JP3102655B2 - Ultrasound controlled drug release formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for releasing an active drug in a living body when needed. More specifically, the present preparation is embedded at an arbitrary position determined by a disease, and the ultrasonic wave generator generates ultrasonic waves having an intensity that does not damage a living body, thereby controlling the penetration rate of the drug through the substance-permeable portion of the preparation. The present invention relates to techniques that can control and optionally control drug release from a formulation.

[0002]

2. Description of the Related Art In recent years, a drug delivery system (Drug) that supplies a required amount of a drug, when necessary, to a required affected area to maximize the efficacy and minimize side effects.
Delivery System, DDS) is being developed. For example, in order to bring out the efficacy of a bioactive substance having a short half-life in a living body, a sustained-release preparation (Japanese Patent Laid-Open No. 62-174031) that extends the living time in the living body, or a drug administered in accordance with the biological rhythm. For this reason, pulsatile drug release by multi-layered preparations and the like (JP-A-63-239212) are also being studied. JP
JP-A-62-174007 and JP-A-62-174031 disclose reservoir-type preparations in which a silicone elastomer film is used as a drug container and the drug enclosed therein is continuously transmitted and released for a long time.

[0003] However, depending on the drug, if it exists in the living body for a long time, the target receptor may be reduced, and the drug effect may be reduced. In addition, the drug may be needed periodically in a living body, and in these cases, conventional sustained release technology alone cannot cope. In addition, the rhythm of the living body is specific to each individual, the time when the drug is required is not constant, and sometimes the time when the medication is required at random, such as a seizure state, may occur. In some cases, it is not possible to cope with a preparation in which the release cycle of the drug is determined in advance, such as a preparation. Therefore, there is a demand for the development of a formulation capable of arbitrarily controlling drug release.

[0004] Such preparations are being actively studied in companies and universities. For example, the following DDS is used in combination with ultrasonic waves for controlling the drug release / elution process. Miyazaki et al. Have shown that insulin can be retained by hydrophilic ethylene-vinyl alcohol copolymer membrane and release can be controlled by heating the carrier by ultrasonic irradiation (J. Pharm. Pharmacol., Vol. 40, pp.716-717,1988). Negishi et al. Show that matrix-type preparations using polyethylene, polymethyl methacrylate, polystyrene, and collagen having different ultrasonic absorption coefficients as carriers, and that the carrier is heated by ultrasonic irradiation to promote the release of the anticancer drug methotrexate from the carrier. (Artificial organs vol. 13 (3), pp.1205-12
08,1984). Further, as a method by ultrasonic irradiation utilizing an action other than heating, R.S. LANGER et al. Used a biodegradable carrier such as a polyanhydride matrix (eg, [bis (p-carboxyphenoxy) alkane anhydride]) or a copolymer of ethylene and vinyl acetate containing insulin or a pheromone. Embedding methods are known. In other words, in addition to drug release due to biodegradation of the carrier, irradiation with ultrasonic waves can increase the drug release amount due to carrier destruction due to shock waves, and release amount due to cavitation caused by ultrasonic irradiation Has been reported (JP-A-63-315).
No. 37). There is also a method in which a drug is put in a resonator and the drug is urged to be released by irradiating a natural resonance ultrasonic wave from outside the body (Japanese Patent Laid-Open No. 2-144075).

[0005]

As described above, various techniques for controlling the release of drugs using ultrasonic waves have been studied, but no satisfactory technique has been found yet. That is, with respect to arbitrary release control, one that utilizes the action of heat becomes a problem when there is an external thermal stimulus. For example, drug release may be caused by seasonal fluctuations or generation of heat in daily life (such as during bathing).
In addition, conventional matrix-type preparations and reservoir-type preparations using a hydrophilic polymer cannot maintain the OFF state because spontaneous release is large for ON-OFF control of release. R. In a matrix-type preparation using a biodegradable carrier of LANGER et al., The drug is released before the irradiation of the ultrasonic wave only by being implanted in the living body. Therefore, it is not suitable when it is desired to obtain drug release only when necessary. In addition, matrix-type formulations generally have problems such as the drug content being limited by the size of the carrier, the amount of release being affected by the surface area of the formulation, and the amount of drug released naturally being large. .

