WO2000040234A1 - Anesthesie locale de la vessie - Google Patents

Anesthesie locale de la vessie Download PDF

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Publication number
WO2000040234A1
WO2000040234A1 PCT/CA2000/000003 CA0000003W WO0040234A1 WO 2000040234 A1 WO2000040234 A1 WO 2000040234A1 CA 0000003 W CA0000003 W CA 0000003W WO 0040234 A1 WO0040234 A1 WO 0040234A1
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Prior art keywords
bladder
local anesthetic
alkalinizing agent
patient
lidocaine
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PCT/CA2000/000003
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English (en)
Inventor
Richard Henry
Original Assignee
Richard Henry
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Publication date
Application filed by Richard Henry filed Critical Richard Henry
Priority to AU18534/00A priority Critical patent/AU1853400A/en
Publication of WO2000040234A1 publication Critical patent/WO2000040234A1/fr
Priority to US11/149,506 priority patent/US20050238733A1/en

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    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • the invention pertains to safe and effective treatment methods for providing topical anesthetic to the urinary bladder to permit pain-free cystoscopic biopsy and cautery of bladder lesions such as bladder cancer, and to provide a means to treat inflammatory conditions of the bladder such as chronic interstitial cystitis and acute bacterial cystitis, as well as to compositions used in these treatment methods.
  • Topical local anesthesia of the urinary bladder remains an elusive yet desirable clinical goal for physicians diagnosing and treating a number of bladder conditions.
  • Local anesthetics have been used in the bladder for the past forty years with limited success, restricting the physician to limited superficial resections and biopsies of small tumors.
  • Clinical studies have confirmed the poor absorption of local anesthetics from the bladder by documenting very low blood levels of local anesthetics in patients who receive large doses of local anesthetics into their bladders. (Brian Birch and Ronald Miller, Absorption Characteristics of Lignocaine following Intravesical Instillation. ScandJofUrol Nephrol 28: 359-364, 1994, J.
  • Birch and Miller found minimal uptake of lidocaine from the bladder when 400mg of lidocaine hydrochloride was used: plasma of levels of 0.12 micrograms/ml. They concluded that the uptake of lidocaine from the bladder is relatively poor and comparable to uptake from the urethra and intact skin, and is sixteen times less than achieved when lidocaine was administered intramuscularly, subcutaneously, and topically to the airway. They further summarized that alkalinisation of the lidocaine solution would be of doubtful value in increasing topical abso ⁇ tion from the bladder. (Brian Birch and Ronald Miller, Absorption Characteristics of Lignocaine following Intravesical Instillation. ScandJofUrol Nephrol 28: 359-364, 1994.)
  • Interstitial cystitis is a chronic inflammatory disease of the urinary bladder in humans of an as yet unknown cause. Many current theories are hypothesized as to the etiology, including infection, auto- immunity, neurogenic, neuropathic and endocrine factors. (Holm-Bentzen M. Lose G: Pathology and Pathogenesis of Interstitial Cystitis. Urology 29 (Supplement):8-13 1987.) Whatever the original stimulus for this disease, mast cells in the bladder seem to be the main mechanism of ongoing disease. (Hohenfeller M, Nunues L, Schmidt RA et al: Interstitial Cystitis: Correlation with Nerve Fibres, Mast Cells and Histamine Content.
  • Local anesthetics possess a wide range of anti-inflammatory, anti- microbial and membrane stabilizing properties, in addition to their well recognized nerve conduction blocking effects. They are known to reduce neuronal transmitter release by impairing activation of presynaptic calcium channels. They may also modify post-synaptic receptors and thus inhibit the post-synaptic acetylcholine receptor.
  • the neurokinin- 1 receptor the target of the neurokinin substance-P
  • Local anesthetics Li Y, Wingrove DE, Too Hp et al: Local Anesthetics Inhibit Substance P Binding and Evoke Increases in Intracellular Calcium. Anesthesiology 82:166-173,1995.
  • Lidocaine also inhibits the release of chemo-attractants, such as leukotrienes and interleukins, from activated leukocytes and consequently reduces the self-perpetuating accumulation of further leukocytes.
  • chemo-attractants such as leukotrienes and interleukins
