CN1293863C - Ibolite fumarate nasal cavity administration preparation - Google Patents

Abstract

The present invention provides an ibutilide preparation whose administration mode adopts a nasal cavity administration mode. The preparation contains ibutilide fumarate, ibutilide free alkali, or other medical salts of ibutilide, which are acceptable on medicine, a stereo isomer which has the pharmacological activity, and an absorption enhancer. The preparation medicine which adopts the nasal cavity administration mode and is provided by the present invention is absorbed by the nasal mucous membrane, the medicine enters blood circulation to exert the function, and the present invention has the advantages of stable performance, controllable quality and no stimulation on the nasal mucous membrane. The preparation which adopts the nasal cavity administration mode and is provided by the present invention is used for treating arrhythmia.

Description

Ibutilide Fumarate Nasal Administration Preparation

field of invention

The invention relates to a preparation for nasal cavity administration, in particular to a preparation for nasal cavity administration of ibutilide fumarate.

Background technique

Arrhythmias are very common and can be caused or induced by many diseases and drugs. According to relevant data, a comparison of the incidence rates of various arrhythmias shows that sinus arrhythmia has the highest incidence rate of 25% to 27%, followed by sinus tachycardia at 20% to 22%. Brady is 13% to 15%, ventricular premature beat is 14% to 16%, atrial premature beat is 5% to 7%, atrial fibrillation is 11% to 15%, atrioventricular block is 5% to 7%, other various arrhythmias about 5% to 8%. Therefore, people have been devoting themselves to prescribing an antiarrhythmic drug that can be administered to patients at the first time, is convenient to use, and has good therapeutic effect.

Ibutilide fumarate (Ibutilide fumarate) is a new type of antiarrhythmic drug, which has fast-acting and safe antiarrhythmic drugs, especially for the rapid termination of atrial flutter and atrial fibrillation. Ibutilide fumarate was approved by the U.S. FDA in December 1995, and it was the first approved intravenous drug for the treatment of atrial flutter and atrial fibrillation in the U.S. in 1996. Its molecular formula is:

Ibutilide (IbutIlIde), a derivative of methylsulfonamide, is a new class III antiarrhythmic drug with ion channel activity. This product was developed by Pharmacia Upjohn Company of the United States. It was approved by the FDA in December 1995. It was launched in the United States in 1996 and has been listed in 11 European and American countries. It is used for acute atrial fibrillation and atrial flutter. Intravenous administration, the therapeutic effect is more significant, and it provides new and excellent drugs for the treatment of atrial fibrillation and atrial flutter conversion to sinus rhythm.

Clinical studies have shown that the drug is highly selective, by activating the slow inward sodium ion flow, blocking the outflow of potassium ions in cardiomyocytes, increasing repolarization, effectively prolonging the action potential duration, and prolonging the effective reactivity of cardiomyocytes. Period (ERP), drug termination of atrial arrhythmia is more effective than ventricular arrhythmia, the ERP effect on the atrium is 10 times more obvious than that on the ventricle, and reduces the defibrillation threshold.

Literature reports: Ibutilide has a remarkable curative effect and is a class of effective short-term and long-term antiarrhythmic drugs. The average time to terminate arrhythmia is short, and 80% of patients can fully improve within 30 minutes after administration. A comprehensive evaluation of the effectiveness and safety of acute attacks shows that the success rate of atrial flutter is 48% to 70%. The conversion rate is 22% to 43%, which is several times higher than that of sotalol and procainamide. It is safe and effective for atrial fibrillation and atrial flutter after heart bypass surgery, and the cardioversion rate reaches 57%. The duration of atrial fibrillation and atrial flutter was 30 days, and 42% of patients were converted after using this product. The conversion rates of atrial flutter and atrial fibrillation in patients with second administration can be increased by 75% and 45% respectively, and there is no effect on hemodynamics. Significant effect, even in patients with reduced left ventricular function, the effect is minimal.

Oral administration of ibutilide, such as the preparation of ibutilide fumarate, has a strong first-pass metabolic effect and low bioavailability, so it is administered intravenously, and intravenous administration must be performed by professional medical personnel operate. For the sick patients who require timely and convenient administration at the first time, as well as the sick patients at home, it is very necessary to provide a drug delivery preparation other than injection.

Contents of the invention

The purpose of the present invention is to overcome the inconvenience of known ibutilide fumarate preparations on the route of administration, overcome the defects of oral administration bioavailability, and develop a new, non-injection route of administration. , anti-arrhythmic, convenient for doctors and patients, rapid administration of ibutilide fumarate nasal administration preparation. The present inventors conducted in-depth studies and found that ibutilide fumarate, ibutilide free base or other pharmaceutically acceptable salts of ibutilide and pharmacologically active stereoisomers of ibutilide and absorption enhancers of nasal administration preparations, especially including osmotic pressure regulators, thickeners, preservatives, pH regulators or other pharmaceutical excipients formulated through nasal administration preparations, can effectively avoid fumarate Bullitt has low oral bioavailability, while avoiding the characteristics of incompatibility of injection administration.

