CA2312234C - Use of methylnaltrexone and related compounds - Google Patents
Use of methylnaltrexone and related compounds Download PDFInfo
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- CA2312234C CA2312234C CA002312234A CA2312234A CA2312234C CA 2312234 C CA2312234 C CA 2312234C CA 002312234 A CA002312234 A CA 002312234A CA 2312234 A CA2312234 A CA 2312234A CA 2312234 C CA2312234 C CA 2312234C
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- noroxymorphone
- quaternary derivative
- derivative
- opioid
- methylnaltrexone
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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
Abstract
A method for preventing or treating opioid induced side effects including dysphoria, pruritus, urinary retention and gastrointestinal dysfunction and non-opioid induced changes in gastrointestinal motility. The method comprises administering methylnaltrexone or another quaternary derivative of noroxymorphone to a patient prior to the administration of an opioid or after the onset of side effects induced by the administration of an opioid, wherein the methylnaltrexone or quaternary derivative is administered by the route selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal, and oral administration, preferably administered orally in an enterically coated form.
Description
tTSli; OF 1~'i I-~YLNALTRE~ONE AN1:1 RELA~'ED COlvI~pIINDS
10 FThLD OF THE INVENTION
The present invention is direceerl at the treatment of certain side effects associated with the use of opioids as analgesics. In partiouiar the presextt invention is directed toward treating opioid-i»dus~cd dysphoria, ogioid~induced pruritus, opiaid-i»duced urinary retention, opioid-and non-opioid induced it~ibition of gastric ez~nptyixig and inhibition 4f gastrointestinal motility, and I S constipation.
_ BACKCR~rUNI~ OF T>;IE INVF.,I~.T'IiON
Opioids are effective analgesics. However, their use is associated with a riutrlber of undesirable side effects. C?ne of these side erects i5 pruritus, ar itching.
Pruritus is a common 2U side effect associated with the use of opioids and may be very severe.
Pruritus can occur when the opioid is administered intramuscularly, intravenously. transdermally, transsnucosally or intrathecally.
It is 6eiieved that the opioid induced pruxitus results flour the release of histamine in response td the administratiotx of opioids. Oploids are thought to stimulate histannine release by 25 binding m opioid receptors on the centrai nezvous systenrt. 'this, in tour, causes peripl3eral nerves and histamine Containing cells to release histamine.
>3ased on this theory a nunnber of treatments have been used to alleviate opioid induced pruritus. The first is the use of antihistamines. 1'-Iowever, antihistamines have a variable effect on opioid induced pruritus. Additionally, the use of antihistamines, when effective, only treats ~0 the syr:uptom a'Rer it has occurred, rather than preventing xts bCCt~rrence.
Another undesirable side effect of apioids 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 axe administered inuamuscnlarly, intFavenously, transn7ucosslly, transdermaily, or intrathecally. It is not clear why opiaids cause urinary 3S retention, but it is thought to be related to the eentrai~anticha3inergie stimulation that opioids induce. Based on this theory, a number of cholinergie-type drugs have been used to treat urinary retention. However, due to the side effects df cholix~ergic 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.
Many subjects, especially those without pain, report unpleasant psychomimetic responses to the administration of an opioid alone. These responses have been previously attributed to activation of centrally located opioid receptors. This 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.
One treatment for side effects such as pruritis, urinary retention, dysphoria, and inhibited I S gastrointestinal motility is the use of 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 pnuitus. Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain-barrier. However, naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
Many 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. In fact, experiments show that to be effective in blocking the opioid receptors in the central nervous system, these antagonists must be injected directly into the central nervous system. However, injection of drugs directly into the central nervous system is undesirable since it increases the possibility of introducing bacterial or viral contamination to the central nervous system.
It is desirable in the treatment of many conditions to have oral medications with prolonged effects. Such 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).
10 FThLD OF THE INVENTION
The present invention is direceerl at the treatment of certain side effects associated with the use of opioids as analgesics. In partiouiar the presextt invention is directed toward treating opioid-i»dus~cd dysphoria, ogioid~induced pruritus, opiaid-i»duced urinary retention, opioid-and non-opioid induced it~ibition of gastric ez~nptyixig and inhibition 4f gastrointestinal motility, and I S constipation.
_ BACKCR~rUNI~ OF T>;IE INVF.,I~.T'IiON
Opioids are effective analgesics. However, their use is associated with a riutrlber of undesirable side effects. C?ne of these side erects i5 pruritus, ar itching.
Pruritus is a common 2U side effect associated with the use of opioids and may be very severe.
Pruritus can occur when the opioid is administered intramuscularly, intravenously. transdermally, transsnucosally or intrathecally.
It is 6eiieved that the opioid induced pruxitus results flour the release of histamine in response td the administratiotx of opioids. Oploids are thought to stimulate histannine release by 25 binding m opioid receptors on the centrai nezvous systenrt. 'this, in tour, causes peripl3eral nerves and histamine Containing cells to release histamine.
>3ased on this theory a nunnber of treatments have been used to alleviate opioid induced pruritus. The first is the use of antihistamines. 1'-Iowever, antihistamines have a variable effect on opioid induced pruritus. Additionally, the use of antihistamines, when effective, only treats ~0 the syr:uptom a'Rer it has occurred, rather than preventing xts bCCt~rrence.
Another undesirable side effect of apioids 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 axe administered inuamuscnlarly, intFavenously, transn7ucosslly, transdermaily, or intrathecally. It is not clear why opiaids cause urinary 3S retention, but it is thought to be related to the eentrai~anticha3inergie stimulation that opioids induce. Based on this theory, a number of cholinergie-type drugs have been used to treat urinary retention. However, due to the side effects df cholix~ergic 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.
Many subjects, especially those without pain, report unpleasant psychomimetic responses to the administration of an opioid alone. These responses have been previously attributed to activation of centrally located opioid receptors. This 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.
One treatment for side effects such as pruritis, urinary retention, dysphoria, and inhibited I S gastrointestinal motility is the use of 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 pnuitus. Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain-barrier. However, naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
Many 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. In fact, experiments show that to be effective in blocking the opioid receptors in the central nervous system, these antagonists must be injected directly into the central nervous system. However, injection of drugs directly into the central nervous system is undesirable since it increases the possibility of introducing bacterial or viral contamination to the central nervous system.
It is desirable in the treatment of many conditions to have oral medications with prolonged effects. Such 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).
It is further desirable to develop a method for the prevention of opioid induced dysphoxia, opioid indtteed pnuritus, urinary retention, opioid-or nonopioid-induced delayed gastric emptying from enteric feeding, inhibition of gut motility, axd constipation, which does not counteract the at7aigesic e'l'ects of the apioid, or xi,sk increased levels of pain. Ideally, such a treatment has feW
side effects either due to low drug toxicity or because adxninistraiion of small amounts are effective andlor adrrrit'istration results in lour circulating levels of the drug.
1 (l SUMMARY OF 'IT~E INVENTION
Tire present invexrtion is directed at methods for preventing and #reatittg opiold-induced pruritus, opioid-induced urinary retention, apioid-or nonopioid-induced inhil3ition of gastric emptying, opioid-or nonopioid induced inhibition of gastrointestinal motility, and opioid-or nonopioid-induced constipation.
15 'the method for preveniidg opioid-induced side effects, including dysphoria, prurltus, urinary retention, inhibition of gastric emptying, decreased gut motility, and constipation, comprises admirdstering nnethylnaltrexone ar enterioally coated rae#hylnaltrexotte, ox ather quatematy derivatives ofnoto'xymotphozie as disclosed in U.S. Patent Na.
x,175,186 to Goldberg et aI. to a patient prior to ox simultaneously with the 20 administration of an apioid wherein the route of administration is selected from the group consistilng of ititravet'tous, intratnusGUlar, intraperitonCal, transrxxucosal, transdernnal, arid oral administration in a standard or entexically coated pzeparation.
The method fartreating opioid-?induced side effects, iTtcluding dysphoria, pruritus, urinary retention, inhibition of gut motility and constipation, comprises administering methylnaltxexone 25 or entxrically coated methylnaltr~cone, or other quaternary derivatives of noroxymoxphorte, to a patient after the oxi~t of the side effect, wherein the route of adruinistxatioxs is selected frarn the group consisting of intravenous, intramuscuiar, transmucosal, tranSdermal and oral administration in a standard or enterically coated preparation.
The method fox preventizag nanopioid-induced side effects, ir~ludir:g gastrointestinal 30 dysfunction (e.g., inhibition ofgastric emptying, of,gastraintestinat motiIitity and constipation), comprises administeritxg methylnaitrexone or enteric coated methylnaltrexone, or other quaternary derivatives of rxoroxymorphone, to a patient prior to the derleloprneut of the side effecrs wherein the mute of administration is selected from the group consisting of intxavenaus, intraznuscular, transmucosal, iransdermal and oral administrzttion ixx a standard ar enterically 35 coated preparation.
The method fox trea'Cing notxopioid-induced side effects, including inhibition of gastric emptying by enteric feeding and constipation, comprises administering tnethylnaItrexone or enteric coated methylxsaltrexone, 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, transderxnal and oral adtnirustration in a standard or enterically coated preparation.
