Medicine solution composition, preparation method thereof, nasal spray and application

Abstract

The invention relates to the technical field of biological medicine, in particular to a medicine solution composition, a preparation method thereof and a nasal spray. The pharmaceutical composition comprises active pharmaceutical ingredients, a pH regulator, an osmotic pressure regulator and water, the active pharmaceutical ingredient is rizatriptan or a salt thereof; the pH regulator is used for regulating the pH of the pharmaceutical composition to 4.0-7.0; and the osmotic pressure regulator is used for regulating the osmotic pressure of the pharmaceutical composition to 280-350mOsm / kg. The nasal spray can be used for rapidly relieving migraine in the acute stage, rapid analgesia is achieved, the drug stability is good, the nasal spray is not affected by food, the components are simple and effective, and the nasal spray has commercial production value.

Description

Technical Field

[0001] The present application relates to the field of biomedicine technology, and in particular to a drug solution composition and a preparation method thereof, a nasal spray and applications thereof. Background Art

[0002] Migraine is a common neurological disease, characterized by recurrent, mostly unilateral, moderate to severe throbbing headaches, often accompanied by nausea, vomiting, photophobia, and phonophobia. Its pathogenesis is still unclear. It is generally believed that migraine patients suffer from a complex interaction between multiple susceptibility genes and between susceptibility genes and environmental factors, which leads to a dysfunctional balance of excitation / inhibition in the central nervous system, and the trigeminovascular pathway is repeatedly activated and sensitized, leading to headache attacks and other accompanying symptoms. The greatest need for the treatment of acute migraine attacks is rapid analgesia, reduction of migraine recurrence, and rapid recovery of patients to normal life.

[0003] Rizatriptan is a specific drug for the treatment of migraine. It can selectively constrict the cerebral vasculature and has a weak effect on peripheral blood vessels, so it has fewer side effects. At present, the formulation types of marketed drugs with rizatriptan as the active ingredient are mainly oral preparations, including oral tablets and oral mucosal preparations. Among them, oral tablets have two specifications of 5 mg and 10 mg, including ordinary oral tablets and orally disintegrating tablets. Oral preparations generally have the defect of being easily affected by food. When taken with food, the peak time of the active ingredients of the drug will be extended beyond expectations, and the onset of migraine is unpredictable. Therefore, the therapeutic effect of oral preparations on the acute stage of migraine is not ideal. In addition, the symptoms of nausea, vomiting, etc. accompanied by migraine attacks will aggravate the problem of slow onset of oral preparations.

[0004] For the acute treatment of migraine, nasal administration is a more attractive alternative route than oral administration, with advantages such as rapid onset of action, no first-pass effect, high bioavailability, convenient administration, and improved patient compliance. Most nasal sprays reported so far are administered to the lower nasal cavity, but its mucosal absorption function is not as good as that of the upper nasal cavity. Administration to the upper nasal cavity can provide good tolerability, rapid and efficient drug absorption, and improved bioavailability.

[0005] Based on this, it is necessary to provide a drug preparation that can be administered nasally to treat migraine. Summary of the invention

[0006] Based on this, the purpose of the present application includes providing a drug solution composition that can be used for nasal administration to treat migraine. The drug solution composition has simpler ingredients, stronger stability, and has a good migraine treatment effect. A preparation method and nasal spray of the drug solution composition are also provided.

[0007] The technical solution of this application includes the following contents:

[0008] A pharmaceutical solution composition, comprising: a pharmaceutical active ingredient, a pH regulator, an osmotic pressure regulator and water;

[0009] The active ingredient of the medicine is rizatriptan or a pharmaceutically acceptable salt thereof;

[0010] The pH regulator is used to adjust the pH of the pharmaceutical solution composition to 4.0-7.0;

[0011] The osmotic pressure regulator is used to adjust the osmotic pressure of the drug solution composition to 280-350 mOsm / kg.

[0012] In one embodiment, in parts by weight, every 100 parts of the pharmaceutical solution composition comprises 0.5-5.5 parts of the pharmaceutical active ingredient, 0.001-0.05 parts of the pH regulator, and 0.5-8 parts of the osmotic pressure regulator.

