CN118121542A

CN118121542A - Nasal pharmaceutical composition, preparation method and application thereof

Info

Publication number: CN118121542A
Application number: CN202410299050.8A
Authority: CN
Inventors: 丁杨; 陆宁姝; 段学哲
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2023-03-31
Filing date: 2024-03-15
Publication date: 2024-06-04

Abstract

The present invention belongs to the field of pharmaceutical preparations, and discloses a nasal pharmaceutical composition, comprising adrenaline or its pharmaceutical salt, 15-hydroxystearic acid polyethylene glycol ester and clove oil. The present invention also discloses a preparation method and application of the nasal pharmaceutical composition, and a nasal spray comprising the nasal pharmaceutical composition. The present invention uses 15-hydroxystearic acid polyethylene glycol ester and clove oil to jointly promote the nasal mucosal absorption of adrenaline, and can achieve an effect similar to intramuscular injection within 15 minutes of administration. The present invention effectively solves the problems of poor stability, easy oxidation and easy racemization of adrenaline, and is placed at 40°C ± 2°C and relative humidity of 75% ± 5% for 3 months, and the total impurity content in the adrenaline nasal spray is less than 0.2%.

Description

Pharmaceutical composition for nose, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a nasal pharmaceutical composition, a preparation method and application thereof.

Background

Epinephrine is a naturally occurring substance in the human body that can directly act on adrenergic alpha and beta receptors, producing strong, rapid and transient effects of exciting alpha and beta types. The medicine is mainly used for emergency treatment of sudden cardiac arrest, bronchial asthma, anaphylactic reaction and the like.

Currently, the main adrenergic formulations on the market are epinephrine injections and self-injection epinephrine pens (e.g.). Epinephrine injections must be administered by specialized medical personnel in hospitals, and many patients delay illness or even die because they are not effectively treated for the first time; while self-injection adrenergic pens are expensive and have poor patient compliance. Moreover, there have been many reports that the exposure of the injected product is highly variable, depending on the location of the injection (intramuscular or subcutaneous), among other factors. In addition, the injection has strict requirements on equipment and environment for preparation in the preparation process, complex preparation process and high cost.

Patent CN110505873a discloses an intranasal adrenergic preparation, which adopts dodecyl maltoside as an absorption promoter to promote the permeation of the drug, but the adrenergic preparation has stability problems, needs to be prepared at present, and has limited mucous membrane permeation promotion capability and limited practical application value.

CN112153966a discloses an epinephrine spray formulation, which is formulated using sodium metabisulfite or sodium bisulphite as an antioxidant, which is associated with some other serious allergic reactions. In addition, sodium bisulfite can react directly with epinephrine to produce the degradation product Epinephrine Sulfonic Acid (ESA), resulting in a substantial decrease in the efficacy of epinephrine. The sulfite or bisulfite related compounds in foods and/or pharmaceuticals may cause severe allergic or asthmatic reactions. Meanwhile, the preparation contains ethanol and propylene glycol, so that mucous membrane irritation exists, and medication compliance is reduced.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a nasal pharmaceutical composition, a preparation method and application thereof.

The technical scheme adopted for solving the technical problems is as follows:

in one aspect, provided herein is a nasal pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, and clove oil.

In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 1-30 mg/mL. In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 5-25 mg/mL. In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 8-22 mg/mL. In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 10-20 mg/mL. In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 10mg/mL. In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 20mg/mL.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable salt of epinephrine, wherein the pharmaceutically acceptable salt of epinephrine is a hydrochloride, tartrate, or citrate salt. In some embodiments, the pharmaceutically acceptable salt of epinephrine is prepared by adding to the pharmaceutical composition about 0.5 to about 1.1 molar equivalents of acid per mole of epinephrine. In some embodiments, the acid is hydrochloric acid.

In some embodiments, the total amount of 15-polyethylene glycol stearate and clove oil is about 5-15 mg/mL, and the mass ratio of 15-polyethylene glycol hydroxystearate to clove oil is 0.5-2: 1.

In some embodiments, the total amount of 15-hydroxystearic acid polyethylene glycol ester and clove oil is about 7.5 to 10mg/mL, with a mass ratio of about 0.5 to 1:1.

The 15-hydroxy stearic acid polyethylene glycol ester can promote the absorption of adrenaline nasal mucosa epithelial cells, and the action mechanisms comprise double mechanisms of cell bypass and transcellular transport, so that the intercellular tight connection, desmosomes and the like (paracellular enhancement mechanism) are opened through the influence on actin tissues in cytoskeleton, and the action mechanism has comprehensive action on cell membranes (transcellular enhancement mechanism); research shows that HS15 enhances the transportation of medicine through mucous membrane and has no toxic effect on nasal mucous membrane, thus being an effective and nontoxic nasal cavity absorption promoter.

The clove oil can reduce the level of extracellular calcium ions, so that the cohesiveness of intercellular desmosomes is reduced, the protein structure is loose, and the permeation of adrenaline nasal mucosa is improved; and the clove oil has a dilating effect on small blood vessels of nasal mucosa, can resist vasoconstriction effect brought by epinephrine, and further promotes the absorption of epinephrine by nasal cavity. The combined use of 15-hydroxystearic acid polyethylene glycol ester and clove oil can jointly promote nasal mucosa absorption of epinephrine from different mechanism angles.

In some embodiments, the nasal pharmaceutical composition comprises optionally one or more pharmaceutical excipients selected from the group consisting of: stabilizers, metal ion chelating agents, and pH adjusters.

In some embodiments, the stabilizer is one or more from the group consisting of cyclodextrin or derivatives thereof, preferably the stabilizer is hydroxypropyl-beta-cyclodextrin (HP-beta-CD).

In some embodiments, the stabilizer is present in an amount of about 0 to 180mg/mL.

In some embodiments, the stabilizer is present in an amount of about 60 to 150mg/mL.

In some embodiments, the metal ion chelating agent is selected from one or more of ethylenediamine tetraacetic acid or a salt thereof, preferably disodium ethylenediamine tetraacetate.

In some embodiments, the metal ion chelating agent is present in an amount of about 0 to about 6mg/mL, in some embodiments, about 0.5 to about 4mg/mL, and in some embodiments, about 2 to about 4mg/mL.

In some embodiments, the pH adjustor is an acid, a base, a buffer, or a combination thereof;

The acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid;

The alkali is sodium hydroxide, sodium citrate, sodium bicarbonate or sodium carbonate; and the buffer is a phosphate buffer, an acetate buffer, or a citrate buffer.

In some embodiments, the buffer is selected from the group consisting of hydrochloric acid, citric acid, and sodium citrate.

In some embodiments, the nasal pharmaceutical composition has a pH of 3 to 4.

In some embodiments, the nasal pharmaceutical composition further comprises a preservative.

In some embodiments, the preservative is selected from one or more of ethanol, propylene glycol, glycerol, benzyl alcohol, phenethyl alcohol, benzalkonium chloride, trichlorot-butyl alcohol, methylparaben, potassium sorbate, and peppermint oil.

In some embodiments, the preservative is benzalkonium chloride.

In some embodiments, the preservative is present in an amount of about 0 to 1mg/mL, preferably about 0 to 0.6mg/mL, more preferably about 0.01 to 0.4mg/mL.

In another aspect, provided herein is a nasal pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil and water, and one or more of hydroxypropyl-beta-cyclodextrin, disodium edetate, citrate buffer, and benzalkonium chloride.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable salt of epinephrine, wherein the pharmaceutically acceptable salt of epinephrine is a hydrochloride, tartrate, or citrate salt. In some embodiments, the pharmaceutically acceptable salt of epinephrine is prepared by the addition of about 0.5 to about 1.1 molar equivalents of acid per mole of epinephrine to a pharmaceutical composition. In some embodiments, the acid is hydrochloric acid.

In some embodiments, the epinephrine content of the nasal pharmaceutical composition is about 8-22 mg/mL. In some embodiments, the epinephrine content of the nasal pharmaceutical composition is about 10mg/mL. In some embodiments, the epinephrine content of the nasal pharmaceutical composition is about 20mg/mL.

In some embodiments, the total amount of 15-hydroxystearic acid polyethylene glycol ester and clove oil is about 7.5 to 10mg/mL mass ratio is about 0.5 to 1:1.

In some embodiments, the 15-stearate polyethylene glycol ester is present in an amount of about 2.5 to 5mg/ml.

In some embodiments, the clove oil is present in an amount of about 5 to 10mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is present in the nasal pharmaceutical composition in an amount of about 60 to 150mg/mL.

In some embodiments, the disodium edetate is present in the nasal pharmaceutical composition in an amount of about 0.5-4 mg/mL.

In some embodiments, the disodium edetate is present in the nasal pharmaceutical composition in an amount of about 2-4 mg/mL.