A large number of experiments have shown that the nasal cavity administration preparation according to the present invention absorbs the drug through the nasal mucosa and then enters the blood circulation to play a role. It has the advantages of stable performance, controllable quality, and no irritation to the nasal mucosa.

The invention has the characteristics of rapid absorption, high bioavailability, definite curative effect and convenient use. Each dosage is adjusted within the range of 0.01mg-2.0mg. Based on body weight, each administration is 0.005-0.035mg/kg.

The ibutilide preparations for nasal administration provided by the present invention include ibutilide fumarate, ibutilide free base or pharmaceutically acceptable other pharmaceutical salts of ibutilide and pharmacologically active steric Isomer, absorption enhancer.

The second ibutilide preparation provided by the present invention includes an osmotic pressure regulator and a surfactant.

The present invention provides the third ibutilide formulation for nasal administration including preservatives and pH regulators.

The present invention provides the fourth nasal administration ibutilide preparation, wherein:

The absorption enhancer is selected from any one of the following (1)-(8):

(1) Cyclodextrins of α, β, or γ-cyclodextrins and alkyl-substituted cyclodextrins, such as methyl-β-cyclodextrin, dimethyl-β-cyclodextrin or hydroxypropyl - beta-cyclodextrin;

(2) Bile salts: such as glycocholate, cholate, deoxycholate, taurocholate, glucocholate, chenodeoxycholate or ursodeoxycholate;

(3) Saturated and unsaturated fatty acids and their esters: such as lauric acid, oleic acid, myristic acid, capric acid, laurate, caprylic acid, caprate, palmitate or ethyl lactate:

(4) Alcohols: such as diol, isopropanol, cetyl alcohol, lauryl alcohol or oleyl alcohol, etc.;

(5) Ethers: polyoxyethylene lauryl ether or polyoxyethylene octyl ether;

(6) Sulfoxides: such as dodecylmethyl sulfoxide or dimethyl sulfoxide;

(7) Lactams: such as laurylazepine or geranylazepine;

(8) Ionic nonionic surfactants: such as sodium lauryl sulfate, caprylic monoglyceride, Tween 80 or Span 20;

The above absorption enhancers include mixtures of two or more thereof;

The osmotic pressure regulator is selected from lactose, glucose, dextran, sorbitol, mannitol or pharmaceutically acceptable inorganic salts thereof;

The thickener is selected from polymer compounds, carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyacrylic acid, polyvinyl acid or carbopol;

The preservative is selected from ethylparaben, p-hydroxybenzoate, benzoic acid and pharmaceutically acceptable salts thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenylethyl alcohol, thimerosal, acetic acid washing Cationic surfactants of bitamate or quaternary ammonium compounds.

The pH regulator is selected from hydrochloric acid, citric acid, fumaric acid or acetic acid.

The present invention provides a fifth nasal cavity administration ibutilide preparation, said preparation contains 0.2-50% ibutilide fumarate, its free base or pharmaceutically acceptable ibutilide special other salts.

The present invention provides the sixth 100 ml preparation for nasal administration containing 50 mg of ibutilide fumarate, 0.3 g of polyvinylpyrrolidone, 0.5 ml of azone, 1.0 g of propylene glycol, and 0.1 g of ethylparaben , hydrochloric acid PH.

The present invention provides 100 milliliters of ibutilide for intranasal administration comprising 50 mg of ibutilide fumarate, 2.5 grams of hydroxypropyl B-cyclodextrin, 0.1 gram of ethylparabide, Mannitol 0.5 g, polyethylene glycol 1.0 ml, purified water to 100 ml. Hydrochloric acid to adjust pH.

The present invention provides the eighth nasal cavity administration of 100 milliliters of ibutilide, said preparation comprising 150 mg of ibutilide fumarate, 5 grams of methyl B-cyclodextrin, 0.1 gram of ethylparaben, poly Vinyl alcohol 0.5 g, mannitol 2-4 g, purified water to 100 ml. Hydrochloric acid to adjust pH.

The ibutilide preparation for nasal administration provided by the present invention is a nasal spray or nasal drops.

The nasal administration preparation provided by the present invention can be used to treat atrial fibrillation and atrial flutter to quickly convert them to sinus rhythm.

According to the present invention, the content of ibutilide fumarate or other pharmaceutically acceptable salts of ibutilide in a unit nasal administration preparation is 0.1-150% (weight %), preferably 0.2-50% (weight %).

The present invention will be further described by the following examples, but it does not mean that the protection scope of the present invention is limited.

