WO2005018600A2 - Method of treating a patient suffering from a solid tumour - Google Patents

Method of treating a patient suffering from a solid tumour Download PDF

Info

Publication number
WO2005018600A2
WO2005018600A2 PCT/DK2004/000560 DK2004000560W WO2005018600A2 WO 2005018600 A2 WO2005018600 A2 WO 2005018600A2 DK 2004000560 W DK2004000560 W DK 2004000560W WO 2005018600 A2 WO2005018600 A2 WO 2005018600A2
Authority
WO
WIPO (PCT)
Prior art keywords
microparticles
method according
agent
particles
tumour
Prior art date
Application number
PCT/DK2004/000560
Other languages
French (fr)
Other versions
WO2005018600A3 (en
Inventor
Erik Andersen
Original Assignee
Cube Medical A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US49690903P priority Critical
Priority to DKPA200301204 priority
Priority to DKPA200301204 priority
Priority to US60/496,909 priority
Application filed by Cube Medical A/S filed Critical Cube Medical A/S
Publication of WO2005018600A2 publication Critical patent/WO2005018600A2/en
Publication of WO2005018600A3 publication Critical patent/WO2005018600A3/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Abstract

Disclosed is treatment of a patient suffering from a solid tumour, where microparticles are administered which have a diametrical size that results in retention of the particles in the tumour's arterioles, so as to release a chemotherapeutical agent to the surrounding tumour tissue while minimally compromising surrounding non-tumour tissue. Preferred embodiments entail that encapsulating microspheres are rendered leaky for the chemotherapeutic agent by means of an electromagnetic or ultrasound shock wave. Other embodiments comprise co-administration to the patient of at least one therapeutic agent comprised in particles to provide an anti-inflammatory effect or inhibition of cell death.

Description

METHOD OF TREATING A PATIENT SUFFERING FROM A SOLID TUMOUR

FIELD OF THE INVENTION

The present invention relates to the field of chemotherapy of neoplastic disorders and especially to medical treatment of solid tumours, malignant as well as non-malignant. In particular, the present invention relates to a method for delivering a chemotherapeutic agent via the vascular system to a solid tumour, while reducing delivery to non-tumour tissue.

BACKGROUND OF THE INVENTION

Over the last decades, the field of cancer chemotherapy has evolved so as to allow effective treatment of a large number of patients. However, a number of solid neoplasms are still associated with a high mortality rate in the patients suffering from such tumours.

One major problem in treatment with chemotherapeutic drugs is the fact that systemic administration of the chemotherapeutic drug results in severe adverse effects that are life- threatening to the patient. It is therefore often impossible to effectively eradicate the tumour cells, simply because the concentration over time of the chemotherapeutic drug is insufficient to effectively kill all tumour cells.

Another major problem is that certain tumours are inoperable - this is especially true for solid tumours of the central nervous system (CNS) where surgical intervention may be impossible - this is even true for solid tumours that are not malignant per se (since they do not invade neighbouring tissue or metastasize), but that are life-threatening simply due to their physical expansion in a very vulnerable environment.

Several ways of improving chemotherapy of such solid tumours are known in the art.

One method has been to exploit the so-called "magic bullet" principle, where the chemotherapeutic drug is coupled to a ligand for a receptor molecule overrepresented in the tumour tissue. The major problem of this technology is, that a large number of tumours do not express any suitable overrepresented receptor molecule. In cases where it is possible to identify one single or very few solid tumours, it is known to administer the chemotherapeutic drug directly to the tumour, e.g. by direct injection of the chemotherapeutic agent into the tumour.

A variation of this technology consists in administering sustained release compositions and/or microspheres containing chemotherapeutic agents into the tumour, so as to ensure a prolonged exposure of the chemotherapeutic agent to the tumour cells. Such technology is disclosed in WO 01/10416, WO 02/051388, and EP 1 053 746 Bl.

A third approach has been to simply compromise the blood supply to the tumour by administering embolic agents to the vessels that supply the tumour with blood. Such technology is discloses in WO 01/66016, WO 01/68720, and WO 87/00062.

A refinement of this technology, known as "active embolisation" comprises use of embolising agents that at the same time function as carriers of anti-tumour drugs. Such technology is the focus of WO 01/72281.

A large number of patents and patent applications disclose microparticles that are useful as carriers of chemotherapeutic drugs. Such disclosures include US 6,447,796 and WO 01/72281.

However, there is still a need for improved delivery of chemotherapeutic drugs so as to render chemotherapy more effective.

