JPH03115219A - Nasal administration preparation - Google Patents

Abstract

PURPOSE:To obtain the title preparation containing denopamine as an active ingredient and capable of quickly absorbing an active ingredient to give high concentration in blood and quickly recovering blood pressure of patient having low blood pressure without accompanying excess increase of blood pressure, tachycardia and arrhythmia. CONSTITUTION:The aimed preparation containing denopamine as an active ingredient. Denopamine having chemical name of [(-)-R-1-(p- hydroxyphenyl)-2-[(3,4-dimethoxyphenetyl)amino]ethanol] and being used as cardiac is used as nasal administration preparation in either one preparation type among solution and aqueous gel. The preparation can be used alone or together with surfactant and thickener. The solution is used by dissolving diluted hydrochloric acid, citric acid buffer solution, etc., in an acidic aqueous solution or acidic buffer. The aqueous gel is prepared using a natural rubber, methyl cellulose, etc. An effective ingredient concentration of the preparation is preferably 0.25-1.0wt.% and pH thereof is preferably 4-6.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a nasal preparation of denopamine useful as an antihypertensive agent.

(Prior Art) Denopamine [chemical name: (-) -R-1-(p-hydroxyphenyl)-2-((3,4-dimethoxyphenethyl)aminocoethanol]) has been used clinically as a cardiotonic agent. It is known as a drug with little effect on heart rate, blood pressure, and arrhythmia [Japanese Journal of Pharmacology (Japan,
J. Pharmacol, ) Vol. 35, 415-4.
23 pages].

However, since this drug is clinically used exclusively as an oral preparation, there are restrictions on who can administer it, such as difficulty in administering it to unconscious patients under anesthesia or patients with gastrointestinal disorders. It is said that it takes 1 hour for an orally administered preparation to reach the maximum blood concentration.

By the way, if a patient undergoes surgery or undergoes anesthesia and suffers from sudden hypotension, severe hypoxia and blood clot formation may occur.
Because it can be life-threatening, vasoconstrictors such as epinephrine, noradrenline, and norphenephrine hydrochloride are clinically used for its treatment.

However, these drugs have drawbacks such as causing an excessive increase in blood pressure and tachycardia, or difficulty in achieving rapid action.

(Structure and Effects of the Invention) The present invention relates to a nasal preparation useful as an antihypertensive agent containing denopamine as an active ingredient.

The formulation of the present invention allows denopamine to be rapidly absorbed by nasal administration to obtain a high blood concentration, thereby quickly reducing the blood pressure of hypotensive patients without causing an excessive increase in blood pressure or tachycardia or arrhythmia. It has an excellent feature of being able to recover.

The nasal preparation of the present invention can be used in either solution or aqueous gel form. Furthermore, denopamine can be used alone or, if necessary, in combination with a surfactant or a thickener.

Solutions of denopamine can be prepared by dissolving it in acidic aqueous solutions or acidic buffers; acidic aqueous solution or phosphate buffer,
Any acidic buffer such as citrate buffer, acetate buffer, tartrate buffer, etc. can be suitably used.

Denopamine aqueous gel is a commonly used gel base,
For example, it can be prepared by gelling denopamine in an aqueous solution using natural rubbers, methylcelluloses, acrylic acid polymers, vinyl polymers, polysaccharides, or the like.

The concentration of denopamine contained in such formulations ranges from 0.025 to
Preferably, the pH of the formulation is in the range of 1.0% by weight.
is preferably in the range of 4 to 6.

Surfactants that can be added to the denopamine solution or aqueous gel include nonionic surfactants such as higher fatty acid glycerin esters, higher fatty acid clamps, polyoxyethylene compounds, and saponin; salts of higher fatty acids, and higher alcohol sulfuric esters. , anionic surfactants such as higher alkyl phosphate esters; cationic surfactants such as substituted or unsubstituted alkyl quaternary ammonium salts; amphoteric surfactants such as lecithin, and the like can be used.

As the thickener, polysaccharides, gelatin, polyvinyl alcohol and its derivatives, polyethylene glycol, etc. can all be suitably used.

