US20110201645A1 - Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate - Google Patents

Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate Download PDF

Info

Publication number
US20110201645A1
US20110201645A1 US13093917 US201113093917A US2011201645A1 US 20110201645 A1 US20110201645 A1 US 20110201645A1 US 13093917 US13093917 US 13093917 US 201113093917 A US201113093917 A US 201113093917A US 2011201645 A1 US2011201645 A1 US 2011201645A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
methylphenidate
threo
attention deficit
threo methylphenidate
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13093917
Inventor
Andrew L. Zeitlin
Maghsoud M. Dariani
David I. Stirling
Original Assignee
Zeitlin Andrew L
Dariani Maghsoud M
Stirling David I
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4458Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10Nitrogen as only ring hetero atom
    • C12P17/12Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Abstract

Methods for treating Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, AIDS Dementia Complex and cognitive decline in HIV-AIDS while minimizing drug hypersensitivity, toxicity, side effects, euphoric effect, and drug abuse potential by administration of d-threo-methylphenidate or pharmaceutically acceptable salts thereof.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. application Ser. No. 12/580,800, filed Oct. 16, 2009, which is a continuation of U.S. application Ser. No. 11/244,924 (now abandoned), filed Oct. 6, 2005, which is a continuation of U.S. application Ser. No. 10/961,122 (now abandoned), filed Oct. 8, 2004; which is a continuation of U.S. application Ser. No. 10/395,444, filed Mar. 24, 2003 (now abandoned); which is a continuation of U.S. application Ser. No. 09/864,617, filed May 24, 2001 (now U.S. Pat. No. 6,602,887; which is a divisional of U.S. application Ser. No. 09/337,310, filed Jun. 21, 1999 (now U.S. Pat. No. 6,255,325); which is a divisional of U.S. application Ser. No. 08/937,684, filed Sep. 29, 1997 (now U.S. Pat. No. 5,922,736); which is a continuation-in-part of U.S. application Ser. No. 08/827,230, filed Apr. 2, 1997 (now U.S. Pat. No. 5,908,850), which is a continuation-in-part of U.S. App. No. 08,647,642, filed May 15, 1996, (now abandoned), which is a continuation-in-part of U.S. application Ser. No. 08/583,317, filed Jan. 5, 1996, (now U.S. Pat. No. 5,733,756), which is a continuation of U.S. application Ser. No. 08/567,131, filed Dec. 4, 1995 (now abandoned); all of which are incorporated herein.
  • FIELD OF THE INVENTION
  • The present invention relates to methods of treating certain Central Nervous System disorders such as Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), HIV/AIDS cognitive decline, and AIDS Dementia Complex with decreased side effects, reduced euphoric effect, and reduced drug abuse potential.
  • BACKGROUND OF THE INVENTION
  • Attention Deficit Disorder (ADD) is the most commonly diagnosed illness in children. Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158 (1987). Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (ADHD), is further characterized by increased symptoms of hyperactivity in patients. Racemic methylphenidate (e.g., Ritalin™) is a mild Central Nervous System stimulant with pharmacological activity qualitatively similar to amphetamines, and has been the drug of choice for symptomatic treatment of ADD in children. Greenhill, L., Child & Adol. Psych. Clin. N.A., Vol. 4, Number 1:123-165 (1995). Current administration of racemic methylphenidate, however, results in notable side effects such as anorexia, weight loss, insomnia, dizziness and dysphoria. Additionally, racemic methylphenidate which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for substance abuse in patients.
  • At least 70% of HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (AIDS) eventually manifest cognitive defects, and many display signs and symptoms of dementia. See Navia et al., Annals of Neurology, 19:517-524 (1986). Complaints of forgetfulness, loss of concentration, fatigue, depression, loss of attentiveness, mood swings, personality change, and thought disturbance are common in patients with Human Immunodeficiency Virus (HIV) disease. Douzenis et al., Proc. 7th Int'l. Conf. AIDS, 1, MB, 2135:215 (1991); Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989). Racemic methylphenidate has been used to treat cognitive decline in AIDS/ARC patients. Brown, G., Intl. J. Psych. Med. 25(1): 21-37 (1995). As described above, racemic methylphenidate which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for drug abuse in AIDS patients.
  • Glutathione is an important antioxidative agent that protects the body against electrophilic reactive compounds and intracellular oxidants. It has been postulated that HIV-AIDS patients suffer from drug hypersensitivity due to drug overload and an acquired glutathione deficiency. See Uetrecht et al., Pharmacol. Res., 6:265-273 (1989). Patients with HIV infection have demonstrated a reduced concentration of glutathione in plasma, cells and broncho-alveolar lavage fluid. Staal et al., Lancet, 339:909-912 (1992). Clinical data suggests that HIV-seropositive individuals display adverse reactions to the simultaneous administration of several otherwise therapeutic drugs. Rieder et al., Ann. Intern. Med., 110:286-289 (1989). It is therefore desirable to provide for the administration of methylphenidate in reduced dosages among patients with drug hypersensitivity due to HIV infection.
  • Methylphenidate possesses two centers of chirality and thus can exist as four separate optical isomers. The four isomers of methylphenidate are as follows:
  • Figure US20110201645A1-20110818-C00001
  • Diastereomers are known in the art to possess differing physical properties, such as melting point and boiling point. For example, while the threo- racemate of methylphenidate produces the desired Central Nervous System action, the erythro- racemate contributes to hypertensive side effects and exhibits lethality in rats.
  • Additional studies in animals, children and adults have demonstrated pharmacological activity in the d-threo isomer of methylphenidate (2R:2′R). See Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158 (1987). Although the role of the l-isomer in toxicity or adverse side effects has not been thoroughly examined, the potential for isomer ballast in methylphenidate is of concern for many patient groups, particularly those drug hypersensitive patients as described above.
  • Although l-threo-methylphenidate is rapidly and stereo-selectively metabolized upon oral administration, intravenous administration or inhalation results in high l-threo-methylphenidate serum levels. Srinivas et al., Pharmacol. Res., 10:14-21 (1993). Intravenous administration and inhalation are the methods of choice by drug abusers of current methylphenidate formulations. The present invention postulates that the euphoric effect produced by current formulations of methylphenidate is due to the action of l-threo-methylphenidate.
  • Accordingly, it has been discovered that the use of the d-threo isomer (2R:2′R) of methylphenidate, substantially free of the l-threo isomer produces a methylphenidate medication which retains high activity levels and simultaneously possesses reduced euphoric effect and reduced potential for abuse among patients.
  • U.S. Pat. No. 2,507,631, to Hartmann et al. describes methylphenidate and processes for making the same.
  • U.S. Pat. No. 2,957,880, to Rometsch et al. describes the conversion of .alpha.-aryl-.alpha.-piperidyl-(2)-acetic acids and derivatives thereof (including methylphenidate) into their respective racemates.
  • Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989) reported on the use of racemic methylphenidate (Ritaline™) and dextroamphetamines in the treatment of cognitive impairment in AIDS patients.
  • Srinivas et al., J. Pharmacol. & Exp. Therap., 241:300-306 (1987) described use of racemic dl-threo-methylphenidate (Ritalin™) in the treatment of ADD in children. This study noted a 5-fold increase in plasma levels of d-threo-methylphenidate in children treated with racemic methylphenidate, but was otherwise inconclusive with regard to the efficacy of a single methylphenidate isomer at therapeutically significant doses.
  • Srinivas et al., Clin. Pharmacol. Ther., 52:561-568 (1992) studied the administration of dl-threo, d-threo and l-threo-methylphenidate to children suffering from ADHD. While Srinivas et al. reported the pharmacodynamic activity of dl-threo-methylphenidate resides in the d-threo isomer, this study investigated neither the adverse side effects of the l-threo isomer, nor the euphoric effects of the single isomers or racemate. Single isomer dosages below ½ of the racemate dosage were not studied.
  • Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158 (1986) examined the pharmacology of the enantiomers of threo-methylphenidate, and assessed the relative contribution of each isomer to central and peripheral actions of Ritalin™.
  • Brown, G., Intl. J. Psych. Med., 25(1):21-37 (1995) reported the use of racemic methylphenidate for the treatment of AIDS cognitive decline.
  • Patrick et al., Psychopharmacology: The Third Generation of Progress, Raven Press, N.Y. (1987) examined the pharmacokinetics and actions of methylphenidate in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Patrick noted the d-threo isomer possesses higher activity than the l-threo isomer, and that d-threo methylphenidate may be responsible for the therapeutic activity in the racemic drug.
  • Aoyama et al., Clin. Pharmacol. Ther., 55:270-276 (1994) reported on the use of (+)-threo-methylphenidate in the treatment of hypersomnia. Aoyama et al. describe a correlation between sleep latency in patients and plasma concentration or (+)-threo-methylphenidate.
  • SUMMARY OF THE INVENTION
  • The present invention is based on the discovery that d-threo-methylphenidate (2R:2′R) possesses enhanced therapeutic activity with reduced side effects, and l-threo-methylphenidate produces undesirable side effects, euphoria and drug abuse potential in patients suffering from Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, AIDS cognitive decline, and AIDS Dementia Complex.
  • The present invention thus relates to methods of treating Attention Deficit Disorder and Attention Deficit Hyperactivity Disorder in children and adults while providing for reduced side effects, reduced euphoric effect and reduced potential for abuse potential through administration of d-threo-methylphenidate (2R:2′R) of the formula:
  • Figure US20110201645A1-20110818-C00002
  • or a pharmaceutically acceptable salt thereof, substantially free of the l-threo isomer.
  • The invention further relates to methods of treating AIDS-related dementia and related cognitive disorders while providing for reduced side effects, reduced euphoric effect, and reduced abuse potential through administration of d-threo-methylphenidate (2R:2′R) of the formula:
  • Figure US20110201645A1-20110818-C00003
  • or a pharmaceutically acceptable salt thereof, substantially free of the l-threo isomer.
  • Prescription of methylphenidate to treat AIDS cognitive decline and AIDS Dementia Complex associated with HIV infection is becoming increasingly popular. However, high doses in excess of 40 mg/day are not well tolerated by a substantial number of HIV-infected patients when treated over weeks or months. Brown, G., Int'l J. Psychiatry. Med., 25:21-37 (1995). The d-threo isomer use of the present invention thus enables a lowered dosing therapy resulting in improved efficacy for diseased patients and particularly HIV-infected patients.
  • Moreover, administration of the d-threo isomer to patients will result in decreased side effects, reduced euphoric effect, and substantially reduce the potential for abuse of the product.
  • DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
  • Racemic methylphenidate and its individual isomers are known. See U.S. Pat. Nos. 2,507,631 and 2,957,880. They can be prepared by conventional techniques, and can be obtained from a variety of commercial sources.
  • The d-threo isomer of the present invention can be administered orally, rectally, parenterally, or transdermally, alone or in combination with other psychostimulants, antidepressants, and the like to a patient in need of treatment. Oral dosage forms include tablets, capsules, dragees, and similar shaped compressed pharmaceutical forms. Isotonic saline solutions containing 20-100 milligrams/milliliter can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter. Transdermal administration can be effected through the use of transdermal patch delivery systems and the like. The preferred routes of administration are oral and parenteral.
  • The dosage employed must be carefully titrated to the patient, considering age, weight, severity of the condition, and clinical-profile. Typically, the amount of d-threo-methylphenidate administered will be in the range of 5-50 mg/day, but the actual decision as to dosage must be made by the attending physician.
  • The present invention provides enhanced relief for patients suffering from Attention Deficit Disorder and Attention Deficit Hyperactivity Disorder while providing for reduced side effects, reduced euphoric effect, and reduced abuse potential through administration of d-threo-methylphenidate substantially free of the l-threo isomer.
  • The invention further provides for treatment of AIDS-related dementia and related cognitive disorders with d-threo-methylphenidate substantially free of the l-threo isomer while providing for reduced side effects, reduced euphoric effect, and reduced abuse potential.
  • The term, “substantially free of the l-threo-isomer” means that the composition contains at least 90% by weight of d-threo-methylphenidate, and 10% by weight of l-threo-methylphenidate. In the most preferred embodiment, the term “substantially free of the l-threo isomer” means that the composition contains at least 99% by weight of d-threo-methylphenidate and 1% or less of l-threo-methylphenidate.
  • The following examples will serve to further typify the nature of the invention, but should not be construed as a limitation on the scope thereof, which is defined solely by the appended claims.
  • Example 1
  • Tablets for chewing, each containing 5 milligrams of d-threo-methylphenidate, can be prepared in the following manner:
  • Composition (for 1000 tablets)
    d-threo-methylphenidate 5.00 grams
    mannitol 15.33 grams 
    lactose 10.00 grams 
    talc 1.40 grams
    glycine 0.83 grams
    stearic acid 0.66 grams
    saccharin 0.10 grams
    5% gelatin solution q.s.
  • All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose are mixed, granulated with the addition of gelatin solution, forced through a sieve of 2 mm mesh width, dried at 50° C. and again forced through a sieve of 1.7 mm mesh width. The d-threo-methylphenidate, the glycine and the saccharin are carefully mixed, the mannitol, the lactose granulate, the stearic acid and the talc are added and the whole is mixed thoroughly and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking groove on the upper side.
  • Example 2
  • Tablets, each containing 10 milligrams of d-threo-methylphenidate, can be prepared in the following manner:
  • Composition (for 1000 tablets)
    d-threo-methylphenidate 10.0 grams
    lactose 328.5 grams 
    corn starch 17.5 grams
    polyethylene glycol 6000  5.0 grams
    talc 25.0 grams
    magnesium stearate  4.0 grams
    demineralized water q.s.
  • The solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the d-threo-methylphenidate, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 milliliters of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 milliliters of water. The resulting paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35° C., forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.
  • Example 3
  • Gelatin dry-filled capsules, each containing 20 milligrams of d-threo-methylphenidate, can be prepared in the following manner:
  • Composition (for 1000 capsules)
    d-threo-methylphenidate 20.0 grams 
    microcrystalline cellulose 6.0 grams
    sodium lauryl sulfate 0.4 grams
    magnesium stearate 1.6 grams
  • Example 3
  • The sodium lauryl sulfate is sieved into the d-threo-methylphenidate through a sieve of 0.2 mm mesh width and the two components are intimately mixed for 10 minutes. The microcrystalline cellulose is then added through a sieve of 0.9 mm mesh width and the whole is again intimately mixed for 10 minutes. Finally, the magnesium stearate is added through a sieve of 0.8 mm width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 28 milligrams each into size 0 (elongated) gelatin dry-fill capsules.
  • Example 4
  • A 0.2% injection or infusion solution can be prepared, for example, in the following manner:
  • d-threo-methylphenidate  5.0 grams
    sodium chloride 22.5 grams
    phosphate buffer pH 7.4 300.0 grams 
    demineralized water to 2500 mL.
  • The d-threo-methylphenidate is dissolved in 1000 milliliters of water and filtered through a microfilter or slurried in 1000 mL of H2O. The buffer solution is added and the whole is made up to 2500 milliliters with water. To prepare dosage unit forms, portions of 1.0 or 2.5 milliliters each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 milligrams of d-threo-methylphenidate).

