US20050119307A1 - Method of treating attention deficit disorders with D-threo methylphenidate - Google Patents
Method of treating attention deficit disorders with D-threo methylphenidate Download PDFInfo
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- US20050119307A1 US20050119307A1 US10/961,122 US96112204A US2005119307A1 US 20050119307 A1 US20050119307 A1 US 20050119307A1 US 96112204 A US96112204 A US 96112204A US 2005119307 A1 US2005119307 A1 US 2005119307A1
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- KFEZCFXLDVZNHQ-UHFFFAOYSA-N [H]C1(C([H])(C(=O)C#O)c2ccccc2)CCCCN1 Chemical compound [H]C1(C([H])(C(=O)C#O)c2ccccc2)CCCCN1 KFEZCFXLDVZNHQ-UHFFFAOYSA-N 0.000 description 2
- PXHBKAPYJZOSLH-UHFFFAOYSA-N [H]C1(C([H])(C(=O)C#O)c2ccccc2)CCCCN1.[H]C1(C([H])(C(=O)C#O)c2ccccc2)CCCCN1.[H]C1(C([H])(C(=O)OC)c2ccccc2)CCCCN1.[H]C1(C([H])(C(=O)OC)c2ccccc2)CCCCN1 Chemical compound [H]C1(C([H])(C(=O)C#O)c2ccccc2)CCCCN1.[H]C1(C([H])(C(=O)C#O)c2ccccc2)CCCCN1.[H]C1(C([H])(C(=O)OC)c2ccccc2)CCCCN1.[H]C1(C([H])(C(=O)OC)c2ccccc2)CCCCN1 PXHBKAPYJZOSLH-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; 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
- A61K9/1676—Agglomerates; 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5073—Microcapsules 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
- A61K9/5078—Microcapsules 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5084—Mixtures 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
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- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic 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
- C07D211/08—Heterocyclic 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
- C07D211/18—Heterocyclic 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
- C07D211/34—Heterocyclic 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
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes 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
Definitions
- 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.
- ADD Attention Deficit Disorder
- ADHD Attention Deficit Hyperactivity Disorder
- HIV/AIDS cognitive decline HIV/AIDS cognitive decline
- AIDS Dementia Complex with decreased side effects, reduced euphoric effect, and reduced drug abuse potential.
- Attention Deficit Disorder 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., RitalinTM) 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).
- ADHD Attention Deficit Hyperactivity Disorder
- 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.
- HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (AIDS) eventually manifest cognitive defects, and many display signs and symptoms of dementia.
- AIDS Acquired Immunodeficiency Syndrome
- 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.
- HIV Human Immunodeficiency Virus
- 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:
- Diastereomers are known in the art to possess differing physical properties, such as melting point and boiling point.
- melting point such as melting point and boiling point.
- erythro-racemate contributes to hypertensive side effects and exhibits lethality in rats.
- 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.
- 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 1 ⁇ 2 of the racemate dosage were not studied.
- 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: 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: or a pharmaceutically acceptable salt thereof, substantially free of the l-threo isomer.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- 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 H 2 O.
- the buffer solution is added and the whole is made up to 2500 milliliters with water.
- 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).
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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
- This application is a divisional application of Ser. No. 10/395,444, filed Mar. 24, 2003; which is a continuation of Ser. No. 09/864,617, filed May 24, 2001; which is a divisional application of application Ser. No. 09/337,310, filed Jun. 21, 1999 (now U.S. Pat. No. 6,255,325); which is a divisional of 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 application Ser. No. 08/827,230, filed Apr. 2, 1997 (now U.S. Pat. No. 5,908,850) and of application Ser. No. 08/647,642, filed May 15, 1996 (now abandoned); the former being a continuation of Ser. No. 08/567,131, filed Dec. 4, 1995, (now abandoned) and the latter being a continuation-in-part of application Ser. No. 08/583,317, filed Jan. 5, 1996, (now U.S. Pat. No. 5,733,756. The above are incorporated herein by reference in their entirety.
- 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.
- 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.
-
- 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.
- 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:
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:
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.
- 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.
- 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.
- 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.
- 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 - 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.
- 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 (12)
1. A method of treating Attention Deficit Disorder on a daily basis while reducing side effects associated with the administration of racemeic threo methylphenidate which comprises administrating on a daily basis to a human in need thereof an amount of D-threo methylphenidate or a pharmaceutically acceptable salt thereof, substantially free of L-threo methylphenidate, wherein the amount administered is effective to treat Attention Deficit Disorder while reducing side effects associated with racemic threo methylphenidate.
2. The method according to claim 1 wherein the amount administered is 5 mg to 50 mg per day.
3. The method according to claim 2 wherein the amount administered is 5 mg per day.
4. 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.
5. 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.
6. The method according to claim 1 wherein the side effects are anorexia, weight loss, insomnia, dizziness, or dysphoria.
7. The method according to claim 1 wherein the side effect is a euphoric effect.
8. The method according to claim 1 wherein the side effect is drug abuse potential.
9. The method according to claim 1 wherein the amount of D-threo methylphenidate enhances therapeutic activity compared to racemic methylphenidate.
10. The method according to claim 1 wherein the administration is daily.
11. The method according to claim 1 wherein the administration is one to four times per day.
12. The method according to claim 1 wherein said amount of D-threo methylphenidate or pharmaceutically acceptable salt thereof comprises a carrier or diluent.
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US6602887B2 (en) | 2003-08-05 |
CA2241611C (en) | 2004-08-17 |
US20060030587A1 (en) | 2006-02-09 |
CY1107748T1 (en) | 2013-04-18 |
DK1032389T3 (en) | 2007-11-12 |
DE69838179T2 (en) | 2008-04-17 |
EP1844777A1 (en) | 2007-10-17 |
US20090088455A1 (en) | 2009-04-02 |
EP1032389A4 (en) | 2002-07-03 |
US20130109719A1 (en) | 2013-05-02 |
IL135288A0 (en) | 2001-05-20 |
DE69838179D1 (en) | 2007-09-13 |
CA2468370A1 (en) | 1999-03-29 |
EP1032389B1 (en) | 2007-08-01 |
US20030232857A1 (en) | 2003-12-18 |
PT1032389E (en) | 2007-09-05 |
AU738521B2 (en) | 2001-09-20 |
WO1999016439A1 (en) | 1999-04-08 |
EP1032389A1 (en) | 2000-09-06 |
US5922736A (en) | 1999-07-13 |
CA2241611A1 (en) | 1999-03-29 |
US20100035928A1 (en) | 2010-02-11 |
ATE368458T1 (en) | 2007-08-15 |
US6255325B1 (en) | 2001-07-03 |
CA2468370C (en) | 2009-02-24 |
ES2289787T3 (en) | 2008-02-01 |
IL135288A (en) | 2007-06-03 |
EP1032389B8 (en) | 2008-05-28 |
US20050049279A1 (en) | 2005-03-03 |
US20010041717A1 (en) | 2001-11-15 |
NZ503571A (en) | 2003-04-29 |
US20110201645A1 (en) | 2011-08-18 |
AU7976598A (en) | 1999-04-23 |
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