Classifications

• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • 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
• • 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
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • 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
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/12—Ophthalmic agents for cataracts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to methods, combinations, and compositions for treating, preventing, or reducing the risk of developing an androgenic or estrogenic hormone deficiency in a male or female subject, or for treating, preventing, or reducing the risk of developing the symptoms associated with, or related to, an androgenic or estrogenic deficiency in a male or female subject.
• the American College of Physicians and the American College of Obstetricians and Gynecologists has released position papers saying post-menopausal women should seriously consider preventive estrogen/progesterone hormone replacement therapy for their benefit in reducing osteoporosis and heart disease. Maintaining estrogen and progesterone levels has also been shown to improve a number of key risk factors for heart disease in post- menopausal women.
• estrogen/progesterone hormone replenishment therapy includes prevention of osteoporosis and heart disease, prevention of vaginal dryness and thinning of the vaginal wall, relief from menopausal symptoms and hot flashes, and the possible benefit of reducing the onset of Alzheimer's disease, dementia, and cataracts. Studies have shown that when estrogen is replenished in conjunction with progesterone, the risks of uterine or breast cancer is nullified.
• Androgens constitute a group of 19-carbon steroid hormones that exert influence on the male genital tract and are involved with the development and maintenance of secondary male sex characteristics such as beard growth, deepening of the voice at puberty, muscle and bone development, body strength, and sexual drive. Androgens are synthesized in the male testis, in the female ovary, and in the adrenal cortex of both sexes. Once released into the blood, these endogenous androgens serve both as hormones and as prohormones for the formation of two different classes of steroids: 5 alpha -reduced androgens, which act as the intracellular mediators of most actions of the male sex hormones, and estrogens, which enhance some androgenic effects and block others.
• Testosterone the major circulating androgen in men, is synthesized from cholesterol.
• testosterone is reduced at the 5 alpha position into dihydrotestosterone, which serves as the intracellular mediator of most hormone actions.
• dihydrotestosterone which serves as the intracellular mediator of most hormone actions.
• Testosterone can be metabolized to dihydrotestosterone ("DHT”) by the enzyme 5 ⁇ -reductase or to estradiol (“E 2 ”) by an aromatase enzyme complex.
• DHT dihydrotestosterone
• E 2 estradiol
• the gut metabolizes orally administered testosterone and the liver clears about 44% in the first pass.
• oral doses as high as 400 mg per day are required.
• the liver does not as extensively metabolize synthetic androgens, such as methyltestosterone and fluoxymesterone, and thus the synthetic androgens are more suitable for oral administration.
• estradiol The major metabolites of androgens in urine are physiologically inactive either as free steroids or as water-soluble conjugates. These metabolites are predominantly etiocholanolone, a 5 alpha -reduced metabolite of testosterone; and androsterone, a metabolite of dihydrotestosterone. It is now also recognized that testosterone (but not dihydrotestosterone) can be aromatized into estradiol in a variety of extraglandular tissues, a pathway that accounts for most estrogen synthesis in men and postmenopausal women. The role, if any, of the approximately 50 micrograms of estradiol synthesized each day in normal men has never been defined. Nevertheless, the production of estradiol is considered a normal phenomenon. Experimental evidence suggests that estradiol affects the proliferation of male sex secondary organs, and that estradiol is necessary to induce prostate cancer in animal models.
• Testosterone circulates in the blood 98% bound to protein. In men, approximately 40% of the binding is to the high-affinity sex hormone binding globulin ("SHBG"). The remaining 60% is bound weakly to albumin. Thus, a number of measurements for testosterone are available from clinical laboratories.
• the term “free” testosterone as used herein refers to the fraction of testosterone in the blood that is not bound to protein.
• the term “total testosterone” or “testosterone” as used herein means the free testosterone plus protein-bound testosterone.
• bioavailable testosterone refers to the non-sex hormone binding globulin bound testosterone and includes that weakly bound to albumin. Plasma concentrations of sex hormone binding globulin determine the ratio of free testosterone to bound testosterone.