Claims (8)

  1. 1. A method of treating Attention Deficit Hyperactivity Disorder comprising administrating on a daily basis to a human having Attention Deficit Hyperactivity Disorder, 5 to 50 mg of D-threo methylphenidate, or a pharmaceutically acceptable salt thereof, substantially free of L-threo methylphenidate, wherein the D-threo methylphenidate, or pharmaceutically acceptable salt, is mixed with a pharmaceutically acceptable carrier, diluent, or excipient.
  2. 2. The method according to claim 1 wherein the amount of D-threo methylphenidate administered is 5 mg per day.
  3. 3. The method according to claim 1 wherein the amount of said D-threo methylphenidate, or a pharmaceutically equivalent salt thereof, is greater than 90% of the total amount of methylphenidate.
  4. 4. The method according to claim 4 wherein the amount of said D-threo methylphenidate, or a pharmaceutically equivalent salt thereof, is greater than 99% of the total amount of methylphenidate.
  5. 5. The method according to claim 1 wherein the amount of D-threo methylphenidate enhances therapeutic activity compared to racemic methylphenidate.
  6. 6. The method according to claim 1 wherein the administration is one to four times per day.
  7. 7. The method according to claim 1 wherein the amount of D-threo methylphenidate administered is 20 mg per day.
  8. 8. The method according to claim 1 wherein the amount of D-threo methylphenidate administered is 50 mg per day.
US13093917 1995-12-04 2011-04-26 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate Abandoned US20110201645A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US56713195 true 1995-12-04 1995-12-04
US08583317 US5733756A (en) 1996-01-05 1996-01-05 Lactams and processes for stereoselective enrichment of lactams, amides, and esters
US64764296 true 1996-05-15 1996-05-15
US08827230 US5908850A (en) 1995-12-04 1997-04-02 Method of treating attention deficit disorders with d-threo methylphenidate
US08937684 US5922736A (en) 1995-12-04 1997-09-29 Chronic, bolus administration of D-threo methylphenidate
US09337310 US6255325B1 (en) 1995-12-04 1999-06-21 Chronic, bolus administration of D-threo methylphenidate
US09864617 US6602887B2 (en) 1995-12-04 2001-05-24 Chronic, bolus administration of D-threo methylphenidate
US10395444 US20030232857A1 (en) 1995-12-04 2003-03-24 Chronic, bolus administration of D-threo methylphenidate
US10961122 US20050119307A1 (en) 1995-12-04 2004-10-08 Method of treating attention deficit disorders with D-threo methylphenidate
US11244924 US20060030587A1 (en) 1995-12-04 2005-10-06 Method of treating attention deficit disorders with d-threo methylphenidate
US12580800 US20100035928A1 (en) 1995-12-04 2009-10-16 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate
US13093917 US20110201645A1 (en) 1995-12-04 2011-04-26 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13093917 US20110201645A1 (en) 1995-12-04 2011-04-26 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate
US13721224 US20130109719A1 (en) 1995-12-04 2012-12-20 Method of treating attention deficit disorders with d-threo methylphenidate

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US12580800 Continuation US20100035928A1 (en) 1995-12-04 2009-10-16 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13721224 Continuation US20130109719A1 (en) 1995-12-04 2012-12-20 Method of treating attention deficit disorders with d-threo methylphenidate

Publications (1)

Publication Number Publication Date
US20110201645A1 true true US20110201645A1 (en) 2011-08-18

Family

ID=25470261

Family Applications (11)

