WO1999022737A1 - Use of methylnaltrexone and related compounds - Google Patents
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- WO1999022737A1 WO1999022737A1 PCT/US1998/023485 US9823485W WO9922737A1 WO 1999022737 A1 WO1999022737 A1 WO 1999022737A1 US 9823485 W US9823485 W US 9823485W WO 9922737 A1 WO9922737 A1 WO 9922737A1
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Definitions
- the present invention is directed at the treatment of certain side effects associated with the use of opioids as analgesics.
- the present invention is directed toward treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, opioid-and non-opioid-induced inhibition of gastric emptying and inhibition of gastrointestinal motility, and constipation.
- Opioids are effective analgesics. However, their use is associated with a number of undesirable side effects. One of these side effects is pruritus, or itching. Pruritus is a common side effect associated with the use of opioids and may be very severe. Pruritus can occur when the opioid is administered intramuscularly, intravenously, transdermally, transmucosally or intrathecally.
- opioid induced pruritus results from the release of histamine in response to the administration of opioids.
- Opioids are thought to stimulate histamine release by binding to opioid receptors on the central nervous system. This, in turn, causes peripheral nerves and histamine containing cells to release histamine.
- antihistamines have a variable effect on opioid induced pruritus. Additionally, the use of antihistamines, when effective, only treats the symptom after it has occurred, rather than preventing its occurrence.
- Another undesirable side effect of opioids is urinary retention, or the patient's inability to spontaneously empty his or her bladder.
- This urinary retention is a common side effect that can occur when opioids or related compounds are administered intramuscularly, intravenously, transmucosally, transdermally, or intrathecally. It is not clear why opioids cause urinary retention, but it is thought to be related to the central anticholinergic stimulation that opioids induce. Based on this theory, a number of cholinergic-type drugs have been used to treat urinary retention. However, due to the side effects of cholinergic drugs, catheterization of the bladder with a tube to drain urine remains the mainstay of treatment. Another opioid-induced side effect is dysphoria, a feeling of unpleasantness or discomfort.
- opioid-induced dysphoria is commonly treated by the addition of other drugs, such as benzodiazepines, to decrease the dysphoria or to blunt the recall of the dysphoria. These drugs, however are associated with increased levels of sedation and may enhance respiratory depression caused by the opioid. Another side effect is constipation. Opioid-induced changes in gastrointestinal motility are almost universal when these drugs are used to treat pain, and at times may limit their use, leaving the patient in pain. Common treatments of bulking agents and laxatives have limited efficacy and may be associated with side effects such as electrolyte imbalances.
- opioid antagonists which cross the blood-brain-barrier, or which are administered directly into the central nervous system.
- Opioid antagonists such as naltrexone and naloxone have been administered intramuscularly or orally to treat opioid induced pruritus.
- Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain-barrier.
- naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
- quaternary amine opioid antagonist derivatives such as methylnaltrexone, do not reduce the analgesic effect of the opioids.
- These quaternary amine opioid antagonist derivatives which have a relatively higher polarity and reduced lipid solubility when compared to the tertiary forms of the drugs, were specifically developed to not traverse the blood-brain-barrier or to traverse it at a greatly reduced rate. Since these quaternary opioid antagonist derivatives do not cross the blood-brain-barrier, peripheral administration of these antagonists would not be expected to be effective in the treatment of an opioid induced side effect caused by the opioid within the central nervous system.
- oral medications are particularly desirable both for the treatment of opioid-induced side effects (such as urinary retention, pruritus, and some forms of constipation) and for the treatment of nonopioid-induced side effects (such as other forms of constipation and delayed gastric emptying or inhibition of gastrointestinal motility from any cause such as abdominal surgery or inflamation, or excessive vagal stimulation).
- opioid-induced side effects such as urinary retention, pruritus, and some forms of constipation
- nonopioid-induced side effects such as other forms of constipation and delayed gastric emptying or inhibition of gastrointestinal motility from any cause such as abdominal surgery or inflamation, or excessive vagal stimulation.
- opioid induced dysphoria opioid induced pruritus
- urinary retention opioid-or nonopioid-induced delayed gastric emptying from enteric feeding, inhibition of gut motility, and constipation
- opioid Ideally, such a treatment has few side effects either due to low drug toxicity or because administration of small amounts are effective and/or administration results in low circulating levels of the drug.
- the present invention is directed at methods for preventing and treating opioid-induced pruritus, opioid-induced urinary retention, opioid-or nonopioid-induced inhibition of gastric emptying, opioid-or nonopioid-induced inhibition of gastrointestinal motility, and opioid-or nonopioid-induced constipation.
- the method for preventing opioid-induced side effects, including dysphoria, pruritus, urinary retention, inhibition of gastric emptying, decreased gut motility, and constipation comprises administering methylnaltrexone or enterically coated methylnaltrexone, or other quaternary derivatives of noroxymorphone as disclosed in U.S. Patent No. 4,176,186 to Goldberg et al.
- the route of administration is selected from the group consisting of intravenous, intramuscular, intraperitoneal, transmucosal, transdermal, and oral administration in a standard or enterically coated preparation.
- the method for treating opioid-induced side effects comprises administering methylnaltrexone or enterically coated methylnaltrexone, or other quaternary derivatives of noroxymorphone, to a patient after the onset of the side effect, wherein the route of administration is selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal and oral administration in a standard or enterically coated preparation.
- the method for preventing nonopioid-induced side effects comprises administering methylnaltrexone or enteric coated methylnaltrexone, or other quaternary derivatives of noroxymorphone, to a patient prior to the development of the side effects wherein the route of administration is selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal and oral administration in a standard or enterically coated preparation.
- the method for treating nonopioid-induced side effects comprises administering methylnaltrexone or enteric coated methylnaltrexone, or other quaternary derivatives of noroxymorphone, to a patient after the onset of the side effect, wherein the route of administration is selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal and oral administration in a standard or enterically coated preparation.
