MXPA00008204A - Fluoxetine hydrochloride for decreasing hot flashes - Google Patents

Abstract

The present invention includes a method for decreasing hot flashes in a human female by administering fluoxetine to that female. Another aspect of the invention is a method for decreasing hot flashes in a human female undergoing raloxifene administration by administrating fluoxetine to that female. Another aspect of the invention is a pharmaceutical formulation comprising fluoxetine and raloxifene.

Description

FLUOXETINE CHLORHYDRATE FOR DECREASE. FROM THE SUDDEN HEAT ACCESS FIELD OF THE INVENTION The present invention relates to the use of fluoxetine hydrochloride for the reduction of hot flashes.

BACKGROUND OF THE INVENTION In general, menopause is associated with vasomotor symptoms, manifested by sudden hot flashes, flushing, or sweating at night, which are variable in frequency and severity, and may persist for several months or a few years. Approximately 75% of menopausal women will experience sudden falls during menopause (McKinlay, S., Jeffreys, M., "The Menopausal Syndrome, "J. Pre v. So c. Med., 28: 108, 1974), with 80% of them who experience for more than a year and 25 to 50% for more than 5 years. Judd, H.L., Cleary, REF .: 122184 R.E., Creasman, .T., Et al. , "Estrogen Replacement Therapy, "Obstet Gynecol., 58: 267, 1981. For some of these women, the symptoms are disability, Gambrell, RD Jr.," The Menopause: Benefits and Risks of Estrogen-Progestogen Replacement Therapy, "Fertile. ., 31: 451, 1982. The standard therapy for the relief of these symptoms is estrogen replacement therapy (ERT). Many women, unfortunately, are not candidates for ERT therapy because such The therapy is facultatively contraindicated (eg, trematoboembolic disease and estrogen-sensitive carcinoma) .In addition, this therapy, although effective, suffers from poor patient compliance, due to unpleasant side effects, poor oral absorption, and deficient spongi- lity of natural estrogens 17 ß-est radi ol and estrone Non-hormonal alternatives for hot flashes are extremely limited in the present and have been associated with poor responses in many patients. The two non-hormonal therapeutic modalities most widely used in the present in the United States are transdermal clonidine and small strips or spatial tabs from Bellargal. None has gained widespread clinical acceptance due to poor effectiveness and collateral effects. A recent report has established in a pilot study that 50% of menopausal women treated with tamoxifen (breast cancer survivors) who suffer from hot flashes reported a significant improvement in their hot flashes during tamoxifen therapy when Sertraline, a selective serotonin reuptake inhibitor (SSRI) of the formula, was also administered: Plouffe, et al. , "An Open Trial of Sertraline for Menopausal Hot Flushes: Potential Involvement of Serotonin in Vasomotor Instability", Del. Med. J., 69 (9): 481-2, 1997. Researchers believe that the mechanism of action of the sudden access of heat can be mediated through serotonin. However, the researchers also note that "unpublished clinical trials with various sex workers on menopausal women have failed to show any relief from hot flashes." ("unpublished clinical triais with various ser oninergi c agents in menopausal women have failed to take any relief from hot flushes.") Id. in 481. Therefore, although the mechanism of sudden heat access can be effectively mediated through serotonin, it can not be predicted at first whether a pharmaceutical product that is classified as an SSRI is effective in decreasing the incidence of the hot flashes.

DESCRIPTION OF THE INVENTION The present invention includes a method for the decrease of the hot flashes in a human female comprising the administration of an effective amount of fluoxetine to a human female or female with the need for it. Another aspect of the invention is a method for the decrease in hot flashes in a human female subject to the administration of raloxifene comprising the administration of fluoxetine to a human female in need thereof in an effective amount of fluoxetine. Another aspect of the invention is a pharmaceutical formulation comprising fluoxetine and raloxifene. Additional aspects of the present invention include a use of 'fluoxetine for the production of a medicament for the decrease of the hot flashes in a human female and a use of fluoxetine for the production of a medicament for the reduction of the sudden accesses of heat in a human woman submitted to the administration of raloxifene.

