Another embodiment of the invention relates to a phar maceutical composition comprising the succinate salt of 11.04 5,8,14-triazatetracyclo[l0.3.l .02 9 ]-hexadeca-2(11 ),3, • • 5,7,9-pentaene and a pharmaceutically acceptable carrier or excipient, particularly, one for use in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (eq., depen dencies on, or addictions to nicotine (and/or tobacco 55 products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TEI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related 60 cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome.

The present invention further relates to a the method of treating inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (e.q., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TEI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzhe imer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome comprises administering to a subject in need of treatment a therapeutically effective amount of the succinate salt of 11 .04 5,8,14-triazatetracyclo[l0.3.

Another more preferred embodiment of the invention relates to a method of treatment for nicotine dependency, addiction and withdrawal, in particular for use in smoking cessation therapy activity, comprising the administration of the succinate salt of 5,8,14-triazatetracyclo 11 .04 [10.3.1.02 9 ]-hexadeca-2(11),3,5,7,9-pentaene to a sub- 30 • • ject in need thereof.

Variations 40 may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as 10 high molecular weight polyethylene glycols.

These studies can help identify problems with low melting points, determined by hot-stage microscopy, and hygroscopicity, if processed on a suitable apparatus (e.g., Dynamic Vapour Sorption Analyser, model DVS-l, Surface Measurement Systems Ltd.).

In parallel with these studies, a preliminary high perfor mance liquid chromatographic (HPLC) method is quickly developed to give an estimate of the purity of the sample, whilst infrared and other spectroscopic techniques may be Vol.

Table 2. a Preformulation studies that are normally considered for comparison of salt forms and parent compound for oral dosage forms test suitable techniques comments dissociation constant and basic physico-chemical properties melting point aqueous solubility pH of solution cosolvent solubility common ion effect on solubility hygroscopicity potentiometry, solubility, UV spectroscopy capillary m.pt., hot stage microscopy, differential scanning calorimetry overnight equilibration at 25 DC; analysis by UV spectroscopy or HPLC overnight equilibration at 25 DC, analysis by UV spectroscopy or HPLC overnight equilibration at 25 DC in suitable media and analysis by UV spectroscopy or HPLC use DVS apparatus or expose to various RH values and measure weight gain after 1 week intrinsic dissolution rate use Wood's apparatus 14 crystal shape and appearance SEM or optical microscopy particle size polymorphismJpseudopolymorphism powder properties stability SEM and laser diffraction recrystallizations, HSM, DSC, TGA bulk density measurement various determine pKa for parent drug perform on each salt and compare to parent Perform on each salt and compare to parent Examine pH of saturated solution if quantities permit.

If 20-50% of the weight of the drug substance is due to inactive counterion, the addition of suitable excipients for encapsulation or tableting may result in a powder volume that is too great, even after granulation, to fit successfully into even the largest acceptable capsule shell.

12 The aim of both the Preformulation and Process Chemistry teams is to finalise the definition of all of the characteristics of the drug substance in readiness for the initiation of Phase IIa clinical trials Acknowledgment We thank our colleagues for their scientific contributions made during these studies and for the stimulating discussions held.

While examples exist in the art suggesting that CR dosage forms may in some cases provide for a reduction in such side effects as nausea (e.g., oxycodone (J, R. Caldwell, et al., J. of Rheumatology.1999, 26, 862-869), venlafaxine (R. Entsuah and R. Chitra, Psychopharmaco/ogy Bulletin, 1997, 33, 671-676) and paroxetine (R. N. Golden, et al., J. Cl/n.

Although consideration of the chemical structure and identification of reactive moieties therein can be used to theorize potential degradation pathways, it remains impossible to predict a priori whether a particular excipient will form an acceptably stable formulation with a given drug.

certainly provide for the benefits described in the present Invention, the inventors have found that to achieve the desired therapeutic blood levels while maintaining the nausea reduction, the drug is administered at a rate of between about 0.06 and 3 mgAlhr; and more preferably between 0.1 and 1 mgA/hr.

Suitable salt derivatives Include halides, thiocyanates, sulfates, bisulfates, sulfites, phosphonates, monohydrogen-phosphates, alkylsulfates, arylsulfonates, bisulfltes, alkanoates, pyrophosphonates, metaphosphates, dihydrogenphosphates, · cycloalkylalkanoates, arylalkonates, adipates, alginates, aspartates, benzoates, fumarates, glucoheptanoates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, camphorates, citrates, tartarates, succlnates, pivalates, picrates, pectinates, camphorsulfonates, digluconates, trifluoroacetates, and the like.

ranu a Ing gen It' A lsoproovl 5.70 o 260.20 q - 333.30 a 333.30 Cl - 50.00 !l - 533.30 o s.ooa 12.50 a 5.70 a 255.20 a 333.30 a - 333.30 o 10.00 g 50.00 g 533.30 o - 5.00 !l 7.50 !l The Inactive Ingredients listed above the granulating agent (water or isopropyl alcohol) in the formulation table were added to a high shear blender and dry mixed for 1 minute at 100 rpm impeller speed.

Howard C. Klein, Brooklyn, N. Y., and Walter Anthony Di Salvo, North Arlington, and Rofand Kapp, Newark, N. J., assignors to Nopco Chemical Company, f'I:?r• rison, N. J., a corporation of New Jersey No Drawing.

A further object of the invention is to provide im proved means for producing salts of choline which are highly suitable for pharmaceutical use.

