U.S. patent application number 10/400337 was filed with the patent office on 2003-10-09 for booster for therapy of diseases with ultrasound and pharmaceutical liquid composition containing the same.
Invention is credited to Tachibana, Katsuro, Tachibana, Shunro.
Application Number | 20030191446 10/400337 |
Document ID | / |
Family ID | 13099707 |
Filed Date | 2003-10-09 |
United States Patent
Application |
20030191446 |
Kind Code |
A1 |
Tachibana, Katsuro ; et
al. |
October 9, 2003 |
Booster for therapy of diseases with ultrasound and pharmaceutical
liquid composition containing the same
Abstract
A booster comprising a plurality of microbubbles of a gas in a
liquid, e.g. about 4.times.10.sup.7 cells/ml of microbubbles of a
gas having a diameter of 0.1 to 100 .mu.m in a 3 to 5% human serum
albumin solution, and a pharmaceutical liquid composition
comprising the booster as set forth above and a medicament, which
are useful for the therapy of various diseases together with
exposure of ultrasonic, where the therapeutic effects of the
medicament is enhanced by the application of ultrasound in the
presence of the booster.
Inventors: |
Tachibana, Katsuro;
(Fukuoka-shi, JP) ; Tachibana, Shunro;
(Fukuoka-shi, JP) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
13099707 |
Appl. No.: |
10/400337 |
Filed: |
March 26, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10400337 |
Mar 26, 2003 |
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09375339 |
Aug 16, 1999 |
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6585678 |
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09375339 |
Aug 16, 1999 |
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08652690 |
May 30, 1996 |
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RE36939 |
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08652690 |
May 30, 1996 |
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07855545 |
Mar 20, 1992 |
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5315998 |
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Current U.S.
Class: |
604/500 ;
424/9.52; 604/22 |
Current CPC
Class: |
A61K 9/0009 20130101;
A61K 41/0028 20130101; A61K 41/0047 20130101; A61K 41/0004
20130101; A61K 49/223 20130101; A61K 9/5052 20130101 |
Class at
Publication: |
604/500 ;
424/9.52; 604/22 |
International
Class: |
A61M 031/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 22, 1991 |
JP |
3-058970 |
Claims
What is claimed is:
1. A booster for enhancing effects of ultrasound in the therapy of
diseases, comprising: a. a medicament and b. microbubbles of a gas
having a diameter of 0.1 to 100 .mu.m in a liquid.
2. The booster according to claim 1, wherein the microbubbles are
formed from air or oxygen gas in the liquid.
3. The booster according to claim 1, wherein the liquid is a 3 to
5% human serum albumin solution.
4. A pharmaceutical liquid composition for the therapy of diseases
with application of ultrasound, comprising: a. microbubbles of a
gas having a diameter of 0.1 to 100 .mu.m and b. a medicament
selected from the group consisting of thrombolytic agents,
hormones, antibiotics and antineoplastic agents in a liquid.
5. The composition according to claim 4, wherein the microbubbles
are formed from air or oxygen gas in the liquid.
6. The composition according to claim 4, wherein the liquid is a 3
to 5% human serum albumin solution.
7. The composition according to claim 4, wherein the medicament is
a member selected from thrombolytic agents, hormones, antibiotics,
and antineoplastic agents.
8. The composition according to claim 4, wherein the medicament is
selected from the group consisting of urokinase, tissue plasminogen
activator, insulin, theophylline, and lidocaine.
9. A method for enhancing the therapeutic effects of a medicament,
comprising: a. applying ultrasound to a pharmaceutical liquid
composition according to claim 4 and b. administering said
pharmaceutical liquid composition.
10. The method according to claim 9, wherein the liquid composition
comprises about 4.times.10.sup.7 cells/ml of microbubbles of a gas
having a diameter of 0.1 to 100 .mu.m and a medicament in the
liquid.
11. The method according to claim 10, wherein the liquid is a 3 to
5% human serum albumin solution.
12. The method according to claim 9, wherein the medicament is
selected from the group consisting of urokinase, tissue plasminogen
activator, insulin, theophylline, and lidocaine.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
09/375,339, filed Aug. 16, 1999, which is a divisional of
application Ser. No. 08/652,690, filed May 30, 1996, now U.S. Pat.
