WO1997007750A1 - Administration de ketamine pour gerer la douleur et reduire la dependance aux medicaments - Google Patents

Administration de ketamine pour gerer la douleur et reduire la dependance aux medicaments Download PDF

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Publication number
WO1997007750A1
WO1997007750A1 PCT/US1996/014095 US9614095W WO9707750A1 WO 1997007750 A1 WO1997007750 A1 WO 1997007750A1 US 9614095 W US9614095 W US 9614095W WO 9707750 A1 WO9707750 A1 WO 9707750A1
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pain
ketamine
administration
dose
transmucosal
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PCT/US1996/014095
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English (en)
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Stuart L. Weg
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Weg Stuart L
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Priority to CA002230690A priority Critical patent/CA2230690C/fr
Priority to US09/029,146 priority patent/US6248789B1/en
Priority to JP9510636A priority patent/JPH11511466A/ja
Publication of WO1997007750A1 publication Critical patent/WO1997007750A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the management of chronic pain without requiring administration of narcotics, or by synergizing with narcotics to allow for a lower effective narcotic dose.
  • the invention also relates to self-management of pain on an outpatient basis.
  • Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is a general anesthetic used by anesthesiologists, veterinarians, and researchers. Usually, ketamine is administered intramuscularly (i.m.) or intravenously (i.v.) for induction of anesthesia. Presently, only ketamine for injection is available for administration (Physician's Desk Reference) . Nasal administration of ketamine, in one instance with midazolam, for an ophthalmic procedure, and prior to elective surgery in healthy children, has been reported (Louon et al., 1993, Br. J. Ophthalmol. 77:529-530; Weksler et al., 1 993, Can. J. Anaesthesia 40:1 19-121 ).
  • Ketamine has also been known to have analgesic properties (Domino et al., 1965, Clin. Pharmacol. Ther. 6:279); analgesia can be achieved with subanesthetic doses of ketamine (Bovill, 1971 , Br. J. Anaesth. 43:496; Sadove et al., 1 971 , Anesth. Analg. 50:452-457) .
  • the drug is administered by various routes, including i.v., i.m., caudal, intrathecal, and subcutaneous (s.c).
  • Subcutaneous administration of ketamine has been used to treat pain following surgery and associated with terminal cancer (see, e.g. , Oshima et al., 1990, Can.
  • Ketamine hydrochloride administered via a subcutaneous cannula was reported to successfully treat phantom limb pain (Stannard and Porter, 1993, Pain 54:227-230) .
  • the first line of treatment usually involves administration of ⁇ -opioid agonists, e.g. , narcotics such as morphine (see, e.g. , Anderson and Brill, 1 992, Semin. Anesth. 1 1 : 1 58-171 ) .
  • narcotics such as morphine
  • morphine see, e.g. , Anderson and Brill, 1 992, Semin. Anesth. 1 1 : 1 58-171
  • Ineffective pain management is a consequence of lack of training, and of fear of narcotics on the part of patients, the medical personnel, and society in general. Children, because of their natural reticence and budding communication skills combined with a greater fear of over-administering "dangerous" narcotics particularly suffer from under treatment for pain.
  • NMDA N-methyl-D-aspartate
  • pain management involves administration of a plethora of drugs, such as narcotics, agonist-antagonist agents, butorphanols, benzodiazepines, GABA stimulators, barbiturates, barbiturate-like drugs, orally, e.g., in a pill or liquid formulation, or by i.v. or i.m. injection.
  • drugs such as narcotics, agonist-antagonist agents, butorphanols, benzodiazepines, GABA stimulators, barbiturates, barbiturate-like drugs, orally, e.g., in a pill or liquid formulation, or by i.v. or i.m. injection.
  • Opioid agonists and antagonists may be combined.
  • a combination of drugs can have offsetting effects. More problematic is the possibility of adverse side effects, particularly gastric distress that accompanies oral administration, or the fear that injections can inspire.
  • a patient suffering from chronic pain will require medication to control stomach and other gastric problems as a result of oral administration of drugs.
  • Alternatives to oral self-administration for most of the analgesic and sedative medications for the treatment of chronic pain are not common, can be cumbersome (e.g., i.v. or s.c. administration requires use of a cannula or needle), and generally require medical training.
  • U.S. Patent No. 4,671 ,953 describes the administration of sedative, analgesic or sedative drugs in a candy matrix, such that the drug enters the bloodstream through the oral mucosal membranes.
  • this method suffers from the disadvantage that a sedated patient may fall asleep with the candy remaining in his or her mouth, which can result in choking.
  • administration of the candy must be medically supervised.
  • the candy is simply unsuitable for everyday use, as sucking on a lollipop is an unseemly practice for an employee or business person.
  • administration is under the control of the patient suffering from pain, i.e. , on an outpatient basis, the potential for overdosing or abuse exists, particularly with respect to narcotics.