OBJECT OF THE INVENTION

It is an object of the invention to provide for improved methods for treatment of solid tumours. It is a further object to provide for improved pharmaceutical compositions useful in therapy of patients suffering from solid tumours.

SUMMARY OF THE INVENTION

The vascular system

The present inventor has realised that it is possible to refine the known method of active embolisation by utilising micropartide carriers having a diametrical size that allows deposition in the pre-capillary environment whereby the distance of diffusion of a chemotherapeutic drug becomes minimal. The effect obtained by using microparticles in this manner is that the microparticles are concentrated in the capillary compartment without being able to enter the afferent vessels that drain the tumour in question. On the other hand, it becomes possible to co-administer, or administer at a later stage, a different drug that e.g. protects surrounding non-tumour tissue from the damage exerted by the chemotherapeutic drug released from the microparticles.

Hence, in its broadest and most general scope, the present invention relates to a method of treating a patient suffering from a solid tumour, the method comprising administering, into at least one vessel that supplies the solid tumour with blood, microparticles loaded with a chemotherapeutical agent, said microparticles having a diametrical size that results in retention thereof in the tumour's arterioles, whereby the microparticles are allowed to release the chemotherapeutical agent to the surrounding tumour tissue while minimally compromising surrounding non-tumour tissue.

Another part of the invention relates to a pharmaceutical composition comprising 1) microparticles containing a chemotherapeutical agent and 2) particles of a larger mean diametrical size than the microparticles, said particles comprising a therapeutic agent different from a chemotherapeutical agent.

DETAILED DISCLOSURE OF THE INVENTION

In the following a number of terms will be defined in the context of the present invention and the present specification and claims.

A "solid tumour" is in the present context meant to denote a malignant or non-malignant tumour having a defined localisation and a defined blood supply. Malignant tumours belonging to the class of solid tumours include, but are not limited to, carcinomas, adenocarcinomas, sarcomas (including liposarcomas, fibrosarcomas, chondrosarcomas, osteosarcomas, leiomyosarcomas, rhabdomyosarcomas), gliomas, neuroblastomas, medullablastomas, malignant melanoma, neurofibrosarcoma, and choriocarcinoma. Non- malignant tumours of interest in the present invention are especially of neuro-ectodermal origin and comprise, but are not limited to, ganglioneuromas, meningioma, schwannomas, and neurofibromas.

"Microparticles" are intended to mean particles that have a mean diametrical size in the range from 1 to 1000 μm. It will be understood by the skilled reader, that the microparticles used according to the present invention are sufficiently large to prevent them from entering the capillary space, since that would entail their subsequent entering the venous system and hence a dissemination of the chemotherapeutic drug. Microparticles can in principle have many forms, but are normally grouped into microspheres and microcapsules, where the latter are substantially hollow, sphere-shaped particles that can carry a substance in the hollow space, whereas "microspheres" are denote solid spherical microparticles, optionally having open cavities.

When stating that microparticles or particles are "loaded" with a substance (such as a chemotherapeutical agent or any other drug) it is intended that the substance is contained in or otherwise bound to the micropartide, and that the microparticles can release the drug to the surrounding environment.

A "chemotherapeutical agent" is broadly intended to mean any chemical substance that is useful in chemotherapy of solid tumours. As such, the term embraces antimetabolites, immune modulators, cytotoxic agents, antibiotic derivatives, nitrogen mustard derivatives, antiangiogenic agents, receptor antagonists, receptor ligands, stimulators, and any combinations thereof.

An "arteriole" is an arterial vessel having a diameter of less than 100 μm, having a wall including from 1 to 3 layers of circularly arranged smooth muscle cells. Arterioles i.a. serve the function of regulating the blood flow to the capillaries in a tissue by changing the diameter of their lumen.

When referring to the "diametrical size" of the microparticles is meant their diametrical size in situ, i.e. after administration and deposition in the arterioles.

The present invention presents a number of improvements to the known technology of active embolisation as this is e.g. described in WO 01/72281 and much earlier in e.g. US 4,536,387. By selecting microparticles having a very well-defined size which ensures deposition of the microparticles in the arterioles, the localisation of the released chemotherapeutic drug becomes optimized from a therapeutic point of view. Very high concentrations of chemotherapeutic agent can be accomplished in the tumour tissue while preserving the function of arteries supplying surrounding tissue, thus rendering possible the co- administration or subsequent administration of drugs that rescues non-tumour tissue from the effects of the chemotherapeutic agent.