- FIG. 1 A is a graph representing plasma concentrations of MNTX following administration of 6.4 mg/kg of uncoated MNTX.
- FIG. 1 B is a graph representing plasma concentrations of MNTX following administration of 6.4 mg/kg of enterically coated MNTX.
- FIG. IC is a graph representing plasma concentrations of MNTX following administration of 3.2 mg/kg of enterically coated MNTX.
- FIG. 2 illustrates the reversal of morphine's effect on oral-cecal transit time following administration of 6.4 mg/kg of uncoated MNTX.
- the darker line represents the average of all points of a given treatment.
- FIG. 3 illustrates the reversal of morphine's effect on oral-cecal transit time and its decrease below baseline following administration of 6.4 mg/kg of enterically coated MNTX.
- the darker line represents the average of all points of a given treatment.
- FIG. 4 illustrates the reversal of morphine's effect on oral-cecal transit time following administration of 3.2 mg/kg of enterically coated MNTX. The darker line represents the average of all points of a given treatment.
- the present invention is directed to methods for preventing and treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, opioid-or nonopioid-induced inhibition of gastric emptying or inhibition of gastrointestinal mobility, and opioid-or nonopioid-induced constipation.
- opioid-and nonopioid-induced side effects orally administered, particularly if enterically coated, methylnaltrexone (MNTX) or other quaternary derivatives of noroxymorphone (QDMN) provides prolonged relief of the side effects.
- MNTX has been demonstrated to have the ability to block the gastrointestinal effects of opioids on motility when administered intravenously or orally.
- non-enterically coated MNTX is associated with plasma levels with an early peak (20 min) and prolonged presence (half-life of about 3 hours after single dose of 6.4 mg/kg).
- an enteric coating on the QDNM designed to prevent dissolution and subsequent absorption of the drug in the stomach, would be expected to produce delayed elevation of plasma levels of the QDNM, and to produce a lower peak plasma level.
- administration of enterically coated MNTX has been found to result in substantially lower plasma levels as compared to non-enterically coated MNTX at the same dosage level, and surprisingly and unexpectedly resulted in enhanced efficacy in the reversal of opioid-induced decreases in gastrointestinal motility.
- MNTX When used as a treatment for the opioid- and nonopioid-induced side effects of constipation and reduction of gastrointestinal motility, orally administered, particularly if enterically coated.
- MNTX or other quaternary derivatives of noroxymorphone provide prolonged relief of the side effects.
- MNTX has been demonstrated to have the ability to block the gastrointestinal effects of opioids on motility when administered intravenously or orally.
- enteric coating surprisingly allows for equal or better efficacy despite lower plasma levels.
- Idiopathic constipation i.e., that due to causes other than exogenous administration of opioids, may be mediated by opioid sensitive mechanisms.
- Endogenous opioid receptors have been identified in the gut, and these receptors may modulate gut motility.
- R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl
- X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
- the presently preferred quaternary derivative of noroxymorphone is methylnaltrexone.
- Methylnaltrexone is a quaternary amine derivative of naltrexone. Methylnaltrexone has been found to have only 2 to 4% of the opiate antagonistic activity of naltrexone in vivo due to its inability to pass the blood-brain-barrier and bind to the opiate receptors in the central nervous system. Opioids are typically administered at a morphine equivalent dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to 1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kg body weight for intramuscular administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal or transdermal administration.
- morphine equivalent dosage is meant representative doses of other opioids which equal one milligram of morphine, for example 10 mg meperidine, 1 mg methadone, and 80 ⁇ g fentanyl.
- methylnaltrexone is administered at a dosage of: 0.03 to 1.0 mg/kg body weight for intravenous administration; 0.03 to 1.0 mg/kg body weight for intramuscular administration; 0.03 to 1.0 mg/kg body weight for transmucosal administration and 0.1 to 80.0 mg/kg body weight for oral administration, including enterically coated methylnaltrexone.
- the administration of the methylnaltrexone is preferably commenced prior to administration of the opioid to prevent opioid-induced dysphoria, pruritus, urinary retention, inhibition of gastric emptying or gastrointestinal motility, or constipation. It is desirable to commence administration of methylnaltrexone about 5 minutes (for parenteral MNTX administration) or 20 minutes (for enteral MNTX administration) prior to administration of opioids in order to prevent opioid-induced side effects. It is also preferable to administer the methylnaltrexone prior to the onset of nonopioid-induced gastric dysfunction symptoms, inhibition of gastric emptying, of gastrointestinal motility, or constipation, in order to prevent these symptoms from manifesting. While the prevention of symptoms is preferred, methylnaltrexone administration may also be commenced concurrent with or after the administration of the opioid or after the onset of opioid induced symptoms as a treatment for those symptoms.
- Methylnaltrexone is rapidly absorbed after oral administration from the stomach and bowel. Initial plasma levels of the drug are seen within 5-10 minutes of the administration of non-enteric coated compound. Addition of an enteric coating which prevents gastric absorption is associated with lower plasma levels of the methylnaltrexone. Surprisingly, the addition of an enteric coating (i.e., a coating which will prevent degradation or release in the stomach, but will release drug in the small and large bowel) enhances the efficacy of methylnaltrexone in the prevention of decreases in gut motility by intravenously administered opioids (morphine).
- an enteric coating i.e., a coating which will prevent degradation or release in the stomach, but will release drug in the small and large bowel
- methylnaltrexone is formulated with saline or other physiologically acceptable carriers; for intramuscular administration, the methylnaltrexone is formulated with saline or other pharmacologically acceptable carriers; for transmucosal administration the methylnaltrexone is formulated with a sugar and cellulose mix or other pharmacologically acceptable carriers known in the art; and for oral administration, the methylnaltrexone is formulated with pharmacologically acceptable binders to make a tablet or capsule with or without an enteric coating. Methods for such formulations are well known to those skilled in the art.
