Internet for Pharmaceutical and Biotech Communities
| Newsletter | Advertising |
 
 
 

  

Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 
   



 

Title:  Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
United States Patent: 
7,115,631
Issued: 
October 3, 2006

Inventors: 
Zeldis; Jerome B (Princeton, NJ), Faleck; Herbert J. (West Orange, NJ), Khetani; Vikram (Short Hills, NJ), Zeitlin; Andrew L. (Basking Ridge, NJ), Dariani; Maghsoud M. (Fanwood, NJ), Sterling; David (Branchburg, NJ)
Assignee: 
Celgene Corporation (Summit, NJ)
Appl. No.:  10/195,974
Filed: 
July 16, 2002


 

Patheon


Abstract

In one aspect, the present invention is directed to methods for treating fatigue, neurobehavioral slowing and other cognitive disorders and defects due to cancers and treatments associated with cancers, and similar conditions. In a further aspect, the present invention is directed to methods for treating disorders related to menopause, including executive function defects. The methods involve the administration of a composition comprising D-threo methylphenidate that is substantially free of L-threo methylphenidate and of erythro forms of methylphenidate.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides methods for treating fatigue, neurobehavioral slowing and cognitive side effects arising from cancer, or from a treatment therefor, such as chemotherapy, radiation therapy and administration of medication to control pain. In further aspects, the invention provides methods for alleviation of depression caused by cognitive dysfunction (a "cognitive side effect") and fatigue associated with cancer, and treatments therefor. The methods of the invention involve the administration of D-threo-methylphenidate or a pharmaceutically acceptable salt thereof, substantially free of both L-threo-methylphenidate and erythro methylphenidates.

In some embodiments of the invention, methods are provided for alleviating fatigue and/or neurobehavioral slowing arising from an oncological condition, said method comprising the steps of identifying a patient suffering from said fatigue or neurobehavioral slowing, and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

In further aspects, the present invention provides methods for alleviating fatigue or neurobehavioral slowing arising from the administration of a treatment for an oncological condition, said method comprising the steps of identifying a patient suffering from said fatigue or neurobehavioral slowing, and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

Also provided in accordance with the present invention are methods for alleviating a cognitive side effect of a treatment for an oncological condition, comprising the steps of identifying a patient suffering from a cognitive side-effect of a treatment for an oncological condition; and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

In some embodiments of the methods of the invention, the treatment for the oncological condition is the administration of pain management and biological therapies, including pain relief medication, chemotherapy, radiation therapy, and surgery. In some particularly preferred embodiments, the treatment for the oncological condition is chemotherapy or the administration of pain relief medication. In further embodiments of the foregoing methods, the pain relief medication is one or more opioid analgesics, nerve blocks or other psychotropic agents.

In further embodiments of the foregoing methods, the oncological condition is a cancer selected from the group consisting of all malginant conditions, inclduing both solid tumors and nonsolid tumors. In some preferred embodiments, the oncological condition is a solid tumor.

In some embodiments of the foregoing methods, the cognitive side effect is sedation, decreased cognitive function, major depressive disorder, or neurobehavioral slowing. In some preferred embodiments, the cognitive side effect is sedation or decreased cognitive function.

In further aspects, the present invention provides methods for treating a symptom of menopause comprising the steps of identifying a patient suffering from a symptom of menpoause; and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

In some embodiments of the foregoing methods, the symptom of menopause is impairment in short term memory, decreased cognitive function, mental depression, vasomotor instability, nervousness, excitability, fatigue, neurobehavioral slowing, and/or apathy.

In some preferred embodiments of the foregoing methods, the administration of the D-threo-methylphenidate (2R:2'R), or the pharmaceutically acceptable salt thereof, gives rise to efficacious treatment without interfering with patient sleep patterns or engendering anoretic behavior.

DETAILED DESCRIPTION OF THE INVENTION

The methods of the invention involve the administration of D-threo-methylphenidate or a pharmaceutically acceptable salt thereof, substantially free of both L-threo-methylphenidate and erythro methylphenidates. It is now believed that the L isomer may contribute to the side effects associated with the commercial drug, and that it is thus desirable to administer only the active D-threo form of the drug.