• Total serum testosterone can be measured by assays such as a radioimmunoassay, see, for example, Furuyama et al., Radioimmunoassay for Plasma Testosterone, Steroids, 16:415-428 (1970).
• assays such as a radioimmunoassay, see, for example, Furuyama et al., Radioimmunoassay for Plasma Testosterone, Steroids, 16:415-428 (1970).
• hypogonadism results from a variety of patho-physiological conditions in which testosterone concentration is diminished below the normal range.
• the hypogonadic condition is sometimes linked with a number of physiological changes, such as diminished interest in sex, impotence, reduced lean body mass, decreased bone density, lowered mood, and energy levels.
• researchers generally classify hypogonadism into one of three types.
• Primary hypogonadism includes the testicular failure due to congenital or acquired anorchia, XYY Syndrome, XX males, Noonan's Syndrome, gonadal dysgenesis, Ley dig cell tumors, maldescended testes, varicocele, Sertoli-Cell-Only Syndrome, cryptorchidism, bilateral torsion, vanishing testis syndrome, orchiectomy, Klinefelter's Syndrome, chemotherapy, toxic damage from alcohol or heavy metals, and general disease (renal failure, liver cirrhosis, diabetes, myotonia dystrophica).
• Patients with primary hypogonadism show an intact feedback mechanism in that the low serum testosterone concentrations are associated with high FSH and LH concentrations. However, because of testicular or other failures, the high LH concentrations are not effective at stimulating testosterone production.
• hypogonadism involves an idiopathic gonadotropin or LH-releasing hormone deficiency.
• This type of hypogonadism includes Kallman's Syndrome, Prader-Labhart-Willi's Syndrome, Laurence-Moon-BiedFs Syndrome, pituitary insufficiency/adenomas, Pasqualini's Syndrome, hemochromatosis, hyperprolactinemia, or pituitary-hypothalamic injury from tumors, trauma, radiation, or obesity. Because patients with secondary hypogonadism do not demonstrate an intact feedback pathway, the lower testosterone concentrations are not associated with increased LH or FSH levels. Thus, these men have low testosterone serum levels but have gonadotropins in the normal to low range.
• hypogonadism may be age-related. Men experience a slow but continuous decline in average serum testosterone after approximately age 20 to 30 years. researchers estimate that the decline is about 1-2% per year. Cross-sectional studies in men have found that the mean testosterone value at age 80 years is approximately 75% of that at age 30 years. Because the serum concentration of SHBG increases as men age, the fall in bioavailable and free testosterone is even greater than the fall in total testosterone. researchers have estimated that approximately 50% of healthy men between the ages of 50 and 70 have levels of bioavailable testosterone that are below the lower normal limit. Moreover, as men age, the circadian rhythm of testosterone concentration is often muted, dampened, or completely lost. The major problem with aging appears to be within the hypothalamic-pituitary unit.
• hypogonadism is the most common hormone deficiency in men, affecting 5 in every 1,000 men. At present, it is estimated that only five percent of the estimated four to five million American men of all ages with hypogonadism currently receive testosterone replacement therapy. Thus, for years, researchers have investigated methods of delivering testosterone to men. These methods include intramuscular injections (43%), oral replacement (24%), pellet implants (23%), and transdermal patches (10%). A summary of these methods is shown in Table 3.
• Subdermal implants have been used as a method of testosterone replacement since the 1940s.
• the implant is produced by melting crystalline testosterone into a cylindrical form.
• pellet implants are manufactured to contain either 100 mg (length 6 mm, surface area 117 mm 2 ) or 200 mg of testosterone (length 12 mm, surface area 202 mm 2 ).
• Patients receive dosages ranging from 100 to 1,200 mg, depending on the individual's requirements.
• the implants are inserted subcutaneously either by using a trocar and cannula or by open surgery into an area where there is relatively little movement. Frequently, the implant is placed in the lower abdominal wall or the buttock. Insertion is made under local anesthesia, and the wound is closed with an adhesive dressing or a fine suture.