- the QDNM or MNTX is enterically coated and administered orally.
- the QDNM or methylnaltrexone is formulated with pharmacologically acceptable binders to make a tablet or capsule with an enteric coating.
- An enteric coating is one which remains intact during passage through the stomach, but dissolves and releases the contents of the tablet or capsule once it reaches the small intestine.
- Most currently used enteric coatings are those which will not dissolve in low pH environments, but readily ionize when the pH rises to about 4 or 5, for example synthetic polymers such as polyacids having a pK a of 3 to 5.
- the enteric coating may be made of any suitable composition. Suitable enteric coatings are described, for example, in U.S. Patent Nos. 4,311,833 to Namikoshi, et al.; 4,377,568 to Chopra; 4,385,078 to Onda, et al; 4,457,907 to Porter; 4,462,839 to McGinley, et al.; 4,518,433 to McGinley, et al.; 4,556,552 to Porter, et al.; 4,606,909 to Bechgaard et al.; 4,615,885 to
- enteric coating compositions include alkyl and hydroxyalkyl celluloses and their aliphatic esters, e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylethylcellulose, hydroxyprophymethylcellulose, hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; carboxyalkylcelluloses and their salts, e.g., carboxymethylethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate, polycarboxymethylene and its salts and derivatives; polyvinyl alcohol and its esters: polyvinyl acetate phthalate; polycarboxymethylene copolymer with sodium formaldehyde carboxylate; acrylic polymers and copolymers, e.g., methacrylic acid-methyl methacrylic
- enteric coatings include polyvinylacetate esters, e.g., polyvinyl acetate phthalate; alkyleneglycolether esters of copolymers such as partial ethylene glycol monomethylether ester of ethylacrylate-maleic anhydride copolymer or diethyleneglycol monomethylether ester of methylacrylate-maleic anhydride copolymer, N-butylacrylate-maleic anhydride copolymer, isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic anhydride copolymer; and polypeptides resistant to degradation in the gastric environment, e.g., polyarginine and polylysine.
- the presently preferred enteric coating comprises cellulose acetate phthalate.
- the enteric coating material may be mixed with various excipients including plasticizers such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate and inert fillers such as chalk or pigments.
- plasticizers such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate and inert fillers such as chalk or pigments.
- composition and thickness of the enteric coating may be selected to dissolve immediately upon contact with the digestive juice of the intestine.
- the composition and thickness of the exterior coating may be selected to be a time-release coating which dissolves over a selected period of time, as is well known in the art.
- the amount of enteric coating depends on the particular enteric coating composition used and is preferably sufficient to substantially prevent the absorption of QDMN or MNTX in the stomach.
- Hydroxyalkyl celluloses and their aliphatic esters, carboxyalkyl celluloses and their salts, polycarboxymethylene and its salts and derivatives, polyvinyl alcohol and its esters, polycarboxymethylene copolymer with sodium formaldehyde carboxylates, poly-vinylpyrrolidone, and polyethylene glycol and its esters can be applied as enteric coatings by first dissolving the compound in a minimum amount of water. Alcohol is then added to the point of incipient cloudiness. The mixture can then be applied by conventional techniques. Application of cellulose acetate phthalate may be accomplished by simply dissolving the cellulose acetate phthalate in a minimum amount of alcohol and then applying by conventional techniques.
- Hydrogenated vegetable oils may be applied by first dissolving the oil in a minimal amount of a non-polymer solvent, such as methylene chloride, chloroform or carbon tetrachloride, then adding alcohol to the point of incipient cloudiness and then applying by conventional techniques.
- a non-polymer solvent such as methylene chloride, chloroform or carbon tetrachloride
- the MNTX is coated with Eudragit LI 00 or S 100, a methacrylic acid copolymer enteric coating, at a 50% coating level to provide stability at gastric pH and dissolution at gut pH per a US Pharmacopeia (USP) standard for enteric coatings.
- transdermal administration is preferably via a patch applied to the skin with a membrane of sufficient permeability to allow diffusion of MNTX at a fixed rate in the range of 1.0 to 10.0 mg/hr.
- the rate of administration may be varied by varying the size of the membrane contact area and/or applying an electrical wiring potential to a drug reservoir.
- the patch preferably holds 25 mg to 1 gram of available drug in the reservoir plus additional drug as needed for the mechanics of the system.
- methylnaltrexone is used as an example of a particularly effective QDNM. It is apparent that other QDNM's may be used as desired.
- the following Examples are intended to illustrate aspects of the invention and are not to be construed as limitations upon it.
- the methylnaltrexone used in the following Examples was manufactured by Mallinckrodt Pharmaceuticals, St. Louis, MO.
- the Enteric Coating was manufactured by Coating Place, Inc., Verona, WI.
- methylnaltrexone at a dosage of 0.3 mg/kg of body weight was administered intravenously as a saline solution containing methylnaltrexone in a concentration of 5 mg/ml to each of the patients. Eighty percent of the 10 patients exhibited relief from the pruritus sixty minutes after receiving methylnaltrexone.
- a control group 8 patients were treated with morphine sulfate administered directly to the central nervous system or intravenously.
- the morphine sulfate was administered at 0.1 mg/kg body weight.
- the patients in the study had been treated for pain resulting from surgery.
- EXAMPLE 2 EFFICACY OF ENTERIC COATING OF METHYLNALTREXONE Morphine (0.05) mg/kg intravenous) was administered to three volunteers after the oral administration of placebo, methylnaltrexone (6.4 mg/kg) in a gelatin capsule (which dissolves readily in the stomach), or methylnaltrexone after enteric coating (12.8 mg/kg of substance to yield a mass of 6.4 mg/kg methylnaltrexone incorporated) which has decreased release and absorption in the stomach. Oral-cecal transit time was measured using the lactulose-hydrogen breath test.
