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CN119214988B - Nasal administration preparation for treating rhinitis, preparation method and application - Google Patents

Nasal administration preparation for treating rhinitis, preparation method and application Download PDF

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Publication number
CN119214988B
CN119214988B CN202411731057.9A CN202411731057A CN119214988B CN 119214988 B CN119214988 B CN 119214988B CN 202411731057 A CN202411731057 A CN 202411731057A CN 119214988 B CN119214988 B CN 119214988B
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polyethylene glycol
nasal
preparation
loratadine
rhinitis
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CN119214988A (en
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马仁强
成艳君
蔡丽音
田玉婷
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Boji Pharmaceutical Technology Co ltd
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Boji Pharmaceutical Technology Co ltd
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
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    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/08—Antiallergic agents

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Abstract

本发明提供了一种治疗鼻炎的鼻腔给药制剂、制备方法及用途，涉及医药技术领域。以制剂总重量为100%计，所述鼻腔给药制剂包括以下重量百分比的组分：氯雷他定0.1‑5%，聚乙二醇3‑20%，促渗剂0.5‑1%，余量为水，其中，所述聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400和聚乙二醇600中的至少两种；所述促渗剂选自月桂醇硫酸钠、胆酸衍生物、牛磺酸、透明质酸、聚氧乙烯月桂醇醚、1‑麻黄碱、d‑麻黄碱、1‑伪麻黄碱、d‑伪麻黄碱中的至少两种。本发明得到的鼻腔给药制剂具有对鼻纤毛刺激性较小、水溶性高、生物利用度高、制剂稳定的特点，用于治疗鼻炎。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