No. RE36,939, which is a reissue of U.S. Pat. No. 5,315,998, filed
Mar. 20, 1992. This application also claims priority under
.sctn.119 to Japanese Application No. 3-058970, filed Mar. 22,
1991. Each of the above-referenced related applications is
incorporated herein by reference in its entirety
FIELD OF THE INVENTION
[0002] This invention relates to a booster useful for enhancing the
effects of ultrasound in the therapy of various diseases and a
pharmaceutical liquid composition containing the booster and a
medicament which shows enhanced diffusion and penetration of the
medicament into the body by applying ultrasound. More particularly,
it relates to a booster useful for therapy of various disease by
applying ultrasound which comprises a plurality of microbubbles of
a gas in a liquid, a pharmaceutical liquid composition comprising a
plurality of microbubbles of a gas and a medicament in a liquid,
and the use thereof in the therapy of various diseases while
applying ultrasound.
PRIOR ART
[0003] It is known that various diseases are remedied by the aid of
ultrasonic vibration. For example, it is described in Japanese
Patent First Publication (Kokai) No. 115591/1977, etc. that
percutaneous absorption of a medicament is enhanced by applying an
ultrasonic vibration. Japanese Patent First Publication (Kokai) No.
180275/1990 discloses a drug-injecting device which is effective on
the diffusion and penetration of the drug by applying an ultrasonic
vibration in the step of injecting a drug into a human body via a
catheter or a drug-injecting tube. U.S. Pat. Nos. 4,953,565 and
5,007,438 also disclose the technique of percutaneous absorption of
medicaments by the aid of ultrasonic vibration. It is also reported
that a tumor can be remedied by concentratedly applying ultrasound
from outside the body.
[0004] In order to enhance the therapeutic effects with ultrasound,
it is required to apply a high energy ultrasonic vibration.
However, ultrasonic vibration at an energy that is too high causes
disadvantageously bums or unnecessary heat at the portion other
than the desired portion. On the other hand, when the energy of an
ultrasonic vibration is lowered for eliminating such disadvantages,
there is a problem of less effect of the ultrasound at the desired
portion.
SUMMARY OF THE INVENTION
[0005] The present inventors have intensively studied enhancing the
effects of ultrasound at a lower energy of an ultrasonic vibration
and have found that a booster comprising a plurality of
microbubbles of a gas in a liquid is useful for the desired
enhancement of the effects of ultrasound.
[0006] An object of the invention is to provide a booster useful
for enhancing the effects of ultrasound which comprises a plurality
of microbubbles of a gas in a liquid. Another object of the
invention is to provide a pharmaceutical liquid composition
containing the booster and a medicament which is useful for the
therapy of various diseases together with the application of
ultrasound. A further object of the invention is to provide a
method for enhancing the effects by the application of ultrasound
in the therapy of various diseases which comprises injecting the
booster or the pharmaceutical liquid composition as set forth above
into the portion to be remedied while applying ultrasound thereto.
These and other objects and advantages of the invention will be
apparent to those skilled in the art from the following
description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 shows a schematic view of one of the microbubbles
contained in the booster of the invention.
[0008] FIG. 2 shows a schematic sectional view of one embodiment of
a drug administration device used for injecting, pouring, applying
or circulating the booster or the pharmaceutical liquid composition
of the invention.
[0009] FIG. 3 shows a schematic sectional view of one embodiment of
a drug administration device used for transdermal administration of
the booster or the pharmaceutical liquid composition of the
invention.
[0010] FIG. 4 and FIG. 5 show graphs showing fibrinolysis by
application of ultrasound with or without the booster of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The booster of the invention comprises a liquid containing a
plurality of microbubbles of a gas having a diameter of 0.1 to 100
.mu.m. The microbubbles are formed by entrapping microspheres of a
gas into a liquid. The booster contains, for example, about
4.times.10.sup.7 of the microbubbles per one milliliter of a
liquid. The microbubbles are made of various gases such as air,
oxygen gas, carbon dioxide gas, inert gases (e.g. xenon, krypton,
argon, neon, helium, etc.), preferably air and oxygen gas. The
liquid includes any liquid which can form microbubbles, for
example, human serum albumin (e.g. 3 to 5% human serum albumin), a
physiological saline solution, a 5% aqueous glucose solution, an
aqueous indocyanine green solution, autoblood, an aqueous solution
of maglumine diatriazoate (=renografin), and any other X-ray
contrast medium.
[0012] The booster can be prepared by a known method, for example,
by agitating the liquid as mentioned above while blowing a gas as
mentioned above into the liquid, or alternatively exposing the
liquid to ultrasound with a sonicator under a gaseous atmosphere,
whereby a vibration is applied to the liquid to form microbubbles
of the gas.