In some embodiments, the nasal pharmaceutical composition comprises benzalkonium chloride in an amount of about 0.01 to about 0.4mg/mL.

In some embodiments, the nasal pharmaceutical composition has a pH of about 3 to 4.

In another aspect, there is provided a pharmaceutical composition for nasal administration comprising the components and amounts thereof:

In some embodiments, the nasal pharmaceutical composition further comprises an antioxidant. The antioxidant is one or more selected from hydroxyquinoline, boric acid, borate, ascorbic acid, malic acid, acetylcysteine and citric acid. In some embodiments, the nasal pharmaceutical composition further comprises an isotonic agent. In some embodiments, the isotonic agent is glucose, glycerol, mannitol, potassium chloride, or sodium chloride. In some embodiments, the isotonic agent is sodium chloride.

Yet another aspect of the present disclosure provides a method of treating anaphylaxis, anaphylactic shock, severe allergy, and/or bronchoconstriction, comprising administering intranasally a nasal pharmaceutical composition herein.

In yet another aspect, the present invention provides the use of a nasal pharmaceutical composition herein in the manufacture of a medicament for the treatment of anaphylaxis, anaphylactic shock, severe allergy and/or bronchoconstriction.

In some embodiments, the allergic reaction is a sudden, severe, systemic allergic reaction, which may involve various parts of the body, such as the skin, respiratory tract, gastrointestinal tract, and cardiovascular system. Symptoms include one or more of the following, typically occurring within about 1 to 15 minutes after exposure to antigen: agitation, restlessness, flushing, palpitations, paresthesia, itching, ear jumping, coughing, sneezing, urticaria, angioedema, dyspnea due to laryngeal edema or bronchospasm, nausea, vomiting, abdominal pain, diarrhea, tics, incontinence, shock, unresponsiveness and death. Allergic reactions may include cardiovascular failure.

In some embodiments, the allergic reaction is a type I allergic reaction. In some embodiments, the type I allergic reaction is selected from the group consisting of allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, and food allergy.

In some embodiments, the epinephrine nasal pharmaceutical composition is administered at 1-2 mg/time epinephrine.

Yet another aspect herein provides a method of preparing the nasal pharmaceutical composition comprising the steps of:

(1) Preparation of epinephrine stock: adding epinephrine into the acidic solution, and stirring until the epinephrine is completely dissolved to obtain epinephrine stock solution;

(2) Preparing auxiliary material diluent: dissolving 15-hydroxystearic acid polyethylene glycol ester and clove oil and one or more of a stabilizer, a metal ion chelating agent and a preservative in pure water, stirring until the mixture is completely dissolved, adding a pH regulator, and regulating the pH value to 2-5 to obtain an auxiliary material diluent;

(3) Preparation of a nasal pharmaceutical composition: mixing the epinephrine stock solution obtained in the step (1) and the auxiliary material diluent obtained in the step (2), uniformly stirring, adding a pH regulator, regulating the pH value to 3-4, and filtering.

In some embodiments of the present invention, in some embodiments,

In step (1), the acidic solution is selected from hydrochloric acid solution, tartaric acid solution or citric acid solution, preferably hydrochloric acid solution, and the molar ratio of HCl to epinephrine in the hydrochloric acid solution is about 1.0-1.2:1, preferably about 1.1:1.

In the step (2), the pH regulator is citric acid and sodium citrate, and the pH value is regulated to about 3-4;

in the step (3), the pH regulator is citric acid and sodium citrate, and the pH value is regulated to about 3-4.

In yet another aspect, provided herein is a nasal spray comprising the nasal pharmaceutical compositions and devices described herein; the device has no metal part in direct contact with the liquid medicine.

In some embodiments, the device is a metered dose spray device.

In some embodiments, the metered dose spray device is a single dose device having a loading of 100 to 200 μl and a spray volume of 100 to 200 μl.

In some embodiments, the metered dose spray device is a single dose device having a loading of about 110 to 150 μl and a spray volume of about 100 μl.

In some embodiments, the metered dose spray device is a dual dose device having a loading of 200 to 500 μl and a spray volume of 100 to 200 μl.

In some embodiments, the metered dose spray device is a dual dose device having a loading of 210 to 250 μl and a spray volume of about 100 μl.

In some embodiments, the metered dose spray device is a multi-dose device; the loading of the multi-dose device is 500-1000 mu L, and the spraying amount per spraying is 50-200 mu L.

In some embodiments, the nasal spray is placed at 40 ℃ ± 2 ℃ with a relative humidity of 75% ± 5% for 3 months, wherein the total impurity content is less than 0.5%.

In some embodiments, the nasal spray is placed at 40 ℃ ± 2 ℃ with a relative humidity of 75% ± 5% for 3 months, wherein the total impurity content is less than 0.4%.

In some embodiments, the nasal spray is placed at 40 ℃ ± 2 ℃ with a relative humidity of 75% ± 5% for 3 months, wherein the total impurity content is less than 0.3%.

In some embodiments, the nasal spray is placed at 40 ℃ ± 2 ℃ with a relative humidity of 75% ± 5% for 3 months, wherein the total impurity content is less than 0.2%.

In yet another aspect, the present invention provides a method of preparing the aforementioned nasal spray, preparing the aforementioned nasal pharmaceutical composition, and subsequently loading into a device; the device has no metal part in direct contact with the liquid medicine.

Advantageous effects

Compared with the prior art, the invention has the following characteristics:

(1) The invention combines 15-hydroxy stearic acid polyethylene glycol ester and clove oil to promote nasal mucosa absorption of epinephrine, and can achieve similar effect of intramuscular injection within 15min of administration.

(2) The problem of solution stability in the storage process is reported in the existing marketed products at present, and the problems of poor epinephrine stability, easy oxidation and easy racemization are effectively solved, the epinephrine nasal spray is placed for 3 months at 40+/-2 ℃ and the relative humidity is 75+/-5 percent, and the total impurity content in the epinephrine nasal spray is less than 0.2%; the nasal spray containing epinephrine has a total impurity content of less than 0.1% when placed at 25 ℃ +/-2 ℃ and a relative humidity of 60% +/-5% for 6 months.

(3) The invention effectively avoids the use of antioxidants such as sodium metabisulfite and the like, and avoids the generation of adrenergic sulfonic acid and the generation of potential anaphylactic reaction.

(4) The invention is administered in the form of spray, solves the problem of delayed illness caused by inconvenient use of the existing epinephrine injection and untimely administration of patients, greatly improves the compliance of the patients, and is hopeful to replace the injection as a stock emergency medicine.

(5) The invention has simple preparation process, low transportation and storage requirements and reduced industrial cost.

Drawings

FIG. 1 is a graph showing the change of epinephrine content of 1 month of the epinephrine solutions of example 1 for different pH values, wherein FIG. 1 shows the epinephrine concentration of the solution at initial configuration as 100% on the ordinate;

FIG. 2 is an in vitro mucous membrane permeation curve of epinephrine for comparative sample 1 and samples 1-5;

FIG. 3 is an in vitro mucous membrane permeation curve of epinephrine for comparative sample 1 and samples 6-10;

FIG. 4 is a graph showing the 3h in vitro mucosal permeability of the 20mg/mL epinephrine nasal spray of comparative examples 4,5 of example 45 and examples 26, 27;

FIG. 5 is a graph showing the in vitro mucosal permeability of 20mg/mL of an epinephrine nasal spray of example 45, comparative examples 4, 5, and examples 26, 27 for 30 min;

FIG. 6 is a graph of the 3h internal pharmacokinetic profile of 10mg/mL epinephrine nasal spray of example 46 blank, comparative examples 2, 3, and example 6;

FIG. 7 is a graph of the drug action of 10mg/mL of the nasal spray of 10mg/mL of the epinephrine of example 46 blank, control 2, 3, and example 6 over 30 minutes;

FIG. 8 is a graph of the drug action of 10mg/mL of the nasal spray of 10mg/mL of the epinephrine of example 46 blank, control 2, 3, and example 6 for 15 min;

FIG. 9 is a graph of the 3h internal pharmacokinetic profile of the 20mg/mL nasal adrenergic sprays of example 46, comparative examples 2,4, and examples 26, 31;

FIG. 10 is a graph showing the pharmacokinetic profile of 20mg/mL of epinephrine nasal spray of comparative example 46, examples 2,4, and examples 26, 31 over 30 minutes;

FIG. 11 is a graph of the pharmacokinetic profile of 20mg/mL nasal epinephrine for 15min for comparative example 46, examples 2,4, and examples 26, 31;

FIG. 12 is a graph showing the concentration of epinephrine in a solution of example 49, wherein epinephrine is present at 100% on the ordinate of epinephrine in a solution for 1 month when the epinephrine solutions are left for different cyclodextrin levels of examples 11, 21, 47, 48;

FIG. 13 is a graph showing the total impurity formation by placing epinephrine solutions of example 49 of examples 11, 21, 47, 48 at different cyclodextrin levels for 1 month;

Fig. 14 is a scan of nasal mucosa tissue morphology observed by HE staining after a single administration of the nasal cavity of rabbits in example 50 blank, comparative example 6 and example 11, and a scan of nasal cilia status observed by SEM.