DETAILED DESCRIPTION OF THE INVENTION Fluoxetine hydrochloride (fluoxetine) is a well-known SSRI. See, for example. , U.S. Patent No. 4,590,213. Relating to clonidine and bellargal, fluoxetine has a favorable lateral effect profile. Fluoxetine has the following structure: The carbon atom denoted by an asterisk (*) is a chiral center. Accordingly, fluoxetine is enantiomeric, ie. , has an "R" and "S" enantiomer, both of which are shown below: • papßom (R) The present invention provides for the use of. a racemic mixture of fluoxetine, the (R) -enantiomer, the (S) -enantiomer, or an improved mixture with an enantiomer. An "improved" mixture is where an enatiomer composes between 50% and 99% of the total of the enantiomeric mixture. A preferred embodiment of the present invention is the use of a racemic mixture or a 90-99% mixture enhanced with the (R) -enantiomer. More preferred is the use of the substantially pure (R) enantiomer. When used in the present application, "substantially pure" means that the enantiomeric mixture contains at least 99% by weight of fluoxetine (R) and 1% or less of fluoxetine (S). Raloxifene hydrochloride (Raloxifene) is described in U.S. Patent No. 4,418,068, and is known to be effective in the treatment of the symptoms of post-menopausal syndrome, particularly osteoporosis. Indeed, raloxifene was approved for distribution as a preventive agent for osteoporosis by the North American Food and Drug Administration at the end of 1997. Raloxifene has the following structure: Clinical studies of raloxifene showed a slight increase in the number of women, relative to placebo, who reported incidences of hot flashes during the clinical trial. (24.6% for raloxifene versus 18.3% for placebo). Accordingly, another aspect of this invention is a method for the reduction of hot flashes in a human female submitted to the administration of raloxifene by the administration of fluoxetine. When "fluoxetine" and / or "raloxifene" are referred to, it is understood that such terms refer to fluoxetine hydrochloride (the racemate, individual enantiomers, or mixtures thereof) and raloxifene hydrochloride, respectively, and include other salts and solvates of the same.

The term "effective amount of fluoxetine" refers to an amount of fluoxetine that is capable of decreasing hot flashes. "Decrease of hot flashes" is defined by including either the reduction of occurrences or severity of hot flashes. The effective amount (per day) of fluoxetine will typically be in the range of about 1 mg to 200 mg per day, usually being in the range of about 5 mg to 80 mg per day, preferably being in the range of about 10 mg. to 60 mg per day, and most preferably being in the range of about 15 mg to 40 g per day. The term "effective amount of raloxifene" refers to an amount which inhibits bone weakness or an amount which is used for any other medical therapeutic reason. When fluoxetine is administered with raloxifene, the effective amount (per day) of raloxifene will typically be in the range of about 10 mg to 1000 mg per day, usually being in the range of about 10 mg to 100 mg per day, preferably being in the range of about 25 mg to 75 mg per day, more preferably being in the range of about 55 mg to 65 mg per day, and most preferably being in the range of 60 mg per day. The term "effective term" refers to the period of time that a human woman suffers from incidences of hot flashes and is usually greater than 6 months. The effective term must be determined by the attending physician in the consultation with the human patient patient of the attending physician. The term "human woman" as used here refers to a human woman who is suffering from hot flashes. These hot flashes are typically associated with the beginning of menopause (and, therefore, includes menopausal and post-menopausal women) but can also occur in "unnatural" environments, eg, when an oophorectomy has been performed. A human woman "undergoing the administration of raloxifene" includes women who are taking raloxifene.

The need for the inhibition of bone weakness in the context of the present invention may result locally in cases of bone fracture, defect, prosthesis implantation, and the like. Such need may also result in cases of systemic bone disease, such as osteoporosis, osteoarthritis, Paget's disease, multiple myeloma and other forms of cancer, bone weakness results from the side effects of other medical treatments (such as steroids), and loss of bone mass related to age. Raloxifene can be produced by established procedures, such as those detailed in U.S. Patent Nos. 4,418,068 and 5,629,425, the teachings of which are incorporated herein by reference. Fluoxetine, as a racemic mixture, can also be produced by established procedures, such as those detailed in U.S. Patent Nos. 4,314,081 and 4,194,009, the teachings of which are incorporated herein by reference. Substantially pure, the individual enantiomers of fluoxetine can be prepared by known procedures such as those taught in U.S. Patent No. 5,708,035, the teachings of which are incorporated herein by reference, and the references cited herein. See also, Robertson, et al. , J. Me d. Ch em. , 31: 1412-1417, 1988 for a synthesis of fluoxetine (S). The pharmaceutical formulations of the invention which include fluoxetine, or fluoxetine and raloxifene, for administration will generally include an effective amount of fluoxetine and an effective amount of raloxifene, when applicable, in addition to a pharmaceutically acceptable excipient. Formulations containing fluoxetine, without raloxifene, are taught in U.S. Patent No. 4,194,009, the teachings of which are incorporated herein by reference. Formulations containing raloxifene, without fluoxetine, are taught in U.S. Patent No. 4,418,068 and European Patent Application 95 / 301291.1, the teachings of which are incorporated herein by reference.