According to one embodiment, there is disclosed the use of a quaternary derivative of noroxymorphone wherein the meihylnaltxexone is provided in a formulation adapted far administration by the route selected from the group consisting of intravenous, iz~tramuscular, transtnucosal, transdermal, and oral adnninistrettion.
According to a further e;x~bodiment, there is disclosed the use of a quaternary derivative of noroxyzziorphone wherein the methylnaltrexone is provided in a, formulation adapted far la providing a dosage 0.03 to 1.0 tng/kg body weight for intravenous or intrarnuscular administration; 1.0 to 10.0 mgllcg for cransdermal administration; and 0.1 to 80.0 mglkg body weight for oral administration of n2eChylnaltrexone.
According to a further embodiment, there is disclosed the use of a quaternary derivative of noroxymorphone wherein the metlxylnaltzexone is provided in a formulation adapted for 15 administration by the route selected frono~ the group consisting of intravenous, intramuseular, transmucosal, transdertnal, and oral administr&tion.
According to a further ernbodim~ent, there is disclosed the use of a tluaternary derivative of noroxymorphone wherein the methyInaltrexone is provided in a 'formulation adapted far administration orally to provide a dosage of 0.1 to 80.0 mglkg body weight.
Accordiung to a further embodiment, there is disclosed the use of a quaternary dezivative of noroxymorphone wherein the rtiethylnaltrexane is provided in a formulation adapted to provide a dosage of about 0.1 to about 10.0 mg/ltg body weight.
According to a furtlt~er embodiment, there is disclosed tl~e use of a quaternary derivative of noroxymorphone wherein the rnethylnaltrexone is provided in a fonmulatioz~
adapted for 25 administration as an enterieally coated tablet or capsule, or as enterically coated ~anules.
According to a further embodiment, there is disclosed the use of a quatexmary derivative of noroxyrrzorphone wherein the methylnaltrexone is provided ins a formulation adapted to provide a dosage of 0, x to 40.0 xng of active drug per Itg holy weight.
According to a further embodiment, there is disclosed the use of a quaterxsary derivative 30 of noroxymorphane wherein the methylnaltrexone is adapted for administration orally to provide a dosage of about 0.1 to about 10 mg/ltg body weight.
-3a-According to a further embodiment, there is disclosed the use of a quaternary derivative of noroxymorphone wherexr~ the methyhnaltrexone is adapted for adnninistration as an enterically coated tablet or capsule, or as enterically coated granules.
According to a further embodiment, there is disclosed the use of a quaternary derivative of n~oroxymorphone wherein the quatearrtary derivative is provided in a formulation adapted for adrninistxation subsequent to the opioid.
-3b-DETAIi,~D DESCR~TI4N 4F DRA~NGS
FICi. lA is a graph ~tiag plasma. concentrations of MNTX following adminisEr~tion of 6.4 mglkg of uneoated ~NTX.
I O FTG.18 is a graph representing pias~na cozlcenirations of MN'T~ following administration of 6.4 rngJkg of enterically coated MN'f.K.
p"iG. iC is a graph xcprese~lting plasma concentrations of MN1'~ following administration of 3.2 mp~kg of enterically coated MNT~.
fiG. 2 illustrates the reversal of morphine's effect on oral-ceoal transit time following 15 administration of 6.4 mgfkg of uncoated A~1NTX. , The darker line represents the average of all points of a given treatanent.
FIG. 3 illustrates the reversal of morphine's effect on oral-cecai transit time and its decrease below baseliae ~ollo,xing administration of 6.4 mglkg of enterically coated Mbl'1~.
The darker line represents the average of all points of a giverx treatment.
24 1~iG. 4 illustrates the reversal of morphine's effect an oral-cecal transit timt following administration of 3.2 rrig/kg of entericalIy coated ivlN'f X. The darker line rep-esents the average of all points of a given treatment.
DE'T'AILED nESC~PTiGN c~F THE FNVENTiON
'fhe present invention is directed to methods ~or preventing arid treating opioid-induced dysphoria, opioid-induced pntritus, opioid-irnlttced urinary retesttion, opioid or saormpioid-induced ixshit7itioa of g~strlc emptying or inhibition of gastroi~ntestimal mobility, and opioid-or nonopioid-induced constipation. When used a5 a treatment for thtse opioid-and 3U nonopioid-i»daced side effects, orally administer8d, particularly if ernerically coated, rn~ethylnaltrexone (M~I'X) or othCr quaternary derivatives of noroxymorphone (QD~1) provides prolonged xelief of tine side e,t~'ects. RR~TfX has been demonstrated to have the ability to bIook the gastrointestinal effects of opioicls on motilify when administered intravenously or orally.
35 The oral administratfon of non-entericatly coated ~~V1 X is associated with plasma levels with an early peak (20 min) and prolonged presence (half life of a'ixaut 3 hours after single dose of 6.4 mglkg). I-Iowev~, an enteric coating on the QlrINM, 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. Suprisingly, however, 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. In fact, it has been found that as compared to non-enterically coated MNTX, a significantly lower dose, e.g., less than half the amount of coated MNTX can be used if enterically coated to achieve the same levels of relief of opioid-induced constipation. Moreover, such reduced dosage levels of MNTX administered with an enteric coating results in exceedingly low peak and sustained plasma levels of MNTX, greatly reducing the potential adverse side effects of the MNTX. This novel improvement in the clinical indication for use of MNTX has led to an increased therapeutic index for this drug.
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. MNfX 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.
Furthermore, for treatment or prevention of constipation and delayed gastrointestinal emptying, whether caused by extrinsic or endogenous opioids, 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. Thus, administration of an opioid antagonist with peripheral action, such a methylnaltrexone or other quaternary derivatives of noroxymorphone, would block the effects of endogenous opioids.
Quaternary derivatives of noroxymorphone are described in full in Goldberg et al., (supra), and in general are represented by the formula:
:H3 HO
side effects either due to low drug toxicity or because adxninistraiion of small amounts are effective andlor adrrrit'istration results in lour circulating levels of the drug.
1 (l SUMMARY OF 'IT~E INVENTION
Tire present invexrtion is directed at methods for preventing and #reatittg opiold-induced pruritus, opioid-induced urinary retention, apioid-or nonopioid-induced inhil3ition of gastric emptying, opioid-or nonopioid induced inhibition of gastrointestinal motility, and opioid-or nonopioid-induced constipation.
15 'the method for preveniidg opioid-induced side effects, including dysphoria, prurltus, urinary retention, inhibition of gastric emptying, decreased gut motility, and constipation, comprises admirdstering nnethylnaltrexone ar enterioally coated rae#hylnaltrexotte, ox ather quatematy derivatives ofnoto'xymotphozie as disclosed in U.S. Patent Na.
x,175,186 to Goldberg et aI. to a patient prior to ox simultaneously with the 20 administration of an apioid wherein the route of administration is selected from the group consistilng of ititravet'tous, intratnusGUlar, intraperitonCal, transrxxucosal, transdernnal, arid oral administration in a standard or entexically coated pzeparation.
The method fartreating opioid-?induced side effects, iTtcluding dysphoria, pruritus, urinary retention, inhibition of gut motility and constipation, comprises administering methylnaltxexone 25 or entxrically coated methylnaltr~cone, or other quaternary derivatives of noroxymoxphorte, to a patient after the oxi~t of the side effect, wherein the route of adruinistxatioxs is selected frarn the group consisting of intravenous, intramuscuiar, transmucosal, tranSdermal and oral administration in a standard or enterically coated preparation.
The method fox preventizag nanopioid-induced side effects, ir~ludir:g gastrointestinal 30 dysfunction (e.g., inhibition ofgastric emptying, of,gastraintestinat motiIitity and constipation), comprises administeritxg methylnaitrexone or enteric coated methylnaltrexone, or other quaternary derivatives of rxoroxymorphone, to a patient prior to the derleloprneut of the side effecrs wherein the mute of administration is selected from the group consisting of intxavenaus, intraznuscular, transmucosal, iransdermal and oral administrzttion ixx a standard ar enterically 35 coated preparation.
The method fox trea'Cing notxopioid-induced side effects, including inhibition of gastric emptying by enteric feeding and constipation, comprises administering tnethylnaItrexone or enteric coated methylxsaltrexone, 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, transderxnal and oral adtnirustration in a standard or enterically coated preparation.
According to one embodiment, there is disclosed the use of a quaternary derivative of noroxymorphone wherein the meihylnaltxexone is provided in a formulation adapted far administration by the route selected from the group consisting of intravenous, iz~tramuscular, transtnucosal, transdermal, and oral adnninistrettion.
According to a further e;x~bodiment, there is disclosed the use of a quaternary derivative of noroxyzziorphone wherein the methylnaltrexone is provided in a, formulation adapted far la providing a dosage 0.03 to 1.0 tng/kg body weight for intravenous or intrarnuscular administration; 1.0 to 10.0 mgllcg for cransdermal administration; and 0.1 to 80.0 mglkg body weight for oral administration of n2eChylnaltrexone.
