Nasal preparation and application thereof

Abstract

The invention relates to a nasal preparation and application thereof. The nasal preparation contains only emedastine or pharmaceutically acceptable salt thereof as an active ingredient.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a nasal preparation and its application. BACKGROUND

[0002] Seasonal allergic rhinitis (SAR) is a common allergic disease, mainly manifested as nasal congestion, rhinorrhea, sneezing and nasal itching, etc., which significantly affects the quality of life of patients. H1 receptor antagonists are the first-line drugs for the treatment of this disease. Emedastine difumarate, as a second-generation H1 receptor antagonist, has good antihistamine effect and lower central nervous system inhibition side effects, and has been widely used for the treatment of allergic conjunctivitis and commercialized as eye drops.

[0003] However, the research and development of emedastine for nasal delivery is still limited. In the prior art, most of the disclosed emedastine preparations are eye drop formulations, and few documents or patents describe the composition, physicochemical properties, atomization characteristics and effects on drug efficacy and safety of emedastine as a liquid nasal preparation. Due to the significant differences in the structure and barrier properties of the nasal mucosa and the eye, directly applying the eye drop formula to the nasal preparation may result in insufficient efficacy or safety problems.

[0004] Currently, there is no literature that clearly reports a liquid nasal spray formulation containing only emedastine as an active ingredient, with clear control of spray particle size, good physicochemical properties and stability. SUMMARY

[0005] The present application provides a novel emedastine liquid nasal preparation. By optimizing the ratio of thickening agent, osmotic pressure regulator, metal ion chelating agent and pH regulator, the retention and local bioavailability of emedastine in nasal delivery are improved. More importantly, the preparation has good physical and chemical stability, and takes into account local efficacy and safety. Specifically, the preparation provided by the present application has one or more of the following advantages:

[0006] 1. Good stability: metal ion complexing agent and buffer system synergistically inhibit the degradation of emedastine in aqueous environment, ensuring the stability of physicochemical properties and efficacy of the preparation during storage;

[0007] 2. High safety: the formulation does not contain additives that may cause irritation, and the combination of thickening agent and specific nasal spray device controls the droplet size within a reasonable range, avoiding inhalation risk and being suitable for a wide range of people including children;

[0008] 3. Significant efficacy: improves the distribution and absorption efficiency of the drug on the nasal mucosa surface, and enhances the relief effect on the symptoms of allergic rhinitis and other diseases;

[0009] 4. Excellent local delivery performance: improves the retention time of the drug on the nasal mucosa surface, reduces drug loss and systemic absorption, and is conducive to the local antihistamine effect of emedastine.

[0010] In one aspect, the present application provides a nasal preparation comprising only emedastine or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] In certain embodiments, the pharmaceutically acceptable salt of emedastine includes emedastine fumarate.

[0012] In certain embodiments, the content of the active ingredient in the nasal preparation is 0.01% to 5% (w / v%).

[0013] In certain embodiments, the nasal preparation has at least one of the following physicochemical properties:

[0014] a) the pH value is 3.0 to 8.0;

[0015] b) the viscosity is 0.5 to 5.0 mPa.s;

[0016] c) the osmolarity is 260 to 350 mOsmol / kg.

[0017] In certain embodiments, the nasal preparation comprises a pH adjuster, a metal ion complexing agent, an osmotic pressure regulator, and a thickening agent.

[0018] In certain embodiments, the pH adjuster is selected from citric acid, sodium citrate, sodium hydroxide, and / or hydrochloric acid.

[0019] In certain embodiments, the content of citric acid is 0.001% to 2% (w / v%), and the content of sodium citrate is 0.001% to 1% (w / v%).

[0020] In certain embodiments, the metal ion complexing agent in the nasal preparation is edetate disodium.

[0021] In certain embodiments, the content of edetate disodium is 0.001% to 0.1% (w / v%).

[0022] In certain embodiments, the osmotic pressure regulator in the nasal preparation is selected from sodium chloride, propylene glycol, glycerol, glucose, or a combination thereof.

[0023] In certain embodiments, the content of sodium chloride is 0.05% to 2% (w / v%).

[0024] In certain embodiments, the propylene glycol, glycerin or glucose is present in an amount of 0.5% to 10% (w / v%).

[0025] In certain embodiments, the thickening agent in the nasal formulation is selected from the group consisting of sucrose, pectin, microcrystalline cellulose carboxymethylcellulose sodium co-processed, carboxymethylcellulose sodium, hypromellose, povidone or a combination thereof.

[0026] In certain embodiments, the viscosity of the 2% aqueous solution of hypromellose is about 1000 to 10000 mPa.s.

[0027] In certain embodiments, the hypromellose is present in an amount of 0.005% to 5% (w / v%).

[0028] In certain embodiments, the povidone is present in an amount of 0.01% to 2% (w / v%).

[0029] In certain embodiments, the nasal formulation comprises: emedastine fumarate in an amount of 0.01% to 5% (w / v%); citric acid in an amount of 0.001% to 2% (w / v%); sodium citrate in an amount of 0.001% to 1% (w / v%); edetate disodium in an amount of 0.001% to 0.1% (w / v%); sodium chloride in an amount of 0.05% to 2% (w / v%); hypromellose in an amount of 0.005% to 5% (w / v%); and the pH is adjusted to 3.0 to 8.0 with sodium hydroxide.

[0030] In certain embodiments, the nasal formulation comprises: 0.4% (w / v%) of emedastine fumarate, 0.048% (w / v%) of citric acid, 0.008% (w / v%) of sodium citrate, 0.01% (w / v%) of edetate disodium, 0.75% (w / v%) of sodium chloride, 0.1% (w / v%) of hypromellose, and the pH is adjusted to 5.5 with sodium hydroxide.

[0031] In certain embodiments, the nasal formulation further comprises a humectant.

[0032] In certain embodiments, the humectant is selected from the group consisting of sorbitol and / or mannitol.

[0033] In certain embodiments, the sorbitol or mannitol is present in an amount of 0.5% to 10% (w / v%).

[0034] In certain embodiments, the nasal formulation further comprises an absorption enhancer.

[0035] In certain embodiments, the absorption enhancer is selected from the group consisting of fatty acids, cholate salts, phospholipids, polyethylene glycol and its derivatives, alkyl glycosides, cyclodextrins and its derivatives, or a combination thereof.

[0036] In certain embodiments, the absorption enhancer is dodecyl maltoside, and the dodecyl maltoside is present in an amount of 0.01% (w / v%).

[0037] In certain embodiments, the nasal formulation is a sterile formulation.

[0038] In certain embodiments, the nasal formulation further comprises a bacteriostatic agent.

[0039] In certain embodiments, the bacteriostatic agent is selected from the group consisting of quaternary ammonium salts, alcohols, organic acids and its salts, parabens, or a combination thereof.

[0040] In certain embodiments, the bacteriostatic agent in the nasal formulation is benzalkonium chloride, benzyl alcohol, phenylethyl alcohol, potassium sorbate, sodium benzoate, or a combination thereof.

[0041] In certain embodiments, the bacteriostatic agent is benzalkonium chloride, and the benzalkonium chloride is present in an amount of 0.001% to 0.5% (w / v%).

[0042] In certain embodiments, the dosage form of the nasal formulation is selected from one or more of the group consisting of a spray, an aerosol, and a nasal drop.

[0043] In certain embodiments, the spray has a spray droplet size distribution with the following characteristics: a D50 particle size of 30 to 150 μm, a percentage of droplets with a particle size of less than 10 μm of less than 5%, and a span of the droplet size distribution of less than 3.0, when measured at a spray distance of 3 cm or 6 cm.

[0044] In certain embodiments, the nasal formulation is an aqueous composition.

[0045] In another aspect, the present application provides a method of treating allergic rhinitis and / or conjunctivitis, comprising administering to a subject an effective amount of the nasal formulation described herein.

[0046] In another aspect, the present application provides use of the nasal formulation described herein in the manufacture of a medicament for treating allergic rhinitis and / or conjunctivitis.

[0047] In another aspect, the present application provides use of the nasal formulation described herein in the treatment of allergic rhinitis and / or conjunctivitis.

[0048] In certain embodiments, the allergic rhinitis includes seasonal allergic rhinitis and perennial allergic rhinitis.

