SELECTIVE AND REVERSIBLE BLOOD-BRAIN BARRIER BREAKDOWN BY ULTRASOUND EMISSION

Abstract

An ultrasound emitting device, configured to selectively and reversibly break the blood-brain barrier of a patient, including a structure configured to be placed on at least one portion of the head of the patient, at least two ultrasound transducers coupled to the structure and configured to emit ultrasounds of diagnostic intensity. Also, a method for improving the bioavailability in brain tissue of at least one inflammation mediator in a patient. Further, a method for treating diseases of the central nervous system using the method for improving the bioavailability of inflammation mediators in a patient in need thereof, and method for treating diseases of the central nervous system using the device. Finally, the use of the device for the treatment of diseases of the central nervous system.

Claims

1-8. (canceled)

9. A device configured to selectively and reversibly break the blood-brain barrier of a subject by emitting ultrasound, comprising: a structure configured to be placed on at least a portion of the head of a user; at least two ultrasonic transducers coupled to said structure and configured to emit ultrasound with diagnostic intensity; wherein said at least two ultrasonic transducers are of capacitive micromachined, piezoelectric micromachined or piezoelectric type and configured to deliver an ultrasound frequency of between 0.5 and 10 MHz, preferably between 1 and 4 MHz, said at least two ultrasonic transducers being adapted to increase the bioavailability in brain tissues of at least one agent against inflammation mediators, preferably at least one anti-inflammatory, even more preferably at least one anti-TNF alpha.

10. The device according to claim 9, wherein said structure consists of a helmet, a cup, a hood or a headband.

11. The device according to claim 9, wherein said at least two ultrasonic transducers are positioned in a frontal plane and/or a sagittal plane.

12. The device according to claim 9, wherein said at least two ultrasonic transducers are movable along a frontal axis and/or a sagittal axis.

13. The device according to claim 9, wherein said device further comprises a control device coupled to the at least two ultrasonic transducers and configured to control the frequency and power of the ultrasound emitted by the at least two ultrasonic transducers.

14. The device according to claim 9, wherein said at least two ultrasonic transducers rest on the surface of the scalp.

15. The device according to claim 9, wherein said device comprises a plurality of ultrasonic transducers forming an array of transducers on the surface of the scalp.

16. The device according to claim 9, wherein said at least two ultrasonic transducers are configured to deliver ultrasound at a power of between 50 and 800 mW/cm.sup.2.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0045] FIG. 1 is a schematic representation of the ultrasound emission device according to an embodiment of the present invention.

[0046] FIG. 2 is a schematic representation of the ultrasound emission device according to another embodiment of the present invention.

[0047] FIG. 3 is a schematic representation of the ultrasound emission device according to another embodiment of the present invention.

[0048] FIG. 4 is a flow chart showing the main steps of the method according to the present invention.

REFERENCES

[0049] 1—ultrasound emitting device

[0050] 2—structure

[0051] 3—ultrasonic transducer

[0052] 4—control device

DETAILED DESCRIPTION

[0053] The following description will be better understood upon reading the drawings. In order to illustrate the invention, the device is shown in preferred embodiments. It should be understood, however, that the present application is not limited to the arrangements, structures, features, embodiments and precise appearance indicated. The drawings are not drawn on the scale and are not intended to limit the scope of the claims to the embodiments shown in these drawings. Therefore, it should be understood that when features mentioned in the claims are followed by references, said references are included only in order to improve the understanding of the claims and do not limit any case in the scope of these claims.

Device

[0054] The present invention relates to an ultrasound emitting device 1, configured to selectively and reversibly break the blood-brain barrier of a subject, comprising a structure 2 configured to be placed on at least a portion of the head of said subject and at least two ultrasonic transducers 3 coupled to said structure 2, configured to emit focused ultrasound with diagnostic intensity. In one embodiment, said device 1 is adapted to increase the bioavailability in brain tissues of at least one agent against inflammation mediators. In a preferred embodiment, said device 1 is suitable for increasing the bioavailability in brain tissues of at least one anti-inflammatory agent. In a still more preferred embodiment, said device 1 is adapted to increase the bioavailability in brain tissues of at least one anti-TNF alpha.