[0013] The pharmaceutical liquid composition of the invention
comprises a plurality of microbubbles of a gas and a medicament in
a liquid. The microbubbles of a gas and liquid are the same as
mentioned above. The medicament includes any known medicaments
effective for the desired therapy which can be absorbed
percutaneously, for example, anti-thrombosis agents (e.g.
urokinase, tissue plasminogen activator, etc.), hormones (e.g.
insulin, etc.), theophylline, lidocaine, antibiotics,
antineoplastic agents which are sensitive to ultrasound (e.g.
doxorublein (=adriamycin), cytarabine (=Ara.C), etc.), and the
like. The medicament can be contained in a therapeutically
effective amount as usually used. The pharmaceutical liquid
composition can be prepared by mixing a medicament with a booster
comprising a plurality of microbubbles of a gas in a liquid. The
mixing ratio may vary depending on the desired amount and kind of
the medicament and the kind of the liquid, but is usually in a
range of 1:100 to 100:1 by weight (a medicament/a booster).
[0014] According to the invention, the therapeutic effect of
ultrasound is boosted by the presence of a booster of the
invention. Particularly, when a pharmaceutical liquid composition
containing the booster and a medicament is poured or injected into
a body in parenteral routes, such as intravenously, percutaneously
or intramuscularly, while applying thereto an ultrasonic vibration,
the therapeutic effects of the medicament is significantly
enhanced. When an ultrasound from an ultrasonic element is applied
to the liquid containing the booster and medicament, cavitation
occurs in the liquid composition, and the medicament is diffused
and penetrated into the desired portion of the biobody by the aid
of vibration induced by the cavitation. The cavitation occurs when
the level of vibration energy exceeds a certain threshold value.
When the ultrasound is applied to the liquid composition of the
invention, the threshold value of the vibration energy is reduced
due to the presence of a plurality of microbubbles of a gas. That
is, the microbubbles of a gas act as nucleus of cavitation and
thereby the cavitation occurs more easily. Therefore, according to
the invention, the desired ultrasonic energy necessary for the
desired diffusion and penetration of a medicament is reduced.
[0015] The desired ultrasound is applied by conventional ultrasonic
devices which can supply an ultrasonic signal of 20 KHz to several
MHz.
[0016] With reference to the accompanying drawings, the invention
is illustrated in more detail.
[0017] FIG. 1 shows a schematic view of one of the plurality of
microbubbles of a gas contained in the booster of the invention,
wherein the microbubble of a gas has a diameter of 0.1 to 100 .mu.m
and is composed of a shell of human serum albumin 1 and gas 2
entrapped within the microbubble. The microbubbles are contained in
a liquid 3 such as 5% human serum albumin solution in an amount of,
for example, above 4.times.10.sup.7 cells/ml.
[0018] The booster is mixed with a medicament to give a
pharmaceutical liquid composition. The pharmaceutical liquid
composition is directly administered to the diseased part with an
appropriate device, for example, with a drug administration device
4 as shown in FIG. 2. The drug administration device 4 comprises a
base tube 5 to which the pharmaceutical liquid composition is
supplied, and an end tube 6 which is to be inserted into the tissue
of the biobody and through which the pharmaceutical liquid
composition is poured or injected into the disease part. The end
tube 6 is provided with an ultrasonic element 7 (e.g. a cylindrical
ceramic oscillator, etc.). The ultrasonic element 7 is supplied by
an ultrasonic signal of 20 KHz to several MHz from an ultrasonic
oscillation circuit 8 via a conductor 9a, connectors 10a and 10b
provided on the side of the base tube 5, a part of the base tube 5
and a conductor 9b provided within the end tube 6.
[0019] The application or injection of a medicament is carried out
in the form of a pharmaceutical liquid composition which is
prepared by previously mixing the medicament with the booster
comprising a plurality of microbubbles of a gas in a liquid,
wherein the medicament and the booster are mixed in a ration of
1:100 to 100:1 by weight. The pharmaceutical liquid composition is
poured into the base tube 5 from the supply opening 11 provided on
the tip of the base tube 5, passes through a flow path 12 within
the base tube 5 and a flow path 13 within the end tube 6 and is
then administered to the diseased part or the portion close thereto
of the patient via a pouring opening 14 provided at the bottom of
the end tube 6.
[0020] When the pharmaceutical liquid composition is administered
into the diseased part or the portion close thereto through the
pouring opening 14, an ultrasonic energy generated from an
ultrasonic element 7 is applied to the liquid composition, by which
cavitation occurs due to the ultrasonic energy. Microbubbles are
formed at the occurrence of cavitation and when the microbubbles
are decomposed, energy is generated, by which diffusion and
penetration of the medicament is promoted. Since the pharmaceutical
liquid composition contains a plurality of microbubbles of a gas,
the microbubbles act as a nucleus for the cavitation by which the
cavitation occurs more easily, in other words, the threshold value
of occurrence of cavitation lowers. Accordingly, it is possible to
generate the cavitation with less energy than the case of using no
booster.