Application Number Title Priority Date Filing Date
US08937684 Expired - Lifetime US5922736A (en) 1995-12-04 1997-09-29 Chronic, bolus administration of D-threo methylphenidate
US09337310 Expired - Lifetime US6255325B1 (en) 1995-12-04 1999-06-21 Chronic, bolus administration of D-threo methylphenidate
US09864617 Expired - Lifetime US6602887B2 (en) 1995-12-04 2001-05-24 Chronic, bolus administration of D-threo methylphenidate
US10395444 Abandoned US20030232857A1 (en) 1995-12-04 2003-03-24 Chronic, bolus administration of D-threo methylphenidate
US10961122 Abandoned US20050119307A1 (en) 1995-12-04 2004-10-08 Method of treating attention deficit disorders with D-threo methylphenidate
US10963460 Abandoned US20050049279A1 (en) 1995-12-04 2004-10-12 Chronic, bolus administration of D-threo methylphenidate
US11244924 Abandoned US20060030587A1 (en) 1995-12-04 2005-10-06 Method of treating attention deficit disorders with d-threo methylphenidate
US12331127 Abandoned US20090088455A1 (en) 1995-12-04 2008-12-09 Chronic, Bolus Adminstration Of D-Threo Methylphenidate
US12580800 Abandoned US20100035928A1 (en) 1995-12-04 2009-10-16 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate
US13093917 Abandoned US20110201645A1 (en) 1995-12-04 2011-04-26 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate
US13721224 Abandoned US20130109719A1 (en) 1995-12-04 2012-12-20 Method of treating attention deficit disorders with d-threo methylphenidate

Family Applications Before (9)

Application Number Title Priority Date Filing Date
US08937684 Expired - Lifetime US5922736A (en) 1995-12-04 1997-09-29 Chronic, bolus administration of D-threo methylphenidate
US09337310 Expired - Lifetime US6255325B1 (en) 1995-12-04 1999-06-21 Chronic, bolus administration of D-threo methylphenidate
US09864617 Expired - Lifetime US6602887B2 (en) 1995-12-04 2001-05-24 Chronic, bolus administration of D-threo methylphenidate
US10395444 Abandoned US20030232857A1 (en) 1995-12-04 2003-03-24 Chronic, bolus administration of D-threo methylphenidate
US10961122 Abandoned US20050119307A1 (en) 1995-12-04 2004-10-08 Method of treating attention deficit disorders with D-threo methylphenidate
US10963460 Abandoned US20050049279A1 (en) 1995-12-04 2004-10-12 Chronic, bolus administration of D-threo methylphenidate
US11244924 Abandoned US20060030587A1 (en) 1995-12-04 2005-10-06 Method of treating attention deficit disorders with d-threo methylphenidate
US12331127 Abandoned US20090088455A1 (en) 1995-12-04 2008-12-09 Chronic, Bolus Adminstration Of D-Threo Methylphenidate
US12580800 Abandoned US20100035928A1 (en) 1995-12-04 2009-10-16 Method Of Treating Attention Deficit Disorders With D-Threo Methylphenidate

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13721224 Abandoned US20130109719A1 (en) 1995-12-04 2012-12-20 Method of treating attention deficit disorders with d-threo methylphenidate

Country Status (7)

Country Link
US (11) US5922736A (en)
EP (2) EP1844777A1 (en)
CA (2) CA2241611C (en)
DE (2) DE69838179T2 (en)
DK (1) DK1032389T3 (en)
ES (1) ES2289787T3 (en)
WO (1) WO1999016439A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916588B2 (en) 2011-03-23 2014-12-23 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US8927010B2 (en) 2011-03-23 2015-01-06 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9028868B2 (en) 2011-03-23 2015-05-12 Ironshore Pharmaceuticals & Development, Inc. Methods and compositions for treatment of attention deficit disorder
US9119809B2 (en) 2011-03-23 2015-09-01 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9498447B2 (en) 2011-03-23 2016-11-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9603809B2 (en) 2011-03-23 2017-03-28 Ironshore Pharmaceuticals & Development, Inc. Methods of treatment of attention deficit hyperactivity disorder

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2222713C (en) 1995-07-14 2003-04-22 Andrew John Mcglashan Richards Composition comprising d-threo-methylphenidate and another drug
US5837284A (en) * 1995-12-04 1998-11-17 Mehta; Atul M. Delivery of multiple doses of medications
US6355656B1 (en) * 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US6486177B2 (en) * 1995-12-04 2002-11-26 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US5922736A (en) * 1995-12-04 1999-07-13 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US6962997B1 (en) * 1997-05-22 2005-11-08 Celgene Corporation Process and intermediates for resolving piperidyl acetamide steroisomers
US20010055613A1 (en) * 1998-10-21 2001-12-27 Beth A. Burnside Oral pulsed dose drug delivery system
US7083808B2 (en) * 1998-12-17 2006-08-01 Euro-Celtique S.A. Controlled/modified release oral methylphenidate formulations
US6419960B1 (en) * 1998-12-17 2002-07-16 Euro-Celtique S.A. Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US6673367B1 (en) * 1998-12-17 2004-01-06 Euro-Celtique, S.A. Controlled/modified release oral methylphenidate formulations
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
EP2316468A1 (en) 2002-02-22 2011-05-04 Shire LLC Delivery system and methods for protecting and administering dextroamphetamine
GB9913458D0 (en) * 1999-06-09 1999-08-11 Medeva Europ Ltd The therapeutic use of d-threo-methylphenidate
WO2002017920A3 (en) * 2000-08-28 2003-01-23 Mel H Epstein Use of methylphenidate compounds to enhance memory
EP1315495A2 (en) * 2000-08-28 2003-06-04 Sention, Inc. Use of threo-methylphenidate compounds to enhance memory
US6855324B2 (en) * 2000-11-20 2005-02-15 Adrian Sandler Therapeutic placebo enhancement of commonly-used medications
US20050136106A1 (en) * 2000-11-20 2005-06-23 Adrian Sandler Therapeutic placebo enhancement of commonly used medications
US20020187192A1 (en) * 2001-04-30 2002-12-12 Yatindra Joshi Pharmaceutical composition which reduces or eliminates drug abuse potential
US20030049272A1 (en) * 2001-08-30 2003-03-13 Yatindra Joshi Pharmaceutical composition which produces irritation
US6638533B2 (en) * 2002-01-03 2003-10-28 George Krsek Pulse dosage formulations of methylphenidate and method to prepare same
JP4878732B2 (en) 2002-02-22 2012-02-15 シャイア エルエルシー The novel sustained release pharmaceutical compound to prevent the abuse of controlled substances
US6726624B2 (en) * 2002-03-06 2004-04-27 The Mclean Hospital Corporation Method and apparatus for determining attention deficit hyperactivity disorder (adhd) medication dosage and for monitoring the effects of adhd medication on people who have adhd using complementary tests
US6913768B2 (en) * 2002-09-24 2005-07-05 Shire Laboratories, Inc. Sustained release delivery of amphetamine salts
US20050239830A1 (en) * 2004-04-26 2005-10-27 Vikram Khetani Methods of diminishing co-abuse potential
ES2314693T3 (en) 2004-08-23 2009-03-16 PEJO ISERLOHN HEILMITTEL-UND DIAT-GMBH & CO.KG Pharmaceutical composition containing psychostimulants.
WO2006063256A3 (en) * 2004-12-09 2007-03-29 Celgene Corp Treatment using d-threo methylphenidate
US20060189655A1 (en) 2005-01-20 2006-08-24 David Bar-Or Methylphenidate derivatives and uses of them
CN101123965B (en) * 2005-01-20 2012-08-22 分子药物研究所公司 Methylphenidate derivatives and uses of methylphenidate derivatives
GB0507298D0 (en) 2005-04-11 2005-05-18 Novartis Ag Organic compounds
US20080020032A1 (en) * 2006-07-21 2008-01-24 Michael Crowley Hydrophobic abuse deterrent delivery system for hydromorphone
US20090076079A1 (en) * 2007-09-15 2009-03-19 Protia, Llc Deuterium-enriched methylphenidate
EP2300011A4 (en) 2008-05-27 2012-06-20 Dmi Life Sciences Inc Therapeutic methods and compounds
CA2936748C (en) 2014-10-31 2017-08-08 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder

Citations (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2507631A (en) * 1944-01-19 1950-05-16 Ciba Pharm Prod Inc Pyridine and piperidine compounds and process of making same
US2838519A (en) * 1953-12-23 1958-06-10 Ciba Pharm Prod Inc Process for the conversion of stereoisomers
US2957880A (en) * 1953-12-23 1960-10-25 Ciba Pharm Prod Inc Process for the conversion of stereoisomers
US4137300A (en) * 1976-08-20 1979-01-30 Ciba-Geigy Corporation Sustained action dosage forms
US4410700A (en) * 1980-07-03 1983-10-18 The United States Of America As Represented By The Department Of Health And Human Services Preparation of chiral 1-benzyl-1,2,3,4-tetrahydroisoquinolines by optical resolution
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
US4882166A (en) * 1981-09-30 1989-11-21 National Research Development Corporation Compositions comprising encapsulated particles and their preparation
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US4968505A (en) * 1988-08-16 1990-11-06 Ss Pharmaceutical Company, Ltd. Long-acting diclofenac sodium preparation
US4986987A (en) * 1986-05-09 1991-01-22 Alza Corporation Pulsed drug delivery
US4992445A (en) * 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5104899A (en) * 1990-08-13 1992-04-14 Sepracor, Inc. Methods and compositions for treating depression using optically pure fluoxetine
US5114946A (en) * 1987-06-12 1992-05-19 American Cyanamid Company Transdermal delivery of pharmaceuticals
US5133974A (en) * 1989-05-05 1992-07-28 Kv Pharmaceutical Company Extended release pharmaceutical formulations
US5137733A (en) * 1990-06-28 1992-08-11 Tanabe Seiyaku Co., Ltd. Controlled release pharmaceutical preparation
US5156850A (en) * 1990-08-31 1992-10-20 Alza Corporation Dosage form for time-varying patterns of drug delivery
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US5160744A (en) * 1991-06-27 1992-11-03 Alza Corporation Verapmil therapy
US5202128A (en) * 1989-01-06 1993-04-13 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
US5217718A (en) * 1989-08-18 1993-06-08 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally
US5223265A (en) * 1992-01-10 1993-06-29 Alza Corporation Osmotic device with delayed activation of drug delivery
US5229131A (en) * 1990-02-05 1993-07-20 University Of Michigan Pulsatile drug delivery system
US5232705A (en) * 1990-08-31 1993-08-03 Alza Corporation Dosage form for time-varying patterns of drug delivery
US5236689A (en) * 1987-06-25 1993-08-17 Alza Corporation Multi-unit delivery system
US5283193A (en) * 1988-06-27 1994-02-01 Asahi Kasei Kogyo K.K. Process for producing optically active α-substituted organic acid and microorganism and enzyme used therefor
US5284769A (en) * 1989-10-16 1994-02-08 Chiros Ltd. Process for preparing a single enantiomer of a lactam using lactamase
US5299121A (en) * 1992-06-04 1994-03-29 Medscreen, Inc. Non-prescription drug medication screening system
US5308348A (en) * 1992-02-18 1994-05-03 Alza Corporation Delivery devices with pulsatile effect
US5326570A (en) * 1991-07-23 1994-07-05 Pharmavene, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US5331000A (en) * 1992-03-09 1994-07-19 Sepracor Inc. Antipyretic and analgesic methods and compositions containing optically pure R(-) ketoprofen
US5362755A (en) * 1990-01-05 1994-11-08 Sepracor, Inc. Method for treating asthma using optically pure (R)-albuterol
US5375693A (en) * 1992-08-03 1994-12-27 Sepracor, Inc. Methods and compositions for treating allergic disorders and other disorders metabolic derivatives of terfenadine
US5391381A (en) * 1987-06-25 1995-02-21 Alza Corporation Dispenser capable of delivering plurality of drug units
US5425950A (en) * 1991-10-30 1995-06-20 Glaxo Group Limited Controlled release pharmaceutical compositions
US5449743A (en) * 1993-01-29 1995-09-12 Shiro Kobayashi Method for ring opening polymerization using a hydrolase catalyst
US5478573A (en) * 1992-12-23 1995-12-26 Kinaform Technology, Inc. Delayed, sustained-release propranolol pharmaceutical preparation
US5496561A (en) * 1993-08-25 1996-03-05 Ss Pharmaceutical Co., Ltd. Controlled release-initiation and controlled release-rate pharmaceutical composition
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
US5512293A (en) * 1992-07-23 1996-04-30 Alza Corporation Oral sustained release drug delivery device
US5567441A (en) * 1995-03-24 1996-10-22 Andrx Pharmaceuticals Inc. Diltiazem controlled release formulation
US5580578A (en) * 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5593694A (en) * 1991-10-04 1997-01-14 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release tablet
US5672360A (en) * 1993-11-23 1997-09-30 Purdue Pharma, L.P. Method of treating pain by administering 24 hour oral opioid formulations
US5733756A (en) * 1996-01-05 1998-03-31 Celgene Corporation Lactams and processes for stereoselective enrichment of lactams, amides, and esters
US5773478A (en) * 1995-07-14 1998-06-30 Medeva Europe Limited Composition comprising methylphenidate and another drug
US5837284A (en) * 1995-12-04 1998-11-17 Mehta; Atul M. Delivery of multiple doses of medications
US5874090A (en) * 1995-07-14 1999-02-23 Medeva Europe Limited Sustained-release formulation of methylphenidate
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US5922736A (en) * 1995-12-04 1999-07-13 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US5936091A (en) * 1997-05-22 1999-08-10 Celgene Corporation Processes and intermediates for resolving piperidyl acetamide stereoisomers
US5965734A (en) * 1997-01-31 1999-10-12 Celgene Corporation Processes and intermediates for preparing 2-substituted piperidine stereoisomers
US6031124A (en) * 1996-03-27 2000-02-29 Medeva Europe Limited 7-amino-2-heptenoates and their use in the preparation of methylphenidate
US6121453A (en) * 1996-03-08 2000-09-19 Medeva Europe Limited Resolution of threo-methylphenidate
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
US6221883B1 (en) * 2000-04-12 2001-04-24 Ross Baldessarini Method of dopamine inhibition using l-threo-methylphenidate
US6228398B1 (en) * 1998-11-02 2001-05-08 Elan Corporation, Plc Multiparticulate modified release composition
US6242464B1 (en) * 1996-01-22 2001-06-05 Chiroscience Limited Single isomer methylphenidate and resolution process
US6344215B1 (en) * 2000-10-27 2002-02-05 Eurand America, Inc. Methylphenidate modified release formulations
US20020019535A1 (en) * 1997-01-17 2002-02-14 Zavareh Hooshang Shahriari Resolution of ritalinic acid salt
US6355656B1 (en) * 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US20020032335A1 (en) * 1996-02-02 2002-03-14 Marianne Langston Manufacture of single isomer methylphenidate
US6359139B1 (en) * 2000-11-07 2002-03-19 Celgene Corporation Methods for production of piperidyl acetamide stereoisomers
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
US20020132793A1 (en) * 2000-08-28 2002-09-19 Mel Epstein Use of methylphenidate compounds to enhance memory
US6486177B2 (en) * 1995-12-04 2002-11-26 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US6962997B1 (en) * 1997-05-22 2005-11-08 Celgene Corporation Process and intermediates for resolving piperidyl acetamide steroisomers