- Plasma levels of methylnaltrexone were measured and after the enteric coated preparation were lower. In each subject morphine alone increased the oral-cecal transit time by 20 -70 minutes, methylnaltrexone blocked this effect, and enteric coated methylnaltrexone blocked the effect to a similar or greater extent than the uncoated methylnaltrexone.
- Two patients receiving morphine (375 mg/day and 18 mg/day) and receiving enteric tube feedings of 200 ml every four (4) hours were studied.
- the first patient had residual stomach contents of 50cc to lOOcc, or 22.0-58.8% of administered feedings measured every 4 hours during a 24 hour control period. Prior to drug administration the residual volume had increased to 260 cc or > 100% of previous feeding volume.
- the residual was 150cc or 58% of the previous bolus feed, after the 3rd dose (12 hours) the residual was 75cc or 30%) of the previous feed, after the 5th dose (20 hours) the residual was 22cc or 13% of the previous feed and after the 6th and final dose (24 hours) the residual was 8cc or 5.5% of previous feed.
- the follow-up residual sampling after the final drug-tube feed interval had increased to 50cc or 38% or previous feed.
- the second patient had greater than 200cc residual or 100% of previous feedings on two consecutive samplings, that is 8 hrs and 4 hrs before drug administration.
- the first residual (4 hrs) was Occ
- the second residual (8 hrs) was 24cc or 15% of previous bolus feed.
- EXAMPLE 4 TREATMENT OF URINARY RETENTION Subjects receiving morphine at a variety of doses (via patient controlled analgesia -PCA) who experience urinary retention are administered Methylnaltrexone 0.45 mg/kg intravenously or a placebo. Those treated with Methylnaltrexone have resolution of their symptoms, while those administered placebo go on to require additional therapy (usually urinary catheterization).
- Methylnaltrexone 0.45 mg/kg intravenously or a placebo. Those treated with Methylnaltrexone have resolution of their symptoms, while those administered placebo go on to require additional therapy (usually urinary catheterization).
- Oral methylnaltrexone whether enterically coated or uncoated, was shown to reverse the inhibitory effects of opioid administration on gastrointestinal motility as measured by oral-cecal transit time. As compared to non-enterically coated MNTX, however, treatment with enterically coated MNTX enhanced the efficacy of the drug at a lower dose while producing lower plasma levels of MNTX.
- Subjects were divided into five treatment groups A-E. With the exception of subjects in Group A, who were given a placebo in place of morphine, all were given an intravenous dose of morphine at 0.05 mg/kg. Prior to morphine administration, subjects were given either a placebo or MNTX in various doses and formulations (see Table 1). The subjects in Group A and B were given a placebo in place of MNTX. Group C received uncoated MNTX at 6.4 mg/kg,
- Group D received enterically coated MNTX at 6.4 mg/kg active drug
- Group E received enterically coated MNTX at 3.2 mg/kg active drug. Table 1 shows the treatments for each group.
- Plasma levels of MNTX were measured following administration of morphine and MNTX or placebo several times over the duration of the six hour monitoring period, at the times shown in FIG. 1. Measurements of plasma and urine MNTX levels were determined by high performance liquid chromatography (HPLC) using the modified method originally reported by Kim et al. (1989) Chromatographia 28:359-63, herein incorporated by reference). Methylnaltrexone was separated from plasma by solid phase extraction (SPE). Plasma samples (100-500 ⁇ l) diluted in water with the internal standard (naltrexone) were passed through SPE columns. Prior to use, the columns were conditioned by methanol and washed with water.
- HPLC high performance liquid chromatography
- the analytes were eluted from the columns by the mixture of n-propanol and trifluoroacetic acid (25 mM) aqueous solution prepared in 2:1 proportion.
- the eluate was evaporated to dryness in a stream of nitrogen at 55°C.
- the residue was reconstituted in the mobile phase, filtered through a nylon HPLC syringe filter and subjected to HPLC analysis.
- a Shimadzu Corporation (Kyoto, Japan) HPLC system was used. It consisted of the LC-10AD pump, SCL-10A system controller, and SIL-10A auto injector equipped with sample cooler. Used HPLC Analytical Column made by Phenomenex (Prodigy C8, Torrance, CA).
- the electrochemical detector (ESA Coulochem, model 5100A) worked at the following settings: detector 1, +360 mV, detector 2 +600 mV, guard cell +650 mV. Data were collected with the use of EZChrom 2-2 HPLC software.
- the mobile phase consisted of 50 mM sodium acetate, 7.5% methanol at pH 4.2. The system was calibrated daily in the range of 5 - 100 ng/ml (3 point calibration). Practical limit of detection for plasma samples was approximately 2 ng/ml (100 pg/injection).
- FIG. 1 shows the plasma levels of MNTX following the treatments in Groups C, D, and E.
- MNTX plasma levels in Group C (given 6.4 mg/kg MNTX, uncoated) peaked at about 15 min. post-MNTX administration and remained at a roughly constant level (between about 35-50 ng/ml) for the duration of the study period (6 hours).
- Group D given 6.4 mg/kg MNTX in an enterically coated formulation, exhibited a constant low plasma level of MNTX (under 10 ng/ml) for the duration of observation (see FIG. IB).
- Group E given 3.2 mg/kg MNTX in an enterically coated formulation, showed plasma levels of MNTX over the course of observation that were undetectable or at the lower limit of detection of the assay (see FIG. IC).
- Oral-cecal transit time was used as a measure of gut motility and propensity for constipation. Oral-cecal transit time was measured by the lactulose-breath hydrogen method.
- Group A demonstrated normal transit times as previously described in the literature (Yuan et al. (1996) Clin. Pharmacol. Ther. 59:469-475; Yuan et al. (1997) Clin. Pharmacol. Ther. 61:467- 475, both herein incorporated by reference).
- Group B had prolongation of their oral-cecal transit times by 50-100%), while Groups C (FIG. 2) and E (FIG. 4) had their transit times return to baseline levels.