  • lidocaine is able to inhibit the release of histamine and other inflammatory substances from activated mast cells.
  • lidocaine at low concentrations has an opposite effect on mast cells and causes them to release their histamine content on contact with low concentrations of lidocaine ( ⁇ lmmol concentration) (Kazimierczak W, Peret M, Maslinski C: The Action of Local Anesthetics on Histamine Release. Biochemical Pharmacology 25:1747-1750, 1976) This would result in a worsening of the inflammatory condition and more pain for the patient. There is convincing evidence that local anesthetics, at sufficient concentrations, have powerful antibacterial and anti-fungal properties. Data on growth response for E.
  • the urothelium of the bladder is almost impermeable to water, charged ions, and small molecules, such as urea and sodium (Negrete HO, Lavelle JP, Berg J, Lewis SA, & Zeidel ML: Permeability Properties of the Intact Mammalian Bladder Epithelium. Am J Physiol 27 ⁇ (Renal Fluid
  • Lidocaine has a pKa of 7.9.
  • the pKa is the pH at which 50% of the drug in an aqueous solution will be in the base form and 50% in the ion or charged form. As the pH of the solution falls, more of the drug converts into the ion form. Since the pH scale is a logarithmic scale, these changes are quite marked over a small pH range. For example, at a pH of 6.8, 5% of the lidocaine will be in the base form, while at a pH of 5.8, only 0.5% will be in the base form.
  • the ion and base forms of local anesthetics have important physical and physiological differences that greatly affect the pharmaco-kinetics of this class of drugs.
  • the base or non-ionized form is highly lipid soluble and readily crosses biological membranes. It is however poorly soluble in water and will precipitate out of an aqueous solution at room temperature.
  • the base form is able to cross membranes and gain access to neurons where it exerts its anesthetic effect, it is the intra-cellular ionized salt form that binds to the sodium channel in the neuron and blocks nerve conduction.
  • the present invention provides a method to achieve optimum topical abso ⁇ tion of local anesthetics through the bladder urothelium into the submucosal region where it can exert its local anesthetic effect on the submucosal nerve plexus.
  • the topical anesthetic formulations useful in the present invention are believed to act directly on the pH of the bladder urine to elevate it to a basic pH level; thereby optimizing abso ⁇ tion of the local anesthetic.
  • a preferred embodiment of the present invention is directed towards a single use therapy to produce deep local anesthesia of the bladder wall to allow painless cystoscopic surgical procedures such as biopsies and cautery of tumors and allow differential diagnosis of the source of pelvic pain.
  • Another embodiment of the present invention is directed towards providing a means of treating acute bacterial infections of the bladder.
  • Another embodiment of the present invention is directed towards chronic use of topical local anesthesia in the bladder to control the chronic neuro- inflammatory response characteristic of IC and systemic lupus erythematosis (SLE) cystitis.
  • SLE systemic lupus erythematosis
  • the methodology of this invention allows the local anesthetic to be delivered to the desired site of action for a sufficient duration and in sufficient concentration to exert the desired anti- inflammatory effect.
  • the antibacterial properties of local anesthetics discussed above make local anesthetics well suited to treat acute bacterial cystitis as well as the possible low-grade bacterial infection thought to be present in IC.
  • the ionized salt form of local anesthetics is highly water-soluble and poorly suited to penetrate tissue and cross biological membranes. This form of the drug is especially ill suited to cross the urothelial membrane. All aqueous preparations of local anesthetics use the ionized, water-soluble form of the drug and maintain the drug in that state by lowering the pH of the solution to below pH 6 with the use of acids such as hydrochloric acid. When used to infiltrate animal tissue in order to block nerve conduction in the area, the pH of the injected solution will equilibrate with that of the surrounding tissue (usually 7.4). As the pH rises, more of the drug will assume the base form and diffuse into the surrounding tissue down the concentration gradient.
  • a means to reliably elevate the intra-vesical pH closer to the pKa of the local anesthetic would increase the non-ionized fraction of the drug and therefore would improve bladder abso ⁇ tion of topical local anesthetic, making abso ⁇ tion more reliable and predictable.