[0013] In one embodiment, the pH adjuster comprises an acid and an ion buffer pair, the acid comprises 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 comprises at least one of a phosphate-phosphate buffer pair, an acetic acid-acetate buffer pair, a phosphate-citrate buffer pair and a tartaric acid-tartrate buffer pair; and / or,

[0014] The osmotic pressure regulator includes at least one of glycerol, glucose, dextran, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and zinc chloride.

[0015] In one embodiment, the pharmaceutical solution composition further includes a preservative; optionally, the preservative includes at least one of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, sodium propionate, sorbic acid and potassium sorbate.

[0016] In one embodiment, the preservative is present in an amount of 0.005-0.03 parts by weight per 100 parts by weight of the pharmaceutical solution composition.

[0017] In one embodiment, the pharmaceutical solution composition satisfies at least one of the following characteristics:

[0018] (1) The pH of the drug solution composition is 5.0-7.0;

[0019] (2) The pH adjuster includes at least one of hydrochloric acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate and potassium dihydrogen phosphate;

[0020] (3) The osmotic pressure regulator is glycerol or sodium chloride.

[0021] In one embodiment, in the pharmaceutical solution composition, when the osmotic pressure regulator is glycerol, the osmotic pressure regulator is included in 0.25 to 3.0 parts by weight per 100 parts of the pharmaceutical solution composition;

[0022] When the osmotic pressure regulator is sodium chloride, the osmotic pressure regulator is contained in 0.2 to 0.9 parts by weight per 100 parts of the pharmaceutical solution composition.

[0023] In one embodiment, the pharmaceutical solution composition further includes an absorption enhancer;

[0024] Optionally, the absorption enhancer includes at least one of dodecyl-β-D-maltoside, tetradecyl-β-D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate.

[0025] A method for preparing the above-mentioned pharmaceutical solution composition comprises the following steps:

[0026] The pharmaceutical active ingredient and the water are mixed to obtain a first solution;

[0027] The osmotic pressure of the first solution is adjusted to 280-350 mOsm / kg using the osmotic pressure regulator to obtain a second solution;

[0028] The pH of the second solution is adjusted to 4.0 to 7.0 using the pH adjuster.

[0029] A nasal spray comprises the above-mentioned drug solution composition.

[0030] In one embodiment, the delivery volume of the nasal spray is 100-200 μL; and / or,

[0031] In the delivery of the nasal spray, the effective delivery amount of the active pharmaceutical ingredient is 5-55 mg / spray.

[0032] A use of the above-mentioned drug solution composition or nasal spray in the preparation of a drug for treating migraine.

[0033] The pharmaceutical solution composition of the present application has a simpler composition ratio, including a pharmaceutical active ingredient, a pH regulator, an osmotic pressure regulator and water, wherein the pH regulator is used to adjust the pH of the pharmaceutical solution composition to 4.0-7.0; the osmotic pressure regulator is used to adjust the osmotic pressure of the pharmaceutical solution composition to 280-350mOsm / kg, thereby achieving better stability and making significant progress compared to the prior art.

[0034] Compared with the marketed rizatriptan benzoate preparation, the drug solution composition and nasal spray of the present application can be rapidly absorbed into the blood through the nasal mucosa by nasal spray administration, and food has no effect on the absorption of the product, which can help patients respond to migraine attacks in a timely manner, thereby better being used for the treatment of acute migraine. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0036] Figure 1 The blood concentration-time curve of rizatriptan in the plasma of SD rats after different administration methods (n=4, different administration methods);

[0037] Figure 2 The blood concentration-time curve of rizatriptan in the plasma of SD rats treated with different drug concentrations (n=4, different drug doses);

[0038] Figure 3 The results are compared on the changes of plasma rizatriptan concentration-time curves in SD rats treated with different administration methods due to the influence of food (n=4, different administration doses). DETAILED DESCRIPTION

[0039] The present application will be further described below in conjunction with the embodiments and examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. In addition, it should be understood that after reading the content taught in the present application, those skilled in the art may make various changes or modifications to the present application, and these equivalent forms also fall within the protection scope of the claims attached to the present application.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0041] the term

[0042] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0043] The term "and / or" used in this article includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of 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, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0044] Herein, "preferred", "preferable", "better", etc. are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of this application.