[0049] On the other hand, this application provides a method for preparing the nasal formulation described in this application, which includes dissolving emestin or a pharmaceutically acceptable salt thereof, and the remaining components of the nasal formulation, in water capable of achieving a desired concentration range in the resulting solution.

[0050] On the other hand, this application provides a packaging device for a nasal preparation described in this application, which includes a nasal spray bottle provided with a nozzle and a pump device for controlling the dosage.

[0051] In some embodiments, the packaging device has a bacterial barrier function.

[0052] Other aspects and advantages of this application will readily be apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this application are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the descriptions in the accompanying drawings and specification of this application are merely exemplary and not restrictive. Attached Figure Description

[0053] The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows:

[0054] Figures 1A-1B The graph shows the average blood drug concentrations in Beagle dogs after nasal administration of the emesitin nasal formulation described in this application and oral administration of emesitin fumarate extended-release capsules. Figure 1A ) and the semi-logarithmic graph of blood drug concentration ( Figure 1B (See figure 1). Group 1 in the figure is the group receiving emesitine nasal spray, and group 2 in the figure is the group receiving emesitine fumarate sustained-release capsules. Detailed Implementation

[0055] The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification.

[0056] Terminology Definition

[0057] In the present application, the term "Emedastine" generally refers to a selective H1 receptor antagonist, which includes its free base form and its pharmaceutically acceptable salt form, unless otherwise specified by the context. The compound can also be referred to as emedastine or emedastine. The chemical name of emedastine can be: 1-(2-ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)benzimidazole, and the molecular formula can be C 17 H 26 N4O. The CAS number of emedastine can be 87233-61-2. Emedastine can have the following structure: .

[0058] In the present application, the term "pharmaceutically acceptable salt" generally refers to a salt form of an active pharmaceutical ingredient, which is widely accepted in the pharmaceutical industry, neither impairing the drug efficacy nor causing adverse reactions to the body. The term includes but is not limited to acid addition salts and base addition salts, as long as it meets the requirements of pharmacy, safety and toxicology, and is suitable for pharmaceutical use. The pharmaceutically acceptable salt of emedastine is generally its acid addition salt, including but not limited to: fumarate, citrate, tartrate, oxalate and hydrochloride, etc.

[0059] In the present application, the term "Emedastine fumarate" generally refers to a salt of emedastine with fumaric acid, such as emedastine difumarate. Emedastine fumarate can exist in different crystal forms or hydration states. Unless otherwise specified, the emedastine fumarate described in the present application generally refers to a compound in which two molecules of fumaric acid are salted with emedastine, i.e. emedastine difumarate. The chemical name of emedastine difumarate is 1-(2-ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)benzimidazole difumarate. The molecular formula of emedastine difumarate can be C 25 H 34 N4O9, and the CAS number of emedastine difumarate can be 87233-62-3.

[0060] In the present application, the term "pH adjusting agent" generally refers to a type of ingredient used to adjust the pH value in the preparation to be within the range of pharmaceutically acceptable. The pH adjusting agent suitable for the present application can include acidic components, basic components or buffer systems. The suitable pH adjusting agents include but are not limited to citric acid (i.e. citric acid), hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium citrate / citric acid system and phosphate buffer system, etc.

[0061] In the present application, the term "metal ion complexing agent" generally refers to a pharmaceutically acceptable excipient that is capable of forming stable complexes with metal ions (such as Ca2+, Mg2+, Fe3+, etc.), whose functions generally include inhibiting formulation instability (such as oxidative degradation, flocculation, discoloration, etc.) caused by metal ions, or enhancing the stability and bioavailability of active ingredients. Suitable metal ion complexing agents for use in the present application include, but are not limited to, edetic acid (i.e., ethylenediaminetetraacetic acid, EDTA), its sodium salts (such as EDTA-2Na or EDTA-4Na), citric acid, tartaric acid, phytic acid and its salts, etc.

[0062] In the present application, the term "osmotic pressure regulator" generally refers to a pharmaceutically acceptable excipient that can be used to adjust the osmotic pressure of a formulation to improve its compatibility with physiological conditions. The osmotic pressure regulator can be used alone or in combination with other excipients to make the composition have an osmotic pressure close to that of the nasal cavity or other administration site, thereby reducing irritation, enhancing comfort, and promoting drug absorption. Suitable osmotic pressure regulators for use in the present application include, but are not limited to, sodium chloride, propylene glycol, glycerol, glucose, or combinations thereof.

[0063] In the present application, the term "thickening agent" generally refers to a pharmaceutically acceptable excipient used to increase the viscosity of a nasal formulation system to improve its physical stability, prolong the residence time of the drug in the nasal mucosa, or enhance the use of the feeling. Suitable thickening agents for use in the present application include, but are not limited to, one or more of the following: sugars such as sucrose; natural or semi-synthetic polysaccharides such as xanthan gum, sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl methyl cellulose (HPMC); co-processed cellulose materials such as microcrystalline cellulose-sodium carboxymethyl cellulose co-processed material; synthetic polymer materials such as povidone (Povidone) and the like. The thickening agent can be used alone or in combination.

[0064] In the present application, the term "moisturizing agent" generally refers to a pharmaceutically acceptable excipient that can maintain or increase moisture in the formulation, reduce nasal mucosa dryness or irritation, and thereby improve the comfort of use and drug delivery effect. The moisturizing agent can function both by adjusting the osmotic pressure and water activity of the formulation, and by forming a protective hydration layer on the surface of the nasal mucosa to prolong the residence time of the drug. Suitable moisturizing agents for use in nasal formulations include, but are not limited to, polyols (such as glycerol, sorbitol, propylene glycol), sugar alcohols (such as mannitol, xylitol, erythritol), sugars (such as sucrose, lactose), etc.

[0065] It should be noted that some of the excipients described in the present application can have multiple pharmaceutical uses. For example, glucose can be used as an osmotic pressure regulator, as well as a thickening agent or a moisturizing agent. Unless otherwise specified, the use of an excipient in a certain category in the present application does not exclude the case where it has other functions in the formulation.

[0066] In the present application, the term "absorption enhancer" generally refers to an additive that can increase the rate and / or extent of absorption of an active ingredient (e.g., emedastine or a pharmaceutically acceptable salt thereof) through the nasal mucosa. Absorption enhancers can act through a variety of mechanisms, including but not limited to: altering mucosal permeability, promoting drug retention on the mucosal surface, inhibiting drug degradation, or stimulating epithelial intercellular space dilation, etc. Suitable absorption enhancers for use in the present application can include, but are not limited to, one or more of the following categories: fatty acids and their salts (e.g., sodium caprylate, sodium caprate); bile salts (e.g., sodium taurodeoxycholate); phospholipids (e.g., lecithin, distearoylphosphatidylcholine, etc.); polyethylene glycol and its derivatives (e.g., PEG-400, PEG-40 hydrogenated castor oil, etc.); alkyl glycoside surfactants (e.g., lauryl glucoside, decyl glucoside, dodecyl maltoside); cyclodextrins and their derivatives (e.g., β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin); and other pharmaceutically acceptable absorption enhancers that have been reported in the literature or pharmacopeia to enhance nasal absorption. The above-mentioned absorption enhancers can be used alone or in combination.

[0067] In the present application, the term "sterile" generally refers to a formulation and its container system that is free of viable microorganisms that can be detected under conventional microbiological testing conditions (e.g., culture plating, membrane filtration, etc.) during the process of formulation, filling, packaging, and storage. The "sterile" can be obtained by aseptic manufacturing process (e.g., aseptic formulation and filling under clean environment) or by terminal sterilization (e.g., filtration sterilization, heat sterilization, radiation sterilization, etc.), and is not limited to a specific process approach.

[0068] In the present application, the term "bacteriostatic agent" generally refers to a pharmaceutically acceptable excipient that can inhibit the growth of microorganisms in a formulation, thereby prolonging the shelf life of the formulation and ensuring its safe use. The main role of the bacteriostatic agent is to prevent the multiplication of microorganisms such as bacteria, fungi, or yeasts caused by external contamination during the production, storage, or use of the formulation. Suitable bacteriostatic agents for use in the present application include, but are not limited to, quaternary ammonium salts (e.g., benzalkonium chloride), alcohols (e.g., benzyl alcohol, phenethyl alcohol), organic acids and their salts (e.g., benzoic acid, sodium benzoate, potassium sorbate), parabens (e.g., methylparaben, ethylparaben, propylparaben), or combinations thereof.

