A 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray and its preparation method

Abstract

The invention discloses a 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride nasal spray and a preparation method thereof, wherein the weight percentage of each component of the nasal spray is as follows: 1% to 15% of 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride, not less than 0.01% of nicotinic acid, not less than 1% of polyethylene glycol, 0.002% to 0.01% of zinc sulfate, 0.005% to 0.05% of antioxidant, 2% to 5% of osmotic pressure regulator, and the remainder is purified water, and the pH is adjusted to 4.5 to 6.0. The invention provides a stable 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride nasal spray, which is administered through the nasal cavity, solves the problem of inconvenience in swallowing for patients, improves clinical compliance, takes effect quickly, and avoids the first pass effect of oral administration. The 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride nasal spray provided by the invention has good absorption, high bioavailability, and high product stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray and a preparation method thereof. Background Art

[0002] Nitrate 2-(4-methylthiazol-5-yl)ethyl ester hydrochloride is a white or off-white crystalline powder with a melting point of 108-110°C. It is very soluble in water, easily soluble in methanol, soluble in ethanol, very slightly soluble in acetone, and insoluble in ether, ethyl acetate, and dichloromethane. The structural formula is shown below:

[0003]

[0004] 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is used for preventing and / or treating cardiovascular and cerebrovascular diseases and neurodegenerative diseases by alleviating individual neurodegeneration, achieving neuroprotection and / or achieving cognitive enhancement.

[0005] These patients are often elderly people who have difficulty swallowing, so oral administration is not the best choice. Injection can avoid swallowing difficulties, but injection usually requires professional caregivers to administer the drug. In addition, long-term administration can cause damage to the skin, and some patients are afraid of "needles", so it is not the best choice either.

[0006] If 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride can be developed into a nasal spray product and administered through the nasal cavity, clinical compliance can be greatly improved. In addition, nasal administration can avoid the first-pass effect of oral administration and has the advantages of rapid onset of action and high bioavailability.

[0007] However, due to the existence of the nasal mucosal barrier, it is often difficult for drugs to achieve ideal absorption effects, resulting in low bioavailability. In addition, drugs in solution state usually have poor stability, which also limits the research and development of this dosage form. Summary of the invention

[0008] In order to solve the problems of the prior art, the present invention provides a 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray and a preparation method thereof, which realizes absorption through the nasal mucosa into the body fluid circulation, has the advantages of rapid onset of action and is suitable for patients with dysphagia. The present invention unexpectedly found that the synergistic effect of nicotinic acid and polyethylene glycol can increase the absorption of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride through the nasal mucosa, and zinc sulfate can enhance the stability of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride. In order to achieve the above-mentioned invention purpose, the technical scheme provided by the present invention is as follows:

[0009] The present invention provides a 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray, wherein the weight percentage of each component is as follows:

[0010] 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride 1%-15%, niacin not less than 0.01%, polyethylene glycol not less than 1%, zinc sulfate 0.002%-0.01%, antioxidant 0.005%-0.05%, osmotic pressure regulator 2%-5%, the balance is purified water, and the pH is adjusted to 4.5-6.0.

[0011] Polyethylene glycol is a commonly used nasal spray excipient. In the present invention, it acts as an absorption enhancer. Nicotinic acid is also added to the present invention. Under the combined effect of the two, the bioavailability of the product can be greatly improved.

[0012] As a preferred solution, the weight percentage of niacin is 0.01% to 0.5%.

[0013] As a preferred solution, the weight percentage of polyethylene glycol is 1% to 10%, more preferably 3% to 6%.

[0014] The polyethylene glycol is selected from at least one of polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 or polyethylene glycol 2000, preferably polyethylene glycol 400 or polyethylene glycol 600.

[0015] Preferably, the antioxidant is one or more of sodium sulfite, sodium bisulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, and cysteine.

[0016] The pH value is adjusted by a pH adjuster, wherein the pH adjuster is selected from one or more of sodium citrate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydrogen phosphate, sodium carbonate, and sodium bicarbonate.

[0017] The osmotic pressure regulator is one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol, and mannitol.

[0018] The solvent is selected from one or more of ethanol and purified water.

[0019] The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray of the present invention further comprises a preservative, wherein the preservative is at least one of potassium sorbate, benzalkonium chloride, phenylethyl alcohol and benzyl alcohol.

[0020] The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray of the present invention can be prepared by the following method, comprising the following steps:

[0021] 1) adding 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol, zinc sulfate, antioxidant, pH adjuster, preservative and osmotic pressure adjuster into purified water according to the prescribed amount, stirring and dissolving to prepare a drug solution;

[0022] 2) Fill the liquid medicine into the nasal spray bottle.