[0055] FIG. 1 shows an embodiment according to the invention in which the device 1 comprises a structure 2 consisting of a band adapted to surround the head of a subject, preferably the band consists of a circular band 2.sub.1 configured to encircle the head of the subject at the temples, a first upper strip 2.sub.2 connected to the circular band along a frontal plane and a second upper strip 2.sub.3 connected to the circular band along a sagittal plane. The two upper bands 2.sub.2 and 2.sub.3 are configured to rest on the top of the head of the subject. In this embodiment, two ultrasonic transducers 3 are coupled to the band 2. A first temporal transducer is coupled to the first front upper band 2.sub.2 and the second front transducer is coupled to the second upper sagittal band 2.sub.3. In this embodiment, the two transducers 3 are movable and are positioned so as to scan the entire surface of the brain of the subject. The temporal transducer is movable in accordance with the choice of a frontal or transverse axis and the frontal transducer is movable along a sagittal axis. As shown in FIG. 1, the two transducers 3 rest on the surface of the scalp. As shown in FIG. 1, the ultrasonic transducers 3 are coupled to a control device 4 configured to control the frequency and power of the ultrasound emitted by said ultrasonic transducers 3. In this embodiment, the control device 4 is coupled to the ultrasonic transducers 3 by an electric cable.

[0056] According to one embodiment, at least two ultrasonic transducers are coupled to the structure 2. In one embodiment, at least one ultrasonic transducer is coupled to the structure 2 according to a frontal plane. In one embodiment, at least one ultrasonic transducer is coupled to the structure 2 in a sagittal plane. In one embodiment, the at least two ultrasonic transducers are coupled to the structure 2 according to a frontal plane. In one embodiment, the at least two ultrasonic transducers are coupled to the structure 2 in a sagittal plane.

[0057] According to one embodiment, the at least two ultrasonic transducers are movable. In one embodiment, the at least two ultrasonic transducers are movable along a frontal axis. In one embodiment, the at least two ultrasonic transducers are movable along a sagittal axis. In these embodiments, a scan on either side of the median plane is possible.

[0058] FIG. 2 shows another embodiment according to the invention in which the device 1 described in FIG. 1 is capable of receiving a plurality of ultrasonic transducers 3. According to one embodiment, a plurality of ultrasonic transducers 3 means from three to five ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least three ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least four ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least five ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least ten ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least fifteen ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least twenty ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least fifty ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least one hundred ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least two hundred ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least three hundred ultrasonic transducers. According to one embodiment, a plurality of ultrasonic transducers 3 means at least four hundred ultrasonic transducers. In this embodiment, the plurality of ultrasonic transducers 3 forms an array of transducers on the surface of the scalp. As shown in FIG. 2, the ultrasonic transducers are coupled to a plurality of strips in a sagittal plane.

[0059] In one embodiment shown in FIG. 3, the transducers of a plurality of ultrasonic transducers 3 are coupled to the structure 2 at the temporal zone. In this embodiment, the ultrasound emission is concentrated on the temporal zone of a subject.

[0060] According to one embodiment, the structure 2 is configured to entirely cover the head of a subject. In one embodiment, the structure 2 is configured to partially cover the head of a subject. In one embodiment, the structure 2 is configured to surround the head of a subject, preferably at the temples of said subject.

[0061] According to one embodiment, the structure 2 consists of a helmet. In one embodiment, the structure 2 consists of a cup. In one embodiment, the structure 2 consists of a hood. According to one embodiment, the structure 2 consists of a headband.

[0062] In one embodiment, the at least two ultrasonic transducers are selected from the capacitive micromachined ultrasonic transducers (CMUT), the piezoelectric micromachined ultrasonic transducers (PMUT) or the piezoelectric transducers. In a preferred embodiment, the at least two ultrasonic transducers are of the capacitive micromachined type (CMUT) or piezoelectric micromachined ultrasound (PMUT). In a preferred embodiment, the at least two ultrasonic transducers are of the capacitive micromachined type (CMUT).

[0063] According to one embodiment, the at least two ultrasonic transducers consist of at least one bar comprising at least two elements. In one embodiment, the at least two ultrasonic transducers are isolated elements.

[0064] According to one embodiment, the control device 4 is external to the device 1. In one embodiment, the control device 4 is coupled to the at least two transducers 3 by an electrical cable. In one embodiment, the control device 4 is integrated with the at least two transducers 3.