Thus, in some embodiments of the invention, methods are provided for alleviating fatigue or neurobehavioral slowing arising from an oncological condition, said method comprising the steps of identifying a patient suffering from said fatigue or neurobehavioral slowing, and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

In further aspects, the present invention provides methods for alleviating fatigue or neurobehavioral slowing arising from the administration of a treatment for an oncological condition, said method comprising the steps of identifying a patient suffering from said fatigue or neurobehavioral slowing, and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

Also provided in accordance with the present invention are methods for alleviating a cognitive side effect (e.g., neurobehavioral slowing) of a treatment for an oncological condition, comprising the steps of identifying a patient suffering from a cognitive side-effect of a treatment for an oncological condition; and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

In some embodiments of the methods of the invention, the treatment for the oncological condition is the administration of pain management and biological therapies, including pain relief medication, chemotherapy, radiation therapy, and surgery. In some particularly preferred embodiments, the treatment for the oncological condition is chemotherapy or the administration of pain relief medication. In further embodiments of the foregoing methods, the pain relief medication is one or more opioid analgesics, nerve blocks or other psychotropic agents.

In further embodiments of the foregoing methods, the oncological condition is a cancer selected from the group consisting of all malginant conditions, inclduing both solid tumors and nonsolid tumors. In some preferred embodiments, the oncological condition is a solid tumor.

In some embodiments of the foregoing methods, the cognitive side effect is sedation, decreased cognitive function, major depressive disorder, or neurobehavioral slowing. In some preferred embodiments, the cognitive side effect is sedation or decreased cognitive function.

In further aspects, the present invention provides methods for treating a symptom of menopause comprising the steps of identifying a patient suffering from a symptom of menpoause; and administering to said patient a therapeutically effective amount of D-threo-methylphenidate (2R:2'R) or a pharmaceutically acceptable salt thereof, substantially free of the 1-threo isomer.

In some embodiments of the foregoing methods, the symptom of menopause is impairment in short term memory, decreased cognitive function, mental depression, vasomotor instability, nervousness, excitability, fatigue, neurobehavioral slowing and/or apathy.

In some preferred embodiments of the foregoing methods, the administration of the D-threo-methylphenidate (2R:2'R), or the pharmaceutically acceptable salt thereof, gives rise to efficacious treatment without interfering with patient sleep patterns or engendering anoretic behavior.

The administration of the pharmacodynamically active D-threo form of methylphenidate may provide efficacious treatment for an entire day with minimal undesirable side effects such as interference with patient sleep patterns or anoretic behavior. It has been surprisingly and unexpectedly discovered that the beneficial effects of the D-threo isomer persist for a longer period time when the D-threo isomer is administered alone than when it is administered in combination with the L-threo isomer.

While it is not intended that the present invention be bound by any particular theory, it is believed that the L isomer functions as an antagonist to the D isomer. Thus, another aspect of the present invention provides methods for ameliorating or counteracting the effects of methylphenidate drugs, comprising administering L-threo methylphenidate to a patient who has a serum level of D-threo methylphenidate.

The present inventors have observed that in the context of ADD, D-threo methylphenidate has a longer duration of action than DL-methylphenidate of at least six hours. Patients who were given the D-threo isomer free of the L isomer performed better in objective tests than patients who received the DL-threo racemate or a placebo, at the 6 hour time point. In contrast, the patients who received DL-threo racemate did not perform better after that time period than those who received a placebo. Furthermore, subjective observations of the same patients indicated that those who received only the D-threo isomer experienced beneficial effects of the drug for longer times than did those who received the DL-threo racemate.

It is expected that D-threo methylphenidate will be particularly useful in treating patients affected by fatigue, neurobehavioral slowing, and other cognitive defects (`cognitive side effects`) that are due to cancer, and that are exacerbated by the administration of treatments for cancer such as chemotherapy, radiation therapy, bone marrow transplants, stem cell transplants and administration of medication to control pain. Examples of such cognitive defects include but are not limited to neurobehavioral slowing, sedation, diminished executive function, decreased cognitive function, major depressive disorder and impaired quality of life.

As used herein, the term "oncological condition" is intended to mean all malignant conditions, including all cancers, for example solid tumors and nonsolid tumors. Examples of "oncological conditions" include cancers of the skin, mouth, brain and other nervous tissue, bone, lung, colon and rectum, pancreas, prostate, urinary tract, leukemias and lymphomas.

As used herein, the term "arising from the administration of a treatment for an oncological condition" is intended to mean that the indicated symptom or condition is in whole or in part caused by (i.e., is a side-effect of) the administration of a therapeutic agent used for the treatment of cancer, or for the management of a symptom of the cancer. Examples of agents used for the treatment of cancer include chemotherapeutic agents, including both chemical and radiotherapeutics, and radiation. Examples of agents used for the management of a symptom of the cancer include pain relief medications such as opioid or opoid-like analgesics and non-steroidal anti-inflammatory agents.