The solid tumours that are targets for the present technology are typically malignant or non- malignant tumours of the CNS (especially the brain), prostate, breast, colon, lung, kidney, bladder, liver, bone, head, neck, stomach, larynx, esophagus, cervix, rectum, uterus, skin, endometrium, pancreas or testis. It is preferred that the tumours are primary tumours with only one single feeding artery or a few feeding arteries. It is especially preferred to utilise the present invention for treatment of tumours in the brain.

The present, invention utilises methods well-established in the art for administering the microparticles to the tumour. The art has described various suitable catheter devices for localised interarterial administration of pharmaceutical compositions - typically such an administration is performed using a catheter that can be positioned correctly by the assistance of real time X-ray visualiszation (or alternatively by using ultrasound or NMR imaging in real time), meaning that the catheter or alternative injection device must be one that can be visualised by one of these methods.

According to the present invention, it is preferred that the microparticles are in the form of microspheres (beads) or (most preferred) microcapsules. Depending on the particular solid tumour to be treated, it is of interest to effect an acute release of drug into the tumour tissue or to effect a sustained release. Further, these two modes of administration may conveniently be combined.

In order to effect a sustained release, any of the methods known to the person skilled in the art for preparing a sustained release of a drug may be utilised. The microparticles may be coated with concentric layers of materials that are degraded over time so as to result in a gradual release of the chemotherapeutic agent loaded therein, the microparticles may themselves be degraded over time to release the drug bound thereto, or the microparticles may carry a composition of matter that slowly releases the chemotherapeutic drug over time. Suitable examples of sustained release microspheres are disclosed in US 4,536,387, WO 92/05866 (which also discloses a method for preparing microparticles of a well-defined size), WO 01/35932 and in many others.

To effect a rapid release it is e.g. possible to utilise loaded microcapsules, where the chemotherapeutic agent is present in the lumen of the microparticles. One possibility is then that the wall of the microcapsule includes "weak spots" that are degraded after the microcapsules have been delivered so as to allow rapid release of the chemotherapeutic agent - the degradation may be spontaneous, or, preferably, it may be the result of a subsequent injection of a substance that induces the degradation of the microcapsule wall (i.e. by injection of an enzyme that specifically digests the material in the "weak spots"). Alternatively, the microcapsule can be made of e.g. amorphous silica that after deposition is subjected to a ultrasonic or electromagnetic shock wave that breaks the microcapsule wall. The skilled person will know how to apply such a shock wave and the precise amplitude and frequency to use. Alternatively, the chemotherapeutic agent can be delivered in the microparticles in a substantially inert pro-form that requires activation before the antitumour effect is brought about. Any one of a multitude of methods can be used: The chemotherapeutic agent may be bound to the particles by a chemical bond that requires the action of an enzyme or other catalyst that has to be administered; the chemotherapeutic agent may be one that has to be activated by means of radiation, enzymatic cleavage or other enzymatic action. The intention is therefore the same as when using microcapsules that are rendered leaky via external control, namely to ensure that the therapy is instigated after correct administration.

Further, whether or not rapid and/or sustained release is desired, it is of interest to be able to control the commencement of the release or of the therapeutic effect. For instance, after introduction of the microparticles containing the chemotherapeutic drug, it is of interest to verify that the microparticles have in fact been localised in all the desired compartments in the tumour. This particular embodiment can be rendered possible by encapsulating the chemotherapeutic agent in microcapules that can be visualised by means of X-rays, ultrasound or NMR imaging (e.g. by incorporating a radioopague substance in the microcapsule wall or together with the chemotherapeutic agent). After administration, the localisation is checked, i.a. in order to verify that the microcapsules are not disseminated into other tissue or for some reason have entered the venous system. When confirmation has been obtained, the release can be effected, cf. above.

It is of course also possible to combine the use of rapid and sustained release, either by co- administering microparticles destined for rapid release of drug with microparticles destine for sustained release, but also by combining these two modes of action into one single micropartide species. Further, the chemotherapeutic agent released rapidly may be the same or different from the drug undergoing sustained release.

At any rate, if a sustained release is desired, it is of interest to effect such a sustained release for a prolonged period of time, e.g. for at least 5 days, at least 10 days, at least 15 days, at least 20 days, and even at least 25 days such as up to 30 days.

The microparticles may be biodegradable or non-biodegradable. Suitable materials for microparticles are disclosed in WO 01/72281, US 6,447,796, WO 00/57852 and the references cited therein.

Suitable biodegradable materials are selected from the group consisting of a biodegradable polymers such as a polysaccharides, polyamino acids, biodegradable polyurethanes, poly(phosphorester) biodegradable polymers, polymers and copolymers of glycolic acid and lactic acid, poly(dioxanone), poly(trimethylene carbonate)copolymers, and poly(α-caprolactone) homopolymers and copolymers.

