WO2014207746A1 - Procédé et dispositif pour administrer des agents thérapeutiques à une région cible, et moyens pour ces derniers - Google Patents

Procédé et dispositif pour administrer des agents thérapeutiques à une région cible, et moyens pour ces derniers Download PDF

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Publication number
WO2014207746A1
WO2014207746A1 PCT/IL2014/050572 IL2014050572W WO2014207746A1 WO 2014207746 A1 WO2014207746 A1 WO 2014207746A1 IL 2014050572 W IL2014050572 W IL 2014050572W WO 2014207746 A1 WO2014207746 A1 WO 2014207746A1
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WIPO (PCT)
Prior art keywords
medication
drug
release
fluid
patient
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PCT/IL2014/050572
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English (en)
Inventor
Dan SADEH HOCHSTADTER
Yuval KAUFMAN
Original Assignee
Sadeh Hochstadter Dan
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Publication of WO2014207746A1 publication Critical patent/WO2014207746A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/0057—Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
    • A61M25/02—Holding devices, e.g. on the body
    • A61M2025/0293—Catheter, guide wire or the like with means for holding, centering, anchoring or frictionally engaging the device within an artificial lumen, e.g. tube
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/1086—Balloon catheters with special features or adapted for special applications having a special balloon surface topography, e.g. pores, protuberances, spikes or grooves

Definitions

  • the present invention generally relates to a drug delivery device, system and method and more particu larly to biodegradable device tor delivering medications to at least one target region via the intraperitoneal (IP) route,
  • IP intraperitoneal
  • US patent No. 487 542 provides a method and a device tor delivering medicinal to animal and human bladders.
  • the device is a polymeric, miniceUular container surrounding an internal reservoir which contains the medicinal.
  • the device delivers the medicinal to the bladder at a prolonged, conti nuous and controlled rate.
  • EP patent application No. 0572932 discloses an implantable device that is capable of delivering a therapeutic agent to a tissue or organ over a long period ot time.
  • the implantable device is especially suited for treating tissues a nd orga ns that are comprised of smooth muscle.
  • the implantable device can deliver either a single therapeutic agent or a plurality of therapeutic agents to the tissue or organ at zero order kinetics.
  • US patent application No. 2010168563 discloses a device for application to a body cavity.
  • the device is insertable into the cavity of a patient.
  • the device includes a non-absorbable, flexible tube of an elongated shape, a removable core element situation within the tube, and a retention mechanism tor maintaining the device within the cavity,
  • US patent application No. 2006254580 describes a volume-adjustable device for the delivery of multiple medications to a patient, the device comprising multiple medication elements; an outer conta inment means having at least one open end into which the medication elements are removable inserted and a closure means removable and adjustably inserted into at least one end of the outer containment means is disclosed. It therefore remains a long felt and unmet need to provide novel means and methods for an device for delivering a drug in a more effective ana selective manner to the body cavity.
  • LDDDD implementable drug delivery device
  • the envelope comprises at least one ingress path for IP's fluid to both inlet and outlet the layer for expulsion of the medication towards the IP by the fluid.
  • DDD biocompatible drug delivery device
  • IP intraperitoneal
  • FS B l separation element having least one protuberance or/and indentation for distancing the hollow container from interior walls of the body cavity; further wherein the first and second chambers provide an ingress path for IP fluid to enter the hollow container and an exit path for expulsion of activated medication.
  • IP intraperitoneal
  • IP fluid contains an actuation element for activating the med ication; the actuation element is selected from the group consisting of IP fluid 's water, IP fluid 's electrolytes, IP fluid 's antibodies, IP flu id 's white blood cells, IP fluid 's bio-chemicals and combination thereof.
  • the drug-releasing component is a selective barrier element attached to at least first chamber selected from a group consisting of membrane, a mesh or a net like having at least one pore allowing some particles or chemicals to pass through.
  • the device as defined above ,wherein the device additionally comprising an anchoring means adapted for securing the device to a body tissue.
  • the medication is selected from a group consisting of aliquot, tablet, caplet, capsule, pill, bolus, particle, micron ized particle, particulate, pellet, core, powder, granu le, granulate, smal l mass, seed, specks, spheres, crystals, beads, agglomerates or any combination thereof.
  • controlled release delivery system is selected from the group consisting of: slow release, immediate release, sustained release and combination thereof.
  • biodegradable is selected from the group consisting of: liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), poly (lactide co-glycolide (co-polymers of lactic acid and glycolic acid) polyanhydrides, polypeptides, hyaluronic acid, collagen, chonaroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, amino acids such as phenyla lanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • a. providing biocompatible drug delivery device for activating and delivering at least one activated medication via the intraperitonea l (IP) route to at least one target region in a patient body comprising:
  • a hol low container having an externa l surface and interna l surface for housing an inactive medication, the inactive medication renderable active by contact with the IP fluid;
  • the method additionally comprising step of providing the device external surface with a functional separation element (FSE) having least one prot uberance or/and indentation for distancing the hollow container from interior walls of the body cavity the FSE; further wherein the method additionally comprising step of providing the chambers comprising an ingress path tor IP fluid to enter the hollow container and an exit path for expulsion of activated medication.
  • FSE functional separation element
  • IP intraperitoneal
  • controlled release delivery system is selected from the group consisting of: slow release, immediate release, sustained release and combination thereof.
  • biodegradable is selected from the group consisting of: liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), poly (lactide co-glycolide (co-polymers of lactic acicl and glycolic acid) polyanhyclricles, polypeptides, hyaluronic acid, collagen, chonclroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • At least one drug-releasing component located between the chambers, adapted for controlling the release of the first and second medications from the chambers;
  • step of releasing of the medication via drug-releasing component further comprising step of associating the drug-releasing component with device's external surface and/or internal surface for controlling the rate of release of the medications; further wherein the method additionally comprising step of delivering the at least first medication and the at least second medication via the intraperitoneal (IP) route to at least one target region in a patient's body ; the at least one medication is actuated when in IP fluid connection.
  • IP intraperitoneal
  • the method additional ly comprising steps of delivering the at least one first medication to the intraperitoneal (IP) route, second to a first target region and third, to a second target region ; further wherein the step b comprising step of functionally associating the drug-releasing component with the device's external surface and/or internal surface for controlling the rate of release of the medications.
  • IP intraperitoneal
  • At least one first chamber and at least one second chamber for loading at least one first medication and at least one second medication respectively; and ii. at least one drug-releasing component located between the chambers adapted for med ication release from the chambers;
  • the method additionally comprising step of delivering the at least one first medication and the at least one second medication via the intraperitonea l (I P) route to at least two target regions in the patient's body; the at least one medication is actuated when in IP fluid connection.
  • I P intraperitonea l
  • the drug-releasing component is selected from the group consisting of: a selective barrier element attached to at least first chamber, selected from the group consisting of membrane, a mesh or net like having at least one pore allowing some particles or chemicals to pass through.
  • the biodegradable from the group consisting of: liposomes, polylactides (poly!actic acid), polyg
  • the drug-releasing component is associated with the device external surface and/or internal surface for controlling the rate of release of the medications dosage; further wherein the at least one first medication is delivered via the intraperitoneal (IP) route to at least two target regions in a patient body; the at least one medication is actuated when in IP fluid connection.
  • IP intraperitoneal
  • the drug-releasing component is a selective barrier element attached to at least first chamber, selected from the group consisting of membrane, a mesh or net like having at least one pore allowing some particles or chemicals to pass through, but not other..
  • biodegradable is selected from the group consisting of: liposomes, polylactides, polyglycolide, poly (lactide co-glycolide (co-polymers of lactic acid and glycolic acid) polyanhydrides, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • a biocompatible drug delivery device comprising:
  • At least one first chamber and at least one second chamber for loading the at least one first medication and the at least one second medication respectively;
  • an applicator adapted for affixing the device to the body tissue
  • the drug-releasing component is adapted for controlling the rate of release of the medication from device external surface or/and internal surface; further wherein the at least first medication is delivered via the intraperitoneal (IP) route to at least two target regions in a patient body; the at least one medication is actuated when in I P fluid connection.