According to a further embodiment, there is disclosed the use of a quaternary derivative of noroxymorphone wherein the metlxylnaltzexone is provided in a formulation adapted for 15 administration by the route selected frono~ the group consisting of intravenous, intramuseular, transmucosal, transdertnal, and oral administr&tion.
According to a further ernbodim~ent, there is disclosed the use of a tluaternary derivative of noroxymorphone wherein the methyInaltrexone is provided in a 'formulation adapted far administration orally to provide a dosage of 0.1 to 80.0 mglkg body weight.
Accordiung to a further embodiment, there is disclosed the use of a quaternary dezivative of noroxymorphone wherein the rtiethylnaltrexane is provided in a formulation adapted to provide a dosage of about 0.1 to about 10.0 mg/ltg body weight.
According to a furtlt~er embodiment, there is disclosed tl~e use of a quaternary derivative of noroxymorphone wherein the rnethylnaltrexone is provided in a fonmulatioz~
adapted for 25 administration as an enterieally coated tablet or capsule, or as enterically coated ~anules.
According to a further embodiment, there is disclosed the use of a quatexmary derivative of noroxyrrzorphone wherein the methylnaltrexone is provided ins a formulation adapted to provide a dosage of 0, x to 40.0 xng of active drug per Itg holy weight.
According to a further embodiment, there is disclosed the use of a quaterxsary derivative 30 of noroxymorphane wherein the methylnaltrexone is adapted for administration orally to provide a dosage of about 0.1 to about 10 mg/ltg body weight.
-3a-According to a further embodiment, there is disclosed the use of a quaternary derivative of noroxymorphone wherexr~ the methyhnaltrexone is adapted for adnninistration as an enterically coated tablet or capsule, or as enterically coated granules.
According to a further embodiment, there is disclosed the use of a quaternary derivative of n~oroxymorphone wherein the quatearrtary derivative is provided in a formulation adapted for adrninistxation subsequent to the opioid.
-3b-DETAIi,~D DESCR~TI4N 4F DRA~NGS
FICi. lA is a graph ~tiag plasma. concentrations of MNTX following adminisEr~tion of 6.4 mglkg of uneoated ~NTX.
I O FTG.18 is a graph representing pias~na cozlcenirations of MN'T~ following administration of 6.4 rngJkg of enterically coated MN'f.K.
p"iG. iC is a graph xcprese~lting plasma concentrations of MN1'~ following administration of 3.2 mp~kg of enterically coated MNT~.
fiG. 2 illustrates the reversal of morphine's effect on oral-ceoal transit time following 15 administration of 6.4 mgfkg of uncoated A~1NTX. , The darker line represents the average of all points of a given treatanent.
FIG. 3 illustrates the reversal of morphine's effect on oral-cecai transit time and its decrease below baseliae ~ollo,xing administration of 6.4 mglkg of enterically coated Mbl'1~.
The darker line represents the average of all points of a giverx treatment.
24 1~iG. 4 illustrates the reversal of morphine's effect an oral-cecal transit timt following administration of 3.2 rrig/kg of entericalIy coated ivlN'f X. The darker line rep-esents the average of all points of a given treatment.
DE'T'AILED nESC~PTiGN c~F THE FNVENTiON
'fhe present invention is directed to methods ~or preventing arid treating opioid-induced dysphoria, opioid-induced pntritus, opioid-irnlttced urinary retesttion, opioid or saormpioid-induced ixshit7itioa of g~strlc emptying or inhibition of gastroi~ntestimal mobility, and opioid-or nonopioid-induced constipation. When used a5 a treatment for thtse opioid-and 3U nonopioid-i»daced side effects, orally administer8d, particularly if ernerically coated, rn~ethylnaltrexone (M~I'X) or othCr quaternary derivatives of noroxymorphone (QD~1) provides prolonged xelief of tine side e,t~'ects. RR~TfX has been demonstrated to have the ability to bIook the gastrointestinal effects of opioicls on motilify when administered intravenously or orally.
35 The oral administratfon of non-entericatly coated ~~V1 X is associated with plasma levels with an early peak (20 min) and prolonged presence (half life of a'ixaut 3 hours after single dose of 6.4 mglkg). I-Iowev~, an enteric coating on the QlrINM, 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. Suprisingly, however, 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. In fact, it has been found that as compared to non-enterically coated MNTX, a significantly lower dose, e.g., less than half the amount of coated MNTX can be used if enterically coated to achieve the same levels of relief of opioid-induced constipation. Moreover, such reduced dosage levels of MNTX administered with an enteric coating results in exceedingly low peak and sustained plasma levels of MNTX, greatly reducing the potential adverse side effects of the MNTX. This novel improvement in the clinical indication for use of MNTX has led to an increased therapeutic index for this drug.
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. MNfX 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.
Furthermore, for treatment or prevention of constipation and delayed gastrointestinal emptying, whether caused by extrinsic or endogenous opioids, 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. Thus, administration of an opioid antagonist with peripheral action, such a methylnaltrexone or other quaternary derivatives of noroxymorphone, would block the effects of endogenous opioids.
Quaternary derivatives of noroxymorphone are described in full in Goldberg et al., (supra), and in general are represented by the formula:
:H3 HO
wherein R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl, and 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-burner 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 I .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. By "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.
In accordance with the present invention, 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 I .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-I 0 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 si'nall and large bowel) ez~ances the effigy of methylnaltrexone in tl?e prevention of decreases irt gut motility by intravenously adnxeriistered opioids (morphine).
Far intravenous administration, methylnaltrexone is foxrnulsted with saline or other physiologically acceptable carriers; for iutramuscular administration, the methylnaltrexone is formulated with soling or other pharmacologically acceptable catxiers; for trar~smucosal administration the ~mtethyinaitre~tor~e is formulated with a sugar and cellulose mix ox other pharmacologically acceptable carriers known in the art; and Far oral administration, the IO nnethylnaltrexone is formulated with pharmacalogi.cally acceptable benders to make a tablet ar capsule with or without an enteric coating. Methods for such formulations are well known to those skilled in rite att_ In a preferred embodiment for the prevention andlor treatment of constipation and inflibition of gastroixltestlnal ri2otility, tire QDNM or Mt3TX is enterically coated and I S adeistered orally. For oral admiz~lstrativn, the QDNM or methylnaltrexane is forxnutated with pharznacolagically acceptable binder's to make a tablet or capsule with as enteric coating_ An enteric coating is one which remains intact during passage through the stomach, but dissolves and releases the eox~tents of the tablet or capsule once it reaches the small intestine. Most currently used enteric coatertgs axe those which will not dissolve in low pI-I
environments, but 20 readily ionize when the pH rises to about 4 or 5, for example synthetic polymers suolx as potyacids having a pICa of 3 to 5.
The enteric coating may be nude of any suitable composition. Suitable enteric coatings arc described, far example, la 1J.S_ Patent Nos. 4,311,833 to htamikoshi, et al.; 4,377,568 to Chopra; 4,385,0?8 to tJnda, et al.; 4,45?>907 to fetter; 4,462,839 to McGirtley, et al.; 4,518,433 25 to McGinley, et al.; 4,556,552 to I?otter, et al.; 4,606,909 to Bechgaard et al.; 4,f15,885 to Nakagame, et al_; 4,6?0,287 to Tsuji; 5,536,507 to Abtamowitz, et al.;
5,567,423 to "Ping; et al.;
5,591,433 to Michael, et al.; 5,59?,5fi4~ to Ying, et al.; 5,609,8'71 to Michael, et al.; 5,614,222 to Kaplan; 5,62b,875 to Rodes, et al:; and 5,629,OOI to Miclsael, et al. _ 3a ~rafe~xed era'taric casting compositions include alkyl and hydtdxyalkyl cellulases and their aliphatic esters, e.g., rnethylcellulase, ethyicell~tlose, hydraxyethylccllulose, hydroxypropylcellrxlose, hydroxybutylctllulose, hydroxyethylethytcelluIose, hydtnxyprophymethylceilulase, hydroxybmylmethylcellulose, hydmxypmpylceltulose phthalate, hydroxypropyImethylcellttlase phthalate and hydroxypropylmethylceilulose acetate succinate;
35 carboxyalicylceIluIases and their salts, e_g., rarboxymethylethylcelhtlose;
cellulose acetate phthalate; cellulose acetate trimellitxte, polycarboxyrnethylene sad its salts and derivatives;
polyvinyl alcohol and its esters: polyvinyl acetate phthalate;
polycaxba3tymethylene colsolymer with sodium formaldehyde carboxylate; acrylic polymers an~I copolymers, e.g_, methacrylic _7_ acid-zr~ethyl methaetylie acid copolymer and znethacrylic acid-methyl acrylate copolymer, edible oils suc3~ as peanut oil, palm oil, olive ail and hydrogenated vegetable oils;
polyvinylpyrrolidone;
polyethylene glycol and its esters- natural producLS such as shellac, and zero.