[0069] In the present application, the term "nasal formulation" generally refers to a pharmaceutical formulation for administration through the nasal route, which can be in the form of a liquid, semi-solid, or powder, with a carrier usually being water or a pharmaceutically acceptable solvent, and can contain appropriate excipients (e.g., pH adjusters, osmotic pressure adjusters, thickening agents, absorption enhancers, bacteriostatic agents, etc.). The purpose of the nasal formulation is to deliver the active ingredient through the nasal mucosa to exert local or systemic pharmacological effects.

[0070] In the present application, the term "spray" generally refers to a liquid nasal preparation that is atomized into fine droplets by a mechanical pump, a hand-tightening cap or other spray device. The spray does not rely on propellants, and its droplet size distribution is usually in the range of tens of microns, suitable for local deposition in the nasal cavity.

[0071] In the present application, the term "aerosol" generally refers to a nasal preparation that is atomized into an aerosol by a propellant (such as Freon substitutes, compressed gases, etc.). The aerosol relies on internal pressure to release droplets when used, and the droplet size can be adjusted according to the prescription and device.

[0072] In the present application, the term "nasal drops" generally refers to a liquid nasal preparation in the form of a solution that is directly dropped into the nasal cavity, usually without the aid of an atomizing device, and the administration method is instillation.

[0073] In the present application, the term "aqueous composition" generally refers to a pharmaceutical composition in which water is the main solvent or dispersion medium, and the water can be purified water, water for injection or other water that meets pharmaceutical standards. The aqueous composition can also contain appropriate amounts of cosolvents, surfactants, buffers, osmotic pressure regulators, thickeners, absorption enhancers, bacteriostatic agents and other pharmaceutically acceptable excipients. Unless otherwise specified, the "aqueous composition" referred to in the present application mainly refers to a liquid preparation, preferably a solution or colloidal dispersion system suitable for local administration in the nasal cavity.

[0074] In the present application, the term "allergic rhinitis" generally refers to a chronic or recurrent disease characterized by inflammation of the nasal mucosa induced by inhaled allergens, usually an IgE-mediated type I hypersensitivity reaction. Its typical clinical manifestations include, but are not limited to, repeated sneezing, rhinorrhea, nasal congestion and nasal itching. Allergic rhinitis can be divided into seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) according to the nature of the allergen or the characteristics of the disease. Seasonal allergic rhinitis is characterized by symptoms such as sneezing, rhinorrhea, nasal congestion and nasal itching that occur in specific seasons, and is usually caused by seasonal allergens such as pollen. It is also commonly referred to as hay fever or pollinosis in clinical practice. Perennial allergic rhinitis usually refers to nasal inflammatory diseases caused by common perennial allergens such as dust mites, mold and animal dander. Its typical manifestations are long-term or perennial nasal congestion, intermittent or persistent rhinorrhea, sneezing and nasal itching, and some patients have symptoms that worsen at night or in the morning. Unless otherwise specified, the term "allergic rhinitis" in the present application broadly encompasses both types of diseases and their clinical manifestations.

[0075] In the present application, the term "conjunctivitis" generally refers to an inflammatory disease occurring in the conjunctiva of the eyeball or the palpebral conjunctiva, and its typical clinical manifestations include, but are not limited to, red eye, tearing, foreign body sensation, itching, increased secretion, etc. The causes of conjunctivitis can include infectious (e.g. caused by bacteria, viruses, fungi or chlamydia, etc.) and non-infectious (e.g. caused by allergy, irritation (such as chemical substances, ultraviolet light), dry eye, etc.). Among them, allergic conjunctivitis is a common type, which is often triggered by inhaled allergens such as pollen, dust mites, animal dander, etc., and often accompanied by or occurs simultaneously with allergic rhinitis. Unless otherwise specified, the term "conjunctivitis" referred to in the present application broadly encompasses conjunctivitis of different causes as described above, and preferably refers to allergic conjunctivitis.

[0076] In the present application, the term "treatment" generally refers to the handling of a subject's condition or disease by administration or other intervention, which includes, but is not limited to, prevention (preventing the disease from occurring or reducing the risk of disease), alleviation (reducing the severity of symptoms), improvement (shortening the course of disease or reducing symptoms), stabilization (delaying the progression of disease or preventing the disease from worsening), and cure.

[0077] In the present application, the term "effective amount" refers to a dosage of a drug sufficient to produce a desired therapeutic effect in a subject, which can include, but is not limited to, alleviation, improvement, control or prevention of symptoms. The effective amount can vary depending on individual differences of patients, administration regimen and severity of symptoms.

[0078] As used in the specification and claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.

[0079] All numerical values or expressions involving quantities of components, etc. used in the present application shall be understood to be "about" in all instances. The term "about" when referring to a quantity or a numerical range means that the quantity or numerical range is an approximation within experimental variability (or statistical experimental error), and thus the quantity or numerical range can vary by, for example, ±5 between the stated quantity or numerical range. All ranges involving the same component or property include the endpoints, which can be independently combined. Since these ranges are continuous, they include every value between the minimum and maximum values. It should also be understood that any numerical range recited in the present application is intended to include all sub-ranges of the range.

[0080] When the application defines a range in terms of a property, such as molecular weight, or in terms of a chemical property, it is intended to include all combinations and subcombinations of the range as well as specific embodiments therein. The term "comprising" (and related terms such as "comprise" or "comprises" or "have" or "has" or "including" or "includes" or "contain" or "contains" or "consisting of") includes those embodiments of the application which "consist essentially of" or "consist of" the described features.

[0081] As used herein, "and / or", shall be understood to mean "one or both" of the components linked by the term. Multiple components listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the components. Other components can optionally be present in addition to those components specifically identified by the "and / or" clause, whether related to those components or not. Thus, as a non-limiting example, a reference to "A and / or B", when used in a conjunctive sense, e.g., "comprising", can refer solely to A (optionally including components other than B), solely to B (optionally including components other than A), or to both A and B (optionally including additional components). DETAILED DESCRIPTION

[0083] In one aspect, the present application provides a nasal formulation, especially a nasal aqueous composition comprising emedastine or a pharmaceutically acceptable salt thereof. The formulation of the present application exhibits good stability, absorption and patient compliance in the treatment of allergic rhinitis and / or conjunctivitis.

[0084] Active ingredient

[0085] In certain embodiments, the active ingredient of the nasal formulation described herein is emedastine or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutically acceptable salt is emedastine fumarate, for example emedastine difumarate. The content of the active ingredient in the nasal formulation described herein can be optionally in the range of 0.01% to 5% (w / v%), preferably 0.05% to 2.5% (w / v%), more preferably 0.1% to 1% (w / v%). In certain embodiments, the nasal formulation described herein comprises 0.01% to 5% (w / v%) of emedastine fumarate.

[0086] Physico-chemical properties

[0087] In certain embodiments, the nasal formulations described herein can have at least one of the following physicochemical properties: a pH of 3.0 to 8.0; a viscosity of 0.5 to 5.0 mPa.s (e.g., as measured at 20°C); and an osmolality of 260 to 350 mOsmol / kg.

[0088] In certain embodiments, the nasal formulations described herein can have a pH of 3.0 to 8.0. In certain embodiments, the nasal formulations described herein can have a pH of 5.0 to 6.0. In certain embodiments, the nasal formulations described herein can have a pH of about 5.5. The pH values described herein can be measured by conventional pH meters, e.g., at 20°C or 25°C.

[0089] In certain embodiments, the nasal formulations described herein can have a viscosity of 0.5 to 5.0 mPa.s at 20°C. In certain embodiments, the nasal formulations described herein can have a viscosity of 1.0 to 3.0 mPa.s at 20°C. In certain embodiments, the nasal formulations described herein can have a viscosity of about 2.0 mPa.s at 20°C. The viscosity values described herein can be measured using a rotational viscometer (e.g., a Brookfield viscometer), e.g., at 20°C ± 2°C.