  • IP intraperitoneal
  • kits as defined in any of the above wherein the applicator is adapted for inserting the device into the body of a patient or/and for removing the device from said patient. It is another object of the present invention to provide the kit as defined in any of the above, wherein said device further comprising an anchoring means for securing said device to a body tissue.
  • DDP implementable drug delivery pump
  • At least one envelope with at least first layering surface for containing a medication said envelope comprises at ieast one ingress path for IP's fluid to both in let and outlet the layer for expulsion of the medication towards the IP by the fluid and further and
  • the medication delivery pump facilitates the deliver/ of the medication from the at least one envelope.
  • DDP implementable drug delivery pump
  • DDD implementable drug delivery device
  • IP intraperitoneal
  • the DDD comprising at least one envelope with at least first layering surface confining at ieast one first volume accomodating at least one first precursor and at least one second precursor; wherein the envelope comprises at least one ingress path for IP's fluid to both inlet and outlet the layer for expulsion of the first and second precursors towards the IP by the fluid; and further wherein at least one first precursor and at least one second precursor forms an effective medication to target the region in a patient body.
  • DDD drug delivery device
  • FDDD feedback implementable drug delivery device
  • At least one envelope with at least one first layering surface confining at least one first volume which accommodates at least one medication;
  • the envelope comprises at least one controllable path for IP's fluid to both inlet and outlet the layer for controlled expulsion of the medication towards the IP by the fluid;
  • controlling means regu lates the path thereby controlling the fluid flow.
  • FDDD feedback implementable drug delivery device
  • IP intraperitoneal
  • b. containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one first drug with the at least one first enveloping layer; c. providing the least one first enveloping layer with an effective a releasing means, by selecting the releasing means from physical means, especially porosivicy parameters, and chemical means, especial ly solubility and selectivity;
  • d. providing, by the releasing means, the system with a drug's release profile, and e. selecting the profile from a group consisting of a parabolic release profi le, a hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • b. containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one first drug with the at least one first enveloping layer.
  • b. containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one first drug with the at least one or second enveloping layer.
  • b. containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one second drug with the at least one or second enveloping layer.
  • FIG. 1 presents the drug delivery device of the present invention
  • FIG, 2 presents a schematic view of the peritoneum surrounding the body organ
  • FIGs. 4A-B present a cross section view of the drug delivery device of the present invention
  • FIG. 5 presents a cross section view of the drug delivery device of the present invention
  • FIG. 6 presents a cross section view of the drug delivery device of the present invention
  • FIGs. 7-12 present a perspective view of a cluster-bomb-like implementable drug delivery systems of the present invention
  • FIGs. 13-19 present graphs of the release profile of the drug delivery device of the present invention
  • the present invention have been defined specifically to provide device, means ana method tor delivering a medication to a predefined location at the abdom inal cavity and more particularly to the peritoneal cavity of a patient for a complementary' medical analysis and treatment.
  • the present invention provides a device, kit and method for localized long-term administration of a therapeutic agent or a medication to a particu lar tissue or organ. T he device can be implanted or inserted once and release variety of drug dosages over an extended period.
  • the present invention provides an implanted device administrating a medication via the intraperitoneal (IP) route in patient's body cavity.
  • IP intraperitoneal
  • Using the IP rout for delivering a medication allows higher medication doses and more frequent administration of drugs, and it is more effective in killing ceils such as cancer cells in the peritoneal cavity, where ovarian cancer is li kely to spread or recur first.
  • the peritoneum is known as a membrane that surrounds the visceral organs forming the mesentery which connects the Bowel loops.
  • the physiologic characteristic of the peritoneal cavity provides a useful portal of entry in the body for variety pharmacological agents.
  • Several medications, such as antibiotics can be given via the intraperitoneal (IP) route to treat episodes of peritonitis .
  • IP intraperitoneal
  • the IP route can further be used for delivering a medication in patients with intra-abdominal malignancies, i.e. gynecological and gastrointestinal cancers.
  • the rate and amount of drug transfer in the peritoneum are dependent on several factors. Factors such as peritoneal inflammation, surface area, peritoneal blood flow, time of contact etc., influence the drug transfer.
  • IP route provides high concentration locally which targets the involved peritoneal tissues directly.
  • the peritoneum is known to support the abdominal organs and serves as a conduit for their blood and lymph vessels and nerves.
  • the structures in the abdomen are classified as intraperitoneal, retroperitoneal or intraperitoneal depending on whether they are covered with visceral peritoneum and whether they are attached by mesenteries (mensentery, mesocolon).
  • the IP fluid surrounds variety of organs such as the stomach, duodenum , jejunum, i leum, cecum, appendix, transverse colon, sigmoid colon, rectum, Liver, spleen, pancreas , uterus, fallopian tubes, ovaries , kidneys, adrenal glands, proximal ureters, renal vessels , urinary bladder and distal ureters, the IP can be an essential route for delivering medication to those organs.
  • organs such as the stomach, duodenum , jejunum, i leum, cecum, appendix, transverse colon, sigmoid colon, rectum, Liver, spleen, pancreas , uterus, fallopian tubes, ovaries , kidneys, adrenal glands, proximal ureters, renal vessels , urinary bladder and distal ureters
  • the IP can be an essential route for delivering medication to those organs.
  • the present invention further provides the usefulness of I P drug therapy device and the factors influencing it, as well as strategies to increase the efficacy, and conclude that IP route is an alternate route to the more conventional drug delivery routes, and can be successfu lly used when the target is within the peritoneal cavity or adjacent tissue.
  • the present invention further provides a device which after introducing into the peritoneal cavity, drug transfer occurs into the surrounding peritoneal tissues, and from there into the body compartments via the circulation.
  • Peritoneal transport occurs via three simultaneous processes: a) diffusion, b) ultrafiltration, and c) fluid reabsorption.
  • a three pore model has been validated, which suggests that transport across the peritoneal membrane occurs by pores of three different sizes.
  • the large pores and small pores with radius of about ⁇ 2 ⁇ responsible for the transport of larger and smaller sized solutes.
  • the absorption of intraperitoneailv admin istered macromolecules is linear in time, irrespective of molecular size or concentration.
  • the transport of the pharmacological agent across the peritoneum is governed by factors such as (a) dosing variables i.e. dose, volume, temperature, duration, composition of carrier solution etc., (b) drug properties i.e. molecular weight, io nic charge, apparent volume of d istribution (Vd), membrane binding, lipid/ water solubility etc, as well as (c) the characteristics of the peritoneum, i.e. surface area, charge, permeability, peritonitis, fibrosis, peritoneal blood flow and lymphatic absorption etc.
  • the rate and amount of drug transfer are dependent on several factors.
  • the kinetics of the drug, as well as factors such as peritoneal inflammation, surface area, peritoneal blood flow, time of contact, etc. influence the drug transfer.
  • Dedrick et ah, Pharmacokinetic Problems in Peritoneal Drug Administration-, Tissue Penetration and Surface Exposure JNCI ] Nad Cancer Inst (1997) 89(7): 480-487 described in a pharmacokinetic model which showed that with IP infusion the drug concentrations in the peritoneal cavity could theoretica lly exceed those in systemic circulation by three log values or more.
  • Maneuvers such as increasing the dwell duration, temperature or pressure, solutions of different ton icity 7 , use of vasoactive agents, and surfactants have been tried in an effort to increase the drug efficacy.
  • the surface area of the peritoneum which actually comes in contact with the therapeutic solution is a small fraction of the total peritoneal surface area.
  • newer icodextrin containing solutions can maintain the osmotic gradient for up to 24 hrs or longer, and have been used as a carrier for drugs such as 5FU for up to 96 hours.
  • Other factors such as the solution volume, patient size, and patient position, all affect the contact surface area.
  • An ambulator/ patient will have most of the fluid in the bottom of the cavity which decreases the contact area .
  • the device of the present invention has potential benefits for the use of IP route instead of using other routes such as intravenous (IV) route.
  • the IP route is with the ability to treat the patient on an outpatient basis, presence of an existing access for ad m inistration, avoidance of cost of IV lines, ana avoidance of IV route related toxicities such as phlebitis, and loss of veins which may need to be preserved.