In addition, lower alkanols, dimethylformamide, glycerin esters, cyclodextrin, sodium salicylate, propylene glycol, dimethylacetamide, etc. may be added as absorption enhancers to the nasal preparations of the present invention, if necessary. Often, or with disinfectants such as paraoxybenzoic acid esters, propylene glycol, benzethonium chloride, and sodium sorbate.
Additional additives such as preservatives and stabilizers may also be added.

Furthermore, commonly used antioxidants such as vitamin E1 butylhydroxyanisole are added to these preparations, and
Natural or artificial flavors such as peppermint oil, lemon oil, olive oil, citral, menthol, vanillin, cinnamaldehyde, etc. may also be added.

The nasal preparation of the present invention can be used by dropping or spraying it into the nostrils, and the dose of denopamine per dose is generally 5 to 50% depending on the age, sex, and weight of the patient, as well as the type and severity of the disease. It is preferable to adjust the amount of dropping and spraying so that the amount is 15 cm/kg.

The nasal preparation of the present invention is said to be capable of restoring the blood pressure of hypotensive patients to the normal range without causing side effects such as an excessive increase in blood pressure, tachycardia, or arrhythmia due to the pharmacological properties of denopamine itself. , has excellent characteristics as an antihypertensive agent.

In addition, since denopamine can be well absorbed by patients through the nasal mucosa, there is no pain during administration as with injections, and continuous administration is possible. It has the advantage that it can be administered even to patients who cannot be administered orally, such as patients without cancer. Moreover, since the maximum blood concentration can be achieved in approximately 10 minutes after nasal administration, the optimal dose can be easily selected while observing the patient's condition, and it can also quickly improve blood pressure in patients with severe hypotension. There is also the advantage of being wet.

Furthermore, since the active ingredient denopamine can enhance myocardial contractility, when administered to a patient, it can also provide a cardiotonic effect.

Clinical case 1 62-year-old male (no past medical history, ASA risk: 1) Name of disease: A combination of thoracic epidural anesthesia and general anesthesia was used to remove a gallbladder stone. Blood pressure and pulse when entering the operating room were 155 (systolic)
/75 (diastolic) 1111g and 75 beats/m
It was in. Local narcotic for epidural anesthesia 2% carbocaine c-g name: mebivacaine hydrochloride/epinephrine] 10ml
was injected into the dural valve cavity. Blood pressure and pulse just before were 165
(systolic)/90 (diastolic) mtlg and 80baa
ts/min. 35 minutes after administration, a 0.5% hydrochloric acid solution containing 10 mg of denopamine was instilled into the nose. Changes in blood pressure, pulse rate, and blood concentration of denopamine over time are as shown in Table 1 below.

Table 1 *: Time elapsed since the first carpo-in administration. Also, 75 minutes and 130 minutes after the first carpo-in administration,
Carpoin was additionally administered for 5 d each, but the systolic blood pressure was 1.
The temperature did not drop below 00 mmHg.

Clinical case 2 73-year-old female [Past history: hypertension, ASA risk: 3, (T wave inversion on electrocardiogram ■2-6)] Disease name: Gallbladder, common bile duct stone. Thoracic epidural anesthesia for cholecystectomy and common bile duct incision. and general anesthesia were used. Blood pressure and pulse when entering the operating room were 2.
10 (systolic)/120 (diastolic) 11g and 8
It was 0 beats/lll1n. 2% Calpoin 10- was injected into the dural valve space. After 50 minutes, an additional dose of 2% carpolytein 5 was administered. Blood pressure and pulse rate at the time of additional administration were 170 (systolic)/95 (diastolic) wllg.
and 55 beats/lll1n. Thirty minutes after the additional administration, a 0.5% hydrochloric acid solution of 10 μm of Denopamine was instilled into the nose. Furthermore, 15 minutes after the administration of denopamine, 2% carbocaine 5- was administered again. Changes over time in blood pressure, pulse rate, and blood concentration of denopamine are shown in Table 2 below.