[0090] In certain embodiments, the nasal formulations described herein can have an osmolality of 260 to 350 mOsmol / kg. In certain embodiments, the nasal formulations described herein can have an osmolality of 285 to 310 mOsmol / kg. In certain embodiments, the nasal formulations described herein can have an osmolality of about 290 mOsmol / kg. The osmolality values described herein can be measured using a freezing point depression method using an osmometer, e.g., at 20°C ± 2°C. Other equivalent methods known to those skilled in the art (e.g., vapor pressure osmometry) can also be used to measure osmolality.

[0091] In certain embodiments, the nasal formulations described herein can have a pH of about 5.5, a viscosity of about 2.0 mPa.s at 20°C, and an osmolality of about 290 mOsmol / kg.

[0092] pH adjusters

[0093] Formulation stability is related to pH, and to ensure that the formulations have suitable stability and that the pH of the formulations is within a range that is tolerable by the nasal mucosa, the nasal formulations described herein are adjusted for pH using pH adjusting agents.

[0094] In certain embodiments, the nasal formulation described herein contains a pH adjusting agent, which can be selected from the group consisting of citric acid, sodium citrate, sodium hydroxide, and / or hydrochloric acid.

[0095] In certain embodiments, the citric acid can be present in an amount of 0.001% to 2% (w / v%). In certain embodiments, the citric acid can be present in an amount of 0.01% to 0.2% (w / v%). In certain embodiments, the citric acid can be present in an amount of 0.0048% to 0.12% (w / v%). In certain embodiments, the citric acid can be present in an amount of 0.03% to 0.08% (w / v%), e.g., about 0.048% (w / v%).

[0096] In certain embodiments, the sodium citrate can be present in an amount of 0.001% to 1% (w / v%). In certain embodiments, the sodium citrate can be present in an amount of 0.005% to 0.05% (w / v%). In certain embodiments, the sodium citrate can be present in an amount of 0.008% to 0.02% (w / v%). In certain embodiments, the sodium citrate can be present in an amount of 0.007% to 0.02% (w / v%), e.g., about 0.008% (w / v%).

[0097] In certain embodiments, the pH of the nasal formulation is adjusted to a range of 3.0 to 8.0 by sodium hydroxide or hydrochloric acid. In certain embodiments, the pH is in the range of 5.0 to 6.0. In certain embodiments, the pH is about 5.5.

[0098] Metal ion complexing agents

[0099] To prevent the active ingredient from being catalytically degraded by metal ions, an appropriate amount of a metal ion complexing agent can be added to the nasal formulation described herein.

[0100] In certain embodiments, the nasal formulation described herein contains a metal ion complexing agent, which can be present in an amount of 0.001% to 0.1% (w / v%). In certain embodiments, the metal ion complexing agent can be present in an amount of 0.005% to 0.05% (w / v%), e.g., about 0.01% (w / v%).

[0101] In certain embodiments, the metal ion complexing agent can include disodium edetate (EDTA-2Na). In certain embodiments, the disodium edetate can be present in an amount of 0.001% to 0.1% (w / v%). In certain embodiments, the disodium edetate can be present in an amount of 0.005% to 0.05% (w / v%), e.g., about 0.01% (w / v%).

[0102] Osmotic pressure regulators

[0103] To reduce the irritation of the nasal mucosa by hypo- or hypertonicity, the nasal formulations of the present application can employ an osmotic pressure adjusting agent to adjust the osmotic pressure of the formulation to isotonicity.

[0104] In certain embodiments, the nasal formulations of the present application contain an osmotic pressure adjusting agent, which can be selected from sodium chloride, propylene glycol, glycerol, glucose, mannitol, sorbitol, or a combination thereof.

[0105] In certain embodiments, the osmotic pressure adjusting agent can include sodium chloride, which can be present in an amount of 0.05% to 2% (w / v%). In certain embodiments, the nasal formulations of the present application contain sodium chloride, which can be present in an amount of 0.2% to 1.0% (w / v%). In certain embodiments, the sodium chloride can be present in an amount of 0.7% to 1% (w / v). In certain embodiments, the sodium chloride can be present in an amount of 0.7% to 0.8% (w / v), for example, about 0.75% (w / v).

[0106] In certain embodiments, the osmotic pressure adjusting agent can include propylene glycol, which can be present in an amount of 0.5% to 5% (w / v). In certain embodiments, the nasal formulations of the present application contain propylene glycol, which can be present in an amount of 1% to 3% (w / v), for example, about 2.6% (w / v).

[0107] In certain embodiments, the osmotic pressure adjusting agent can include glycerol, which can be present in an amount of 0.5% to 10% (w / v). In certain embodiments, the nasal formulations of the present application contain glycerol, which can be present in an amount of 1% to 5% (w / v), for example, about 2.6% (w / v).

[0108] In certain embodiments, the osmotic pressure adjusting agent can include glucose, which can be present in an amount of 0.5% to 10% (w / v). In certain embodiments, the nasal formulations of the present application contain glucose, which can be present in an amount of 3% to 7% (w / v), for example, about 5% (w / v).

[0109] In certain embodiments, the osmotic pressure adjusting agent can include mannitol, which can be present in an amount of 0.5% to 10% (w / v). In certain embodiments, the nasal formulations of the present application contain mannitol, which can be present in an amount of 3% to 7% (w / v), for example, about 5.48% (w / v).

[0110] In some embodiments, the osmotic pressure regulator can include sorbitol, which can be present in an amount of 0.5% to 10% (w / v%). In some embodiments, the nasal formulation described herein can include sorbitol, which can be present in an amount of 3% to 7% (w / v), such as about 5% (w / v).

[0111] In some embodiments, the nasal formulation described herein can include one, two, or more osmotic pressure regulators. In some embodiments, the nasal formulation described herein can include a combination of sodium chloride and propylene glycol, sodium chloride and glycerol, sodium chloride and sorbitol, sodium chloride and mannitol, or any other two or more osmotic pressure regulators.

[0112] In some embodiments, some of the osmotic pressure regulators described herein can also have other functions. For example, glycerol, propylene glycol, sorbitol, and mannitol can not only regulate osmotic pressure, but also act as humectants to improve the moisture of the nasal cavity and the stability of the liquid. In addition to regulating osmotic pressure, glucose can also increase the viscosity of the liquid to some extent, thereby acting as a thickening agent.

[0113] Thickening agents

[0114] To improve the viscosity of the formulation and achieve appropriate droplet distribution characteristics when the formulation is sprayed, the nasal formulation described herein can further include a thickening agent to achieve better delivery efficiency and targeting. At the same time, the thickening agent can prolong the residence time of the drug on the surface of the nasal mucosa, reduce the rapid clearance or swallowing of the liquid, and thereby enhance the local efficacy of the drug.

[0115] In some embodiments, the nasal formulation described herein includes a thickening agent, which can be selected from sucrose, pectin, microcrystalline cellulose-sodium carboxymethyl cellulose co-treatment, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose (HPMC), povidone (PVP), or a combination thereof.

[0116] In certain embodiments, the thickening agent comprises hydroxypropyl methylcellulose. The hydroxypropyl methylcellulose contained in the nasal formulations described herein can be hydroxypropyl methylcellulose having a viscosity of about 1000 to 10000 mPa.s as a 2% aqueous solution at 20°C, for example, hydroxypropyl methylcellulose having a viscosity of about 4000 mPa.s as a 2% aqueous solution at 20°C. For example, the hydroxypropyl methylcellulose can be pharmaceutical grade, having a methoxyl content of about 28-30%, a hydroxypropoxyl content of about 7-12%, and a viscosity of about 4000 mPa.s as a 2% aqueous solution at 20°C. In the nasal formulations of the present application, the hydroxypropyl methylcellulose can be present in an amount of 0.005% to 5% (w / v%). In certain embodiments, the hydroxypropyl methylcellulose can be present in an amount of 0.1 (w / v%) to 0.2% (w / v%). In certain embodiments, the hydroxypropyl methylcellulose can be present in an amount of 0.05% to 2.0% (w / v%). In certain embodiments, the hydroxypropyl methylcellulose can be present in an amount of 0.05% to 1.5% (w / v%), for example, about 0.1% (w / v%).

[0117] In certain embodiments, the thickening agent comprises povidone. In the nasal formulations of the present application, the povidone can be present in an amount of 0.01% to 2% (w / v%). In certain embodiments, the povidone can be present in an amount of 0.05% to 1.0% (w / v%).