As used herein, the term "alleviating a cognitive side effect of a treatment for an oncological condition" means the lessening of the severity of a cognitive side effect caused in whole or in part by the administration of a treatment for an oncological condition. The term "cognitive side effect" as used herein denotes an impairment of one or more cognitive functions that results in whole or in part from the administration of an agent used for the treatment of cancer. Examples of cognitive side effects include sedation, neurobehavioral slowing, decreased cognitive function, depression, apathy, decreased libido and derpersonalization. The term "decreased cognitive function" is intended to mean a decrease in any or all aspects of thought, attention, perception, and/or memory.

As used herein, the term "menopause" is given its normal meaning of the period during which marks the permanent cessation of menstrual activity. The term "symptom of menopause" in intended to include those symptoms associated with menopause, including vasomotor instability, nervousness, excitability, fatigue, neurobehavioral slowing, apathy, mental depression and impairment of short term memory. As used herein, the term "executive function defect" is intended to include but is not limited to one or more defects in the cognitive mechanisms responsible for focusing attention, goal-related behavior, strategic planning and problem solving.

The methods of the invention will find use with patients, including outpatients, with all types of cancer, either primary or metastatic.

According to one method of the present invention, dosage forms are administered of D-threo methylphenidate substantially free of L-threo methylphenidate and of erythro methylphenidates. "Substantially free", as used herein, means that the dosage forms comprise at least about 95 percent, preferably at least about 97 percent, and more preferably at least about 99 percent of the D-threo isomer, to the exclusion of the L-threo and erythro forms. The D-threo form can be isolated by methods known to those skilled in the art.

In accordance with the present invention, the D-threo methylphenidate can be administered in any of a variety of dosage regimes. Such regimes include chronic single, bolus dosages, i.e., where one dose being administered in a predetermined time period, for example twenty four hours. Further dosage regimes include those where multiple dosages are manually administered, and dosage forms where a single dosage form is administered that effectively mimics multiple dosages, such as pulsatile release dosage forms. Further dosage forms useful with the present invention include delay release and extended release (i.e., "time release") dosage forms. The selection of appropriate dosage forms for an individual patient will depend upon the individual circumstances, and will be apparent to those of skill in the art.

"Chronic", as used herein, refers to continuous, regular, long-term therapeutic administration, i.e. periodic administration without substantial interruption, such as, for example, daily, for a time period of at least several weeks or months to several years, for the purpose of treating a patient needing treatment.

"Bolus", as used herein, refers to administration of a drug as a single event. The term "bolus" is intended to exclude dosage forms such as sustained release, pulsed release, and time release, and includes any dosage form which can be used to deliver a single dose. According to the present invention, a bolus is preferably administered to a patient in need of treatment once daily, more preferably in the morning. The bolus dosages of the present invention may be adminstered in any conventional form known to those skilled in the art. Suitable methods for administration include oral dosage forms, injection, and infusion.

For pharmaceutical use, the D-threo methylphenidate substantially free of L-threo methylphenidate and of erythro methylphenidates as described herein can be taken up in pharmaceutically acceptable carriers, such as, for example, solutions, suspensions, tablets, capsules, ointments, elixirs and injectable compositions. Pharmaceutical preparations generally can contain from about 1% to about 90% by weight of active ingredient. Preparations which are in single dose form, "unit dosage form", preferably contain from about 20% to about 90% active ingredient. As used herein, the term "active ingredient" refers to D-threo methylphenidate substantially free of L-threo methylphenidate and of erythro methylphenidates as described herein, salts thereof, and mixtures of D-threo methylphenidate as described herein with other pharmaceutically active compounds. Dosage unit forms such as, for example, tablets or capsules, typically contain from about 0.001 to about 1.0 g of active ingredient. Pharmaceutical preparations may be administered orally, parenterally, or topically. Pharmaceutical preparations containing compounds described herein may be prepared by methods known to those skilled in the art, such as, for example, conventional mixing, granulating, dissolving, or lyophilizing. Oral dosage forms include capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions and emulsions. The oral dosage forms provided by the invention can be in the form of tablets, caplets, and the like and can be of any shape suitable for oral administration of a drug, such as spheroidal, cube-shaped, oval, bean shaped, or ellipsoidal. For oral dosage forms, for example, the compounds may be combined with one or more solid pharmaceutically acceptable carriers, optionally granulating the resulting mixture. Pharmaceutically acceptable adjuvants may optionally be included, such as, for example, flow-regulating agents and lubricants. Suitable carriers include, for example, fillers such as sugars, cellulose preparations, calcium phosphates; and binders such as methylcellulose, hydroxymethylcellulose, and starches, such as, for example, maize starch, potato starch, rice starch, and wheat starch. The dosage form may be in the form of granules, which may be irregularly shaped. The dosage form can comprise a capsule containing particles. Examples of orally administrable pharmaceutical preparations are dry-filled capsules consisting of gelatin, and soft sealed capsules consisting of gelatin and a plasticizer such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, binders, glidants, and stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid adjuvant, such as, for example, a fatty oil, paraffin oil, or liquid polyethylene glycol, optionally in the presence of stabilizers. Other oral administrable forms include syrups containing active ingredient, for example, in suspended form at a concentration of from about 0.01% to 20%, or in a similar concentration that provides a suitable single dose when administered, for example, in measures of from about 2 to about 5 milliliters. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example ethanol, benzyl alcohol and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Also suitable are powdered or liquid concentrates for combining with liquids such as milk. Such concentrates may also be packed in single dose quantities.