  • I P route is an alternate manner to deliver a medication, especially where the target is contained within the peritoneal cavity. Gene therapy delivery may further use the IP route.
  • the device is configured to be insertable and/or implanted via natural body orifice or any opening to a cavity or passage of the body.
  • the drug is released into the surround ing of the peritoneal tissues and from there into the body compartments via the circulation. T he med ication rate and amount released are dependent on several factors such as the kinetics of the drug, peritoneal inflammation, surface area, peritoneal blood flow and time of contact, the medication adm inistrated vi the IP route provides high concentration locally of the medication which further targets the involved peritoneal tissues directly.
  • the major advantage of IP therapy is regional dose intensity. After intracavitary drug administration, the peritoneal cavity is exposed to higher concentrations compared to other parts of the body. The concentration differential occurs because drug movement from peritoneal cavity 7 to plasma (peritoneal clearance) is generally slow relative to drug clearance from the body.
  • the peritoneal cavity is the site of disease in several cancers, including ovarian, gastrointestinal and peritoneal mesothelioma.
  • Endometriosis a gynecological medical condition in which cells from the lining of the uterus (endometrium) appear and flourish outside the uterine cavity, most commonly on the membrane which lines the abdominal cavity.
  • the uterine cavity is lined with endometrial cells, which are under the influence of female hormones.
  • Endometrial-! ike cells in areas outside the uterus (endometriosis) are influenced by hormonal changes and respond in a way that is similar to the cells found inside the uterus. Symptoms often worsen with the menstrua l cycle.
  • Endometriosis is typically seen during the reproductive years. Symptoms may depend on the site of active endometriosis. Its main but not universal symptom is pelvic pain in various manifestations. Endometriosis is a common finding in women with infertility. Endometriosis can be treated in a variety of ways, includ ing pain medication, hormonal treatments, and surgery. In Endometriosis disease endometrial glands and stroma implant and grow in areas outside the uterus. The location a nd inflammatory response to these lesions are believed to play key role in symptoms ana signs associated with endometriosis.
  • the present invention provides an device which enables a medication delivery to a target region, organ or area related and affected of Endometriosis disease within the body cavity of a patient.
  • the device of the present invention may be further provided for the treatment of Endometriosis and for variety types of Cancer such as Ovarian, Peritoneal, Pseudomyxoma peritonei, Mucinous, adenocarcinoma of the appendix, Mesothelioma and Colorectal carcinoma.
  • the device may further be provided for treating variety of Infection such as: Peritonitis, P! L) - acute, PID - chronic and Tuberculosis.
  • the device may further be provided for treating Familial Mediterranean fever (FMF) ana for prevention of adhesions: Post-operative and Post-infectious.
  • FMF Familial Mediterranean fever
  • the device may further be provided for the treatment of extraperitoneal pathology: such as Inflammatory Bowel Disease- IB D (Crohn's disease and Ulcerative colitis) and reservoir for chronic system ic treatment.
  • controlled release system refers hereinafter to but is not limited to , drug delivery- systems (DDS), controlled release systems, delayed release systems, modified release systems, slow release systems, pH dependent systems, pH independent coatings systems, and any combinations thereof. It is further in the scope of the invention, wherein the term “controlled release” refers hereinafter to but is not limited to sustained release, sustained action, controlled release, extended action, timed release dosage forms and other parallel terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after the administration of single dose.
  • Physically enabled systems are selected, in a non-limiting manner, from osmotic pressure- activated DDS; hydrodynamic pressure-activated DDS; vapor pressure-activated DDS; Mechanically activated DDS; magnetica lly activated DDS; mono-phoresis activated DDS; iontophoresis activated DDS; hydration-activated DDS etc.
  • Chemically enabled systems are selected, in a non-limiting manner, from pH- activated DDS; ion- activated DDS; hydrolysis- activated DDS etc.
  • Biochemically enabled systems are selected, in a non-limiting manner from enzyme- activated DDS and other biochemical- activated DDS.
  • an implemeritable drug delivery pump useful for facilitating the delivery of a medication via the intraperitoneal (IP) to a target region in a patient body.
  • the DDP comprises a. at least one envelope with at least first layering surface for containing a medication; the envelope comprises at least one ingress path for IP's fluid to both inlet and outlet the layer for expulsion of the medication towards the IP by the fluid; and at least one first volume confined by the envelope, comprising effective measure of the med ication; and a medication delivery pump; wherein the medication delivery pump facilitates the delivery of the medication from the at least one envelope.
  • a method of facilitating the delivery of a medication via the intraperitoneal (IP) to a target region in a patient body comprises a step of providing an implementable drug delivery pump (DDP) by containing a medication within at least one envelope with at least first layering surface; providing the envelope with at least one ingress path for IP's fluid to both inlet and outlet the layer for expulsion of the medication towards the I P by the fluid; a step of confining by the envelope at least one first volume, comprising effective measure of the medication; and a step of facilitating the delivery of the medication from the at least one envelope by means of a medication delivery pump.
  • DDP implementable drug delivery pump
  • the DDS are in connection with or comprises drug's or fluid's pump such that a DDP is provided.
  • a DDP is provided.
  • an Alzet® - like osmotic pump is utilized.
  • Combitally available ALZET osmotic pumps and their like are miniature, infusion pumps for the continuous dosing.
  • another DDP is provided, namely a hydrodynamic pressure-activated drug delivery system (e.g., push- pull osmotic pump) is utilized.
  • This system is fabricated by enclosing a collapsible, impermeable container, which contains liquid drug formulation to form a drug reservoir compartment inside rigid shape-retaining housing.
  • a composite laminate of an adsorbent layer and a swellable, hyd roph ilic polymer layer is sandwiched.
  • another DDP is provided, namely a vapor pressure-activated drug delivery system is utilized.
  • the drug reservoir in a solution formulation is contained inside an infusate chamber. It is physically separated from the vapor pressure chamber by a freely movable bellows.
  • the vapor chamber contains a vaporizabie fluid, which vaporizes at body temperature and creates a vapor pressure. Under the vapor pressure created, the bellows moves upward & forces the drug solution in the infusate chamber to release, through a series of flow regulators and delivery cannula into the blood circulation at a constant flow rate.
  • DDP a mechanically activated drug delivery system
  • drug reservoir is in solution form retained in a container equipped with mechanically activated pumping system.
  • another DDP is provided, namely magnetically activated drug delivery system is utilized.
  • drug reservoir is a dispersion of peptide or protein powders in polymer matrix from, which macromolecular drug can be delivered only at a relatively slow rate. ' Ibis low rate of delivery can be improved by incorporating electromagneticaliy triggered vibration mechanism into polymeric device combined with a hemispherical design. Device is fabricated by positioning a tiny magnet ring in core of hemispherical drug dispersing polymer matrix.
  • This delivery device is fabricated by positioning a tiny magnet ring in core of hemispherical drug dispersing polymer matrix. T he external surface is coated with drug impermeable polymer (ethylene vinyl acetate or silicon elastomer) except one cavity at the center of the flat surface.
  • This delivery device used to deliver protein drugs such as bovine serum albumin, at a low basal rate, by a simple diffusion process under non triggering condition, As the magnet is activated to vibrate by external electromagnetic field, drug molecules are delivered at much higher rate.
  • another DDP is provided, namely sonophoresis - activated drug delivery system (phonophoresis) is utilized. This type of system utilizes ultrasonic energy to activate or trigger the delivery of drug from polymeric drug delivery device.
  • Non-degradable polymer ethylene vinyl acetate
  • bioerodiable polymer poly[bis(p-carboxyphenoxy) alkane an hydride.
  • iontophoresis activated drug delivery system is utilized. This type of system uses electrical current to activate and to modu late the diffusion of charged drug across biological membrane.
  • another DDP is provided, namely hydration activated drug delivery system is utilized, in this system, the drug reservoir is homogeneously dispersed in a swellable polymer matrix fabricated from a hydrophilic polymer (ethylene glyxomethacrylate). The release of drug is controlled by the rate of swelling of polymer matrix.
  • a pH- activated drug delivery system is utilized.