Preferred non-biodegradable materials are selected from the group consisting of amorphous silica, carbon, a metal, a ceramic material, and a non-biodegradable polymer.

One particular interesting embodiment of the present invention utilises amorphous silica as the material of which the microparticles are made. WO 00/09652 discloses a convenient method for preparing amorphous silica microcapsules of well-defined size that are completely inert before they are rendered leaky by e.g. Shockwave exposure. Even though WO 00/09652 describes mainly cosmetic applications of the technology, it can without any problems be utilised for preparing drug-containing microparticles of the desired size.

Needless to say that it is preferred that the materials, biodegradable or not, are preferably biocompatible, meaning that the particles in their own right are not responsible for any adverse effects due to immunological or toxic reactions.

The diametrical size of the microparticles in situ (i.e. after administration) are preferably in the range between 10 and 100 μm, such as between 11 and 90 μm, preferably between 12 and 80 μm, and most preferred between 15 and 40 μm. This latter size range ensures that the microparticles are confined exclusively to the arterioles upon administration.

The chemotherapeutic agent used in the invention can be any substance that is useful in effecting killing of tumour cells by local administration as taught herein, but is preferably selected from carboplatin, mitomycin C, 5-fluorouracil, pirarubicin, cisplatin, carmustine, paclitaxel, doxorubicin, adiramycin, lomustine, teniposide, etoposide, 06-benzylguanine, vincristine, vinblastine, vinorelbine, gemcitabine, cyclophosphamide, temasolamide, 4-HC, methotrexate, and any combination thereof. Most preferred are carboplatin, mitomycin C, 5- fluorouracil, and pirarubicin.

It should be noted that an alternative embodiment of the present invention where inert microcapsules such as those of amorphous silica are used will be to load the microcapsules with a radiotherapeutic agent that has a short half-life. This would mean that a local radiation is not spread to the rest of the body when scavenger cells at some stage are clearing the microcapsules from the site of introduction. One particular advantageous version of this embodiment is the use of a radiotherapeutic agent that emits alpha radiation, because the amorphous silica will effectivel prevent harmful radiation from entering the surrounding tissue before the capsules are rendered leaky. As indicated above, the present invention also contemplates that the chemotherapeutical action in the solid tumour tissue be combined with co-administration of other drugs that primarily serve as protection of surrounding tissue. Even though it is believed that the presently claimed invention will result in a highly focussed localised action of the chemotherapeutical agent, it is expected that some adverse effects are observed in the neighboring tissue.

For instance, when tumour tissue degrades, it is inevitable that an inflammatory process is instigated, and it is not uncommon that the inflammatory process in its own right is capable of inducing destruction in surrounding tissue, a so-called "innocent bystander" effect. However, since the present invention does not compromise the arterial bloodflow as such but only affects the arterioles of the solid tumour, it is possible to administer, either at the same time (co-administration) or at a later stage (e.g. merely as a second stage of the administration of the invention), therapeutic agents that will help to protect the surrounding tissue from these effects.

Therefore, an embodiment of the invention comprises co-administration or later administration to the patient of at least one therapeutic agent. It is preferred that this therapeutic agent is comprised in particles (e.g. as microparticles) in order to ensure correct deposition of the therapeutic agent, but in the event that the microparticles used in the method of the invention have been effective in occluding the arterioles, a systemic administration of an anti-inflammatory drug would be sufficient.

In preferred embodiments, this therapeutic drug is comprised in particles having a different mean diametrical size than the particles that comprise the at least one therapeutic agent; normally the microparticles (with the chemotherapeutic agent) have a smaller mean diametrical size than the particles comprising the at least one therapeutic agent, meaning that administration of both the microparticles and the larger particles will result in a different distribution of the drug effects, the therapeutic agent being deposited upstream of the chemotherapeutic agent. In preferred embodiments, these larger particles are of such a size and structure, that they do not compromise the blood flow, meaning that tissue supplied down-stream is still supplied with blood.

The larger particles are thus preferably retained in the supplying blood vessels relative to their mean diametrical size, thereby giving rise to delivery of the therapeutic agent to the peritumoural tissue from vessels of a defined size. And, since the microparticles containing the chemotherapeutic agent may be capable of stopping the blood-flow to the tumour tissue, no limitation is imposed on the antitumour effect of the chemotherapeutic agent. The at least one therapeutic agent is preferably an anti-inflammatory drug (e.g. an NSAID or a corticosteroid or analogue thereof) and a drug inhibiting cell death.

