Pharmaceutical solution composition and preparation method therefor, and nasal spray thereof and use thereof

Abstract

The present application relates to the technical field of biomedicine, and in particular to a pharmaceutical solution composition and a preparation method therefor, and a nasal spray. The pharmaceutical composition comprises an active pharmaceutical ingredient, a pH adjuster, an osmotic pressure adjuster and water, wherein the active pharmaceutical ingredient is rizatriptan or a salt thereof; the pH adjuster is used for adjusting the pH of the pharmaceutical composition to 4.0-7.0; and the osmotic pressure adjuster is used for adjusting the osmotic pressure of the pharmaceutical composition to 280-350 mOsm / kg. The nasal spray of the present application can be used for the rapid relief of migraines in the acute phase, thereby achieving rapid analgesia. Moreover, the nasal spray exhibits a high drug stability, is not affected by food, has simple and effective ingredients, and thus holds value for commercial production.

Description

A pharmaceutical solution composition, its preparation method, nasal spray, and its application.

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. 2024116979805, filed on November 25, 2024, entitled "A pharmaceutical solution composition and its preparation method, nasal spray and application", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of biomedical technology, and in particular to a pharmaceutical solution composition, its preparation method, a nasal spray, and its application. Background Technology

[0004] Migraine is a common neurological disorder characterized by recurrent, usually unilateral, moderate to severe throbbing headaches, often accompanied by nausea, vomiting, photophobia, and phonophobia. Its pathogenesis is currently unclear. It is generally believed that migraine patients experience a complex interaction between multiple susceptibility genes and between these genes and environmental factors, leading to an imbalance in the excitation / inhibition function of the central nervous system. This results in repeated activation and sensitization of the trigeminal vascular pathway, causing headache attacks and other accompanying symptoms. The greatest treatment need for acute migraine attacks is rapid analgesia, reducing recurrence, and quickly restoring the patient to a normal life.

[0005] Rizatriptan is a highly effective drug for treating migraines. It selectively constricts the cerebral vasculature and has very weak effects on peripheral blood vessels, thus resulting in fewer side effects. Currently, the main formulations of marketed drugs with rizatriptan as the active ingredient are oral dosage forms, including oral tablets and oral mucosal preparations. Oral tablets are available in 5mg and 10mg strengths, including regular oral tablets and orally disintegrating tablets. Oral dosage forms generally suffer from the drawback of being easily affected by food. When taken with food, the time to peak effect of the active ingredient is prolonged beyond expectations. Since migraine attacks are unpredictable, oral dosage forms are not ideal for treating acute migraine attacks. Furthermore, the nausea and vomiting that accompany migraine attacks further exacerbate the slow onset of action of oral dosage forms.

[0006] For the treatment of acute migraines, nasal administration is a more attractive alternative to oral administration, offering advantages such as rapid onset of action, absence of first-pass effect, high bioavailability, convenient administration, and improved patient compliance. Most currently reported nasal sprays target the lower nasal cavity, but their mucosal absorption is inferior to that of the upper nasal cavity. Upper nasal administration provides good tolerability, rapid and efficient drug absorption, and improved bioavailability.

[0007] Therefore, it is necessary to provide a pharmaceutical formulation that can be administered via nasal administration to treat migraines. Summary of the Invention

[0008] Based on this, the purpose of this application includes providing a pharmaceutical solution composition that can be used for nasal administration to treat migraines, as well as a method for preparing the pharmaceutical solution composition and a nasal spray.

[0009] The technical solution of this application includes the following:

[0010] A pharmaceutical solution composition comprising: a pharmaceutical active ingredient, a pH adjuster, an osmotic pressure adjuster, and water;

[0011] The active pharmaceutical ingredient is rizatriptan or a pharmaceutically acceptable salt thereof;

[0012] The pH adjuster is used to adjust the pH of the drug solution composition to 4.0–7.0;

[0013] The osmotic pressure regulator is used to adjust the osmotic pressure of the drug solution composition to 280–350 mOsm / kg.

[0014] In one embodiment, by weight, every 100 parts of the pharmaceutical solution composition comprises 0.5 to 5.5 parts of the active pharmaceutical ingredient, 0.001 to 0.05 parts of the pH adjuster, and 0.5 to 8 parts of the osmotic pressure adjuster.