Other preferred entezic coatings include polyvinylacetate esters, e.g_, polyvinyl acetate gk~thalate; alkyleneglycoIethex esters of copolymers suoh as partial ethylene glycol maztomethyletlser ester of ethylacrylate-malefic azthydrida eopolyznez Qr diei3tyleneglycal monomethylether ester ofmethylac~ylate-malefic anhydride copolymer, N-butylacrylat~-mateic 1 Q anhydride copolymer, ispbutylacrylate-malefic anhydride copolymer or ethylacrylate-malefic anhydride copvlynner, and polypeptides resistant to degadation itt the gastric environment, e.g., polyarginine and polylysi~ne. Qther suitable coatings and methods to make and use such ~arnxulations ate well known to those skilled in the art (see; e_g., ~"tm~an:
The science and P>a~~ ofFhazmacy 19th ed. (1995) Mack Publishing Gotnpany, Easton, Petinsylvatua, )_ h~ixtures oftwo or rnoxe of the above corxipour~ds stray be used as desired.
The presently preferred enteric coating comprises cellulose acetate phthalate.
'1~he enteric coating tnatetial nz~ be mixed with various excipients including plasticizers such as triethyl ciliate, acetyl triethyl citrate, diethyl phthalate, tiibutyl phthalate, dibuty!
subacute, dibutyl taztrate, dlbutyl rnaleate, dibutyl succinaze and diethyl suecinate and inert Tiers such as chalk or pigmctrts.
The composition atsd thiclcrtess of the enteric coating xnay be selected to dissolve immnedistely upon contact with the digestive ~uiee of the intestine.
~,Iternatively, the composition and thickness ofthe exterioz coating tnay be selected to be a time-release coating which dissolves over' a selected period of tithe, as is well known in the art.
The amount of enteric coating depends on the particular enteric coating, composition used and is pxeferably suftlcient to substantially prevent the absorption of QDM'N
or lvlin the stoxrzach.
T-Iydm~cyaikyl celluloses atui their aliphatic esters, earboxyalicyl celluloses and their salts, polycarboxymethylene and its salts and derivatives, polyvinyl ~leoboi and its esters, polycarboxymethylene copolymer with sodium forrtxaldehyde carboxylates, poly vitlylpywolidone, and polyethylene glycol and its esters can ba applied as enteric coatings by fizst dzssolvir~ the compound in a mirximum amount of water_ Alcohoj is then added to the point of incipient cloudiness- T3te mixture can then be applied by eartvex~tioxsal techniques.
.Application of cellulose acetate phthalate may be accomp3islaed by sitttply dissolving tt;e cellulose acetate phthalate in a miz5imutn amount of aIcohai and then applyiag by conventional techniques. I~ydrogenated vegetable oils tnay be applied by first dissolving tl~e oiI in a minimal amount of a non-polyrriex solvent, such as methyiene chloride, chloroform or carbon .g-tetrachloride, then adding alcohol to the point of incipient cloudiness and then applying by conventional techniques.
In a particularly preferred embodiment, the MNTX is coated with Eudragit L100 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.
Any art-known transdermal application may be used, but 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.
In the above description, 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.
Ten 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. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. Subsequent to the onset of the pruritus, 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.
In 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.
All the patients exhibited pruritus as a side effect of the morphine sulfate administration. A
placebo, saline at a volume equivalent to the volume administered to patients receiving active drug, was administered intravenously to each of the patients. Only 50% of the patients exhibited relief from the pruritus within sixty minutes.
The study indicates that methylnaltrexone was effective in treating pruritus induced by morphine sulfate.
EFFICACY OF ENTERIC COATING OF METHYLNALTREXONE
S 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 -70 minutes, methylnaltrexone blocked this effect, and enteric coated methylnaltrexone blocked the effect to a similar or greater extent than the uncoated methylnaltrexone.
ENHANCEMENT OF ENTERIC FEEDING
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 SOcc to 100cc, or 22.0-58.8% of administered feedings measured every 4 hours 20 during a 24 hour control period. Prior to drug administration the residual volume had increased to 260 cc or > 100% of previous feeding volume. Methylnaltrexone, 0.45 mg/kg, was administered intravenously every 4 hours for 24 hours, after the control period. After the first dose (4 hours) of MNTX, the residual was 1 SOcc 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 SOcc 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.
After initiation of Methylnaltrexone, 0.45 mg/kg, administered intravenously every 4 hours, the first residual (4 hrs) was Occ, the second residual (8 hrs)was 24cc or 15% of previous bolus feed.
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).
In a double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone to decrease subjective effects after administering morphine to IO normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on "nauseous", "skin itch", "stimulated", and "flushing".
Compared to baseline, significant increases were obtained on "nauseous", "Skin itch", "stimulated", and "flushing" ratings after placebo and morphine administration (P < 0.05, P < 0.05, P < 0.01 and P < 0.01, respectively). Oral methylnaltrexone (19.2 mg/kg) significantly decreased these four ratings (P < 0.05, P < 0.05, P < 0.01 and P < 0.01, respectively) compared to placebo and morphine and resulted in no change when compared to baseline.
Plasma methylnaltrexone concentrations were also measured and correlation between pharmacological effects of the compound and its plasma levels was shown. Our results indicate that methylnaltrexone decreases dysphoria and some other undesirable subjective effects associated with opioid medications.
EFFECTS OF ENTERICALLY COATED MNTX ON ORAL-CECAL TRANSIT
TIME AND PLASMA LEVELS OF MNTX
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, and Group E
received enterically coated MNTX at 3.2 mg/kg active drug. Table 1 shows the treatments for each group.
'x"A:BLE 1 Grou Treatment combination 'FIG.
A placebo placebo ~ morphine (D.C?5placebo Fig.
C mglkg) methylnaltrexone uncoated 2 17 xnotphme (0.05 (b.4 m~lkgj mgllc~ methylnaltxexone er~teri.c Fig.
ICI morphine (0.05 coated (5.4 mglkg 3 mg/kg) methylnaltrexone enteric coatedFig.
mozphine (D.OS (3.2 mgllsg 4 mg/kg) active dru Plasma levels of MNTX were measured following administration of morphine and MNTX ox placebo several times over the duration of the six hour monitoring period, at the times 15 shown in F'ICr. I . Measurements of plasma arid urine MNTX levels were determined by high performance liquid chromatography (IIfLC) using the trxodiFxed method originally reported by iC.izn et al. (I9S9) Chromatographic 28:359-63 ).
Methylnaltrexone was separated from plasma by sand phase extraction (Sp~).
Plasma samples (I 00-Sb0 p.l) diluted in Water mith the interltat standard (naittexone) were passed through SPE
Zp columns. Prior to use, the columns were conditioned by methanol and washed with water. The analytes were eluted from the columns by the mixture of n-propanol and trifluoroaeetio acid (ZS
mM) aqueous solution pregaxed in 2_I proportion. The eluate was evaporated to dryness in a stream of nitrogen at 55°C. The residue was reconstituted in the 17~.obile phase, filtered through a nylon HPLC syrixrge filter arid subjected to PLC analysis. A Shimadzu Corporation (Kyoto, 'i 5 Japan) HPLC system was used. It consisted of the LC-I OAD purttp, SCI~lOA
system cvrstroller, and SIIrI4A auto injector equipped with sample cooler. Used kIPLC Analytical Column rtxade by Phenouienex (prodigy C8, Torrance, CA). The ele~ctr~claemical detector (ESA. Coulochem, model SIDDA) worked aithe following sett~gs: detector 1, -f-3bU mV, detector 2 ~6DD mV, guard cell n-65D mV. Data were collected with the use of ~ZChrom 2-2 Hl'LC software.
The mobile phase consisted of 50 naM sodium acetate, 7.5% methanol at pH 4.2. The system was calibrated daily in the range of 5 - 104 nglml (3 point caiibradon). Practical limit of detection for plasma samples was approxitxiately 2 nglml (1 (IO pg/injection).
Figure 7 shows the plasma levels of MNTX folIowirag tlae tr8atmettts in C7roups C, f3, anal E, I» Fig. I A, MNTX plastga levels in Group C (given 6.4 mglhg MNTX, uncoated) peaked at 35 about 1 S min. post Madnninistration 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 mglkg MhITX in an enterically coated formulation, exhibited a constant low plasma level of MNT'~~
(undez IO ngltnl) for the duration; of observation (see PIG. II3). Group E, given 3.2 mglkg MN'1~' in an enterieally Coated fortrtulatian, showed plasma levels ofMNTX
over the course of obsexvatiozl that were undetectable or at the lower limit of detection of tile assay (see FTG. 1 C}.
C?ral-cecaI transit time was used as a measure of gut motility and propensity For constipation. Oral-cecal transit time was measured by the lactulnse-bzeath hydrogen method.
Group A demonstc'ated noxrnal trapsit times as previously described in the literature (Yuan et al (I99f>} Clip. Pharmacol. "her. 5'x:469-475; Yuan et al. (1997) Clip Pharmacal.
"her. 51:46?-475 ). t3raup >3 had prolongation ofthelr oral-cecaI transit times by 50-i00°rb, white Groups C (FIG. 2} and E {F1G. 4} had their transit times return to baseline levels, rxroup 1~ showed an obvious decrease in oral-cecal transit time (FIG. 3}.
