JP4857430B2 - Patch-type cardiotonic - Google Patents

Description

  The present invention relates to a patch type cardiotonic drug. In particular, it relates to a patch type cardiotonic agent for chronic heart failure.

  Cardiotonic drugs are drugs that increase the concentration of free calcium in the myocardium and increase the contractile force of the myocardium, and cardiac glycosides such as digitalis are generally used. Inotropic drugs are classified into cardiac glycosides (digitalis), phosphodiesterase inhibitors, adrenergic beta receptor agonists and vasodilators.

The mechanism of action of cardiotonic drugs is roughly classified into two. One is binding to Na + / K + ATPase in the cardiomyocyte membrane to increase Na + in cardiomyocytes, thereby inhibiting Ca2 + outflow by Na + / Ca2 + exchanger using Na + concentration gradient, resulting in cells Myocardial contractile force increases with increasing Ca2 + concentration. Second, increase cAMP concentration in cardiomyocytes. An increase in intracellular cAMP concentration leads to activation of protein kinases and activation of Ca channels, and also increases intracellular Ca ion concentration. There are two additional mechanisms. One is an increase in cAMP production by the activation of adenylate cyclase via β receptor stimulation. Examples of drugs based on this mechanism include catecholamines and β receptor stimulants. The other is suppression of cAMP degradation by inhibiting phosphodiesterase activity. Examples of drugs based on this mechanism include caffeine and methylxanthines.
Japanese Unexamined Patent Publication No. 4-99720 Japanese Patent Laid-Open No. 7-285854 Japanese Patent Laid-Open No. 11-228395 WO97 / 14411

  By the way, among the above-mentioned cardiotonic drugs, β receptor stimulants which are cardiotonic drugs used for the treatment of chronic heart failure are administered intravenously. However, repeated intravenous administration and long-term continuous intravenous administration not only suffer from pain and risk of infection and bleeding, but also cause inflammation in the blood vessel of the administration subject and eventually make it unusable as an administration site. There are internal medicines (oral medicines), but when used in combination with other oral medicines, there is a problem that the number of combined use increases. In the case of internal medicine (oral medicine), there is also a problem that the change in the blood concentration of the active ingredient is large. Furthermore, in unconscious patients or patients with ventilators, there are only drug administration methods such as administration of internal medicine from a stomach tube or long-term continuous intravenous administration. In the former case, there is a risk of aspiration pneumonia or suffocation if the tube is mistakenly inserted into the trachea, and in the latter case, there is a risk of infection / bleeding or vasculitis from the puncture site.

  Accordingly, an object of the present invention is to provide a cardiotonic agent capable of treating chronic heart failure without using intravenous injection or oral administration.

  This invention which solves the said subject is a cardiotonic agent which is a patch which contains tulobuterol as an active ingredient. This cardiotonic drug is particularly effective for the treatment of chronic heart failure.

According to the present invention, a cardiotonic drug capable of treating chronic heart failure without depending on intravenous administration can be provided. The patch type cardiotonic agent of the present invention has the following effects.
1) Since a drip needle is not used, the risk of bleeding and infection associated with administration is reduced.
2) Can be used under the supervision of a doctor, even if you are not qualified for intravenous injection.
3) Since the oral route is not used, the number and types of oral drugs are not increased.
4) Remove the drip, increase the range of activities, and increase the possibility of being discharged.
5) It can be easily reduced or removed during adverse effects.
6) The patient can be administered without risk of aspiration pneumonia / suffocation, infection of the puncture site, bleeding, or vasculitis even in an unconscious patient or a patient with a ventilator.
7) Patches containing tulobuterol as an active ingredient (Hoknarine tape) have already been confirmed to be safe for humans as bronchial asthma drugs.
8) Since the cardiotonic effect was confirmed in dogs, it is also effective for the treatment of animals (mammals) other than humans such as pets. In animals other than humans (mammals), oral administration and intravenous administration may be difficult. However, since the patch-type cardiotonic agent of the present invention is a patch, it can be easily administered.

  The present invention is a cardiotonic agent which is a patch containing tulobuterol as an active ingredient. Tulobuterol has already been put to practical use as a therapeutic agent for bronchial asthma, bronchitis, emphysema and the like because it has a bronchodilating action.

  A patch (percutaneous absorption type preparation) containing tulobuterol as an active ingredient has already been put into practical use as a therapeutic agent for bronchial asthma, bronchitis, emphysema and the like.

  For example, JP-A-4-99720 (Patent Document 1), JP-A-7-285854 (Patent Document 2), JP-A-11-228395 (Patent Document 3) include patches containing tulobuterol as an active ingredient. ) And WO97 / 14411 (Patent Document 4).

  In Japanese Patent Laid-Open No. 4-99720, a base material layer containing tulobuterol in a pressure-sensitive adhesive is formed on a carrier, and the pressure-sensitive adhesive is mainly composed of polyisobutylene. Pharmaceutical formulations for skin administration are disclosed. By using polyisobutylene as a pressure-sensitive adhesive, it is possible to ensure sustained release and stability of tulobuterol. In particular, the pressure sensitive adhesive has a first polyisobutylene having a viscosity average molecular weight of 500-4000, a second polyisobutylene having a viscosity average molecular weight of 10,000-200000, and a third polyisobutylene having a viscosity average molecular weight of 900,000-200000. It is described that it is a mixture of two or more kinds of polyisobutylenes selected from the group consisting of: Preference is given to pressure sensitive adhesives comprising 10 to 80% by weight of third polyisobutylene, 0 to 80% by weight of first polyisobutylene and 0 to 90% by weight of second polyisobutylene. Furthermore, a thermoplastic resin can be contained in the pressure-sensitive adhesive.