- Group D showed an obvious decrease in oral-cecal transit time (FIG. 3).
- enterically coated MNTX provides the therapeutic effects on gastrointestinal motility of uncoated MNTX, but requires a lower dose of active drug and results in significantly reduced plasma levels of MNTX.
- FIG. 2 shows plasma MNTX levels of over 40 ng MNTX/ml, while patients given the same dose in an enterically coated formulation showed oral-cecal transit times below baseline levels (FIG. 3) and plasma MNTX levels under 10 ng/ml.
- Enterically coated formulations of MNTX with one half the dose of active drug (3.2 mg/kg) were required to return oral-cecal transit times to normal without increasing gut motility. At this dosage, plasma levels of MNTX were negligible.
- MNTX As with most drugs, it is desirable to maintain the lowest possible systemic levels of MNTX which are sufficient to provide the desired therapeutic effect. For example, elevated circulating levels of MNTX can result in orthostatic hypotension.
- the present discovery provides an unexpected means to avoid such undesirable drug side effects by lowering the dose administered and subsequently minimizing circulating levels of the drug. Since endogenous and externally supplied opioid-induced inhibition of gastrointestinal motility and constipation is thought to result from opioid receptors located within the gastrointestinal tract, enterically coated MNTX or other QDNMs may provide a local administration of the drug that does not require a circulating level for effective prevention or treatment of symptoms. Thus, the amount and/or frequency of drug administered can be reduced.
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CA002312234A CA2312234C (en) | 1997-11-03 | 1998-11-03 | Use of methylnaltrexone and related compounds |
DE69841663T DE69841663D1 (en) | 1997-11-03 | 1998-11-03 | USE OF METHYL NALTREXONE AND RELATED COMPOUNDS |
AU13802/99A AU758416B2 (en) | 1997-11-03 | 1998-11-03 | Use of methylnaltrexone and related compounds |
EP98957573A EP1047426B1 (en) | 1997-11-03 | 1998-11-03 | Use of methylnaltrexone and related compounds |
AT98957573T ATE467415T1 (en) | 1997-11-03 | 1998-11-03 | USE OF METHYLNALTREXONE AND RELATED COMPOUNDS |
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US08/962,742 | 1997-11-03 | ||
US08/962,742 US5972954A (en) | 1997-11-03 | 1997-11-03 | Use of methylnaltrexone and related compounds |
US09/120,703 US6274591B1 (en) | 1997-11-03 | 1998-07-22 | Use of methylnaltrexone and related compounds |
US09/120,703 | 1998-07-22 |
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DE10059415A1 (en) * | 2000-11-30 | 2002-06-06 | Gruenenthal Gmbh | Use of weak opioids and mixed opioid agonists / antagonists for the treatment of urinary incontinence |
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US6469030B2 (en) | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
WO2002098422A1 (en) | 2001-06-05 | 2002-12-12 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
US6608075B2 (en) | 1997-11-03 | 2003-08-19 | The University Of Chicago | Use of methylnaltrexone and related compounds |
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US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US8003794B2 (en) | 2005-05-25 | 2011-08-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
US8846091B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
US8932630B1 (en) | 1997-12-22 | 2015-01-13 | Purdue Pharma L.P | Opioid agonist/antagonist combinations |
US8936808B1 (en) | 1997-12-22 | 2015-01-20 | Purdue Pharma L.P. | Opioid agonist/opioid antagonist/acetaminophen combinations |
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US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
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US9717725B2 (en) | 2005-03-07 | 2017-08-01 | The University Of Chicago | Use of opioid antagonists |
US10071089B2 (en) | 2013-07-23 | 2018-09-11 | Euro-Celtique S.A. | Combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
US10258235B2 (en) | 2005-02-28 | 2019-04-16 | Purdue Pharma L.P. | Method and device for the assessment of bowel function |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030158220A1 (en) * | 1997-11-03 | 2003-08-21 | Foss Joseph F. | Use of methylnaltrexone and related compounds to treat chronic opioid use side effects |
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
AU2002316738B2 (en) | 2001-07-18 | 2009-01-08 | Euro-Celtique S.A. | Pharmaceutical combinations of oxycodone and naloxone |
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AU2002368150A1 (en) * | 2002-02-04 | 2004-02-25 | Jonathan Moss | Use of methylnaltrexone in treating gastrointestinal dysfunction in equines |
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JP2006522819A (en) * | 2003-04-08 | 2006-10-05 | プロジェニックス ファーマシューティカルズ,インコーポレーテッド | Combination therapy of constipation combined with laxatives and peripheral opioid antagonists |
MXPA05010819A (en) * | 2003-04-08 | 2006-03-30 | Progenics Pharm Inc | The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome. |
MY135852A (en) | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
AU2003279702A1 (en) * | 2003-08-12 | 2005-03-10 | Endo Pharmaceuticals, Inc. | Method for deterring abuse of opioids by combination with non-release formulation of emetic |
WO2005032555A2 (en) * | 2003-09-25 | 2005-04-14 | Euro-Celtique S.A. | Pharmaceutical combinations of hydrocodone and naltrexone |
CN101137378A (en) * | 2005-01-20 | 2008-03-05 | 普罗热尼奇制药公司 | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
US20080194611A1 (en) * | 2005-06-03 | 2008-08-14 | Alverdy John C | Modulation of Cell Barrier Dysfunction |