• Implants have several major drawbacks. First, implants require a surgical procedure that many hypogonadal men simply do not wish to endure. Second, implant therapy includes a risk ofextrusion (8.5%), bleeding (2.3%), or infection (0.6%). Scarring is also a risk. Perhaps most important, the pharmacokinetic profile of testosterone pellet implant therapy fails to provide men with a suitable consistent testosterone level. In general, subdermal testosterone implants produce supra-physiologically high serum testosterone levels that slowly decline so that before the next injection subnormally low levels of testosterone are reached. For example, in one recent pharmacokinetic study, hypogonadal patients who received six implants (1 ,200 mg testosterone) showed an initial short-lived burst release of testosterone within the first two days after application.
• testosterone esters such as enanthate, cypionate
• testosterone esters such as enanthate, cypionate
• More recent studies have involved injection of testosterone buciclate or testosterone undecanoate in an oil-based vehicle.
• Other researchers have injected testosterone microcapsule formulations.
• Testosterone ester injection treatments suffer from many problems. Patients receiving injection therapy often complain that the delivery mechanism is painful and causes local skin reactions.
• testosterone microcapsule treatment requires two simultaneous intramuscular injections of a relatively large volume, which may be difficult to administer due to the high viscosity of the solution and the tendency to block the needle.
• Other men generally find testosterone injection therapy inconvenient because injection usually requires the patient to visit his physician every two to three weeks.
• testosterone injections have largely been unsuccessful in influencing these variables. Thus, testosterone injection remains an undesirable testosterone replacement treatment method. Oral/Sublingual Buccal Preparations of Androgens
• TESTODERM ® (Alza Pharmaceuticals, Mountain View, CA) was the first testosterone- containing patch developed.
• the TESTODERM ® patch is currently available in two sizes (40 or 60 cm 2 ).
• the patch contains 10 or 15 mg of testosterone and delivers 4.0 mg or 6.0 mg of testosterone per day.
• TESTODERM ® is placed on shaved scrotal skin, aided by application of heat for a few seconds from a hair dryer.
• the most recently developed non-scrotal patch is TESTODERM ® TTS (Alza Pharmaceuticals, Mountain View, CA). It is an occlusive patch applied once daily to the arm, back, or upper buttocks.
• the system is comprised of a flexible backing of transparent polyester/ethyl ene-vinyl acetate copolymer film, a drug reservoir of testosterone, and an ethylene-vinyl acetate copolymer membrane coated with a layer of polyisobutylene adhesive formulation.
• a protective liner of silicone-coated polyester covers the adhesive surface.
• Table 5 Hormone Levels Using TESTODERM ® and TESTODERM ® TTS
• TESTODERM TTS treatment creates a DHT/T ratio that is not different from that of a placebo treatment. Both systems, however, suffer from similar problems. In clinical studies, TESTODERM ® TTS is associated with transient itching in 12% of patients, erythema in 3% of patients, and puritus in 2% of patients. Moreover, in one 14-day study, 42% of patients reported three or more detachments, 33% of which occurred during exercise.
• ANDRODERM ® (Watson Laboratories, Inc., Corona, CA) is a testosterone-containing patch applied to non-scrotal skin.
• the circular patch has a total surface area of 37 cm.
• the patch consists of a liquid reservoir containing 12.2 mg of testosterone and a permeation- enhanced vehicle containing ethanol, water, monoglycerides, fatty acid esters, and gelling agents.
• the suggested dose of two patches, applied each night in a rotating manner on the back, abdomen, upper arm, or thigh delivers 4.1 to 6.8 mg of testosterone.
• serum testosterone levels increase gradually for eight hours after each application and then remain at this plateau level for about another eight hours before declining.
• ANDRODERM ® is associated with skin irritation in about a third of the patients, and 10% to 15% of subjects have been reported to discontinue the treatment because of chronic skin irritation.