  In JP-A-7-285854, a paste layer containing tulobuterol having a saturation solubility or higher with respect to the adhesive is laminated on one side of a support, and the content ratio of crystalline tulobuterol to dissolved tulobuterol in the plaster layer Disclosed is a transdermally absorbable preparation having an A of 0.1 to 10. This transdermal preparation reduces discomfort and skin irritation during application to patients, prevents terminal peeling and dropout due to decreased skin adhesion, and causes serious damage due to rapid increase in blood concentration of drugs. Prevent the development of unwanted side effects. Moreover, it is not necessary to contain an excessive drug in the plaster layer, which is excellent in economic efficiency. Tulobuterol is continuously and efficiently released to the skin surface and percutaneously absorbed into the living body for a long period of time, so that sustained drug efficacy can be achieved. Therefore, maintenance of effective blood concentration, that is, sustained drug efficacy is excellent. Since the number of administrations (number of application per unit time) can be reduced, skin irritation is reduced.

  Japanese Patent Application Laid-Open No. 11-228395 discloses a percutaneously absorbable preparation in which a paste layer containing tulobuterol and an adhesive is laminated on a support, and 5 in the dissolved state in the paste layer. A percutaneous absorption preparation containing at least wt% is disclosed. This percutaneous absorption-type preparation is retained in the plaster layer in a state where tulobuterol, which is a medicinal ingredient, is completely dissolved, so that there is no change in the drug release property and adhesive physical properties associated with drug crystal precipitation over time, Excellent percutaneous absorption of drugs, especially percutaneous absorption rate at the initial stage of administration, long-lasting efficacy by maintaining effective blood concentration for a long time, and changes in adhesive physical properties such as skin adhesion over time It has been reduced.

  WO97 / 14411 discloses a transdermal absorption type tulobuterol preparation, particularly a fine crystal, in which an adhesive layer mainly composed of a synthetic rubber containing fine crystalline tulobuterol having an average particle diameter of 2 to 20 μm and a support are laminated. Disclosed is a transdermal tulobuterol preparation in which a tubular tulobuterol is obtained by recrystallizing after dissolving tulobuterol and an adhesive mainly composed of synthetic rubber in a good solvent. This percutaneously absorbable tulobuterol preparation is excellent in the sustained efficacy of tulobuterol.

  The patch type cardiotonic agent of the present invention is any of the percutaneously absorbable tulobuterol formulations described in JP-A-4-99720, JP-A-7-285854, JP-A-11-228395, and WO97 / 14411. It can also be.

  The patch type cardiotonic agent of the present invention is administered by being applied to the skin. The dose is appropriately determined based on the judgment of the doctor when the recipient is a human in consideration of the situation of the recipient, but usually, for example, 0.5 to 10 mg / sheet of patch is administered per day. This is done by sticking once. In addition, the patch type cardiotonic drug of the present invention can be administered to a mammal other than a human, and the dosage in that case depends on the type of mammal (other than a human) that is the recipient. It is determined as appropriate based on the judgment of the doctor.

  The patch type cardiotonic agent of the present invention is useful as a percutaneous absorption type therapeutic agent for heart failure.

Hereinafter, the present invention will be described in more detail with reference to examples.
Experimental method A beagle dog was ligated with silk thread under the left anterior descending branch under anesthesia, and a myocardial infarction model was prepared. The dog was closed and extubated and recovered, and tulobuterol was administered 2 weeks later with chronic heart failure. Five dogs were reapplied under anesthesia and the abdominal shaved part was applied with 1 mg / kg of hokunarin tape (2 mg / sheet) as tulobuterol. The following physiological indicators were measured and compared using arterial catheterization, thermodilution catheterization, and echocardiography immediately before application and 2 hours after application. The results are shown in Table 1.

Physiological indicators Heart rate (HR), mean blood pressure (mAP), cardiac output (CO), pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP), left ventricular pressure first derivative maximum (maxdP / dt), left ventricular pressure first derivative minimum (mindP / dt), peripheral vascular resistance (SVR), left ventricular end-diastolic diameter (LVDd), left ventricular myocardial shortening rate (LVFS), left ventricular ejection fraction (LVEF).

  For statistical analysis, paired t test was performed using StatView statistical package (SAS Institute). Data were expressed as mean ± standard deviation, and p <0.05 was determined to be statistically significant. NS was indicated as no significant difference.

From the above results, the following can be said.
1) The dog myocardial infarction model showed heart failure before administration (CO, maxdP / dt, mindP / dt, LVFS, LVEF low, PCWP, LVEDP, SVR high).
2) Transcutaneous administration of tulobuterol in this post-myocardial infarction heart failure model not only improved the cardiac contractility index (CO, maxdP / dt, LVFS, LVEF) but also the cardiac expansion index (mindP / dt, PCWP, LVEDP) ) Also improved. These were considered to show the effect of tulobuterol as a therapeutic agent for heart failure.
3) This effect was presumed to be due to the cardiotonic action (indicated by improvement in CO, maxdP / dt, mindP / dt, LVFS, LVEF) and vasodilatory action (indicated by improvement in PCWP, LVEDP). . Although no statistically significant difference was detected, the decrease in MAP (p = 0.06) and SVR (p = 0.05) was considered to indicate vasodilatory effect.

According to the present invention, a patch type cardiotonic drug can be provided.

Claims (2)

A therapeutic agent for chronic heart failure , which is a patch containing tulobuterol as an active ingredient. The therapeutic agent for chronic heart failure according to claim 1 , which is used for treatment of humans and mammals other than humans.