  • ketamine can surprisingly be administered nasally to alleviate pain safely and effectively, in conjunction with or independently of other pain management regimens.
  • the present invention is broadly directed to a method for treating pain in a subject comprising administering via a transmucosal route a dose of ketamine effective to alleviate pain to a subject suffering from pain.
  • administration of ketamine can be via transbuccal, sublingual, vaginal, and rectal routes.
  • the pain-relieving effects of the present invention can be accomplished by administration via oral administration (via the gastrointestinal tract, rather than the oral-pharyngeal mucosa).
  • the present invention provides for pulmonary administration of ketamine by inhalation.
  • the invention provides an effective pain-relieving dose of ketamine by transdermal administration.
  • Administration of an analgesic dose of ketamine advantageously allows for patient self administration of the drug, which provides for pain management on an outpatient basis.
  • ketamine administration via transmucosal and transdermal delivery are generally socially acceptable.
  • Transmucosal administration of ketamine is rapid, allowing for fast action of the drug.
  • both transmucosal and transdermal administration are easily accomplished by a non-medically trained patient.
  • the present invention is based, in part, on the discovery that high levels of analgesia can be achieved with small doses of ketamine, particularly ketamine administered by a transmucosal route (e.g., transbuccal, sublingual, vaginal, and rectal), or by a transdermal route.
  • transmucosal route e.g., transbuccal, sublingual, vaginal, and rectal
  • effective pain treatment is better achieved by establishing small doses via transdermal or transmucosal delivery, and that these routes of administration avoid side effects associated with a bolus dose of ketamine delivered i.v. or i.m. administration.
  • a small transmucosal or transdermal dose of ketamine can be administered more frequently, which achieves
  • the present invention further advantageously provides for outpatient treatment of episodic and breakthrough pain conditions, which are not amenable to treatment with i.v. or i.m. bolus administration of the drug because of the need for medical intervention for these procedures./
  • the present invention contemplates using ketamine synergistically with a traditional pain relief medication, preferably a narcotic pain reliever.
  • ketamine can be administered in combination with a lower dose of a second pain relief drug, preferably a narcotic, than would otherwise be indicated for the condition if used alone.
  • the invention contemplates administration of ketamine transmucosally, more preferably, nasally.
  • the present invention provides for pulmonary administration of ketamine by inhalation. Where a patient's condition prevents nasal administration of ketamine, ocular administration, using, e.g., ketamine drops, can be substituted.
  • the invention contemplates transdermal administration as well.
  • the invention contemplates oral administration (via the gastrointestinal tract, rather than the oral-pharyngeal mucosa), and parenteral administration, e.g., intravenous, intraarterial, intraperitoneal, intradermal, intramuscular, intraventricular, or subcutaneous.
  • parenteral administration e.g., intravenous, intraarterial, intraperitoneal, intradermal, intramuscular, intraventricular, or subcutaneous.
  • the second pain medication can be administered via the same route as ketamine, where appropriate, or via a different route, e.g. , orally while the ketamine is administered transdermally or transbucally.
  • ketamine administration to manage pain on top of an ongoing pain management regimen involving other medications allows for reduction over time of the other analgesic, particularly a narcotic analgesic.
  • other analgesic particularly a narcotic analgesic.
  • ketamine administration provides the added benefit of reducing drug, particularly narcotic, dependency of individuals who are suffering from a pain condition.
  • the present invention advantageously provides for treatment of drug dependency developed as a result of medical treatment (rather than drug abuse, for example) .
  • Pain therapy on an outpatient basis advantageously reduces the demands on hospital services, results in a substantial decrease in the cost of treatment, and provides the patient with a more normal living and working environment, which can positively affect treatment outcome.
  • reduction in dependency on other pain medications, particularly narcotics can further reduce the need for medical intervention and the cost of treatment.
  • Another advantage of the invention is that it avoids or reduces the need to administer narcotic agents for the treatment of chronic pain.
  • narcotics can lose effectiveness due to tolerance or resistance. Narcotics are also highly addictive.
  • narcotics induce side effects such as nausea, constipation, dizziness, etc., in proportion to dosage.
  • another advantage of the present invention is that it helps avoid adverse side effects of administration of narcotics.
  • ketamine is an inexpensive, readily available drug, with minor adverse side effects, especially when administered in small doses transmucosally, transdermally, or orally.
  • the invention contemplates additional savings to the overburdened health care system.
  • the pain-alleviating dose of ketamine is approximately 0.01 to approximately 1 mg/kg of body weight. In a more preferred aspect, the dose of ketamine is approximately 0.05 to approximately 0.7 mg/kg of body weight. In another embodiment, the total dose of ketamine per nasal administration ranges from about 1 to about 30 mg.
  • the dose of ketamine is effective to alleviate breakthrough pain in a patient suffering from a chronic pain condition.