In accordance with the present invention, D-threo methylphenidate as described herein may be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier. Solutions for parenteral administration may be in the form of infusion solutions. A pharmaceutical carrier may be, for example, a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as as ethanol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as poly(ethyleneglycol)400, oils, fatty acids, fatty acid esters or glycerides, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent or other pharmaceutically acceptable adjuvants. Examples of oils which may be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils such as, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include, for example, oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters include ethyl oleate and isopropyl myristate. Suitable soaps include alkaline metal, ammonium and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides and alkyl pyridinium halides; anionic detergents such as alkyl, aryl and olefin sulfonates, monoglyceride sulfates and sulfosuccinates; nonionic detergents such as fatty amino oxides, fatty acid alkanolamides and polyoxyethylenepropylene copolymers; and amphoteric detergents such as alkyl-(-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; as well as mixtures of detergents. Parenteral preparations will typically contain at least about 0.01% by weight of active ingredient in solution. Preservatives and buffers may also be used advantageously. Injection suspensions may include viscosity-increasing substances such as, for example, sodium carboxymethylcellulose, sorbitol or dextran, and may also include stabilizers. In order to minimize irritation at the site of injection, injectable compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB or a mixture of two or more components having the desired HLB. Particular examples of useful surfactants include polyethylene sorbitan fatty acid esters, such as, for example, sorbitan monooleate.

In addition to parenteral administration, D-threo methylphenidate as described herein can be-formulated for nasal administration, particularly in the form of powders, nasal drops, or aerosols. The compounds of the invention also can be administered dermally, via, for example, trans-dermal patches.

The preferred quantity of D-threo methylphenidate to be used in a dosage for treating a particular patient can be readily determined by one skilled in the art. Factors determining the appropriate dosage include the weight and age of the patient, the type and extent of the disorder being treated, and other conditions of the patient including other disorders and other medications, if any, that the patient is taking. Generally, the dosage of D-threo methylphenidate will be from about 0.01 mg/kg of patient body weight to about 1 mg/kg of patient body weight. Appropriate quantities can be determined by one skilled in the art. For example, a relatively small child will generally require a dose of from about 0.03 to about 0.3 mg/kg, while a larger child or an adult may require a dose of from about 0.1 mg/kg to about 0.4 or 0.5 mg/kg.

A physician treating a patient with cancer will generally titrate the dose of methylphenidate until the desired therapeutic effects is achieved. For example, a patient with cancer receiving an opioid analgesic for pain management will initially be administered a minimum dose of 2.5 mg of d-MPH b.i.d. at the time of the opioid analgesic, with dose increasing a clinically warranted.

Response by patients with cognitive deficiencies described herein is generally determined by two types of measurements: objective measures of a patient's ability to concentrate and remain focused on a task such as performing a math test; and subjective scores of a patient's performance.
 


Claim 1 of 56 Claims

1. A method for alleviating fatigue arising from an oncological condition, said method comprising the steps of: identifying a patient suffering from said fatigue, and administering to said patient a unit dosage comprising a compound having the formula ##STR00002## (see Original Patent) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier or diluent, said dosage having less than 10% by weight of other stereoisomers of the compound or salt.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]