As demonstrated in FIGS. 1-4, enterically coated MN'f~ provides the therapeutic effects on gastrointestinal motility of uncoated MNTX, but requires a lower dose of active drug and results in significantly reduced plasnsa levels of >,rrifTX.. Patiexits provided with a dose of 6.4 I 5 mglkg of uncoated IvIN'TX had gut rrtotility return to baseline follawang morphine administration (FIG_ 2) and showed plasma Mi~TI'~ levels of over 44 ng M1V'fXlml, while patients given tire same dose in an enterically coated formulation showed oral-cecal transit ties be ow baseline levels (FxG. 3) and plasma ~TI~X levels under 10 nglznl. EntericaIly coated formulations of MNT~ with one half the dose of active drug {3.2 txxglkg} were required to return oral-cecal transit times to normal without increasing gut motility. At this dosage, plasma levels of Ml~'fX
ware negligible.
As with most drugs, it is desirable to maintain the lowest possible systemic levels of MNTX which are suf~cisnt to provide the desired therapeutic effect. p'or example, elevated circulating levels of ~ can rtsult in drthostatie liypotension. Tkre present discovery 2S provides an unexpected nneans to avoid such undesirable drug side effects by lowering the dose admiriistered acrd subsegu~tlyminirn~izing Circulating levels ofthe drug.
Since endogenous and externally supplied apioid-induced inhibition of gastrointestinal motility and constipation is thought to result from opioid receptors located within tire gastrointestinal tract, enterically coated MNT X or other QDI~Ms may pmvide a local administration of the drug that does not require a circulating level for effective prevention ax treatrnen# of symptoms. Thus, the amount and~or frequency of drug admfnistered can be reduced.
'1"he preceding, descriptioxt and Examples are intended to be illustrative.
Those skilled in 2lxe art to which the invention pertaizts will appreciate that alterations and changes in the described protocols may be practiced without departing from the meaning, spirit, and scope of this invention. Therefore, the foregoing description should be read consistent wittz and as support to the following Claims, whlcll are to have their fullest and fair scope.
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-burner 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 I .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. By "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.
In accordance with the present invention, 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 I .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-I 0 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 si'nall and large bowel) ez~ances the effigy of methylnaltrexone in tl?e prevention of decreases irt gut motility by intravenously adnxeriistered opioids (morphine).
Far intravenous administration, methylnaltrexone is foxrnulsted with saline or other physiologically acceptable carriers; for iutramuscular administration, the methylnaltrexone is formulated with soling or other pharmacologically acceptable catxiers; for trar~smucosal administration the ~mtethyinaitre~tor~e is formulated with a sugar and cellulose mix ox other pharmacologically acceptable carriers known in the art; and Far oral administration, the IO nnethylnaltrexone is formulated with pharmacalogi.cally acceptable benders to make a tablet ar capsule with or without an enteric coating. Methods for such formulations are well known to those skilled in rite att_ In a preferred embodiment for the prevention andlor treatment of constipation and inflibition of gastroixltestlnal ri2otility, tire QDNM or Mt3TX is enterically coated and I S adeistered orally. For oral admiz~lstrativn, the QDNM or methylnaltrexane is forxnutated with pharznacolagically acceptable binder's to make a tablet or capsule with as enteric coating_ An enteric coating is one which remains intact during passage through the stomach, but dissolves and releases the eox~tents of the tablet or capsule once it reaches the small intestine. Most currently used enteric coatertgs axe those which will not dissolve in low pI-I
environments, but 20 readily ionize when the pH rises to about 4 or 5, for example synthetic polymers suolx as potyacids having a pICa of 3 to 5.
The enteric coating may be nude of any suitable composition. Suitable enteric coatings arc described, far example, la 1J.S_ Patent Nos. 4,311,833 to htamikoshi, et al.; 4,377,568 to Chopra; 4,385,0?8 to tJnda, et al.; 4,45?>907 to fetter; 4,462,839 to McGirtley, et al.; 4,518,433 25 to McGinley, et al.; 4,556,552 to I?otter, et al.; 4,606,909 to Bechgaard et al.; 4,f15,885 to Nakagame, et al_; 4,6?0,287 to Tsuji; 5,536,507 to Abtamowitz, et al.;
5,567,423 to "Ping; et al.;
5,591,433 to Michael, et al.; 5,59?,5fi4~ to Ying, et al.; 5,609,8'71 to Michael, et al.; 5,614,222 to Kaplan; 5,62b,875 to Rodes, et al:; and 5,629,OOI to Miclsael, et al. _ 3a ~rafe~xed era'taric casting compositions include alkyl and hydtdxyalkyl cellulases and their aliphatic esters, e.g., rnethylcellulase, ethyicell~tlose, hydraxyethylccllulose, hydroxypropylcellrxlose, hydroxybutylctllulose, hydroxyethylethytcelluIose, hydtnxyprophymethylceilulase, hydroxybmylmethylcellulose, hydmxypmpylceltulose phthalate, hydroxypropyImethylcellttlase phthalate and hydroxypropylmethylceilulose acetate succinate;
35 carboxyalicylceIluIases and their salts, e_g., rarboxymethylethylcelhtlose;
cellulose acetate phthalate; cellulose acetate trimellitxte, polycarboxyrnethylene sad its salts and derivatives;
polyvinyl alcohol and its esters: polyvinyl acetate phthalate;
polycaxba3tymethylene colsolymer with sodium formaldehyde carboxylate; acrylic polymers an~I copolymers, e.g_, methacrylic _7_ acid-zr~ethyl methaetylie acid copolymer and znethacrylic acid-methyl acrylate copolymer, edible oils suc3~ as peanut oil, palm oil, olive ail and hydrogenated vegetable oils;
polyvinylpyrrolidone;
polyethylene glycol and its esters- natural producLS such as shellac, and zero.
Other preferred entezic coatings include polyvinylacetate esters, e.g_, polyvinyl acetate gk~thalate; alkyleneglycoIethex esters of copolymers suoh as partial ethylene glycol maztomethyletlser ester of ethylacrylate-malefic azthydrida eopolyznez Qr diei3tyleneglycal monomethylether ester ofmethylac~ylate-malefic anhydride copolymer, N-butylacrylat~-mateic 1 Q anhydride copolymer, ispbutylacrylate-malefic anhydride copolymer or ethylacrylate-malefic anhydride copvlynner, and polypeptides resistant to degadation itt the gastric environment, e.g., polyarginine and polylysi~ne. Qther suitable coatings and methods to make and use such ~arnxulations ate well known to those skilled in the art (see; e_g., ~"tm~an:
The science and P>a~~ ofFhazmacy 19th ed. (1995) Mack Publishing Gotnpany, Easton, Petinsylvatua, )_ h~ixtures oftwo or rnoxe of the above corxipour~ds stray be used as desired.
The presently preferred enteric coating comprises cellulose acetate phthalate.
'1~he enteric coating tnatetial nz~ be mixed with various excipients including plasticizers such as triethyl ciliate, acetyl triethyl citrate, diethyl phthalate, tiibutyl phthalate, dibuty!
subacute, dibutyl taztrate, dlbutyl rnaleate, dibutyl succinaze and diethyl suecinate and inert Tiers such as chalk or pigmctrts.
The composition atsd thiclcrtess of the enteric coating xnay be selected to dissolve immnedistely upon contact with the digestive ~uiee of the intestine.
~,Iternatively, the composition and thickness ofthe exterioz coating tnay be selected to be a time-release coating which dissolves over' a selected period of tithe, as is well known in the art.
The amount of enteric coating depends on the particular enteric coating, composition used and is pxeferably suftlcient to substantially prevent the absorption of QDM'N
or lvlin the stoxrzach.
T-Iydm~cyaikyl celluloses atui their aliphatic esters, earboxyalicyl celluloses and their salts, polycarboxymethylene and its salts and derivatives, polyvinyl ~leoboi and its esters, polycarboxymethylene copolymer with sodium forrtxaldehyde carboxylates, poly vitlylpywolidone, and polyethylene glycol and its esters can ba applied as enteric coatings by fizst dzssolvir~ the compound in a mirximum amount of water_ Alcohoj is then added to the point of incipient cloudiness- T3te mixture can then be applied by eartvex~tioxsal techniques.
.Application of cellulose acetate phthalate may be accomp3islaed by sitttply dissolving tt;e cellulose acetate phthalate in a miz5imutn amount of aIcohai and then applyiag by conventional techniques. I~ydrogenated vegetable oils tnay be applied by first dissolving tl~e oiI in a minimal amount of a non-polyrriex solvent, such as methyiene chloride, chloroform or carbon .g-tetrachloride, then adding alcohol to the point of incipient cloudiness and then applying by conventional techniques.
In a particularly preferred embodiment, the MNTX is coated with Eudragit L100 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.
Any art-known transdermal application may be used, but 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.
In the above description, 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.
Ten 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. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. Subsequent to the onset of the pruritus, 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.