  • the dose of ketamine is effective to alleviate breakthrough pain associated with labor, particularly transition labor.
  • nasal administration of ketamine is effective for treating migraine headache pain.
  • administration of ketamine can be a supplemental therapy in a pain management regimen that includes administration of one or more of narcotics, analgesics, and sedatives, e.g., as described above.
  • a further advantage of the instant invention is that it avoids dosing a patient with dysphoric or hallucinogenic amounts of ketamine by providing only an analgesic dose, which is well below the level associated with dysphoria or hallucination. Thus, it avoids the need to administer a dysphoria-suppressive drug, such as a benzodiazepine.
  • the present invention contemplates administering a lower dose of a narcotic analgesic than would be effective taken alone to alleviate pain with the ketamine; preferably the narcotic analgesic is administered via the mucosal or transdermal route with the ketamine.
  • the invention provides various pharmaceutical carriers for patient self- administration of ketamine.
  • examples of such carriers include, but are not limited to, a suppository, a gum, a candy or lozenge; other carriers include a transbuccal patch and a transdermal patch.
  • an object of the invention to provide for self administration of a safe, non- narcotic drug for outpatient treatment of pain.
  • Yet a further object of the invention is to provide a device that can be used outside a hospital or medical office by non-medical personnel for nasal self administration of ketamine.
  • One aspect of the invention provides for transmucosal, transdermal, or oral administration of ketamine for the treatment of pain.
  • the invention provides a method and device for patient self administration of ketamine for pain management.
  • the invention can alleviate pain from many causes, including but not limited to shock; limb amputation; severe chemical or thermal burn injury; sprains, ligament tears, fractures, wounds and other tissue injuries; dental surgery, procedures and maladies; labor and delivery; migraine; during physical therapy; post operative pain; radiation poisoning; cancer; acquired immunodeficiency syndrome (AIDS); epidural (or peridural) fibrosis; failed back surgery and failed laminectomy; sciatica; painful sickle cell crisis; arthritis; autoimmune disease; intractable bladder pain; and the like.
  • Mucosal administration of ketamine is also amenable to hospice use, particularly hospices that specialize in the care of cancer and AIDS patients.
  • the present invention is particularly effective for the treatment of intractible pain, whatever its cause.
  • transmucosal, transdermal, or oral administration of ketamine can relieve or alleviate episodes of acute breakthrough pain that can occur in a chronic pain condition.
  • administration of ketamine via any route can be used as an adjunct therapy to a conventional treatment regimen for a chronic pain condition to alleviate breakthrough pain.
  • a particular advantage of the present invention for reducing labor and delivery pain is that ketamine in low doses is not known to have significant adverse effects on the fetus.
  • transmucosal, transdermal, or oral administration can be used as an adjunct or directly to treat an acute asthma attack. Since unrelated pain conditions can induce asthma, the present invention advantageously provides for alleviating pain, thus blocking the cause of the attack.
  • ketamine in contrast to narcotic pain medications is a bronchodilator.
  • transmucosal, transdermal, or oral administration of ketamine can be used in the treatment of acute nausea. Rectal or transdermal ketamine is particularly suitable for this condition, as nausea precludes the use of oral medications.
  • rectal or transdermal ketamine can alleviate pain that may be causing the nausea, and can alleviate the abdominal pain that frequently accompanies sever nausea, without stimulating gag responses or involving oral or nasal passages.
  • transmucosal, transdermal, or oral administration of ketamine can be used to treat acute agitation, for example, agitation exhibited by an alcohol or drug intoxicated individual, or by a person placed under arrest by the police.
  • transmucosal, transdermal, or oral ketamine may be useful in the treatment of shock resulting from severe injuries.
  • shock resulting from severe injuries.
  • the present invention is based on the surprising and unexpected discovery that transmucosal administration of ketamine can alleviate symptoms of chronic pain.
  • infra a patient suffering from intractable bladder pain, and taking a variety of narcotics, analgesics, and sedatives in an unsuccessful attempt to control the pain, was able to achieve more satisfactory pain management by nasal administration of 16-32 mg of ketamine, corresponding to about 0.2-0.6 mg/kg of body weight.
  • a dosage of 1 6-32 mg corresponds to 0.27- 0.53 mg/kg of body weight.
  • the dosage was effective for about 1 5 minutes to about 1 hour for alleviating pain.
  • the patient was able to reduce the amount of a oral pain medications, which had caused gastric distress.
  • the present invention is directed to methods for alleviating chronic or breakthrough pain on an outpatient basis by transmucosal, transdermal, or oral administration of ketamine, and to devices usable by non-medical personnel for transmucosal, transdermal, or oral self-administration of ketamine.