[0118] In certain embodiments, the thickening agent comprises pectin. In the nasal formulations of the present application, the pectin can be present in an amount of 0.001% to 1% (w / v%). In certain embodiments, the pectin can be present in an amount of 0.005% to 0.1% (w / v%).

[0119] In certain embodiments, the thickening agent comprises sodium carboxymethylcellulose. In the nasal formulations of the present application, the sodium carboxymethylcellulose can be present in an amount of 0.01% to 2% (w / v%). In certain embodiments, the sodium carboxymethylcellulose can be present in an amount of 0.05% to 1.0% (w / v%).

[0120] In certain embodiments, the thickening agent comprises microcrystalline cellulose-sodium carboxymethylcellulose co-processed. In the nasal formulations of the present application, the microcrystalline cellulose-sodium carboxymethylcellulose co-processed can be present in an amount of 0.05% to 4.0% (w / v%); in certain embodiments, the microcrystalline cellulose-sodium carboxymethylcellulose co-processed can be present in an amount of 0.5% to 2.2% (w / v%).

[0121] In some embodiments, the thickening agent comprises sucrose. In the nasal formulations of the present application, the sucrose can be present in an amount of 0.1% to 5% (w / v%). In some embodiments, the sucrose can be present in an amount of 0.5% to 2% (w / v).

[0122] In some embodiments, the nasal formulations of the present application can comprise one, two or more thickening agents. In some embodiments, some of the thickening agents of the present application can also have other functions. For example, sucrose, at a certain concentration, can not only increase the viscosity of the formulation, but also adjust the osmotic pressure to a certain extent; HPMC can not only improve the droplet size distribution, but also improve the physical stability of the formulation during storage; povidone can not only improve the viscosity, but also act as a cosolvent to improve the solubility stability of some components in the formulation.

[0123] Humectants

[0124] In some embodiments, the nasal formulations of the present application can not comprise a humectant. Even without a humectant, the nasal formulations can still maintain good stability and use effect.

[0125] In some embodiments, the nasal formulations of the present application comprise a humectant to improve the moisture of the liquid medicine in the nasal cavity and reduce the dryness of the mucosa. In some embodiments, the humectant can be present in an amount of 0.5% to 10% (w / v). In some embodiments, the humectant can be present in an amount of 1% to 5% (w / v).

[0126] In some embodiments, the humectant can comprise sorbitol and / or mannitol. In some embodiments, the nasal formulations of the present application comprise sorbitol, which can be present in an amount of 0.5% to 10% (w / v). In some embodiments, the sorbitol can be present in an amount of 1% to 5% (w / v), for example, about 4.7% (w / v). In some embodiments, the nasal formulations of the present application comprise mannitol, which can be present in an amount of 0.5% to 10% (w / v). In some embodiments, the mannitol can be present in an amount of 1% to 5% (w / v), for example, about 4.2% (w / v).

[0127] In some embodiments, the humectants of the present application can also be replaced by the aforementioned partial osmotic pressure regulators. For example, propylene glycol and glycerol, when used as osmotic pressure regulators, can also have a humectant effect, thereby improving the local environment of the nasal cavity without the need to introduce new excipients.

[0128] Absorption enhancers

[0129] In certain embodiments, the nasal formulation described herein can not comprise a absorption enhancer. Even without the absorption enhancer, the nasal formulation can achieve effective nasal delivery of epinastine or its salt and good pharmacodynamics.

[0130] In certain embodiments, the nasal formulation described herein comprises an absorption enhancer to further improve the permeation and absorption of the active ingredient through the nasal epithelium.

[0131] In certain embodiments, the absorption enhancer can be selected from the group consisting of fatty acids, cholate salts, phospholipids, polyethylene glycol and its derivatives, alkyl glycosides, cyclodextrins and its derivatives, or a combination thereof. In certain embodiments, the absorption enhancer can include sodium caprylate, sodium caprate, sodium taurodeoxycholate, lecithin, distearoylphosphatidylcholine, PEG-400, PEG-40 hydrogenated castor oil, lauryl glucoside, decyl glucoside, dodecyl maltoside, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or a combination thereof.

[0132] In certain embodiments, the absorption enhancer includes dodecyl maltoside. In certain embodiments, the nasal formulation described herein comprises dodecyl maltoside, which can be present in an amount of 0.001% to 0.5% (w / v%). In certain embodiments, the dodecyl maltoside can be present in an amount of 0.005% to 0.05% (w / v%), for example, about 0.01% (w / v%).

[0133] Bacteriostatic agents

[0134] In certain embodiments, the nasal formulation described herein is a non-sterile formulation, which requires an additional bacteriostatic agent.

[0135] In certain embodiments, the bacteriostatic agent is selected from the group consisting of quaternary ammonium salts, alcohols, organic acids and their salts, parabens, or a combination thereof. In certain embodiments, the bacteriostatic agent can include benzalkonium chloride, benzyl alcohol, phenylethyl alcohol, potassium sorbate, sodium benzoate, or a combination thereof.

[0136] In certain embodiments, the bacteriostatic agent includes benzalkonium chloride. In certain embodiments, the nasal formulation described herein comprises benzalkonium chloride, which can be present in an amount of 0.001% to 0.5% (w / v%). In certain embodiments, the benzalkonium chloride can be present in an amount of 0.005% to 0.05% (w / v%), for example, about 0.015% (w / v%).

[0137] In certain embodiments, the nasal formulation described herein is a sterile formulation without the need for additional bacteriostatic agents. The sterile formulation described herein can be achieved in a number of ways, for example, by being prepared by conventional sterilization processes (e.g., autoclaving, filtration, irradiation, etc.) and / or being prepared and filled under aseptic conditions, or using packaging materials that have a bacterial barrier function, so as to maintain the sterility of the formulation during storage and use without the need for additional bacteriostatic agents.

[0138] Nasal formulations

[0139] In certain embodiments, the nasal formulation described herein comprises the following ingredients: emedastine fumarate at a concentration of 0.01% to 5% (w / v%); citric acid at a concentration of 0.001% to 2% (w / v%); sodium citrate at a concentration of 0.001% to 1% (w / v%); edetate disodium at a concentration of 0.001% to 0.1% (w / v%); sodium chloride at a concentration of 0.05% to 2% (w / v%); hypromellose at a concentration of 0.005% to 5% (w / v%); and sodium hydroxide is used to adjust the pH to 3.0 to 8.0. In certain embodiments, the aforementioned nasal formulation further comprises benzalkonium chloride at a concentration of 0.001% to 0.5% (w / v%).

[0140] In certain embodiments, the nasal formulation described herein comprises the following ingredients: 0.4% (w / v%) emedastine fumarate, 0.048% (w / v%) citric acid, 0.008% (w / v%) sodium citrate, 0.01% (w / v%) edetate disodium, 0.75% (w / v%) sodium chloride, 0.1% (w / v%) hypromellose, and sodium hydroxide is used to adjust the pH to 5.5. In certain embodiments, the aforementioned nasal formulation further comprises benzalkonium chloride at a concentration of 0.015% (w / v%).

[0141] In certain embodiments, the nasal formulation described herein, in addition to comprising emedastine fumarate, citric acid, sodium citrate, edetate disodium, sodium chloride, hypromellose, and optionally benzalkonium chloride, can further comprise one or two of the following ingredients: povidone, propylene glycol, glycerin, dextrose, mannitol, sorbitol, and dodecyl maltoside.

[0142] The nasal preparation described in the present application can be a spray, an aerosol, and a nasal drop. In some embodiments, the nasal preparation described in the present application is a spray, and the spray droplet size distribution thereof has the following characteristics when measured at a spray distance of 3 cm or 6 cm: D50 particle size is 30-150 μm, the proportion of droplets with a particle size of less than 10 μm is less than 5%, and the span of the droplet size distribution is less than 3.0. In some embodiments, the spray droplet size distribution of the spray described in the present application has the following characteristics when measured at a spray distance of 3 cm or 6 cm: D50 particle size is 45-60 μm, the proportion of droplets with a particle size of less than 10 μm is less than 2%, and the span of the droplet size distribution is less than 2.0.