[0006] The method using a resonator has a wide range of drug types, but has an advantage. However, there is a problem with a resonance container that opens and closes for drug release in resonance with ultrasonic waves (sound waves). There is no practical product that irradiates ultrasonic waves with a frequency that matches the frequency to open and close the valve port of the container in vivo.
Probably, one of the problems is that the ultrasonic energy level for opening and closing the container valve opening against the body tissue pressure or the blood pressure becomes very high.
Thus, there is no release of a drug due to a natural stimulus such as heat, and the release of the drug is controlled only by a stimulus that has been established to be safe for the living body. There is a situation in which the development of new formulations is desired.

[0007]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted intensive studies. As a result, the use of a silicone elastomer as a substance permeable portion of a reservoir-type preparation allows the use of a drug at the time of non-irradiation of ultrasonic waves. Is not released,
It has been found that the drug is released only during the ultrasonic irradiation (ON-OFF release), and the present invention has been completed.

That is, the present invention holds a drug inside,
It is used by being placed in any specific position of the living body, and increases the permeation rate of the drug by ultrasonic irradiation, and after the ultrasonic irradiation is stopped, a substance made of a silicone elastomer substantially impermeable to the drug permeates. The present invention relates to an in-vivo indwelling reservoir-type preparation characterized by having a portion. More specifically, the formulation of the present invention is a reservoir-type formulation in which a drug is held, and is a formulation in which the whole or a part of the reservoir is composed of a substance permeable portion. The formulation of the present invention emits almost no drug when not irradiated with ultrasonic waves.However, when irradiated with ultrasonic waves, the sound field effect significantly changes the network structure in the substance permeable portion, thereby significantly increasing the permeation rate of the drug. Is to be released.

According to the present invention, regardless of the shape and size of the drug storage container, ultrasonic waves are applied to the tissue structure interval or the membrane channel characteristics of the substance permeable portion to release the material. And thus the amount of drug released. That is, it is not the intrinsic resonance characteristics depending on the shape and size of the container described above, but rather the drug permeation characteristics of the preparation itself or the membrane itself as a wall of the preparation. The ultrasonic energy level that controls the amount of drug permeated through the membrane is not so high and can be controlled at a level applicable to the living body.

[0010] In the present invention, the substance permeable portion is made of a silicone elastomer. In the present invention, the silicone elastomer is an elastic body composed of a silicone polymer such as methylpolysiloxane, dimethylpolysiloxane, and dimethylmethylvinylpolysiloxane, and is not particularly limited as long as it is physiologically acceptable. Considering the easiness of the heat treatment and the stability of the substance to heat, a room temperature-curable silicone elastomer is preferable.
This is obtained by adding a vulcanizing agent (for example, stannas octate, chloroplatinic acid) to a liquid elastomer base to obtain a solid rubber.

Embedded image [In the formula, n represents an integer of 100 to 5000, and R represents a methyl group, a hydroxy group, or a vinyl group. A dimethylpolysiloxane such as Dow Corning (registered trademark) manufactured by Dow Corning.
360, Silastic® 382,
Dow Corning (registered trademark) MDX-
4-4210 and the like.

Or the formula:

Embedded image Wherein n is an integer of 100 to 10000, and m is 1 to 10
Indicates an integer of 0. Such as Silastic (registered trademark) Medical Grade ETR manufactured by Dow Corning.
The use of silicone polymers such as is recommended. Also,
The degree of crosslinking of the silicone elastomer can also be adjusted according to the drug or the permeation rate.