  • Ketamine will preferably be prepared in a formulation or pharmaceutical composition appropriate for transmucosal, transdermal, or oral administration. Suitable formulations are discussed in detail, infra. In a further embodiment, ketamine can be formulated with a mucosal or dermal penetration enhancer to facilitate delivery of the drug. The formulation can also be prepared with pH optimized for solubility, drug stability, absorption through mucosa or skin, and other considerations.
  • the invention provides for administration of a therapeutically effective dose of ketamine, i.e. , a dose effective to alleviate pain, or to facilitate reduction in dependence on other pain medications, particularly narcotic medications.
  • a therapeutically effective dose of ketamine i.e. , a dose effective to alleviate pain, or to facilitate reduction in dependence on other pain medications, particularly narcotic medications.
  • the actual dose will vary, depending on the body weight of the patient, the severity of the pain, the route of administration, the nature of medications administered concurrently, the number of doses to be administered per day, and other factors generally considered by the ordinary skilled physician in the administration of drugs.
  • the amount of ketamine administered to a patient suffering from chronic pain is about 10% to about 20% of the amount used to induce anesthesia.
  • the dose of ketamine is about 0.01 mg per kg of body weight (0.01 mg/kg) to about 1 mg/kg; preferably about 0.05 mg/kg to about 0.7 mg/kg. In yet another embodiment, the dose ranges from about 1 mg to about 30 mg.
  • the effective dose is titrated under the supervision of a physician or medical care provider, so that the optimum dose for the particular application is accurately determined.
  • the present invention provides a dose suited to each individual patient.
  • a further advantage of the invention is that the patient can administer ketamine on an as-needed, dose-to-effect basis.
  • the frequency of administration is under control of the patient.
  • the relatively low dose with each administration will reduce the possibilities for abuse.
  • Yet another particular advantage of the present invention is that transmucosal, transdermal, or oral administration of ketamine is non-invasive, and provides for introduction into the bloodstream almost as fast as i.v. administration.
  • transmucosal, transdermal, or oral administration provides for precise control over the dosage and effect of the drug used to offset changes in activity and pain levels throughout a day.
  • Transmucosal, transdermal, or oral administration of ketamine optimally provides for dose-to-effect administration of the drug.
  • the patient can safely administer an amount of drug effective to alleviate pain by controlling the amount and frequency of administration of a formulation according to the invention.
  • Safe patient regulated control of pain medication is an important advantage because pain is such a subjective condition.
  • the advantage is two-fold here, as the patient can effectively alleviate pain, and the power to alleviate the pain will have significant psychological benefits.
  • a positive psychological attitude can significantly improve the course and outcome of a treatment regimen, as well as making the entire process more bearable to the patient.
  • ketamine which is not itself addictive, surprisingly acts synergistically with other pain therapies, particularly pain medications, and especially narcotics.
  • administration of ketamine allows for reduction of the levels of other pain medications, particularly narcotics, with associated savings in cost and avoidance of addiction.
  • ketamine refers to ketamine [(2-o-chlorophenyl)-2-(methylamino)-cyclohexanone], pharmaceutically acceptable salts thereof, and biologically equivalent derivatives and analogs thereof, e.g. , ketamine aspartate, ketamine succinate, etc.
  • ketamine refers to ketamine hydrochloride.
  • Other names for ketamine include ketaject, ketalar, ketanest, ketaset, ketalar, calypos, and feldeross.
  • isomers and enantiomers thereof that demonstrate analgesic properties, e.g., with greater potency or fewer side effects, or both.
  • mucosal refers to a tissue comprising a mucous membranes, such as the nasal mucosa pulmonary mucosa, oral-pharyngeal mucosa, stomach and intestines, rectal mucosa, and vaginal mucosa.
  • transmucosal in all its grammatical forms refers to administration of a drug through the mucous membrane to the bloodstream for systemic delivery of the drug.
  • transdermal in all its grammatical forms refers to administration of a drug through the skin to the bloodstream for systemic delivery of the drug.
  • oral refers to administration of a drug through the mouth and into the stomach or intestines, or both.
  • transmucosal, transdermal, and oral administration for drug delivery are that they do not require injection using a syringe and needle, they avoid necrosis that can accompany i.m. administration of drugs, and all three are highly amenable to self administration.
  • microcosal penetration enhancer refers to a reagent that increases the rate or facility of transmucosal penetration of ketamine, such as but not limited to, a bile salt, fatty acid, surfactant, or alcohol.
  • the permeation enhancer can be sodium cholate, sodium dodecyl sulphate, sodium deoxycholate, taurodeoxycholate, sodium glycocholate, dimethylsulfoxide or ethanol.
  • Suitable penetration enhancers also include glycyrrhetinic acid (U.S. Patent No.
  • polysorbate-80 the latter preferably in combination with an non-ionic surfactant such as nonoxynol-9, laureth-9, poloxamer-124, octoxynol-9, or lauramide- DEA (European Patent EP 0 242 643 B1 by Stoltz) .