Embodiment 1: the preparation of ibutilide fumarate spray

Ingredient Quantity

Ibutilide Fumarate 50mg

Polyvinylpyrrolidone 0.3g

Laurozone 0.5ml

Propylene Glycol 1.0g

Ethylparaben 0.1g

Distilled water up to 100ml

Preparation method: Fully stir the above-mentioned amount of polyvinylpyrrolidone, ibutilide fumarate, propylene glycol, and lauryl nitrogen statistical ethylparaben to dissolve them all, and finally add distilled water to 100ml. Hydrochloric acid to adjust pH. The obtained solution is distributed in a spray pump or a quantitative drop pump.

Embodiment 2: the preparation of ibutilide fumarate spray

Ingredient Quantity

Ibutilide Fumarate 50mg

Hydroxypropyl-β-cyclodextrin 2.5g

Ethylparaben 0.1g

Mannitol 0.5g

Macrogol 400 1.0ml

Distilled water up to 100ml

Preparation method: After shaking the above-mentioned amount of ibutilide fumarate, hydroxypropyl-β-cyclodextrin, ethylparaben, mannitol and distilled water to dissolve, add the above-mentioned polyethylene glycol 400, and finally add Add distilled water to 100ml. Hydrochloric acid to adjust pH.

Embodiment 3: the preparation of ibutilide fumarate spray

Ingredient Quantity

Ibutilide Fumarate 150mg

Methyl-β-cyclodextrin 5g

Ethylparaben 0.1g

Polyvinyl alcohol 0.5g

Mannitol 2-4g

Distilled water up to 100ml

Preparation method: add distilled water to the above amount of ibutilide fumarate, methyl-β-cyclodextrin, ethylparaben, polyvinyl alcohol, shake to dissolve all, and finally add distilled water to 100ml. Hydrochloric acid to adjust pH.

Pharmacological experiment

Carry out the pharmacokinetic test in beagle dogs after the administration of 1 fumaric acid ililide nasal spray and fumarate ililide injection, the results are shown in Table 1

Table 1 After administration of Iilide Fumarate Nasal Spray and Iilide Fumarate Injection

Comparison of Plasma Protein Binding and Plasma Clearance in Beagle Dogs drug dose plasma clearance Plasma protein binding nasal spray injection 0.3mg/kg5mg/kg0.3mg/kg5mg/kg 5.3L/h/kg3.7L/h/kg5.6L/h/kg4.0L/h/kg 39% 40% 41% 42%

The results of the pharmacokinetic test comparison between Ibutilide nasal spray and injection showed that the metabolism of the two was consistent.

Experiment 2. Ibutilide Fumarate Nasal Spray and Injection Treating Dog Arrhythmia (Atrial Flutter) Cardioversion Percentage

Table 2 Ibutilide Fumarate Nasal Spray and Injection Treat Dog Arrhythmia (Atrial Flutter) Cardioversion Percentage Cardioversion Percentage in Canine Arrhythmia Model placebo Ibutilide Fumarate Nasal Spray Ibutilide Fumarate Injection 0.005mg/kg 0.035mg/kg 0.100mg/kg 0.300mg/kg 0.005mg/kg 0.035mg/kg 0.100mg/kg 0.300mg/kg quantity 15 15 16 15 15 16 16 15 16 atrial flutter initial# 0 17 30 40 70 17 31 46 68 24 hours later## 0 16 30 58 59 15 33 60 61 #Percentage of dogs cardioverted within 70 minutes after starting nasal spray ## Percentage of Dogs Maintaining Sinus Rhythm for 24 Hours After Dosing Nasal Spray

Ibutilide slows down the local conduction of the reentry loop, which increases the length of the atrial flutter reentry loop and terminates the atrial flutter. The effect of injection and nasal spray is equivalent.

The results of Experiment 1 and Experiment 2 show that ibutilide fumarate nasal spray and ibutilide fumarate injection are consistent in pharmacokinetic and pharmacological effects.

After reading the description of this patent application, technical personnel can make various changes and modifications, but these changes and modifications are all within the protection scope of the pending claims.

Claims (2)

1, a kind of Ibolite fumarate spray of via intranasal application administration is characterized in that comprising in 100 milliliters the described preparation:

50 milligrams of Ibolite fumarates,

Absorption enhancer HP-2.5 grams,

Antiseptic ethyl hydroxybenzoate 0.1 gram,

Osmotic pressure regulator mannitol 0.5 gram,

1.0 milliliters of thickening agent PEG400s,

Distilled water to 100 milliliter.

2, a kind of Ibolite fumarate spray of via intranasal application administration is characterized in that comprising in 100 milliliters the described preparation:

150 milligrams of Ibolite fumarates,

Absorption enhancer methyl-beta-schardinger dextrin-5.0 grams,

Antiseptic ethyl hydroxybenzoate 0.1 gram,

Osmotic pressure regulator mannitol 2-4 gram

Thickening agent polyvinyl alcohol 0.5 gram,

Distilled water to 100 milliliter.