  • This type of chemically activated system permits targeting the delivery of drug only in the region with selected pH range. It fabricated by coating the drug-containing core with a pH - sensitive polymer combination. For instances, a gastric fluid labile drug is protected by encapsulating it inside a polymer membrane that resist the degradative action of gastric pH.
  • another DDP is provided, namely ion- activated drug delivery system is utilized. An ionic or a charged drug can be delivered by this method and this system are prepared by first compiexing an ionic drug with an ion-exchange resin containing a suitable counter ion.
  • a complex between a cationic drug with a resin having a SO 3 group or between an anionic drug with a resin having a N(CHi)3 group by forming a complex between a cationic drug with a resin having a SO 3 group or between an anionic drug with a resin having a N(CHi)3 group.
  • the granules of drug-resin complex are first treated with an impregnating agent & then coated with a water-insoluble but water-permeable polymeric membrane.
  • This membrane serves as a rate- controlling barrier to modulate the influx of ions as well as the release of drug from the system
  • an electrolyte medium such as gastric fluid ions diffuse into the system react with drug resin complex & trigger the release of ionic drug.
  • hydrolysis- activated drug delivery system is utilized. This type of system depends on the hydrolysis process to activate the release of drug.
  • Drug reservoir is either encapsulated in microcapsules or homogeneously dispersed in microspheres or nano particles tor injection. It can also be fabricated as an implantable device. All these systems can be prepared from bioerodib!e or biodegradable polymers (polyanhydride, polyorthoesters). It is activated by hydrolysis-induced degradation of polymer chain & is controlled by rate of polymer degradation.
  • DDP an enzyme - activated drug delivery system
  • This type of biochemical system depends on the enzymatic process to activate the release of drug.
  • Drug reservoir is either physically entrapped in microspheres or chemically bound to polymer chains from biopolymers (albumins or polypeptides).
  • the release of drug is activated by enzymatic hydrolysis of biopolymers (albumins or polypeptides) by specific enzyme in target tissue.
  • another DDP is provided, namely a feedback regulated drug delivery system is utilized. In this group the release of drug molecules from the delivery system is activated by a triggering agent. Rate of drug release is control led by concentration of triggering agent.
  • bioerosion-regulated drug delivery system namely bioerosion-regulated drug delivery system is utilized.
  • the system consisted of drug-dispersed bioerodible matrix fabricated from poly (vinyl methyl ether) ester which is coated with layer of immobilized urease. In a solution with near neutral pH, the polymer only erodes very slowly. In presence of urea, urease metabolizes urea to form ammonia. This causes increase in pH & rapid degradation of polymer with release of drug molecule.
  • bioresponsive drug deliver/ system Drug reservoir is contained in device enclosed by bioresponsive polymeric membrane whose drug permeability is controlled by concentration of biochemica l agent.
  • a lternatively or additional ly another DDP is provided, namely a self-regulating drug delivery system is utilized.
  • This type of system depends on a reversible & competitive binding mechanism to activate and to regulate the release of drug.
  • Drug reservoir is drug complex encapsulated within a semi permeable polymeric membrane. The release of drug from the delivery system is activated by the membrane permeation of biochemical agent from the tissue in which the system is located.
  • unit dosage form or “dose form” or “drug” or “medication” or “therapeutic agent” interchangeably refers hereinafter to a pharmaceutically acceptable forms of a liquid, gel, solid, gas or semisolid dosage forms drug selected from the group consisting of aliquot, tablet, caplet, capsule, pill, bolus, particle, micronized particle, particulate, pellet, core, powder, granule, granulate, small mass, seed, specks, spheres, crystals, beads, agglomerates, Emulsion, Hydrogel, Molecular encapsulation, Soitgel, Solution, Suspension, Syrup, Tincture, Tisane or any combination thereof, in a sustained-release formulations.
  • the core of the unit dosage form may be coated with at least one functional coating or film which may modify the release properties of the formulation.
  • the unit dosage form of the present invention may further comprise d ifferent drug release profiles from d ifferent layers.
  • I ' he medications can be any compound that is biologically active and requires long term ad m inistration to a tissue or organ for maximum efficacy.
  • Therapeutic agents that can be used in accordance with the present invention include, but are not limited to, antimuscarinic agents, anticholinergic agents, antispasniodic agents, calcium, antagonist agents, potassium, channel openers, musculotropic relaxants, antineoplastic agents, polysynaptic inhibitors, and beta- ad renergic stimulators.
  • anticholinergic agents are propantheline bromide, imipramine, mepenzolate bromide, isopropamide iodide, clidinium bromide, anisotropine methyl bromide, scopolamine hyd rochloride, and their derivatives.
  • antimuscarinic agents include, but are not limited to, hyoscyamine sulfate, atropine, methantheline bromide, emepronium. bromide, anisotropine methyl bromide, and their derivatives.
  • polysynaptic inhibitors are baclofen and its derivatives.
  • 8-adrenergic stimulators are ter-butaline and its derivatives.
  • Examples of calcium antagonists are terodiline and its derivatives.
  • Examples of musculotropic relaxants include, but are not limited to, dicyclomine hydrochloride, flavoxate hydrochloride, papaverine hydrochloride, oxybutynin chloride, and their derivatives.
  • antineoplastic agents include, but are not limited to, carmusti ne levamisole hyd rochloride, flutamide, (w-methy!-N-[4-nitro-3-(tri.fluorom.ethy! phenyl]), adriarnycin, doxorubicin hydrochloride, idamycin, fluorouracil, Cytoxan, mutamycin, mustargen and leucovorin calcium.
  • the device may contain medication in a gas form (e.g Nitric Oxide,NO) such that when the inner structure of the device is in contact with the I P fluid a gas material is released.
  • a gas form e.g Nitric Oxide,NO
  • the gas material may further provide antimicrobial, anti- infection, and/or therapeutic activity and characteristics.
  • one of the uses for the control release delivery' of drugs to a specific tissue or organ is for internal organs that can be classified as mechanically dynamic organs.
  • mechanically dynamic organs include, but are not limited to, the stomach, intestines, heart, bladder, ureter, urethra, various sphincter muscles, and the esophagus.
  • the functions of these organs are maintained by their normal and timely mechanical contractions. Should the mechanical properties be lost, the intended functions of these organs are partially or completely lost- Reference is now made to Fig.
  • FIG. 1 which illustrates a biocompatible drug delivery device 1 for the delivery of at least a first med ication and at least second med ication to a patient body cavity, comprising: at least one first chamber 3 and at least one second chamber 4 for loading at least one first med ication and at least one second medication respectively, (b)at least one drug- releasing component 2 adapted for medication release; and optionally, (c)an anchoring means 6 adapted for securing the device to a body tissue.
  • the drug-releasing component is adapted for controlling the rate of release of the medication from the device internal surface or external surface.
  • the medication is delivered via the intraperitoneal (IP) route to at least two target regions in a patient body.
  • IP intraperitoneal
  • the present invention further provides an implementable drug delivery device (DDL)) for delivering a medication via the intraperitoneal (I P) to a target region in a patient body, the DDD comprising:(a)at least one envelope with at least first layering surface for containing a medicamen; and, (b)at least one first volume confined by the envelope, comprising effective measure of the medication; wherein the envelope comprises at least one ingress path for IP's fluid to both inlet and outlet the layer for expulsion of the medication towards the I P by the fluid.
  • DDL implementable drug delivery device
  • the present invention further provides a drug delivery device (DDD) for activating and delivering at least one activated medication via the intraperitoneal (IP) route to a target region in a patient body
  • DDD drug delivery device
  • the DDD comprising: (a) a hollow container having an external surface and internal su rface for housing an inactive medication, the inactive med ication renderable active by contact with the IP fluid; (b) at least one first chamber for loading the medication into the hollow container; and, (c) at least one second chamber for releasing the at least one activated medication into the interior body cavity; wherein the external surface is provided with a functional separation element (FSE) having least one protuberance or/ and indentation for distancing the hollow container from interior walls of the body cavity; further wherein the first and second chambers provide an ingress path for IP fluid to enter the hollow conta iner and an exit path for expulsion of activated medication.