  • an non-ionic surfactant such as nonoxynol-9, laureth-9, poloxamer-124, octoxynol-9, or lauramide- DEA (European Patent EP 0 242 643 B1 by Stoltz) .
  • a “therapeutically effective amount” of a drug is an amount effective to demonstrate a desired activity of the drug.
  • a therapeutically effective amount of ketamine is an amount effective to alleviate, i.e. , noticeably reduce, pain in a patient.
  • a therapeutically effective amount is an amount effective to act synergistically with another pain therapy, e.g. , a pain medication such as a narcotic.
  • a pain medication such as a narcotic.
  • the synergistic activity of ketamine co- administration is reflected by reduced dependency on the other pain therapy, particularly a narcotic analgesic, without reducing, and preferably enhancing, the level of pain relief.
  • the term "pharmaceutically acceptable” refers to a biologically or pharmacologically compatible for in vivo use, and preferably means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • breakthrough pain is used herein in accordance with its usual meaning in pain treatment. For example, breakthrough pain can refer to pain experienced by a subject receiving treatment for pain, but who experiences a level of pain that is not treatable by the current treatment regimen. "Spike pain” is an acute form of breakthrough pain. Usually medications or therapies for chronic pain do not provide adequate relief for breakthrough pain, either because the maximum pain relief effects of these regimens have been achieved, because of tolerance to medications that has developed, or because the treatment is not fast enough.
  • a subject in whom administration of ketamine is an effective therapeutic regimen for management of pain, or for synergism with alternative pain therapy is preferably a human, but can be any animal.
  • the methods and devices of the present invention are particularly suited to administration of ketamine to any animal, particularly a mammal, and including, but by no means limited to, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., i.e. , for veterinary medical use.
  • rectal administration or transdermal administration are convenient and allow for minimal aggravation or irritation of the animal.
  • the present invention is directed inter alia to transmucosal administration of ketamine.
  • Initial studies have demonstrated that nasal administration of ketamine, either via the nasal mucosa or pulmonary inhalation and absorption via pulmonary mucosa, is higly effective for the treatment of pain. Subsequently, it has been discovered that other routes of transmucosal administration of ketamine are also effective for treatment of pain, as set forth above.
  • transmucosal administration of ketamine allows for effective pharmacokinetics with low doses of the drug, thus avoiding dysphoria or other side effects associated with bolus i.v. or i.m. dosing.
  • Transmucosal ketamine is particularly indicated for breakthrough and spike pain, e.g. , as described in greater detail above.
  • any transmucosal route of administration including but not limited to rectal, oral, vaginal, buccal, etc.
  • the present invention is directed to the following transmucosal routes of administration.
  • any of the transmucosal routes of administration may be enhanced by use of a mucosal penetration enhancer, e.g. , as described supra.
  • the selection of a particular mucosal penetration enhancer may depend on the characteristics of the specific mucosa. These factors are addressed in greater detail below.
  • ketamine is formulated in a matrix suitable for rectal (or vaginal) insertion, i.e. , in a suppository.
  • the invention is not limited to any particular suppository formulation. Indeed, many suppository formulations are known in the art, e.g, as described in Remington's Pharmaceutical Sciences, Physician's Desk Reference, and U.S. Pharmacopeia.
  • Administration via suppositories may be preferred in certain situations, e.g. , because convention and custom prefers it, or where nasal administration is deemed unacceptable.
  • ketamine can be formulated in a buccal patch for administration via the interior of the cheek. It may be appreciated that a buccal patch constitutes another form of transmucosal administration.
  • the technology for preparing buccal patch formulations is known in the art, e.g. , Remington 's Pharmaceutical Sciences, supra.
  • ketamine can be formulated for oral-pharyngeal, including sublingual and transbuccal, administration.
  • ketamine can be incorporated in a "candy" matrix, such as that described in U.S. Patent No. 4,671 ,953, in a gum base, or a lozenge.
  • the ketamine can be formulated in a capsule or pill form for sublingual placement.
  • ketamine for oral-pharyngeal administration may be formulated with a flavor masking agent or coating.
  • flavor masking agents for use with oral pharmaceuticals are known in the art, and can be selected for use with the present invention.
  • ketamine can be formulated for oral administration via the stomach and intestinal mucosa.
  • ketamine can be administered in a carrier designed for drug release in either the stomach (an acidic environment), or the intestines, or both.
  • Many capsules, pills, and matrices for oral administration of a drug are known in the art, and can be selected on the basis of compatibility with ketamine, and the desired point and rate of drug release by the ordinary skilled physician.
  • Oral administration of ketamine may require higher dosages than other routes of administration to overcome the effects of first pass metabolism by the liver.