Further, by adding, for example, tungsten, carbon, or titanium, which does not affect the activity of the drug, to the substance permeable portion, the rate of transmission of the drug through the material permeable portion, which is increased by ultrasonic waves, can be suppressed. Therefore,
If this is applied, spontaneous release can be suppressed even for a drug having a large spontaneous release in the substance permeable portion, and the range of drugs applicable to the present invention can be expanded. These contents are not particularly limited as long as the necessary strength of the preparation is maintained in the living body implanted portion, but is preferably 50% or less of the silicone elastomer.

[0013] The thickness of the silicone elastomer constituting the substance-permeable portion is usually determined when the drug is a high-molecular substance such as human serum albumin or interferon, or a water-soluble low-molecular substance such as prostaglandin or 5-FU. The range is from 0.01 to less than 0.5 mm, preferably from 0.01 to 0.3 mm, particularly preferably from 0.01 to 0.15 mm. When the drug is a fat-soluble low molecular weight substance such as indomethacin, usually 0.1
~ 20mm, preferably 0.2 ~ 10mm, particularly preferably 0.5 ~
The range is 3mm. When a part of the reservoir is a material permeable portion, a portion other than the material permeable portion may be made of any material, but is preferably biocompatible, for example, polyurethane, Teflon, ceramic, or polypropylene.

According to the preparation of the present invention, not only can the drug be administered in accordance with the rhythm of the living body, but also the feedback mechanism of the living body due to excessive administration can be avoided. Further, in an emergency, a third party can irradiate the medicine even if the person is not conscious.
The drug in the present invention is not particularly limited from high molecular substances such as peptides, proteins, glycoproteins and polysaccharides to low molecular substances, but preferably has a molecular weight of 1,000,000 or less.
Further, for application to the present invention, a drug having a low permeability to the permeable portion of the silicone elastomer, or a drug whose permeability can be reduced to a level not exhibiting a medicinal effect by adding tungsten, carbon, or titanium to the silicone elastomer is preferable. .

[0015] Examples of applied drugs include growth regulating action,
Substances having a bone metabolism-related action, a thrombolytic action, an immunomodulatory action, an asthma suppressing action, an antipyretic analgesic / inflammation action, a cardiac function adjusting action, a blood sugar level adjusting action, a hypnotic sedative action, a cerebral circulation metabolism improving action, and the like. For example, applying indomethacin having an analgesic and anti-inflammatory effect to the present invention, for example, implanting in the vicinity of a joint, preventing the occurrence of side effects by administering a drug amount according to the degree of pain by ultrasound, and preventing pain You can respond immediately. Further, specific examples of applicable drugs are shown below.

As substances having a growth regulating action, for example, growth hormone (GH), growth hormone releasing factor (G
RF), and somatomedin (SM). G
RF is a peptide exhibiting GH releasing activity, and has several types of peptides consisting of 44, 40, 37 or 29 amino acids. The activity of each peptide has been recognized, but any of them may be used in the present invention. It may be a mixture. SM is recognized as a somatomedin group and includes SM-A, SM-B, SM-C and IGF (insulin-like growth factor) -I and IGF-II, as well as MSA (multiplication stimulating activity). Furthermore, SM-C is IGF
Although there is a report that the substance is the same as -I, any drug may be used in the present invention, or a mixture thereof. Examples of brain cell growth regulator include neurotrophic factor (NGF), brain-derived neurotrophic factor (BDNF), neurotropin-3 (NT-3), acidic or basic fibroblast growth factor (FGF), neuroblast Seed growth inhibitory factor (NGIF) and the like. It is more natural in terms of maintaining biological homeostasis that they repeatedly exist and disappear at a specific rhythm during the day than they always exist.
Therefore, it is suitable for the present invention.