  • FSE functional separation element
  • the present invention further provides a biocompatible drug delivery device for the deliver/ of at least one medication to a target region within patient body cavity, comprising: (a) at least one first chamber and at least one second chamber for containing at least one first medication and at least one second medication respectively? (b) at least one drug-releasing component adapted for medication release, located between the chambers, and optiona lly, (c)an anchoring means adapted for securing the device to a body tissue.
  • the each of the chambers are easily connected or disconnected from the device when loading a medication especial ly in surgical or emergency procedure.
  • the med ication is delivered first to the intraperitoneal (IP) route second to a first target region and third to a second target region.
  • the drug-releasing component is adapted for controlling the rate of release of the medication when in IP fluid connection.
  • the drug transfer via the I P route achieves therapeutic efficacy in the region of interest while minimizing the systemic toxicities.
  • the present invention further provides an intraperitoneal (I P) administrable device useful for treating endometriosis, the device comprising: at least a first chamber and a second chamber for containing the at least a first medication and at least a second medication respectively; and , an anchoring means adapted for securing the device to a body tissue; wherein the device is configured for controlling the rate of release of the medication when the medication is delivered to a target region via the intraperitoneal (IP) route .
  • I P intraperitoneal
  • IP intraperitoneal
  • the drug-releasing component may be a selective barrier element (not shown) attached to at least first chamber containing at least one medication.
  • the separating element may be a membrane, a mesh or net like having at least one pore allowing some particles or chemicals to pass through, but not other. T he selective barrier shape and structure may further control the time of release of each medication within each chamber.
  • the medication may further be based upon a controlled release delivery system of the medication.
  • the controlled release delivery system may be a slow release, immediate release, sustained release and combination thereof.
  • the drug-releasing component may further be a combination of a separating element and a controlled release delivery system of at least first medication.
  • the drug delivery device may be composed of a biodegradable material selected from the group consisting ot: liposomes, polylactides (polylactic acid), polyglycolide (polymer ot glycolic acid), poly (lactide co-glycolide (co-polymers ot lactic acid and glycolic acid) polyanhydrides, polypeptides, hyaluronic acid, collagen, chonclroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone container.
  • the drug delivery device contains at least first medication which is physically trapped, or covalently or ionically immobilized in a biodegrad able matrix.
  • the device is adapted for loading a medication having a dosage form selected from a group consisting ot aliquot, tablet, caplet, capsule, pi ll, bolus, particle, micronized particle, particulate, pellet, core, powder, granu le, granulate, small mass, seed, specks, spheres, crystals, beads, agglomerates or any combination thereof.
  • the dosage form is further based upon controlled release delivery system.
  • the controlled release delivery ; system may be a slow release, immediate release, sustained release and combination thereof.
  • T herefore at least first medication is based upon a slow release manner whilst at least second medication is based upon immediate release manner.
  • at least first medication is based upon a slow release manner whilst at least second medication is based upon sustained release manner
  • the device is a 3D container having a cylinder shape, a tube like, a star like, a ball like, a roll like.
  • the device is composed of a semi permeable wall having at least one opening channel for IP fluid entrance and medication release.
  • the device is a non-absorbable, flexible container having an elongated shape.
  • the device is adapted to release at least first medication at a rate of at least approximately 0. 1 meg day whilst at least second medication is released at a rate of at least approximately 0.5 meg/day over a period of at least approximately one week.
  • the medications may be transported via a) diffusion, b) ultrafiltration, c) fluid re- absorption and combination thereof.
  • the device may contain medications for treating at least one diseases, disorder or condition having different dosages for long treatment.
  • the device is used for treating Endometriotic disease.
  • the device of the present invention is a volume-adjustable device. Thereby it may be adjusted to the volume or number or medication elements contained within the medication delivery device.
  • the medications for IP delivery for treating of endometriosis are selected in a non- limiting manner from the group consisting of Progestatives - e.g. dienogest, Progesterone antagon ists / modulators such as mifepristone, GN RH agon ists - e.g. leuprolide acetate, Aromatase inhibitors - e.g. letrezo!e, NTHEs - e.g. parecoxib, Anti-inflammatory', Anti- angiogenic DA - e.g. cabergoline, N F Kappa-b medications, Vitamin D, Estrogen and a combination or mixtures thereof.
  • the device may Last and provide treatment within patient's body cavity tor at least a week.
  • the device may comprise an anchoring means for maintaining the device with in the body cavity.
  • the device is flexible and shaped to be insertable and/or implanted into the body IP cavity.
  • the device may be preferably liquid impermeable or at least liquid sem i-permeable.
  • the device further comprises at least one opening through which the medication can be employed and/or release.
  • the medication is situated and released from at any one of the following locations: a. the external surface of the device, b. the internal surface of device within at least one of the chambers and, c. within a network of pores of wh ich the device may comprise.
  • the regions within the body cavity may be chosen from the group consisting of. rectum, large intestine, small intestine, esophagus, stomach, trachea, bronchus, outer ear canal, inner ear canal, nasal canal, air sinuses, vagina, cervix, uterus, fallopian tubes, urethra (including prostate), bladder and, intra-articuiar cavity.
  • the device is capable of deliver/ for local treatment and/or systemic treatment.
  • the device of the present invention may combine several medications in order to increase the therapy effect in several body regions or organs and further reduce side effects.
  • the device may contain variety of substance combinations, shapes or presentations (capsules, tablets, soft gels) without chemical interaction.
  • the device of the present invention provides controlled release of drug in vivo by diffusion of the drug out of a polymer and/or by degradation of the polymer over a predetermined period following administration to the patient.
  • the medication may be employed into the implanted device using a syringe or catheter.
  • the device may additionally comprise an applicator for affixing the device to the body tissue via anchoring means.
  • the applicator may further be used for reloading the device chambers with additional medications.
  • the applicator may further be used tor better implantation ot the device within the body cavity of the patient.
  • the applicator is configured to enable the device to collapse easily into the body cavity.
  • Fig 2 is a prior art, presenting the peritoneal cavity.
  • the peritoneum is a membrane that forms the lining of the abdom inal cavity or the coelom it covers most ot the intra-abdominal (or coelomic) organs in amniotes ana some invertebrates (annelids, for instance). It is composed of a layer of mesothelium supported by a thin layer of connective tissue.
  • the peritoneum both supports the abdominal organs ana serves as a conduit for their blood and lymph vessels and nerves.
  • the structures in the abdomen are classified as intraperitoneal, retroperitoneal or intraperitoneal depending on whether they are covered with visceral peritoneum and whether they are attached by mesenteries (mensentery, mesocolon).
  • Figs. 3a-c illustrate the configuration of a biocompatible drug delivery device for activating and delivering at least one activated medication via the intraperitoneal (IP) route to at least one target region in a patient body, comprising: (a)a hollow container having an external surface and internal surface for housing an inactive medication, the inactive med ication renderable active by contact with the IP fluid, (b) at least one first chamber tor loading the at least one inactive medication into the hollow container, and (c)at least one second chamber for releasing the at least one activated medication into the interior body cavity; wherein the external surface is provided with a functional separation element (FSE) having least one protruberance or/ and indentation for distancing the hollow container from interior walls ot the body cavity the FSE; further wherein the chambers provide an ingress path for IP fluid to enter the hollow container and an exit path for expulsion of activated medication.
  • FSE functional separation element
  • a biocompatible drug delivery device for the delivery of at least one first medication to patient's body cavity via the intraperitoneal (IP) route to at least one target region in a patient body, comprising: an implant for housing and releasing the medication, wherein the implant further comprises at least one chamber for containing the drug; the implant is adapted for introduction and placement into the Peritoneal cavity via the Douglas pouch, the belly-button or any other natural body enter. .
  • the interior walls referees to the device walls, the interior surface of the device or/ana the central surface of the device.
  • the release of the medication from the implant may be by an actuation element selected from a group consisting of: IP fluid water, IP fluid electrolytes, I P fluid antibodies, I P fluid white blood cells, IP fluid bio-chemicals or any of the martials which the IP fluid consist.
  • an actuation element selected from a group consisting of: IP fluid water, IP fluid electrolytes, I P fluid antibodies, I P fluid white blood cells, IP fluid bio-chemicals or any of the martials which the IP fluid consist.
  • the device may 7 further comprise a shielding material (not shown) as an external coating surrounding the device.