[0045] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0046] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0047] In this application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges included therein.

[0048] In order to solve the problem that migraine patients cannot get rapid relief through oral medications during the acute phase of the disease, the present application provides a drug solution composition that can be used for nasal administration to treat migraine. The solution composition has a faster therapeutic effect through nasal absorption, and has simple ingredients, easy preparation, and greater stability.

[0049] The pharmaceutical solution composition of one embodiment of the present application comprises: a pharmaceutical active ingredient, a pH regulator, an osmotic pressure regulator and water;

[0050] The active ingredient of the drug is rizatriptan or a pharmaceutically acceptable salt thereof;

[0051] The pH regulator is used to adjust the pH of the pharmaceutical solution composition to 4.0 to 7.0;

[0052] The osmotic pressure regulator is used to adjust the osmotic pressure of the drug solution composition to 280-350 mOsm / kg.

[0053] As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0054] As used herein, "pharmaceutically acceptable salts" refer to salts of compounds of the present application, prepared from compounds with specific substituents found in the present application and relatively non-toxic acids or bases. When the compounds of the present 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 the present 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, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present application contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt. The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. The above-mentioned pharmaceutically acceptable salts can be used to improve the physicochemical properties (such as solubility, stability, etc.) of the drug to meet the needs of storage, preparation manufacturing or clinical medication. These salts will not change the pharmacological effects of the drug, but may affect its pharmacokinetic properties.

[0055] In one embodiment, the pharmaceutically active ingredient is the benzoate salt of rizatriptan, also known as rizatriptan benzoate.

[0056] In one embodiment, by weight, every 100 parts of the pharmaceutical solution composition includes 0.5-5.5 parts of the active pharmaceutical ingredient, 0.001-0.05 parts of the pH regulator, and 0.5-8 parts of the osmotic pressure regulator.

[0057] In one embodiment, the pH adjuster comprises an acid and an ion buffer pair, the acid comprises 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 comprises at least one of a phosphate-phosphate buffer pair, an acetic acid-acetate buffer pair, a phosphate-citrate buffer pair and a tartaric acid-tartrate buffer pair; and / or,

[0058] The osmotic pressure regulator includes at least one of glycerol, glucose, dextran, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and zinc chloride.

[0059] In one embodiment, the drug solution composition also includes a preservative; optionally, the preservative includes at least one of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, sodium propionate, sorbic acid and potassium sorbate.

[0060] In one embodiment, by weight, every 100 parts of the pharmaceutical solution composition comprises 0.005-0.03 parts of preservative.

[0061] In one embodiment, the pharmaceutical solution composition satisfies at least one of the following characteristics:

[0062] (1) The pH of the drug solution composition is 5.0 to 7.0;

[0063] (2) the pH adjusting agent includes at least one of hydrochloric acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate and potassium dihydrogen phosphate;

[0064] (3) The osmotic pressure regulator is glycerol or sodium chloride.

[0065] In one embodiment, in the pharmaceutical solution composition, when the osmotic pressure regulator is glycerol, the osmotic pressure regulator is included in 0.25 to 3 parts by weight per 100 parts of the pharmaceutical solution composition;

[0066] When the osmotic pressure regulator is sodium chloride, the osmotic pressure regulator is included in 0.2 to 0.9 parts by weight per 100 parts of the pharmaceutical solution composition.

[0067] In one embodiment, the pharmaceutical solution composition further includes an absorption enhancer;

[0068] Optionally, the absorption enhancer includes at least one of dodecyl-β-D-maltoside, tetradecyl-β-D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate.

[0069] In one embodiment, the absorption enhancer is dodecyl-β-D-maltoside.

[0070] A method for preparing the above pharmaceutical solution composition comprises the following steps:

[0071] The active pharmaceutical ingredient and water are mixed to obtain a first solution;

[0072] The osmotic pressure of the first solution is adjusted to 280-350 mOsm / kg using an osmotic pressure regulator to obtain a second solution;

[0073] The pH of the second solution is adjusted to 4.0 to 7.0 using a pH adjuster.