Examples of drugs having a bone metabolism-related effect include calcitonin, parathyroid hormone, interleukin-1 (IL-1), tumor necrosis factor (TNF), and IGF. Examples of the drug having a thrombolytic action include tissue plasminogen activator (t-PA). Examples of drugs having an immunomodulatory effect include interferon (IFN), interleukin (IL), colony stimulating factor (CSF), macrophage activating factor (MAF), and macrophage migration inhibitory factor (MIF). The interferon mentioned here may be α, β, γ or any other interferon, or a combination thereof.
Similarly, interleukins are IL-1, IL-2, IL-2
-3 or any other, and the colony stimulating factor is multi
-CSF (multifunctional CSF), GM-CSF (granulocyte-
Monocyte macrophage CSF), G-CSF (granulocyte-C
SF) or M-CSF (monocyte macrophage CSF)
Any other CSF may be used, or a mixture thereof. Regarding MAF and MIF, each subtype expected to be purified and separated by future research is expected to be a glycoprotein or a protein having the same molecular weight. It is considered possible. Rather than continuous administration, administration of the drug again after the response due to the appearance of the activity has subsided can avoid overdose of the drug. Also, the present invention can reduce the frequency with which patients go to the hospital to receive administration. The peptides, proteins, glycoproteins and the like used in the present invention may be any of substances extracted from living organisms, artificially synthesized substances or those obtained by genetic recombination, without depending on the production method.

Examples of the drug having an asthma suppressing effect include theophylline. Examples of the drug having an antipyretic analgesic / inflammation effect include indomethacin, ibuprofen, ketoprofen, diclofenac sodium and the like. Examples of the drug having a cardiac function-regulating action include nitroglycerin, dopamine hydrochloride, digoxin, prossilalidine and the like. Drugs having a blood glucose level controlling action include, for example, insulin, and drugs having a hypnotic / sedating action include, for example, estazolam, rilmazahon hydrochloride, alprazolam and the like. Drugs having a cerebral circulation metabolism improving effect include prostacyclin and the like.

The content of the drug in the preparation of the present invention may be adjusted depending on the dose of the drug, the desired number of times of release and the amount, and the like. The drug remains in the body even after the release of the drug is completed.If the drug cannot be taken in and out frequently, it is preferable to fill the drug with an excessive amount, or a structure that allows external drug replenishment. It is desirable to keep it. Further, addition of an amino acid, glycerin, surfactant, albumin or the like together with the drug for improving the stability of the drug does not cause any problem as long as the spontaneous release is not affected. The ultrasonic wave used in the preparation of the present invention, when irradiated, may be any condition that does not damage the living body (does not cause cavitation), and the frequency is the kind and size of the preparation, the material, the film thickness, the properties of the substance, The optimum frequency may be selected according to the administration site. The preferred frequency is 20KH
The range is from Z to 20 MHz, more preferably from 50 KHz to 3 MHz. Regarding the safety of ultrasound for living organisms, the Committee on Ultrasound Medical Devices of Nippon Medical and Ultrasonics in 1984, about 1 W / cm ² for continuous waves and 240 mW / cm ² for SPTA (spatial peak time average intensity) for pulse waves. It is reported to be the minimum strength showing any effect. Therefore, for continuous waves, 1W / cm ² or less,
For pulse waves, SPTA of 240 mW / cm ² or less is suitable.
The waveform of the irradiation ultrasonic wave is a continuous wave, a periodic pulse-like waveform (the period may be regular, irregular or pseudo irregular).
Alternatively, a high-frequency pulse-like waveform (the period may be regular, irregular, or pseudo-irregular) may be selected, and the amplitude thereof may be selected to have a constant value over time, repeated decay, or increased repetition. Note that it is also possible to adopt a configuration composed of a combination of each waveform and amplitude.

The ultrasonic generator used in the present invention is not particularly limited. For example, (A) an ultrasonic generator (probe), (B) a transducer driving circuit, (C) a waveform generating circuit,
It comprises (D) a biological synchronization circuit, (E) a probe fixture, (F) a device portable holder, and (G) a power supply unit, or a part thereof. Further, a function of arbitrarily setting the ultrasonic irradiation time can be provided. The irradiating ultrasonic generator (probe) can have a shape according to a fixed part in a living body or a living body, and the generated ultrasonic sound field formed by the ultrasonic probe is obtained from the body surface of the drug in the living body. In the case of a plurality of container composites, the focal point of the ultrasonic sound field beam and the sound field forming position can be adjusted to match the position of each container. However, this includes non-focus.

