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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to a method for using duloxetine for the treatment of hot flashes.
• Hot flashes or flushing is characterized by a sudden onset of warmth in the face and neck and often progressing to the chest . Such an episode generally lasts several minutes and is evidenced by a visible flushing of the skin. Often such episodes are accompanied by sweating, dizziness, nausea, palpitations and diaphoresis. Such symptoms can disrupt sleep and interfere with the quality of life.
• menopause is associated with vasomotor symptoms, manifested by hot flashes, which are variable in frequency and severity, and may persist for several months or a few years. Approximately 75% of menopausal women will experience hot flashes during menopause (McKinlay, S.,
• ERT estrogen replacement therapy
• this therapy while effective, suffers from poor patient compliance, due to unpleasant side-effects, poor oral absorption, and poor bio-availability of the natural estrogens 17 ⁇ -estradiol and estrone.
• Non-hormonal alternatives for hot-flashes are extremely limited at present and have been associated with poor response in many patients.
• the two most widely used no- hormonal therapeutic modalities at present in the United States are clonidine and Bellargal spacetabs . Neither has gained wide clinical acceptance because of poor effectiveness and side effects.
• the hot flash activity may be alleviated via treatment with venlafaxine.
• venlafaxine treated menopausal women did not report a 50% decrease in hot flash frequency. Id. at 2059.
• any venlafaxine "efficacy must be balanced against the drug's side-effects.”
• the hot flash mechanism may indeed be mediated through serotonin and norepinephrine reuptake inhibition, it can not be predicted a priori whether a pharmaceutical that is classified as a SSRI is effective at decreasing the incidence of hot flashes. Further, it would be optimal to find a method of treatment for hot flashes with greater efficacy and/or greater safety.
• Another aspect of the invention is a method for treating hot flashes in a human female undergoing ERT comprising administering duloxetine to a human female in need thereof an effective amount of duloxetine.
• Another aspect of the invention is a method for treating hot flashes comprising administering duloxetine to a human female where estrogen replacement thereof is contradicted.
• Another aspect of the invention is a method for treating hot flashes in a human female undergoing raloxifene administration comprising administering duloxetine to a human female in need thereof an effective amount of duloxetine.
• Further aspects of the present invention include a use of duloxetine for the manufacture of a medicament for treating hot flashes in a human, use of duloxetine for the manufacture of a medicament for treating hot flashes in a human undergoing ERT and a use of duloxetine for the manufacture of a medicament for treating hot flashes in a human female undergoing raloxifene administration.
• Duloxetine is N-methyl-3- (1-naphthalenyloxy) -3- (2- thienyl)propanamine. It is usually administered as the (+) enantiomer, and as the hydrochloride salt. It was first taught by U.S. Patent 4,956,388, which teaches the synthesis of the compound as well as its high potency as an uptake inhibitor of both serotonin and norepinephrine . The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule, as well as to either an enantiomer or the racemate. It is to be understood, however, that the (+) enantiomer is preferred.
• the term "active ingredient” refers to duloxetine as it is usually administered.
• the term “treating” includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, decreasing the incidences or reversing progression, severity, of a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
• the term "effective amount” refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment.
• An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
• a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
• a typical daily dose may contain from about 60 to about 80 mg of the active ingredient.
• the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
• the term "patient” refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
• the compound is particularly selective, having few if any physiological effects besides those on norepinephrine and serotonin processing, and therefore is free of side effects and unwanted activities. Further, it is effective at relatively low doses, as discussed below, and may safely and effectively be administered once or twice per day. Thus, difficulties created by the multiple dosing of patients, who are children and disorganized adults, are completely avoided.
• duloxetine for the treatment of a given patient with any particular disorder will vary, depending on the characteristics of the patient, as all clinicians and medical doctors are aware. Factors such as other diseases from which the patient suffers, the patient's age and size, and other medications which the patient may be using will have an effect on the duloxetine dose and will be taken into account. In general, however, the daily dose of duloxetine is from about 1 to about 80 mg. A more preferred dose range is from about 60 to about 80 mg daily.
• Another preferred dose is about 60mg taken once per day. Another preferred dose is 40 mg taken twice per day.
• Duloxetine is orally available and presently is orally administered, in the form of a tablet or a capsule full of enteric coated granules. Oral administration in such forms is preferred in the practice of the present invention. However, other routes of administration are also practical and may be preferred in certain cases. For example, transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine. Sustained release formulations, oral or percutaneous, may be prepared, but are not preferred because duloxetine is quite effective when administered once or twice daily and there is little benefit from the additional effort of preparing the sustained action product.