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US49205A (en) * 1865-08-01 Improvement in machines for hulling grain
US105134A (en) * 1870-07-05 Thomas sheehan
US19535A (en) * 1858-03-02 Improvement in sewing-machines
US32335A (en) * 1861-05-14 Island
US2738303A (en) * 1952-07-18 1956-03-13 Smith Kline French Lab Sympathomimetic preparation
US3048526A (en) * 1958-08-04 1962-08-07 Wander Company Medicinal tablet
US3365365A (en) * 1965-08-09 1968-01-23 Hoffmann La Roche Repeat action pharmaceutical compositions in the form of discrete beadlets
US4728512A (en) * 1985-05-06 1988-03-01 American Home Products Corporation Formulations providing three distinct releases
JPH04230625A (en) * 1990-12-27 1992-08-19 Standard Chem & Pharmaceut Corp Ltd Production of finely dispersed tablet composition comprising microcapsule containing spray-dried diclofenac sodium and having enteric coating
US5784090A (en) * 1993-04-30 1998-07-21 Hewlett-Packard Company Use of densitometer for adaptive control of printer heater output to optimize drying time for different print media
US5387284A (en) * 1994-03-07 1995-02-07 James River Paper Company, Inc. Apparatus and method for forming coreless paper roll products
EP0839038A1 (en) * 1995-07-14 1998-05-06 Chiroscience Limited THERAPEUTIC USE OF d-threo-METHYLPHENIDATE
US5733478A (en) * 1996-09-24 1998-03-31 Gowan Company Method and composition for reducing the degradation rate of agrochemicals in storage
DK0946151T3 (en) 1996-11-25 2006-08-28 Alza Corp Dosage Form with increasing dose release
CA2366791A1 (en) * 1999-04-06 2000-10-12 Kamal K. Midha Pharmaceutical dosage form for pulsatile delivery of d-threo-methylphenidate and a second cns stimulant
US20030170181A1 (en) * 1999-04-06 2003-09-11 Midha Kamal K. Method for preventing abuse of methylphenidate
EP1315495A2 (en) * 2000-08-28 2003-06-04 Sention, Inc. Use of threo-methylphenidate compounds to enhance memory

