Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
  • A61P25/24—Antidepressants

Definitions

• Depression in its many variations has recently become much more visible to the general public than it has previously been. It is now recognized as an extremely damaging disorder, and one that afflicts a surprisingly large fraction of the population. Suicide is the most extreme symptom of depression, but millions of people, not quite so drastically afflicted, live in misery and partial or complete uselessness, and afflict their families as well by their affliction.
• the introduction of fluoxetine, a serotonin reuptake inhibitor (SRI) was a breakthrough in the treatment of depression, and depressives are now much more likely to be diagnosed and treated than they were only a decade ago.
• Depression is often associated with other diseases and conditions, or caused by such other conditions. For example, it is associated with Parkinson's disease; with HIV; with Alzheimer's disease; and with abuse of anabolic steroids. Depression may also be associated with abuse of any substance, or may be associated with behavioral problems resulting from or occurring in combination with head injuries, mental retardation or stroke.
• a side effect sometimes associated with serotonin reuptake inhibitors concerns the gastrointestinal system wherein symptoms are often manifested as nausea and occasional vomiting.
• An additional troubling side effect associated with serotonin reuptake inhibitors is sexual dysfunction. It has been estimated that such sexual dysfunction is as high as 34%. [See F.M. Jacobsen, J. Clin . Psychiatry, 53, 119, (1992)].
• These side effects often result in depressed patients not maintaining the SRI therapy for a period that is long enough in duration to recognize any significant improvement in the patient's condition.
• a benefit of the present adjunctive therapy is a reduction of the above-noted gastrointestinal side effects and/or improvement of the sexual dysfunction known to be associated with the administration of serotonin reuptake inhibitors. It is believed that such a reduction in gastrointestinal side effects and/or improvement of sexual dysfunction will result in increased patient compliance with the SRI therapy, and ultimately, an improvement in lifestyle.
• the present invention provides a method for treating a patient suffering from depression, comprising administering to said patient an effective amount of a first component which is a 5-HT 3 receptor antagonist, in combination with an effective amount of a second component which is a serotonin reuptake inhibitor.
• the invention further provides a method for treating a patient suffering from anxiety disorders, premenstrual syndrome (PMS) and anorexia nervosa, comprising administering to said patient an effective amount of a first component which is a 5-HT 3 receptor antagonist, in combination with an effective amount of a second component which is a serotonin reuptake inhibitor.
• the invention also provides a pharmaceutical composition which comprises a first component which is a 5- HT 3 receptor antagonist, and a second component which is a serotonin reuptake inhibitor.
• the above adjunctive therapies of the present invention result in a reduction of gastrointestinal side effects and/or improvement of sexual dysfunction.
• the present invention provides the advantage of treatment of depression with a serotonin reuptake inhibitor with a reduction in gastrointestinal side effects or improvement in sexual dysfunction observed with such treatment, conferring a marked and unexpected benefit on the patient.
• the first component is a compound which functions as a 5-HT 3 receptor antagonist.
• 5-HT 3 receptor antagonists include but are not limited to the following compounds:
• 5-HT 3 receptor antagonists are Ondansetron; Granisetron; Bemesetron; Tropisetron; FK1052; YM-060; and MDL 72222.
• the second component is a compound which functions as a serotonin reuptake inhibitor.
• the measurement of a compound's activity in that utility is now a standard pharmacological assay. Wong, et al . ,
• reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong supra .
• Serotonin reuptake inhibitors include, but are not limited to:
• Fluoxetine N-methyl-3- (p-trifluoromethylphenoxy) - 3-phenylpropylamine, is marketed in the hydrochloride salt form, and as the racemic mixture of its two enantiomers.
• fluoxetine will be used to mean any acid addition salt or the free base, and to include either the racemic mixture or either of the R and S enantiomers;
• Duloxetine N-methyl-3- (1-naphthalenyloxy) -3- (2- thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Patent 4,956,388, which shows its high potency. The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule; Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Patent 4,761,501.