  • the shielding is adapted as a barrier or a septum to prevent contact of the device outer surface with the body tissue and furtherniore preventing increment of the concentration release of the medication.
  • ⁇ he shielding material may comprise plurality of holes.
  • ⁇ he device of the present invention may be inserted via the Douglas pouch, rectum, vagina or any other natural body enter.
  • the device of the present invention may 7 further be inserted placed and transported via other fluidly routes or humid regions such as the eye area, the digestive system, the bladder, the vagina or the like.
  • Fig 3c illustrates a cylindrical body configuration of the device of the present invention having an external surface comprising a plurality 7 of protrusion such as actuation flaps or pins allowing the movement of the device within the body cavity and further allowing the device transported with the IP fluid flow 7 to wonder around the organs.
  • the pins allow 7 movement of the device in the IP fluid and further to deliver at least one medication to a targeted region.
  • the device may comprise a monitor unit or a detecting unit for measuring physical or/and chemical characteristics or parameter with the device and fluid conditions such as temperature, humidity, pressure, pH, ionic change, osmolarity, concentration of substances such as acid-lactic, glucose, lipids, hormones, gases, enzymes, inflammatory mediators, plasmin, albumin, lactoferrin, creat.in.in, proteins and the like.
  • the monitor may be programed to begin or stop the release of the medication according to a pre-programed range of at least one of the mentioned parameters.
  • the monitor may further be programed to instruct and control the medication dosage release from the device.
  • the device may further comprise anchoring means for securing the device implanted to a wall of an organ within a patient body cavity.
  • the anchoring means may be located in the distal portion or the proximal portion of the device.
  • the illustrated configuration advantageously increases flexibility of the device and allow the device to be more effectively navigated through the IP fluid without damaging the device or injuring the patient tissues or organs.
  • Fig. 4a-h illustrates the inner surface of the biocompatible drug delivery device for the delivery of at least one first medication to patient's body cavity.
  • the device has an inner configuration comprising plurality of pores 42 providing a control release mechanism for the medication within the device.
  • the inner surface has a resilient structure perforated by pores through which the drug may be delivered from the chambers of the device.
  • the medicament may further be placed in any location or side within the device such that when the device is in fluid contact with the I P fluid the medication is released.
  • the device when placed in contact, with the patient's organ or I P fluid, provides active delivery of at least one medication into the IP fluid.
  • the pores may be expandable for enhancing the diffusion and the medication release from, the device.
  • the outer surface of the devise may comprise severa l layers having pores in different diameters in order to control the rate of the medication release from the device.
  • the device may comprise a first outer layer having pores with smal ler pore diameter and a second layer below the first layer having larger pore diameter for controlling the drug release from the device.
  • the drug may further be d ispersed in the polymer and re leasable when, the intra surface of the device is in contact with a liquid.
  • the rate of drug release may be dependent on the particular porous structure upon at least one outer layer of the device, which can be specifically formed to achieve a desired rate of release.
  • the pores may have round or other cross-sectional shapes and may have different, sizes.
  • a pore diameter refers to die average or ettective diameter of die cross- sections ot the pores. ⁇ he effective diameter of a cross-section that is not circular equals the diameter of a circular cross-section that has die same cross-sectional area as that of t e non-circular cross- section.
  • the pores may be filled with peritoneal fluid; the sizes of the pores may change dependi ng on the peritoneal fluid content in the device.
  • The. outer layer may thus behave like a sponge.
  • the pore diameter may be in the range from about 10 to 1 00 nm such that when the outer layer is in a dry condition wherein the peritoneal fl id content of the outer layer is at or near minimum .Furthermore, while a larger pore diameter may provide taster release initially, a smaller pore d iameter with increased lengt of interconnected pores can provide a more steady release at a similar rate.
  • the release rate may also be affected by the manner in which, the drug is incorporated in the device surface. When the drug is initially located in the device matrix, the rate may be slower. When the drug is initially located i the fluid, the rate may be higher.
  • the drug delivery rate may be controlled by controlling the pore structure and the manner in which the drug is incorporated in the device.
  • the diameter of the pores 41 may be between a 1 micrometer to about 1000 micrometers (1 mm), allowing exit of the medication in a dosage adjacent to the desired treatment.
  • Fig. 5 illustrates the cross section, of the external surface and the internal surface of the biocompatible drug delivery device for the delivery of at least one first medication to patient's body cavity.
  • the device may be composed of at least one medication or having different layer of several medications or different dosages of the same medication.
  • the internal surface of the device may be made of at least one medication 52 as an inner layer.
  • the device may further contain plurality of pores 52 allowing the entrance of the IP fluid and exit of the medication dissolved in the IP fluid.
  • Fig 5 further illustrates the outer layer of the device comprising plurality of pins adapted for preventing contact with the body tissue.
  • Fig 5 further illustrates the outer surface comprising plurality of protrusions having a pin like shape adapted to prevent any contact and further to distance the device from the patient's body tissue.
  • Fig, 6 presents a cross section view oi the biocompatible drug delivery device for the delivery of at least one medication to patient's body cavity.
  • the device comprises an outer shielding comprising plurality of pores 60 adapted to control the medication release from the device and in parallel preventing contact with the body tissue.
  • the device of Fig. 6 has a tubular configuration comprising an inner hollow tubu lar 61 structure allowing entrance of the IP fluid and an inner channel for loading at least one medication 62. T he device configuration allows the entrance of the I P fluid and exit of the medication dissolved in the IP fluid. The medication is released when in fluid contact with the IP fluid.
  • the device may be permeable or semipermeable to the IP fluid such that the IP fluid transports the med ication to a target region.
  • the device outer shielding prevents physical contact with the body tissue attached or anchored to the device and therefore preventing medication release with in the tissue.
  • the I P medication transport may occur via. pores having d ifferent sizes located in the outer shield ing of the device.
  • the absorption of intraperitoneally administered medication is linear in time, irrespective of molecular size or concentration.
  • the device of the present invention provides minimal fluctuations caused by temperature, humidity, pressure, pH, ionic change, osmolarity, concentration of su bstances such as acid-lactic, glucose, lipids, hormones, gases, en zymes, inflammatory mediators, plasmin, albumin, lactorerrin, creatinin, proteins and the like.
  • su bstances such as acid-lactic, glucose, lipids, hormones, gases, en zymes, inflammatory mediators, plasmin, albumin, lactorerrin, creatinin, proteins and the like.
  • the device is further Light weight and configured to prevent any friction with a surrounding tissue more particularly when the device is placed between organs.
  • the device is easily inserted and i n parallel easily retrieved.
  • the device is biocompatible and hypoallergenic therefore does not cause any side-effects.
  • the device is radiopaque therefore is opaque to one or another form of radiation, such as X-rays.
  • the device may further block radiation rather than allow it to pass through.
  • Table 1 below presents a variety of regions in the peritonea ! cavity which the device can be located in and further release a medication.
  • the present invention further provides a method for admi nostiring a dosage form to a patient, comprising steps of (a) providing a biocompatible drug delivery device for the delivery ot at least a first medication and at least second medication to a patient body cavity, comprising: (i)at least a first chamber and a second chamber for containing the at least one first medication and at least one second medication respectively, (iii) at least one drug-releasing component adapted for medication loading and release; optionally, (iv)an anchoring means adapted for securing the device to a body tissue; (b) inserting the drug delivery device to a body cavity of the patient, (c) optimally anchoring the drug delivery device to the body tissue of the patient; (d)releasing of the dosage form via drug-releasing component of the device into a the body cavity of the patient body.
  • the releasing of a dosage form via drug-releasing component is associated with the device internal surface or/and external surface for controlling the rate of release of the medication.
  • the method of the present invention further comprising the step of delivering the medication via the intraperitoneal (I P) route to at least two target regions in a patient body.
  • I P intraperitoneal
  • the present invention further provides a method of manufacturing a biocompatible drug delivery' device for the delivery of at least a first medication and a second medication to a patient body cavity, comprising steps or: (a) providing a container containing at least a first chamber and a second chamber for containing the at least a first medication and the second medication respectively; (b) attaching anchoring means to at least one edge of the container; (c) connecting at least one drug-releasing component to at least one first chamber, the drug- releasing component is adapted for medication loading and release, and (d) providing a drug- releasing component for medication release.