[0065] In one embodiment, the control device 4 is configured to generate an electrical signal making it possible to activate the at least two ultrasonic transducers 3.

[0066] In one embodiment, the control device 4 is configured to generate signals separately in order to independently activate each of said at least two ultrasonic transducers 3. In one embodiment, the control device 4 is configured to generate a single signal enabling simultaneous activation of all the ultrasonic transducers 3.

[0067] In one embodiment, the control device 4 is configured to control different parameters of the at least two ultrasonic transducers 3. In one embodiment, the control device 4 is configured to control the frequency of the ultrasound emitted by the at least two ultrasonic transducers 3. In one embodiment, the control device 4 is configured to control the power of the ultrasound emitted by the at least two ultrasound transducers 3. In one embodiment, the control device 4 is configured to control the amplitude of the ultrasound emitted by the at least two ultrasound transducers 3.

[0068] According to one embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a low frequency. In one embodiment, the at least two ultrasonic transducers are configured to deliver an ultrasound frequency of between 0.5 and 10 MHz. In one embodiment, the at least two ultrasonic transducers are configured to deliver an ultrasound frequency of between 1 and 4 MHz. In one embodiment, the at least two ultrasonic transducers are configured to deliver an ultrasound frequency of between 0.5 and 1 MHz. In one embodiment, the at least two ultrasonic transducers are configured to deliver an ultrasound frequency of between 4 and 10 MHz. In a preferred embodiment, the at least two ultrasonic transducers are configured to deliver an ultrasound frequency of about 1.5 MHz.

[0069] According to one embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a power of between 50 and 800 mW/cm.sup.2. In one embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a power of between 50 and 100 mW/cm.sup.2. In one embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a power of between 100 and 400 mW/cm.sup.2. In one embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a power of between 400 and 600 mW/cm.sup.2. In one embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a power of between 600 and 800 mW/cm.sup.2. In a preferred embodiment, the at least two ultrasonic transducers are configured to deliver ultrasound at a power of about 800 mW/cm.sup.2.

[0070] In one embodiment, the at least two ultrasonic transducers 3 rest on the surface of the scalp of a subject. In this embodiment, a uniform pressure is exerted on the head of the subject thus making it possible to minimize energy loss and the effect of heating due to the emitted ultrasound.

Method

[0071] The invention also relates to a method for improving the bioavailability of agents against inflammation mediators in a subject. For this purpose, the method is configured to emit focused ultrasound onto at least one specific site of the brain of a subject to selectively and reversibly break the blood-brain barrier.

[0072] Thus, the invention relates to a method for improving bioavailability in at least one region of the brain tissue of at least one agent against inflammation mediators in a subject in need thereof comprising the steps of: administering to said subject a therapeutically effective amount of at least one agent against inflammation mediators, injecting microbubbles of gas to said subject, applying the device of the present invention to at least a portion of the head of said subject, and emitting focused ultrasound onto at least one site of the brain of said subject with said device, preferentially over the entire brain tissue.

[0073] As shown in FIG. 4, the method of the present invention comprises four main steps. In a first step 100, a dose of agents against inflammation mediators is administered to a subject. The second step 200 consists in injecting microbubbles of gas to said subject. In a third step 300, the device of the present invention is applied to at least a portion of the head of said subject, preferentially to the surface of the skull of said subject. Finally, the fourth step 400 consists in emitting focused ultrasound onto at least one site of the brain.

[0074] According to one embodiment, the step of administering an anti-TNF alpha dose 100 is carried out before the injection of gas microbubbles 200, which is itself carried out before or concomitantly with the emission of focused ultrasound with diagnostic intensity 400 on at least one site of the brain of said subject. Step 300 during which the device of the present invention is applied to at least a portion of the head of said subject can be performed prior to administration of an anti-TNF alpha dose 100, between administration of an anti-TNF alpha dose 100 and the injection of gas microbubbles 200, or between injection of gas microbubbles 200 and the diagnostic intensity focused ultrasound emission 400 on at least one site of the brain of said subject.