Detailed Description

The following detailed description is of further details of the invention herein.

As used herein, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Moreover, the laboratory procedures used herein are all conventional procedures widely used in the respective fields.

Terminology:

The terms "having," "including," and "comprising" are to be construed as open-ended, meaning the presence of the recited elements but not preclude the presence, or addition of any other element or elements not recited.

All ranges recited herein include those endpoints that list ranges between the two values. All values recited herein, whether or not stated, include the degree of expected experimental error, technical error, and instrumental error for a given technique for measuring the value.

Herein,% is weight/weight (w/w) percent unless otherwise indicated.

In this document, unless otherwise indicated, the term "about" is intended to define the numerical values of its modifications, meaning that such values may vary within a range. When ranges are not recited (e.g., error ranges or standard deviations of the means presented in the charts or data tables), the term "about" is to be understood as meaning a larger range containing the recited values, as well as ranges encompassed by rounding to that number and inclusion of the recited value plus or minus 10% by taking into account the significant figures.

T _max herein refers to: time to peak concentration.

Herein, C _max refers to: peak plasma concentration was reached.

AUC _(0-15min) herein refers to: area under the blood concentration-time curve within 0-15 min.

AUC _(0-30min) herein refers to: area under the blood concentration-time curve within 0-30 min.

AUC _(0-t) herein refers to: area under the plasma concentration-time curve within 0 to infinity.

M herein refers to mol/L.

QS herein refers to a specified volume.

NA herein refers to undetected.

SEM herein refers to the standard error of the mean.

Epinephrine or pharmaceutically acceptable salts thereof

In this context, the term epinephrine (also known as epiephrine) refers to the compound (R) -4- (1-hydroxy-2- (methylamino) ethyl) benzene-1, 2-diol, which is shown below and has the following structure, elemental composition, molecular weight, and CAS accession number:

A pharmaceutically acceptable salt:

by "pharmaceutically acceptable salt" is meant a salt that is biologically or otherwise undesirable (e.g., is neither toxic nor harmful to its recipient).

In this context, any dosage, whether expressed in milligrams or as a weight percent or as a ratio to another component, should be considered as referring to the amount of epinephrine in free form, without explicitly referring to a particular pharmaceutically acceptable salt of epinephrine.

Absorption promoter:

By "absorption enhancer" is meant a functional excipient contained in a formulation to improve the absorption of an active agent, such as a pharmacologically active drug. The term generally refers to agents whose function is to increase absorption by enhancing nasal mucosal penetration, rather than to increase solubility. Thus, such agents are sometimes referred to as penetration enhancers or permeation enhancers.

Clove oil:

The clove oil may be an essential oil extract of a clove plant, for example, from the leaves, stems or flower buds of a clove plant. The lilac plant may be lilac (Syzygium aromaticum). The plant extract may comprise 20-95% eugenol, 40-95% eugenol, 60-95% eugenol, and for example 80-95% eugenol. The extract may also comprise 5% to 15% eugenol acetate. The extract may also contain caryophyllene. The extract may also contain up to 2.1% of a-rhythmic graphene. Other volatile compounds contained in clove oil at lower concentrations may be β -pinene, limonene, farnesol, benzaldehyde, 2-heptanone, and ethyl hexanoate.

Stabilizing agent

"Stabilizer" refers to a functional excipient included in a formulation to improve the stability of an active agent, such as a pharmacologically active drug.

Metal ion chelating agent

A metal ion chelating agent refers to a compound that is capable of providing a ligand for an electron pair and forming a complex with a metal ion. Such as: ethylenediamine tetraacetic acid (EDTA) or a salt thereof, aminotriacetic acid (also known as nitrilotriacetic acid NTA) or a salt thereof, diethylenetriamine pentaacetic acid or a salt thereof.

PH regulator

The pH adjustor is an acid, a base, a buffer, or a combination thereof;

The acid includes, but is not limited to, adipic acid, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid;

the base includes, but is not limited to, sodium hydroxide, sodium citrate, sodium bicarbonate, or sodium carbonate; and

Such buffers include, but are not limited to, phosphate buffers, acetate buffers, or citrate buffers.

Preservative agent

"Preservative" refers to a functional excipient contained in a formulation to inhibit microbial growth.

The device comprises:

"device" refers to an apparatus capable of delivering a drug to a patient in need thereof. Herein, a "device" may be a metered dose spray device, such as a single dose (UDS) device, a double dose (BDS) device, or a multi-dose device.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate and clove oil, and one or more of a stabilizer, a metal ion chelating agent, and a pH adjuster.

In some embodiments, the pharmaceutically acceptable salt of epinephrine includes, but is not limited to, hydrochloride, tartrate, citrate, halide, sulfate, bitartrate, phosphate, acetate, malate, maleate, succinate, ascorbate, carbonate, mesylate, or lactate.

In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, tartrate or citrate salt.

In at least one embodiment, the pharmaceutically acceptable salt is the hydrochloride salt.

In some embodiments, the total amount of 15-polyethylene glycol stearate and clove oil is about 5-15 mg/mL, such as about 5mg/mL, about 5.5mg/mL, about 6mg/mL, about 6.5mg/mL, about 7mg/mL, about 7.5mg/mL, about 8mg/mL, about 8.5mg/mL, about 9mg/mL, about 9.5mg/mL, about 10mg/mL, about 10.5mg/mL, about 11mg/mL, about 11.5mg/mL, about 12mg/mL, about 12.5mg/mL, about 13mg/mL, about 13.5mg/mL, about 14mg/mL, about 14.5mg/mL, about 15mg/mL; the mass ratio of the 15-hydroxy stearic acid polyethylene glycol ester to the clove oil is 0.5-2: 1, such as about 0.5:1, about 0.75:1, about 1:1, about 1.25:1, about 1.5:1, about 1.75:1, about 2:1.

In some embodiments, the total amount of 15-hydroxystearic acid polyethylene glycol ester and clove oil is about 7.5 to 10mg/mL, such as about 7.5mg/mL, about 8mg/mL, about 8.5mg/mL, about 9mg/mL, about 9.5mg/mL, about 10mg/mL; the mass ratio is about 0.5 to 1:1, such as about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1.

In some embodiments, the total amount of 15-hydroxystearic acid polyethylene glycol ester and clove oil is about 7.5mg/mL, mass ratio is 0.5:1.

In some embodiments, the total amount of 15-hydroxystearic acid polyethylene glycol ester and clove oil is about 10mg/mL, in a mass ratio of 1:1.

In some embodiments, the total amount of 15-hydroxystearic acid polyethylene glycol ester and clove oil is about 15mg/mL, mass ratio is 0.5:1.

In some embodiments, the stabilizing agent in the nasal pharmaceutical composition is selected from one or more of cyclodextrin or a derivative thereof. Cyclodextrin refers to a cyclic oligosaccharide consisting of six or more monosaccharide units having a central cavity, which forms an inclusion complex with a hydrophobic molecule. Cyclodextrins or derivatives thereof herein are e.g. alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and randomly methylated beta-cyclodextrin.

In some embodiments, the stabilizing agent is present in the nasal pharmaceutical composition in an amount of 0 to 180mg/mL. Such as about 0mg/mL, about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, about 150mg/mL, about 160mg/mL, about 170mg/mL, about 180mg/mL.

In some embodiments, the stabilizing agent is present in the nasal pharmaceutical composition in an amount of about 60 to 150mg/mL. Such as about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, about 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL.

In some embodiments, the stabilizing agent is present in the nasal pharmaceutical composition in an amount of about 60 to 70mg/mL. Such as about 60mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, about 65mg/mL, about 66mg/mL, about 67mg/mL, about 68mg/mL, about 69mg/mL, about 70mg/mL.

In some embodiments, the stabilizing agent is present in the nasal pharmaceutical composition in an amount of about 65-70 mg/mL, such as about 65mg/mL,66mg/m, about 67mg/mL, about 67.5mg/mL, about 67.6mg/mL, about 67.7mg/mL, about 67.8mg/mL, about 67.9mg/mL, about 68mg/mL, about 69mg/mL, about 70mg/mL.

