A nasal drug delivery preparation for treating rhinitis, preparation method and use thereof

Abstract

The present invention provides a nasal administration preparation, preparation method and use for treating rhinitis, and relates to the field of medical technology. Taking the total weight of the preparation as 100%, the nasal administration preparation includes the following components in weight percentage: loratadine 0.1-5%, polyethylene glycol 3-20%, penetration enhancer 0.5-1%, and the remainder is water, wherein the polyethylene glycol is selected from at least two of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600; the penetration enhancer is selected from at least two of sodium lauryl sulfate, bile acid derivatives, taurine, hyaluronic acid, polyoxyethylene lauryl alcohol ether, 1-ephedrine, d-ephedrine, 1-pseudoephedrine, and d-pseudoephedrine. The nasal administration preparation obtained by the present invention has the characteristics of less irritation to nasal cilia, high water solubility, high bioavailability and stable preparation, and is used to treat rhinitis.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a nasal administration preparation for treating rhinitis, a preparation method and use thereof. Background Art

[0002] Loratadine is a derivative of azatadine, a long-acting tricyclic antihistamine that has a good effect on the treatment of allergic skin diseases such as allergic rhinitis, chronic urticaria, eczema, contact dermatitis, etc., among which the anti-allergic effect is the most eye-catching. In recent years, research on its application in the treatment of anti-allergy has attracted the interest of more and more researchers. However, since loratadine is almost insoluble in water, its effective utilization rate is low, and it is easy to cause gastrointestinal adverse reactions and liver damage through oral administration, which limits its clinical role. By making loratadine into a nasal preparation, the first-pass effect can be avoided, the bioavailability can be improved, and the gastrointestinal adverse reactions and liver damage can be avoided at the same time, and the onset time can be accelerated.

[0003] US invention patent US9993468B2 discloses a topical pharmaceutical composition, a pharmaceutical composition comprising a solution with a pH of 5 to 7.5, including loratadine and / or desloratadine, and the composition is suitable for treating, for example, allergic rhinitis and allergic conjunctivitis. The pharmaceutical composition contains polyethylene glycol, propylene glycol, a nonionic block copolymer, and polyoxyethylene sorbitan monolaurate and / or monooleate. The composition contains a large number of excipients, and the concentration of loratadine in the composition is low, and the effect of treating allergic rhinitis needs to be further improved.

[0004] Chinese invention patent application CN110693816A discloses a loratadine nasal in-situ gel and a preparation method thereof, wherein the loratadine nasal in-situ gel comprises the following components: loratadine 7.6 mg / mL, gellan gum 3 mg / mL, sodium alginate 2 mg / mL, HPMC 2 mg / mL, Tween 80 1 mg / mL, ethanol 1 mL / mL, and the remainder is deionized water; gellan gum and sodium alginate are used as gel matrix, and the viscosity, gelation time, gel strength, drug content, adhesion, stability and in vitro drug release of the gel are studied, and a comprehensive evaluation is performed to determine an optimal loratadine nasal in-situ gel prescription. However, the patent application does not disclose its efficacy results.

[0005] Therefore, there is an urgent need to provide a nasal preparation for treating rhinitis that can improve the solubility of loratadine in aqueous solution, has less irritation to nasal cilia, has good therapeutic effect and is stable in preparation. Summary of the invention

[0006] The present invention aims to solve the problems existing in the prior art and provides a novel nasal preparation containing loratadine and a preparation method and application thereof. It is found through research that the specific composition of polyethylene glycol and the specific composition of the penetration enhancer have a significant effect on the blood concentration of loratadine after administration. The nasal preparation provided by the present invention shows the characteristics of rapid drug absorption, low irritation to the nasal mucosa, high stability and high bioavailability, which is superior to the known reported nasal preparation of loratadine.

[0007] The first aspect of the present invention provides a nasal preparation, which comprises the following components in weight percentage based on the total weight of the preparation as 100%: 0.15-5% of loratadine, 3-20% of polyethylene glycol (PEG), and 0.5-1% of a penetration enhancer; wherein the polyethylene glycol is selected from at least two of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600; and the penetration enhancer is selected from at least two of sodium lauryl sulfate, bile acid derivatives, taurine, hyaluronic acid, polyoxyethylene lauryl ether, 1-ephedrine, d-ephedrine, 1-pseudoephedrine, and d-pseudoephedrine.

[0008] Preferably, the penetration enhancer is selected from at least two of sodium lauryl sulfate, bile acid derivatives, taurine, hyaluronic acid, and polyoxyethylene lauryl ether.