• ANDRODERM ® has been reported to decrease the incidence and severity of the skin irritation. A recent study, however, found that the incidence of skin reactions sufficiently noxious enough to interrupt therapy was as high as 52%. See Parker et al., Experience with Transdermal Testosterone Replacement in Hypogonadal Men, 50 CLINICAL ENDOCRINOLOGY (OXF) 57-62 (1999). The study reported:
• the transdermal patch generally offers an improved pharmacokinetic profile compared to other prior art testosterone delivery mechanisms.
• the clinical and survey data shows that all of these patches suffer from significant drawbacks, such as buritus, burn-like blisters, and erythema.
• the adverse effects associated with transdermal patch systems are "substantially higher" than reported in clinical trials. See Parker, supra.
• the transdermal patch still remains an inadequate testosterone replacement therapy alternative for most men.
• testosterone has been shown to lower cholesterol and normalize the abnormal electrocardiograms of patients. Testosterone can also improve diabetic retinopathy as well as lower the insulin requirements of diabetic patients and decrease the percentage of body fat. Administration of testosterone to men has been reported to decrease risk factors for heart attack and low testosterone is also correlated with hypertension, obesity, and increased waist-to- hip ratio.
• Estradiol (l,3,5(10)-Estratriene-3, 17 beta-diol) is secreted by the ovary and placenta. It is synthesized by the aromatization of androgens in the thecal and granulosa cells of the ovary and placenta. The aromatization is stimulated by follitropin (FSH). Estradiol synthesis in turn stimulates production of leutinizing hormone (Lutropin or LH) receptors necessary for the synthesis of androgen precursors. Estradiol is important for female sexual differentiation during gestation, sexual development at the onset of puberty, and regulation of the menstrual cycle.
• FSH follitropin
• LH leutinizing hormone
• the menstrual cycle is the result of a precise coordination of the functional characteristics of the central nervous system, the hypothalamus, the pituitary, the ovary, and the endometrium which regulate the cyclic release of Gonadotropin Releasing Hormone (GnRH), LH and follitropin, and ovarian steroids (estradiol and progesterone).
• GnRH Gonadotropin Releasing Hormone
• LH and follitropin LH and follitropin
• ovarian steroids estradiol and progesterone
• estradiol stimulates endometrial growth (repairing the endometrium after menses).
• LH production increases and results in the release of the ovum by the rupture of the developed follicle.
• estradiol secretion declines slightly.
• estradiol along with progesterone are secreted by the corpus luteum stimulating further endometrial growth. If the ovum is not fertilized, there is a further drop in estradiol and progesterone. This drop in estradiol and progesterone initiates menses.
• estradiol When the ovaries do not function properly due to age, menopause or disease or have been removed, the consequent lack of endogenous estradiol may produce a number of symptoms, such as hot flushes, pain and increased hypocalcemia which may eventually lead to osteoporosis.
• Total serum estrogen can be measured by assays known in the art, such as a an ammonium sulfate precipitation assay, see for example, Nankin et al., radioimmunoassay, see, for example, Furuyama et al., (1975).
• Total serum estrogen refers to the sum of the free estrogen (that is, estrogen unattached to any protein), estrogen weakly bound to serum proteins, such as albumin-bound estrogen, and estrogen tightly bound to high affinity serum proteins, such as sex hormone binding globulin-bound estrogen.
• the serum levels of estradiol required for clinical efficacy are in the range of between 40- 60 pg/ml. This range of values is the physiologic serum level of the premenopausal women during the early follicular phase.
• Estrogenic hormones are currently available in a number of formulations.
• Transdermal preparations containing estradiol include ERC ALORA®, CLIMARA®, DERMESTRIL®, ESTRADERM®, ESTRADERM® TTS, ESTRADERM MX®, EVOREL®, FEMATRIX®, FEMPATCH®, FEMSEVEN®, MENOREST®, PROGYNOVA® TS, and VIVELLE®.
• Estrogen gels containing estradiol include ESTROGEL®, and SANDRENA®.