In some embodiments, the stabilizing agent is present in the nasal pharmaceutical composition in an amount of about 120 to 150mg/mL. Such as about 120mg/mL, about 121mg/mL, about 122mg/mL, about 123mg/mL, about 124mg/mL, about 125mg/mL, about 126mg/mL, about 127mg/mL, about 128mg/mL, about 129mg/mL, about 130mg/mL, about 131mg/mL, about 132mg/mL, about 133mg/mL, about 134mg/mL, about 135mg/mL, about 136mg/mL, about 137mg/mL, about 138mg/mL, about 139mg/mL, about 140mg/mL, about 141mg/mL, about 142mg/mL, about 143mg/mL, about 144mg/mL, about 145mg/mL, about 146mg/mL, about 147mg/mL, about 148mg/mL, about 149mg/mL, about 150mg/mL.

In some embodiments, the stabilizing agent is present in the nasal pharmaceutical composition in an amount of about 130-140 mg/mL. Such as about 130mg/mL, about 130.5mg/mL, about 131mg/mL, about 131.5mg/mL, about 132mg/mL, about 132.5mg/mL, about 133mg/mL, about 133.5mg/mL, about 134mg/mL, about 134.5mg/mL, about 135mg/mL, about 135.1mg/mL, about 135.2mg/mL, about 135.3mg/mL, about 135.4mg/mL, about 135.5mg/mL, about 135.6mg/mL, about 135.7mg/mL, about 135.8mg/mL, about 135.9mg/mL, about 136mg/mL,136.5mg/mL, about 137mg/mL, about 137.5mg/mL, about 138mg/mL, about 138.5mg/mL, about 139mg/mL, about 139.5mg/mL, about 140mg/mL.

In at least one embodiment, the stabilizing agent in the nasal pharmaceutical composition is hydroxypropyl-beta-cyclodextrin.

In at least one embodiment, the stabilizing agent in the nasal pharmaceutical composition is hydroxypropyl-beta-cyclodextrin, in an amount of about 67.7mg/mL.

In at least one embodiment, the stabilizing agent in the nasal pharmaceutical composition is hydroxypropyl-beta-cyclodextrin, in an amount of about 135.4mg/mL.

In some embodiments, the metal ion chelator in the nasal pharmaceutical composition is selected from one or more of ethylenediamine tetraacetic acid or a salt thereof, such as ethylenediamine tetraacetic acid, disodium ethylenediamine tetraacetic acid, and calcium sodium ethylenediamine tetraacetic acid.

In some embodiments, the metal ion chelator in the nasal pharmaceutical composition is disodium ethylenediamine tetraacetate.

In some embodiments, the metal ion chelator content in the nasal pharmaceutical composition is about 0-6 mg/mL; such as about 0.5mg/mL, about 1mg/mL, about 1.5mg/mL, about 2mg/mL, about 2.5mg/mL, about 3mg/mL, about 3.5mg/mL, about 4mg/mL, about 4.5mg/mL, about 5mg/mL, about 5.5mg/mL, about 6mg/mL.

In some embodiments, the metal ion chelator content in the nasal pharmaceutical composition is about 0.5-4 mg/mL; such as about 0.5mg/mL, about 1mg/mL, about 1.5mg/mL, about 2mg/mL, about 2.5mg/mL, about 3mg/mL, about 3.5mg/mL, about 4mg/mL.

In some embodiments, the metal ion chelator content in the nasal pharmaceutical composition is about 2-4 mg/mL; such as about 2mg/mL, about 2.5mg/mL, about 3mg/mL, about 3.5mg/mL, about 4mg/mL.

In at least one embodiment, the metal ion chelating agent in the nasal pharmaceutical composition is disodium edetate in an amount of about 2mg/mL.

In at least one embodiment, the metal ion chelating agent in the nasal pharmaceutical composition is disodium edetate in an amount of about 3mg/mL.

In at least one embodiment, the metal ion chelating agent in the nasal pharmaceutical composition is disodium edetate in an amount of about 4mg/mL.

In some embodiments, the buffer in the nasal pharmaceutical composition is selected from the group consisting of hydrochloric acid, citric acid, and sodium citrate.

In some embodiments, the pH of the adrenergic nasal pharmaceutical composition is adjusted to a value of about 3 to 4, such as about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0.

In some embodiments, the preservative in the nasal pharmaceutical composition is selected from one or more of ethanol, propylene glycol, glycerin, benzyl alcohol, phenethyl alcohol, benzalkonium chloride, trichlorot-butyl alcohol, methylparaben, potassium sorbate, peppermint oil, and.

In some embodiments, the preservative in the nasal pharmaceutical composition is benzalkonium chloride.

In some embodiments, the amount of preservative in the nasal pharmaceutical composition is about 0 to 1mg/mL, such as: about 0.2mg/mL, about 0.4mg/mL, about 0.6mg/mL, about 0.8mg/mL, about 1.0mg/mL.

In some embodiments, the amount of preservative in the nasal pharmaceutical composition is about 0 to 0.6mg/mL, such as: about 0.1mg/mL, about 0.2mg/mL, about 0.3mg/mL, about 0.4mg/mL, about 0.5mg/mL, about 0.6mg/mL.

In some embodiments, the amount of preservative in the nasal pharmaceutical composition is about 0.01 to 0.4mg/mL, such as: about 0.01mg/mL, about 0.02mg/mL, about 0.03mg/mL, about 0.04mg/mL, about 0.05mg/mL, about 0.06mg/mL, about 0.07mg/mL, about 0.08mg/mL, about 0.09mg/mL, about 0.1mg/mL, about 0.2mg/mL, about 0.3mg/mL, about 0.4mg/mL.

In at least one embodiment, the preservative in the nasal pharmaceutical composition is benzalkonium chloride in an amount of about 0.4mg/mL.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, disodium edetate, citrate buffer, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, disodium edetate, citrate buffer, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, disodium edetate, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, citrate buffer, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, disodium edetate, citrate buffer, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, disodium edetate, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, citrate buffer, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, disodium edetate, citrate buffer, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, disodium edetate, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, citrate buffer, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil, hydroxypropyl- β -cyclodextrin, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, disodium edetate, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, citrate buffer, and water.

In some embodiments, the nasal pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, polyethylene glycol 15-hydroxystearate, clove oil, benzalkonium chloride, and water.

In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 1-30 mg/mL. In some embodiments, the epinephrine content is about 1-25 mg/mL, such as about 1mg/mL, about 2mg/mL, about 3mg/mL, about 4mg/mL, about 5mg/mL, about 6mg/mL, about 7mg/mL, about 8mg/mL, about 9mg/mL, about 10mg/mL, about 11mg/mL, about 12mg/mL, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/mL, about 19mg/mL, about 20mg/mL, about 21mg/mL, about 22mg/mL, about 23mg/mL, about 24mg/mL, or about 25mg/mL.

In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 5-25 mg/mL, such as about 5mg/mL, about 5.5mg/mL, about 6mg/mL, about 6.5mg/mL, about 7mg/mL, about 7.5mg/mL,8mg/mL, about 8.5mg/mL, about 9mg/mL, about 9.5mg/mL, about 10mg/mL, about 10.5mg/mL, about 11mg/mL, about 11.5mg/mL, about 12mg/mL, about 12.5mg/mL, about 13mg/mL, about 13.5mg/mL, about 14mg/mL, about 14.5mg/mL, about 15mg/mL, about 15.5mg/mL, about 16mg/mL, about 16.5mg/mL, about 17mg/mL, about 18mg/mL, about 18.5mg/mL, about 19mg/mL, about 19.5mg/mL, about 20mg/mL, about 21.5mg/mL, or about 21.5 mg/mL. About 21mg/mL, about 22mg/mL, about 23mg/mL, about 24mg/mL or about 25mg/mL.

In some embodiments, the nasal pharmaceutical composition has an epinephrine content of about 8-22 mg/mL, such as about 8mg/mL, about 8.5mg/mL, about 9mg/mL, about 9.5mg/mL, about 10mg/mL, about 10.5mg/mL, about 11mg/mL, about 11.5mg/mL, about 12mg/mL, about 12.5mg/mL, about 13mg/mL, about 13.5mg/mL, about 14mg/mL, about 14.5mg/mL, about 15mg/mL, about 15.5mg/mL, about 16mg/mL, about 16.5mg/mL, about 17mg/mL, about 17.5mg/mL, about 18mg/mL, about 18.5mg/mL, about 19mg/mL, about 19.5mg/mL, about 20mg/mL, about 20.5mg/mL, about 21mg/mL, about 21.5mg/mL, or about 22mg/mL.

