Alprazolam nasal spray and preparation method thereof

Abstract

The invention discloses an alprazolam nasal spray and a preparation method thereof, and provides the alprazolam nasal spray which is good in stability, small in irritation, convenient, quick to take effect and extremely small in side effect, so that the medication compliance of a patient and the convenience of clinical medication are improved, and the preparation process is simple to operate, safe, environment-friendly and suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to an alprazolam nasal spray and a preparation method thereof. Background Art

[0002] Alprazolam is a benzodiazepine hypnotic, sedative, and anxiolytic. It acts on the benzodiazepine receptors (BZR) in the central nervous system, strengthening the binding of the central inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA receptor, promoting the opening of chloride channels, causing cell hyperpolarization, and enhancing synaptic inhibition mediated by GABAergic neurons, thereby reducing neuronal excitability.

[0003] BZR is divided into type I and type II. It is believed that the stimulation of type I receptors can explain the anxiolytic effects of BZ drugs, while type II receptors are related to the sedative and skeletal muscle relaxation effects of this class of drugs. It can cause inhibition in different parts of the central nervous system. As the dosage increases, the clinical manifestations can range from mild sedation to hypnosis and even coma. As a new type of benzodiazepine nasal spray, alprazolam nasal spray can bind to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABAA receptors, promote the opening of chloride channels, hyperpolarize cells, enhance synaptic inhibition mediated by GABAergic neurons, reduce neuronal excitability, and achieve sedative and anxiolytic effects.

[0004] Compared with other routes of administration such as intramuscular injection and oral gavage, intravenous injection of drugs has the characteristics of good absorption and rapid onset of action. However, for patients with different degrees of illness, intravenous injection is difficult to perform during the onset period. At this time, oral gavage, intramuscular injection or sublingual administration are also used for treatment. However, the former is difficult to stop convulsions quickly due to slow absorption, and most patients with the latter suffer from rigidity and are unable to put the drug under the tongue, resulting in failure. Therefore, among the above treatment methods, except intravenous injection, it is difficult to achieve a good therapeutic effect.

[0005] Therefore, there is an urgent need to develop a stable pharmaceutical composition preparation of alprazolam suitable for immediate treatment of patients at home or under simple conditions and a simple and easy preparation process thereof, so as to control impurities in the drug and ensure drug safety. The nasal administration route can avoid the degradation and metabolism of the drug by the gastrointestinal tract and avoid the first-pass effect of the liver, which is more conducive to use by children and people who cannot swallow or are prone to vomiting. It has unique advantages and broad market prospects. Summary of the Invention

[0006] The following is a summary of some aspects of the present invention and is not intended to limit the present invention. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0007] In view of the shortcomings of traditional alprazolam tablets and injections, the present invention has developed a method for preparing a new dosage form of alprazolam nasal spray. The development of this product aims to provide patients with a convenient, effective and fast-acting dosage form.

[0008] The invention provides an alprazolam nasal spray comprising alprazolam and a cosolvent.

[0009] Furthermore, the alprazolam nasal spray further comprises an excipient, wherein the excipient is selected from at least one of polyethylene glycol monomethyl ether, polyethylene glycol monomethyl ether 350, polyethylene glycol monomethyl ether 500, and polyethylene glycol monomethyl ether 750, preferably polyethylene glycol monomethyl ether 350.

[0010] Furthermore, the alprazolam nasal spray is characterized in that it also includes an absorption promoter and an antioxidant, wherein the absorption promoter is selected from at least one of n-dodecyl-β-D-maltoside, tetradecyl-β-D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate, preferably poly-n-dodecyl-β-D-maltoside; and the antioxidant is selected from at least one of vitamin A, vitamin C, vitamin E, and polyphenols, preferably vitamin E.

[0011] Furthermore, the alprazolam nasal spray is characterized in that the cosolvent is selected from at least one of propylene glycol, glycerol, ethylene glycol, polyethylene glycol, anhydrous ethanol, and benzyl alcohol, preferably at least one of propylene glycol, anhydrous ethanol, and benzyl alcohol.

[0012] Furthermore, the alprazolam nasal spray is characterized in that, based on the mass grams (i.e., m / v, unit: g / ml) of the corresponding component in 10 ml of nasal spray liquid, it satisfies one of the following conditions:

[0013] (1) The alprazolam nasal spray comprises:

[0014]

[0015] and an appropriate amount of purified water;

[0016] (2) The alprazolam nasal spray comprises:

[0017]

[0018] And an appropriate amount of vitamin E.