In 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.
All the patients exhibited pruritus as a side effect of the morphine sulfate administration. A
placebo, saline at a volume equivalent to the volume administered to patients receiving active drug, was administered intravenously to each of the patients. Only 50% of the patients exhibited relief from the pruritus within sixty minutes.
The study indicates that methylnaltrexone was effective in treating pruritus induced by morphine sulfate.
EFFICACY OF ENTERIC COATING OF METHYLNALTREXONE
S 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 -70 minutes, methylnaltrexone blocked this effect, and enteric coated methylnaltrexone blocked the effect to a similar or greater extent than the uncoated methylnaltrexone.
ENHANCEMENT OF ENTERIC FEEDING
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 SOcc to 100cc, or 22.0-58.8% of administered feedings measured every 4 hours 20 during a 24 hour control period. Prior to drug administration the residual volume had increased to 260 cc or > 100% of previous feeding volume. Methylnaltrexone, 0.45 mg/kg, was administered intravenously every 4 hours for 24 hours, after the control period. After the first dose (4 hours) of MNTX, the residual was 1 SOcc 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 SOcc 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.
After initiation of Methylnaltrexone, 0.45 mg/kg, administered intravenously every 4 hours, the first residual (4 hrs) was Occ, the second residual (8 hrs)was 24cc or 15% of previous bolus feed.
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).
In a double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone to decrease subjective effects after administering morphine to IO normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on "nauseous", "skin itch", "stimulated", and "flushing".
Compared to baseline, significant increases were obtained on "nauseous", "Skin itch", "stimulated", and "flushing" ratings after placebo and morphine administration (P < 0.05, P < 0.05, P < 0.01 and P < 0.01, respectively). Oral methylnaltrexone (19.2 mg/kg) significantly decreased these four ratings (P < 0.05, P < 0.05, P < 0.01 and P < 0.01, respectively) compared to placebo and morphine and resulted in no change when compared to baseline.
Plasma methylnaltrexone concentrations were also measured and correlation between pharmacological effects of the compound and its plasma levels was shown. Our results indicate that methylnaltrexone decreases dysphoria and some other undesirable subjective effects associated with opioid medications.
EFFECTS OF ENTERICALLY COATED MNTX ON ORAL-CECAL TRANSIT
TIME AND PLASMA LEVELS OF MNTX
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, and Group E
received enterically coated MNTX at 3.2 mg/kg active drug. Table 1 shows the treatments for each group.
'x"A:BLE 1 Grou Treatment combination 'FIG.
A placebo placebo ~ morphine (D.C?5placebo Fig.
C mglkg) methylnaltrexone uncoated 2 17 xnotphme (0.05 (b.4 m~lkgj mgllc~ methylnaltxexone er~teri.c Fig.
ICI morphine (0.05 coated (5.4 mglkg 3 mg/kg) methylnaltrexone enteric coatedFig.
mozphine (D.OS (3.2 mgllsg 4 mg/kg) active dru Plasma levels of MNTX were measured following administration of morphine and MNTX ox placebo several times over the duration of the six hour monitoring period, at the times 15 shown in F'ICr. I . Measurements of plasma arid urine MNTX levels were determined by high performance liquid chromatography (IIfLC) using the trxodiFxed method originally reported by iC.izn et al. (I9S9) Chromatographic 28:359-63 ).
Methylnaltrexone was separated from plasma by sand phase extraction (Sp~).
Plasma samples (I 00-Sb0 p.l) diluted in Water mith the interltat standard (naittexone) were passed through SPE
Zp columns. Prior to use, the columns were conditioned by methanol and washed with water. The analytes were eluted from the columns by the mixture of n-propanol and trifluoroaeetio acid (ZS
mM) aqueous solution pregaxed in 2_I proportion. The eluate was evaporated to dryness in a stream of nitrogen at 55°C. The residue was reconstituted in the 17~.obile phase, filtered through a nylon HPLC syrixrge filter arid subjected to PLC analysis. A Shimadzu Corporation (Kyoto, 'i 5 Japan) HPLC system was used. It consisted of the LC-I OAD purttp, SCI~lOA
system cvrstroller, and SIIrI4A auto injector equipped with sample cooler. Used kIPLC Analytical Column rtxade by Phenouienex (prodigy C8, Torrance, CA). The ele~ctr~claemical detector (ESA. Coulochem, model SIDDA) worked aithe following sett~gs: detector 1, -f-3bU mV, detector 2 ~6DD mV, guard cell n-65D mV. Data were collected with the use of ~ZChrom 2-2 Hl'LC software.
The mobile phase consisted of 50 naM sodium acetate, 7.5% methanol at pH 4.2. The system was calibrated daily in the range of 5 - 104 nglml (3 point caiibradon). Practical limit of detection for plasma samples was approxitxiately 2 nglml (1 (IO pg/injection).
Figure 7 shows the plasma levels of MNTX folIowirag tlae tr8atmettts in C7roups C, f3, anal E, I» Fig. I A, MNTX plastga levels in Group C (given 6.4 mglhg MNTX, uncoated) peaked at 35 about 1 S min. post Madnninistration 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 mglkg MhITX in an enterically coated formulation, exhibited a constant low plasma level of MNT'~~
(undez IO ngltnl) for the duration; of observation (see PIG. II3). Group E, given 3.2 mglkg MN'1~' in an enterieally Coated fortrtulatian, showed plasma levels ofMNTX
over the course of obsexvatiozl that were undetectable or at the lower limit of detection of tile assay (see FTG. 1 C}.
C?ral-cecaI transit time was used as a measure of gut motility and propensity For constipation. Oral-cecal transit time was measured by the lactulnse-bzeath hydrogen method.
Group A demonstc'ated noxrnal trapsit times as previously described in the literature (Yuan et al (I99f>} Clip. Pharmacol. "her. 5'x:469-475; Yuan et al. (1997) Clip Pharmacal.
"her. 51:46?-475 ). t3raup >3 had prolongation ofthelr oral-cecaI transit times by 50-i00°rb, white Groups C (FIG. 2} and E {F1G. 4} had their transit times return to baseline levels, rxroup 1~ showed an obvious decrease in oral-cecal transit time (FIG. 3}.
As demonstrated in FIGS. 1-4, enterically coated MN'f~ provides the therapeutic effects on gastrointestinal motility of uncoated MNTX, but requires a lower dose of active drug and results in significantly reduced plasnsa levels of >,rrifTX.. Patiexits provided with a dose of 6.4 I 5 mglkg of uncoated IvIN'TX had gut rrtotility return to baseline follawang morphine administration (FIG_ 2) and showed plasma Mi~TI'~ levels of over 44 ng M1V'fXlml, while patients given tire same dose in an enterically coated formulation showed oral-cecal transit ties be ow baseline levels (FxG. 3) and plasma ~TI~X levels under 10 nglznl. EntericaIly coated formulations of MNT~ with one half the dose of active drug {3.2 txxglkg} were required to return oral-cecal transit times to normal without increasing gut motility. At this dosage, plasma levels of Ml~'fX
ware negligible.
As with most drugs, it is desirable to maintain the lowest possible systemic levels of MNTX which are suf~cisnt to provide the desired therapeutic effect. p'or example, elevated circulating levels of ~ can rtsult in drthostatie liypotension. Tkre present discovery 2S provides an unexpected nneans to avoid such undesirable drug side effects by lowering the dose admiriistered acrd subsegu~tlyminirn~izing Circulating levels ofthe drug.
Since endogenous and externally supplied apioid-induced inhibition of gastrointestinal motility and constipation is thought to result from opioid receptors located within tire gastrointestinal tract, enterically coated MNT X or other QDI~Ms may pmvide a local administration of the drug that does not require a circulating level for effective prevention ax treatrnen# of symptoms. Thus, the amount and~or frequency of drug admfnistered can be reduced.
'1"he preceding, descriptioxt and Examples are intended to be illustrative.
Those skilled in 2lxe art to which the invention pertaizts will appreciate that alterations and changes in the described protocols may be practiced without departing from the meaning, spirit, and scope of this invention. Therefore, the foregoing description should be read consistent wittz and as support to the following Claims, whlcll are to have their fullest and fair scope.
Claims (100)
1. The use of a quaternary derivative of noroxymorphone prior to the administration of an opioid to prevent opioid induced side effects in a patient, the side effect selected from the group consisting of dysphoria, pruritus, and urinary retention.
2. The use of a quaternary derivative of noroxymorphone subsequent to the administration of an opioid to treat opioid induced side effects in a patient, the side effect selected from the group consisting of dysphoria, pruritus, and urinary retention.
3. The use of a quaternary derivative of noroxymorphone according to claim 1 or 2 wherein the quaternary derivative is methylnaltrexone.
4. The use of a quaternary derivative of noroxymorphone according to claim 1, 2, or 3 wherein the side effect is dysphoria.
5. The use of a quaternary derivative of noroxymorphone according to claim 1, 2, or 3 wherein the side effect is pruritus.
6. The use of a quaternary derivative of noroxymorphone according to claim 1, 2, or 3 wherein the side effect is urinary retention.