  • topical local anesthetic in the bladder could be used to anesthetize the bladder wall as well as provide a treatment method for a number of disorders including IC and acute bacterial cystitis.
  • the present method involves instilling a concentrated dose of aqueous local anesthetic into the bladder via a urinary catheter or similar device and following this with a dose of an alkalinizing buffer agent such as sodium bicarbonate.
  • the buffer base serves two functions: it raises the pH of both the aqueous local anesthetic and the residual urine within the bladder. Sufficient buffer base is required to increase the pH to about 8.0. At a pH of around 8.0, about 50% of the local anesthetic will convert into the base form and be able to cross the bladder mucosa and diffuse down the concentration gradient into the bladder submucosal nerve plexus, which is the target site.
  • the present invention is based upon the discovery that there is an optimum pH in the bladder at which abso ⁇ tion of lidocaine is five times greater than at lower or higher pHs. Su ⁇ risingly, as the pH is increased beyond this optimum range, the abso ⁇ tion of lidocaine declines rapidly, providing a narrow pH range at which abso ⁇ tion is optimal. As the pH increases above 8.0 the lidocaine is believed to precipitate out of the aqueous solution as a higher percentage of it is converted to its lipid soluble base form before it can be absorbed into the bladder. Precipitation of the lidocaine out of solution markedly decreases the concentration of lidocaine in solution, resulting in slower abso ⁇ tion across the urothelial membrane.
  • This invention also contemplates the topical anesthesia of the bladder for diagnostic pu ⁇ oses.
  • the anesthetic is administered to a patient suffering from pelvic pain where the origin of the pain is not precisely known. This administration reliably blocks bladder pain for a temporary period of time. This allows differentiating this source of pain from pain emanating from other sources such as surrounding organs.
  • FIG. 1 is a graphical depiction of the tissue levels of radioactive labeled lidocaine found in the bladder mucosa at different intra-vesical pH levels after the lidocaine was left in situ for forty five minutes in a live rabbit bladder.
  • Tissue levels remained low at pH levels below 8.0 at around 500,000 to 1,000,000 CPM/g tissue.
  • the peak tissue levels of around 3,500,000 CPM/g of tissue occurred at a pH between 8.1 and 8.25.
  • the tissue levels declined rapidly to almost the same as at the pH levels below 8.0.
  • Figure 2 is a graphical depiction of the blood levels of radiolabeled lidocaine in the same anesthetized rabbits treated with the same intravesical radiolabeled lidocaine at different pH levels. Blood levels were found to peak at a pH of 8.1 to 800CPM/0.1ml of blood and remained fairly constant for the duration of the instillation time. At pH levels above and below 8.1 the abso ⁇ tion rate was similar in all groups and was only 25% of that at 8.1.
  • Figure 3 is a graphical depiction of the blood levels of lidocaine found in human volunteers to whom intravesical lidocaine was administered with sodium bicarbonate to elevate the intra-luminal pH to 8.0. Volunteers were given either 4, 5 or 6 mg/kg 5% lidocaine with 10 cc of 8.4% sodium bicarbonate. The blood levels at regular intervals over 3 hours are measured in micrograms per milliliter of serum. All subjects attained peak levels within the desirable therapeutic range of 0.5-2ug/cc within the first hour.
  • Local anesthetics are a class of drugs which block sodium channels in nerve axons, thereby temporarily inhibiting nerve conduction.
  • Local anesthetics are generally divided into two major subgroups based on their chemical structure. Both groups of chemicals are made up generally of an aromatic hydrophobic ring linked to a hydrophilic amino group. The linkage can be either an ester link or an amide link and it is this linkage that defines these groups.
  • the amide group is also known as N-arylamides or carboxamides, and includes, for example, lidocaine, prilocaine, bupivacaine, ropivacaine, etidocaine, dibucaine, and mepivacaine.
  • the ester group or aminoalkylbenzoates include, for example, cocaine, procaine, chloroprocaine, tetracaine and benzocaine.
  • Local anesthetics are weak bases and are highly lipid soluble in their base form.