  • the present invention is directed to transdermal administration of ketamine. It has been discovered that transdermal administration of ketamine is also effective for treatment of pain, as set forth above, for many of the same reasons transmucosal administration is effective. In particular, it has surprisingly been discovered that transdermal administration of ketamine allows for effective pharmacokinetics with low doses of the drug, thus avoiding dysphoria or other side effects associated with bolus i.v. or i.m. dosing. Transdermal ketamine is particularly indicated for breakthrough and spike pain, e.g., as described in greater detail above.
  • Transdermal patches are described in, for example, U.S. Patent No. 5,407,713, issued April 18, 1995 to Rolando et al.; U.S. Patent No. 5,352,456, issued October 4, 1004 to Fallon et al.; U.S. Patent No.
  • a transdermal route of administration may be enhanced by use of a dermal penetration enhancer, e.g., such as enhancers described in U.S. Patent No. 5,164, 1 89 [supra), U.S. Patent No. 5,008, 1 10 (supra), and U.S. Patent No. 4,879, 1 1 9, issued November 7, 1989 to Aruga et al., the disclosure of each of which is incorporated herein by reference in its entirety.
  • a dermal penetration enhancer e.g., such as enhancers described in U.S. Patent No. 5,164, 1 89 [supra), U.S. Patent No. 5,008, 1 10 (supra), and U.S. Patent No. 4,879, 1 1 9, issued November 7, 1989 to Aruga et al., the disclosure of each of which is incorporated herein by reference in its entirety.
  • the present invention is directed to administration of ketamine via any route, including parenteral administration in addition to transmucosal, transdermal, and oral administration.
  • parenteral administration of ketamine can be effected to synergistically treat pain with other pain therapies.
  • Alternate pain therapies include non-pharmaceutical treatments, such as but not limited to, chiropractic medicine, acupuncture, biofeedback, and other alternative therapies.
  • the synergistic effects of ketamine administration are reflected by reduced dependency on other pain therapies, or by an reduction in the level of pain experienced, or both.
  • This aspect of the invention is based on the surprising discovery that ketamine allows for a reduction over time of narcotic analgesics. Such a reduction over time runs counter to the normal course of pain treatment, where progressively larger doses of analgesics, particularly narcotic analgesics, are required to overcome tolerance.
  • Parenteral administration generally refers to intravenous injection, and also includes, but is not limited to, intra-arteriole, intramuscular, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration.
  • the ketamine can be delivered in a vesicle, in particular a liposome (see Langer, 1 990, Science 249: 1 527-1 533; Treat et al., 1 989, in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.) , Liss: New York, pp. 353-365; Lopez-Berestein, ibid, pp. 317-327; see generally ibid) .
  • this may be a preferred method for introducing ketamine.
  • ketamine may be delivered in a controlled release system.
  • ketamine may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of sustained release administration.
  • a pump may be used (see Langer, supra; Se ton, 1 987, CRC Crit. Ref. Biomed. Eng. 14:201 ; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321 :574).
  • polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York ( 1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 ; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351 ; Howard et al., 1989, J. Neurosurg. 71 : 105).
  • Ketamine (10 mg/cc) drip was administered i.v. over one hour, for a total dose of 40 mg ketamine. This resulted in reduction of the pain level by a factor of 2 (from #20 to about #10-1 2) as subjectively evaluated by the patient. About 1 hour after ketamine infusion was discontinued, the patient reported that the level of pain had increased to about #1 5, and thereafter rapidly to its previous level. The patient continued to take the other pain medications without effect.
  • a 5 ml bottle containing 100 mg/ml ketamine solution was prepared.
  • a single spray from the bottle delivered approximately 1 /6 ml of solution, i.e. , 16 mg of ketamine.
  • the patient was instructed to self- administer 1 -2 sprays from the bottle for severe pain.
  • the nasal spray bottle was prepared in order to provide sustainable pain medication on an outpatient basis.
  • the patient has demonstrated remarkable pain management with nasal administration of ketamine.
  • Nasal ketamine has been particulariy effective for control of breakthrough pain.
  • the patient has decreased the amount of the other pain medications.

Abstract

Procédé de gestion de la douleur qui ne nécessite pas l'administration de narcotiques ou en permet la réduction, et de gestion personnelle de la douleur sur la base de consultations externes. La présente invention concerne donc, de manière générale, un procédé de traitement de la douleur chez un sujet, qui consiste à administrer à travers les muqueuses, par voie percutanée ou orale une dose de kétamine efficace pour soulager la douleur chez un sujet qui y est en proie. Le présente invention concerne en outre un procédé de traitement synergique de la douleur chez un sujet, qui consiste à administrer, par une voie quelconque, une dose de kétamine efficace pour permettre la réduction des substances administrées dans le cadre de la thérapie de lutte contre la douleur en cours, ou pour réduire la douleur (améliorer le niveau de soulagement de la douleur), ou les deux. L'administration par les muqueuses, percutanée ou orale de kétamine permet avantageusement au patient de s'administrer lui-même le médicament, ce qui conduit à une gestion de la douleur sur la base de consultations externes. De plus, l'administration de kétamine par des dispositifs percutanés (suppositoires, pastilles, timbres buccaux) est en général socialement acceptable. Dans un exemple spécifique, un patient souffrant de douleurs rebelles de la vessie a pu lutter contre l'apparition des douleurs par administration à travers les muqueuses (nasale) d'environ 16 à environ 32 mg de kétamine par dose.