Suitable excipients include more approved carriers for parenteral administration, including water, saline, Ringer's solution, Hank's solution, and glucose, lactose, dextrose, ethanol, glycerol, albumin, and the like. These compositions can. optionally include stabilizers, antioxidants, antimicrobials, antiseptics, buffering agents, surfactants, and other secondary additives. Fluoxetine, or fluoxetine and raloxifene, can also be administered in an iontophoretic patch. A complete discussion of the appropriate vehicles for parenteral administration can be found in E. Martin, "Remington's Pharmaceutical Sciences" (Mack Pub. Co., the sections of this edition related to excipient vehicles and the formulation are incorporated here as reference to reveal them). Such formulations are generally known to those skilled in the art and are administered at the same time to provide systemic treatment. If a combination of fluoxetine and raloxifene is administered as a single composition, the molar ratio of raloxifene to fluoxetine will be about 10: 1 to 1:10, preferably about 4: 1 to 1: 3, and most preferably about 2.1. : 1 to 1.9: 1. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention. The term "active ingredients" refers to fluoxetine and raloxifene. Hard gelatin capsules are prepared using the following: Formulation 1 Gelatin Capsules Ingredient Quantity (mg / capsule) Fluoxe tina 0.1 - 1000 Raloxifene 0.1 - 1000 Starch, NF 0 - 650 Starch flowing powder 0 - 650 350 centistoke Silicone Fluid 0 - 15 The above formulation can be charged in accordance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients: Formulation 2 Tablets Ingredient Quantity (mg / tablet) Fluoxe tine 2.5 1000 Raloxy f ene 2.5 1000 Cellulose, microcrystalline 200 650 Silicon dioxide, smoking 10 650 Stearate Acid 5 15 The components are mixed and compressed to form tablets. Alternatively, each of the tablets containing 2.5-1000 mg of each of the active ingredients are made as follows: Formulation 1 Tablets Ingredients Amount (mg / tablet Fluoxetine 25 - 1000 Raloxy pheno 25 - 1000 Fécula 45 Cellulose, micr ocr i s talin 35 Polyvinylpyrrolidone 4 (as 10% solution in water) sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talc 1 The active ingredients, starch, cellulose are passed through a strainer of E.U.A. No. 45 mesh and mix thoroughly. The poly-inylpyrrolidone solution is mixed with the resulting powders which are passed through an E.U.A. No. 14. The granules thus produced are dried at 50 ° C-60 ° C and passed through a No. 18 mesh North American sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a US sieve No. 60, are then added to the granules which, after mixing, are compressed on a tablet-forming machine to give tablets. Each of the suspensions containing 0.1 - 1000 mg of each of the active ingredients per 5 ml dose are made as follows: Formulation 4 Ion suspensions Ingredient e Quantity (mg / 5 ml Fluoxetine 0.1 - 1000 mg Raloxi feno 0.1 - 1000 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavor c. v. C color . V. Water purified at 5 ml The active ingredients are passed through a sieve of E.U.A. No. 45 mesh and mixed with the sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared to contain the following ingredients: Formulation 5 Aero sun Ingredi e te Amount in pes o Fluoxetine 0.25 Ral oxy phene 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane 70.00 The active ingredients are mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C, and transferred to a refilling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container. Suppositories are prepared as follows: Formulation 6 Suppositories Ingredient e Quantity (mg / supos i t ori) Fluoxetine 250 Raloxy pheno 250 Fatty acid glycerides 2, 000 Saturated The active ingredients are passed through the No. 60 mesh U.S.A. sieve and become slurry in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. An intravenous formulation is prepared as follows Formulation 7 Intravenous Solution Ingredient Amount Fluoxetine 50 mg Raloxy pheno 50 mg Isotonic saline 1,000 mL The solution of the above ingredients is administered intra-thickly to a patient at a rate of about 1 ml per minute.

When both fluoxetine and raloxifene are employed, they may be administered sequentially, concurrently, or simultaneously as a unique composition to the subject. If administered sequentially, the period between the administration of fluoxetine and raloxifene will typically be from one week to one month, and optionally, one day to one week. In a preferred administration scheme, the human female will receive fluoxetine and raloxifene concurrently or concurrently.