Nasal administration preparation for treating rhinitis, preparation method and application
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a nasal administration preparation for treating rhinitis, a preparation method and application thereof.
Background
Loratadine is a derivative of azatadine, is a long-acting tricyclic antihistamine, has good curative effect on allergic skin diseases such as allergic rhinitis, chronic urticaria, eczema, contact dermatitis and the like, and has the most attractive antiallergic effect. In recent years, there has been an increasing interest in researchers for research applied in the treatment of antiallergic conditions. However, loratadine is hardly soluble in water, has a low effective utilization rate, and is liable to cause adverse reactions of gastrointestinal tract and impairment of liver function by oral administration, thereby limiting its clinical effects. The loratadine is customized into a nasal administration preparation, so that the first pass effect can be avoided, the bioavailability is improved, meanwhile, adverse reactions of gastrointestinal tracts and liver function injury are avoided, and the onset time is shortened.
U.S. patent No. 9993468B2 discloses a pharmaceutical composition for topical application, one comprising a solution at a pH of 5 to 7.5, including loratadine and/or desloratadine, which is useful in the treatment of, for example, allergic rhinitis and allergic conjunctivitis. The pharmaceutical composition contains polyethylene glycol, propylene glycol, nonionic block copolymer and polyoxyethylene sorbitan monolaurate and/or monooleate, the auxiliary materials in the composition are more in variety, the concentration of loratadine in the composition is lower, and the effect of treating allergic rhinitis is required to be further improved.
The Chinese patent application CN110693816A discloses a loratadine nasal cavity in-situ gel and a preparation method thereof, wherein the loratadine nasal cavity in-situ gel comprises the following components of 7.6 mg/mL of loratadine, 3mg/mL of gellan gum, 2mg/mL of sodium alginate, 2mg/mL of HPMC, 1 mg/mL of Tween 80, 1mL/mL of ethanol and the balance of deionized water, the gellan gum and the sodium alginate are taken as gel matrixes, and the aspects of viscosity, gel forming time, gel strength, drug content, adhesion, stability, in-vitro drug release and the like of the gel are researched, comprehensively evaluated, and an optimal loratadine nasal cavity in-situ gel prescription is determined. However, the patent application does not disclose the results of the drug effect.
Therefore, there is a need for providing a nasal administration preparation for treating rhinitis, which can improve the solubility of loratadine in an aqueous solution, has less irritation to nasal cilia, has a good therapeutic effect, and is stable.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a novel loratadine-containing nasal administration preparation, and a preparation method and application thereof. The research shows that the specific composition of polyethylene glycol and the specific composition of the permeation enhancer have obvious influence on the blood concentration of the loratadine after administration, and the nasal administration preparation provided by the invention has the characteristics of rapid drug absorption, small irritation to nasal mucosa, high stability and high bioavailability, and is superior to the known reported loratadine nasal administration preparation.
The first aspect of the invention provides a nasal administration preparation, which comprises, by weight, 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, cholic acid derivatives, taurine, hyaluronic acid, polyoxyethylene lauryl ether, 1-ephedrine, d-ephedrine, 1-pseudoephedrine and d-pseudoephedrine, based on 100% of the total weight of the preparation.
Preferably, the penetration enhancer is selected from at least two of sodium lauryl sulfate, cholic acid derivatives, taurine, hyaluronic acid and polyoxyethylene lauryl alcohol ether.
Preferably, the nasal administration preparation comprises 1-3% of loratadine, 8-15% of polyethylene glycol and 0.5-1% of penetration enhancer by weight percent based on 100% of the total weight of the preparation.
Preferably, the nasal administration preparation comprises 1.5% of loratadine, 12% of polyethylene glycol and 0.8% of penetration enhancer by weight percent based on 100% of the total weight of the preparation.
Preferably, the mass ratio of the loratadine to the penetration enhancer is 1.5-2:1.
Preferably, the mass ratio of the polyethylene glycol to the penetration enhancer is 12-18:1.
Preferably, the nasal administration preparation is a spray, nose drops, ointment, gel, film or emulsion.
Preferably, the nasal administration formulation component further comprises at least one of a pH buffer, a thickener, a preservative, an antioxidant, a chelating agent, a fragrance, and an osmotic pressure regulator.
Preferably, the pH buffer is selected from one of acetate buffer salt, citrate buffer salt, carbonate buffer salt and phosphate buffer salt, and the concentration of the pH buffer is 0.25mol/L-0.5mol/L, and the final pH value of the nasal administration preparation is adjusted to 5.5-7.0.
Preferably, the thickener is at least one selected from xanthan gum, acacia gum, tragacanth gum and chitosan, and is used in an amount of 0.1 to 0.5% by weight in the nasal administration preparation.
Preferably, the preservative is at least one selected from parahydroxybenzoate, benzoic acid and salts thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethyl alcohol, chlorhexidine acetate, thimerosal and quaternary ammonium compound cationic surfactant, and the weight ratio of the preservative in the nasal administration preparation is 0.01-0.05%.
Preferably, the aromatic is selected from at least one of cinnamaldehyde, vanillin and peppermint oil, and the weight ratio of the aromatic in the nasal administration preparation is 0.01-0.05%.
Preferably, the antioxidant is at least one selected from sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate, ascorbic acid, thiourea, cysteine, tocopherol and lecithin, and the weight ratio of the antioxidant in the nasal administration preparation is 0.3% -2%.
Preferably, the chelating agent is at least one selected from ethylenediamine tetraacetic acid, disodium ethylenediamine tetraacetic acid, citric acid and tartaric acid, and the weight ratio of the chelating agent in the nasal administration preparation is 0.01% -0.03%.
Preferably, the osmotic pressure regulator is at least one selected from sodium chloride, glucose, lactose, mannose and mannitol, and the weight ratio of the osmotic pressure regulator in the nasal administration preparation is 0.6% -1.2%.
The second aspect of the present invention relates to a preparation method of the nasal administration preparation, which can be prepared according to a conventional method in the art, for example, mixing loratadine, polyethylene glycol, a penetration enhancer, and optionally, other pharmaceutical excipients with stirring.
Preferably, the preparation method of the nasal administration preparation comprises the following steps:
(1) Mixing polyethylene glycol, and dissolving loratadine in the polyethylene glycol to obtain a solution A;
(2) Adding the penetration enhancer and other auxiliary materials into the solution A, and stirring and mixing to obtain the water-soluble emulsion.
The third aspect of the invention relates to the application of the nasal administration preparation in preparing medicines for treating rhinitis.
Preferably, the rhinitis includes acute rhinitis, chronic rhinitis, sinusitis, allergic rhinitis, atrophic rhinitis, and vasomotor rhinitis.
Compared with the prior art, the preparation has the beneficial effects that the nasal administration preparation obtained by screening the nasal administration preparation solvent and the penetration enhancer has small nasal cilia irritation, quick effect, high bioavailability and stable preparation, and can be effectively used for treating rhinitis.
Detailed Description
Example 1:
PEG200 and PEG400 are mixed, loratadine is dissolved in polyethylene glycol mixed solution, sodium laurylsulfate and hyaluronic acid are added, water for injection is fixed to a sufficient volume, the mixture is stirred and mixed to prepare clear solution, and the clear solution is packaged in a quantitative spray pump to obtain the loratadine nasal spray (15 mg loratadine/g).
Example 2:
PEG300 and PEG600 are mixed, loratadine is dissolved in polyethylene glycol mixed solution, polyoxyethylene lauryl ether and hyaluronic acid are added, water for injection is fixed to a sufficient volume, the mixture is stirred and mixed, clear solution is prepared, and the clear solution is packaged in a quantitative spray pump, so that the loratadine nasal spray (15 mg loratadine/g) is obtained.