In some embodiments, the epinephrine content is about 10-20 mg/mL, such as about 10mg/mL, about 10.5mg/mL, about 11mg/mL, about 11.5mg/mL, about 12mg/mL, about 12.5mg/mL, about 13mg/mL, about 13.5mg/mL, about 14mg/mL, about 14.5mg/mL, about 15mg/mL, about 15.5mg/mL, about 16mg/mL, about 16.5mg/mL, about 17mg/mL, about 17.5mg/mL, about 18mg/mL, about 18.5mg/mL, about 19mg/mL, about 19.5mg/mL, or about 20mg/mL.

In some embodiments, the epinephrine content is about 10mg/mL.

In some embodiments, the epinephrine content is about 20mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is 0 to 180mg/mL. Such as about 0mg/mL, about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, about 150mg/mL, about 160mg/mL, about 170mg/mL, about 180mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is about 60 to 150mg/mL. Such as about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, about 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is present in an amount of about 60 to 70mg/mL. Such as about 60mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, about 65mg/mL, about 66mg/mL, about 67mg/mL, about 68mg/mL, about 69mg/mL, about 70mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is present in an amount of about 65 to 70mg/mL, such as about 65mg/mL,66mg/m, about 67mg/mL, about 67.5mg/mL, about 67.6mg/mL, about 67.7mg/mL, about 67.8mg/mL, about 67.9mg/mL, about 68mg/mL, about 69mg/mL, about 70mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is present in an amount of about 120 to 150mg/mL. Such as about 120mg/mL, about 121mg/mL, about 122mg/mL, about 123mg/mL, about 124mg/mL, about 125mg/mL, about 126mg/mL, about 127mg/mL, about 128mg/mL, about 129mg/mL, about 130mg/mL, about 131mg/mL, about 132mg/mL, about 133mg/mL, about 134mg/mL, about 135mg/mL, about 136mg/mL, about 137mg/mL, about 138mg/mL, about 139mg/mL, about 140mg/mL, about 141mg/mL, about 142mg/mL, about 143mg/mL, about 144mg/mL, about 145mg/mL, about 146mg/mL, about 147mg/mL, about 148mg/mL, about 149mg/mL, about 150mg/mL.

In some embodiments, the hydroxypropyl-beta-cyclodextrin is present in an amount of about 130 to 140mg/mL. Such as about 130mg/mL, about 130.5mg/mL, about 131mg/mL, about 131.5mg/mL, about 132mg/mL, about 132.5mg/mL, about 133mg/mL, about 133.5mg/mL, about 134mg/mL, about 134.5mg/mL, about 135mg/mL, about 135.1mg/mL, about 135.2mg/mL, about 135.3mg/mL, about 135.4mg/mL, about 135.5mg/mL, about 135.6mg/mL, about 135.7mg/mL, about 135.8mg/mL, about 135.9mg/mL, about 136mg/mL,136.5mg/mL, about 137mg/mL, about 137.5mg/mL, about 138mg/mL, about 138.5mg/mL, about 139mg/mL, about 139.5mg/mL, about 140mg/mL.

In at least one embodiment, the hydroxypropyl-beta-cyclodextrin content is about 67.7mg/mL.

In at least one embodiment, the hydroxypropyl-beta-cyclodextrin content is about 135.4mg/mL.

In some embodiments, the disodium edetate is present in an amount of about 0 to 6mg/mL; such as about 0.5mg/mL, about 1mg/mL, about 1.5mg/mL, about 2mg/mL, about 2.5mg/mL, about 3mg/mL, about 3.5mg/mL, about 4mg/mL, about 4.5mg/mL, about 5mg/mL, about 5.5mg/mL, about 6mg/mL.

In some embodiments, the disodium edetate is present in an amount of about 0.5 to 4mg/mL; such as about 0.5mg/mL, about 1mg/mL, about 1.5mg/mL, about 2mg/mL, about 2.5mg/mL, about 3mg/mL, about 3.5mg/mL, about 4mg/mL.

In some embodiments, the disodium edetate is present in an amount of about 2 to 4mg/mL; such as about 2mg/mL, about 2.5mg/mL, about 3mg/mL, about 3.5mg/mL, about 4mg/mL.

In at least one embodiment, the disodium edetate is present in an amount of about 2mg/mL.

In some embodiments, the benzalkonium chloride is present in an amount of about 0 to 1mg/mL, such as: about 0.2mg/mL, about 0.4mg/mL, about 0.6mg/mL, about 0.8mg/mL, about 1.0mg/mL.

In some embodiments, the benzalkonium chloride is present in an amount of about 0 to 0.6mg/mL, such as: about 0.1mg/mL, about 0.2mg/mL, about 0.3mg/mL, about 0.4mg/mL, about 0.5mg/mL, about 0.6mg/mL.

In some embodiments, the benzalkonium chloride is present in an amount of about 0.01 to 0.4mg/mL, such as: about 0.01mg/mL, about 0.02mg/mL, about 0.03mg/mL, about 0.04mg/mL, about 0.05mg/mL, about 0.06mg/mL, about 0.07mg/mL, about 0.08mg/mL, about 0.09mg/mL, about 0.1mg/mL, about 0.2mg/mL, about 0.3mg/mL, about 0.4mg/mL.

In at least one embodiment, the benzalkonium chloride is present in an amount of about 0.4mg/mL.

In some embodiments, the nasal pharmaceutical composition is free of sodium metabisulfite and sodium bisulfite.

In some embodiments, the nasal pharmaceutical composition is administered via the nasal mucosal route.

In some embodiments, the nasal pharmaceutical composition is filled into a metered dose spray device, and the metered dose spray device is free of metal parts in direct contact with the medical fluid.

In some embodiments, the metered dose spray device is a single dose device, such as the Aptar company UDS and model Adella devices; the loading amount is 0.1-0.2 mL, such as 0.10mL,0.15mL and 0.20mL; the amount of the liquid to be sprayed was 100. Mu.L.

In some embodiments, the metered dose spray device is a dual dose device, such as a Aptar company BDS model device; the dual dose device is loaded at 0.2 to 0.5mL, such as 0.2mL,0.3mL,0.4mL,0.5mL, and 100. Mu.L per spray.

In some embodiments, the metered dose spray device is a multi-dose device, such as the Aptar company APF model device; the loading amount is 0.5-10 mL, such as 0.5mL,1mL,1.5mL,2mL,3mL,4mL,5mL,6mL,7mL,8mL,9mL,10mL; the amount of the liquid to be sprayed is 50 to 200. Mu.L, such as 50. Mu.L, 60. Mu.L, 70. Mu.L, 80. Mu.L, 90. Mu.L, 100. Mu.L, 150. Mu.L, 200. Mu.L, per one spray.

The high performance liquid phase method detection method adopted by the invention has the following chromatographic conditions:

mobile phase: tetramethyl ammonium bisulfate solution (tetramethyl ammonium bisulfate 4.0g, sodium heptanesulfonate 1.l g, disodium ethylenediamine tetraacetate 0.1mol/L solution 2mL, dissolved in water and diluted to 950 mL) -methanol (95:5) (pH was adjusted to 3.5 with 1mol/L sodium hydroxide solution);

Sample injection amount: 20. Mu.L;

Detection wavelength: 280nm;

Column temperature: 25 ℃;

flow rate: 2mL/min.

The following examples are intended to illustrate the disclosure, but are not intended to limit the scope thereof in any way.

Comparison sample and preparation:

Comparative sample 1: 10mg/ml epinephrine nasal spray without absorption enhancer was formulated as follows and prepared in the same manner as example 2.

Comparative sample 2: commercial epinephrine hydrochloride injection (Shanghai Hefeng pharmaceutical Co., ltd.)

Comparative sample 3: intranasal epinephrine formulations as disclosed in patent CN110505873a and prepared according to the methods disclosed in that patent

Comparative sample 4: intranasal epinephrine formulations as disclosed in patent CN110505873a and prepared according to the methods disclosed in that patent

Comparative example 5A 20mg/ml nasal spray without absorption enhancer was formulated as follows and prepared in the same manner as in example 2.

Comparative sample 6: 10mg/ml epinephrine nasal spray without absorption enhancer and cyclodextrin was formulated as follows and prepared in the same manner as example 2.

Example 1: stability study of epinephrine solutions

Precisely weighing 10mg of epinephrine, adding the epinephrine into an eggplant type bottle, adding 0.3mL of 0.2M hydrochloric acid solution, stirring until the epinephrine is completely dissolved, adding 0.7mL of pure water until the total volume is 1mL, adding pH regulator citric acid and sodium citrate, respectively adjusting the final pH value to 2.5, 3.5, 4.5, 5.5 and 6.5, and obtaining epinephrine solutions with different pH values, wherein the initial concentration of epinephrine in the solution is 10mg/mL. After the above solution was left for 1 month, the color change of the solution was observed, and the epinephrine content of the solution was detected. The epinephrine content changes in the solutions at different pH values were recorded in FIG. 1 at an initial concentration of 10mg/mL at 100%. The epinephrine solution with the pH of more than or equal to 4.5 can be observed along with the lengthening of the standing time, the epinephrine content in the solution is obviously reduced, the color of the solution is obviously changed, and the impurity content is obviously increased; an epinephrine solution with pH less than 4.5, wherein the epinephrine content in the solution has small change, and the solution has no obvious color change. Since too low a pH may cause irritation of nasal mucosa, it is preferable to control the pH of the nasal pharmaceutical composition to be between 3 and 4.