  • the drug-releasing component is associated with the device internal surface or/ and externa! surface for controlling the rate of release of the medication via the intraperitoneal (IP) route to at least two target regions in a patient abdominal cavity.
  • IP intraperitoneal
  • the device may be introduced via natura l body entrance, by injection procedure or by a surgical procedure.
  • the method as described above wherein the releasing the medication is from a first configuration suited for passage of the drug delivery device through the drug-releasing component to a second configuration suited for retaining the drug delivery device with the intraperitoneal (IP) direction route.
  • IP intraperitoneal
  • the medication dosage form is selected from a group consisting of aliquot, tablet, caplet, capsule, pill, bolus, particle, micronized particle, particulate, pellet, core, powder, granule, granulate, small mass, seed, specks, spheres, crystals, beads, agglomerates or any combination thereof.
  • the method as described above wherein the method comprising the step of providing a medication in a liquid phase, gas phase or solid phase.
  • the method as described above comprising the step of providing a medication based upon a controlled release delivery system.
  • controlled release delivery system is selected from the group consisting of: slow release, immediate release, sustained release and combination thereof.
  • the device is a biodegradable container containing the medication that has been physically trapped, or covalently or ionically immobilized in the biodegradable matrix.
  • the biodegradable is selected from the group consisting of: liposomes, po!y!actides (polylactic acid), polyglycolide (polymer of glycolic acid), poly (lactide co-glycoltde (co-polymers of lactic acid and glycolic acid) po!yanhydrides, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • the container is a cylinder or tube like implanted device.
  • the method as described above wherein the device is a non-absorbable, flexible container having an elongated shape.
  • the method as described above comprising the step of releasing the at least first medication at a rate of at least approximately 0.1 meg/day and at least second medication at a rate of at least 0,5 meg/day over a period of at least approximately one week.
  • the regions are selected from the group consisting of: rectum, large intestine, small intestine, esophagus, stomach, trachea, bronchus, outer ear canal, inner ear canal, nasal canal, air sinuses, vagina, cervix, uterus, fallopian tubes, urethra, bladder and, intra-articular cavity, eye and combination thereof.
  • the method as described above wherein the method comprising the step of transporting the medication to the Peritoneal fluid via a) diffusion, b) ultrafiltration, c) fluid re-absorption and combination thereof.
  • the present invention further provides a kit for the delivery of at least a first medication and a second medication to a patient body cavity, comprising: (a)a biocompatible drug delivery device comprising: (i) at least a first chamber and at least second chamber for loading and releasing the at least a first medication and the second medication respectively, (ii) optionally an anchoring means adapted for securing the device to a body tissue; and (iii) a drug-releasing component for controlling the rate of release of the medication, (b) an applicator adapted for affixing the device to the body tissue via anchoring means.
  • a biocompatible drug delivery device comprising: (i) at least a first chamber and at least second chamber for loading and releasing the at least a first medication and the second medication respectively, (ii) optionally an anchoring means adapted for securing the device to a body tissue; and (iii) a drug-releasing component for controlling the rate of release of the medication, (b) an applicator adapted for affixing the device
  • the device can travel and wander around the peritoneal cavity without any anchoring means.
  • At least first medication is delivered via the intraperitoneal (IP) route to at least two target regions in a patient body.
  • IP intraperitoneal
  • the kit as described above, wherein the applicator is adapted for inserting the device into the body or an individual or/and for removing the device from the patient.
  • the kit as describee! above wherein the applicator is further adapted tor reloading the first medication and/or second medication into the device cham bers.
  • kits as described above, wherein the kit is useful for treating endometriosis.
  • an implementable drug delivery device useful for delivering a medication via the intraperitoneal (IP) to a target region in a patient body.
  • the DDD comprises at least one envelope with at least first layering surface confining at least one first volume accommodating at least one first precursor and at least one second precursor.
  • the envelope comprises at least one ingress path for IP's fluid to both inlet and outlet the layer for expulsion of the first and second precursors towards the IP by the fluid.
  • At least one first precursor and at least one second precursor forms an effective medication to target the region in a patient body.
  • a method of targeting a region in a patient body comprises steps as follows: providing a drug delivery device (DDD) with at least one envelope, comprising at least first layering surface; confining within the envelope at least one first precursor and at least one second precursor; providing within the envelope at least one ingress path tor I P's fluid to both in let and outlet the layer for expulsion of the first and second precursors towards the IP by the fluid; forming, by means of the at least one first precursor and at least one second precursor, an effective medication; and targeting the newly formed medication the region in a patient body.
  • DDD drug delivery device
  • the at least one first and at least one second precursors forms the medication(s) by reaction, polymerization, condensation, oxidation and reduction, complexation, acid-base reactions, precipitation, solid-state reactions, photochemical reactions, substitution, addition and elimination, rearrangement reaction, biochemical reactions etc.
  • the at least one first and at least one second precursors forms the medication(s) within the DDD, outside the DDD, adjacent the targeted organ, on the targeted organ etc.
  • FDDD feedbacked implementable drug delivery device
  • the FDD D comprises e.g., at least one envelope with at least one first layering surface confining at least one first volume which accommodates at least one medication; the envelope comprises at least one controllable path for I P's f lu id to both inlet and outlet the layer for controlled expulsion of the medication towards the IP by the fluid; and a fluid's flow control ling means; wherein the controlling means regulates the path thereby controlling the fluid flow.
  • the fluid flow is selected from a group consisting of IP's fluid inflow, the medication's outflow or a combination of the same.
  • the device further comprises a sensing means in communication with the controlling means, for analyzing one or more mem bers of a group consisting of IP's parameters and targeted region of the body, thereby controlling the fluid flow in a feedbacked manner.
  • a method of delivering a time-resolved dose of one or more medications via. the intraperitoneal (IP) to a target region in a patient body comprises steps as follows: providing a feedbacked implementable drug delivery device (FDDD) with at least one envelope with at least one first layering surface confining at least one first volume which accommodates at least one medication; the envelope comprises at least one controllable path for IP's fluid to both inlet and outlet the layer for controlled expulsion of the medication towards the IP by the fluid; further providing the FDDD with a fluid's f low controlling means; and regulating the path by means of the controlling means, thereby controlling the fluid flow.
  • FDDD feedbacked implementable drug delivery device
  • the method as defined above further comprises a step of selecting the fluid flow from a group consisting of IP's f lu id inf low, the medication's outf low or a combination of the same.
  • the method as defined above further comprises a step of communicating the sensing means with the controlling means, and one or more steps ol analyzing one or more members of a group consisting of IP's parameters and targeted region of the body, thereby controlling the fucid flow in a feedbacked manner.
  • the implementable drug delivery device as defined in any of the above, further comprising a pain relieving agents as medications, such as analgesic compositions.
  • a cluster-bomb-like implementable drug delivery system comprising at least one first envelope containing at least one first medication to be released from the envelope in predefined release profile; wherein the envelope is adapted to be deployed within the intraperitoneal (IP).
  • IP intraperitoneal
  • Figs 7 to 12 further illustrate a ciuster-bomb-like implementable drug delivery system having several envelopes to accommodate a at least one first medication .
  • the envelop may further adapted for loading and releasing at least one first medication and/or at least one second medication respectively.
  • at least one medication may be a controlled release medication.
  • the envelopes may be in a structure of a chamber, a cell, a shell, a carrier, or a matrix of medication.
  • the envelopes may contain at least one medication in each envelope or severa l medications (i.e., drugs) in one envelope.
  • the envelopes may be configured in a structure selected from a group consisting of a spherical shape (7a-b) , cylindrical shape (8a-b), a ring or tablet-like shape (9a-b, lOa-b) , a rectangu lar shape (8a- b), a tubular shape(lla-b-12a-b) a capsule shape, or any polygon known in the art.
  • the envelope may further comprise at least one aperture 100 for medications' release.
  • the envelope comprises a distal portion and a proximal portion whilst the proximal portion comprises at least one aperture adapted to be opened to permit medication to eject via the IP to a target region in a patient body.