Patent Citations (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2507631A (en) * 1944-01-19 1950-05-16 Ciba Pharm Prod Inc Pyridine and piperidine compounds and process of making same
US2838519A (en) * 1953-12-23 1958-06-10 Ciba Pharm Prod Inc Process for the conversion of stereoisomers
US2957880A (en) * 1953-12-23 1960-10-25 Ciba Pharm Prod Inc Process for the conversion of stereoisomers
US4137300A (en) * 1976-08-20 1979-01-30 Ciba-Geigy Corporation Sustained action dosage forms
US4410700A (en) * 1980-07-03 1983-10-18 The United States Of America As Represented By The Department Of Health And Human Services Preparation of chiral 1-benzyl-1,2,3,4-tetrahydroisoquinolines by optical resolution
US4882166A (en) * 1981-09-30 1989-11-21 National Research Development Corporation Compositions comprising encapsulated particles and their preparation
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
US4904476A (en) * 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US4986987A (en) * 1986-05-09 1991-01-22 Alza Corporation Pulsed drug delivery
US5114946A (en) * 1987-06-12 1992-05-19 American Cyanamid Company Transdermal delivery of pharmaceuticals
US4992445A (en) * 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5391381A (en) * 1987-06-25 1995-02-21 Alza Corporation Dispenser capable of delivering plurality of drug units
US5236689A (en) * 1987-06-25 1993-08-17 Alza Corporation Multi-unit delivery system
US5283193A (en) * 1988-06-27 1994-02-01 Asahi Kasei Kogyo K.K. Process for producing optically active α-substituted organic acid and microorganism and enzyme used therefor
US4968505A (en) * 1988-08-16 1990-11-06 Ss Pharmaceutical Company, Ltd. Long-acting diclofenac sodium preparation
US5202128A (en) * 1989-01-06 1993-04-13 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
US5133974A (en) * 1989-05-05 1992-07-28 Kv Pharmaceutical Company Extended release pharmaceutical formulations
US5217718A (en) * 1989-08-18 1993-06-08 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally
US5284769A (en) * 1989-10-16 1994-02-08 Chiros Ltd. Process for preparing a single enantiomer of a lactam using lactamase
US5362755A (en) * 1990-01-05 1994-11-08 Sepracor, Inc. Method for treating asthma using optically pure (R)-albuterol
US5229131A (en) * 1990-02-05 1993-07-20 University Of Michigan Pulsatile drug delivery system
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US5137733A (en) * 1990-06-28 1992-08-11 Tanabe Seiyaku Co., Ltd. Controlled release pharmaceutical preparation
US5104899A (en) * 1990-08-13 1992-04-14 Sepracor, Inc. Methods and compositions for treating depression using optically pure fluoxetine
US5232705A (en) * 1990-08-31 1993-08-03 Alza Corporation Dosage form for time-varying patterns of drug delivery
US5156850A (en) * 1990-08-31 1992-10-20 Alza Corporation Dosage form for time-varying patterns of drug delivery
US5160744A (en) * 1991-06-27 1992-11-03 Alza Corporation Verapmil therapy
US5326570A (en) * 1991-07-23 1994-07-05 Pharmavene, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US5593694A (en) * 1991-10-04 1997-01-14 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release tablet
US5425950A (en) * 1991-10-30 1995-06-20 Glaxo Group Limited Controlled release pharmaceutical compositions
US5223265A (en) * 1992-01-10 1993-06-29 Alza Corporation Osmotic device with delayed activation of drug delivery
US5580578A (en) * 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5639476A (en) * 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5308348A (en) * 1992-02-18 1994-05-03 Alza Corporation Delivery devices with pulsatile effect
US5331000A (en) * 1992-03-09 1994-07-19 Sepracor Inc. Antipyretic and analgesic methods and compositions containing optically pure R(-) ketoprofen
US5299121A (en) * 1992-06-04 1994-03-29 Medscreen, Inc. Non-prescription drug medication screening system
US5512293A (en) * 1992-07-23 1996-04-30 Alza Corporation Oral sustained release drug delivery device
US5375693A (en) * 1992-08-03 1994-12-27 Sepracor, Inc. Methods and compositions for treating allergic disorders and other disorders metabolic derivatives of terfenadine
US5478573A (en) * 1992-12-23 1995-12-26 Kinaform Technology, Inc. Delayed, sustained-release propranolol pharmaceutical preparation
US5449743A (en) * 1993-01-29 1995-09-12 Shiro Kobayashi Method for ring opening polymerization using a hydrolase catalyst
US5496561A (en) * 1993-08-25 1996-03-05 Ss Pharmaceutical Co., Ltd. Controlled release-initiation and controlled release-rate pharmaceutical composition
US5672360A (en) * 1993-11-23 1997-09-30 Purdue Pharma, L.P. Method of treating pain by administering 24 hour oral opioid formulations
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
US5567441A (en) * 1995-03-24 1996-10-22 Andrx Pharmaceuticals Inc. Diltiazem controlled release formulation
US20030049205A1 (en) * 1995-07-14 2003-03-13 Richards Andrew John Mcglashan Composition comprising methylphenidate and another drug
US5773478A (en) * 1995-07-14 1998-06-30 Medeva Europe Limited Composition comprising methylphenidate and another drug
US6468504B1 (en) * 1995-07-14 2002-10-22 Medeva Europe, Ltd. Composition comprising methylphenidate and another drug
US5874090A (en) * 1995-07-14 1999-02-23 Medeva Europe Limited Sustained-release formulation of methylphenidate
US6113879A (en) * 1995-07-14 2000-09-05 Medeva Europe Limited Composition comprising methylphenidate and another drug
US6255325B1 (en) * 1995-12-04 2001-07-03 Celgene Corporation Chronic, bolus administration of D-threo methylphenidate
US6635284B2 (en) * 1995-12-04 2003-10-21 Celegene Corporation Delivery of multiple doses of medications
US6602887B2 (en) * 1995-12-04 2003-08-05 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US5922736A (en) * 1995-12-04 1999-07-13 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US6528530B2 (en) * 1995-12-04 2003-03-04 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US6486177B2 (en) * 1995-12-04 2002-11-26 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US5837284A (en) * 1995-12-04 1998-11-17 Mehta; Atul M. Delivery of multiple doses of medications
US6355656B1 (en) * 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US7115631B2 (en) * 1995-12-04 2006-10-03 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US5733756A (en) * 1996-01-05 1998-03-31 Celgene Corporation Lactams and processes for stereoselective enrichment of lactams, amides, and esters
US20030105134A1 (en) * 1996-01-22 2003-06-05 Harris Michael Christopher James Single isomer methylphenidate and resolution process
US6242464B1 (en) * 1996-01-22 2001-06-05 Chiroscience Limited Single isomer methylphenidate and resolution process
US6531489B2 (en) * 1996-01-22 2003-03-11 Chiroscience, Ltd. Single isomer methylphenidate and resolution process
US20020032335A1 (en) * 1996-02-02 2002-03-14 Marianne Langston Manufacture of single isomer methylphenidate
US6121453A (en) * 1996-03-08 2000-09-19 Medeva Europe Limited Resolution of threo-methylphenidate
US6031124A (en) * 1996-03-27 2000-02-29 Medeva Europe Limited 7-amino-2-heptenoates and their use in the preparation of methylphenidate
US6441178B2 (en) * 1997-01-17 2002-08-27 Medeva Europe Limited Resolution of ritalinic acid salt
US20020019535A1 (en) * 1997-01-17 2002-02-14 Zavareh Hooshang Shahriari Resolution of ritalinic acid salt
US5965734A (en) * 1997-01-31 1999-10-12 Celgene Corporation Processes and intermediates for preparing 2-substituted piperidine stereoisomers
US5936091A (en) * 1997-05-22 1999-08-10 Celgene Corporation Processes and intermediates for resolving piperidyl acetamide stereoisomers
US6962997B1 (en) * 1997-05-22 2005-11-08 Celgene Corporation Process and intermediates for resolving piperidyl acetamide steroisomers
US6730325B2 (en) * 1998-11-02 2004-05-04 Elan Corporation, Plc Multiparticulate modified release composition
US6228398B1 (en) * 1998-11-02 2001-05-08 Elan Corporation, Plc Multiparticulate modified release composition
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
US6221883B1 (en) * 2000-04-12 2001-04-24 Ross Baldessarini Method of dopamine inhibition using l-threo-methylphenidate
US20020132793A1 (en) * 2000-08-28 2002-09-19 Mel Epstein Use of methylphenidate compounds to enhance memory
US6344215B1 (en) * 2000-10-27 2002-02-05 Eurand America, Inc. Methylphenidate modified release formulations
US6359139B1 (en) * 2000-11-07 2002-03-19 Celgene Corporation Methods for production of piperidyl acetamide stereoisomers