[0075] In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject undergoing ultrasound. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least once a week. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least twice per week. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least three days per week. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least four days per week. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least five days per week. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least six days per week. In one embodiment, a dose of at least one agent for controlling inflammation mediators is administered to the subject seven days per week.

[0076] In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject for at least 24 weeks. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject for at least 2 weeks. In one embodiment, a dose of at least one agent for controlling inflammation mediators is administered to the subject for at least 4 weeks. In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject for at least 8 weeks. In one embodiment, a dose of at least one agent for controlling inflammation mediators is administered to the subject for at least 12 weeks.

[0077] In one embodiment, a dose of at least one agent against inflammation mediators is administered to the subject at least once per week and for at least 24 weeks.

[0078] In practice, the therapeutically effective dose of agents against inflammation mediators to be administered depends on one or more parameters, including, in particular, the material used for administration, age, sex, size, weight, physical condition and degree of severity of the disorder to be treated. A person skilled in the art knows the therapeutically effective dose of anti-TNF alpha agents to be administered for controlling inflammation mediators.

[0079] In one embodiment, a dose of at least 25 mg of at least one agent against inflammation mediators is administered to the subject. In one embodiment, a dose of 25 mg of at least one agent against inflammation mediators is administered to the subject. In one embodiment, a dose of 50 mg of at least one agent for controlling inflammation mediators is administered to the subject. In one embodiment, the dose of at least one agent against inflammation mediators is administered by subcutaneous injection.

[0080] According to a preferred embodiment, said at least one agent for controlling inflammation mediators is an anti-inflammatory agent. According to a more preferred embodiment, said at least one agent for controlling inflammation mediators is an anti-TNF-alpha.

[0081] In one embodiment, the anti-TNF alpha is selected from Etanercept, Infliximab, Adalimumab, Golimumab, Certolizumab. In a preferred embodiment, the anti-TNF alpha administered is Etanercept.

[0082] According to one embodiment, the gas microbubbles are injected into said subject intravenously. In one embodiment, the microbubbles of gas injected into said subject are microbubbles of air, carbon dioxide, nitrogen, sulphur hexafluoride or perfluorocarbon such as perfluorohexane, perfluoropropane, perfluoropentane, it being understood that these microbubbles can be stabilized or encapsulated.

[0083] In this embodiment, an ultrasound contrast agent is preferably injected into said subject to generate the microbubbles of gas in the blood. In one embodiment, a solution of sulfur hexafluoride is injected into said subject. In one embodiment, a solution comprising iodipamide di-ester or diatrizoate is injected into said subject. In one embodiment, a solution comprising perfluorooctyl bromide or perfluorocarbon such as perfluorohexane, octafluoropropane, dodecabopentane, perfluoropentane is injected into said subject. In one embodiment, a solution comprising Echovist®, Perflubron™, IDE, Sonavist®, Levovist®, Albunex®, EchoGen®, Optison®, SonoVue®, Definity®, Imagent™, Imavist®, Sonazoid, Quantison™, Myomap™ ou SonoGen® is injected into said subject.

[0084] In one embodiment, the microbubbles have an average diameter of about 2.5 μm. In one embodiment, the microbubbles have a diameter of between 2 μm and 11 μm. In one embodiment, the microbubbles have a diameter of between 2 μm and 6 μm.

[0085] According to one embodiment, the device of the present invention is applied so as to entirely cover the head of a subject. In one embodiment, the device of the present invention is applied to partially cover the head of a subject. In one embodiment, the device of the present invention is applied so as to cover or surround the head of a subject, preferably at the temples of said subject. In one embodiment, the device of the present invention is applied so that the at least two ultrasonic transducers rest on the surface of the scalp.

[0086] In one embodiment, said subject is subjected to ultrasound focused on at least one specific site of the brain of said subject. In one embodiment, the subject is subjected to ultrasound for a period of between 5 min and 1 hour. In one embodiment, said subject is subjected to ultrasound for a period of between 5 min and 30 min. In one embodiment, said subject is subjected to ultrasound for a period of between 30 min and 1 hour. In one embodiment, said subject is subjected to ultrasound for a period of at least 30 minutes. In a preferred embodiment, said subject is subjected to ultrasound for a period of 30 minutes.