[0009] Preferably, based on 100% of the total weight of the preparation, the nasal administration preparation comprises the following components in weight percentage: 1-3% loratadine, 8-15% polyethylene glycol, and 0.5-1% penetration enhancer.

[0010] Preferably, based on 100% of the total weight of the preparation, the nasal administration preparation comprises the following components in weight percentage: 1.5% loratadine, 12% polyethylene glycol, and 0.8% penetration enhancer.

[0011] Preferably, the mass ratio of loratadine to penetration enhancer is 1.5-2:1.

[0012] Preferably, the mass ratio of the polyethylene glycol to the penetration enhancer is 12-18:1.

[0013] Preferably, the nasal administration preparation is a spray, nasal drops, ointment, gel, film or emulsion.

[0014] Preferably, the nasal administration preparation components further include at least one of a pH buffer, a thickener, a preservative, an antioxidant, a chelating agent, a fragrance and an osmotic pressure regulator.

[0015] Preferably, the pH buffer is selected from one of acetate buffer, citrate buffer, carbonate buffer and phosphate buffer, the pH buffer concentration is 0.25 mol / L-0.5 mol / L, and the final pH value of the nasal administration preparation is adjusted to 5.5-7.0.

[0016] Preferably, the thickener is selected from at least one of xanthan gum, gum arabic, tragacanth gum and chitosan, and the weight proportion of the thickener in the nasal administration preparation is 0.1-0.5%.

[0017] Preferably, the preservative is selected from at least one of p-hydroxybenzoic acid esters, benzoic acid and its salts, sorbic acid, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorhexidine acetate, thimerosal and quaternary ammonium compound cationic surfactants; the weight proportion of the preservative in the nasal administration preparation is 0.01-0.05%.

[0018] Preferably, the aromatic agent is selected from at least one of cinnamaldehyde, vanillin and peppermint oil; the weight proportion of the aromatic agent in the nasal administration preparation is 0.01-0.05%.

[0019] Preferably, the antioxidant is selected from at least one of sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate, ascorbic acid, thiourea, cysteine, tocopherol and lecithin; the weight proportion of the antioxidant in the nasal administration preparation is 0.3%-2%.

[0020] Preferably, the chelating agent is selected from at least one of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, citric acid and tartaric acid; the weight proportion of the chelating agent in the nasal administration preparation is 0.01%-0.03%.

[0021] Preferably, the osmotic pressure regulator is selected from at least one of sodium chloride, glucose, lactose, mannose and mannitol; the weight proportion of the osmotic pressure regulator in the nasal administration preparation is 0.6%-1.2%.

[0022] The second aspect of the present invention relates to a method for preparing the above-mentioned nasal preparation, which can be prepared according to conventional methods in the art, for example, by stirring and mixing loratadine, polyethylene glycol, a penetration enhancer, and, if necessary or selectively, other pharmaceutical excipients.

[0023] Preferably, the preparation method of the above-mentioned nasal administration preparation is:

[0024] (1) mixing polyethylene glycol and dissolving loratadine in the polyethylene glycol to obtain solution A;

[0025] (2) Add penetration enhancer and other auxiliary materials to solution A, stir and mix.

[0026] The third aspect of the present invention relates to the use of the above-mentioned nasal administration preparation in the preparation of a drug for treating rhinitis.

[0027] Preferably, the rhinitis includes acute rhinitis, chronic rhinitis, sinusitis, allergic rhinitis, atrophic rhinitis, and vasomotor rhinitis.

[0028] Compared with the prior art, the present invention has the following beneficial effects: by screening solvents and penetration enhancers for nasal preparations, the present invention obtains nasal preparations that are less irritating to nasal cilia, have a rapid onset of action, high bioavailability, and stable preparations, and can be effectively used to treat rhinitis. DETAILED DESCRIPTION

[0029] Embodiment 1:

[0030]

[0031] Mix PEG200 and PEG400, dissolve loratadine in the polyethylene glycol mixture, add sodium lauryl sulfate and hyaluronic acid, make up to a sufficient volume with water for injection, stir and mix to prepare a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0032] Embodiment 2:

[0033]

[0034] Mix PEG300 and PEG600, dissolve loratadine in the polyethylene glycol mixture, add polyoxyethylene lauryl alcohol ether and hyaluronic acid, make up to a sufficient volume with water for injection, stir and mix to prepare a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0035] Embodiment 3:

[0036]

[0037] Mix PEG300 and PEG400, dissolve loratadine in the polyethylene glycol mixture, add sodium lauryl sulfate and taurine, dilute to a sufficient volume with water for injection, stir and mix to obtain a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0038] Comparative Example 1:

[0039] Referring to the dosage of prescription 1 in CN110693816A, specifically:

[0040] Loratadine 7.6 mg / mL; gellan gum 4 mg / mL; sodium alginate 1 mg / mL; HPMC 1 mg / mL; Tween 80 1 mg / mL; deionized water was added to make the volume to 100 mL to prepare the nasal in situ gel.