• Oral preparations of estrogen are also available in a capsule shaped, sugar coated oral tablet, containing 1.25 mg of esterified estrogen and 2.5 mg of methyltestosterone marketed under the brand ESTRATEST® (Solvay Pharmaceuticals, Inc.).
• a half-strength formulation is also available under the brand ESTRATEST® HS (Solvay Pharmaceuticals, Inc.).
• a variety of methods have been used to quantify the serum concentrations of sex hormone binding globulin, including ammonium sulfate precipitation, gel filtration, equilibrium dialysis, dextran- coated charcoal, and radioimmunoassay (see, for example, Kahn et al., Radioimmunoassay for Human Testerone-Estradiol Binding Globulin, J Clinical Endocrinology and Metabolism, Vol. 54:705-710 (1982).
• the mean serum sex hormone level in healthy premenopausal women is about 84 nmole/L and the normal range is about 36 nmole/L to about 185 nmole/L.
• Serum sex hormone binding globulin levels are known to be elevated in women treated with oral estrogens, estrogen-containing oral contraceptives, clomiphene, tamoxifen, raloxifene, phenytoin, and sodium valproate, as well as in women who are pregnant, hyperthyroid, have chronic liver disease and HIV infection. See, for example, Bond et al., Sex Hormone Binding Globulin in Clinical Perspective, Acta. Obstet. Gynecol. Scand., Vol. 66:255-262 (1987). See also, for example, Miller et al., (1998).
• testosterone and estradiol replacement therapy for example, tablets, injectable, implants and transdermal devices (patches or gel), etc. Oral therapy, using tablets is well accepted by the patient.
• testosterone and estradiol is rapidly metabolized during the liver first pass.
• a high dose of testosterone or estradiol is necessary to achieve clinical appropriate serum levels.
• Absorption via the gastrointestinal tract results in enhanced delivery of the circulating testosterone or estrogen to the liver, where much of it is metabolized to inactive conjugates, and only a fraction of the active hormone enter general circulation.
• the liver responds to this enhanced delivery with increased protein and lipid metabolism, and these activities may carry potential risks. Examples of these changes include enhanced hepatic synthesis of renin substrates, sex hormone binding globulin, and changes in cholesterol and lipid lipoprotein metabolism.
• Testosterone or estradiol transdermal administration is cutaneous delivery that delivers testosterone or estradiol into the systemic circulation via the stratum corneum at a constant rate.
• Transdermal administration of drugs offers several therapeutic and compliance advantages over the more traditional routes of administration.
• a major drawback of this therapy is the limitation of the amount of drug that can be transported across the skin. This limitation is due to several factors. Since the skin is a protective barrier by nature, the rates of transport of most compounds through the skin are quite slow. It is generally accepted that a
• transdermal semisolid dosage form such as a gel, cream, ointment, liquid, etc.
• augment the patient's compliance and the surface of application can be extended.
• estrogen supplementation is an increase in sex hormone binding globulin.
• Sex hormone binding globulin is a serum protein that binds both testosterone and 17 beta- estradiol, and this binding affects the biological availability of those hormones. Therefore, the increase in sex hormone binding globulin that occurs with estrogen and progestin supplementation results in lower levels of free androgens and estrogens, both of which bind to sex hormone binding globulin, and higher levels of estrogens must be administered in order to achieve the desired biological activity. All of the testosterone and estradiol replacement methods currently employed, however, suffer from one or more drawbacks. For example, subdermal pellet implants and ester injections are painful and require doctor visits.
• any other inhibitor of the synthesis of sex hormone binding globulin can, if desired, be substituted in whole or in part for methyltestosterone in the methods, combinations and compositions herein described.
• testosterone it will be understood that any other steroid in the testosterone anabolic or catabolic pathway can, if desired, be substituted in whole or in part for testosterone in the methods, combinations and compositions herein described.
• estradiol it will be understood that any other estrogenic hormone can, if desired, be substituted in whole or in part for estradiol in the methods, combinations and compositions herein described.