US20070185145A1 (en) * | 2006-02-03 | 2007-08-09 | Royds Robert B | Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same |
US20080027579A1 (en) * | 2006-07-31 | 2008-01-31 | Van Der Hoop Roland Gerritsen | Dosage limiting medication dispensing method and apparatus |
TW200815451A (en) * | 2006-08-04 | 2008-04-01 | Wyeth Corp | 6-carboxy-normorphinan derivatives, synthesis and uses thereof |
TW200817048A (en) * | 2006-09-08 | 2008-04-16 | Wyeth Corp | Dry powder compound formulations and uses thereof |
WO2009009292A2 (en) * | 2007-07-11 | 2009-01-15 | Mallinckrodt Inc. | Crystalline forms of naltrexone methobromide |
US8748448B2 (en) | 2007-10-18 | 2014-06-10 | Aiko Biotechnology | Combination analgesic employing opioid agonist and neutral antagonist |
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US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US20140179727A1 (en) | 2012-12-14 | 2014-06-26 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
EP3206491B1 (en) | 2014-10-17 | 2019-11-27 | Salix Pharmaceuticals, Inc. | Use of methylnaltrexone to attenuate tumor progression |
CA3106995A1 (en) | 2018-07-23 | 2020-01-30 | Trevi Therapeutics, Inc. | Treatment of chronic cough, breathlessness, or dyspnea with nalbuphine compositions |
AU2020268767A1 (en) | 2019-05-07 | 2021-10-28 | Bausch Health Ireland Limited | Liquid oral dosage formulations of methylnaltrexone |
CA3177250A1 (en) | 2020-05-02 | 2021-11-11 | Bausch Health Ireland Limited | Methods of reducing mortality risk in subjects suffering from an underlying disease or condition by administration of methylnaltrexone |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4176186A (en) | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
Family Cites Families (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US222911A (en) * | 1879-12-23 | Improvement in book-cases | ||
US2003A (en) * | 1841-03-12 | Improvement in horizontal windivhlls | ||
US1047726A (en) * | 1912-03-12 | 1912-12-17 | Anthony J Yoggerst | Pipe-cleaner. |
US2625457A (en) * | 1951-07-26 | 1953-01-13 | Bernard J Baecher | Course recorder |
JPS5535031A (en) | 1978-09-04 | 1980-03-11 | Shin Etsu Chem Co Ltd | Enteric coating composition |
US4311833A (en) | 1979-03-06 | 1982-01-19 | Daicel Chemical Industries Ltd. | Process for preparing ethylcarboxymethylcellulose |
US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
US4377568A (en) | 1981-08-12 | 1983-03-22 | Merck Sharp & Dohme (I.A.) Corp. | Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same |
DK150008C (en) | 1981-11-20 | 1987-05-25 | Benzon As Alfred | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL ORAL POLYDEPOT PREPARATION |
US4987136A (en) | 1982-03-16 | 1991-01-22 | The Rockefeller University | Method for controlling gastrointestinal dysmotility |
DE3381877D1 (en) | 1982-03-16 | 1990-10-18 | Univ Rockefeller | USE OF OPIUM ANTAGONISTS FOR THE PRODUCTION OF MEDICINAL PRODUCTS FOR THE REMEDY OF GASTRO-INTESTINAL DISORDERS. |
US4457907A (en) | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
US4518433A (en) | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4462839A (en) | 1983-06-16 | 1984-07-31 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4556552A (en) | 1983-09-19 | 1985-12-03 | Colorcon, Inc. | Enteric film-coating compositions |
DE3474511D1 (en) | 1983-11-01 | 1988-11-17 | Terumo Corp | Pharmaceutical composition containing urokinase |
US5266574A (en) | 1984-04-09 | 1993-11-30 | Ian S. Zagon | Growth regulation and related applications of opioid antagonists |
JPS6229515A (en) | 1985-07-30 | 1987-02-07 | Shinjiro Tsuji | Method for film-coating of hard capsule |
US4719215A (en) * | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4861781A (en) * | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
JP2593501B2 (en) | 1986-08-28 | 1997-03-26 | コーテクス・リミテッド | Animal growth promoter |
US5597564A (en) | 1986-08-28 | 1997-01-28 | Enzacor Properties Limited | Method of administering a microgranular preparation to the intestinal region of animals |
US4888346A (en) * | 1986-10-07 | 1989-12-19 | Bernard Bihari | Method for the treatment of persons infected with HTLV-III (AIDS) virus |
FR2609632B1 (en) | 1987-01-21 | 1991-03-29 | Shelly Marc | NOVEL THERAPEUTIC APPLICATION OF 17- (CYCLOPROPYLMETHYL) -4,5-EPOXY-3,14-DIHYDROXYMORPHINON-6-ONE AND PHARMACEUTICAL COMPOSITIONS FOR THIS USE |
US4857833A (en) * | 1987-08-27 | 1989-08-15 | Teradyne, Inc. | Diagnosis of faults on circuit board |
CA1315689C (en) | 1987-09-03 | 1993-04-06 | Leon I. Goldberg | Quarternary derivatives of noroxymorphone which relieve nausea and emesis |
ATE78687T1 (en) * | 1987-09-10 | 1992-08-15 | Univ Chicago | QUATERNARY DERIVATIVES OF NOROXYMORPHONE FOR THE TREATMENT OF NAUSEA AND VOMITING. |
EP0352361A1 (en) | 1988-07-29 | 1990-01-31 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US5102887A (en) * | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
US4965269A (en) * | 1989-12-20 | 1990-10-23 | Ab Hassle | Therapeutically active chloro substituted benzimidazoles |
JPH04230625A (en) * | 1990-12-27 | 1992-08-19 | Standard Chem & Pharmaceut Corp Ltd | Method for production of finely dispersed tablet composition consisting of microcapsule containing sprayed and dried sodium dichlofenac and having enteric coating |
US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
US5270328A (en) | 1991-03-29 | 1993-12-14 | Eli Lilly And Company | Peripherally selective piperidine opioid antagonists |
ES2109362T3 (en) | 1991-06-21 | 1998-01-16 | Univ Cincinnati | ADMINISTRABLE PROTEINS ORALLY AND METHOD TO MAKE THEM. |
US5614219A (en) * | 1991-12-05 | 1997-03-25 | Alfatec-Pharma Gmbh | Oral administration form for peptide pharmaceutical substances, in particular insulin |