[0074] It can be understood that in the determined formula, the ranges of osmotic pressure and pH value are within the expected range. In actual preparation, the components can be directly mixed according to the appropriate ratio, and then water is added to a fixed volume to obtain a drug solution composition having a pH of 4.0-7.0 and an osmotic pressure of 280-350 mOsm / kg.

[0075] In one embodiment, the formula of the determined drug solution composition is as follows: in parts by weight, every 100 parts of the drug solution composition includes 0.5-5.5 parts of the active pharmaceutical ingredient, 0.001-0.05 parts of the pH regulator, 0.5-8 parts of the osmotic pressure regulator, 0-0.03 parts of the preservative and 0-0.5 parts of the absorption enhancer; wherein the weight parts 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 proportion of the pH regulator can be selected from 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, etc., the weight proportion of the osmotic pressure regulator can be selected from 0.5, 1, 2, 3, 4, 5, 6, 7, 8, etc., the weight proportion of the preservative can be selected from 0, 0.005, 0.01, 0.02, 0.03, etc., and the weight proportion of the absorption enhancer can be selected from 0, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, etc.

[0076] In one embodiment, the preparation method of the drug solution composition comprises the following steps: mixing 0.5-5.5 g of a drug active ingredient, 0.5-8 g of an osmotic pressure regulator and a portion of water, optionally adding an aqueous solution of a preservative (containing 0.005-0.03 g of a preservative) and mixing, then adding 0.001-0.05 g of a pH regulator and mixing, and finally adding the remaining water until the total amount is 100 g.

[0077] A nasal spray comprising the above pharmaceutical solution composition.

[0078] In one embodiment, the delivery volume of the nasal spray is 100-200 μL; and / or,

[0079] In the delivery of nasal sprays, the effective delivery amount of active drug ingredients is 5~55 mg / spray.

[0080] A use of the above pharmaceutical solution composition or nasal spray in the preparation of a drug for treating migraine. Further, the drug is used in the acute attack period of migraine.

[0081] The drug solution composition of the present application has a simpler composition ratio and better stability, and has made significant progress compared to the prior art. Compared with the marketed rizatriptan benzoate preparation, the drug solution composition and nasal spray of the present application can be quickly absorbed into the blood through the nasal mucosa by nasal spray administration, and food has no effect on the absorption of the product, which can help patients respond to migraine attacks in time, thereby better used for the treatment of acute migraine.

[0082] The following are some specific embodiments.

[0083] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0084] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0085] Example 1

[0086] This embodiment provides a nasal spray of the present application, and the preparation method is as follows:

[0087] (1) Prepare the raw materials for each preparation according to Table 1.

[0088] Table 1 Raw material formula

[0089]

[0090] In Table 1, “——” means that the substance is not added, and “make up to 100 g” means that water is added to the part less than 100 g of each preparation until the total weight of the preparation is 100 g according to the weight of the listed ingredients; “——” and “make up to 100 g” have the same meaning when appearing in other tables below.

[0091] (2) According to the formula in Table 1, each raw material was weighed and the corresponding preparations (Preparation 1 to Preparation 7) were prepared. The general steps were as follows: using a glass container for preparation, benzalkonium chloride was dissolved in an appropriate amount of water (about 6 g) to obtain a benzalkonium chloride solution; the osmotic pressure regulator, rizatriptan benzoate, benzalkonium chloride solution and an appropriate amount of water (about 90 g) were stirred and dissolved, and the osmotic pressure was measured to be qualified; then a pH regulator was added to adjust the pH to 6.0. After adjustment, the weight was about 100 g. If it was insufficient, a small amount of water was added until the total weight was 100 g.

[0092] The test results of pH value, osmotic pressure and active ingredient content of each preparation are shown in Table 2.

[0093] Table 2 Test results of each preparation

[0094]

[0095] (3) Fill Preparation 1 to Preparation 7 into different nasal spray devices respectively and cap them.