The present apparatus can be housed in a cylindrical body integrating the above A to E, or, for example, an ultrasonic wave generating unit,
Each part of the apparatus can be separated via an electric wire, such as a part consisting of the probe fixture for the living body and the remaining part. It can be placed on a desk or bed, or carried directly by a human. The biological synchronization circuit has a function of synchronizing drug release with biological fluctuations, such as synchronizing ultrasonic irradiation with a heartbeat or synchronizing with respiration.

Next, the method for producing the preparation of the present invention will be described in detail. For example, a hollow preparation of a silicone elastomer having an arbitrary shape such as a tube is first obtained by casting. Next, a liquid preparation, a powder preparation, or a solid preparation of a silicone elastomer hollow preparation containing a drug to which additives such as a pharmaceutically acceptable stabilizer, preservative, release controlling agent, or dissolution aid are added as required. And then sealing both ends with silicone elastomer. In other words, the outside is made of a silicone elastomer, and a drug is contained in the inside of the silicone elastomer, thereby obtaining a membrane-permeable ultrasonic controlled release formulation that suppresses the permeation and release of the drug from the outside silicone elastomer. At this time, the encapsulated form of the drug is not limited, such as the drug alone, or a drug dispersed in a pharmaceutically acceptable carrier, such as a powder or granular drug dispersed in a fluid silicone elastomer. Can be The state of the enclosed contents is liquid, gel,
It is not particularly limited, such as solid. Examples of various pharmaceutically acceptable additives include water-soluble admixtures (eg, polyethylene glycol 400, polyethylene glycol 200, ethylene glycol, glycerol, polysorbetol 80, sodium alginate, L
-Alanine, sodium chloride), or a fat-soluble admixture (eg, polydimethyltylsiloxane).

The preparations of the present invention obtained by these methods can be spherical, hemispherical, cylindrical, button-shaped, sheet-shaped,
Any shape such as a capsule shape or a mushroom shape may be used as long as it is suitable for the site to be used. The administration method can be, for example, subcutaneous administration, implantation in a living body, insertion into the body and vagina, or placement in the brain. Although the size of the preparation is not limited, the diameter is particularly 4 mm or less (preferably 0.5 mm to 2 mm).
If it is formed into a column having a length of about 50 mm or less (preferably about 5 mm to 30 mm), it can be easily administered to a living body without surgery. That is, injection administration can be performed using an administration instrument such as a fiberscope, a forceps needle, or an indwelling needle described in JP-A-60-227772. More preferably, if the diameter is formed to be 1.7 mm or less, administration can be carried out more easily using a normal indwelling needle (14G). The button-shaped preparation is used by surgical placement, and its size is specified by the placement site and drug content. The size ranges from about 10 mm in diameter and about 5 mm in thickness to about 150 mm in diameter and about 40 mm in thickness. Is preferred. The sheet-shaped preparation is 10 mm on a side and 5 mm thick, like the button-shaped preparation.
A rectangular parallelepiped having a side of about 100 mm and a thickness of about 40 mm is preferable. Capsule preparation is 5mm in diameter and 10mm in length
It is preferable that the diameter is about 30 mm and the length is about 100 mm. For example, a mushroom-like preparation can be used by enclosing a drug in a mushroom cap portion and using the handle portion as a pipe for guiding the drug. This is particularly useful when it is desired to deliver a drug deep within the body. The size of this formulation is 20 mm to 100 mm in diameter of the shade part and 2 mm to 30 mm in thickness of the shade.
The length of the handle is not particularly limited as long as it is the length of the target organ.