[0041] Comparative Example 2:

[0042] Referring to the prescription composition in Table 1 of US9993468B2, specifically:

[0043]

[0044] Comparative Example 3:

[0045]

[0046] Mix PEG200 and PEG400, dissolve loratadine in the polyethylene glycol mixture, add hyaluronic acid, make up to a sufficient volume with water for injection, stir and mix to prepare a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0047] The difference from Example 1 is that Comparative Example 3 contains only hyaluronic acid but no sodium lauryl sulfate.

[0048] Comparative Example 4:

[0049]

[0050] Mix PEG200 and PEG400, dissolve loratadine in the polyethylene glycol mixture, add sodium lauryl sulfate, dilute to a sufficient volume with water for injection, stir and mix to prepare a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0051] The difference from Example 1 is that Comparative Example 4 contains only sodium lauryl sulfate but no hyaluronic acid.

[0052] Comparative Example 5:

[0053]

[0054] Dissolve loratadine in PEG400, add sodium lauryl sulfate and hyaluronic acid, dilute to a sufficient volume with water for injection, stir and mix to prepare a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0055] The difference from Example 1 is that Comparative Example 5 contains only polyethylene glycol PEG400 but no PEG200.

[0056] Comparative Example 6:

[0057]

[0058] Dissolve loratadine in PEG200, add sodium lauryl sulfate and hyaluronic acid, dilute to a sufficient volume with water for injection, stir and mix to prepare a clear solution, and dispense into a quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine / g).

[0059] The difference from Example 1 is that Comparative Example 6 contains only polyethylene glycol PEG200 but no PEG400.

[0060] Test Example 1:

[0061] Rabbit, body weight (2.43 ± 0.21) kg, male and female are not limited, do not take any medicine. Randomly divided into 7 groups, respectively embodiment 1-3 group, comparative example 1-6 group, 5 in every group, every group of 0.1mL loratadine is given by nose drops respectively. 24h fasting before administration, and blank blood 3mL is taken by ear vein before administration for comparison, after administration, 3mL of blood is taken by 5min, 15min, 30min, 45min, 1h, 2h, 3h, 6h hour, with heparin anticoagulation, gently shake, take drug-containing plasma and blank plasma 1mL after centrifugation, cryopreservation is standby. Take above-mentioned blood sample, naturally warm up to room temperature, add mobile phase 1.5mL, mix centrifugation, HPLC method measures loratadine content, calculates its blood drug concentration, and calculates area under the curve AUC when medicine.

[0062] Chromatographic conditions: octadecylsilane bonded silica gel as filler; phosphate buffer (take 2.28 g of dipotassium hydrogen phosphate, add 800 mL of water to dissolve, adjust the pH value to 6.0 with phosphoric acid, and then add water to 1000 mL)-methanol (20:80) as mobile phase; detection wavelength is 247 nm, and injection volume is 20 μL.

[0063] Reference solution: Take an appropriate amount of loratadine reference substance, weigh accurately, add mobile phase to dissolve and quantitatively dilute to make a solution containing approximately 0.2 mg per 1 mL.

[0064] System suitability requirements: The number of theoretical plates calculated based on the loratadine peak should not be less than 2000, and the separation between the loratadine peak and the adjacent impurity peak should meet the requirements.

[0065] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the peak area according to the external standard method. The results are shown in Table 1.

[0066] Table 1: Blood drug concentration results of different groups (n=5)

[0067]

[0068] Note: Compared with Example 1, among the groups, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0069] From the above table AUC 0-240 As a result, it can be seen that Examples 1-3 of the present invention are significantly higher than Comparative Examples 1-6, wherein Comparative Examples 1 and 2 are different from Example 1 in solvent system, resulting in different amounts of loratadine dissolved in the preparation, especially in Comparative Example 2, the content of loratadine in the preparation is only 0.06%, which is 1 / 25 of Example 1, resulting in a small dosage of loratadine in the final administration, which seriously affects the blood concentration after administration; Comparative Examples 3 or 4 are compared with Example 1, the total amount of penetration enhancers is unchanged, and the combination of two penetration enhancers is changed to one of them, and its bioavailability decreases, and the difference is statistically significant compared with Example 1 (P < 0.05). Comparative Examples 5 or 6 are compared with Example 1, the total amount of polyethylene glycol is unchanged, and the type of PEG is changed from two to one of them, and its bioavailability decreases, and the difference is statistically significant compared with Example 1 (P < 0.05). Therefore, the composition of components in the preparation, the dosage range of related components and the dosage ratio between each component have a significant effect on the effect of the drug.