• Venlafaxine is identified as compound A in that patent; Milnacipran (N,N-diethyl-2-aminomethyl-l- phenylcyclopropanecarboxamide) is taught by U.S. Patent 4,478,836, which prepared milnacipran as its Example 4. The patent describes its compounds as antidepressants. Moret et al., Neuropharmacology 24, 1211-19 (1985), describe its pharmacological activities as an inhibitor of serotonin and norepinephrine reuptake;
• Sertraline, (lS-cis) -4- (3, 4-dichlorophenyl) - 1,2,3 , 4-tetrahydro-N-methyl-1-naphthylamine hydrochloride, is a serotonin reuptake inhibitor which is marketed as an antidepressant . It is disclosed by U.S. Patent 4,536,518. All of the U.S. patents which have been mentioned above in connection with compounds used in the present invention are incorporated herein by reference. It is understood that all of the 5-HT 3 receptor antagonists and serotonin reuptake inhibitors mentioned hereinabove for use in the present invention are readily prepared by one of ordinary skill in the art using known techniques and procedures .
• combinations and methods of treatment using fluoxetine or duloxetine as the second component are preferred.
• combinations and methods of treatment using Zatosetron as the first component and fluoxetine as the second component are preferred.
• Many of the compounds used in this invention are amines, and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
• Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, -bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
• organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, -bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
• salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxyben- zoate, methoxybenzoate, phthalate, sulfonate, xylenesulfon- ate, phenylacetate, phenylprop
• Preferred pathological conditions to be treated by the present method of adjunctive therapy include depression, bulimia, obsessive- compulsive disease, premenstrual dysphoric disorder, anxiety and obesity.
• Another preferred condition more specific to combinations including preferably duloxetine but also venlafaxine and milnacipran is urinary incontinence.
• Depression in all its variations is an especially preferred target of treatment with the present adjunctive therapy and compositions.
• Anxiety and its frequent concomitant, panic disorder may be particularly mentioned in connection with the present compounds. The subject is carefully explained by the Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association, which classifies anxiety under its category 300.02.
• Obsessive-compulsive disease appears in a great variety of degrees and symptoms, generally linked by the patient's uncontrollable urge to perform needless, ritualistic acts. Acts of acquiring, ordering, cleansing and the like, beyond any rational need or rationale, are the outward characteristic of the disease. A badly afflicted patient may be unable to do anything but carry out the rituals required by the disease. Fluoxetine is approved in the United States and other countries for the treatment of obsessive- compulsive disease and has been found to be effective.
• Obesity is a frequent condition in the American population. It has been found that fluoxetine will enable an obese patient to lose weight, with the resulting benefit to the patient's circulation and heart condition, as well as general well being and energy.
• Urinary incontinence is classified generally as stress or urge incontinence, depending on whether its root cause is the inability of the sphincter muscles to keep control, or the overactivity of the bladder muscles.
• Duloxetine controls both types of incontinence, or both types at once, and so is important to the many people who suffer from this embarrassing and disabling disorder.
• the present combination is useful for treating many other diseases, disorders and conditions as well, as set out below.
• the diseases to be mentioned here are classified in the International Classification of Diseases, 9th Edition (ICD) , or in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Version Revised, published by the American Psychiatric Association (DSM) .
• ICD International Classification of Diseases
• DSM Diagnostic and Statistical Manual of Mental Disorders, 3rd Version Revised, published by the American Psychiatric Association
• the ICD or DSM code numbers are supplied below for the convenience of the reader. depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81,
• sexual dysfunction refers to a decrease in sexual functioning or a decrease in sexual interest or desire, or a combination of both a decrease in sexual functioning and a decrease in sexual interest or desire.
• sexual dysfunction includes the following symptoms alone or in any combination; a decrease in the ability to become sexually excited, an increased latency of time to achieve orgasm, an inability to achieve orgasm, a decrease in the male's ability to get an erection or to maintain an erection, failure of the male to obtain an erection, decreased libido, and the like. It is understood that the term “sexual dysfunction” includes within its scope "substance-induced sexual dysfunction".
• subject-induced sexual dysfunction refers to a clinically significant sexual dysfunction that results in marked distress or interpersonal difficulty.
• the sexual dysfunction is judged to be fully explained by the direct physiological effects of a substance (i.e., a drug of abuse, a medication, or toxin exposure) .
• the sexual dysfunction is not better accounted for by a sexual dysfunction that is not substance- induced.
• an improvement in sexual dysfunction means there has been an increase in sexual functioning or an increase in sexual interest or desire, or a combination of both an increase in sexual functioning and an increase in sexual interest or desire.
• an improvement in sexual dysfunction includes the following symptoms alone or in any combination; an increase in the ability to become sexually excited, a decreased latency of time to achieve orgasm, an increased ability to achieve orgasm, an increase in the male's ability to get an erection or to maintain an erection, increased libido, and the like.