[0015] In one embodiment, the pH adjuster comprises an acid and an ion buffer pair, wherein the acid comprises at least one selected from hydrochloric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, ascorbic acid, and acetic acid, and the ion buffer pair comprises at least one selected from phosphate-phosphate buffer pair, acetate-acetate buffer pair, phosphate-citrate buffer pair, and tartaric acid-tartrate buffer pair; and / or,

[0016] The osmotic pressure regulator includes at least one of glycerol, glucose, dextran, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and zinc chloride.

[0017] In one embodiment, the pharmaceutical solution composition further includes a preservative; optionally, the preservative includes at least one selected from benzalkonium chloride, benzyl chloride, benzoic acid, sodium benzoate, benzyl alcohol, bromonitrobenzene glycol, trimethylammonium bromophthalate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, cetylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, xylenephenol, cresol, hexacodyl, imidureus, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, sodium propionate, sorbic acid, and potassium sorbate.

[0018] In one embodiment, the preservative is included in every 100 parts by weight of the pharmaceutical solution composition.

[0019] In one embodiment, the drug solution composition satisfies at least one of the following characteristics:

[0020] (1) The pH of the drug solution composition is 5.0 to 7.0;

[0021] (2) The pH adjuster includes at least one of hydrochloric acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate;

[0022] (3) The osmotic pressure regulator is glycerol or sodium chloride.

[0023] In one embodiment, when the osmotic pressure regulator is glycerol, the drug solution composition comprises 0.25 to 3.0 parts by weight per 100 parts of the drug solution composition.

[0024] When the osmotic pressure regulator is sodium chloride, the osmotic pressure regulator comprises 0.2 to 0.9 parts by weight per 100 parts of the drug solution composition.

[0025] In one embodiment, the drug solution composition further includes an absorption enhancer;

[0026] Optionally, the absorption enhancer includes at least one of dodecyl-β-D-maltodextrin, tetradecyl-β-D-maltodextrin, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate.

[0027] A method for preparing the drug solution composition described above includes the following steps:

[0028] The active pharmaceutical ingredient and the water are mixed to obtain a first solution;

[0029] The osmotic pressure of the first solution is adjusted to 280–350 mOsm / kg using the osmotic pressure regulator to obtain the second solution;

[0030] The pH of the second solution is adjusted to 4.0–7.0 using the pH adjuster.

[0031] A nasal spray comprising the pharmaceutical solution composition described above.

[0032] In one embodiment, the delivery volume of the nasal spray is 100–200 μL; and / or,

[0033] In the delivery of the nasal spray, the effective delivery amount of the active pharmaceutical ingredient is 5–55 mg / spray.

[0034] The use of the above-described drug solution composition or nasal spray in the preparation of a drug for treating migraines.

[0035] The above description is only an overview of the technical solution of this application. In order to better understand the technical means of this application and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this application more obvious and understandable, the following are specific embodiments of this application. Attached Figure Description

[0036] To more clearly illustrate the technical solutions of this application, the accompanying drawings used in this application will be briefly described below. Obviously, the drawings described below are merely some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without any creative effort.

[0037] Figure 1 shows the plasma concentration-time curves of rizatriptan in SD rats after different administration methods (n=4, different administration methods);

[0038] Figure 2 shows the plasma concentration-time curves of rizatriptan in SD rats after treatment with different drug concentrations (n=4, different drug doses);

[0039] Figure 3 shows the comparison of the plasma rizatriptan concentration-time curves in SD rats after different administration methods (n=4, different dosages). Detailed Implementation

[0040] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0042] the term

[0043] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0044] The term "and / or" as used herein includes any one of two or more related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations encompass any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," or "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0045] In this document, terms such as "preferred," "better," and "more preferred" are merely descriptions of implementation methods or examples that achieve better results, and should be understood as not constituting a limitation on the scope of protection of this application.

[0046] In this application, terms such as "further," "even more," and "particularly" are used for descriptive purposes and to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0047] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0048] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, optional numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0049] To address the problem that migraine sufferers cannot quickly relieve their symptoms with oral medication during the acute phase of an attack, this application provides a drug solution composition that can be used for nasal administration to treat migraines. This solution composition has a faster therapeutic effect when absorbed through the nose, and it is simple in composition, easy to prepare, and has stronger stability.