[0019] Furthermore, the alprazolam nasal spray is characterized in that, based on the mass grams (i.e., m / v, unit: g / ml) of the corresponding component in 10 ml of nasal spray liquid, it satisfies one of the following conditions:

[0020] 1) The alprazolam nasal spray comprises:

[0021]

[0022]

[0023] and an appropriate amount of purified water;

[0024] (2) The alprazolam nasal spray comprises:

[0025]

[0026] And an appropriate amount of vitamin E.

[0027] Another object of the present invention is to provide a method for preparing an alprazolam nasal spray based on the prior art, and to provide the following technical solutions:

[0028] A method for preparing an alprazolam nasal spray, characterized in that weighing, liquid preparation, filtration, filling, and assembly are performed, and one of the following conditions is met:

[0029] A: The preparation method of the alprazolam nasal spray comprises:

[0030] 1) Weighing: Weigh polyethylene glycol monomethyl ether 350, propylene glycol, anhydrous ethanol, alprazolam, and purified water;

[0031] 2) Prepare the solution: Add weighed polyethylene glycol monomethyl ether 350, anhydrous ethanol, and propylene glycol to alprazolam, stir, and then add purified water;

[0032] 3) Filtration: The liquid medicine is filtered through a filter;

[0033] 4) Filling and assembly: control the nitrogen blowing pressure during the filling process, filling and assembly;

[0034] B: The preparation method of the alprazolam nasal spray comprises:

[0035] 1) Weighing: Weigh benzyl alcohol, anhydrous ethanol, vitamin E, alprazolam, and n-dodecyl β-D-maltoside;

[0036] 2) Prepare the solution: Add weighed benzyl alcohol, anhydrous ethanol, and vitamin E to alprazolam, stir, and then add n-dodecyl β-D-maltoside;

[0037] 3) Filtration: The liquid medicine is filtered through a filter;

[0038] 4) Filling and assembly: Control the nitrogen blowing pressure during the filling process, filling and assembly.

[0039] Furthermore, the method for preparing the alprazolam nasal spray of the present invention is characterized in that the temperature is controlled at 18-25°C during the liquid preparation process.

[0040] Furthermore, the method for preparing the alprazolam nasal spray of the present invention is characterized in that the filter is 0.45 μm.

[0041] Furthermore, the method for preparing the alprazolam nasal spray of the present invention is characterized in that the nitrogen blowing flow rate is 5-20 L / min.

[0042] The present invention also provides a method for detecting the content of alprazolam in a nasal spray, comprising:

[0043] Prepare the test sample by taking alprazolam nasal spray and using acetonitrile-water as the diluent. Inject the sample into the liquid chromatograph and elute according to the gradient in the table below. Record the chromatogram.

[0044]

[0045] The chromatographic conditions are as follows: an octadecylsilane bonded silica gel column is selected, phosphate buffer is used as mobile phase A, and acetonitrile is used as mobile phase B.

[0046] Furthermore, in the method for detecting the content of alprazolam nasal spray of the present invention, mobile phase A is a phosphate buffer composed of potassium dihydrogen phosphate and dipotassium hydrogen phosphate and water, and the pH value is adjusted to 5.5-6.5, preferably 6.0, with phosphoric acid; mobile phase B is acetonitrile;

[0047] Furthermore, in the method for detecting the content of alprazolam nasal spray described in the present invention, the flow rate is 0.5-2 ml per minute, preferably 1.0 ml; the column temperature is 25-40°C, preferably 30°C; the detection wavelength is 254-275 nm, preferably 260 nm; and the injection volume is 15-30 μl, preferably 25 μl.

[0048] Beneficial technical effects of the present invention

[0049] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0050] 1. In view of the shortcomings of traditional alprazolam preparations, the present invention provides an alprazolam nasal spray with good stability, low irritation, convenience, rapid onset and minimal side effects, thereby improving patient compliance with medication and the convenience of clinical medication.

[0051] 2. The preparation method of the present invention is simple to operate, safe and environmentally friendly, and is suitable for large-scale industrial production. The obtained alprazolam nasal spray has a low impurity content and high preparation stability, which greatly improves the safety of medication.

[0052] 3. Alprazolam is made into a nasal spray. After being absorbed by the nasal capillaries, the drug enters the systemic circulation directly without passing through the portal-hepatic system, thus avoiding the first-pass effect of the liver. It has high bioavailability, is not only convenient to administer, but also has a rapid onset of action and complete absorption, which can achieve better therapeutic effects. DETAILED DESCRIPTION

[0053] Unless otherwise indicated or there is an obvious conflict in the context, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0054] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the reagents or instruments used are not specified by manufacturer, they are all conventional products that can be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0055] Example 1

[0056] A: Spray composition

[0057] Dosage content Proportion Alprazolam 2mg 2％ Polyethylene glycol monomethyl ether 350 55mg 55％ Anhydrous ethanol 19mg 19％ Propylene glycol 5mg 5％ purified water Add to 0.1ml 19％

[0058] B: Preparation method

[0059] 1) Weighing: Weigh 55 g of polyethylene glycol monomethyl ether 350, 5 g of propylene glycol, 19 g of anhydrous ethanol, and 2 g of alprazolam. After the alprazolam is dissolved, weigh 22 g of purified water.