EXAMPLE 2 preparation of nasal spray

A representative nasal spray was prepared as follows:

(1) Preparation of epinephrine stock: accurately weighing 10mg of epinephrine, adding the epinephrine into an eggplant type bottle, adding 0.3mL of 0.2M hydrochloric acid solution, stirring until the epinephrine is completely dissolved, and obtaining epinephrine stock solution (product I), wherein the process is completed in a dark place.

(2) Preparing auxiliary material diluent: precisely weighing the prescribed amount of hydroxypropyl-beta-cyclodextrin, an absorption accelerator and a metal ion chelating agent of disodium ethylenediamine tetraacetate (EDTA 2 Na), adding pure water, adjusting the temperature to 25 ℃, rotating the rotor at 100r/min, stopping heating after stirring for 2 hours, naturally cooling to room temperature (20+/-1 ℃), adjusting the pH value of the mixed solution to 3-4 by using a pH regulator of citric acid and sodium citrate, and obtaining an auxiliary material diluent (product II), wherein the total volume of the product II and the product I after being combined is 1mL in full.

(3) Preparation of a nasal pharmaceutical composition: mixing the first product and the second product, stirring uniformly, regulating the pH value of the mixed solution to 3-4 by using a pH regulator of citric acid and sodium citrate, and filtering to remove insoluble substances to obtain the nasal pharmaceutical composition, wherein the epinephrine content is 10mg/mL.

(4) Preparation of nasal spray: quantitatively filling the nasal pharmaceutical composition prepared in the step (3) into a spraying device.

Nasal pharmaceutical composition samples numbered 1-20 were prepared according to the above method, and specific prescriptions are shown in tables 1-4:

Wherein in samples 1 to 5, the absorption enhancer is dodecyl maltoside (manufacturer: shanghai Michlin Biochemical technology Co., ltd.);

In samples 5 to 10, the absorption enhancer was a combination of 15-hydroxystearic acid polyethylene glycol ester (manufacturer: basiff (China Co., ltd.) and clove oil (manufacturer: hunan Erkang pharmaceutical Co., ltd.).

In addition, control 1, which is a blank without the absorption enhancer, was prepared in the same manner as the preparation of the representative nasal spray except that no absorption enhancer was added.

TABLE 1 nasal pharmaceutical composition samples with varying amounts of dodecyl maltoside

Prescription composition	Sample 1	Sample 2	Sample 3	Sample 4	Sample 5
						Epinephrine (mg)	10	10	10	10	10
0.2M hydrochloric acid (mL)	0.3	0.3	0.3	0.3	0.3
						Hydroxypropyl-beta-cyclodextrin (mg)	67.7	67.7	67.7	67.7	67.7
Dodecyl maltoside (mg)	1	2.5	5	10	20
						EDTA2Na(mg)	2	2	2	2	2
Citric acid (mg)	13.8	13.8	13.8	13.8	13.8
						Sodium citrate (mg)	10.1	10.1	10.1	10.1	10.1
Pure water (mL)	0.7	0.7	0.7	0.7	0.7
						pH	About 3.5	About 3.5	About 3.5	About 3.5	About 3.5

TABLE 2 nasal pharmaceutical composition samples of polyethylene glycol 15-hydroxystearate in combination with clove oil

Example 3 in vitro nasal mucosa permeability study

The porcine nasal mucosa is selected as an experimental model and is divided into in vitro nasal mucosa permeability researches for a comparison sample 1 and samples 1-10. Franz diffusion cells were selected for in vitro permeation experiments, and samples were taken at 0, 5, 10, 15, 20, 30, 40, 60, 90, 120, 180min after dosing, and the epinephrine content was detected by high performance liquid chromatography and compared to control 1. The in vitro mucosal permeability of epinephrine in control 1 and samples 1-10 is shown in FIGS. 2-3. The results of the mucous membrane permeation parameters within 30 minutes of epinephrine are shown in tables 3-4.

Table 3 mucous membrane permeation parameters (mean±sem, n=3) within 30min of epinephrine at different levels of dodecyl maltoside

Table 4 polyethylene glycol 15-hydroxystearate in combination with clove oil within 30min of the mucosal permeation parameters of epinephrine (mean±sem, n=3)

As shown in the results of the above table 3 and table 4, the different kinds of absorption accelerators have different degrees of ability to promote the absorption of epinephrine by the nasal mucosa, the effect of promoting the absorption of epinephrine by the nasal mucosa is obviously improved along with the increase of the dosage of the absorption accelerator, and the effect is not obvious when the dosage of the absorption accelerator reaches 10mg/mL and the dosage of the absorption accelerator is increased. Wherein, 0.25% dodecyl maltoside (sample 2) adopted in patent CN110505873A has a cumulative permeation percentage of adrenaline nasal mucosa of 19% within 30min, and the effect is improved by 2.0 times compared with that of a blank solution group (comparative sample 1); when the dodecyl maltoside dosage is continuously increased to 1 percent (sample 4), the nasal mucosa accumulated penetration is 28 percent, and the effect is improved by 3.5 times compared with that of a blank solution group (comparative sample 1); the dosage of dodecyl maltoside is continuously increased, and the permeation promoting effect is not obviously improved. The preparation group using 15-hydroxystearic acid polyethylene glycol ester and clove oil as the absorption enhancer is significantly better than dodecyl maltoside, when the dosage of 15-hydroxystearic acid polyethylene glycol ester is 0.25%, and the dosage of clove oil is 0.5% (sample 8), the nasal mucosa penetration of epinephrine in 30min can reach 54%, which is 8.7 times of the effect of the blank solution group (comparative sample 1), and 1.9 times of the effect of 0.25% dodecyl maltoside (sample 2) adopted in patent CN110505873 a; the penetration-promoting effect of the 15-hydroxystearic acid polyethylene glycol ester and the clove oil is not obviously improved.

Examples 4 to 43 nasal formulations of epinephrine

Tables 5 to 12 show the formulation compositions and contents of the epinephrine nasal preparations of examples 4 to 43, and the preparation method is the same as that of example 2, and the epinephrine nasal spray can be prepared by using the conventional nasal spray preparation method in the prior art. The following examples are intended to illustrate the disclosure, but are not intended to limit the scope thereof in any way.

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

Table 10

TABLE 11

Table 12

EXAMPLE 44 stability study of nasal pharmaceutical compositions

Nasal spray formulations were prepared by loading the nasal pharmaceutical compositions of comparative examples 1,3 and example 6 into a Aptar APF model device. The nasal pharmaceutical composition was left for 3 months at 40.+ -. 2 ℃ and 75%.+ -. 5% relative humidity, and samples were taken at 0,1 and 3 months, and the stability of the pharmaceutical composition for nasal administration was examined for indexes such as color, pH, impurity formation, and epinephrine content of each group of pharmaceutical solutions, and the results are shown in Table 13. The nasal pharmaceutical composition was left for 6 months at 25.+ -. 2 ℃ and 60%.+ -. 5% relative humidity, and samples were taken at 0, 3 and 6 months, and the stability of the pharmaceutical composition for nasal administration was examined for indexes such as color, pH, impurity formation, and epinephrine content of each group of pharmaceutical solutions, and the results are shown in Table 14. The impurity A in the table is epinephrine, and the impurity B is norepinephrine. The detection method comprises the following steps: and measuring the content of the medicine and the impurity by adopting a high performance liquid phase method. The chromatographic conditions were as follows: mobile phase: tetramethyl ammonium bisulfate solution (tetramethyl ammonium bisulfate 4.0g, sodium heptanesulfonate 1.l g, disodium ethylenediamine tetraacetate 0.1mol/L solution 2mL, dissolved in water and diluted to 950 mL) -methanol (95:5) (pH was adjusted to 3.5 with 1mol/L sodium hydroxide solution); sample injection amount: 20. Mu.L; detection wavelength: 280nm; column temperature: 25 ℃; flow rate: 2mL/min.

