1. Field of the Invention
The present invention relates to a method in a drug delivery system (hereinunder referred to as "DDS") and, more particularly, to a drug release controlling method which enables the release of any given drug on a carrier or a drug holding structure to be controlled from the outside in a non-contacting state by using a resonant sound wave (acoustic oscillatory wave including an ultrasonic wave) having a frequency corresponding to the resonance frequency of the drug carrier or the drug holding structure. This method is useful in the medical field and the like.
2. Description of the Related Art
Cancer which ranks as one of the principal death causes of Japanese and thrombosis in ischaemic heart diseases the case rate of which has recently been increasing are local lesions. However, since they are lethal, it is often inevitable to use drugs having a strong effect against such diseases even if the side effects of the drugs to the whole body are strong. Development of a method of administering a drug only to the diseased region has therefore been strongly demanded.
To meet such demand, various DDS's (drug delivery systems) for executing the maximal effective cure by drugs while suppressing the side effects by controlling the desired absorption passage, degradation rate, metabolization rate and the like in place of simply administering the drug as it is have been proposed. For example, the following techniques and systems have been proposed: (1) a technique of forming an effective drug into a prodrug or an antidrug, (2) a pharmaceutical technique such as a technique of improving a base of a long-time acting drug for oral administration and a technique of forming a drug contained in microcapsules or liposomes, (3) prevention of the long-time action and the first pass in the liver (metabolization of a drug at the first circulation in the liver after absorption) of an endermic drug, (4) what is called missile cure in which a drug is connected with a monoclonal antibody as a targeting therapy, (5) a system in which a drug is connected with a magnetic material so as to electrically induce the drug from the outside of the body and (6) a system in which a persistent pouring pump embedded in the body is used.
A comparatively similar technique to that of the present invention in the respect that an ultrasonic wave is utilized for the control of the release of a drug is reported under the title of "Ultrasonic Control of Drug Releasing" in Jpn. J. Artificial Organs, Vol. 13, No. 3, pp. 1205 to 1208 (1984). According to this report, a planar substrate is formed from a matrix with a drug dispersed therein and the planar substrate is heated by strong ultrasonic irradiation so as to accelerate the drug release. However, this technique does not solve the problem in the applicability to the living body.
It is conventionally known that an ultrasonic wave exerts an effect on special chemical substances themselves. For example, an alkali solution of luminol causes an especially strong chemical luminescence by ultrasonic irradiation. Although drugs having such an acoustochemical action are greatly restricted, it is reported as the result of study of the application of photodynamic therapy to an ultrasonic range that some anticancer agents such as hematoporphyrin, which is a porphyrin derivative, enhance the cytotoxicitic effect as an acoustochemical action. This is reported in "Combination treatment of Ultrasound and Drug on Tumor" in Proceddings of the 54-th Meeting of the Japan Society of Ultraxonics in Medicine, pp. 257 to 258 (1989), and, as a serial report, the localization of a strong ultrasonic sound field and enhancement of the cytotoxicitic effect realized by the focalization of an ultrasonic beam is described under the title of "Localization of Sonodynamic Effect for Cancer Treatment: Study of Acoustic Chemical Therapy (II)" in Proceedings of the 55-th Meeting of the Japan Society of Ultrasonics in Medicince, pp. 683 to 684 (1989).
None of these methods described above, however, satisfy all of the following five important conditions that the drug delivery systems are required to satisfy in the clinical application thereof: 1) that it is possible to control drug delivery so that only an organ unit or a diseased region spatially limited in the body is targeted or subjected to concentrated administration of the drug, 2) that it is possible to release or activate a drug at any time after administration, 3) that there is a method of observing the distribution state and the concentration of a drug in order to satisfy the conditions 1) and 2), 4) that the drug delivery system is applicable to any kind of drug and 5) that the drug delivery system is non-invasive. Although there are techniques which satisfy one to about three of these conditions, if any one of these conditions is unsatisfactory, the drug delivery system cannot be said to be complete as medication.
For example, a missile cure which is one of targeting therapies and in which a drug is combined with a monoclonal antibody by applying an immunological technique is thought to satisfy the above conditions. However, since cross-reaction, which is a binding of non-specific antibodies between various tissues, is considerably large, it is often difficult to satisfy the condition 1). In addition, even the pre-stage process in which the drug is combined with the antibody while keeping the activity of the drug is not easy. Even if these problems are solved, it is impossible to control the targeting of the drug after administration from the outside of the body. Furthermore, in the observation of the distribution state of the drug from the outside of the body, it is impossible to observe even the rough distribution of the drug in the body unless a substance harmful to the living body such as radioactive isotope is added to the drug.
A drug releasing method using a planar substrate with a drug applied thereto and a method of utilizing an acoustochemical action has the following defects which make the application thereof to the living body difficult.
The method of irradiating a planar substrate with a drug applied thereto with a strong ultrasonic wave so as to raise the temperature and accelerate the drug release is defective 1) in that a large planar substrate put into the body is invasive and it is impossible to form a planar substrate so smaller than the erythrocyte (not more than about 0.008 mm in major axis) as to enable intravenous injection into the vessel, and to hold planar substrates in the state in which the planes are arranged in the same direction, 2) in that since the drug releasing effect is different depending upon the angle between the projected beam of an ultrasonic wave and the planar substrate, quantitative control is difficult and 3) in that there is no drug releasing effect unless the sound pressure exceeding the value tolerable to the living body is used. According to "Ultrasonic Control of Drug Releasing" described above, in the experiment of a system in which 2.4% of methyl orange as an indicator drug was dispersed in the matrix of a planar substrate of polymethyl methacrylate, the drug release showed a high value by ultrasonic irradiation at any of the sound energy intensities of 1, 2, and 3 W/cm.sup.2. However, the intensity of ultrasonic wave which is permitted by the spatial average-temporal average intensity standard for electronic scanning ultrasonic diagnostic apparatuses which is regulated by JIS is not more than 100 mW/cm.sup.2 in the mode A, 10 mW/cm.sup.2 in the mode B and not more than 40 mW/cm.sup.2 in the mode M except for embryos, and not more than 10 mW/cm.sup.2 in each mode for embryos. The permissible intensity of ultrasonic wave applied to the living body is 240 to 1,000 mW/cm.sup.2. Therefore, the strong ultrasonic wave at a sound energy density of 1 to 3 W/cm.sup.2 has many problems in the application to the living body.
The application of the method of utilizing an acoustochemical action to the living body is defective 1) in that since this method utilizes an acoustochemical effect on a drug itself and few drugs exhibit an ultrasonic chemical action, this method is applicable only to the limited drugs which show an acoustochemical effect, 2) in that even in the case of applying this method to the drugs which show an acoustochemical effect, a sound pressure required usually exceeds the value permissible to the living body and 3) in that since it is impossible to observe the distribution of administered drug in the body, feedback control for the optimum drug release is difficult.