[0050] One embodiment of the pharmaceutical solution composition of this application includes: an active pharmaceutical ingredient, a pH adjuster, an osmotic pressure adjuster, and water;

[0051] The active pharmaceutical ingredient is rizatriptan or a pharmaceutically acceptable salt thereof;

[0052] pH adjusters are used to adjust the pH of drug solution compositions to 4.0–7.0;

[0053] Osmotic pressure regulators are used to adjust the osmotic pressure of drug solution compositions to 280–350 mOsm / kg.

[0054] The drug solution composition of the present application embodiment has a simpler composition, stronger stability, and a good migraine treatment effect.

[0055] The drug solution composition of this application embodiment has a simpler component ratio, including the active pharmaceutical ingredient, pH adjuster, osmotic pressure adjuster and water, wherein the pH adjuster is used to adjust the pH of the drug solution composition to 4.0 to 7.0; the osmotic pressure adjuster is used to adjust the osmotic pressure of the drug solution composition to 280 to 350 mOsm / kg, thereby achieving better stability and representing a significant improvement over the prior art.

[0056] Compared to marketed rizatriptan benzoate formulations, the drug solution composition and nasal spray of this application can be rapidly absorbed into the bloodstream through the nasal mucosa by nasal spray administration. Food has no effect on the absorption of this product, which can help patients cope with migraine attacks in a timely manner, and thus be better used for the treatment of acute migraine attacks.

[0057] In this article, "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0058] In this document, "pharmaceutically acceptable salt" refers to the salt of the compounds of this application, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this application, with a specific substituent. When the compounds of this application contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this application contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of this application contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt. Pharmaceutically acceptable salts of this application can be synthesized from parent compounds containing acid radicals or bases using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of both. These pharmaceutically acceptable salts can be used to improve the physicochemical properties of drugs (such as solubility and stability) to suit storage, formulation, or clinical use needs. These salts do not alter the pharmacological action of the drug, but may affect its pharmacokinetic properties.

[0059] In one embodiment, the active pharmaceutical ingredient is the benzoate of rizatriptan, also known as rizatriptan benzoate.

[0060] In one embodiment, by weight, every 100 parts of the drug solution composition includes 0.5 to 5.5 parts of the active pharmaceutical ingredient, 0.001 to 0.05 parts of the pH adjuster, and 0.5 to 8 parts of the osmotic pressure adjuster.

[0061] In one embodiment, the pH adjuster comprises an acid and an ion buffer pair, wherein the acid comprises at least one selected from hydrochloric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, ascorbic acid, and acetic acid, and the ion buffer pair comprises at least one selected from phosphate-phosphate buffer pair, acetate-acetate buffer pair, phosphate-citrate buffer pair, and tartaric acid-tartrate buffer pair; and / or,

[0062] Osmotic pressure regulators include at least one of the following: glycerol, glucose, dextran, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and zinc chloride.

[0063] In one embodiment, the pharmaceutical solution composition further includes a preservative; optionally, the preservative includes at least one selected from benzalkonium chloride, benzyl chloride, benzoic acid, sodium benzoate, benzyl alcohol, bromonitrobenzene glycol, trimethylammonium bromophthalate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, cetylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, hexadiazine, imidureus, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, sodium propionate, sorbic acid, and potassium sorbate.

[0064] In one embodiment, the pharmaceutical solution composition comprises 0.005 to 0.03 parts by weight of preservative per 100 parts.

[0065] In one embodiment, the drug solution composition satisfies at least one of the following characteristics:

[0066] (1) The pH of the drug solution composition is 5.0 to 7.0;

[0067] (2) The pH adjuster includes at least one of hydrochloric acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate;

[0068] (3) The osmotic pressure regulator is glycerol or sodium chloride.

[0069] In one embodiment, when the osmotic pressure regulator is glycerol, the drug solution composition includes 0.25 to 3 parts by weight per 100 parts of the drug solution composition.

[0070] When the osmotic pressure regulator is sodium chloride, the composition comprises 0.2 to 0.9 parts by weight per 100 parts of the drug solution composition.

[0071] In one embodiment, the drug solution composition further includes an absorption enhancer;

[0072] Optionally, the absorption enhancer includes at least one of dodecyl-β-D-maltodextrin, tetradecyl-β-D-maltodextrin, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate.

[0073] In one embodiment, the absorption enhancer is dodecyl-β-D-maltodextrin.