  • the distal portion may comprise at least one aperture or may additiona lly comprise braking means adapted to bring the cluster bomb-like to a sudden deceleration or acceleration, whereby when the braking means bring the cluster bomb-like to the sudden deceleration or acceleration the at least one first medication is ejected through the proximal portion.
  • the device may further comprise at least one channel 110, 120 having a tube-like, ring-like or/and cylindrical shape for directing at least one medication to the evlepoe's aperture, thereby releasing the medication via the IP route.
  • the medication's release is characterized by a profile selected from the group consisting of: a parabo lic release profile, hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • the envelop is configured to be introduced or implanted via a natural body orifice selected from the group consisting of Douglas pouch, belly- button, rectum, vagina and any combination thereof.
  • the envelop is configured to be introduced or implanted via a guiding tool such as catheter.
  • the profile is selected from the group consisting of a parabolic release profile, a hyperbolic release, profi le, an exponential release profile, a linear release profile and any combination thereof.
  • an envelope device for delivering at least one first control led release medication form the intraperitoneal (IP) to a target region in a patient body, the at least one first medication is contained, carried, doped, coated, dissolved, accommodated, immersed, diffused, infused, absorbed or otherwise provided in connection with the envelop; wherein the controlled release is characterized by a profile selected from the group consisting of: a parabolic release profile, a hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body.
  • the system comprising at least one first enveloping layer and at least one first drug which is contained, carried, doped, coated, dissolved, accommodated, immersed, diffused, infused, absorbed or otherwise provided in connection with the envelope; wherein the enveloping layer is characterized by a releasing means, and the releasing means are selected from physical means, especially porosivity parameters, and chemical means, especially solubility and selectivity; the releasing means provides the system with a drug's release profile selected from, a group consisting of a parabolic release profile, a hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • an implantable drug delivery system for delivering at least one first drug form the intraperitonea l (IP) to a target region located with a patient' body, as defined in any of the above is disclosed.
  • the system further eomp>rising at least one second enveloping layer in which the at least one first drug is contained, carried, doped, coated, d issolved, accommodated, immersed, diffused, infused, absorbed or otherwise provided in connection with the second enveloping layer.
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region, located with, a patient' body, as defined in any of the above is disclosed.
  • the system further comprising at least one second drug.
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above is disclosed.
  • IP intraperitoneal
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above is disclosed.
  • the system first drug's release profile is selected from a group consisting of a parabolic release profile; hyperbolic release profile, an. exponential
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above.
  • IP intraperitoneal
  • the system is configured by means of size of shape to be introduced or implanted via a natural body orifice selected from the group consisting of Douglas pouch, belly-button rectum, vagina and any combination thereof.
  • the drug delivery system of claim 110 wherein the system is configured by means of size or shape to be introduced or implanted via a guiding tool, especially a catheter.
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above is disclosed.
  • the second drug's release profile is selected from a group consisting of a parabolic release profile; hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • an implantable drug delivery system for delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above is disclosed.
  • IP intraperitoneal
  • the system first and second drug's release profile are different.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body comprising steps as follows: providing an implantable drug delivery system with at least one first enveloping layer and at least one first drug; containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one first drug with the at least one first enveloping layer; providing the least one first enveloping layer with an effective a releasing means, by selecting the releasing means from physical means, especially porosivity parameters, and chemical means, especially solubility and selectivity; providing, by the releasing means, the system with a drug's release profile, and selecting the profile from a group consisting of a parabolic release profile, a hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body is disclosed.
  • the method further comprising steps of providing the system with at least one second enveloping layer; and containing, carrying, eloping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one first drug with the at least one first enveloping layer.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above, is d isclosed .
  • the method further comprising step of providing the system at least one second drug.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body is disclosed.
  • the method further comprising steps as follows: providing the system with at least one second enveloping layer; and containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one first drug with the at least one or second enveloping layer.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body is disclosed.
  • the method further comprising steps as follows: providing the system with at least one second drug; and containing, carrying, doping, coating, dissolving, accommodating, immersing, diffusing, infusing, absorbing, or otherwise providing the at least one second drug with the at least one or second enveloping layer.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body is disclosed.
  • the method further comprising a step of providing the system's at least one first drug's release profile is selected from a group consisting of a parabolic release profile; hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body, as defined in any of the above, is d isclosed .
  • the method iurther comprising a step of providing the system's at least one first second drug's release profile is selected from a group consisting of a parabolic release profile; hyperbolic release profile, an exponential release profile, a linear release profile and any combination thereof.
  • a method of delivering at least one first drug form the intraperitoneal (IP) to a target region located with a patient' body is disclosed.
  • the method further comprising a step of configuring the drug delivery system by means of size of shape to be introduced or implanted via a natural body orifice selected from the group consisting of Douglas pouch, belly-button rectum, vagina and any combination thereof.
  • a method of implanting a drug delivery system as defined in any of the above id disclosed comprising step of introducing or implanting the same via a natural body orifice selected from the group consisting of Douglas pouch, belly-button rectum, vagina and any combination thereof.
  • a method of implanting a drug delivery system as defined in any of the above id disclosed The method step of configuring the system by means of size or shape to be introduced or implanted via a guiding tool, especially a catheter.
  • a method of implanting a drug delivery system as defined in any of the above id disclosed further coniprising a step of configuring first and second drug's release profiles to be different.
  • Figs. 13 and 17 present a release polynomial profile thereby, the medication release rate (t) decreases for a period of time ,(ii) increases for a period of time , (iii) exhibits a zero order release for a period of time and a combination thereof.
  • the release profile may further include a parabolic release curve, a hyperbolic curve and a combination thereof, relative to time.
  • the release profile thereby, the release of the med ication may be adjusted by the medication controlled release system, or/and by the device configuration having apertures controlling the medication release rate relative to time.
  • Fig. 14 further presents a linear release profile thereby, the medication release rate may exhibits a zero order release for a period of time i.e constantly , increase linearly or decrease linearly with time.
  • Fig. 15 presents an exponential release profile thereby, the medication release rate decreases exponentially with time until the medication is exhausted.
  • Fig, 16 presents an exponential release profile thereby, the medication release rate increases exponentially with time as d e envelope and/or the medication moves forward to the target region.
  • Fig. 18-19 further illustrates a release profile of at least one first medication and a second medication or additional dosage based upon a controlled release system such that Fig. 18 presents an exponential release growth of one first med ication (red) and an exponential release decline (blue) of a second medication.
  • Fig. 19 presents a polynomial release profile of the first and second medication

Abstract

La présente invention concerne un dispositif d'administration de médicament (DDL) applicable pour administrer un médicament par l'intermédiaire d'une administration par voie intrapéritonéale (IP) à une région cible dans un corps de patient, et son système et son procédé. Le dispositif d'administration de médicament applicable comprend au moins une enveloppe ayant au moins une première surface de superposition pour contenir un médicament et au moins un premier volume confiné par ladite enveloppe, comprenant une mesure efficace du médicament. L'enveloppe comprend en outre au moins un trajet d'entrée pour un fluide intrapéritonéal afin de faire entrer et sortir ladite couche pour expulser ledit médicament vers la voie intrapéritonéale par le fluide.
PCT/IL2014/050572 2013-06-25 2014-06-25 Procédé et dispositif pour administrer des agents thérapeutiques à une région cible, et moyens pour ces derniers WO2014207746A1 (fr)

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US201361847571P 2013-07-18 2013-07-18
US61/847,571 2013-07-18
US201361887394P 2013-10-06 2013-10-06
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WO2022262862A1 (fr) * 2021-06-17 2022-12-22 苏州医本生命科技有限公司 Tube de stockage de particules médicales, procédé de chargement de médicament et procédé d'administration de microparticules chargées de médicament

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US4449983A (en) * 1982-03-22 1984-05-22 Alza Corporation Simultaneous delivery of two drugs from unit delivery device
US7699834B2 (en) * 2005-11-09 2010-04-20 Searete Llc Method and system for control of osmotic pump device

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022262862A1 (fr) * 2021-06-17 2022-12-22 苏州医本生命科技有限公司 Tube de stockage de particules médicales, procédé de chargement de médicament et procédé d'administration de microparticules chargées de médicament

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