Simultaneous administration of the two set of particles may be problematic, because the particles carrying the larger may block delivery to the tumour of the microparticles. Therefore, it may be advantageous to deliver the larger particles at a later stage, but alternatively, a catheter containing both set of particles may have the microparticles in the distal end so that these are administered first, followed directly by administration of the larger particles.

Another part of the invention pertains to a pharmaceutical composition that includes 1) microparticles containing a chemotherapeutical agent and 2) particles of a larger mean diametrical size than the microparticles, said particles comprising a therapeutic agent different from a chemotherapeutical agent. The microparticles and the chemotherapeutic agent are preferably as discussed above and the same is true for the therapeutic agent and the larger particles.

The invention also pertains to a catheter for injection of a micropartide preparation, said catheter comprising, in the distal (delivering) end microparticles having a smaller mean diametrical size than particles that are present in the proximal (opposite end) of the catheter. Thus, the catheter comprises 1) microparticles and 2) particles of a larger mean diametrical size than the microparticles, wherein the microparticles are predominantly situated in the distal end of the cathether and wherein the particles are predominantly situated in the proximal end of the catheter, whereby administration of the microparticles and particles from the catheter results in administration of the microparticles prior to administration of the particles. The microparticles and the particles as well as their respective contents and functionality are as disclosed above.

Claims

1. A method of treating a patient suffering from a solid tumour, the method comprising administering, into at least one vessel that supplies the solid tumour with blood, microparticles loaded with a chemotherapeutical agent, said microparticles having a diametrical size that results in retention thereof in the tumour's arterioles, whereby the microparticles are allowed to release the chemotherapeutical agent to the surrounding tumour tissue while minimally compromising surrounding non-tumour tissue.
2. The method of claim 1, wherein the solid tumour is a tumour of the brain, prostate, breast, colon, lung, kidney, bladder, liver, bone, head, neck, stomach, larynx, esophagus, cervix, rectum, uterus, skin, endometrium, pancreas or testis.
3. The method according to claim 1 or 2, wherein the tumour is malignant.
4. The method according to any one of the preceding claims, wherein the tumour is non- malignant.
5. The method according to any one of the preceding claims, wherein the microparticles are administered by means of an injection needle, a catheter or microcatheter or any other device suitable for ensuring localised injection into the at least one artery, so as to avoid undesired administration of the chemotherapeutic agent to other tissue.
6. The method according to any one of the preceding claims, wherein the microparticles are selected from microspheres and microcapsules.
7. The method according to any one of the preceding claims, wherein the microparticles are capable of sustained release of the chemotherapeutical agent.
8. The method according to claim 7, wherein the microparticles comprise a sustained release composition comprising the chemotherapeutical agent.
9. The method according to claim 7 or 8, wherein the chemotherapeutical agent is released as a consequence of degradation of a coating of the micropartide and/or of the micropartide as such.
10. The method according to any one of claims 7-9, wherein the sustained release takes place for a period of up to 30 days after administration of the microparticles.
11. The method according to any one of the preceding claims, wherein the microparticles are biodegradable.
12. The method according to claim 11, wherein the microparticles are of a material selected from the group consisting of a biodegradable polymer such as a polysaccharide, a polyamino acid, a poly(phosphorester) biodegradable polymer, a polymers or copolymers of glycolic acid and lactic acid, a poly(dioxanone), a poly(trimethylene carbonate)copolymer, and a poly(α-caprolactone) homopolymer or copolymer.
13. The method according to any one of claims 1-10, wherein the microparticles are non- biodegradable.
14. The method according to claim 13, wherein the microparticles are of a material selected from the group consisting of amorphous silica, carbon, a ceramic material, a metal, and a non-biodegradable polymer.
15. The method according to any one of the preceding claims, wherein the microparticles are in the form of microspheres that encapsulate the chemotherapeutic agent and wherein release of the chemotherapeutic agent commences after the administration.
16. The method according to claim 15, wherein the encapsulating microspheres are rendered leaky for the chemotherapeutic agent by means of an electromagnetic or ultrasound shock wave.
17. The method according to any one of the preceding claims, wherein the chemotherapeutic agent is selected from the group consisting of an antimetabolite, an immune modulator, a cytotoxic agent, an antibiotic derivative, a nitrogen mustard derivative, an antiangiogenic agent, a receptor antagonist, a receptor ligand, a stimulator, and any combination thereof.
18. The method according to claim 8, wherein the chemotherapeutic agent is selected from carboplatin, mitomycin C, 5-fluorouracil, pirarubicin, cisplatin, carmustine, paclitaxel, doxorubicin, adiramycin, lomustine, teniposide, etoposide, 06-benzylguanine, vincristine, vinblastine, vinorelbine, gemcitabine, cyclophosphamide, temasolamide, 4-HC, methotrexate, and any combination thereof.
19. The method to any of the preceding claims wherein the diametrical size of the microparticles in situ are in the range between 10 and 100 μm, such as between 11 and 90 μm, preferably between 12 and 80 μm, and most preferred between 15 and 40 μm.
20. The method according to any one of the preceding claims, which comprises co- administration to the patient of at least one therapeutic agent, preferably comprised in particles.
21. The method according to claim 20, wherein the microparticles have a different mean diametrical size than the particles that comprise the at least one therapeutic agent.
22. The method according to claim 13, wherein the microparticles have a smaller mean diametrical size than the particles comprising the at least one therapeutic agent.
23. The method according to any one of claims 20-22, wherein the at least one therapeutic agent is selected from the group consisting of an anti-inflammatory drug and a drug inhibiting cell death.
24. The method according to any one of claims 20-23, wherein the particles are retained in the supplying blood vessels relative to their mean diametrical size, thereby giving rise to delivery of the therapeutic agent to the peritumoural tissue from vessels of a defined size.
25. A pharmaceutical composition comprising 1) microparticles containing a chemotherapeutical agent and 2) particles of a larger mean diametrical size than the microparticles, said particles comprising a therapeutic agent different from a chemotherapeutical agent.
26. A catheter comprising 1) microparticles and 2) particles of a larger mean diametrical size than the microparticles, wherein the microparticles are predominantly situated in the distal end of the cathether and wherein the particles are predominantly situated in the proximal end of the catheter, whereby administration of the microparticles and particles from the catheter results in administration of the microparticles prior to administration of the particles.
PCT/DK2004/000560 2003-08-22 2004-08-23 Method of treating a patient suffering from a solid tumour WO2005018600A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US49690903P true 2003-08-22 2003-08-22
DKPA200301204 2003-08-22
DKPA200301204 2003-08-22
US60/496,909 2003-08-22