[0023] The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray of the present invention can be used for preventing and / or treating cardiovascular and cerebrovascular diseases and neurodegenerative diseases.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The present invention provides a stable 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray, which is administered through the nasal cavity, solves the problem of patients' difficulty in swallowing, improves clinical compliance, has a rapid onset of action, and avoids the first-pass effect of oral administration;

[0026] 2. The formula provided by the present invention significantly improves the blood concentration of the drug through the synergistic effect of niacin and polyethylene glycol, achieves a good drug absorption effect, and has high bioavailability; at the same time, the present invention adopts zinc sulfate, which is an uncommon ingredient in nasal sprays, to achieve long-term storage stability of the drug and ensure reliable quality of the product within the service life; and provides a new idea for the prescription development of nasal sprays. DETAILED DESCRIPTION

[0027] The technical scheme of the present invention is further described in detail below in conjunction with specific examples and with reference to data. It should be understood that these embodiments are only for illustrating the present invention, and are not intended to limit the scope of the present invention in any way. The terms used in the present invention, unless otherwise specified, generally have the meanings commonly understood by those of ordinary skill in the art.

[0028] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0029] The present invention provides a method for preparing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray, comprising the following steps:

[0030] 1) Add 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol, zinc sulfate, antioxidant, pH adjuster, preservative and osmotic pressure adjuster into purified water according to the prescribed amount, stir and dissolve to prepare a drug solution.

[0031] 2) Fill the liquid medicine into the nasal spray bottle.

[0032] As an optional embodiment, the antioxidant is an antioxidant commonly used in the pharmaceutical field, and can be one or a combination of sodium sulfite, sodium bisulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, cysteine, etc.

[0033] As an optional embodiment, the pH adjuster is selected from one or a combination of sodium citrate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydrogen phosphate, sodium carbonate, and sodium bicarbonate.

[0034] As an optional embodiment, the osmotic pressure regulator is one or a combination of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol, and mannitol.

[0035] As an optional embodiment, the solvent is selected from ethanol, purified water or a combination of them.

[0036] As an optional embodiment, the preservative is at least one of potassium sorbate, benzalkonium chloride, phenethyl alcohol and benzyl alcohol.

[0037] As an optional embodiment, the weight percentage of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride as an active ingredient can be 1%, 5%, 10%, 15% and values ​​therebetween, the weight percentage of niacin can be 0.01%, 0.1%, 0.3%, 0.5% and values ​​in between, the weight percentage of polyethylene glycol can be 1%, 3%, 6%, 10% and values ​​in between, the weight percentage of zinc sulfate can be 0.002%, 0.006%, 0.01% and values ​​in between, the weight percentage of antioxidant can be 0.005%, 0.01%, 0.05% and values ​​in between, and the weight percentage of osmotic pressure regulator can be 2%, 3%, 5% and values ​​in between.

[0038] Examples 1 to 5: 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray

[0039] Preparation method:

[0040] 1. Referring to Table 1, add 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol 400, sodium bisulfite, glycerol, potassium sorbate, etc. into purified water, stir to dissolve, and adjust the pH with sodium hydroxide solution to prepare a drug solution.

[0041] 2. Fill the liquid medicine into the nasal spray bottle.

[0042] Table 1 Prescriptions of Comparative Examples 1 to 2 and Examples 1 to 5

[0043]

[0044] Pharmacokinetic study in rats:

[0045] Twenty rats were selected, half male and half female, and divided into 5 groups, 4 rats in each group (male-female ratio was 1:1). The drug was administered at a dose of 10 mg / kg. The main pharmacokinetic parameters of each experimental animal were determined: peak time, maximum blood drug concentration and AUC 0～t The measurement results are shown in Table 2 below.

[0046] Table 2 Pharmacokinetic test results in rats

[0047]

[0048] As shown in Table 2, the bioavailability of Comparative Examples 1 and 2 is poor when nicotinic acid and polyethylene glycol are added separately, but the bioavailability can be greatly improved when nicotinic acid and polyethylene glycol are added simultaneously; and when the mass percentage of nicotinic acid in the nasal spray is in the range of 0.01% to 0.5% and the mass percentage of polyethylene glycol in the nasal spray is in the range of 1% to 10%, the bioavailability of nasal spray administration can be greatly improved, thereby playing a good role in promoting absorption. And as the dosage increases, the absorption effect is better.

[0049] Examples 6-8 Effects of different types of polyethylene glycol on the bioavailability of the nasal spray of the present invention

[0050] According to the prescription described in Example 3, samples were prepared using polyethylene glycol 600, polyethylene glycol 1000, and polyethylene glycol 2000, and pharmacokinetic tests were conducted on rats (administered at about 10 mg / kg). The results are shown in Table 3, wherein polyethylene glycol 600, polyethylene glycol 1000, and polyethylene glycol 2000 are Examples 6, 7, and 8, respectively.

[0051] Table 3 Effect of different types of polyethylene glycol on the bioavailability of the nasal spray of the present invention

[0052]

[0053] It can be seen from Table 3 that different types of polyethylene glycol can achieve good bioavailability.