[0060] 2) Liquid preparation: Add weighed polyethylene glycol monomethyl ether 350, anhydrous ethanol, and propylene glycol to a beaker containing alprazolam. Stir until the solution is clarified, then add weighed purified water. The temperature during the preparation process should be controlled at 18-25°C.

[0061] 3) Filtration: The drug solution was filtered through a 0.45 μm PTFE filter.

[0062] 4) Filling and assembly: Control the nitrogen blowing pressure during the filling process, the nitrogen blowing flow rate is 5-20L / min, and the target filling volume is 10ml for filling and assembly.

[0063] Example 2:

[0064] A: Spray composition

[0065] Dosage content Proportion Alprazolam 2mg 2％ Benzyl alcohol 10.5mg 11％ Anhydrous ethanol 19mg 19％ n-Dodecyl β-D-maltoside 25mg 25％ Vitamin E Add to 0.1ml 40％

[0066] B: Preparation method

[0067] 1) Weighing: Weigh 10.5 g of benzyl alcohol, 19 g of anhydrous ethanol, 40 g of vitamin E, and 2 g of alprazolam. After the alprazolam is dissolved, weigh 25 g of n-dodecyl β-D-maltoside.

[0068] 2) Liquid preparation: Add weighed benzyl alcohol, anhydrous ethanol, and vitamin E to a beaker containing alprazolam. Stir until the solution is clarified, then add weighed n-dodecyl β-D-maltoside. Control the temperature at 18-25°C during the liquid preparation process.

[0069] 3) Filtration: The drug solution was filtered through a 0.45 μm PTFE filter.

[0070] 4) Filling and assembly: Control the nitrogen blowing pressure during the filling process, the nitrogen blowing flow rate is 5-20L / min, and the target filling volume is 10ml for filling and assembly.

[0071] Example 3: Pharmacokinetic Study of Alprazolam Nasal Spray in Rats

[0072] 1) Experimental Protocol: Nine male SD rats were randomly divided into three groups, each containing three rats. All rats were fasted for 8 hours prior to the experiment and had free access to water. Groups 1 and 2 were administered alprazolam solution via tail vein injection (1 mg / kg) and oral gavage (2 mg / kg), respectively. (The alprazolam solution used in Groups 1 and 2 consisted of the alprazolam API, whose solvent was 20% Hp-B-CD.) Group 3 was administered a 2 mg / kg alprazolam nasal spray (preparation according to Example 2, 20 μL of the formulation administered over approximately 5 minutes) via nasal injection. Whole blood was collected from the rats' jugular vein at various time points after administration, and plasma was obtained by centrifugation. Plasma concentrations at various times were measured using LC-MS / MS. Pharmacokinetic parameters and absolute bioavailability were calculated using WinNolin 8.0 software.

[0073] Table 2 Average plasma concentrations and pharmacokinetic parameters of alprazolam in SD rats in different drug groups

[0074]

[0075]

[0076] NA: Not applicable

[0077] The test results showed that alprazolam nasal spray was rapidly absorbed in rats after administration, reaching a peak bioavailability of 47.89% after approximately 0.14 hours. In contrast, the intragastric administration group reached a peak bioavailability of only 6.29% after approximately 0.58 hours. The nasal spray exhibited superior absorption speed and extent. The nasal spray of the present invention offers the advantages of rapid onset of action and high bioavailability, resulting in superior therapeutic efficacy.

[0078] Example 4: Detection method

[0079] Test solution: dilute the product with acetonitrile-water (40:60) to make a solution containing approximately 10 mg of alprazolam per 1 ml and shake well.

[0080] Control solution: Accurately measure an appropriate amount of the test solution and dilute it with acetonitrile-water (40:60) to make a solution containing approximately 200 μg of alprazolam per 1 ml, and shake well.

[0081] Chromatographic conditions: Use octadecylsilane bonded silica gel as the packing (Agilent Eclipse XDB C8, 4.6 × 150 mm, 5 μm, or equivalent performance column); phosphate buffer (8 g of potassium dihydrogen phosphate and 2 g of dipotassium hydrogen phosphate, dissolved in water and diluted to 1000 ml, pH adjusted to 6.0 with phosphoric acid) as mobile phase A, and acetonitrile as mobile phase B. Linear gradient elution according to the table below; flow rate: 1.0 ml / min; column temperature: 30°C; detection wavelength: 260 nm; injection volume: 25 μl.