Example 3:
PEG300 and PEG400 are mixed, loratadine is dissolved in polyethylene glycol mixed solution, sodium laurylsulfate and taurine are added, water for injection is fixed to a sufficient volume, the mixture is stirred and mixed to prepare clear solution, and the clear solution is subpackaged in a quantitative spray pump to obtain the loratadine nasal spray (15 mg loratadine/g).
Comparative example 1:
referring to the dose of recipe 1 in CN110693816a, specific is:
Loratadine 7.6mg/mL, gellan gum 4mg/mL, sodium alginate 1mg/mL, HPMC 1mg/mL, tween 801 mg/mL, deionized water to volume of 100 ML.
Comparative example 2:
referring to the formulation composition in table 1 of US9993468B2, specific is:
Comparative example 3:
PEG200 and PEG400 are mixed, loratadine is dissolved in polyethylene glycol mixed solution, hyaluronic acid is added, water for injection is fixed to a sufficient volume, the mixture is stirred and mixed to prepare clear solution, and the clear solution is packaged in a quantitative spray pump to obtain the loratadine nasal spray (15 mg loratadine/g).
The difference from example 1 is that comparative example 3 contains only hyaluronic acid and no sodium lauryl sulfate.
Comparative example 4:
PEG200 and PEG400 are mixed, loratadine is dissolved in polyethylene glycol mixed solution, sodium laurylsulfate is added, water for injection is used for constant volume to a sufficient amount, the mixture is stirred and mixed to prepare clear solution, and the clear solution is packaged in a quantitative spray pump to obtain the loratadine nasal spray (15 mg loratadine/g).
The difference from example 1 is that comparative example 4 contains sodium lauryl sulfate alone and no hyaluronic acid.
Comparative example 5:
Dissolving loratadine in PEG400, adding sodium laurylsulfate and hyaluronic acid, metering volume with injectable water to a sufficient amount, stirring, mixing to obtain clear solution, and packaging in quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine/g).
The difference from example 1 is that comparative example 5 contains only polyethylene glycol PEG400 and no PEG200.
Comparative example 6:
Dissolving loratadine in PEG200, adding sodium laurylsulfate and hyaluronic acid, metering volume with injectable water to a sufficient amount, stirring, mixing to obtain clear solution, and packaging in quantitative spray pump to obtain loratadine nasal spray (15 mg loratadine/g).
The difference from example 1 is that comparative example 6 contains only polyethylene glycol PEG200 and no PEG400.
Test example 1:
The rabbit body weight (2.43+/-0.21) kg, the male and female are not limited, and no medicine is taken. The cells were randomly divided into 7 groups, examples 1-3, comparative examples 1-6, 5 each, and each group was given 0.1mL of loratadine by nasal drip. Taking 3mL of blank blood from the auricular vein as a control 24h before administration, taking 3mL of blood from 5min, 15min, 30min, 45min, 1h, 2h, 3h and 6h after administration, anticoagulating with heparin, gently shaking, centrifuging, taking 1mL of drug-containing plasma and blank plasma, and preserving at low temperature for later use. Taking the blood sample, naturally heating to room temperature, adding 1.5mL of mobile phase, mixing, centrifuging, measuring the content of loratadine by an HPLC method, calculating the blood concentration, and calculating the area under the curve AUC when in medicine.
The chromatographic conditions were that octadecylsilane chemically bonded silica was used as a filler, phosphate buffer (dipotassium hydrogen phosphate 2.28g, water 800mL was added to dissolve the filler, phosphoric acid was used to adjust the pH to 6.0, water was added to 1000 mL) -methanol (20:80) was used as a mobile phase, the detection wavelength was 247nm, and the sample volume was 20. Mu.L.
The control solution is prepared by taking a proper amount of loratadine control, precisely weighing, adding a mobile phase for dissolution and quantitatively diluting to prepare a solution containing about 0.2mg per 1 mL.
The system applicability requires that the theoretical plate number is not lower than 2000 calculated according to the loratadine peak, and the separation degree between the loratadine peak and the adjacent impurity peak meets the requirement.
The measuring method comprises precisely measuring the solution of the sample and the solution of the reference substance, respectively injecting into a liquid chromatograph, and recording the chromatograms. Calculated as peak area according to the external standard method. The results are shown in Table 1.
TABLE 1 blood concentration results for different groups (n=5)
Note that, compared with example 1, between groups, P <0.05, P <0.01, and P <0.001.
As can be seen from the results of Table AUC 0-240, examples 1-3 of the present invention are significantly higher than comparative examples 1-6, wherein the difference in solvent system between comparative examples 1 and 2 compared with example 1 resulted in a difference in the amount of dissolved loratadine in the formulation, especially in comparative example 2, the loratadine content in the formulation was only 0.06%, which is 1/25 of example 1, resulting in a small dose of loratadine to be administered in the final administration, which seriously affects the blood concentration after administration, and comparative examples 3 or 4 were unchanged in the total amount of the permeation enhancer compared with example 1, and the use of the two permeation enhancers was changed to either one of them, and the difference in bioavailability was statistically significant (P < 0.05) compared with example 1. Comparative examples 5 and 6 were statistically significant (P < 0.05) compared with example 1, in which the bioavailability was decreased by changing the PEG type from two to either one without changing the total amount of polyethylene glycol as compared with example 1. Therefore, the composition of the components in the preparation, the dosage range of the related components and the dosage ratio among the components have obvious influence on the action result of the medicine.
Test example 2 toxicity study of nasal mucosa cilia
For the preparations of examples 1 to 3 and comparative examples 1 to 6 of the present invention, cilia toxicity was evaluated by using an in vitro toad palate model (Jiang Xinguo, cui Jing, fang Xiaoling, etc., nasal mucosa cilia toxicity of the drug and evaluation method, pharmaceutical report 1995,30 (11): 848). It is generally believed that the duration of the mucociliary movement of the palate of the toad in the test group is greater than 70% of that of the normal saline control group, and that the test formulation is less ciliated and within a clinically acceptable range. The specific experimental results are shown in Table 2.
TABLE 2 results of influence on the mucociliary movement of the palate of Bufo siccus
Group of Relative duration of movement of cilia of palate mucosa of Bufo siccus
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%*
Note that between groups, P <0.05 and P <0.01 are indicated as compared to example 1.
The results show that the relative average duration of movement of the cilia of the palate mucosa of the toad after 30min of administration of the preparation of examples 1-3 and comparative examples 3-6 is above 70%, and especially the relative average duration of movement of the cilia of the palate mucosa of the toad after 30min of administration of the preparation of examples 1-3 is above 80%, and the toxic effect on the nasal cilia can be clinically accepted, thus having necessary clinical medication safety. As the formulation of comparative example 1 or 2 contains substances such as Tween 80, the relative average continuous movement time of the cilia of the palate mucosa of the toad after 30min administration is below 70%, and the toad has certain toxicity of the cilia of the nasal mucosa.
Test example 3 stability investigation experiment
The formulations of example 1, comparative example 2, comparative example 3 were subjected to a high temperature stability test at 60 ℃ based on 100% of the amount of loratadine in the initial loratadine formulation. The HPLC method for measuring the loratadine content, the chromatographic conditions and the measuring method are the same as those of test example 1, and the experimental results are shown in Table 3.
TABLE 3 high temperature stability test
According to the data in the table, the preparation provided by the invention has better stability under the specific component composition, and the stability of the loratadine preparation is reduced when the components are changed.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (6)