7. The use of a quaternary derivative of noroxymorphone according to claim 3 wherein the methylnaltrexone is provided in a formulation adapted for administration by the route selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal, and oral administration.
8. The use of a quaternary derivative of noroxymorphone according to claim 1, 2, or 3 wherein the quaternary derivative is coated with an enteric coating.
9. The use of a quaternary derivative of noroxymorphone according to claim 3 wherein the methylnaltrexone is provided in a formulation adapted for providing a dosage 0.03 to 1.0 mg/kg body weight for intravenous or intramuscular administration; 1.0 to 10.0 mg/kg for transdermal administration; and 0.1 to 80.0 mg/kg body weight for oral administration of methylnaltrexone.
10. The use of a quaternary derivative of noroxymorphone according to claim 3 wherein the methylnaltrexone is administered orally as an enterically coated tablet at a dosage of about 0.1 to about 40 mg/kg body weight.
11. The use of a quaternary derivative of noroxymorphone, prior to the onset of nonopioid induced gastrointestinal dysfunction, to prevent nonopioid induced gastrointestinal dysfunction in a patient.
12. The use of a quaternary derivative of noroxymorphone, after the onset of nonopioid induced gastrointestinal dysfunction, to treat nonopioid induced gastrointestinal dysfunction in a patient.
13. The use of a quaternary derivative of noroxymorphone according to claim 11 or 12 wherein the quaternary derivative is methylnaltrexone.
14. The use of a quaternary derivative of noroxymorphone according to claim 11 or 12 wherein the gastrointestinal dysfunction is selected from the group consisting of inhibition of gastric emptying and constipation.
15. The use of a quaternary derivative of noroxymorphone according to claim 13 wherein the methylnaltrexone is provided in a formulation adapted for administration by the route selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal, and oral administration.
16. The use of a quaternary derivative of noroxymorphone according to claim 13 wherein the methylnaltrexone is provided in a formulation adapted for administration orally to provide a dosage of 0.1 to 80.0 mg/kg body weight.
17. The use of a quaternary- derivative of noroxymorphone according to claim 11, 12, or 13 wherein the quaternary derivative is formulated as a tablet and the tablet is coated with an enteric coating.
18. The use of an orally administered, enterically coated, quaternary derivative of noroxymorphone prior to administration of an opioid to prevent opioid induced inhibition of gastrointestinal motility in a patient, wherein substantially no quaternary derivative is released in the stomach.
19. The use of a quaternary derivative of noroxymorphone according to claim 18 wherein the quaternary derivative is methylnaltrexone.
20. The use of a quaternary derivative of noroxymorphone according to claim 18 or 19 wherein the inhibition of gastrointestinal motility is manifested as constipation.
21. The use of a quaternary derivative of noroxymorphone according to claim 19 wherein the methylnaltrexone is provided in a formulation adapted to provide a dosage of about 0.1 to about 10.0 mg/kg body weight.
22. The use of a quaternary derivative of noroxymorphone according to claim 19 wherein the methylnaltrexone is provided in a formulation adapted for administration as an enterically coated tablet or capsule, or as enterically coated granules.
23. The use of a quaternary derivative of noroxymorphone according to claim 19 wherein the patient's plasma level of methylnaltrexone remains below 50 ng/ml.
24. The use of an orally administered, enterically coated, quaternary derivative of noroxymorphone subsequent to administration of an opioid to treat opioid induced inhibition of gastrointestinal motility in a patient, wherein substantially no quaternary derivative is released in the stomach.
25. The use of a quaternary derivative of noroxymorphone according to claim 24 wherein the quaternary derivative is methylnaltrexone.
26. The use of a quaternary derivative of noroxymorphone according to claim 24 or 25 wherein the inhibition of gastrointestinal motility is manifested as constipation.
27. The use of a quaternary derivative of noroxymorphone according to claim 25 wherein the patient's plasma level of methylnaltrexone remains below 50 ng/ml.
28. The use of a quaternary derivative of noroxymorphone according to claim 25 wherein the methylnaltrexone is provided in a formulation adapted to provide a dosage of 0.1 to 40.0 mg of active drug per kg body weight.
29. The use of a quaternary derivative of noroxymorphone according to claim 25 wherein the methylnaltrexone is adapted for administration orally to provide a dosage of about 0.1 to about 10 mg/kg body weight.
30. The use of a quaternary derivative of noroxymorphone according to claim 25 wherein the methylnaltrexone is adapted for administration as an enterically coated tablet or capsule, or as enterically coated granules.
31. The use of an orally administered, enterically coated, quaternary derivative of noroxymorphone to treat opioid induced inhibition of gastrointestinal motility in a patient, wherein the inhibition of gastrointestinal motility is induced by endogenous opioids.
32. The use of a quaternary derivative of noroxymorphone according to claim 19 wherein the enteric coating provides time release of the methylnaltrexone.
33. The use of an enterically coated quaternary derivative of noroxymorphone to formulate a composition for preventing or treating opioid induced inhibition of gastrointestinal motility which when orally administered to a patient releases substantially no quaternary derivative in the stomach and induces peak and sustained plasma levels of the quaternary derivative that are substantially lower than such levels would be with the same dose of quaternary derivative that is non-enterically coated.
34. The use of a quaternary derivative of noroxymorphone according to claim 33 wherein the composition is in the form of a pill, tablet, capsule, or granules.
35. The use of a quaternary derivative of noroxyroorphone according to claim 33 wherein the quaternary derivative of noroxymorphone is methylnaltrexone.
36. The use of a quaternary derivative of noroxymorphone according to claim 18 or 24 wherein the patient's peak and sustained plasma levels of the quaternary derivative are below about 50 ng/ml.
37. The use of a quaternary derivative of noroxymorphone according to claim 18 or 24, wherein the patient's peak blood plasma levels are lower than they would be if 10% or more of the same dose of quaternary derivative were released in the stomach and the rest was released enterically.
38. The use of an orally administered, enterically coated, quaternary derivative of noroxymorphone to treat or prevent opioid induced inhibition of gastrointestinal motility in a patient, wherein the patient's peak plasma levels of the quaternary derivative do not exceed about 50 ng/ml.
39. The use of a quaternary derivative of noroxymorphone according to claim 38 wherein the patient's peak plasma levels of the quaternary derivative do not exceed about 40 ng/ml.
40. The use of a quaternary derivative of noroxymorphone according to claim 38 wherein the patient's peak plasma levels of the quaternary derivative do not exceed about 30 ng/ml.
41. The use of a quaternary derivative of noroxymorphone according to claim 38 wherein the patient's peak plasma levels of the quaternary derivative do not exceed about 20 ng/ml.
42. The use of a quaternary derivative of noroxymorphone according to claim 38 wherein the patient's peak plasma levels of the quaternary derivative do not exceed about 10 ng/ml.
43. The use of a quaternary derivative of noroxymorphone according to claim 38 wherein the patient's peak plasma levels of the quaternary derivative do not exceed about 2 ng/
ml.
ml.
44. The use of a quaternary derivative of noroxymmorphone to prevent idiopathic constipation in a patient.
45. The use of a quaternary derivative of noroxymorphone to treat idiopathic constipation in a patient.
46. The use of a quaternary derivative according to claim 44 or 45 wherein the quaternary derivative is methylnaltrexone.
47. The use of a quaternary derivative of noroxymorphone to treat inhibition of gastrointestinal motility in a patient, wherein the inhibition of gastrointestinal motility is induced by an endogenous opioid.
48. The use of a quaternary derivative of noroxymorphone according to claim 47, wherein the quaternary derivative is methylnaltrexone.
49. The use of a quaternary derivative of noroxymorphone to prevent inhibition of gastrointestinal motility in a patient receiving an opioid for pain resulting from surgery.
50. The use of a quaternary derivative of methylnaltrexone to treat inhibition of gastrointestinal motility in a patient receiving an opioid for pain resulting from surgery.
51. The use of a quaternary derivative of noroxymorphone according to claim 49 or 50, wherein the quaternary derivative is methylnaltrexone.
52. The use of a quaternary derivative of noroxymorphone according to claim 49 or 50, wherein the quaternary derivative is provided in a formulation adapted for administration subsequent to the opioid.
53. Use of a quaternary derivative of noroxymorphone for the manufacture of a medicament for treating or preventing opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention.
54. A use as claimed in claim 53, wherein the medicament is for administration to a patient;
a) prior to the administration of an opioid and the use is for preventing opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention; or b) subsequent to administration of an opioid and the use is for treating opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention.
a) prior to the administration of an opioid and the use is for preventing opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention; or b) subsequent to administration of an opioid and the use is for treating opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention.
55. Use of a quaternary derivative of noroxymorphone for the manufacture of a medicament for preventing or treating non-opioid induced gastrointestinal dysfunction, administration of the medicament to a patient being prior to or after the onset of gastrointestinal dysfunction.
56. A use as claimed in claim 55, wherein the gastrointestinal dysfunction is gastric emptying or constipation.
57. Use of a quaternary derivative of noroxymorphone for the manufacture of a medicament for treating or preventing non-opioid induced inhibition of gastric emptying, non-opioid induced inhibition of gastrointestinal motility or non-opioid induced constipation.