[0074] A method for preparing the above-described pharmaceutical solution composition includes the following steps:

[0075] The active pharmaceutical ingredient is mixed with water to obtain the first solution;

[0076] The osmotic pressure of the first solution was adjusted to 280–350 mOsm / kg using an osmotic pressure regulator to obtain the second solution;

[0077] Adjust the pH of the second solution to 4.0–7.0 using a pH adjuster.

[0078] Understandably, in a given formulation, the osmotic pressure and pH value are within a predictable range. In actual preparation, the components can be directly mixed according to a suitable ratio, and then water can be added to a fixed volume to obtain a drug solution composition with a pH of 4.0 to 7.0 and an osmotic pressure of 280 to 350 mOsm / kg.

[0079] In one embodiment, the formulation of the determined drug solution composition is as follows: by weight, every 100 parts of the drug solution composition includes 0.5 to 5.5 parts of active pharmaceutical ingredient, 0.001 to 0.05 parts of pH adjuster, 0.5 to 8 parts of osmotic pressure adjuster, 0 to 0.03 parts of preservative, and 0 to 0.5 parts of absorption enhancer; wherein the weight percentage of the active pharmaceutical ingredient can be selected from 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, etc. The weight percentages of pH adjusters can be selected from 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, etc.; the weight percentages of osmotic pressure adjusters can be selected from 0.5, 1, 2, 3, 4, 5, 6, 7, 8, etc.; the weight percentages of preservatives can be selected from 0, 0.005, 0.01, 0.02, 0.03, etc.; and the weight percentages of absorption promoters can be selected from 0, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, etc.

[0080] In one embodiment, the preparation method of the drug solution composition includes the following steps: mixing 0.5-5.5g of active pharmaceutical ingredient, 0.5-8g of osmotic pressure regulator and a portion of water, optionally adding an aqueous solution of preservative (containing 0.005-0.03g of preservative) and mixing, then adding 0.001-0.05g of pH regulator and mixing, and finally adding the remaining water until the total amount is 100g.

[0081] A nasal spray comprising the pharmaceutical solution composition described above.

[0082] In one embodiment, the delivery volume of the nasal spray is 100–200 μL; and / or,

[0083] In nasal spray delivery, the effective delivery amount of the active pharmaceutical ingredient is 5–55 mg / spray.

[0084] The use of the above-described pharmaceutical solution composition or nasal spray in the preparation of a medication for treating migraines. Further, the medication is used during an acute migraine attack.

[0085] The drug solution composition of this application has a simpler ingredient ratio and better stability, representing a significant improvement over existing technologies. Compared to marketed rizatriptan benzoate formulations, the drug solution composition and nasal spray of this application, administered via nasal spray, can be rapidly absorbed into the bloodstream through the nasal mucosa. Food has no effect on the absorption of this product, which can help patients cope with migraine attacks in a timely manner, thus making it better suited for the treatment of acute migraine attacks.

[0086] The following are some specific examples.

[0087] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0088] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0089] Example 1

[0090] This embodiment provides a nasal spray according to the present application, and the preparation method is as follows:

[0091] (1) Prepare the raw materials for each preparation according to Table 1.

[0092] Table 1 Raw Material Formula

[0093] In Table 1, “——” means that the substance is not added, and “to make up to 100g” means that the weight of each preparation is calculated according to the ingredients listed, and water is added to the portion less than 100g until the total weight of the preparation is 100g; “——” and “to make up to 100g” have the same meaning when they appear in other tables below.

[0094] (2) Weigh each raw material according to the formula in Table 1 and prepare the corresponding formulations (Formulation 1 to Formulation 7). The general steps are as follows: Use a glass container to prepare the formulation. Dissolve benzalkonium chloride in an appropriate amount of water (about 6g) to obtain a benzalkonium chloride solution. Stir and dissolve the osmotic pressure regulator, rizatriptan benzoate, benzalkonium chloride solution and an appropriate amount of water (about 90g), and measure the osmotic pressure to ensure it is qualified. Then add pH regulator to adjust the pH to 6.0. After adjustment, the weight is about 100g. If it is insufficient, add a small amount of water until the total weight is 100g.

[0095] The results of pH value, osmotic pressure and active ingredient content of each preparation are shown in Table 2.

[0096] Table 2. Detection results of each formulation

[0097] (3) Fill formulations 1 to 7 into different nasal spray devices and cap them to obtain the final product.