TABLE 13 epinephrine stability (40 ℃ + -2 ℃,75% RH+ -5% RH)

Table 14 epinephrine stability (25 ℃ ± 2 ℃,60% rh ± 5% rh)

The results of the same spraying device (APF) and 3 months of accelerated experiments (40 ℃ +/-2 ℃ and 75%RH+/-5%RH) of different formulations are shown in table 13, and although the three formulations under the prescriptions are still clear and transparent, the main drug content, the impurity content and the like meet the quality requirements, the stability of epinephrine is obviously improved compared with the comparative sample 1 and the comparative sample 3 in the group of example 6, and the total impurities are respectively about 50% of the comparative sample 1 and 60% of the comparative sample 3 after 30 days; the results of long-term experiments (25 ℃ +/-2 ℃ and 60%RH+/-5%RH) for 6 months are shown in table 14, the three formulations under the prescription are still clear and transparent, the content of main drugs, the content of impurities and the like meet the quality requirements, the total impurities after 30 days are respectively about 50% of that of a comparative sample 1 and a comparative sample 3, and the stability of the epinephrine nasal spray is good.

EXAMPLE 45 in vitro nasal mucosa permeability study of 20mg/mL adrenergic nasal spray

Porcine nasal mucosa was chosen as the experimental model for in vitro nasal mucosa permeability studies of comparative sample 4, comparative sample 5, example 26 and example 27, respectively, of the epinephrine nasal spray. Franz diffusion cells were selected for in vitro permeation experiments, and samples were taken at 0, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180min after dosing, and the epinephrine content was detected by high performance liquid chromatography and compared to control samples. The in vitro mucosal permeabilities of epinephrine of comparative example 4, comparative example 5, example 26 and example 27 are shown in fig. 4 to 5. Among them, the results of the mucous membrane permeation parameters within 30 minutes of epinephrine are shown in Table 15.

Table 15 mucosal permeation parameters within 30min (mean±sem, n=3

The in vitro nasal mucosa permeation result of the 20mg/mL epinephrine nasal spray for 30min is shown in table 13, 0.25% dodecyl maltoside (comparative sample 4) adopted in patent CN110505873A, the cumulative permeation percentage of epinephrine nasal mucosa within 30min is 23%, and the effect is improved by 1.4 times compared with that of a blank solution group (comparative sample 5); when 0.25% of 15-hydroxystearic acid polyethylene glycol ester and 0.5% of clove oil are used as the absorption accelerator (example 26), nasal mucosa penetration of epinephrine can reach 36% within 30min, which is 2.2 times of that of a blank solution group (comparative sample 5), and the penetration effect is 1.6 times of that of 0.25% dodecyl maltoside (comparative sample 4) adopted in patent CN110505873a, which has remarkable advantages; when the amount of polyethylene glycol 15-hydroxystearate was increased to 0.5% (example 27), the penetration effect was no longer significantly increased.

EXAMPLE 46 in vivo pharmacokinetic Studies

In vivo pharmacokinetic study of 10mg/mL epinephrine nasal spray

Rabbits were selected and randomly divided into 5 groups, and they were used for in vivo pharmacokinetic studies of epinephrine preparations obtained in blank 1 (intramuscular saline), blank 2 (nasal saline), control 2 (intramuscular administration), control 3 (nasal administration), and example 6 (nasal administration), respectively.

After 12h of fasting, 0.3mg was administered by intramuscular injection or 1mg was administered by nasal administration, respectively, and 0, 2, 4, 6, 8, 10, 12, 15, 18, 20, 25, 30, 45, 60, 90, 120, 180min after administration, 0.5mL of blood was collected from the rabbit ear vein, placed in heparinized EP tubes, upper plasma was collected by centrifugation and the epinephrine content in the plasma was extracted by solid phase extraction process, and the bioavailability of the nasal pharmaceutical composition of example 6 was evaluated by comparison with the blank and the control (as shown in fig. 6 to 8). Wherein the results of the measurements of blank 1 and blank 2 are at baseline in vivo, and the results of the measurements of comparative sample 2, comparative sample 3, and example 6 are shown in Table 16.

Table 16 in vivo pharmacokinetic parameters of epinephrine (mean±sem, n=3)

Pharmacokinetic analysis was performed using SPSS software and T _max、C_max、AUC_(0-15min)、AUC_(0-30min)、AUC_(0-t) between groups was compared using analysis of variance (ANOVA) model. Among them, blank groups 1 and 2 measured normal baseline levels of epinephrine content in the body, without interfering with the experimental results.

The results of in vivo pharmacokinetic studies of 10mg/mL of epinephrine nasal spray are shown in Table 15 and FIGS. 6-8, the optimal prescription group (comparative sample 3) in patent CN110505873A has an epinephrine absorption effect similar to that of the intramuscular injection group (comparative sample 2), tmax is 24.2min, AUC _(0-15min) is 298.6 ng/mL.min, and AUC _(0-30min) is 947.6 ng/mL.min; when 0.25% of 15-hydroxystearic acid polyethylene glycol ester and 0.5% of clove oil were used in combination as an epinephrine absorption enhancer (example 6), T _max was shortened to 13.7min, 43% shorter than the optimal prescription group of patent CN110505873a (comparative sample 3); AUC _(0-15min) is increased to 634.2 ng/mL.min, increased by 112.4%; AUC _(0-30min) was increased to 1529.5ng/mL min, increasing by 61.4%. The combination of 15-hydroxystearic acid polyethylene glycol ester and clove oil as the mucous membrane absorption promoter of the adrenaline nasal cavity can effectively improve the peak reaching time and the AUC value in the earlier 15min, quickly achieve the treatment effect and more meet the clinical treatment requirement.

In vivo pharmacokinetic study of 20mg/mL epinephrine nasal spray

Rabbits were selected and randomly divided into 4 groups for in vivo pharmacokinetic studies of epinephrine formulations obtained in control 2 (intramuscular administration), control 4 (nasal administration), and example 26 (nasal administration) and example 31 (nasal administration), respectively.

The bioavailability of 20mg/mL of the pharmaceutical composition for use in the nasal cavity of epinephrine was evaluated using the same assay and assay as the in vivo pharmacokinetic study of 10mg/mL of the nasal spray and comparing with comparative sample 2 and comparative sample 4 (as depicted in FIGS. 9-11). The results of the tests of comparative sample 2, comparative sample 4, and examples 26 and 31 are shown in Table 17.

Table 17 in vivo pharmacokinetic parameters of epinephrine (mean±sem, n=3)

The results of in vivo pharmacokinetic studies of 20mg/mL epinephrine nasal spray are shown in Table 15 and FIGS. 9-11, and the optimal prescription group (comparative sample 4) epinephrine absorption peak time T _max in patent CN110505873A is 25.0min closer to that of the intramuscular injection group (comparative sample 2); when 0.25% of 15-hydroxystearic acid polyethylene glycol ester and 0.5% of clove oil are used as an epinephrine absorption enhancer (example 26), the drug has significant advantages over the optimal prescription group (comparative sample 4) in patent CN110505873a, the onset of action is faster, T _max can be shortened to 15.8min, and the advance is about 37%; more absorbed, AUC _(0-15min) was about 1.56 times that of the optimal prescription set (control 4) in patent CN110505873a, and AUC _(0-30min) was about 1.22 times; comparing pharmacokinetic parameters of the nasal spray with or without benzalkonium chloride (examples 26 and 31), the results show that the nasal spray with or without benzalkonium chloride has no influence on the nasal absorption of epinephrine, the effects are similar, and the pharmacokinetic parameters have no significant difference.

Examples 47 to 48 nasal formulations of epinephrine

The formulation compositions and contents of the epinephrine nasal preparations of examples 47 to 48 are shown in Table 18, and the preparation method is the same as that of example 2.

TABLE 18

EXAMPLE 49 cyclodextrin enhanced epinephrine stability study

The stability of the formulations at molar ratios 1:0, 1:0.5, 1:1, 1:2 for epinephrine and HP-beta-CD were investigated and the specific formulations are shown in Table 18 for examples 21, 47, 11, 48, respectively. The above nasal pharmaceutical composition was filled into penicillin bottles, and left to stand at a temperature of 40 ℃ ± 2 ℃ and a relative humidity of 75% ± 5% for 30 days, and sampled for 0, 5, 10, 15, 20, and 30 days, respectively, during which the properties of the intermediate solution, pH, content, and changes in the related substances were examined, the changes in epinephrine content were recorded in fig. 12, and the total impurity production was recorded in fig. 13. It was found by 1 month acceleration experiments that the solutions of each of the nasal pharmaceutical compositions remained colorless and clear. Meanwhile, when the dosage of epinephrine and HP-beta-CD is 1:1 according to the molar ratio, the impurity content is not increased compared with the initial impurity content, and the stability of the epinephrine intermediate solution is obviously improved; the stability of the nasal adrenergic compositions is no longer improved by continuing to increase the amount of HP-beta-CD.