[0087] In one embodiment, said subject is subjected to ultrasound at least once per day. In one embodiment, said subject is subjected to ultrasound at least twice per day. In one embodiment, said subject is subjected to ultrasound twice daily.

[0088] In one embodiment, said subject is subjected to ultrasound at least one day per week. In one embodiment, said subject is subjected to ultrasound at least two days per week. In one embodiment, said subject is subjected to ultrasound at least three days per week. In one embodiment, said subject is subjected to ultrasound at least four days per week. In one embodiment, said subject is subjected to ultrasound at least five days per week. In one embodiment, said subject is subjected to ultrasound at least six days per week. In one embodiment, said subject is subjected to ultrasound seven days per week.

[0089] In one embodiment, the subject is subjected to ultrasound for at least 2 weeks. In one embodiment, the subject is subjected to ultrasound for at least 4 weeks. In one embodiment, the subject is subjected to ultrasound for at least 8 weeks. In one embodiment, the subject is subjected to ultrasound for at least 12 weeks. In one embodiment, the subject is subjected to ultrasound for at least 24 weeks. In one embodiment, the subject is subjected to ultrasound for 24 weeks.

[0090] According to a preferred embodiment, the subject is subjected to ultrasound for 30 minutes, twice daily, at least five days per week and for at least 24 weeks.

[0091] In one embodiment, the subject is subjected to ultrasound at a frequency of between 0.5 and 10 MHz. In one embodiment, the subject is subjected to ultrasound at a frequency of between 1 and 4 MHz. In one embodiment, the subject is subjected to ultrasound at a frequency of between 0.5 and 1 MHz. In one embodiment, the subject is subjected to ultrasound at a frequency of between 4 and 10 MHz. In one embodiment, the subject is subjected to ultrasound at a frequency of 1.5 MHz.

[0092] In one embodiment, the subject is subjected to ultrasound at a power of between 50 and 800 mW/cm.sup.2. In one embodiment, the subject is subjected to ultrasound at a power of between 50 and 100 mW/cm.sup.2. In one embodiment, the subject is subjected to ultrasound at a power of between 100 and 400 mW/cm.sup.2. In one embodiment, the subject is subjected to ultrasound at a power of between 400 and 600 mW/cm.sup.2. In one embodiment, the subject is subjected to ultrasound at a power of between 400 and 800 mW/cm.sup.2. In one embodiment, the subject is subjected to ultrasound at a power of about 800 mW/cm.sup.2.

[0093] Advantageously, the frequency and power of the ultrasound are chosen such that sufficient energy is transferred to the skull of the subject in order to cause the injected microbubbles to oscillate and increase the vascular porosity at the level of at least one targeted site of the brain, thus allowing the blood-brain barrier to be selectively broken by mechanical action.

[0094] According to one embodiment, steps 200 to 400 are repeated as many times as necessary.

[0095] As described above, the device of the present invention enables selective and reversible breaking of the blood-brain barrier by emitting focused ultrasound onto at least one specific site of the brain of said subject. The localized disruption of the blood-brain barrier allows the dose of the modulator of the inflammation, that is to say agent against the mediators of inflammation, administered circulating in the blood to more effectively penetrate through the open region of the blood-brain barrier, thereby delivering the effective dose necessary for the treatment of the targeted disease.

[0096] According to one embodiment, the method for improving the bioavailability of agents against inflammation mediators according to the invention is used for the treatment of diseases of the central nervous system.

[0097] The present invention also relates to a method of treating central nervous system diseases using the method of the present invention for improving the bioavailability of agents against inflammation mediators in a subject in need thereof.

[0098] The present invention also relates to a method for treating diseases of the central nervous system using the device of the present invention.

[0099] According to one embodiment, the device of the present invention is used for the treatment of diseases of the central nervous system.

[0100] In one embodiment, the central nervous system disease is selected from Alzheimer's disease, Parkinson's disease, epilepsy, cerebrovascular diseases, including stroke, migraine, multiple sclerosis, nervous system infections, brain tumors, traumatic nervous system disorders such as cranial trauma, depression and malnutrition-related neurological disorders.

[0101] Although various embodiments have been described and illustrated, the detailed description should not be considered to be limited thereto. Various modifications can be made to the embodiments by a person skilled in the art without departing from the true spirit and scope of the disclosure as defined by the claims.