[0098] Example 2

[0099] The dehydration properties of formulations 3, 4, and 5 from Example 1 were investigated. Samples were tested under accelerated conditions (40°C, 25% RCH), and weights were recorded at each time point. Samples were then tested under stability conditions, and the results were recorded until the stability test was completed. The dehydration rate was calculated as follows: Dehydration rate (%) = (Weight at 0 days - Weight at test time points) / Weight at 0 days × 100%. The average dehydration rate of rizatrope benzoate nasal spray for the same device combination at each time point was calculated. The experimental results under accelerated conditions are shown in the table below. In the table, "d" is an abbreviation for "day," representing the number of days.

[0100] Table 3. Results of water loss rate for different formulations

[0101] The results showed that there was no significant weight change in any of the formulations in the first 59 days, and there was no significant difference in the water loss rate among the formulations.

[0102] Example 3

[0103] This embodiment provides a nasal spray according to the present application, and the preparation method is as follows:

[0104] (1) Prepare the raw materials for each preparation according to Table 4.

[0105] Table 4 Raw Material Formula

[0106] (2) Weigh each raw material according to the formula in Table 4 and prepare the corresponding formulations (Formulation 8, Formulation 9). The general steps are as follows: Use a glass container for preparation. Dissolve benzalkonium chloride in an appropriate amount of water (about 6g) to obtain benzalkonium chloride solution. Stir and dissolve the osmotic pressure regulator, rizatriptan benzoate, benzalkonium chloride solution and an appropriate amount of water (about 90g), and measure the osmotic pressure to be qualified. Then add pH regulator to adjust the pH to 5.5-6.5. After adjustment, the weight is about 100g. If it is insufficient, add a small amount of water until the total weight is 100g.

[0107] (3) Fill formulations 8 and 9 into different nasal spray devices and cap them to obtain the final product.

[0108] Example 4

[0109] The stability results of the nasal spray prepared in Example 4 after 2 months of storage under accelerated conditions (40±2℃, 25±5RH%) and long-term conditions (25±2℃, 40±5RH%) are shown in the table below. The nasal spray showed good stability after 2 months of storage, with pH and osmolality remaining essentially stable.

[0110] Table 5. Results of stability studies for formulation 8

[0111] Table 6. Results of stability studies for formulation 9

[0112] Example 5

[0113] This example provides a nasal spray according to this application. The preparation method is as follows:

[0114] Prepare the raw materials for each formulation according to Table 7.

[0115] Table 7 Raw Material Formula

[0116] (2) Weigh each raw material according to the formula in Table 7 and prepare the corresponding formulations (Formulations 10-12). The general steps are as follows: Use a glass container for preparation. Dissolve benzalkonium chloride in an appropriate amount of water (about 6g) to obtain benzalkonium chloride solution. Stir and dissolve the osmotic pressure regulator, rizatriptan benzoate, dodecyl-β-D-maltodextrin (DDM), benzalkonium chloride solution and an appropriate amount of water (about 90g), and measure the osmotic pressure to be qualified. Then add pH regulator (0.3M hydrochloric acid solution) to adjust the pH to 6.0. After adjustment, the volume is about 100g. If it is insufficient, add a small amount of water until the total volume is 100g.

[0117] Example 6

[0118] According to Example 5, the effects of different absorption enhancers on pharmacokinetics in rats were investigated using dodecyl-β-D-maltose as an absorption enhancer.

[0119] Pharmacokinetic studies have shown that intranasal administration of nasal spray formulations with different contents of dodecyl-β-D-maltose resulted in varying plasma T values ​​of rizatriptan in different animal groups. max C max AUC last No significant differences were observed. Based on the principle of using excipients sparingly, it was ultimately determined that dodecyl-β-D-maltodextrin was not required in the formulation. Specific pharmacokinetic results are shown in Table 8.

[0120] Table 8. Main pharmacokinetic parameters of rizatriptan in rat plasma of different DDM contents - intranasal administration groups (N=4)

[0121] Example 7

[0122] This embodiment provides a nasal spray according to the present application, and the preparation method is as follows:

[0123] (1) Prepare the raw materials for each preparation according to Table 9.

[0124] Table 9 Raw Material Formula

[0125] (2) Weigh each raw material according to the formula in Table 9 and prepare the corresponding formulations (Formulations 13-15). The general steps are as follows: Use a glass container for preparation. Dissolve benzalkonium chloride in an appropriate amount of water (about 6g) to obtain a benzalkonium chloride solution. Stir and dissolve the osmotic pressure regulator, rizatriptan benzoate, benzalkonium chloride solution and an appropriate amount of water (about 90g), and measure the osmotic pressure to be qualified. Then add pH regulator (0.3M hydrochloric acid solution) to adjust the pH to 6.0. After adjustment, the volume is about 100g. If it is insufficient, add a small amount of water until the total volume is 100g.