Table 2*: Time elapsed since the second carbocaine administration Clinical case
3. 53-year-old male [Past history: hypertension, ASA risk: 2, (complete right bundle branch block on electrocardiogram)] Diagnosis: blind gallbladder stone. Thoracic epidural anesthesia and general anesthesia were administered in combination for removal of the gallbladder. Blood pressure and pulse when entering the operating room were 155 (systolic)
/98 (diastolic) mHg and 92 beats/min
, it was torn. 2% carbocaine 101Ri was injected into the dural valve space. Blood pressure and pulse just before were 150 (systolic)
/98 (diastolic) n+1g and 92 beats/m
It was in. 40 minutes after administration, 21 nl of a 0.5% hydrochloric acid solution containing 10 μl of Denopamine was intranasally administered. Changes over time in blood pressure, pulse rate, and blood concentration of denopamine are shown in Table 3 below.

Table 3 *: Time elapsed since carbocaine administration Also, after denopamine administration, 2% carpocaine was administered for 5 m
Despite administering 1 dose twice, the systolic blood pressure did not fall below 1100n11.

pn Clinical case 4 58-year-old male [Past history: adhesive ileus, ASA risk =
2 (Moderate decline in renal function) Disease name: Adhesive ileus Intestinal incision was performed to relieve the ileus. A combination of thoracic epidural anesthesia and general anesthesia was used. Blood pressure and pulse rate at the time of admission to the operating room were 110 (systolic) 150 (diastolic) l11 (g and 85 beats/min). 2% carbocaine 10d was injected into the dural valve space. Pulse is 115 (systolic) 150 (diastolic) + nHg and 8
It was 3 beats/min. 15 minutes after administration,
A 0.5% hydrochloric acid solution containing 10 μm of Denopamine was instilled into the nose.

Changes over time in blood pressure, pulse rate, and blood concentration of denopamine are as shown in Table 4 below.

Table 4 *: Time elapsed since carbocaine administration Further, 2% carbocaine 5N1 was additionally administered 38 minutes after carbocaine administration, but there was no blood pressure change.

Clinical case 5 64-year-old male [Past history: None, ASA risk: 2 (left ventricular hypertrophy found on chest X-ray and electrocardiogram)] Disease name: Rectal tumor Rectal amputation was performed in combination with thoracic epidural anesthesia and general anesthesia. . Blood pressure and pulse when entering the operating room were 170 (systolic)
/93 (diastolic) mmHg and 70 beats/mi
It was n. 2% Carpozein 12- was injected into the dural valve space. Blood pressure and pulse just before were 165 (systolic)/
80 (diastolic) mHg and 75 beats/min,
Met. 35 minutes after administration, 2% carpolytein 5- was additionally administered. Twenty-two minutes after the additional administration, 2 ml of a 0.5% hydrochloric acid solution containing 10 drops of Denopamine was intranasally administered. Furthermore, 2% carpolyne 5- was administered again 20 minutes after the administration of denopamine. Changes over time in blood pressure, pulse rate, and blood concentration of denopamine are as shown in Table 5 below.

Table 5 *: Time elapsed since the first administration of carpolyte In addition, 5 doses of 2% carpolyne were administered 72 and 117 minutes after the administration of denopamine, but the blood pressure did not decrease.

Clinical case 6 68-year-old male [Past history: hypertension and adhesive ASA
Risk: 3] Disease name: Pancreatic head tumor Due to residual pancreatic drip, thoracic epidural anesthesia and general anesthesia were administered in combination. Blood pressure and pulse when entering the operating room were 135 (systolic)
/70 (diastolic) mmtlg and 95 beats/
It was min. 7 ml of 2% carbocaine was injected into the dural valve space. Blood pressure and pulse just before were 140 (systolic)/70 (diastolic) + nHg and 95 beats/
It was min.

Twenty-five minutes after administration, a solution of 10 μm of Denopamine in 0.5% hydrochloric acid was intranasally administered. Changes over time in blood pressure, pulse rate, and blood concentration of denopamine are shown in Table 6 below.

Table 6 *

Claims (1)

[Claims] 1. A nasal preparation containing denopamine as an active ingredient. 2. The nasal preparation according to item 1, which is obtained by dissolving denopamine in an acidic aqueous solution or an acidic buffer. 3. The nasal preparation according to item 1 or 2, which is an antihypertensive agent.