[0054] Examples 9-13 Effect of different amounts of zinc sulfate on the stability of the nasal spray of the present invention

[0055] This product is a solution-type nasal spray. 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride has poor stability. It was unexpectedly discovered during the study that adding zinc sulfate to the prescription can improve the stability of this product.

[0056] Referring to the prescription of Example 3, different dosages of zinc sulfate were designed, as shown in Table 4.

[0057] Table 4 Effect of different dosages of zinc sulfate on the stability of the nasal spray of the present invention

[0058]

[0059] The samples prepared by the above prescription were placed in a stability test chamber for accelerated testing (temperature 40°C ± 2°C / humidity 75% ± 5%), and the key indicators were tested at 0, 1 and 3 months to test the stability of the product. The stability results at 0 and 3 months are shown in Table 5.

[0060] Table 5 Stability test results

[0061]

[0062] The results in Table 5 show that when the dosage of zinc sulfate is in the range of 0.002% to 0.01%, the stability of the sample accelerated for 3 months is good.

[0063] Comparative Example Effect of other commonly used absorption enhancers on the bioavailability of the nasal spray of the present invention

[0064] Commonly used absorption enhancers include cyclodextrins (methyl β-cyclodextrin, dimethyl β-cyclodextrin, hydroxypropyl β-cyclodextrin), bile salts (taurocholate, hepatic bile salt), fatty acids and their esters (lauric acid, oleic acid), alcohols (lauryl alcohol, propylene glycol), sulfoxides (dimethyl sulfoxide, dimethylformamide), surfactants (polysorbate, sodium dodecyl sulfate), salicylates (sodium salicylate), protease inhibitors (azone) and chitosan, etc.

[0065] Pharmacokinetic tests were conducted on rats using different types of commonly used absorption enhancers, such as hydroxypropyl β-cyclodextrin, taurocholate, polysorbate 80, and oleic acid (administered at approximately 10 mg / kg), but the ideal bioavailability effect was not achieved. The prescription is shown in Table 6, and the bioavailability results are shown in Table 7.

[0066] Table 6 Comparative Examples Containing Other Commonly Used Absorption Promoters

[0067]

[0068] Preparation method:

[0069] 1. Referring to Table 6, add 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, absorption promoter, sodium bisulfite, zinc sulfate, glycerol, potassium sorbate, etc. into purified water, stir to dissolve, and adjust the pH with sodium hydroxide solution to prepare a drug solution.

[0070] 2. Fill the liquid medicine into the nasal spray bottle.

[0071] Table 7 Effect of different absorption enhancers on bioavailability

[0072]

[0073]

[0074] It can be seen that for 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray, when several commonly used absorption enhancers are used, the bioavailability is low and the full absorption and utilization of the drug cannot be guaranteed.

[0075] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray, characterized in that: The weight percentage of each component is as follows: 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride 1%-15%, nicotinic acid 0.01%-0.5%, polyethylene glycol 1%-10%, zinc sulfate 0.002%-0.01%, antioxidant 0.005%-0.05%, osmotic pressure regulator 2%-5%, the balance is purified water, and the pH is adjusted to 4.5-6.

0.

2. The nasal spray according to claim 1, characterized in that The weight percentage of polyethylene glycol is 3% to 6%.

3. The nasal spray according to claim 1, characterized in that The polyethylene glycol is selected from at least one of polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 or polyethylene glycol 2000.

4. The nasal spray according to claim 1, characterized in that The polyethylene glycol is selected from polyethylene glycol 400 or polyethylene glycol 600.

5. The nasal spray according to claim 1, characterized in that The antioxidant is one or more of sodium sulfite, sodium bisulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, and cysteine.

6. The nasal spray according to claim 1, characterized in that The pH value is adjusted by a pH adjuster, wherein the pH adjuster is selected from one or more of sodium citrate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydrogen phosphate, sodium carbonate, and sodium bicarbonate.

7. The nasal spray according to claim 1, characterized in that The osmotic pressure regulator is one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol, and mannitol.

8. The nasal spray according to claim 1, characterized in that The invention also comprises a preservative, which is at least one of potassium sorbate, benzalkonium chloride, phenethyl alcohol and benzyl alcohol.

9. A method for preparing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride nasal spray, characterized in that: The weight percentage of each component of the nasal spray is as follows: 1% to 15% of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, 0.01% to 0.5% of nicotinic acid, 1% to 10% of polyethylene glycol, 0.002% to 0.01% of zinc sulfate, 0.005% to 0.05% of antioxidant, 2% to 5% of osmotic pressure regulator, and the balance is purified water, and the pH is adjusted to 4.5 to 6.0; The following steps are involved: 1) adding 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol, zinc sulfate, antioxidant, pH adjuster, preservative and osmotic pressure adjuster into purified water according to the prescribed amount, stirring and dissolving to prepare a drug solution; 2) Fill the liquid medicine into the nasal spray bottle.

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