[0096] Example 2

[0097] The water loss of preparations 3, 4 and 5 of Example 1 was investigated. The samples were placed under accelerated conditions (40°C, 25 RCH%), and the weight was weighed and recorded at the same time point. The samples were placed under stability conditions and recorded until the stability test was completed. The water loss rate was calculated according to water loss rate (%) = (0d weight - weight at the time of investigation) / 0d weight × 100%. The average water loss rate of rizatriptolide benzoate nasal spray for the same device combination at each time node was calculated. The experimental results under accelerated conditions are shown in the following table. "d" in the table is an abbreviation for "day" and represents the number of days.

[0098] Table 3 Water loss results of different prescription preparations

[0099]

[0100] The results showed that there was no significant weight change in the first 59 days for each preparation sample, and there was no significant difference in the water loss rate of each preparation.

[0101] Example 3

[0102] This embodiment provides a nasal spray of the present application, and the preparation method is as follows:

[0103] (1) Prepare the raw materials for each preparation according to Table 4.

[0104] Table 4 Raw material formula

[0105]

[0106] (2) According to the formula in Table 4, each raw material was weighed and the corresponding preparations (Preparation 8, Preparation 9) were prepared. The general steps were as follows: using a glass container for preparation, benzalkonium chloride was dissolved in an appropriate amount of water (about 6 g) to obtain a benzalkonium chloride solution; the osmotic pressure regulator, rizatriptan benzoate, benzalkonium chloride solution and an appropriate amount of water (about 90 g) were stirred and dissolved, and the osmotic pressure was measured to be qualified; then a pH regulator was added to adjust the pH to 5.5-6.5. After adjustment, the weight was about 100 g. If it was insufficient, a small amount of water was added until the total weight was 100 g.

[0107] (3) Fill Preparation 8 and Preparation 9 into different nasal spray devices respectively and cap them.

[0108] Example 4

[0109] The stability results of the nasal spray prepared in Example 4 after being placed for 2 months under accelerated conditions (40±2°C, 25±5RH%) and long-term conditions (25±2°C, 40±5RH%) are shown in the following table. The nasal spray has good stability after being placed for 2 months, and the pH value and osmotic pressure molar concentration remain basically stable.

[0110] Table 5 Stability test results of preparation 8

[0111]

[0112] Table 6 Stability test results of preparation 9

[0113]

[0114] Example 5

[0115] This example provides a nasal spray of the present application. The preparation method is as follows:

[0116] Prepare the raw materials for each preparation according to Table 7.

[0117] Table 7 Raw material formula

[0118]

[0119] (2) According to the formula in Table 7, each raw material was weighed and the corresponding preparations (preparations 10 to 12) were prepared. The general steps were as follows: using a glass container for preparation, benzalkonium chloride was dissolved in an appropriate amount of water (about 6 g) to obtain a benzalkonium chloride solution; the osmotic pressure regulator, rizatriptan benzoate, dodecyl-β-D-maltoside (DDM), benzalkonium chloride solution and an appropriate amount of water (about 90 g) were stirred and dissolved, and the osmotic pressure was measured to be qualified; then a pH regulator (0.3 M hydrochloric acid solution) was added to adjust the pH to 6.0. After adjustment, the volume was about 100 g. If it was insufficient, a small amount of water was added until the total volume was 100 g.

[0120] Example 6

[0121] According to Example 5, dodecyl-β-D-maltoside was used as an absorption enhancer to investigate the effects of different absorption enhancers on the pharmacokinetics in rats.

[0122] Through the pharmacokinetic study, it was found that the T of rizatriptan in the plasma of each group of animals was significantly increased after nasal administration of nasal spray preparations with different contents of dodecyl-β-D-maltoside. max , Cmax , AUC last There is no significant difference. According to the principle of excipient application, it is necessary to use as little as possible, and finally it is determined that do not need to add dodecyl-β-D-maltoside in the prescription. The specific pharmacokinetic test results are shown in Table 8.

[0123] Table 8 Main pharmacokinetic parameters of rizatriptan in plasma of rats in different DDM content-nasal administration groups (N=4)

[0124]

[0125] Example 7

[0126] This embodiment provides a nasal spray of the present application, and the preparation method is as follows:

[0127] (1) Prepare the raw materials for each preparation according to Table 9.