[0143] The nasal preparation described in the present application can be an aqueous composition, in which each component is dissolved or dispersed in water to ensure good nasal tolerance and preparation stability. In some embodiments, the solvent of the nasal preparation described in the present application is water, such as purified water, water for injection, or sterilized water. In some embodiments, the aqueous composition can further contain a small amount of a pharmaceutically acceptable cosolvent or adjuvant to improve the solubility and compatibility stability of the active ingredient or adjuvant.

[0144] Pharmaceutical uses and methods of treatment

[0145] In another aspect, the present application also provides the use of the nasal preparation described in the present application in the preparation of a medicament for treating allergic rhinitis and / or conjunctivitis.

[0146] In another aspect, the present application also provides a method for treating allergic rhinitis and / or conjunctivitis, which comprises administering to a subject in need thereof an effective amount of the nasal preparation described in the present application.

[0147] In another aspect, the present application also provides the use of the nasal preparation described in the present application in the treatment of allergic rhinitis and / or conjunctivitis.

[0148] In some embodiments, the allergic rhinitis includes seasonal allergic rhinitis and perennial allergic rhinitis.

[0149] In some embodiments, the conjunctivitis includes allergic conjunctivitis, including cases occurring alone or simultaneously with allergic rhinitis.

[0150] The treatment of allergic rhinitis and / or conjunctivitis described herein can include, but is not limited to, symptom relief (e.g., reduction or elimination of nasal symptoms such as nasal itching, sneezing, rhinorrhea, nasal congestion, and conjunctivitis-related symptoms such as ocular itching, tearing, redness, etc.), symptom improvement (e.g., reduction in the frequency or duration of symptoms, and improvement in the quality of life of the patient), disease control and stabilization (e.g., reduction in the frequency and intensity of acute episodes, and delay or prevention of disease progression), and prophylactic effects (e.g., reduction in the likelihood of symptoms, and reduction in adverse reactions caused by allergen exposure).

[0151] In certain embodiments, the nasal formulation described herein is administered by intranasal administration, such as by a spray, an aerosol, or a nasal drop. In certain embodiments, the administration frequency can be from once to several times per day.

[0152] In certain embodiments, the "subject" described herein can be an individual in need of treatment of allergic rhinitis and / or conjunctivitis. The subject can be a human patient, including adults and children. In certain embodiments, the subject is an individual suffering from seasonal allergic rhinitis, perennial allergic rhinitis, allergic conjunctivitis, or a combination thereof. In certain embodiments, the subject can also be an individual in need of prevention of allergic reactions or reduction in the risk of symptoms.

[0153] Preparation methods

[0154] In another aspect, the present application provides a method for preparing the nasal formulation, which comprises dissolving emedastine or a pharmaceutically acceptable salt thereof, and the remaining components in the nasal formulation (e.g., excipients required for the formulation) in water to achieve a desired concentration range of the resulting solution.

[0155] In certain embodiments, the method for preparation described herein can comprise one or more of the following steps:

[0156] a) Dissolution: dissolving the active ingredient (e.g., emedastine fumarate) and soluble excipients (e.g., citric acid, sodium citrate, sodium chloride, etc.) in purified water;

[0157] b) Dispersion: dispersing or dissolving the insoluble or thickening excipients (e.g., hypromellose, povidone, etc.) in water, which can be pre-dissolved or pre-hydrated under stirring if necessary;

[0158] c) Mixing: mixing the above solutions / dispersions, and making them uniform under stirring;

[0159] d) pH adjustment: adjusting the pH to 3.0-8.0 using a pharmaceutically acceptable acid or base (e.g., sodium hydroxide);

[0160] e) make up solvent: make up to target volume with purified water and mix well; and

[0161] f) filtration: if necessary, sterile filtration through a filter membrane (e.g. 0.22 μm filter membrane) can be performed.

[0162] In certain embodiments, the preparation can further be subjected to sterilization treatment (e.g. moist heat sterilization, irradiation sterilization), or be filled into a nasal spray bottle, a nasal dropper bottle or an aerosol device under aseptic condition.

[0163] In certain embodiments, the preparation method can comprise filling the prepared pharmaceutical solution into a packaging device with bacterial barrier function, so as to maintain sterility without adding bacteriostatic agents.

[0164] In certain embodiments, the preparation sequence of the nasal preparation described in the present application can be varied. For example, epinastine or its salt can be dissolved first, and then other excipients can be added; or a buffer (e.g. citric acid / citric acid sodium buffer) can be prepared first, and then the active ingredient and other excipients can be added in sequence.

[0165] Packaging devices

[0166] In certain embodiments, the nasal preparation described in the present application can be filled into a suitable nasal administration device, so as to facilitate clinical use.

[0167] In another aspect, the present application also provides a packaging device containing the nasal preparation described in the present application. In certain embodiments, the packaging device is a nasal spray bottle, which is provided with a nozzle and a pump device for controlling the dosage, through which the stable dosage and uniform distribution of mist droplets can be ensured for each administration. In certain embodiments, the packaging device has a bacterial barrier function, for example by introducing a bacterial barrier membrane, a one-way valve or other pharmaceutically acceptable filter element into the pump head or valve part, so as to effectively prevent microbial contamination caused by air backflow during repeated use when the preparation is a non-sterile preparation and does not contain bacteriostatic agents.

[0168] In certain embodiments, the packaging device can be a multi-dose container, which is suitable for repeated pressing use. In certain embodiments, the packaging device can be a single-dose container, which is used for one-time administration. In certain embodiments, the bottle body material of the packaging device can be selected from pharmaceutically acceptable plastics or glass, such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), borosilicate glass, etc.

[0169] In certain embodiments, the packaging device can further comprise a protective cover to avoid contamination of the nozzle during transportation and storage. In certain embodiments, the packaging device can be an opaque or light-proof bottle body, so as to reduce the influence of light on the stability of the preparation.

[0170] The present application provides the following embodiments:

[0171] 1. A nasal preparation comprising only emedastine or a pharmaceutically acceptable salt thereof as an active ingredient.

[0172] 2. The nasal preparation according to embodiment 1, wherein the pharmaceutically acceptable salt of emedastine comprises emedastine fumarate.

[0173] 3. The nasal preparation according to any one of embodiments 1-2, wherein the active ingredient is contained in an amount of 0.01-5% (w / v%).

[0174] 4. The nasal preparation according to any one of embodiments 1-3, which has at least one of the following physicochemical properties:

[0175] a) a pH of 3.0-8.0;

[0176] b) a viscosity of 0.5-5.0 mPa.s;

[0177] c) an osmolarity of 260-350 mOsmol / kg.

[0178] 5. The nasal preparation according to any one of embodiments 1-4, which comprises a pH adjuster, a metal ion complexing agent, an osmotic pressure adjuster, and a thickening agent.

[0179] 6. The nasal preparation according to embodiment 5, wherein the pH adjuster is selected from the group consisting of citric acid, sodium citrate, sodium hydroxide, and / or hydrochloric acid.

[0180] 7. The nasal preparation according to embodiment 6, wherein the citric acid is contained in an amount of 0.001-2% (w / v%) and the sodium citrate is contained in an amount of 0.001-1% (w / v%).

[0181] 8. The nasal preparation according to embodiment 5, wherein the metal ion complexing agent is edetate disodium.

[0182] 9. The nasal preparation according to embodiment 8, wherein the edetate disodium is contained in an amount of 0.001-0.1% (w / v%).

[0183] 10. The nasal preparation according to any one of embodiments 5-9, wherein the osmotic pressure adjuster is selected from the group consisting of sodium chloride, propylene glycol, glycerol, glucose, or a combination thereof.

[0184] 11. The nasal preparation according to embodiment 10, wherein the sodium chloride is contained in an amount of 0.05-2% (w / v%).

[0185] 12. The nasal preparation according to any one of embodiments 10-11, wherein the propylene glycol, glycerol or glucose is present in an amount of 0.5-10% (w / v%).

[0186] 13. The nasal preparation according to any one of embodiments 5-12, wherein the thickening agent is selected from the group consisting of sucrose, pectin, microcrystalline cellulose carboxymethylcellulose sodium co-processed, carboxymethylcellulose sodium, hypromellose, povidone or a combination thereof.