• gastrointestinal side effect includes but is not limited to nausea, vomiting or diarrhea, or any combination thereof.
• the dosages of the drugs used in the present invention must, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of -li ⁇
• the term "effective amount” is the amount or dose of the compound which provides the desired effect in the patient under diagnosis or particular treatment, such as treatment for depression.
• Zatosetron about 0.25 to 200 mg, once/day; preferred, about 0.5 to 100 mg, once/day; most preferably about 0.5 to 50 mg once/day; and most especially preferred about 0.5 to 10 mg once/day.
• Olanzapine about 0.25 to 200 mg, once/day; preferred, about 1 to 40 mg, once/day; most preferably about 2.5 to 30 mg once/day; and most especially preferred about 5 to 25 mg once/day.
• Fluoxetine from about 1 to about 80 mg, once/day; preferred, from about 10 to about 40 mg once/day; preferred for bulimia and obsessive-compulsive disease, from about 20 to about 80 mg once/day;
• Duloxetine from about 1 to about 30 mg once/day; preferred, from about 5 to about 20 mg once/day;
• Venlafaxine from about 10 to about 150 mg once- thrice/day; preferred, from about 25 to about 125 mg thrice/day;
• Milnacipran from about 10 to about 100 mg once- twice/day; preferred, from about 25 to about 50 mg twice/day;
• Citalopram from about 5 to about 50 mg once/day; preferred, from about 10 to about 30 mg once/day;
• Fluvoxamine from about 20 to about 500 mg once/day; preferred, from about 50 to about 300 mg once/day;
• Paroxetine from about 20 to about 50 mg once/day; preferred, from about 20 to about 30 mg once/day.
• Sertraline from about 20 to about 500 mg once/day; preferred, from about 50 to about 200 mg once/day;
• the term "patient” refers to a warmblooded mammal such as a dog, rat, mouse, human and the like.
• the preferred patient is a human.
• the adjunctive therapy of the present invention is carried out by administering a first component together with the second component in any manner which provides effective levels of the compounds in the body at the same time. All of the compounds concerned are orally available and are normally administered orally, and so oral administration of the adjunctive combination is preferred. They may be administered together, in a single dosage form, or may be administered separately.
• oral administration is not the only route or even the only preferred route.
• transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine.
• One of the drugs may be administered by one route, such as oral, and the others may be administered by the transdermal , percutaneous, intravenous, intramuscular, intranasal or intrarectal route, in particular circumstances.
• the route of administration may be varied in any way, limited by the physical properties of the drugs and the convenience of the patient and the caregiver.
• the adjunctive combination may be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both compounds are important embodiments of the present invention.
• Such compositions may take any physical form which is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred.
• Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered.
• Each adjunctive dosage unit may contain the daily doses of all compounds, or may contain a fraction of the daily doses, such as one-third of the doses.
• each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compounds. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compounds .
• the amounts of each drug to be contained in each dosage unit depends on the identity of the drugs chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given.
• compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used.
• the amount of the compounds is best defined as the effective amount, that is, the amount of each compound which provides the desired dose to the patient in need of such treatment.
• adjunctive combinations do not depend on the nature of the composition, so the compositions are chosen and formulated solely for convenience and economy. Any of the combinations may be formulated in any desired form of composition. Some discussion of different compositions will be provided, followed by some typical formulations.
• Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
• the usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders .
• Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like.
• Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
• a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
• the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
• Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums.
• corn and potato starches methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
• Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. It is preferred to formulate duloxetine and duloxetine- containing combinations as enteric compositions, and even more preferred to formulate them as enteric pellets.
• a preferred duloxetine enteric formulation is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer.
• HPMCAS hydroxypropylmethylcellulose acetate succinate
• Tablets are often coated with sugar as a flavor and sealant.
• the compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice.
• Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.
• the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
• Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.
• Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with innumerable pores through which the drugs are pumped by osmotic action.
• Hard gelatin capsules are prepared using the following ingredients:
• a tablet is prepared using the ingredients below:
• the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool .
• Purified water to total 5 ml
• the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
• the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
• composition 6 An intravenous formulation may be prepared as follows:

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• 1999
  • 1999-05-10 CA CA002332253A patent/CA2332253A1/en not_active Abandoned
  • 1999-05-10 AU AU38912/99A patent/AU3891299A/en not_active Abandoned
  • 1999-05-10 EP EP99921795A patent/EP1077704A4/de not_active Withdrawn
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