[0128] Table 9 Raw material formula

[0129]

[0130] (2) According to the formula in Table 9, each raw material was weighed and the corresponding preparations (Preparations 13 to 15) were prepared. The general steps were as follows: using a glass container for preparation, benzalkonium chloride was dissolved in an appropriate amount of water (about 6 g) to obtain a benzalkonium chloride solution; the osmotic pressure regulator, rizatriptan benzoate, benzalkonium chloride solution and an appropriate amount of water (about 90 g) were stirred and dissolved, and the osmotic pressure was measured to be qualified; then a pH regulator (0.3 M hydrochloric acid solution) was added to adjust the pH to 6.0. After adjustment, the volume was about 100 g. If it was insufficient, a small amount of water was added until the total volume was 100 g.

[0131] Example 8

[0132] The present application conducted in vivo pharmacokinetic verification on preparations 13 to 15 of Example 7, and the experimental scheme is as follows:

[0133] (1) Animal grouping and drug administration

[0134] The 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 with 0.3-0.4 mL / 100 g (about 350 mg / kg) of 7% chloral hydrate injected intraperitoneally; while the OC and OD groups were administered with the animals awake.

[0135] At the corresponding time point, 0.3 mL of whole blood was collected from each group into a blood collection tube containing sodium heparin anticoagulation, and plasma was separated by centrifugation within 1 hour after collection. The blood samples were centrifuged at 4°C and 1600 g for 10 min, and the supernatant was collected.

[0136] Table 10

[0137]

[0138] In Table 10, except for the ND group and the OF group, the animals in the other groups were fasted from 12 hours before administration, but not water.

[0139] (2) Animal experiments

[0140] The steps for preparing the rizatriptan benzoate solution are as follows: weigh 8 mg of rizatriptan benzoate into a 20 ml volumetric flask, add physiological saline to the mark, and dissolve. The solution is used for the oral gavage administration group of rats.

[0141] Nasal administration group: Before administration, the rats were weighed and anesthetized with 7% chloral hydrate (anesthetic dose of 0.35 mL / 100 g) intraperitoneally. After anesthesia, ear tags were marked and the animal serial number was recorded. The rats were turned over, held in the hand, the rat heads were fixed, and the drug administration hose was inserted into the rat nasal cavity about 1.3 cm to administer the drug. The administration volume was 50 μL.

[0142] Intragastric administration group: hold the intragastric syringe in the right hand and grasp the skin of the rat's neck with the left hand to make the rat's head, neck and trunk in a straight line. Insert the intragastric needle from the corner of the mouth, press the tongue, press against the upper palate, and gently push inward. Slowly insert the intragastric needle into the esophagus along the posterior wall of the pharynx. After withdrawing the syringe without air backflow, inject the drug solution (the intragastric volume is 0.5 mL, and the drug solution needs to be vortexed and dispersed evenly before intragastric administration).

[0143] (3) Experimental results

[0144] Table 11 shows the main pharmacokinetic parameters of rizatriptan in rat plasma under different administration routes. According to Table 11, it can be found that under the same 1 mg / kg administration dose of rizatriptan benzoate, the peak time of nasal administration in rats is shorter than that of oral administration, and the peak concentration C in plasma is max and plasma exposure AUC last Higher, the relative bioavailability of nasal administration is about 612%. The above conclusion can also be seen from Figure 1 Verified in.

[0145] Table 11 Main pharmacokinetic parameters of rizatriptan in rat plasma after different administration routes (n=4, different administration routes)

[0146]

[0147] Table 12 shows the main pharmacokinetic parameters of rizatriptan in rat plasma after different administration routes. According to Table 12, it can be found that the relationship between the in vivo drug dose and exposure level of rizatriptan benzoate administered intranasally is clear and has a linear characteristic, which is specifically manifested in that as the dose increases, T max Almost unchanged, C max and AUClast As the dose increases, the above conclusions can also be seen from Figure 2 Verified in.