[0187] 14. The nasal preparation according to embodiment 13, wherein the viscosity of a 2% aqueous solution of the hypromellose is about 1000-10000 m Pa.s.

[0188] 15. The nasal preparation according to any one of embodiments 13-14, wherein the hypromellose is present in an amount of 0.005-5% (w / v%).

[0189] 16. The nasal preparation according to embodiment 13, wherein the povidone is present in an amount of 0.01-2% (w / v%).

[0190] 17. The nasal preparation according to any one of embodiments 1-16, comprising the following ingredients: emedastine fumarate in an amount of 0.01-5% (w / v%); citric acid in an amount of 0.001-2% (w / v%); sodium citrate in an amount of 0.001-1% (w / v%); edetate disodium in an amount of 0.001-0.1% (w / v%); sodium chloride in an amount of 0.05-2% (w / v%); hypromellose in an amount of 0.005-5% (w / v%); and the pH is adjusted to 3.0-8.0 with sodium hydroxide.

[0191] 18. The nasal preparation according to any one of embodiments 1-17, comprising the following ingredients: 0.4% (w / v%) of emedastine fumarate, 0.048% (w / v%) of citric acid, 0.008% (w / v%) of sodium citrate, 0.01% (w / v%) of edetate disodium, 0.75% (w / v%) of sodium chloride, 0.1% (w / v%) of hypromellose, and the pH is adjusted to 5.5 with sodium hydroxide.

[0192] 19. The nasal preparation according to any one of embodiments 1-18, further comprising a humectant.

[0193] 20. The nasal preparation according to embodiment 19, wherein the humectant is selected from the group consisting of sorbitol and / or mannitol.

[0194] 21. The nasal preparation according to embodiment 20, wherein the sorbitol or mannitol is present in an amount of 0.5-10% (w / v%).

[0195] 22. The nasal preparation according to any one of embodiments 1-21, further comprising an absorption enhancer.

[0196] 23. The nasal preparation according to embodiment 22, wherein the absorption enhancer is selected from the group consisting of fatty acids, cholate salts, phospholipids, polyethylene glycol and its derivatives, alkyl glycosides, cyclodextrins and its derivatives, or a combination thereof.

[0197] 24. The nasal preparation according to embodiment 23, wherein the absorption enhancer is dodecyl maltoside, and the content of the dodecyl maltoside is 0.01% (w / v%).

[0198] 25. The nasal preparation according to any one of embodiments 1-24, which is a sterile preparation.

[0199] 26. The nasal preparation according to any one of embodiments 1-25, further comprising a bacteriostatic agent.

[0200] 27. The nasal preparation according to embodiment 26, wherein the bacteriostatic agent is selected from the group consisting of quaternary ammonium salts, alcohols, organic acids and their salts, parabens, or a combination thereof.

[0201] 28. The nasal preparation according to embodiment 27, wherein the bacteriostatic agent is selected from the group consisting of benzalkonium chloride, benzyl alcohol, phenylethyl alcohol, potassium sorbate, sodium benzoate, or a combination thereof.

[0202] 29. The nasal preparation according to any one of embodiments 26-28, wherein the bacteriostatic agent is benzalkonium chloride, and the content of the benzalkonium chloride is 0.001% to 0.5% (w / v%).

[0203] 30. The nasal preparation according to any one of embodiments 1-29, which is in a dosage form selected from one or more of the group consisting of a spray, an aerosol, and a nasal drop.

[0204] 31. The nasal preparation according to embodiment 30, wherein the spray has a spray droplet size distribution with the following characteristics: D50 particle size is 30-150 μm, the proportion of droplets with a particle size of less than 10 μm is less than 5%, and the span of the droplet size distribution is less than 3.0, when measured at a spray distance of 3 cm or 6 cm.

[0205] 32. The nasal preparation according to any one of embodiments 1-31, which is an aqueous composition.

[0206] 33. A method of treating allergic rhinitis and / or conjunctivitis, comprising administering to a subject an effective amount of the nasal preparation according to any one of embodiments 1-32.

[0207] 34. Use of a nasal preparation according to any one of embodiments 1 to 32 in the manufacture of a medicament for the treatment of allergic rhinitis and / or conjunctivitis.

[0208] 35. Use of a nasal preparation according to any one of embodiments 1 to 32 in the treatment of allergic rhinitis and / or conjunctivitis.

[0209] 36. The method according to embodiment 33 or the use according to any one of embodiments 34 to 35, wherein the allergic rhinitis comprises seasonal allergic rhinitis and perennial allergic rhinitis.

[0210] 37. A method of preparing a nasal preparation according to any one of embodiments 1 to 32, comprising dissolving emedastine or a pharmaceutically acceptable salt thereof, and the remaining components of the nasal preparation in water in an amount such that the resulting solution is in the desired concentration range.

[0211] 38. A packaging device comprising a nasal preparation according to any one of embodiments 1 to 32, comprising a nasal spray bottle provided with a nozzle and a pump device for controlling the dose.

[0212] 39. The packaging device according to embodiment 38, having a bacterial barrier function.

[0213] Without wishing to be bound by any theory, the examples below are merely intended to illustrate the nasal preparations and uses of the present application and are not intended to limit the scope of the present application.

[0214] Examples

[0215] Example 1. Base formulation design

[0216] Based on the physicochemical properties of the active ingredient and the characteristics of the dosage form, five formulations shown in Table 1 were designed and their stability was tested.

[0217] Table 1. Formulation composition and amount

[0218]

[0219] The samples were placed at 50°C for 30 days. The related substances in the samples were analyzed by HPLC:

[0220] 1. HPLC analysis conditions are shown in Table 2

[0221] Table 2. HPLC analysis of related substances conditions

[0222]

[0223] 2. Treatment method

[0224] Accurately weigh about 1 mg of the sample into a 10 ml volumetric flask, dissolve and dilute with the solvent (mobile phase A-mobile phase B-60:40) to make a solution containing about 1 mg / ml. Accurately weigh the control, impurity C control, impurity D control, impurity E control and impurity F control, dissolve and dilute with the solvent to make a solution containing about 1 mg of the main drug and 5 μg of each impurity per 1 ml.

[0225] The test results are shown in Table 3.

[0226] Table 3: Stability of the formulation

[0227]

[0228] Note: ND means not detected

[0229] Each formulation was placed at 50℃ for 30 days. The properties of Formulation 1, Formulation 2 and Formulation 5 did not change significantly. At the same time, the related substance level of Formulation 1 was the lowest, showing good stability. Subsequent optimization was carried out on the basis of Formulation 1.

[0230] Example 2: Hydroxypropyl methyl cellulose dosage study

[0231] On the basis of Example 1, the dosage of hydroxypropyl methyl cellulose was systematically investigated to evaluate the delivery characteristics and viscosity of the formulation. Samples without hydroxypropyl methyl cellulose, with 0.5 mg / mL, 1 mg / mL, 1.5 mg / mL and 2 mg / mL hydroxypropyl methyl cellulose were prepared, and the viscosity was determined. At the same time, the formulations were filled into a simulated nasal spray device, and the spray droplet size and droplet distribution at a distance of 3 cm and 6 cm from the nozzle were directly determined by laser scattering method. The results are shown in Table 4 below.

[0232] Table 4: Hydroxypropyl methyl cellulose dosage study

[0233]

[0234] With the increase of the dosage of hydroxypropyl methyl cellulose, the viscosity of the liquid medicine increased. The spray particle size results showed that the spray droplet size at a distance of 3 cm and 6 cm from the nozzle increased with the increase of the dosage of hydroxypropyl methyl cellulose.

[0235] Example 3: Sodium chloride dosage study

[0236] On the basis of Example 1, the dosage of sodium chloride was investigated. The target osmolarity of the preparation product was 270-320 mOsmol / kg. The osmolarity of the preparation product was adjusted by the dosage of sodium chloride. In this way, the dosage range of sodium chloride was screened. The results are shown in Table 5 below.

[0237] Table 5: Sodium chloride dosage study

[0238]

[0239] The above results show that when the concentration of sodium chloride in the formula is 7 mg / ml to 8 mg / ml, the osmotic pressure molarity of the drug solution is between 270 and 320 mOsmol / kg, and the preferred amount of sodium chloride in the formula is 7.5 mg / ml.