[0070] Test Example 2: Nasal mucociliary toxicity study

[0071] For the preparations of Examples 1-3 and Comparative Examples 1-6 of the present invention, the ciliary toxicity was evaluated using an isolated toad palate model (Jiang Xinguo, Cui Jingbin, Fang Xiaoling, et al., Nasal mucociliary toxicity of drugs and evaluation methods, Acta Pharmaceutica Sinica 1995, 30(11): 848). It is generally believed that if the duration of the toad palate mucociliary movement in the test group is more than 70% of that in the saline control group, the ciliary toxicity of the test preparation is relatively small and within the clinically acceptable range. The specific experimental results are shown in Table 2.

[0072] Table 2: Effects on the ciliary movement of the toad palate

[0073] Group Relative duration of mucociliary movement in toad's upper jaw Example 1 85.5±3.9% Example 2 84.2±2.2% Example 3 83.8±2.7% Comparative Example 1 63.4±3.1%** Comparative Example 2 54.8±2.6%** Comparative Example 3 74.3±3.3%* Comparative Example 4 71.9±2.2%* Comparative Example 5 72.2±2.5%* Comparative Example 6 73.5±2.0%*

[0074] Note: Compared with Example 1, among the groups, * indicates P < 0.05, ** indicates P < 0.01.

[0075] The results show that the relative average continuous motion time of the toad's palate mucociliary cilia in Examples 1-3 and Comparative Examples 3-6 after 30 minutes of administration is more than 70%, especially the relative average continuous motion time of the toad's palate mucociliary cilia in the preparations of Examples 1-3 after 30 minutes of administration is more than 80%, and the toxic effect on the nasal cilia is clinically acceptable, and has the necessary clinical drug safety. Since the formulations of Comparative Examples 1 or 2 contain substances such as Tween 80, the relative average continuous motion time of the toad's palate mucociliary cilia after 30 minutes of administration is less than 70%, and there is a certain nasal mucociliary toxicity.

[0076] Test Example 3: Stability Test

[0077] Taking the amount of loratadine in the initial loratadine preparation as 100%, the preparations of Example 1, Comparative Example 2 and Comparative Example 3 were subjected to a high temperature stability test at 60° C. The loratadine content was determined by HPLC, and the chromatographic conditions and determination method were the same as those of Test Example 1. The experimental results are shown in Table 3.

[0078] Table 3: High temperature stability test

[0079]

[0080] According to the data in the table, the preparation provided by the present invention has good stability under a specific component composition. When the components are changed, the stability of the loratadine preparation decreases.

[0081] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A nasal preparation, which comprises the following components in weight percentages, based on the total weight of the preparation being 100%: 1-3% loratadine, 8-15% polyethylene glycol, and 0.5-1% penetration enhancer; wherein: The polyethylene glycol is selected from at least two of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600, and the penetration enhancer is selected from at least two of sodium lauryl sulfate, taurine, hyaluronic acid and polyoxyethylene lauryl alcohol ether; The mass ratio of loratadine, penetration enhancer and polyethylene glycol is 1.5-2:1:12-18; The preparation method of the nasal administration preparation is as follows: (1) mixing polyethylene glycol and dissolving loratadine in the polyethylene glycol to obtain solution A; (2) Add penetration enhancer and other auxiliary materials to solution A, stir and mix.

2. The nasal administration preparation according to claim 1, characterized in that: Based on the total weight of the preparation being 100%, the nasal administration preparation comprises the following components in weight percentage: 1.5% loratadine, 12% polyethylene glycol, and 0.8% penetration enhancer.

3. The nasal administration preparation according to any one of claims 1 to 2, characterized in that: The nasal administration preparation is a spray, nasal drops, ointment, gel, film or emulsion.

4. The nasal administration preparation according to any one of claims 1 to 2, characterized in that: The nasal administration preparation components also include at least one of a pH buffer, an emulsifier, a thickener, a preservative, an antioxidant, a chelating agent, a fragrance, and an osmotic pressure regulator.

5. Use of the nasal administration preparation according to any one of claims 1 to 4 in the preparation of a drug for treating rhinitis.

6. The use according to claim 5, characterized in that: The rhinitis includes acute rhinitis, chronic rhinitis, sinusitis, allergic rhinitis, atrophic rhinitis, and vasomotor rhinitis.

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