The above and other objects of the invention are ac complished by first reacting trimethylamine with ethylene oxide and water in an aqueous alcohol solution containing one mole of water for each mole of trimethylamine, treat- ing the resulting reaction mixture with whatever acid is to be used for producing the choline salt, preferably using an alcoholic solution of the acid, cooling the reaction mixture to a relatively low temperature, and then sepa rating from the cooled reaction mixture the choline salt which crystallizes therefrom at the low temperature; Choline salts produced in this manner are anhydrous and In addition, the yields have a purity of 99% or better.

The white crys- talline choline dihydrogen citrate which formed was sepa rated from the solvent mixture by filtration and dried in vacuo.

A process for preparing a crystalline anhyd_rous salt of choline having a purity of at least 99% which com prises the steps of ( 1) reacting at least one mol of ethyl ene oxide with one mo!

THE “DUMB cops" IMAGE One day this past fall we Were going through the daily Washington ritual of reviewing the current issue of the Federal Register—which is the principal means of keeping track of what is happening in the executive branch of government—when we spotted reference to a Presidential Proclamation which caught our eye.

In recent months, we have seen repeated instances where official notices, proposals, or finalized regulations issuing from DEA and published in the Federal Register have used terminology and nomenclature to describe the drugs involved which have been confusing, inconsistent, or otherwise inaccurate.

Iodide Isethionate' Lactate Lactobionate Malate Maleate Mandelate Mesylate Methylbromide Methylnitrate Methylsulfate Mucate Napsylate Nitrate Pamoate (Embonate) Pantothenate Phosphate/diphosphate Polygalacturonate - Salicylate Stearate Subacetate Succinate Sulfate Tannate Tartrate _ TeoclateJ Triethiodide Cation Metallic: Aluminum Calcium Lithium Magnesium Potassium Sodium Zinc 2.02 0.88 0.76 0.13 0.13 .

I Table II—Non-FDA—Approved Commercially Marketed Saltsf——————-—— Anion Percent‘zW Adipate Alginate _ Aminosalicylate Anhydromethylenecrtrate Arecolirie Aspartate Bisulfate Butylbromide Camphflrate Digluconate _ Dihydrobromide Disuccinate Glycerophosphate Hemisulfate Hydrofluoride Hydroiodide Methylenebis(salicylate) _ Napadisylate” , Oxalate Pectinate Persulfate Phenylethylbarbiturate Picrate Propionate Thiocyanate Tosylate Undecanoate ‘ .

molecules and colloidal particles have an affinity for the 3' 13mlphatic system, streptomycin, neomycin, viomycin, and streptothrycin were combined with high molecular weight compounds such as polyacrylic acids, sulfonic or phos- phorylated polysaccharides, and polyuronic derivatives.

The combined organic phases were washed with water and evaporated to give the free base of the title compound in 700 g yield.

The reac­ tion mixture was stirred until a clear solution was obtained, then the methylene chloride phase was separated and washed twice with water (2 1).

The solution was slowly cooled under stirring to 5°-10° C. and the precipitate was collected by filtration and dried to give the desired product in 980 g (90%) yield.

Recrystallization from warm (80° C.) 2-propanol (5 1) added activated carbon (10 g) gave after filtration and cooling to 5°-10° C. pure crystals of the title compound.

A method of treating cognitive dysfunction caused by Alzheimer’s disease in a mammal comprising administering an effective amount of the compound according to claim 1.

Slovenia Slovakia Senegal Swaziland Chad Togo Tajikistan Turkmenistan Turkey Trinidad and Tobago Ukraine Uganda United States of America Uzbekistan Viet Nam Yugoslavia Zimbabwe

Establisment of water content a) Thermogravirnetric assay Thennogravimetn'c measurements performed showed that the anhydrous form of (R)—3— N,N-dicyclobutylamino-8-fluoro—3,4-dihydro-2H~ 1 -benzopyran—5—carboxamide hydrogen (2R,3R)-tartrate obtained in Example 1 had an initial weight loss of 0.997% w/w.

The use according to claim 8 in the manufacture of a medicament in prevention or in the treatment of 5-HT1A receptor antagonist activity related CNS disorders and medical disturbances.

The use according to claim 7 in the manufacture of a medicament in prevention or in the treatment of 5-HTIA receptor antagonist activity related CNS disorders and medical disturbances.

Claims Nos: because they relate to subject matter not required to be searched by this Authority, namely: A method for treatment of the human or animal body by therapy, see Rule 39.1.

Ath letic food preparations containing L-carnitine are widely used, since they contribute significantly to sup plying the muscles with energy and promote endurance performance.

Such preparations have great importance since they improve muscle activity and thereby bring about increased endurance and stress tolerance as well as delaying fatigue and shortening recovery time.

The object of the invention is to make available a nonhygroscopic and odorless form of L-carnitine, 45 which contains no physiologically unsafe additives and which is preferably suitable in particular for producing tablets or capsules.

Production of L-carnitine-L-tartrate L-tartaric acid was dissolved in the required quantity of hot 90 percent aqueous ethanol, the calculated quan tity of L-carnitine was added, the salt was brought to crystallization by cooling, filtered and dried.

microcrystalline silicon dioxide (Aerosil ® 200) talc magnesium stcarate 4.392 kg 2.028 kg 420 g 360 g 60 g 480 g 60 g The L-carnitine-L-tartrate was homogeneously mixed with the wheat starch and the cellulose and sifted.