[0148] Table 12 Main pharmacokinetic parameters of rizatriptan in rat plasma after different administration routes (n=4, different dosages)

[0149]

[0150] Table 13 shows the main pharmacokinetic parameters of rizatriptan in rat plasma. According to Table 13, it can be found that the food effect of oral administration of rizatriptan benzoate is obvious. The peak time of drug in rats after ingestion is T max It will prolong the time for the drug to reach its peak concentration in plasma. max The food effect of intranasal administration of rizatriptan benzoate was not obvious, and the peak time of the drug after ingestion was T max and peak plasma concentrations C max There is no significant change, and the above conclusions can also be drawn from Figure 3 Verified in.

[0151] Table 13 Main pharmacokinetic parameters of rizatriptan in rat plasma (n=4, fasting and non-fasting)

[0152]

[0153] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0154] The technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. To make the description concise, not all possible combinations of the technical features in the above-mentioned implementation modes 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.

[0155] The above-described embodiments only express several implementation methods of the present application, but they cannot be understood as limiting the scope of the patent application. It should be pointed out that, for those of ordinary skill in the art, without departing from the concept of the present application, several variations and improvements can also be made, which all belong to the protection scope of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art on the basis of the technical solutions provided in the present application through logical analysis, reasoning or limited experiments are all within the protection scope of the claims attached to the present application. Therefore, the protection scope of the patent of the present application shall be based on the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A pharmaceutical solution composition, characterized in that: The pharmaceutical solution composition comprises: a pharmaceutical active ingredient, a pH regulator, an osmotic pressure regulator and water; The active ingredient of the medicine is rizatriptan or a pharmaceutically acceptable salt thereof; The pH regulator is used to adjust the pH of the pharmaceutical 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 In parts by weight, every 100 parts of the pharmaceutical solution composition comprises 0.5 to 5.5 parts of the pharmaceutical active ingredient, 0.001 to 0.05 parts of the pH regulator and 0.5 to 8 parts of the osmotic pressure regulator.

3. The pharmaceutical solution composition according to claim 1 or 2, characterized in that: The pH adjuster comprises an acid and an ion buffer pair, wherein the acid comprises 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 comprises at least one of a phosphate-phosphate buffer pair, an acetic acid-acetate buffer pair, a phosphate-citrate buffer pair and a tartaric acid-tartrate buffer pair; and / or, 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 claim 1 or 2, characterized in that: The pharmaceutical solution composition also includes a preservative; optionally, the preservative includes at least one of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, sodium propionate, sorbic acid and potassium sorbate.

5. The pharmaceutical solution composition according to claim 4, characterized in that: In parts by weight, every 100 parts of the pharmaceutical solution composition comprises 0.005 to 0.03 parts of the preservative.

6. The pharmaceutical solution composition according to any one of claims 1, 2 and 5, characterized in that: Satisfy at least one of the following characteristics: (1) The pH of the drug solution composition is 5.0-7.0; (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.

7. The pharmaceutical solution composition according to claim 6, characterized in that: When the osmotic pressure regulator is glycerol, the osmotic pressure regulator is included in 0.25 to 3 parts by weight per 100 parts of the pharmaceutical solution composition; When the osmotic pressure regulator is sodium chloride, the osmotic pressure regulator is contained in 0.2 to 0.9 parts by weight per 100 parts of the pharmaceutical solution composition.

8. The pharmaceutical solution composition according to any one of claims 1, 2, 5 and 7, characterized in that: The pharmaceutical solution composition also includes an absorption enhancer; Optionally, the absorption enhancer includes at least one of dodecyl-β-D-maltoside, tetradecyl-β-D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate.

9. A method for preparing the pharmaceutical solution composition according to any one of claims 1 to 8, characterized in that: The steps include: The pharmaceutical active 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 a second solution; The pH of the second solution is adjusted to 4.0 to 7.0 using the pH adjuster.

10. A rizatriptan benzoate nasal spray, characterized in that: A pharmaceutical solution composition comprising any one of claims 1 to 8.

11. The nasal spray according to claim 10, characterized in that The delivery volume of the nasal spray is 100-200 μL; and / or, In the delivery of the nasal spray, the effective delivery amount of the active pharmaceutical ingredient is 5 to 55 mg / spray.

12. Use of the pharmaceutical solution composition according to any one of claims 1 to 8, or the nasal spray according to claim 10 or 11 in the preparation of a drug for treating migraine.

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