Publications (2)

Publication Number Publication Date
WO2005018600A2 true WO2005018600A2 (en) 2005-03-03
WO2005018600A3 WO2005018600A3 (en) 2005-05-12

Family

ID=34219532

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2004/000560 WO2005018600A2 (en) 2003-08-22 2004-08-23 Method of treating a patient suffering from a solid tumour

Country Status (1)

Country Link
WO (1) WO2005018600A2 (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1741463A1 (en) 2005-07-05 2007-01-10 Millimed A/S A guiding and an embolization catheter
US7470240B2 (en) 2004-10-22 2008-12-30 General Patent, Llc Pressure pulse/shock wave therapy methods and an apparatus for conducting the therapeutic methods
US7497836B2 (en) 2004-10-22 2009-03-03 General Patent Llc Germicidal method for treating or preventing sinusitis
US7497834B2 (en) 2004-10-22 2009-03-03 General Patent Llc Germicidal method for eradicating or preventing the formation of biofilms
US7497835B2 (en) 2004-10-22 2009-03-03 General Patent Llc Method of treatment for and prevention of periodontal disease
US7507213B2 (en) 2004-03-16 2009-03-24 General Patent Llc Pressure pulse/shock wave therapy methods for organs
US7537572B2 (en) 2004-10-22 2009-05-26 General Patent, Llc Treatment or pre-treatment for radiation/chemical exposure
US7544171B2 (en) 2004-10-22 2009-06-09 General Patent Llc Methods for promoting nerve regeneration and neuronal growth and elongation
US7578796B2 (en) 2004-10-22 2009-08-25 General Patent Llc Method of shockwave treating fish and shellfish
US7601127B2 (en) 2004-10-22 2009-10-13 General Patent, Llc Therapeutic stimulation of genital tissue or reproductive organ of an infertility or impotence diagnosed patient
US7600343B2 (en) 2004-10-22 2009-10-13 General Patent, Llc Method of stimulating plant growth
US20140086971A1 (en) * 2012-09-21 2014-03-27 Merit Medical Systems, Inc. Drug-eluting rotational spun coatings and methods of use
US9655710B2 (en) 2011-01-28 2017-05-23 Merit Medical Systems, Inc. Process of making a stent
US9784730B2 (en) 2013-03-21 2017-10-10 University Of Washington Through Its Center For Commercialization Nanoparticle for targeting brain tumors and delivery of O6-benzylguanine
US9827703B2 (en) 2013-03-13 2017-11-28 Merit Medical Systems, Inc. Methods, systems, and apparatuses for manufacturing rotational spun appliances
US9856588B2 (en) 2009-01-16 2018-01-02 Zeus Industrial Products, Inc. Electrospinning of PTFE
US9987833B2 (en) 2012-01-16 2018-06-05 Merit Medical Systems, Inc. Rotational spun material covered medical appliances and methods of manufacture
US10010395B2 (en) 2012-04-05 2018-07-03 Zeus Industrial Products, Inc. Composite prosthetic devices
US10028852B2 (en) 2015-02-26 2018-07-24 Merit Medical Systems, Inc. Layered medical appliances and methods