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916588B2 (en) 2011-03-23 2014-12-23 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US8927010B2 (en) 2011-03-23 2015-01-06 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9023389B1 (en) 2011-03-23 2015-05-05 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9028868B2 (en) 2011-03-23 2015-05-12 Ironshore Pharmaceuticals & Development, Inc. Methods and compositions for treatment of attention deficit disorder
US9034902B2 (en) 2011-03-23 2015-05-19 Ironshore Pharmaceuticals & Development, Inc. Methods for treatment of attention deficit hyperactivity disorder
US9119809B2 (en) 2011-03-23 2015-09-01 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9289394B2 (en) 2011-03-23 2016-03-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9498447B2 (en) 2011-03-23 2016-11-22 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9511032B2 (en) 2011-03-23 2016-12-06 Ironshore Pharmaceuticals & Development, Inc. Compositions for treatment of attention deficit hyperactivity disorder
US9603809B2 (en) 2011-03-23 2017-03-28 Ironshore Pharmaceuticals & Development, Inc. Methods of treatment of attention deficit hyperactivity disorder
US9603808B2 (en) 2011-03-23 2017-03-28 Ironshore Pharmaceuticals & Development, Inc. Method of treatment of attention deficit hyperactivity disorder

Also Published As

Publication number Publication date Type
US20060030587A1 (en) 2006-02-09 application
WO1999016439A1 (en) 1999-04-08 application
US20030232857A1 (en) 2003-12-18 application
US6255325B1 (en) 2001-07-03 grant
CA2241611C (en) 2004-08-17 grant
US20050049279A1 (en) 2005-03-03 application
US5922736A (en) 1999-07-13 grant
US20130109719A1 (en) 2013-05-02 application
EP1032389A4 (en) 2002-07-03 application
DK1032389T3 (en) 2007-11-12 grant
EP1032389A1 (en) 2000-09-06 application
DE69838179T2 (en) 2008-04-17 grant
DE69838179D1 (en) 2007-09-13 grant
EP1844777A1 (en) 2007-10-17 application
US20010041717A1 (en) 2001-11-15 application
CA2468370A1 (en) 1999-03-29 application
US20090088455A1 (en) 2009-04-02 application
US20050119307A1 (en) 2005-06-02 application
EP1032389B8 (en) 2008-05-28 grant
US6602887B2 (en) 2003-08-05 grant
EP1032389B1 (en) 2007-08-01 grant
CA2241611A1 (en) 1999-03-29 application
ES2289787T3 (en) 2008-02-01 grant
CA2468370C (en) 2009-02-24 grant
US20100035928A1 (en) 2010-02-11 application

Similar Documents

Publication Publication Date Title
US5064858A (en) Protected complex of procaine for the treatment of symptoms from narcotics addiction, tinnitus and Alzheimer's disease
US5071642A (en) Dihydropyridine containing compositions
US6217904B1 (en) Pharmaceutical dosage form for pulsatile delivery of d-threo-methylphenidate and a second CNS stimulant
US5942503A (en) Use of Epinastine for the treatment of pain
US6039974A (en) Pharmaceutical composition for combination of piperidinoalkanol-decongestant
US20040116532A1 (en) Pharmaceutical formulations of modafinil
US6200958B1 (en) Agent for treating high-risk impaired glucose tolerance
US4942040A (en) Pharmaceutical preparation and a process for its preparation
US5837284A (en) Delivery of multiple doses of medications
US4330558A (en) Pharmaceutical composition and method for treating peripheral orthostatic hypotension
US20060258640A1 (en) Use of Flibanserin in the treatment of chronic pain
US6455544B1 (en) Use of cholinesterase inhibitors to treat disorders of attention
US20020187192A1 (en) Pharmaceutical composition which reduces or eliminates drug abuse potential
US6372790B1 (en) Pharmaceutical composition comprising a combination of metformin and fibrate, and its use for the preparation of medicines intended to reduce hyperglycaemia
US5712293A (en) Methods for treating gastro-esophageal reflux disease and other disorders associated with the digestive tract using optically pure (-) norcisapride
US6339086B1 (en) Methods of making and using N-desmethylzopiclone
US5965571A (en) Cholinesterase inhibitors for treatment of Parkinson's disease
WO1998003173A1 (en) Methods for treating emesis and central nervous system disorders using optically pure (+) norcisapride
US5023244A (en) Anti-dementia agents
WO1994006429A1 (en) Compositions for treating allergic disorders using (-) cetirizine
US20060241133A1 (en) Electrically variable pneumatic structural element
US5955478A (en) Methods for treating gastrointestinal motility dysfunction using optically pure (+) cisapride
US6486177B2 (en) Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
WO1994001112A1 (en) Methods of using (-) cisapride for the treatment of gastro-esophageal reflux disease and other disorders
US7776858B2 (en) Methods of treatment of chronic pain using eszopiclone