Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1999-02-03
2001-07-10
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S001210, C424S009321, C424S009510, C424S812000, C436S829000
Reexamination Certificate
active
06258378
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns a method and compositions or formulations for administering and controllably delivering bioactive substances or media to selected sites, e.g. organs or tissues, in the body of patients. The formulations comprise ingestible or injectable aqueous suspension of liposomes bearing active substances such as drugs or diagnostic agents encapsulated therein. The formulation is also available in kit form, the kits comprising sterile precursor components.
BACKGROUND ART
The targeted delivery via the circulation of liposomes encapsulating bioactive media like therapeutic or diagnostic substances towards selected areas in the organism combined with the assisted release of said substances at specific sites is attracting much attention in the medical field. For instance, N. Shoucheng et al.,
Int. J. Radiat. Oncol. Biol. Phys.
29 (1994), 827-834 have 25 disclosed injecting long lived liposomes (stealth) containing doxorubicine into the circulation of experimental animals and thereafter inducing controlled release of the doxorubicine at selected sites in the body via local hyperthermia induced by focused ultrasonic energy. Similarly, Bednarski et al.
Radiology
204 (1997), 263-268 have disclosed the magnetic resonance guided targeting of liposome vesicles incorporating pharmaceuticals towards specific areas in the body, this being followed by the ultrasound controlled release into tissues of said pharmaceuticals, the effect being due to hyperthermialysis of the liposomal membrane.
In WO94/28873 and WO96/39079, there is disclosed a technique in which injectable targeted gas-filled microspheres, for instance gas-filled liposomes, comprising therapeutics embedded within the liposome bilayer membrane wall are directed to specific organs where they are caused to explode by ultrasonic irradiation in order to release said embedded therapeutic substances. It is difficult to incorporate drug into the gas filled liposomes (i.e. in the gas-phase or the surface membrane) without affecting their stability. If even a drug can be load in this kind of vesicles, it must be of a hydrophobic nature and the payload should be very low. Thus this method shows very limited practical utility. And also because after explosion, the therapeutic substance may stick some time to the constituents of the broken liposome membrane in which they were embedded, or the splintered parts of the liposome membranes may be simply “washed away” by the blood stream so that the active substance may not be released on the targeted site but elsewhere.
WO93/25241 discloses an ultrasound imaging technique in which a suspension of microspheres is targeted to organs of the body and caused to collapse under stimulation by ultrasonic energy, whereby a broad-band acoustic signal pulse is emitted and echo-detected by colour Doppler systems.
Although the techniques of the art have merit, a problem may arise due to the level of energy required to break the membrane of the liposomes and release the content thereof to a targeted area; if the area is located deep down in the body, the penetration of the energy beam into the body can have damaging effects to the intervening tissues. Hence searches have been undertaken to find a non-invasive energy releasing agent, closely associated with the liposome vesicles, which can innocuously help breaking the liposome membrane and release the trapped content thereof. In other words, it is strongly desired to make available an agent containing sufficient potential energy stored therein to open the liposome vesicles without harming the nearby or intervening tissues, said energy being liberated at will by external triggering means, so that the liposome encapsulated bioactive media be set free at a chosen site. The effect sought can be compared to that of a hypothetic prearmed spring to be remotely triggered and whose energy when released will cause the liposome content to be discharged at will. The present invention is set out to achieve this desired effect.
SUMMARY OF THE INVENTION
In brief, the method of the invention involves directing drug containing liposomes to selected areas in the organism and subsequently breaking or opening the liposomes to release the encapsulated content at a given site. In this method, the potential energy-containing agent to be used in association with the liposome vesicles and whose energy can be liberated at will to assist releasing the liposome encapsulated content consists of microparticles (microbodies) with confined air or gas. The microparticles are preferably air- or gas-filled microspheres, micro-vesicles, or microcapsules, more preferably air- or gas-filled microbubbles or microballoons. When air or gas-filled microspheres in close vicinity to liposome vesicles are caused to break or explode, the liberated cavitation energy will spread around and assist in opening the liposome membrane to free the encapsulated content or by changing the membrane permeability to enhance the drug diffusion. The triggering pulses of, for instance, radio or sound energy to burst the microspheres or microcapsules filled with the confined gas need not be as energetic as those required for directly acting on the liposomes membrane, hence the impact on nearby tissues is reduced.
The method of the invention is implemented via injectable compositions or formulations comprising liposomes (optionally targeted towards specific sites or organs) carrying encapsulated therein therapeutically or diagnostically useful agents and air or gas filled microspheres, i.e. microbubbles or microballoons which, optionally, may be associated with the liposomes. The microbubbles or microballoons are those disclosed in EP-A-0 474 833; EP-A-0 458 745; EP-A-0 502 814; EP-A-0 554 213; EP-A-0 619 743 and EP-A-0 682 530, all incorporated herein by reference.
The invention also includes precursor systems or kits which may include suspensions of liposomes encapsulating bioactive substances and suspensions of air- or gas-containing microspheres (stable microbubbles or microballoons), or dried liposomes having bioactive substances encapsulated therein in stabilised powder form, as well as suspensions in a carrier liquid of air- or gas-containing stable microbubbles or microballoons, or dried liposomes having bioactive substances encapsulated therein and microballoons in dry powder form, or microbubble precursors as pulverulent laminarized phospholipids stored in contact with air or a physiologically acceptable gas.
DETAILED DESCRIPTION OF THE INVENTION
The main aspects of the invention as set out in the accompanying claims are based on an unexpected finding that extremely efficient targeted delivery of biologically active ingredients may be achieved via a method in which an injectable composition comprising (a) liposomes containing encapsulated therapeutically or diagnostically useful agents and (b) air or gas filled microspheres, i.e. microbubbles or microballoons is administered to a patient. The injected formulation is allowed to reach via the circulation a selected/desired organ or tissue and then the targeted organ or tissues is irradiated with an energy beam (preferably ultrasonic) to burst or cause burst of the gas or air-filled microspheres, the released gas energy thereby opening the adjacent liposomes vesicles, thus causing dispense of the encapsulated biologically active substance(s) at the desired site in the organism of the patient.
Upon administration of an effective amount of such formulation into the vascular or the lymphatic systems of said patient, the progression in the circulation of the administered formulation toward the selected site may be monitored by ultrasonic or MRI imaging means, so that the irradiation and consecutive burst of the gas filled microspheres by sonolysis or otherwise is effected only when the formulation reaches or passes over or through the desired site. Clearly, the process of irradiation may be carried out continuously or intermittently during each cyclic circulation of the formulation through or by the targeted site.
The ultras
Hiver Agnés
Schneider Michel
Yan Feng
Bracco Research S.A.
Kishore Gollamudi S.
Nixon & Vanderhye P.C.
LandOfFree
Delivery of biologically active substance to target sites in... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Delivery of biologically active substance to target sites in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Delivery of biologically active substance to target sites in... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2514266