[0021] When an ultrasonic vibration is applied to a liquid, if the
liquid contains any material being able to become a nucleus, the
cavitation occurs generally at a lower threshold value of energy,
but it has been found that the cavitation occurs most easily where
the liquid contains microbubbles of a gas having a diameter of 0.1
to 100 .mu.m.
[0022] The drug administration device 4 as shown in FIG. 2 can be
used, for example, for administering a pharmaceutical liquid
composition into a blood vessel. For instance, in the treatment of
coronary thrombosis, a pharmaceutical liquid composition comprising
a booster of the invention and a urokinase is injected into the
part of thrombosis or the close portion thereof with the drug
administration device 4 where the tip of the end tube 6 is inserted
into the portion close to the thrombosis with applying ultrasound,
by which the thrombolytic effects of the medicament are
significantly increased and further the blood flow is recovered
within a shorter period of time in comparison with the
administration of the medicament without the booster. The drug
administration device 4 may also be used for the removing hematoma
in bleeding of brain. For example, a pharmaceutical liquid
composition comprising a booster of the invention and a
thrombolytic agent (e.g. urokinase) is administered to the portion
of hematoma with the drug administration device 4 with applying
ultrasound like the above, by which the hematoma is easily
lysed.
[0023] In another embodiment of the invention, the pharmaceutical
liquid composition can be administered transdermally with a drug
administration device 15 as shown in FIG. 3.
[0024] In the drug administration device 15 suitable for
transdermal administration of a medicament, a layer of a medicament
17 is provided below an ultrasonic element 16 (e.g. a disc shaped
ceramic oscillator, etc.), under which an adhesive layer 18 having
a medicament permeability is laminated, the whole of which is
covered with a plastic cover 19. The ultrasonic element 16 is
supplied by ultrasonic signal from an ultrasonic oscillation
circuit provided outside via a connector 20, as shown in the drug
administration device 4 in FIG. 2.
[0025] In the device 15 of FIG. 3, a pharmaceutical liquid
composition comprising a mixture of a booster and a medicament is
contained in the layer of a medicament 17. When this device 15 is
used, it is adhered onto the skin with facing the adhesive layer 18
to the skin, and then an ultrasonic signal is supplied to the
ultrasonic element 16, by which an ultrasonic vibration from the
ultrasonic element 16 is given to both of the medicament layer 17
and the skin and thereby the medicament contained in the medicament
layer 17 is passed through the skin and is penetrated into the
tissue to be treated. In this embodiment, since microbubbles of a
gas are contained in the medicament layer 17, cavitation occurs
easily within the medicament layer 17 by application of ultrasound,
and hence even when lower energy of the ultrasonic vibration is
supplied from the ultrasonic element 16, the diffusion and
penetration of the medicament can effectively be done to result in
rapid absorption of the medicament.
[0026] The booster of the invention may also be used alone without
mixing with a medicament in the therapy with ultrasound. For
example, in the therapy of tumors by heating the diseased part of
the tissue with ultrasound, that is, by concentratedly applying an
ultrasonic vibration outside the biobody, a booster comprising a
plurality of microbubbles of a gas in a liquid of the invention is
previously injected into the blood vessel or to the portion close
to the diseased part before application of ultrasound, by which the
effect of heating with ultrasound is enhanced and thereby the
therapeutic effects are significantly improved. In this embodiment,
cavitation occurs also by the ultrasonic vibration more easily
because of using a liquid containing microbubbles of a gas, and
hence, even by less energy of the ultrasonic vibration supplied
from the ultrasonic element, the ultrasonic energy sufficient to
the therapy is obtained and thereby the undesirable bums and
unnecessary heating at other portions can be avoided.
[0027] In the treatment of tumors, it is, of course, more effective
to use it together with a chemotherapeutic agent suitable for the
treatment of the tumors, by which the effects of the
chemotherapeutic agent are more enhanced, where the diffusion and
penetration of the medicament are improved owing to the
booster.
[0028] The substance such as human serum albumin in the booster of
the invention is easily metabolized within the biobody and excreted
outside the biobody, and hence, it is not harmful to human body.
Besides, the amount of gas trapped within the microbubbles is
extremely small and is easily dissolved in the blood fluid.
Accordingly, the booster of the invention has no problem in the
safety thereof.