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017698A1 (en) 2009-08-07 2011-02-10 Zeus, Inc. Prosthetic device including electrostatically spun fibrous layer and method for making the same

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238714A (en) * 1990-10-02 1993-08-24 Board Of Regents, The University Of Texas System Efficient microcapsule preparation and method of use
US5470582A (en) * 1992-02-07 1995-11-28 Syntex (U.S.A.) Inc. Controlled delivery of pharmaceuticals from preformed porous polymeric microparticles
WO2000023054A1 (en) * 1998-10-16 2000-04-27 Biosphere Medical, S.A. Polyvinyl alcohol microspheres, and methods for making and therapeutic uses of the same
WO2000066183A1 (en) * 1999-05-03 2000-11-09 Lee, Kyu-Ho Vascular embolic materials having multifunctions
EP1155689A2 (en) * 1993-07-19 2001-11-21 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
WO2002000192A2 (en) * 2000-06-23 2002-01-03 Carbon Medical Technologies, Inc. Embolization using carbon coated particles
WO2002003955A1 (en) * 2000-07-10 2002-01-17 F.T. Holding S.A. Fast release bioadhesive microspheres for the sublingual administration of proximate principles
WO2002051388A2 (en) * 2000-12-22 2002-07-04 Ethypharm Treatment of inoperable tumors by stereotactic injection of microspheres
WO2003094930A1 (en) * 2002-05-08 2003-11-20 Biosphere Medical, Inc. Embolization using degradable crosslinked hydrogels

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238714A (en) * 1990-10-02 1993-08-24 Board Of Regents, The University Of Texas System Efficient microcapsule preparation and method of use
US5470582A (en) * 1992-02-07 1995-11-28 Syntex (U.S.A.) Inc. Controlled delivery of pharmaceuticals from preformed porous polymeric microparticles
EP1155689A2 (en) * 1993-07-19 2001-11-21 Angiotech Pharmaceuticals, Inc. Anti-angiogenic compositions and methods of use
WO2000023054A1 (en) * 1998-10-16 2000-04-27 Biosphere Medical, S.A. Polyvinyl alcohol microspheres, and methods for making and therapeutic uses of the same
WO2000066183A1 (en) * 1999-05-03 2000-11-09 Lee, Kyu-Ho Vascular embolic materials having multifunctions
WO2002000192A2 (en) * 2000-06-23 2002-01-03 Carbon Medical Technologies, Inc. Embolization using carbon coated particles
WO2002003955A1 (en) * 2000-07-10 2002-01-17 F.T. Holding S.A. Fast release bioadhesive microspheres for the sublingual administration of proximate principles
WO2002051388A2 (en) * 2000-12-22 2002-07-04 Ethypharm Treatment of inoperable tumors by stereotactic injection of microspheres
WO2003094930A1 (en) * 2002-05-08 2003-11-20 Biosphere Medical, Inc. Embolization using degradable crosslinked hydrogels