US5580876A (en) | 1992-09-21 | 1996-12-03 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US6096756A (en) | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5472943A (en) | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
USRE36547E (en) | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US5512578A (en) | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
ES2095001T5 (en) | 1992-12-22 | 2001-03-16 | Univ Cincinnati | AN ORALALLY ADMINISTRABLE THERAPEUTIC COMPOSITION AND ITS METHOD OF OBTAINING. |
US5585348A (en) | 1993-02-10 | 1996-12-17 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia |
US5656290A (en) * | 1993-02-26 | 1997-08-12 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
US5391372A (en) * | 1993-06-28 | 1995-02-21 | Campbell; Elizabeth | Methods of treating colic and founder in horses |
AU2360195A (en) * | 1994-05-05 | 1995-11-29 | Beckman Instruments, Inc. | Oligonucleotide repeat arrays |
IT1269826B (en) | 1994-05-24 | 1997-04-15 | Paolo Minoia | USE OF OPTIACEAN ANTAGONISTS AND CALCIUM SALTS FOR THE PREPARATION OF MEDICATIONS FOR THE TREATMENT OF ENDORPHINE-MEDIATED PATHOLOGICAL FORMS |
US5536507A (en) | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
US5866154A (en) * | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
US5614222A (en) | 1994-10-25 | 1997-03-25 | Kaplan; Milton R. | Stable aqueous drug suspensions and methods for preparation thereof |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
ES2094694B1 (en) | 1995-02-01 | 1997-12-16 | Esteve Quimica Sa | NEW PHARMACEUTICALLY STABLE FORMULATION OF A COMPOUND OF BENZMIDAZOLE AND ITS PROCESS OF OBTAINING. |
US6025154A (en) * | 1995-06-06 | 2000-02-15 | Human Genome Sciences, Inc. | Polynucleotides encoding human G-protein chemokine receptor HDGNR10 |
US5804595A (en) * | 1995-12-05 | 1998-09-08 | Regents Of The University Of Minnesota | Kappa opioid receptor agonists |
EP0914097B1 (en) | 1996-03-12 | 2002-01-16 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
DE19651551C2 (en) | 1996-12-11 | 2000-02-03 | Klinge Co Chem Pharm Fab | Opioid antagonist-containing galenic formulation |
US6353004B1 (en) * | 1997-07-14 | 2002-03-05 | Adolor Coporation | Peripherally acting anti-pruritic opiates |
US5972954A (en) | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
US6274591B1 (en) * | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
US20030158220A1 (en) * | 1997-11-03 | 2003-08-21 | Foss Joseph F. | Use of methylnaltrexone and related compounds to treat chronic opioid use side effects |
US6194382B1 (en) | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
EP1206264A2 (en) | 1999-08-25 | 2002-05-22 | Barrett R. Cooper | Compositions and methods for treating opiate intolerance |
US6451806B2 (en) | 1999-09-29 | 2002-09-17 | Adolor Corporation | Methods and compositions involving opioids and antagonists thereof |
ES2329004T3 (en) | 1999-11-29 | 2009-11-20 | Adolor Corporation | NEW PROCEDURES FOR THE TREATMENT AND PREVENTION OF ILEO. |
US6469030B2 (en) | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
DK1244447T3 (en) | 1999-11-29 | 2007-04-23 | Adolor Corp | New methods and compositions containing opioids and their antagonists |
WO2001041705A2 (en) | 1999-11-29 | 2001-06-14 | Adolor Corporation | Novel methods for the treatment and prevention of dizziness and pruritus |
US6967075B2 (en) * | 2000-04-07 | 2005-11-22 | Schering Corporation | HCV replicase complexes |
WO2001085257A2 (en) | 2000-05-05 | 2001-11-15 | Pain Therapeutics, Inc. | Opioid antagonist compositions and dosage forms |
SI1296714T1 (en) * | 2000-06-22 | 2010-01-29 | S For Entpr University Of Iowa | Combination of CpG and antibodies directed against CD19,CD20, CD22 or CD40 for the treatment or prevention of cancer. |
ATE446751T1 (en) * | 2001-06-05 | 2009-11-15 | Univ Chicago | USE OF METHYLNALTREXONE TO TREAT IMMUNOSUPRESSION |
PT1436012T (en) * | 2001-10-18 | 2018-03-27 | Nektar Therapeutics | Polymer conjugates of opioid antagonists |
US20030191147A1 (en) * | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
DK2368553T3 (en) * | 2003-04-08 | 2015-02-09 | Progenics Pharm Inc | Pharmaceutical preparation comprising methylnaltrexone |
MXPA05010819A (en) * | 2003-04-08 | 2006-03-30 | Progenics Pharm Inc | The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome. |
JP2006522819A (en) * | 2003-04-08 | 2006-10-05 | プロジェニックス ファーマシューティカルズ,インコーポレーテッド | Combination therapy of constipation combined with laxatives and peripheral opioid antagonists |
JP2007509722A (en) * | 2003-10-29 | 2007-04-19 | アレズ フィジオニックス リミテッド | Method and apparatus for determining the flow centerline of an ultrasonic fluid |
CN101137378A (en) * | 2005-01-20 | 2008-03-05 | 普罗热尼奇制药公司 | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
-
1998
- 1998-07-22 US US09/120,703 patent/US6274591B1/en not_active Expired - Lifetime
- 1998-11-03 WO PCT/US1998/023485 patent/WO1999022737A1/en active IP Right Grant
- 1998-11-03 EP EP98957573A patent/EP1047426B1/en not_active Expired - Lifetime
- 1998-11-03 AU AU13802/99A patent/AU758416B2/en not_active Expired
- 1998-11-03 CA CA002312234A patent/CA2312234C/en not_active Expired - Lifetime
-
2001
- 2001-05-21 US US09/862,169 patent/US6608075B2/en not_active Expired - Lifetime
-
2002
- 2002-10-23 US US10/278,630 patent/US20030065003A1/en not_active Abandoned
-
2004
- 2004-02-12 US US10/779,129 patent/US20040162308A1/en not_active Abandoned
- 2004-10-12 US US10/962,729 patent/US20050048117A1/en not_active Abandoned
-
2008
- 2008-12-12 US US12/333,912 patent/US20090312359A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4176186A (en) | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