According to a method of use, fluoxetine and raloxifene can be administered tho sically, orally and / or parently, including subcutaneous or intravenous injection, and / or in t rana s almen t e. The precise dosage necessary will vary with the age, size, sex and condition of the subject, the nature and severity of the disorder to be treated, and the like; thus, an accurate effective amount must be determined by the attending physician. In general terms, an effective dose of fluoxetine will vary from about 0.001 mg / kg to about 5 mg / kg of body weight, per day. An effective dose for raloxifene is from approximately 0.001 mg / kg to 10 mg / kg body weight, per day. The total dosage (per day) of fluoxetine will typically be in the range of about 1 mg to 200 mg per day, usually being in the range of about 5 mg to 80 mg per day, preferably being in the range of about 10 mg to 60 mg. mg per day, and more preferably it is in the range from about 15 mg to 40 mg per day.

When fluoxetine is administered with raloxifene, the total dosage (per day) of raloxifene will typically be in the range of about 1 mg to 1000 mg per day, usually in the range of about 10 mg to 100 mg per day, preferably in the range from about 25 mg to 75 mg per day, in shape, more preferred is in the range from about 55 mg to 65 mg per day, and most preferably is 60 mg per day. The following description is thus employed to provide those of ordinary skill in the art with a complete discussion and description of the effectiveness of the compositions and methods of the invention and is not proposed to limit the scope of what the inventors regard as their invention. . A total of 120 - 160 women met for a clinical trial. These women are either 1) naturally menopausal; or 2) premenopausal patients but have undergone bilateral oophorectomy surgery within four weeks prior to the start of the study. All women in the study experience a minimum of thirty-five hot flashes per week. The women are divided into four groups for a randomized double-blind placebo-controlled study. The groups receive drug or placebo as illustrated below: Group 1: Fluoxetine (20 mg of CD racemic mixture) + Placebo Group 2: Placebo + Placebo Group 3: Raloxifene (60 mg CD) + Placebo Group 4: Raloxifene (60 mg CD) + Fluoxetine (20 mg of CD racemic mixture) For three weeks the four groups are given placebo only. For eight to twelve weeks after this, each group is given a drug, placebo, or some combination as summarized above. The data is collected (numbers / s and truth of the hot flashes experienced) from each participant during and at the end of the trial period. The treatment of clinical trial participants with fluoxetine results in a decrease, relative to the placebo groups (Groups 2 and 3), of the incidence of hot flashes in the fluoxetine group only (Group 1) and the fluoxe tine / raloxifene group (Group 4). This decrease indicates the utility of the invention It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which refers to the manufacture of the objects to which it refers. Having described the invention as above, the content of the following is claimed as property.

Claims (16)

1. A use of fluoxetine for the production of a medicine for the decrease of the hot flashes in a human woman.

2. The use according to claim 1 wherein fluoxetine is a racemic mixture of fluoxetine hydrochloride.

3. The use according to claim 1 wherein the fluoxetine is substantially pure fluoxetine (R) hydrochloride.

4. The use according to either claim 2 or claim 3 wherein the human female is menopausal.

5. The use according to either claim 2 or claim 3 wherein the human female is post-menopausal.

6. A use of fluoxetine for the production of a medicament for the reduction of hot flashes in a human woman submitted to the administration of raloxi fe? O.

7. The use according to claim 6 wherein fluoxetine is a racemic mixture of fluoxetine hydrochloride and raloxifene is raloxifene hydrochloride.

8. The use according to claim 6 wherein the fluoxetine is the substantially pure fluoxetine (R) hydrochloride and the raloxifene is raloxifene hydrochloride.

9. The use according to either claim 7 or claim 8 wherein the human female is menopausal.

10. The use in accordance with either the rei indication 7 or claim- 8 where the human woman is post-menopausal.

11. The use according to claim 6 wherein the administration of raloxifene results from the existence of osteoporosis, or probable principle of os t eoporos i s.

12. A pharmaceutical formulation characterized in that it comprises fluoxetine and raloxifene in a pharmaceutically acceptable excipient.

13. The formulation according to claim 12, characterized in that fluoxetine is a racemic mixture of fluoxetine hydrochloride and raloxifene is raloxy phenohydrochloride.

14. The formulation according to claim 12, characterized in that the fluoxetine is substantially pure fluoxetine (R) hydrochloride and the raloxifene is raloxifene hydrochloride.

15. The formulation according to either claim 13 or rei indication 14, characterized in that the molar ratio of raloxifene to fluoxetine is 3: 1 to 1: 2.

16. The formulation according to either claim 13 or claim 14, characterized in that the molar ratio of raloxifene to fluoxetine is 2.1: 1 to 1.9: 1.