EXAMPLE 50 safety study of epinephrine nasal spray

The nasal preparation compositions of blank group (normal saline), comparative sample 6 and example 11 were administered singly through the nasal cavity of rabbit respectively in combination with the characteristic of single administration of epinephrine in bed, and the mucous membrane safety of epinephrine drug itself and absorption accelerator was examined. Observing and recording the whole body condition and local irritation symptoms of the rabbits before and after administration, and not finding symptoms such as runny nose, sneeze, asphyxia and the like; the nasal cavity pH value of the rabbit before and after administration is measured by a precise pH test paper to be normal. After the experiment is finished, the rabbit is sacrificed, the nasal cavity is opened to remove the nasal septum, the nasal mucosa is peeled off, no congestion and red swelling phenomenon of the nasal mucosa tissue of the rabbit is observed, and the removed nasal mucosa is respectively used for examining the characteristics of the nasal mucosa and the state of nasal cilia.

Placing nasal mucosa in 4% paraformaldehyde for fixing for more than 24h, embedding paraffin, slicing, dewaxing the slices in xylene twice for 10min each time; then washing with absolute ethanol twice, 5min each time with 95% ethanol, 5min each time with 90% ethanol, 5min each time with 80% ethanol, 5min each time with 70% ethanol, and 5min each time with distilled water. The slices are put into hematoxylin for dip dyeing for 5-8 min, distilled water is used for washing for 2min, then 1% hydrochloric acid alcohol is used for differentiation for a few seconds, after washing by distilled water, the slices are immersed into 0.6% ammonia water for returning blue, after washing by running water, the slices are put into eosin dye for dyeing for 1-3 min. Sequentially washing the slices with 95% ethanol twice for 5min each time; washing with absolute ethanol twice for 5min each time; the nasal mucosa tissue morphology was observed under an inverted fluorescence microscope after the sections were dehydrated twice in xylene for 5min each, air-dried and sealed with neutral resin, as shown in fig. 14. The nasal preparation compositions of the comparison samples 6 and 11 are the same as the blank group after nasal administration, the nasal mucosa structure is clear and complete, submucosal glands and capillaries are clear and visible, the cell morphology is not changed obviously, and the phenomenon of mucosa breakage is not found.

And (3) placing the other part of nasal mucosa in a precooled culture dish in which the electron microscope fixing liquid is dripped, cutting into small blocks with the side length smaller than 7mm by a blade, and fixing for 2 hours at the temperature of 4 ℃ by using the electron microscope fixing liquid. Wash 4 times with PBS buffer at pH 7.2 for 10min each and fix with 1% osmium acid for 2h at 4 ℃. Washing with PBS buffer solution of pH 7.2 for 4 times each for 10min, dewatering with 30%, 50%, 70%, 80%, 90%, 100% ethanol and n-amyl acetate sequentially for 15min, and drying in HCP-2 critical point dryer for 2h. The samples were stuck on a sample platform, sprayed with gold for 3min, and observed for the status of nasal cilia under a scanning electron microscope, as shown in fig. 14. The nasal formulations of comparative examples 6 and 11 were given to the same blank group after nasal administration, and the nasal cilia were dense and orderly arranged, and no cilia fall-off was observed.

Other embodiments

Embodiments are also provided herein, wherein any of the above embodiments may be combined with any one or more of the embodiments, provided that the combination is not mutually exclusive. Also provided herein are uses for treating an indication as disclosed herein, or one or more symptoms thereof, and for preparing a medicament for treating an indication as disclosed herein, or one or more symptoms thereof, to the extent equivalent to any embodiment disclosed above, or any combination of embodiments not mutually exclusive. The methods and uses may use any of the devices disclosed herein, or any combination of devices that are not mutually exclusive, or any pharmaceutical formulation disclosed herein, or any combination of pharmaceutical formulations that are not mutually exclusive. Although the present disclosure has been described with reference to specific details of certain implementations in the examples described above, it is to be understood that modifications and variations are intended to be included within the spirit and scope of the present disclosure.

Claims

1. A nasal pharmaceutical composition comprises epinephrine or pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester and oleum Caryophylli.

2. The nasal pharmaceutical composition according to claim 1, wherein the epinephrine content is about 1-30 mg/mL, preferably about 8-22 mg/mL, more preferably 10-20 mg/mL.

3. The nasal pharmaceutical composition according to claim 1, wherein the total amount of 15-polyethylene glycol stearate and clove oil is about 5-15 mg/mL, and the mass ratio of 15-polyethylene glycol hydroxystearate to clove oil is 0.5-2: 1, a step of; preferably, the total amount of the 15-hydroxystearic acid polyethylene glycol ester and the clove oil is about 7.5-10 mg/mL, and the mass ratio is about 0.5-1:1.

4. A nasal pharmaceutical composition according to any one of claims 1 to 3, comprising optionally one or more pharmaceutical excipients selected from the group consisting of: stabilizers, metal ion chelating agents, and pH adjusters.

5. The nasal pharmaceutical composition of claim 4, wherein the stabilizer is one or more of cyclodextrin or its derivatives in an amount of about 0-180 mg/mL; preferably the stabilizer is hydroxypropyl-beta-cyclodextrin in an amount of about 60 to 150mg/mL.

6. The nasal pharmaceutical composition according to claim 4, wherein the metal ion chelating agent is selected from one or more of ethylenediamine tetraacetic acid or a salt thereof in an amount of about 0 to 6mg/mL; preferably disodium edetate in an amount of about 0.5 to 4mg/mL.

7. The nasal pharmaceutical composition of claim 4, wherein the pH modifier is an acid, a base, a buffer, or a combination thereof;

The alkali is sodium hydroxide, sodium citrate, sodium bicarbonate or sodium carbonate; and

The buffer is a phosphate buffer, an acetate buffer, or a citrate buffer.

8. The nasal pharmaceutical composition according to any one of claims 1-7, wherein the nasal pharmaceutical composition has a pH of 3 to 4.

9. The nasal pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition further comprises a preservative; preferably, the preservative is benzalkonium chloride, and the content of the preservative is 0-1 mg/mL.

10. A nasal pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof, 15-hydroxystearic acid polyethylene glycol ester, clove oil and water, and one or more of hydroxypropyl-beta-cyclodextrin, disodium edetate, citrate buffer and benzalkonium chloride, characterized in that,

The medicinal salt is hydrochloride, tartrate or citrate;

the content of epinephrine is about 8-22 mg/mL;

15-hydroxystearic acid polyethylene glycol ester in an amount of about 2.5 to 5mg/ml;

The content of the clove oil is about 5-10 mg/mL;

The content of the hydroxypropyl-beta-cyclodextrin is about 60-150 mg/ml;

disodium edetate is present in an amount of about 0.5 to 4mg/ml;

the content of benzalkonium chloride is about 0.01-0.4 mg/mL;

the pharmaceutical composition has a pH of about 3 to 4.

11. Use of a nasal pharmaceutical composition according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of anaphylaxis, anaphylactic shock, severe allergy and/or bronchoconstriction.

12. The use according to claim 12, wherein the allergic reaction is a type I allergic reaction and the nasal pharmaceutical composition is administered at 1-2 mg/time on epinephrine basis.

13. A method of preparing a nasal pharmaceutical composition according to any one of claims 1 to 10, comprising the steps of:

(2) Preparing auxiliary material diluent: dissolving 15-hydroxystearic acid polyethylene glycol ester and clove oil, one or more of a stabilizer, a metal ion chelating agent and a preservative in pure water, stirring until the mixture is completely dissolved, adding a pH regulator, and regulating the pH value to 2-5 to obtain an auxiliary material diluent;

14. The method for preparing a pharmaceutical composition for nasal administration according to claim 13,

In the step (2), the pH regulator is citric acid and sodium citrate, and the pH value is regulated to 3-4;

15. A nasal spray comprising a nasal pharmaceutical composition and device according to claims 1-10; the device has no metal part in direct contact with the liquid medicine.

16. The nasal spray of claim 15, wherein the device is a metered dose spray device;

Preferably, the quantitative spraying device is a single-dose device, the loading of the single-dose device is 100-200 mu L, and the spraying amount per spraying is 100-200 mu L; preferably, the loading is about 110 to 150. Mu.L, and the spraying amount is about 100. Mu.L; or (b)

The quantitative spraying device is a double-dosage device, the loading amount of the double-dosage device is 200-500 mu L, and the spraying amount per spraying amount is 100-200 mu L; preferably, the loading is 210 to 250 mu L, and each spraying amount is about 100 mu L; or (b)

The quantitative spraying device is a multi-dose device; the loading of the multi-dose device is 500-1000 mu L, and the spraying amount per spraying is 50-200 mu L.

17. A method of preparing a nasal spray according to claim 16 or 15, wherein the nasal pharmaceutical composition according to claims 1 to 10 is prepared and filled into a container; the container has no metal part and is in direct contact with the liquid medicine.