  • the ionic or ionized salt form is highly water soluble and best suited for stable aqueous pharmacological preparations with a low pH.
  • the chloride or hydrochloride salt is the most commonly used salt and is the preferred preparation for this invention.
  • Other suitable salts include bromide, sulfate, fumarate, citrate, malate, proprionate and phosphate salts.
  • Local anesthetics are weak bases with pKa's in the 7.7-9.1 range (e.g., pKa 7.7 for etidocaine, pKa 9.05 for procaine (Lidocaine has a pKa of 7.9)).
  • the pKa is the pH at which 50% of the drug in solution will be in the base form and 50% in the salt form. As the pH rises above the pKa, more of the drug will dissociate and convert into the free base non-ionic form. Since the pH scale is a logarithmic scale, a rise in pH of 1.0 above the pKa would result in 90% of the drug being in the base form.
  • Local anesthetics and their pharmacology are discussed in detail in Remington's Pharmaceutical Sciences, A.Osol, ed., Mack Pub. Co., Easton, PA (16 th ed. 1980) and the Merck Index (11 th ed., 1989).
  • Sodium bicarbonate (CHNaO 3 ) is a well known biological buffer that is readily soluble in water and dissociates into carbon dioxide and sodium carbonate, which in turn combine with a hydrogen ion to form water and sodium. It is this ability to take up free hydrogen ions and convert them into water that makes this buffer biologically useful.
  • a 0.1 molar aqueous solution of sodium bicarbonate at 25 C has a pH of 8.3.
  • Sodium bicarbonate is the preferred alkalanizing agent for use in this invention; however, other pharmaceutically acceptable buffers which can raise the pH within the bladder, and take up free hydrogen ions, may also be used in the practice of this invention.
  • Pharmaceutically stable solutions of local anesthetics are formulated by lowering the pH of the water to below a pH of 6.
  • the pH of the solution is well below the pKa of the local anesthetic and almost all the drug is in the water soluble ionic salt form.
  • this solution is injected into animal tissue to anesthetize it, the tissue pH of 7.4 buffers the acidic fluid and the pH rises, and the local anesthetic begins to base itself into the lipid soluble form and the based form is able to penetrate the tissue, thus gaining access to the surrounding nerves where nerve conduction is temporarily blocked.
  • this same local anesthetic solution is instilled into the urinary bladder to provide topical anesthesia, the pH of the urine is usually in the range of 5-6. Hence, there is not the same pH rise in the urinary bladder as in other tissues which allows the local anesthetic to convert into the lipid soluble form and penetrate the tissue.
  • This invention provides a method to achieve bladder abso ⁇ tion of local anesthetic by increasing the pH in the bladder to an optimum level to maximize abso ⁇ tion.
  • this invention utilizes a sodium bicarbonate solution having a pH between 7.5 and 8.5 to alkalinize the bladder contents.
  • an injectable solution of an alkalinizing agent e.g., sodium bicarbonate
  • a local anesthetic e.g., lidocaine
  • a suitable pre-filled syringe that separates these two solutions (e.g., a double barreled syringe or the like) until they are injected into the urinary bladder via a urinary catheter or other means of urethral injection.
  • the volume of bicarbonate is preferably 5-50 milliliters (ml) and the concentration preferably ranges from 2-10%.
  • the preferred dose is 10ml of 8.4% sodium bicarbonate.
  • the local anesthetic dose varies according to the specific potency of each of the specific local anesthetics and can be identified by those skilled in the art of medicine or pharmacology.
  • the volume of lidocaine hydrochloride solution is preferably 2- 20ml and the concentration preferably ranges from 1-10%.
  • the preferred dose is 5ml of 10% lidocaine.
  • topical anesthesia may be administered to patients with pelvic pain to determine whether or not the pain is derived from the bladder or from other sources (e.g., surrounding organs).
  • sufficient anesthesia is administered topically together with an alkalinizing agent. If the patient's pain subsides, it can be determined that the source of the pain is likely the bladder.
  • FIGS 1 and 2 show the blood and tissue levels of radio-labeled lidocaine and clearly show an optimum pH level for the abso ⁇ tion of lidocaine (preferably between 7.8 and 8.45, and most preferably between 8.0 and 8.3).
  • Other local anesthetics e.g., procaine, cocaine, chloroprocaine, tetracaine, mepivacaine, lidocaine, bupivacaine, etidiocaine, ropivacaine, and benzocaine