[0024]

According to the present invention, a drug can be released using ultrasonic waves when necessary, so that a more natural effect can be expected and unnecessary side effects can be avoided. In addition, even when the person is unconscious due to seizures, a third party can operate ultrasound to administer the drug, and as an example of administering the drug to the brain, the drug is placed inside the skull. It is possible to administer the drug simply by irradiating it with ultrasonic waves from the scalp after being placed by surgery. This significantly reduces the risk of infection of the patient and the burden on the operation. Also, unlike conventional controlled release preparations by heat, drug release occurs depending on the strength of the sound field, so that drug release due to heating in daily life does not occur, and more secure and strict control is possible.

[0025]

The present invention will be described below in detail with reference to examples and experimental examples. Example 1 A silicone elastomer tube (Shirasucon (registered trademark) RX-5) having an outer diameter of 5 mm, an inner diameter of 4.92 mm, and a length of 13 mm.
0), 25% human serum albumin (HSA) aqueous solution 1
Add 60μl and add silicone elastomer adhesive (SILA
STIC® Q7-2947, Medical Adhesive Silicon
e) Sealed both ends to obtain a preparation. HSA content is 40mg
/ Formulation.

Example 2 A tube made of silicone elastomer having an outer diameter of 5 mm, an inner diameter of 4 mm, and a length of 10 mm (Silascon (registered trademark) RX-50)
And 40% of indomethacin suspended at a concentration of 5 mg / ml.
A polyethylene glycol aqueous solution (70 ml) was charged, and both ends were sealed with a silicone elastomer adhesive in the same manner as in Example 1 to obtain a preparation. Indomethacin content is 350 μg / formulation.

Example 3 Using a silicone elastomer tube (Silascon (registered trademark) RX-50) having an outer diameter of 5 mm, an inner diameter of 4.6 mm (film thickness of 0.2 mm) and a length of 10 mm, containing indomethacin in the same manner as in Example 2. A silicone reservoir type preparation was obtained. Example 4 Both ends of a silicone elastomer tube (Silascon (registered trademark) RX-50) containing 5 mm in outer diameter, 4.9 mm in inner diameter (0.05 mm in thickness), and 10 mm in length and containing tungsten were attached to a silicone elastomer formulation adhesive (SILASTIC ( (Registered trademark) Q7
-2947, Medical Adheslve Silicone), and 80 μl of a 40% aqueous solution of polyethylene glycol in which indomethacin was suspended at a concentration of 5 mg / ml was added to obtain a silicone reservoir formulation containing indomethacin. Indomethacin content averaged 400 μg / formulation.

Example 5 Using a silicone elastomer tube (Silascon (registered trademark) RX-50) having an outer diameter of 5 mm, an inner diameter of 4.92 mm (film thickness 0.04 mm) and a length of 10 mm, containing indomethacin in the same manner as in Example 2. A silicone reservoir formulation was obtained. Experimental Example 1 The preparation prepared in Example 1 was placed in a phosphate buffer (pH 7.4) kept at 37 ° C., and the amount of HSA released into the buffer over time was measured using a protein assay solution manufactured by BIORAD. , H
Quantification was performed using SA as a standard, and the effect of ultrasonic irradiation was examined. Ultrasonic conditions were 1 MHz, 0.6 w, and irradiation for 6 hours. As shown in FIG. 1, when the measurement was repeated three times, the emission amount was significantly increased during irradiation, while the detection amount was lower than the detection limit when not irradiated. After the irradiation was stopped, the emission amount returned to the state before the irradiation, indicating that the emission was promoted by reversible ultrasonic waves.