[0029] The preparation of the booster and pharmaceutical liquid
composition of the invention and effects thereof are illustrated by
the following Examples and Experiment, but it should not be
construed to be limited thereto.
EXAMPLE 1
[0030] Preparation of a Booster:
[0031] A 5% human serum albumin (8 ml) in a 10 ml-volume syringe is
exposed to ultrasound with a sonicator (frequency, 20 KHz) by which
vibration is given to the human serum albumin and a plurality of
microbubbles of air are formed in the human serum albumin to give a
booster comprising a human serum albumin containing a plurality of
microbubbles of air.
EXAMPLE 2
[0032] Preparation of a Pharmaceutical Liquid Composition:
[0033] The 5% human serum albumin containing a plurality of
microbubbles of air prepared in Example 1 is mixed with urokinase
(concentration 1200 IU/ml) to give the desired pharmaceutical
liquid composition.
Experiment
[0034] 1. Forming Artificial Thrombosis
[0035] An artificial thrombosis was formed by Chandler's method.
Blood (1 ml) that was collected from healthy humans (two persons)
was entered into a flexible tube (inside diameter 3 mm, length 265
mm) and thereto was added calcium chloride, and then the tube was
made a loop like shape, which was rotated at 12 rpm for 20 minutes
to give an artificial thrombosis model.
[0036] 2. Ultrasonic Catheter
[0037] A ceramic ultrasonic element (width 2 mm, length 5 mm,
thickness 1 mm) was inserted into the tip of a catheter (diameter 2
mm), and an oscillating element was connected to an oscillator
provided outside with a fine connector passed through the catheter.
A fine tube for pouring a test solution was provided at an opening
opposite to the opening of the catheter end.
[0038] 3. Test Method
[0039] The artificial thrombosis prepared above was added to a test
tube together with blood, and the ultrasonic catheter was inserted
into the test tube so that the end of the catheter was set close to
the portion of the artificial thrombosis (at a distance of about 5
mm), and to the test tube a mixture of urokinase and a booster
prepared in Example 1 was added at a rate of 1 ml per minute,
wherein urokinase (concentration 1200 IU/ml) and the booster were
mixed immediately before pouring at a mixing ration of 1:1 by
weight. The mixture was refluxed while keeping the volume of the
test solution at a constant level by removing excess volume of the
solution by suction. The ultrasound (170 KHz) was exposed to the
mixture by a pulse method (exposed for 2 seconds and stopped for 4
seconds) for 2 minutes (total exposing time 40 seconds). After the
exposure, the ultrasonic catheter was removed from the test tube,
and the mixture was incubated at 37 degrees C. for 5 to 120
minutes, washed with a physiological saline solution several times
and dried overnight. Thereafter, the dried mixture was weighed. As
a control, the above was repeated by using only a physiological
saline solution.
[0040] 4. Test Results
[0041] The rate of fibrinolysis was calculated by the following
equation: 1 Fibrinolysis rate ( % ) = Weight of thrombosis in
control - Weight of thrombosis treated Weight of thrombosis in
control .times. 100
[0042] The results are shown in the accompanying FIGS. 4 and 5
wherein there are shown in average of twice tests.
[0043] FIG. 4 shows the results in the thrombosis prepared by using
blood collected from one person, wherein the
symbol--.quadrature.--is the data obtained in the addition of
urokinase alone without exposure of
ultrasound,--.diamond-solid.--is the data obtained in the addition
of urokinase alone with exposure of ultrasound,
and--.box-solid.--is the data obtained in the addition of a mixture
of urokinase and the booster with exposure of ultrasound.
[0044] As shown in FIG. 4, the time for achieving 20% fibrinolysis
was 45 minutes by urokinase alone without exposure of ultrasound,
30 minutes by a combination of urokinase and exposure of
ultrasound, and only 10 minutes by a combination of a mixture of
urokinase and a booster and exposure of ultrasound. The
fibrinolytic effects of urokinase (both the rate of fibrinolysis
and the fibrinolytic time) were significantly enhanced by using a
booster with application of ultrasound.
[0045] FIG. 5 shows the results in the thrombosis prepared by using
blood collected from another person and with reduced energy of
ultrasound by 15%, wherein the symbols are the same as in FIG. 4.
As shown in FIG. 5, the fibrinolytic effects were significantly
enhanced by using a mixture of urokinase and the booster. That is,
in case of using urokinase alone with exposure of ultrasound, the
50% fibrinolysis was achieved by the treatment for 60 minutes, but
in case of using a mixture of urokinase and the booster with
exposure of ultrasound, it reduced to one fourth, i.e. it was
achieved by the treatment only for 15 minutes.
* * * * *