• duloxetine for use in the present invention follows the methods used in formulating duloxetine for other purposes, and indeed methods usual in pharmaceutical science are appropriate.
• a preferred formulation of duloxetine comprises enteric pellets, or granules, of which a number. are charged in a gelatin capsule.
• Raloxifene hydrochloride (raloxifene) is described in U.S. Patent No. 4,418,068 and is known to be effective in treating the symptoms of post menopausal syndrome, particularly osteoporosis. Indeed, raloxifene was approved for marketing as a preventive agent for osteoporosis by the U.S. Food and Drug Administration in late 1997.
• Raloxifene has the following structure:
• the preferred duloxetine enteric formulation comprises 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
• the duloxetine layer was built up by suspending duloxetine in a 4% w/w solution of the hydroxypropylmethylcellulose in water, and milling the suspension with a CoBall Mill (Fryma Mashinen AG, Rheinfelden, Switzerland) model MS- 12. A fluid bed dryer with a Wurster column was used to make this product, at a batch size of 1.0 kg. The separating layer was added from a 4% w/w solution of the hydroxypropyl-methylcellulose in water, in which the sucrose was also dissolved.
• the enteric coating suspension In order to prepare the enteric coating suspension, purified water was cooled to 10°C and the polysorbate, triethyl citrate and silicone emulsion were added and dispersed or dissolved. Then the HPMCAS and talc were added and agitated until homogeneity was obtained, and the HPMCAS was fully neutralized by addition of ammonium hydroxide until solution of the polymer was complete. To this suspension, a carboxymethylcellulose aqueous solution, 0.5% w/w, was added and blended thoroughly. The enteric suspension was maintained at 20°C during the coating process. The enteric suspension was then added to the partially completed pellets in the Wurster column at a spray rate of about 15 ml/min, holding the temperature of the inlet air at about 50°C.
• duloxetine and raloxifene are both employed, they may be administered sequentially, concurrently, or simultaneously as a single composition to the subject. If administered sequentially, the period between the administration of duloxetine and raloxifene will typically be one week to one month, and optimally, one day to one week. In a preferred administration scheme, the human will receive duloxetine and raloxifene concurrently or simultaneously.
• duloxetine and raloxifene may be administered systemically orally.
• an effective dose of duloxetine will range between values described above.
• the total dosage (per day) of raloxifene will typically be in the range from about 1 mg to 1000 mg per day, usually being in the range from about 10 mg to 100 mg per day, preferably being in the range from about 25 mg to 75 mg per day, more preferably being in the range from about 55 mg to 65 mg per day, and most preferably being 60 mg per day.
• the patient to be benefited by practice of the present invention is a patient experiencing vasomotor symptoms such as hot flashes, a sudden brief flushing and sensation of heat caused by dilation of skin capillaries. Diagnosis of this disorder is to be made by a physician. It is presently believed that duloxetine' s potency in inhibiting the uptake of serotonin and norepinephrine is the mechanism by which it benefits such patients, by alleviating the effects of the disorder from which the patient suffers, or even eliminating the disorder completely.
• Patients eligible for a clinical trial include women who are either 1) naturally menopausal; or 2) pre-menopausal but had undergone bilateral oophorectomy surgery within four weeks prior to the commencement of the study. All the women in the study experience a minimum of thirty five hot flashes per week. Men considered for a clinical trial would have androgen deprivation therapy for prostate cancer scheduled to continue at least 6 weeks beyond the trial entry date. Men have bothersome hot flashes for at least the previous month a minimum of fourteen times weekly of sufficient severity to desire therapeutic intervention. The women or men are divided into two groups for a randomized double- blind placebo controlled study.
• the groups receive drug or placebo as illustrated below:
• both groups are administered placebo only.
• each group is administered drug or placebo.
• Data is collected (numbers/severity of hot flashes experienced) from each participant during and at the end of the test period.

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• 2002
  • 2002-03-15 EP EP02707828A patent/EP1383495A1/de not_active Withdrawn
  • 2002-03-15 WO PCT/US2002/005113 patent/WO2002078691A1/en not_active Application Discontinuation
  • 2002-03-15 JP JP2002576957A patent/JP2004525940A/ja active Pending
  • 2002-03-15 CA CA002442410A patent/CA2442410A1/en not_active Abandoned

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