58. A use as claimed in claim 57, wherein the medicament is for treating or preventing idiopathic constipation.
59. A use as claimed in claim 57, wherein the medicament is for treating inhibition of gastrointestinal motility induced by an endogenous opioid.
60. A use as claimed in claim 57, wherein the medicament is for treating or preventing inhibition of gastrointestinal motility caused by abdominal surgery, inflammation or excessive vagal stimulation.
61. A use according to any one of claims 53 through 60, wherein the medicament is administrable by a route selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal, and oral administration.
62. A use according to any one of claims 53 through 61, wherein the quaternary derivative of noroxymorphone is coated with an enteric coating.
63. A use as claimed in claim 62, wherein the quaternary derivative of noroxymorphone is formulated as a tablet and the tablet is coated with an enteric coating.
64. A use according to any one of claims 53 through 63, wherein the quaternary derivative of noroxymorphone is methylnaltrexone.
65. A use as claimed in claim 64, wherein the medicament is formulated to provide a methylnaltrexone dosage of 0.03 to 1.0mg/kg body weight by intravenous or intramuscular administration, 1.2 to 10.0mg/kg by transdermal administration or 0.1 to 80mg/kg body weight by oral administration.
66. A use as claimed in claim 64, wherein the medicament is formulated to provide methylnaltrexone in tablet form at a dosage of 0.1 to 40.0mg/kg body weight.
67. Use of methylnaltrexone for the manufacture of a medicament for use in a method of treating or preventing opioid induced inhibition of gastric emptying, opioid induced inhibition of gastrointestinal motility, or opioid induced constipation in a patient, wherein the patient's plasma level of methylnaltrexone remains below 25 mg/ml.
68. An enterically coated derivative of noroxymorphone.
69. An enterically coated derivative of noroxymorphone as claimed in claim 68, wherein the derivative of noroxymorphone is formulated in a tablet or capsule with an enteric coating.
70. An enterically coated derivative of noroxymorphone as claimed in claim 68 or 69, for use in treating or preventing gastrointestinal dysfunction, opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention.
71. An enterically coated derivative of noroxymorphone as claimed in any one of claims 68 through 70, wherein the derivative of noroxymorphone is methylnaltrexone.
72. An enterically coated derivative of noroxymorphone as claimed in claim 71.
formulated to provide a patient plasma level of methylnaltrexone of below 25 ng/ml.
formulated to provide a patient plasma level of methylnaltrexone of below 25 ng/ml.
73. An enterically coated derivative of noroxymorphone as claimed in claim 71, formulated to provide an oral dose of 0.1 to 10 mg/kg body weight.
74. An enterically coated derivative of noroxymorphone as claimed in any one of claims 68 through 73, wherein the enteric coating dissolves substantially immediately upon contact with the digestive juice of the intestine, or is a time release coating.
75. Use of a quarternary derivative of noroxymorphone for treating or preventing non-opioid induced inhibition of gastric emptying, non-opioid induced inhibition of gastrointestinal motility or non-opioid induced constipation.
76. A use as claimed in claim 75 for treating or preventing idiopathic constipation.
77. A use as claimed in claim 75 for treating inhibition of gastrointestinal motility induced by an endogenous opioid.
78. A use as claimed in claim 75 for treating or preventing inhibition of gastrointestinal motility caused by abdominal surgery, inflammation or excessive vagal stimulation.
79. A use according to any one of claims 75 through 78, wherein the quaternary derivative of noroxymorphone is coated with an enteric coating.
80. The use according to any one of claims 75 through 78, wherein the quaternary derivative of noroxymorphone is formulated as a tablet and the tablet is coated with an enteric coating.
81. A use according to any one of claims 75 to 78 wherein the quarternary derivative of noroxymorphone is methylnaltrexone.
82. Use of methylnaltrexone for treating or preventing opioid-induced inhibition of gastric emptying, opioid-induced inhibition of gastrointestinal motility, or opioid-induced constipation in a patient, wherein the patient's plasma level of methylnaltrexone remains below 25 mg/ml.
83. A pharmaceutical preparation for oral administration comprising an enterically coated derivative of noroxymorphone wherein the pharmaceutical preparation releases substantially no quarternary derivative in the stomach.
84. The pharmaceutical preparation as claimed in claim 83, wherein the derivative of noroxymorphone is formulated in a tablet or capsule with an enteric coating.
85. The pharmaceutical preparation as claimed in claim 83 or 84, for use in treating or preventing gastrointestinal dysfunction, opioid induced dysphoria, opioid induced pruritus or opioid induced urinary retention.
86. The pharmaceutical preparation as claimed in any one of claims 83 through 85, wherein the derivative of noroxymorphone is methylnaltrexone.
87. The pharmaceutical preparation as claimed in claim 86, formulated to provide a patient plasma level of methylnaltrexone of below 25 ng/ml.
88. The pharmaceutical preparation as claimed in claim 86, formulated to provide an oral dose of 0.1 to 10 mg/kg body weight.
89. The pharmaceutical preparation as claimed in any one of claims 83 through 88, wherein the enteric coating dissolves substantially immediately upon contact with the digestive juice of the intestine, or is a time release coating.
90. Use of a quaternary derivative of noroxymorphone for the manufacture of a medicament for treatment or prevention of non-opioid induced inhibition of gastrointestinal motility caused by abdominal surgery.
91. Use of a quarternary derivative of noroxymorphone for treatment or prevention of non-opioid induced inhibition of gastrointestinal motility caused by abdominal surgery.
92. A quaternary derivative of noroxymorphone for use in the manufacture of a medicament for treatment or prevention of non-opioid induced inhibition of gastrointestinal motility caused by abdominal surgery.
93. A quaternary derivative of noroxymorphone for use in treatment or prevention of non-opioid induced inhibition of gastrointestinal motility caused by abdominal surgery.
94. Use of a quaternary derivative of noroxymorphone for the manufacture of a medicament for treatment or prevention of inhibition of gastrointestinal motility induced by an endogenous opioid.
95. Use of a quaternary derivative of noroxymorphone for treatment or prevention of inhibition of gastrointestinal motility induced by an endogenous opioid.
96. A quaternary derivative of noroxymorphone for use in the manufacture of a medicament for treatment or prevention of inhibition of gastrointestinal motility induced by an endogenous opioid.
97. A quaternary derivative of noroxymorphone for use in treatment or prevention of inhibition of gastrointestinal motility induced by an endogenous opioid.
98. The use according to any one of claims 75 through 78, wherein the quaternary derivative of noroxymorphone is in a formulation suitable for administration by a route selected from the group consisting of intravenous, intramuscular, transmucosal, transdermal and oral administration.
99. The use according to any one of claims 90, 91, 94, 95 and 98, wherein the quaternary derivative of noroxymorphone is methylnaltrexone.
100. The derivative of any one of claims 92, 93, 96 and 97, wherein the derivative of noroxymorphone is methylnaltrexone.
Applications Claiming Priority (5)
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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 | 1998-07-22 | ||
| US09/120,703 US6274591B1 (en) | 1997-11-03 | 1998-07-22 | Use of methylnaltrexone and related compounds |
| PCT/US1998/023485 WO1999022737A1 (en) | 1997-11-03 | 1998-11-03 | Use of methylnaltrexone and related compounds |
Publications (2)
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| CA2312234A1 CA2312234A1 (en) | 1999-05-14 |
| CA2312234C true CA2312234C (en) | 2005-03-22 |
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|---|---|---|---|
| CA002312234A Expired - Lifetime CA2312234C (en) | 1997-11-03 | 1998-11-03 | Use of methylnaltrexone and related compounds |
Country Status (5)
| Country | Link |
|---|---|
| US (6) | US6274591B1 (en) |
| EP (1) | EP1047426B1 (en) |
| AU (1) | AU758416B2 (en) |
| CA (1) | CA2312234C (en) |
| WO (1) | WO1999022737A1 (en) |
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| US8772310B2 (en) | 2007-03-29 | 2014-07-08 | 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 |
| US8916706B2 (en) | 2008-02-06 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
| US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| 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 |
| US9180125B2 (en) | 2008-09-30 | 2015-11-10 | 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1047426A4 (en) | 2004-07-14 |
| CA2312234A1 (en) | 1999-05-14 |
| US20040162308A1 (en) | 2004-08-19 |
| US20020028825A1 (en) | 2002-03-07 |
| US20090312359A1 (en) | 2009-12-17 |
| US6608075B2 (en) | 2003-08-19 |
| WO1999022737A1 (en) | 1999-05-14 |
| US20030065003A1 (en) | 2003-04-03 |
| EP1047426B1 (en) | 2010-05-12 |
| US20050048117A1 (en) | 2005-03-03 |
| US6274591B1 (en) | 2001-08-14 |
| EP1047426A1 (en) | 2000-11-02 |
| AU1380299A (en) | 1999-05-24 |
| AU758416B2 (en) | 2003-03-20 |
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