[0126] Example 8

[0127] This application conducted in vivo pharmacokinetic validation of formulations 13-15 from Example 7, and the experimental protocol is as follows:

[0128] (1) Animal grouping and administration

[0129] Animals were grouped according to Table 10. Rats in the NA, NB, NC, and ND groups were anesthetized before administration. The animals were weighed and anesthetized by intraperitoneal injection of 7% chloral hydrate at a dose of 0.3-0.4 mL / 100g (approximately 350 mg / kg). Rats in the OC and OD groups were administered the drug while the animals were awake.

[0130] At the corresponding time point, 0.3 mL of whole blood was collected from each group into blood collection tubes containing heparin sodium anticoagulation. Plasma was separated from the blood within 1 hour after collection. The blood samples were centrifuged at 4°C and 1600g for 10 minutes, and the supernatant was collected.

[0131] Table 10

[0132] In Table 10, except for the ND group and OF group, the animals in the other groups were fasted for 12 hours before administration, but water was allowed.

[0133] (2) Animal experiments

[0134] The rizatriptan benzoate solution was prepared as follows: 8 mg of rizatriptan benzoate was weighed into a 20 ml volumetric flask, physiological saline was added to the mark, and the solution was dissolved. This solution was used in the oral gavage administration group of rats.

[0135] Nasal administration group: Before administration, the rats were weighed and anesthetized by intraperitoneal injection of 7% chloral hydrate (anesthetic dose: 0.35 mL / 100 g). After anesthesia, the rats were tagged with ear tags and their serial numbers were recorded. The rats were turned over, held in the hand, and their heads were fixed. The administration tube was inserted into the rat's nasal cavity about 1.3 cm to administer the drug, with an administration volume of 50 μL.

[0136] In the gavage administration group: Hold the gavage syringe in your right hand and grasp the skin of the rat's neck with your left hand, so that the rat's head, neck and trunk are in a straight line. Insert the gavage syringe into the corner of the mouth, press down on the tongue and the palate, and gently push it inward. Slowly insert the gavage syringe along the posterior pharyngeal wall into the esophagus. After aspirating the syringe and finding no air backflow, inject the drug solution (the gavage volume is 0.5 mL, and the drug solution should be swirled and evenly dispersed before gavage).

[0137] (3) Experimental Results

[0138] Table 11 shows the main pharmacokinetic parameters of rizatriptan in rat plasma under different administration routes. According to Table 11, at the same dose of 1 mg / kg, nasal administration of rizatriptan to rats resulted in a shorter time to peak concentration compared to oral administration, and a higher peak plasma concentration (C0). max and plasma exposure AUC last The relative bioavailability of nasal administration is higher, at approximately 612%, a conclusion further supported by Figure 1.

[0139] Table 11. Major pharmacokinetic parameters of rizatriptan in rat plasma under different administration routes (n=4, different administration routes)

[0140] Table 12 shows the main pharmacokinetic parameters of rizatriptan in rat plasma under different administration routes. According to Table 12, the dose-exposure relationship of rizatriptan benzoate administered intranasally is clear and linear, specifically, as the dose increases, T... max Almost unchanged, C max and AUC last The above conclusion can also be verified by increasing the dosage proportionally.

[0141] Table 12. Main pharmacokinetic parameters of rizatriptan in rat plasma under different routes of administration (n=4, different dosages)

[0142] Table 13 shows the main pharmacokinetic parameters of rizatriptan in rat plasma. According to Table 13, oral administration of rizatriptan benzoate showed a significant food effect, with the peak drug concentration time Ts in rats after ingestion being [not specified]. max It will prolong the time it takes for the drug to reach its peak concentration (C) in plasma. max The effect of nasal administration of rizatriptan benzoate on food was not significant; the time to peak drug concentration after food intake was T0.max and peak concentration C in plasma max There were no significant changes, and the above conclusions can also be verified by Figure 3.