PCT/US1996/014095 1995-08-30 1996-08-29 Administration de ketamine pour gerer la douleur et reduire la dependance aux medicaments WO1997007750A1 (fr)

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CA002230690A CA2230690C (fr) 1995-08-30 1996-08-29 Administration de ketamine pour gerer la douleur et reduire la dependance aux medicaments
US09/029,146 US6248789B1 (en) 1996-08-29 1996-08-29 Administration of ketamine to manage pain and to reduce drug dependency
JP9510636A JPH11511466A (ja) 1995-08-30 1996-08-29 苦痛を管理しおよび薬物依存性を軽減するための、ケタミンの投与

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US294695P 1995-08-30 1995-08-30
US60/002,946 1995-08-30

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EP1103256A1 (fr) * 1999-11-26 2001-05-30 Claudius Dr. med. Böck Utilisation de la kétamine pour le traitement de la dysfonction immunitaire neuroendocrine et du psyhosyndrome algogénique
DE10025946A1 (de) * 2000-05-26 2001-11-29 Gruenenthal Gmbh Wirkstoffkombination
WO2004045601A1 (fr) * 2002-11-18 2004-06-03 Yaupon Therapeutics, Inc. Utilisations analgesiques de norketamine et de promedicaments de ketamine/norketamine
WO2004087209A1 (fr) * 2003-03-27 2004-10-14 Hisamitsu Pharmaceutical Co., Inc. Preparation pour assurer une concentration sanguine therapeutiquement efficace d'un potentialisateur d'activite analgesique
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
WO2013056229A1 (fr) * 2011-10-14 2013-04-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Utilisation de (2r, 6r)-hydroxynorkétamine, (s)-déshydronorkétamine et autres métabolites déshydro et hydroxylés stéréo-isomères de (r,s)-kétamine dans le traitement de la dépression et de la douleur neuropathique
WO2014020155A1 (fr) * 2012-08-02 2014-02-06 Clinpharm Reform Gmbh Formes d'administration transmuqueuse orale de kétamine s
US9963435B2 (en) 2016-08-31 2018-05-08 Dart Neuroscience, Llc Compounds for therapeutic use
WO2019137381A1 (fr) * 2018-01-10 2019-07-18 Xw Laboratories, Inc. Promédicaments à base de kétamine, compositions et utilisations de ceux-ci
US10858394B2 (en) 2017-08-17 2020-12-08 Xw Laboratories Inc. Preparation and uses of reactive oxygen species scavenger derivatives
US10869844B2 (en) 2014-09-15 2020-12-22 Janssen Pharmaceutica Nv Methods for the treatment of depression
US10889572B2 (en) 2017-09-04 2021-01-12 Xw Laboratories Inc. Reactive oxygen species scavengers and use for treating diseases
US11191734B2 (en) * 2015-06-27 2021-12-07 Shenox Pharmaceuticals, Llc Ketamine transdermal delivery system
US11446260B2 (en) 2013-03-15 2022-09-20 Janssen Pharmaceutica Nv Pharmaceutical composition of S-ketamine hydrochloride
US11690811B2 (en) 2021-08-13 2023-07-04 XWPharma Ltd. Pharmaceutical compositions and oral dosage forms of ketamine derivatives
US11707440B2 (en) 2017-12-22 2023-07-25 Janssen Pharmaceuticals, Inc. Esketamine for the treatment of depression
US11883526B2 (en) 2019-03-05 2024-01-30 Janssen Pharmaceutica Nv Esketamine for the treatment of depression
US11980596B2 (en) 2020-12-15 2024-05-14 Janssen Pharmaceutica Nv Delivery of esketamine for the treatment of depression

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Publication number Priority date Publication date Assignee Title
EP1103256A1 (fr) * 1999-11-26 2001-05-30 Claudius Dr. med. Böck Utilisation de la kétamine pour le traitement de la dysfonction immunitaire neuroendocrine et du psyhosyndrome algogénique
DE10025946A1 (de) * 2000-05-26 2001-11-29 Gruenenthal Gmbh Wirkstoffkombination
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
WO2004045601A1 (fr) * 2002-11-18 2004-06-03 Yaupon Therapeutics, Inc. Utilisations analgesiques de norketamine et de promedicaments de ketamine/norketamine
EP2027854A1 (fr) * 2002-11-18 2009-02-25 Yaupon Therapeutics, Inc. Utilisations analgésiques pour les promédicaments à base de norkétamine et kétamine/norkétamine