Experimental Example 2 The indomethacin-containing preparation prepared in Example 2 was placed in an aqueous solution of polyethylene glycol kept at 37 ° C., and the amount of indomethacin released into the aqueous solution was quantified by high performance liquid chromatography, and the effect of ultrasonic irradiation was obtained. Was examined.
The ultrasonic conditions were 1 MHz, 0.6 w, and irradiation for 2 hours.
When the test was repeated three times, a significant increase in the release was observed as compared with the case without irradiation. The result is shown in FIG. Experimental Example 3 Using the indomethacin-containing preparation prepared in Example 2, the effect of temperature on release was examined. The polyethylene glycol aqueous solution containing the formulation was replaced with a water bath at each temperature, such as 37 ° C. → 42 ° C. → 37 ° C., and the effect of temperature on the release was examined. As a result, as shown in FIG. 3, a slight increase in the amount of release was observed, but the increase was smaller than that during ultrasonic irradiation. Therefore, the result of FIG. 2 was confirmed to be an emission effect by ultrasonic waves.

Experimental Example 4 The indomethacin-containing preparation prepared in Example 3 was placed in an aqueous solution of polyethylene glycol kept at 37 ° C., the amount of indomethacin detected in the aqueous solution was quantified, and the amount of release before and after ultrasonic irradiation was examined. Was. The result was as shown in FIG. 4 below. The ultrasonic conditions were 1 MHz, 0.6 w, and irradiation for 2 hours. When the test was repeated three times, a significant release was observed as compared with the case without irradiation. Experimental Example 5 The indomethacin-containing preparation prepared in Example 4 was placed in an aqueous solution of polyethylene glycol kept at 37 ° C., the amount of indomethacin detected in the aqueous solution was quantified, and the amount of release before and after ultrasonic irradiation was examined. The result was as shown in FIG. 5 below. Ultrasonic conditions were 1 MHz, 0.6 w, and irradiation for 2 hours. Repeated twice. Spontaneous release is suppressed by using a tube containing tangstain,
There was a significant increase in release upon irradiation.

Experimental Example 6 The indomethacin-containing preparation prepared in Example 5 was placed in a polyethylene glycol aqueous solution kept at 37 ° C., the amount of indomethacin detected in the aqueous solution was quantified, and the amount of spontaneous release was examined. These were compared with the spontaneous release amounts of the indomethacin preparations in Experimental Examples 2, 4 and 5. The result was as shown in FIG. From these results, it was confirmed that the spontaneous release of indomethacin from the preparation was reduced because the hardness of the silicone elastomer film was increased by incorporating tungsten into the silicone elastomer film. It was revealed that spontaneous release from the preparation can be suppressed by mixing tungsten into the silicone elastomer film.

[0032]

[Brief description of the drawings]

FIG. 1 shows the change in the amount of HSA released by ultrasonic irradiation of the preparation obtained in Example 1.

FIG. 2 shows changes in the amount of indomethacin released by ultrasonic irradiation of the preparation obtained in Example 2.

FIG. 3 shows changes in the amount of indomethacin released by heat of the preparation obtained in Example 2.

FIG. 4 shows changes in the amount of indomethacin released by ultrasonic irradiation of the preparation obtained in Example 3.

FIG. 5 shows changes in the amount of indomethacin released by ultrasonic irradiation of the preparation obtained in Example 4.

FIG. 6 shows the spontaneous release of the formulations obtained in Examples 2, 3, 4 and 5.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Keiji Fujioka 1-3-45 Kuragakiuchi, Ibaraki-shi, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Yoshio Sasaki 1-3-45 Kurakinai, Ibaraki-shi, Osaka Resident (56) References JP-A-63-31537 (JP, A) JP-A-4-135571 (JP, A) JP-A-62-174007 (JP, A) JP-A-62-174031 (JP JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/00-9/72 A61M 31/00

Claims (2)

(57) [Claims] The present invention relates to a method for holding a drug therein, placing the drug at an arbitrary specific position in a living body, increasing the penetration rate of the drug by ultrasonic irradiation, and substantially stopping the ultrasonic irradiation. An in-vivo indwelling reservoir-type preparation, which has a substance permeable portion made of a silicone elastomer that does not allow a drug to permeate. 2. The preparation according to claim 1, wherein the substance permeable portion contains at least one of tungsten, carbon, and titanium.