[0143] Table 13. Main pharmacokinetic parameters of rizatriptan in rat plasma (n=4, fasting and non-fasting)

[0144] All references to this application are incorporated herein by reference as if each document were individually incorporated herein by reference. Unless they conflict with the purpose and / or technical solution of this application, all cited references are incorporated herein by reference in their entirety and for all purposes. When references are cited in this application, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. Examples and preferred embodiments of the cited technical features may also be incorporated herein by reference, but only to the extent that they enable the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptably to the description in this application.

[0145] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0146] The embodiments described above merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A pharmaceutical solution composition, characterized in that, The drug solution composition comprises: a pharmaceutical active ingredient, a pH adjuster, an osmotic pressure adjuster, and water; The active pharmaceutical ingredient is rizatriptan or a pharmaceutically acceptable salt thereof; The pH adjuster is used to adjust the pH of the drug solution composition to 4.0–7.0; The osmotic pressure regulator is used to adjust the osmotic pressure of the drug solution composition to 280–350 mOsm / kg.

2. The pharmaceutical solution composition according to claim 1, characterized in that, By weight, each 100 parts of the pharmaceutical solution composition comprises 0.5 to 5.5 parts of the active pharmaceutical ingredient, 0.001 to 0.05 parts of the pH adjuster, and 0.5 to 8 parts of the osmotic pressure adjuster.

3. The pharmaceutical solution composition according to claim 1 or 2, characterized in that, It satisfies at least one of the following characteristics: (1) The pH adjuster includes an acid and an ion buffer pair, wherein the acid includes at least one of hydrochloric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, ascorbic acid and acetic acid, and the ion buffer pair includes at least one of phosphate-phosphate buffer pair, acetic acid-acetate buffer pair, phosphate-citrate buffer pair and tartaric acid-tartrate buffer pair. (2) The osmotic pressure regulator includes at least one of glycerol, glucose, dextran, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and zinc chloride.

4. The pharmaceutical solution composition according to any one of claims 1-3, characterized in that, The drug solution composition also includes a preservative.

5. The pharmaceutical solution composition according to claim 4, characterized in that, The preservatives include at least one of benzalkonium chloride, benzyl chloride, benzoic acid, sodium benzoate, benzyl alcohol, bromonitrobenzene glycol, bromobrown trimethylammonium, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, cetylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, hexadiazine, imidureus, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, sodium propionate, sorbic acid, and potassium sorbate.

6. The pharmaceutical solution composition according to claim 4 or 5, characterized in that, The preservative is included in every 100 parts by weight of the pharmaceutical solution composition.

7. The pharmaceutical solution composition according to any one of claims 1-6, characterized in that, It satisfies at least one of the following characteristics: (1) The pH of the drug solution composition is 5.0 to 7.0; (2) The pH adjuster includes at least one of hydrochloric acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; (3) The osmotic pressure regulator is glycerol or sodium chloride.

8. The pharmaceutical solution composition according to claim 7, characterized in that, When the osmotic pressure regulator is glycerol, the osmotic pressure regulator is 0.25 to 3 parts by weight per 100 parts of the drug solution composition; When the osmotic pressure regulator is sodium chloride, the osmotic pressure regulator comprises 0.2 to 0.9 parts by weight per 100 parts of the drug solution composition.

9. The pharmaceutical solution composition according to any one of claims 1-8, characterized in that, The drug solution composition also includes an absorption enhancer.

10. The pharmaceutical solution composition according to claim 9, characterized in that, The absorption enhancer includes at least one of dodecyl-β-D-maltodextrin, tetradecyl-β-D-maltodextrin, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate.

11. A method for preparing the pharmaceutical solution composition according to any one of claims 1-10, characterized in that, Includes the following steps: The active pharmaceutical ingredient and the water are mixed to obtain a first solution; The osmotic pressure of the first solution is adjusted to 280–350 mOsm / kg using the osmotic pressure regulator to obtain the second solution; The pH of the second solution is adjusted to 4.0–7.0 using the pH adjuster.

12. A nasal spray containing rizatriptan benzoate, characterized in that, Includes the pharmaceutical solution composition according to any one of claims 1-10.

13. The nasal spray according to claim 12, characterized in that, The delivery volume of the nasal spray is 100–200 μL.

14. The nasal spray according to claim 12 or 13, characterized in that, In the delivery of the nasal spray, the effective delivery amount of the active pharmaceutical ingredient is 5–55 mg / spray.

15. The use of a pharmaceutical solution composition according to any one of claims 1-10, or the use of a nasal spray according to claim 12 or 13 in the preparation of a medicament for treating migraines.

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