WO2004087209A1 (fr) * 2003-03-27 2004-10-14 Hisamitsu Pharmaceutical Co., Inc. Preparation pour assurer une concentration sanguine therapeutiquement efficace d'un potentialisateur d'activite analgesique
WO2013056229A1 (fr) * 2011-10-14 2013-04-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Utilisation de (2r, 6r)-hydroxynorkétamine, (s)-déshydronorkétamine et autres métabolites déshydro et hydroxylés stéréo-isomères de (r,s)-kétamine dans le traitement de la dépression et de la douleur neuropathique
EP3904332A1 (fr) * 2011-10-14 2021-11-03 The United States of America, as represented by The Secretary, Department of Health and Human Services Utilisation de (2r, 6r)-hydroxynorkétamine, (s)-déshydronorkétamine et autres métabolites déshydro et hydroxylés stéréo-isomères de (r,s)-kétamine dans le traitement de la dépression et de la douleur neuropathique
US9650352B2 (en) 2011-10-14 2017-05-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of (2R, 6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain
US9867830B2 (en) 2011-10-14 2018-01-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Office Of Technology Transfer, National Institutes Of Health Use of (2R, 6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain
WO2014020155A1 (fr) * 2012-08-02 2014-02-06 Clinpharm Reform Gmbh Formes d'administration transmuqueuse orale de kétamine s
US11446260B2 (en) 2013-03-15 2022-09-20 Janssen Pharmaceutica Nv Pharmaceutical composition of S-ketamine hydrochloride
US11311500B2 (en) 2014-09-15 2022-04-26 Janssen Pharmaceutica Nv Methods for the treatment of depression
US10869844B2 (en) 2014-09-15 2020-12-22 Janssen Pharmaceutica Nv Methods for the treatment of depression
US11173134B2 (en) 2014-09-15 2021-11-16 Janssen Pharmaceutica Nv Methods for the treatment of depression
US11191734B2 (en) * 2015-06-27 2021-12-07 Shenox Pharmaceuticals, Llc Ketamine transdermal delivery system
US10738018B2 (en) 2016-08-31 2020-08-11 Dart Neuroscience, Llc Compounds for therapeutic use
US9963435B2 (en) 2016-08-31 2018-05-08 Dart Neuroscience, Llc Compounds for therapeutic use
US10858394B2 (en) 2017-08-17 2020-12-08 Xw Laboratories Inc. Preparation and uses of reactive oxygen species scavenger derivatives
US11692008B2 (en) 2017-08-17 2023-07-04 XWPharma Ltd. Preparation and uses of reactive oxygen species scavenger derivatives
US11312703B2 (en) 2017-09-04 2022-04-26 XWPharma Ltd. Reactive oxygen species scavengers and use for treating diseases
US10889572B2 (en) 2017-09-04 2021-01-12 Xw Laboratories Inc. Reactive oxygen species scavengers and use for treating diseases
US11707440B2 (en) 2017-12-22 2023-07-25 Janssen Pharmaceuticals, Inc. Esketamine for the treatment of depression
US11440874B2 (en) 2018-01-10 2022-09-13 XWPharma Ltd. Ketamine derivatives and compositions thereof
CN114805139A (zh) * 2018-01-10 2022-07-29 凯瑞康宁生物工程（武汉）有限公司 氯胺酮的前药、其组合物和用途
CN111836798A (zh) * 2018-01-10 2020-10-27 凯瑞康宁生物工程（武汉）有限公司 氯胺酮的前药、其组合物和用途
WO2019137381A1 (fr) * 2018-01-10 2019-07-18 Xw Laboratories, Inc. Promédicaments à base de kétamine, compositions et utilisations de ceux-ci
CN111836798B (zh) * 2018-01-10 2022-04-15 凯瑞康宁生物工程（武汉）有限公司 氯胺酮的前药、其组合物和用途
US10836714B2 (en) 2018-01-10 2020-11-17 Xw Laboratories Inc. Ketamine derivatives and compositions thereof
CN114805139B (zh) * 2018-01-10 2023-10-20 凯瑞康宁生物工程（武汉）有限公司 氯胺酮的前药、其组合物和用途
IL275968B1 (en) * 2018-01-10 2024-03-01 Xwpharma Ltd Ketamine prodrugs, preparations containing them and their uses
US11883526B2 (en) 2019-03-05 2024-01-30 Janssen Pharmaceutica Nv Esketamine for the treatment of depression
US11980596B2 (en) 2020-12-15 2024-05-14 Janssen Pharmaceutica Nv Delivery of esketamine for the treatment of depression
US11690811B2 (en) 2021-08-13 2023-07-04 XWPharma Ltd. Pharmaceutical compositions and oral dosage forms of ketamine derivatives

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CA2230690C (fr) 2008-12-23
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JP2009073842A (ja) 2009-04-09

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