1. The nasal administration preparation comprises, by weight, 1-3% of loratadine, 8-15% of polyethylene glycol 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, taurine, hyaluronic acid and polyoxyethylene lauryl ether;
the mass ratio of the loratadine to the penetration enhancer to the polyethylene glycol is 1.5-2:1:12-18;
the preparation method of the nasal administration preparation comprises the following steps:
(1) Mixing polyethylene glycol, and dissolving loratadine in the polyethylene glycol to obtain a solution A;
(2) Adding the penetration enhancer and other auxiliary materials into the solution A, and stirring and mixing to obtain the water-soluble emulsion.
2. The nasal preparation according to claim 1, wherein the nasal preparation comprises 1.5% of loratadine, 12% of polyethylene glycol and 0.8% of penetration enhancer by weight percent based on 100% of the total weight of the preparation.
3. The nasal formulation according to any one of claims 1-2, wherein the nasal formulation is a spray, nasal drops, ointment, gel, film or emulsion.
4. The nasal delivery formulation of any one of claims 1-2, wherein the nasal delivery formulation component further comprises 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 a nasal formulation according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of rhinitis.
6. The use according to claim 5, wherein the rhinitis comprises acute rhinitis, chronic rhinitis, sinusitis, allergic rhinitis, atrophic rhinitis, vasomotor rhinitis.
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Citations (2)

* Cited by examiner, † Cited by third party
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WO2004082589A2 (en) * 2003-03-20 2004-09-30 Ranbaxy Laboratories Limited Nasally administrable, bioavailable pharmaceutical composition of loratadine
CN1969814A (en) * 2005-11-24 2007-05-30 中国人民解放军军事医学科学院毒物药物研究所 Nasal administered preparation of melatonin

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101502515A (en) * 2008-09-04 2009-08-12 山东淄博新达制药有限公司 Hydrochloride loratadine enteric-coated formulation composition and method for preparing the same
CN111603478B (en) * 2020-06-29 2021-07-30 华熙生物科技股份有限公司 Composition for nasal cavity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082589A2 (en) * 2003-03-20 2004-09-30 Ranbaxy Laboratories Limited Nasally administrable, bioavailable pharmaceutical composition of loratadine
CN1969814A (en) * 2005-11-24 2007-05-30 中国人民解放军军事医学科学院毒物药物研究所 Nasal administered preparation of melatonin

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