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7507213B2 (en) 2004-03-16 2009-03-24 General Patent Llc Pressure pulse/shock wave therapy methods for organs
US7905845B2 (en) 2004-10-22 2011-03-15 General Patent, Llc Pressure pulse/shock wave therapy methods and an apparatus for conducting the therapeutic methods
US7497836B2 (en) 2004-10-22 2009-03-03 General Patent Llc Germicidal method for treating or preventing sinusitis
US7497834B2 (en) 2004-10-22 2009-03-03 General Patent Llc Germicidal method for eradicating or preventing the formation of biofilms
US7497835B2 (en) 2004-10-22 2009-03-03 General Patent Llc Method of treatment for and prevention of periodontal disease
US7470240B2 (en) 2004-10-22 2008-12-30 General Patent, Llc Pressure pulse/shock wave therapy methods and an apparatus for conducting the therapeutic methods
US7537572B2 (en) 2004-10-22 2009-05-26 General Patent, Llc Treatment or pre-treatment for radiation/chemical exposure
US7544171B2 (en) 2004-10-22 2009-06-09 General Patent Llc Methods for promoting nerve regeneration and neuronal growth and elongation
US7578796B2 (en) 2004-10-22 2009-08-25 General Patent Llc Method of shockwave treating fish and shellfish
US7601127B2 (en) 2004-10-22 2009-10-13 General Patent, Llc Therapeutic stimulation of genital tissue or reproductive organ of an infertility or impotence diagnosed patient
US7600343B2 (en) 2004-10-22 2009-10-13 General Patent, Llc Method of stimulating plant growth
US7841995B2 (en) 2004-10-22 2010-11-30 General Patent, Llc Pressure pulse/shock wave therapy methods and an apparatus for conducting the therapeutic methods
US7883482B2 (en) 2004-10-22 2011-02-08 General Patent, Llc Pressure pulse/shock wave therapy methods and an apparatus for conducting the therapeutic methods
EP1741463A1 (en) 2005-07-05 2007-01-10 Millimed A/S A guiding and an embolization catheter
US9856588B2 (en) 2009-01-16 2018-01-02 Zeus Industrial Products, Inc. Electrospinning of PTFE
US9655710B2 (en) 2011-01-28 2017-05-23 Merit Medical Systems, Inc. Process of making a stent
US9987833B2 (en) 2012-01-16 2018-06-05 Merit Medical Systems, Inc. Rotational spun material covered medical appliances and methods of manufacture
US10005269B2 (en) 2012-01-16 2018-06-26 Merit Medical Systems, Inc. Rotational spun material covered medical appliances and methods of manufacture
US10010395B2 (en) 2012-04-05 2018-07-03 Zeus Industrial Products, Inc. Composite prosthetic devices
US20140086971A1 (en) * 2012-09-21 2014-03-27 Merit Medical Systems, Inc. Drug-eluting rotational spun coatings and methods of use
US9198999B2 (en) * 2012-09-21 2015-12-01 Merit Medical Systems, Inc. Drug-eluting rotational spun coatings and methods of use
US9827703B2 (en) 2013-03-13 2017-11-28 Merit Medical Systems, Inc. Methods, systems, and apparatuses for manufacturing rotational spun appliances
US9784730B2 (en) 2013-03-21 2017-10-10 University Of Washington Through Its Center For Commercialization Nanoparticle for targeting brain tumors and delivery of O6-benzylguanine
US10028852B2 (en) 2015-02-26 2018-07-24 Merit Medical Systems, Inc. Layered medical appliances and methods

Also Published As

Publication number Publication date
WO2005018600A3 (en) 2005-05-12

Similar Documents

Publication Publication Date Title
Fung et al. Polymeric implants for cancer chemotherapy
Autorino et al. The use of tamsulosin in the medical treatment of ureteral calculi: where do we stand?
Hynynen Ultrasound for drug and gene delivery to the brain
EP2292225B1 (en) Dosage form comprising taxol in crystalline form
JP5081228B2 (en) Methods of drug depot implant design and implantation
JP3704151B2 (en) Therapy device with a drug deep diseased portion of the body
Lange et al. Antiplatelet therapy for ischemic heart disease
Menei et al. Effect of stereotactic implantation of biodegradable 5-fluorouracil-loaded microspheres in healthy and C6 glioma-bearing rats
US6015541A (en) Radioactive embolizing compositions
EP0906129B1 (en) Implantable medical device
Bidros et al. Novel drug delivery strategies in neuro-oncology
Brem Polymers to treat brain tumours
US20020165424A1 (en) Combination ionizing radiation and immunomodulator delivery devices and methods for inhibiting hyperplasia
US5236410A (en) Tumor treatment method
Wallace et al. Basilar artery rethrombosis: successful treatment with platelet glycoprotein IIB/IIIA receptor inhibitor.
Wolinsky et al. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers
Sheleg et al. Local chemotherapy with cisplatin-depot for glioblastoma multiforme
Menei et al. Local and sustained delivery of 5‐fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: A pilot study
US5662609A (en) Method and apparatus for treatment of focal disease in hollow tubular organs and other tissue lumens
Lincoff et al. Local drug delivery for the prevention of restenosis. Fact, fancy, and future.
US6599540B1 (en) Use of a Serenoa repens extract for the production of a medicament to treat prostate cancer
EP0724429B1 (en) Composition and method for delivery of drugs
Benoit et al. Development of microspheres for neurological disorders: from basics to clinical applications
JP5230045B2 (en) The use of biodegradable microspheres which release an anticancer agent for the treatment of glioblastoma
US20010034503A1 (en) Device for directly delivering an active substance within a cell tissue, means for implanting said device and appliances for injecting active substance into said device

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase