive azelastine eye drop on the market.

[0009] Therefore, developing an azelastine eye drops with good biocompatibility and stability has good social and market value. Summary of the invention

[0010] In order to solve the above technical problems existing in the prior art, the present invention provides an azelastine hydrochloride eye drops, comprising: azelastine hydrochloride, a gel matrix, a preservative, an isotonicity regulator, a cyclodextrin auxiliary material and water for injection;

[0011] The gel matrix is ​​poloxamer 407, poloxamer 188, hydroxypropyl methylcellulose and carboxymethyl chitosan;

[0012] The raw material composition includes, by weight percentage: azelastine hydrochloride 0.1%-5%, poloxamer 407 5%-30%, poloxamer 188 1%-10%, hydroxypropyl methylcellulose 0.1%-5%, carboxymethyl chitosan 0.1%-5%, preservative 0.1%-3%, isotonicity regulator 0.1%-8%, cyclodextrin excipient 0.1%-3%, and the balance is water for injection.

[0013] Preferably, the raw material composition includes, by weight percentage: azelastine hydrochloride 0.1%-0.5%, poloxamer 407 16%-20%, poloxamer 188 3%-5%, hydroxypropyl methylcellulose 0.1%-1%, carboxymethyl chitosan 0.5%-1.5%, preservative 0.1%-1%, isotonicity regulator 1%-3%, cyclodextrin excipient 0.1%-1%, and the balance is water for injection.

[0014] Preferably, the raw material composition includes, by weight percentage: azelastine hydrochloride 0.1%-0.4%, poloxamer 407 17%-19%, poloxamer 188 3.5%-4.5%, hydroxypropyl methylcellulose 0.4%-0.5%, carboxymethyl chitosan 0.6%-1.2%, preservative 0.3%-0.4%, isotonicity regulator 1.2%-2.0%, cyclodextrin excipient 0.1%-0.5%, and the balance is water for injection.

[0015] Preferably, the preservative is selected from one or more of benzalkonium chloride, benzalkonium bromide, chlorobutanol and thimerosal.

[0016] Preferably, the isotonicity regulator is selected from one or more of sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, glucose, mannitol, sorbitol, glycerol, and propylene glycol; more preferably, it is one or more of sodium chloride, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0017] Preferably, the cyclodextrin excipient is selected from one or more of β-cyclodextrin, dimethyl β-cyclodextrin, and hydroxypropyl β-cyclodextrin, and more preferably β-cyclodextrin.

[0018] Preferably, the eye drops are temperature sensitive.

[0019] Preferably, the gelling temperature of the eye drops is 30-32°C.

[0020] The difficulties in preparing temperature-sensitive eye drops mainly include the following aspects: 1. Temperature sensitivity control: Thermosensitive eye drops need to undergo a phase change at a specific temperature, from liquid to gel. The concentration and ratio of the polymer need to be precisely controlled during the preparation process to ensure that the phase change occurs at body temperature (about 35°C). Currently, more thermosensitive matrices are used, such as poloxamer 407 (P407) and poloxamer 188 (P188). The concentration has a significant effect on the phase change temperature, and the optimal concentration needs to be determined through optimization experiments. 2. Drug release control: Thermosensitive eye drops need to achieve continuous and stable release of drugs in the eye. The release patterns of different drug ingredients may be different, and the formula needs to be optimized through in vitro dissolution kinetics studies to achieve continuous and stable release of active ingredients. 3. Biocompatibility and safety: Since the eye drops are in direct contact with the eye, their biocompatibility and safety are crucial. It is necessary to select a thermosensitive gel matrix suitable for eye use. 4. Stability of the preparation: Thermosensitive eye drops need to remain stable during storage and use without degradation or deterioration. 5. Fluidity and spreadability of the preparation: Thermosensitive eye drops are liquids under non-physiological conditions. They need to be affected by temperature in the conjunctival sac to undergo a sol-gel phase transition and transform into a viscous gel, which significantly prolongs the retention time of the drug and the cornea. Tear secretion and blinking reflex will cause the eyelids to continuously mix the gel and tears, causing gel dissolution. In summary, the preparation of thermosensitive eye drops requires comprehensive consideration of temperature sensitivity, drug release, biocompatibility, stability, fluidity and other factors, which together constitute the main difficulties in the preparation process.

[0021] Therefore, although some thermosensitive eye drops are reported in the prior art, due to the different active ingredients, their active release and stability in the eye are different. Directly borrowing the formula of the prior art is not applicable to azelastine hydrochloride, and a large number of experiments are needed to optimize and improve the formula. When the present invention refers to the preparation method of thermosensitive gel of azelastine hydrochloride reported in the prior art (China New Drug Journal, 2016, Vol. 25, No. 8, pp. 954-960), it is found that when other excipients, preservatives (such as benzalkonium chloride, chlorobutanol, etc.), isotonic agents (such as sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, etc.), and β-cyclodextrin are added to the preparation, the gel temperature of the eye drops changes significantly. Under the proportion reported in the literature, it is difficult to achieve gelation at the temperature of the eyeball. This may be due to the addition of other excipients, which causes the composition of the eye drops to change, thereby affecting the realization of its gel function.

[0022] The inventors of the present invention, through a lot of creative work, provide an azelastine hydrochloride eye drop, which has good temperature sensitivity and can achieve gelation at the surface temperature of the eyeball (32-33°C), and is in liquid form at room temperature (about 25°C); at the same time, the eye drop of the present invention has good stability and is easy to store.

[0023] As a pharmaceutical excipient, carboxymethyl chitosan can be combined with drugs to make preparations such as eye drops. Due to its high viscosity, the residence time of the drug in the eye can be prolonged and the antibacterial effect can be enhanced. However, the inventor unexpectedly found that when preparing the temperature-sensitive eye drops of the present invention, adding a small amount of carboxymethyl chitosan not only contributes to the formation of gel, but also can improve the drug stability of the eye drops, which is unexpected. Analyzing the reason, it may be that carboxymethyl chitosan is amphiphilic and can self-assemble to form nano-micelles, which has a gel and stable effect. The present invention provides a kind of temperature-sensitive eye drops that are easy to use and have good stability for clinical use. DETAILED DESCRIPTION

[0024] The following examples are provided to illustrate the present invention in detail. The following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0025] Therefore, before describing the present invention in detail, it should be understood that the present invention is not limited to the system or process parameters of the specific examples which may vary of course. It should also be understood that the terms used herein are only for the purpose of describing a specific embodiment of the present invention, and are not intended to limit the scope of the present invention in any way. The examples used anywhere in this specification (including the examples of any terms discussed herein) are merely illustrative and in no way limit the scope and meaning of the present invention or any illustrative terms. Similarly, the present invention is not limited to the various embodiments given in this specification. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. In the event of a conflict, this document (including definitions) shall prevail.

[0026] Example 1 Preparation of Azelastine Hydrochloride Eye Drops

[0027] To 50 mL of water for injection, add 0.4 g of benzalkonium chloride, 0.1 g of azelastine hydrochloride, 0.8 g of sodium dihydrogen phosphate, 0.4 g of disodium hydrogen phosphate and 0.4 g of sodium chloride, stir to dissolve, then add 0.3 g of β-cyclodextrin, heat and stir to dissolve, and obtain liquid A. Heat about 20 mL of water for injection to about 90°C, add 0.5 g of hydroxypropyl methylcellulose, stir, and cool in a water bath to obtain liquid B. Add liquid B to liquid A, stir well, then add 18.0 g of poloxamer 407, 4.0 g of poloxamer 188 and 1.0 g of carboxymethyl chitosan, add water for injection to 1000 mL, stir well, filter finely, steam sterilize for 15 min, package aseptically, and store at 2-8°C.

[0028] Example 2 Preparation of Azelastine Hydrochloride Eye Drops

[0029] To 50 mL of water for injection, add 0.3 g of chlorobutanol, 0.1 g of azelastine hydrochloride, 0.8 g of sodium dihydrogen phosphate, 0.4 g of disodium hydrogen phosphate and 0.4 g of sodium chloride, stir to dissolve, then add 0.3 g of β-cyclodextrin, heat and stir to dissolve, and obtain liquid A. Heat about 20 mL of water for injection to about 90°C, add 0.5 g of hydroxypropyl methylcellulose, stir, and cool in a water bath to obtain liquid B. Add liquid B to liquid A, stir well, then add 17.0 g of poloxamer 407, 3.8 g of poloxamer 188 and 1.2 g of carboxymethyl chitosan, add water for injection to 1000 mL, stir well, filter finely, steam sterilize for 15 min, aseptically package, and store at 2-8°C.

[0030] Example 3 Preparation of Azelastine Hydrochloride Eye Drops

[0031] To 50 mL of water for injection, add 0.4 g of benzalkonium bromide, 0.1 g of azelastine hydrochloride, 0.8 g of sodium dihydrogen phosphate, 0.4 g of disodium hydrogen phosphate and 0.4 g of sodium chloride, stir to dissolve, then add 0.3 g of β-cyclodextrin, heat and stir to dissolve, and obtain liquid A. Heat about 20 mL of water for injection to about 90°C, add 0.5 g of hydroxypropyl methylcellulose, stir, and cool in a water bath to obtain liquid B. Add liquid B to liquid A, stir well, then add 19.0 g of poloxamer 407, 4.5 g of poloxamer 188 and 0.6 g of carboxymethyl chitosan, add water for injection to 1000 mL, stir well, filter finely, steam sterilize for 15 min, package aseptically, and store at 2-8°C.

[0032] Example 4 Preparation of Azelastine Hydrochloride Eye Drops

[0033] To 50 mL of water for injection, add 0.4 g of benzalkonium bromide, 0.1 g of azelastine hydrochloride, 0.8 g of sodium dihydrogen phosphate, 0.4 g of disodium hydrogen phosphate and 0.4 g of sodium chloride, stir to dissolve, then add 0.3 g of β-cyclodextrin, heat and stir to dissolve, and obtain liquid A. Heat about 20 mL of water for injection to about 90°C, add 0.4 g of hydroxypropyl methylcellulose, stir, and cool in a water bath to obtain liquid B. Add liquid B to liquid A, stir well, then add 17.0 g of poloxamer 407, 3.5 g of poloxamer 188 and 0.8 g of carboxymethyl chitosan, add water for injection to 1000 mL, stir well, filter finely, steam sterilize for 15 min, package aseptically, and store at 2-8°C.

[0034] Comparative Example 1 Preparation of Azelastine Hydrochloride Eye Drops

[0035] Azelastine hydrochloride eye drops were prepared in the same manner as in Example 1, except that carboxymethyl chitosan was not added.

[0036] Comparative Example 2 Preparation of Azelastine Hydrochloride Eye Drops

[0037] Azelastine hydrochloride eye drops were prepared in the same manner as in Example 1, except that 5.0 g of carboxymethyl chitosan was added.

[0038] Comparative Example 3 Preparation of Azelastine Hydrochloride Eye Drops

[0039] Azelastine hydrochloride eye drops were prepared in the same manner as in Example 1, except that 2.0 g of poloxamer 188 was added.

[0040] Comparative Example 4 Preparation of Azelastine Hydrochloride Eye Drops

[0041] Azelastine hydrochloride eye drops were prepared in the same manner as in Example 1, except that 26.0 g of poloxamer 407 was added.

[0042] Example 5 Determination of gelling temperature of eye drops

[0043] Referring to the method reported by Bie Haiyan et al. (China New Drug Journal, 2016, Vol. 25, No. 8, pp. 954-960), the gel temperature of different eye drops was tested: using the test tube inversion method, 2 mL of eye drops were taken with a pipette and added to a 10 mL glass test tube, sealed, placed in a circulating water bath, and slowly heated in the water bath. Every time the temperature rises by 0.1°C, the test tube is tilted 90° until the liquid surface stops flowing, and the mercury ball of the precision thermometer (measuring range 0-50°C, graduation value 0.1°C) and the gel matrix in the test tube are at the same level. At this time, the temperature displayed by the precision thermometer is the gelation temperature (GT), retaining one estimated value, and taking the average value of 3 measurements. The test results are shown in Table 1 below.

[0044]

[0045] It can be seen from the results in Table 1 that the eye drops of the present invention have good temperature sensitivity and can achieve good gelation at the surface temperature of the eyeball.