[0240] Example 4: pH value range study

[0241] On the basis of Example 1, the pH value of the formula was investigated. The pH values of 3.0, 4.0, 4.5, 5.0, 5.5, and 6.0 were designed, and the samples were placed at 40°C for 30 days. The results are shown in Tables 6-7 below.

[0242] Table 6: pH value range study

[0243]

[0244] Table 7: Results of the pH value range study

[0245]

[0246] Note: "ND" represents not detected.

[0247] The above results show that the pH values of the drug solutions at different pH values did not change significantly after being placed at 40°C for 30 days, the related substances did not increase significantly, and the total impurities did not differ significantly. The drug solution is relatively stable between pH values of 3.0 and 6.0. Therefore, the pH value range of the drug solution is 3.0 to 6.0, and the preferred pH value is 5.5.

[0248] Example 5: Citric acid / citric acid sodium amount range study

[0249] On the basis of Example 1, the amount range of citric acid / citric acid sodium was investigated. The samples with different amounts of citric acid / citric acid sodium were placed at 40°C for 30 days. The results are shown in Tables 8-9 below.

[0250] Table 8: Study of different amounts of citric acid / citric acid

[0251]

[0252] Table 9: Results of the citric acid / citric acid amount study

[0253]

[0254] Note: "ND" represents not detected.

[0255] The above results show that increasing the amount of citric acid / citric acid sodium does not affect the stability of the formula. Therefore, the amount of citric acid is 0.48 to 1.2 mg / ml, and the amount of citric acid sodium is 0.08 to 0.2 mg / ml.

[0256] Example 6 Raw material concentration study

[0257] On the basis of Example 1, the raw material dosage range was investigated. Samples of 0.5 mg / ml, 5 mg / ml, 10 mg / ml and 25 mg / ml were prepared, and the samples were placed at 60°C for 10 days. The results are shown in Table 10-11.

[0258] Table 10: Formulation composition of different raw material contents

[0259]

[0260] Table 11: Results of light exposure investigation

[0261]

[0262] Note: "ND" represents not detected.

[0263] The above results show that the samples with different raw material concentrations have no significant difference in stability after being investigated at 60°C for 10 days. The raw material concentration range is 0.5 mg / ml to 25 mg / ml.

[0264] Example 7 Stability study

[0265] The stability of Formulation 1 at 25°C was investigated, and the results are shown in Table 12.

[0266] Table 12: Stability study

[0267]

[0268] The results show that Formulation 1 has no significant change in pH value, content and related substances after being placed at 25°C for 4 months, and the formulation is stable.

[0269] Example 8 Pharmacokinetic study

[0270] This example shows that the relative bioavailability of emedastine administered to Beagle dogs nasally is about 8 times higher than that administered orally. The plasma drug exposure and local tissue exposure of emedastine administered nasally to allergic rhinitis model rats are much higher than those administered orally, and the drug exposure at the nasal mucosa target site of rats in the emedastine nasal spray administration group is about 170 times that of the fumaric acid emedastine sustained-release capsule oral administration group. Emedastine nasal spray has the clinical advantages of fast onset, direct action on the nasal mucosa target site, and the potential to improve efficacy and reduce adverse drug reactions.

[0271] The analysis method of the pharmacokinetic parameters is as follows:

[0272] 1. The HPLC analysis conditions are shown in Table 13:

[0273] Table 13: HPLC analysis conditions

[0274]

[0275] 2. Mass spectrometry analysis conditions are shown in Table 14:

[0276] Table 14: Mass spectrometry analysis conditions

[0277]

[0278] 3. Linear range of the standard curve: 0.05000-50.00 ng / mL.

[0279] 4. Pretreatment method: 20 μL of the plasma sample was taken and placed in a 1.5 mL polyethylene centrifuge tube, 20 uL of 50% methanol aqueous solution was added, followed by 20 μL of the internal standard working solution (10.00 ng / mL) and 140 uL of 0.1% formic acid methanol solution, vortexed for 30 s, centrifuged at 14000 rpm for 10 min, and the supernatant was mixed with 0.2% formic acid water (v:v=2:1) before injection for analysis.

[0280] 5. Pharmacokinetic parameter calculation method: WinNonlin software was used for non-compartment model fitting.

[0281] 8.1 In a Beagle dog in vivo pharmacokinetic study, the relative bioavailability (F relative) of a single intranasal administration of 2 mg of emedastine (equivalent to 1.7 times the clinical oral dose in humans according to animal body surface area) to Beagle dogs was 8 times that of a single oral administration.

[0282] After Beagle dogs were given emedastine nasal spray (formulation 1) intranasally and were given fumaric acid emedastine sustained-release capsules orally, the main pharmacokinetic parameters AUC0-t, Cmax, Tmax were shown in Table 15, and the average plasma concentration graph and semilogarithmic plasma concentration graph were shown in Figure 1.

[0283] Table 15: Summary of main pharmacokinetic parameters of Beagle dogs given emedastine nasal spray intranasally and fumaric acid emedastine sustained-release capsules orally (mean ± SD)

[0284]

[0285] 8.2 In the in vivo pharmacodynamic and pharmacokinetic study of allergic rhinitis model rats, the relative bioavailability (F relative) of emedastine was much higher in rats given intranasal administration of about 0.36 mg / kg (calculated according to the animal body surface area, about equivalent to the adult clinical daily dose) for 7 consecutive days than that given orally. The plasma exposure of emedastine in rats of emedastine nasal spray (formulation 1) administration group was significantly higher than that of fumaric acid emedastine sustained-release capsule administration group, and the drug exposure of emedastine in the target site of nasal mucosa tissue of animals in emedastine nasal spray administration group was about 65.8~170.5 times that of fumaric acid emedastine sustained-release capsule group. The individual blood drug concentration data of emedastine in rats of emedastine nasal spray administration group and fumaric acid emedastine sustained-release capsule administration group are shown in Table 16, the main pharmacokinetic parameters of emedastine in rats of emedastine nasal spray administration group are shown in Table 17 (the blood drug concentration of rats of fumaric acid emedastine sustained-release capsule administration group was mostly lower than the lower limit of quantification, and the pharmacokinetic parameters could not be calculated), and the drug concentration data of emedastine in tissues of rats of emedastine nasal spray administration group and fumaric acid emedastine sustained-release capsule administration group are shown in Table 18.

[0286] Table 16: Individual blood drug concentration data of emedastine in rats of emedastine nasal spray administration group and fumaric acid emedastine sustained-release capsule administration group

[0287]

[0288] Table 17: Main pharmacokinetic parameters of emedastine in rats of emedastine nasal spray administration group ±S)

[0289]

[0290] Table 18: Average drug content in tissues of rats of emedastine nasal spray administration group and fumaric acid emedastine sustained-release capsule administration group

[0291]

Claims

1. A nasal preparation comprising only emeslin or a pharmaceutically acceptable salt thereof as its active ingredient.

2. The nasal preparation according to claim 1, wherein the pharmaceutically acceptable salt of emestin comprises emestin fumarate.

3. The nasal preparation according to any one of claims 1-2, wherein the content of the active ingredient is 0.01% to 5% (w / v%).

4. The nasal preparation according to any one of claims 1-3, wherein it has at least one of the following physicochemical properties: a) pH value is 3.0~8.0; b) Viscosity is 0.5~5.0 mPa·s; c) The osmolar concentration is 260~350 mOsmol / kg.

5. The nasal preparation according to any one of claims 1-4, wherein the nasal preparation comprises a pH adjuster, a metal ion complexing agent, an osmotic pressure regulator, and a thickener.

6. The nasal preparation according to claim 5, wherein the pH adjuster is selected from citric acid, sodium citrate, sodium hydroxide and / or hydrochloric acid.

7. The nasal preparation according to claim 6, wherein the citric acid content is 0.001%~2% (w / v%) and the sodium citrate content is 0.001%~1% (w / v%).

8. The nasal preparation according to claim 5, wherein the metal ion chelating agent is disodium edetate.

9. The nasal preparation according to claim 8, wherein the content of disodium edetate is 0.001%~0.1% (w / v%).

10. The nasal preparation according to any one of claims 5-9, wherein the osmotic pressure regulator is selected from sodium chloride, propylene glycol, glycerin, glucose, or a combination thereof.

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