Non-Patent Citations (3)
Title |
---|
See also references of EP1047426A4 * |
YUAN C.-S., ET AL.: "CLINICAL TRIALS AND THERAPEUTICS.", CLINICAL PHARMACOLOGY AND THERAPEUTICS, NATURE PUBLISHING GROUP, US, vol. 61., no. 04., 1 April 1997 (1997-04-01), US, pages 467 - 475., XP002915586, ISSN: 0009-9236, DOI: 10.1016/S0009-9236(97)90197-1 * |
YUAN ET AL., CLINICAL PHARMACOLOGY & THERAPEUTICS, vol. 61, no. 4, April 1997 (1997-04-01), pages 467 - 475 |
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US7008939B2 (en) | 2000-11-30 | 2006-03-07 | Gruenenthal Gmbh | Use of weak opioids and mixed opioid agonists/antagonists for treatment of urinary incontinence |
DE10059415A1 (en) * | 2000-11-30 | 2002-06-06 | Gruenenthal Gmbh | Use of weak opioids and mixed opioid agonists / antagonists for the treatment of urinary incontinence |
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US9084729B2 (en) | 2001-05-11 | 2015-07-21 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
US9511066B2 (en) | 2001-05-11 | 2016-12-06 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
US9161937B2 (en) | 2001-05-11 | 2015-10-20 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
US9480685B2 (en) | 2001-05-11 | 2016-11-01 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
US9056051B2 (en) | 2001-05-11 | 2015-06-16 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
EP1404323A4 (en) * | 2001-06-05 | 2006-10-11 | Univ Chicago | Use of methylnaltrexone to treat immune suppression |
EP1404323A1 (en) * | 2001-06-05 | 2004-04-07 | The University of Chicago | Use of methylnaltrexone to treat immune suppression |
WO2002098422A1 (en) | 2001-06-05 | 2002-12-12 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
US8846091B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
US10420762B2 (en) | 2002-04-05 | 2019-09-24 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
US9555000B2 (en) | 2002-04-05 | 2017-01-31 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
US9655855B2 (en) | 2002-04-05 | 2017-05-23 | Purdue Pharma L.P. | Matrix for sustained, invariant and independent release of active compounds |
US8846090B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
US9907793B2 (en) | 2002-04-05 | 2018-03-06 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
US10376584B2 (en) | 2003-04-08 | 2019-08-13 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
US9669096B2 (en) | 2003-04-08 | 2017-06-06 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
EP1844792A1 (en) * | 2004-12-14 | 2007-10-17 | Shionogi Co., Ltd. | Therapeutic agent for constipation |
EP1844792A4 (en) * | 2004-12-14 | 2008-05-21 | Shionogi & Co | Therapeutic agent for constipation |
US10258235B2 (en) | 2005-02-28 | 2019-04-16 | Purdue Pharma L.P. | Method and device for the assessment of bowel function |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9675602B2 (en) | 2005-03-07 | 2017-06-13 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9717725B2 (en) | 2005-03-07 | 2017-08-01 | The University Of Chicago | Use of opioid antagonists |
US9662390B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US8003794B2 (en) | 2005-05-25 | 2011-08-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US8343992B2 (en) | 2005-05-25 | 2013-01-01 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US9597327B2 (en) | 2005-05-25 | 2017-03-21 | Progenics Pharmaceuticals, Inc. | Synthesis of (R)-N-methylnaltrexone |
US8916581B2 (en) | 2005-05-25 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US8772310B2 (en) | 2007-03-29 | 2014-07-08 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US9879024B2 (en) | 2007-03-29 | 2018-01-30 | Progenics Pharmaceuticals., Inc. | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US8853232B2 (en) | 2007-03-29 | 2014-10-07 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US8916706B2 (en) | 2008-02-06 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US10383869B2 (en) | 2008-03-21 | 2019-08-20 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
WO2010002576A1 (en) | 2008-07-01 | 2010-01-07 | University Of Chicago | Particles containing an opioid receptor antagonist and methods of use |
US8420663B2 (en) | 2008-09-30 | 2013-04-16 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US8822490B2 (en) | 2008-09-30 | 2014-09-02 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8455644B2 (en) | 2008-09-30 | 2013-06-04 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US9492445B2 (en) | 2008-09-30 | 2016-11-15 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US9724343B2 (en) | 2008-09-30 | 2017-08-08 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US9180125B2 (en) | 2008-09-30 | 2015-11-10 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US9820983B2 (en) | 2009-03-10 | 2017-11-21 | Purdue Pharma L.P. | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
US9271940B2 (en) | 2009-03-10 | 2016-03-01 | Purdue Pharma L.P. | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
US10071089B2 (en) | 2013-07-23 | 2018-09-11 | Euro-Celtique S.A. | Combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
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US20040162308A1 (en) | 2004-08-19 |
US20020028825A1 (en) | 2002-03-07 |
EP1047426A4 (en) | 2004-07-14 |
US20090312359A1 (en) | 2009-12-17 |
US20050048117A1 (en) | 2005-03-03 |
US6274591B1 (en) | 2001-08-14 |
EP1047426B1 (en) | 2010-05-12 |
AU758416B2 (en) | 2003-03-20 |
AU1380299A (en) | 1999-05-24 |
EP1047426A1 (en) | 2000-11-02 |
CA2312234A1 (en) | 1999-05-14 |
CA2312234C (en) | 2005-03-22 |
US6608075B2 (en) | 2003-08-19 |
US20030065003A1 (en) | 2003-04-03 |
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