[0082]

[0083] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0084] The above is a description of a specific embodiment of the present invention. It should be understood that the present invention is not limited to the above embodiment, and the above embodiment and description are only for illustrating the principle of the present invention.

[0085] Those skilled in the art may make various non-substantial changes and improvements to the present invention without departing from the concept of the present invention, and all of these fall within the scope of protection claimed by the present invention.

Claims

1. An alprazolam nasal spray comprising alprazolam and a cosolvent.

2. The alprazolam nasal spray according to claim 1, characterized in that The invention also includes an excipient, which is selected from at least one of polyethylene glycol monomethyl ether, polyethylene glycol monomethyl ether 350, polyethylene glycol monomethyl ether 500, and polyethylene glycol monomethyl ether 750, preferably polyethylene glycol monomethyl ether 350.

3. The alprazolam nasal spray according to claim 1, characterized in that It also includes an absorption promoter and an antioxidant, wherein the absorption promoter is selected from at least one of n-dodecyl-β-D-maltoside, tetradecyl-β-D-maltoside, chitosan, sucrose dodecanoate, carboxymethyl chitosan, and sodium taurocholate, preferably n-dodecyl-β-D-maltoside; the antioxidant is selected from at least one of vitamin A, vitamin C, vitamin E, and polyphenols, preferably vitamin E.

4. The alprazolam nasal spray according to any one of claims 1 to 3, characterized in that The cosolvent is selected from at least one of propylene glycol, glycerol, ethylene glycol, polyethylene glycol, anhydrous ethanol, and benzyl alcohol, preferably at least one of propylene glycol, anhydrous ethanol, and benzyl alcohol.

5. The alprazolam nasal spray according to claim 1, characterized in that Calculated on the basis of the mass of the corresponding component in 10 ml of nasal spray liquid (i.e., m / v, unit: g / ml), it meets one of the following conditions: (1) The alprazolam nasal spray comprises: and an appropriate amount of purified water; (2) The alprazolam nasal spray comprises: And an appropriate amount of vitamin E.

6. A method for preparing an alprazolam nasal spray, characterized in that: Weighing, liquid preparation, filtration, filling and assembly are carried out, which meets one of the following conditions: A: The preparation method of the alprazolam nasal spray comprises: 1) Weighing: Weigh polyethylene glycol monomethyl ether 350, propylene glycol, anhydrous ethanol, alprazolam, and purified water; 2) Prepare the solution: Add weighed polyethylene glycol monomethyl ether 350, anhydrous ethanol, and propylene glycol to alprazolam, stir, and then add purified water; 3) Filtration: The liquid medicine is filtered through a filter; 4) Filling and assembly: control the nitrogen blowing pressure during the filling process, filling and assembly; B: The preparation method of the alprazolam nasal spray comprises: 1) Weighing: Weigh benzyl alcohol, anhydrous ethanol, vitamin E, alprazolam, and n-dodecyl β-D-maltoside; 2) Prepare the solution: Add weighed benzyl alcohol, anhydrous ethanol, and vitamin E to alprazolam, stir, and then add n-dodecyl β-D-maltoside; 3) Filtration: The liquid medicine is filtered through a filter; 4) Filling and assembly: Control the nitrogen blowing pressure during the filling process, filling and assembly.

7. The method for preparing the alprazolam nasal spray according to claim 6, wherein: The temperature during the liquid preparation process is controlled at 18-25° C.; the filter is 0.45 μm; and the nitrogen blowing flow rate is 5-20 L / min.

8. A method for detecting the content of alprazolam nasal spray, comprising: Prepare the test sample by taking alprazolam nasal spray and using acetonitrile-water as the diluent. Inject the sample into the liquid chromatograph and elute according to the gradient in the table below. Record the chromatogram. The chromatographic conditions are as follows: an octadecylsilane bonded silica gel column is selected, phosphate buffer is used as mobile phase A, and acetonitrile is used as mobile phase B.

9. The method for detecting alprazolam nasal spray according to claim 8, wherein: The mobile phase A is a phosphate buffer solution composed of potassium dihydrogen phosphate and dipotassium hydrogen phosphate and water, and the pH value is adjusted to 5.5-6.5, preferably 6.0, with phosphoric acid; the mobile phase B is acetonitrile.

10. The method for detecting alprazolam nasal spray according to claim 8, characterized in that: The flow rate is 0.5-2 ml per minute, preferably 1.0 ml; the column temperature is 25-40° C., preferably 30° C.; the detection wavelength is 254-275 nm, preferably 260 nm; and the injection volume is 15-30 μl, preferably 25 μl.

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