[0046] Example 6 Stability Test

[0047] 1) Chromatographic conditions and system suitability test. Chromatographic column: Kromasil C18 (250 mm × 4.6 mm, 5 μm); mobile phase: 4% triethylamine (adjust pH to 6.0 with acetic acid)-acetonitrile-methanol (45:20:35), flow rate: 1.0 mL•min -1 ; Sample volume: 20 μL; Measurement wavelength: 287 nm. The number of theoretical plates should not be less than 2000 based on the azelastine hydrochloride peak.

[0048] 2) Preparation of solutions. Blank excipient solution: Accurately measure 5 mL of blank excipient solution and place it in a 10 mL volumetric flask, add mobile phase to dilute to the scale, shake well, and obtain. Test solution: Accurately measure 5 mL of the samples of Example 1 and Comparative Example 1 and place it in a 10 mL volumetric flask, add mobile phase to dilute to the scale, shake well, and obtain. Control solution: Accurately measure 1 mL of the above test solution and place it in a 100 mL volumetric flask, add mobile phase to dilute to the scale, shake well, and obtain.

[0049] 3) Excipient interference test. Take a blank excipient solution for analysis and record the chromatogram. The result shows that the excipient has a solvent peak and an excipient peak before the retention time of 4 minutes, but it is well separated from the main peak of the sample and the impurity peak, and should be deducted when calculating related substances.

[0050] 4) Detection concentration selection: Dilute with mobile phase to make a solution containing 250 μg per 1 mL, and inject for analysis.

[0051] 5) Determination method of related substances. Accurately measure 20 μL of the control solution, inject, and adjust the detection sensitivity so that the peak height of the main component peak is 10%-20% of the full scale; then measure the sample solution and control solution of Example 1 and Comparative Example 1, and record the chromatogram to twice the retention time of the main component peak. If there are impurity peaks in the chromatogram of the test solution, measure the sum of the peak areas of each impurity peak and compare it with the peak area of ​​the main component of the control solution (minus the auxiliary material peak).

[0052] The samples of Example 1-2 and Comparative Example 1-2 were placed under high temperature (60±2)°C, low temperature (0-5°C) and light (4500±500) lx conditions, and samples were taken regularly at 0, 5 and 10 days, and then the contents of related substances were examined. The measurement results are shown in Table 2.

[0053]

[0054] It can be seen from the results in Table 2 that the eye drops prepared by the present invention have good stability.

[0055] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. For ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should fall within the scope of protection of the claims attached to the present invention.

Claims

1. Azelastine hydrochloride eye drops, characterized in that: It contains azelastine hydrochloride, gel matrix, preservative, isotonicity regulator, cyclodextrin excipients and water for injection; The gel matrix is ​​poloxamer 407, poloxamer 188, hydroxypropyl methylcellulose and carboxymethyl chitosan; The cyclodextrin excipient is selected from one or more of β-cyclodextrin, dimethyl β-cyclodextrin, and hydroxypropyl β-cyclodextrin; The raw material composition includes by weight percentage: Azelastine hydrochloride 0.1%-0.4%, poloxamer 407 17%-19%, poloxamer 188 3.5%-4.5%, hydroxypropyl methylcellulose 0.4%-0.5%, carboxymethyl chitosan 0.6%-1.2%, preservative 0.3%-0.4%, isotonicity regulator 1.2%-2.0%, cyclodextrin excipient 0.1%-0.5%, and the balance is water for injection.

2. The azelastine hydrochloride eye drops according to claim 1, characterized in that: The preservative is selected from one or more of benzalkonium chloride, benzalkonium bromide, chlorobutanol and thimerosal.

3. The azelastine hydrochloride eye drops according to claim 1, characterized in that: The isotonicity regulator is selected from one or more of sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, glucose, mannitol, sorbitol, glycerol, and propylene glycol.

4. The azelastine hydrochloride eye drops according to claim 3, characterized in that: The isotonicity adjusting agent is selected from one or more of sodium chloride, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

5. The azelastine hydrochloride eye drops according to claim 1, characterized in that: The cyclodextrin auxiliary material is selected from β-cyclodextrin.

6. The azelastine hydrochloride eye drops according to claim 1, characterized in that: The eye drops are temperature sensitive.

7. The azelastine hydrochloride eye drops according to claim 6, characterized in that: The gelling temperature of the eye drops is 30-32°C.

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