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Anesthesiology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
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  • Engineering & Computer Science (AREA)
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Abstract

Une solution aqueuse d'un anesthésique local est instillée dans la vessie en une concentration suffisante avec l'addition d'un agent alcalinisant tel que le bicarbonate de sodium afin d'élever le pH intravésical à approximativement 8,0. On laisse la combinaison in situ dans la vessie pendant au moins 15 minutes afin de ménager un temps d'absorption de la forme de base de l'anesthésique local. Cette méthode constitue une anesthésie locale sans danger et efficace permettant une biopsie cytoscopique sans douleur et une cautérisation de lésions de la vessie telles qu'un cancer de la vessie et constitue un moyen de traitement d'états inflammatoires de la vessie tels que la cystite interstitielle chronique et la cystite bactérienne aiguë.
PCT/CA2000/000003 1999-01-06 2000-01-05 Anesthesie locale de la vessie WO2000040234A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU18534/00A AU1853400A (en) 1999-01-06 2000-01-05 Topical anesthesia of the urinary bladder
US11/149,506 US20050238733A1 (en) 2000-01-05 2005-06-10 Topical anesthesia of the urinary bladder

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US11485799P 1999-01-06 1999-01-06
US60/114,857 1999-01-06

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Cited By (12)

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WO2004066990A2 (fr) * 2003-01-30 2004-08-12 Dynogen Pharmaceuticals, Inc. Methodes destinees a traiter les troubles du tractus urinaire inferieur au moyen de modulateurs du canal sodique
US8182464B2 (en) 2005-08-11 2012-05-22 Massachusetts Institute Of Technology Method for intravesical drug delivery
US8507561B2 (en) 2009-01-22 2013-08-13 Absorption Pharmaceuticals, LLC Desensitizing drug product
US9017312B2 (en) 2009-09-10 2015-04-28 Taris Biomedical Llc Implantable device for controlled drug delivery
CN105250217A (zh) * 2015-10-10 2016-01-20 山西省肿瘤研究所 含有利多卡因的抗肿瘤药物
US9283361B2 (en) 2010-08-05 2016-03-15 Taris Biomedical Llc Implantable drug delivery devices for genitourinary sites
US9586035B2 (en) 2007-12-11 2017-03-07 Massachusetts Institute Of Technology Implantable drug delivery device and methods for treatment of the bladder and other body vesicles or lumens
US10137078B2 (en) 2009-06-26 2018-11-27 Taris Biomedical Llc Methods for intravesical drug delivery and methods and systems for loading devices with drug tablets
US10286199B2 (en) 2013-03-15 2019-05-14 Taris Biomedical Llc Drug delivery devices with drug-permeable component and methods
US10532132B2 (en) 2005-08-11 2020-01-14 Children's Medical Center Corporation Implantable drug delivery device and methods
US10729823B2 (en) 2013-08-19 2020-08-04 Taris Biomedical Llc Multi-unit drug delivery devices and methods
US10894150B2 (en) 2015-04-23 2021-01-19 Taris Biomedical Llc Drug delivery devices with drug-permeable component and methods

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004066990A3 (fr) * 2003-01-30 2004-11-04 Dynogen Pharmaceuticals Inc Methodes destinees a traiter les troubles du tractus urinaire inferieur au moyen de modulateurs du canal sodique
WO2004066990A2 (fr) * 2003-01-30 2004-08-12 Dynogen Pharmaceuticals, Inc. Methodes destinees a traiter les troubles du tractus urinaire inferieur au moyen de modulateurs du canal sodique
US8801694B2 (en) 2005-08-11 2014-08-12 Massachusetts Institute Of Technology Intravesical drug delivery device
US8182464B2 (en) 2005-08-11 2012-05-22 Massachusetts Institute Of Technology Method for intravesical drug delivery
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