• the present invention is directed to methods, combinations, and compositions for treating, preventing or reducing the risk of developing an androgenic or estrogenic hormone deficiency, or a male or female menopause disorder, or the symptoms associated with, or related to an androgenic or estrogenic hormone deficiency, or a male or female menopause disorder, in a male or female mammal in need thereof.
• the method comprises administering to the mammal in a combination therapy an amount of a sex hormone binding globulin synthesis inhibiting agent and one or more steroids, including for example androgen and/or estrogen, where the sex hormone binding globulin synthesis inhibiting agent and the steroid together make a menopause disorder effective amount.
• the present invention includes methods of halting or slowing the progression of a menopausal disorder once it becomes clinically evident, or treating the symptoms related to the menopausal disorder.
• the patient may already have a menopausal disorder at the time of administration, or be at risk for developing a menopausal disorder.
• pharmaceutical compositions comprising a sex hormone binding globulin synthesis inhibiting agent and one or more steroids, including for example androgen and/or estrogen, where the individual agents together make a menopause disorder effective amount.
• the present invention also includes kits comprising a sex hormone binding globulin synthesis inhibiting agent and one or more steroids, including for example androgen and/or estrogen.
• kits also contain a set of instructions for the patient.
• the sex hormone binding globulin synthesis inhibiting agent together with the steroid provide enhanced treatment options for treating menopause in a mammal as compared to administration of either a sex hormone binding globulin synthesis inhibiting agent or a steroid alone.
• the present invention is also useful for veterinary treatment of companion mammals, exotic animals and farm animals, including mammals, rodents, and the like.
• the mammals include horses, dogs, and cats.
• Contemplated methods, combinations and compositions are useful to treat a variety of menopausal disorders, or the symptoms associated with, or related to a menopausal disorder, including but not limited to hypogonadism, sexual or erectile dysfunction, decreased libido, hyperglycemia, hyperglyceridemia, hypercholesterolemia, hypertension, atherosclerosis, cardiovascular disorders and diseases, vasomotor symptoms, obesity, diabetes, osteoporosis, osteopenia, vaginal dryness, thinning of the vaginal wall, relieving menopausal symptoms and hot flashes, improving cognitive dysfunction, Alzheimer's disease, dementia, cataracts, cervical cancer, uterine cancer, breast cancer, Klinefelter's syndrome, teratogenic disorder, and cervical dysplasia.
• combination therapy embraces the administration of a sex hormone binding globulin synthesis inhibiting agent and one or more steroids, including for example, androgen and/or estrogen, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents for the treatment of menopause.
• the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
• Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days, weeks, months or years depending upon the combination selected).
• “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
• “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, where each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule or tablet having a fixed ratio of each therapeutic agent or in multiple, single capsules, tablets, or gels for each of the therapeutic agents.
• each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, percutaneous routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
• the therapeutic agents can be administered by the same route or by different routes.
• a first therapeutic agent of the combination selected may be administered orally, while the other therapeutic agents of the combination may be administered percutaneously.
• all therapeutic agents may be administered orally, or all therapeutic agents may be administered percutaneously, or all therapeutic agents may be administered intravenously, or all therapeutic agents may be administered intramuscularly, or all therapeutic agents can be administered by direct absorption through mucous membrane tissues.
• the sequence in which the therapeutic agents are administered is not narrowly critical.
• Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients, such as, but not limited to, agents for improving sexual performance or impotence, including agents to treat erectile dysfunction, such as VIAGRA®, or increasing libido by increasing testosterone levels in men, and non-drug therapies, such as, but not limited to, surgery.
• agents for improving sexual performance or impotence including agents to treat erectile dysfunction, such as VIAGRA®, or increasing libido by increasing testosterone levels in men
• non-drug therapies such as, but not limited to, surgery.
• menopause disorder or “menopausal disorder” encompasses both male “andropausal” and female menopausal disorders, and includes either a peri-menopausal condition or a post-menopausal condition.
• Periodopausal condition refers to a condition that occurs either during menopausal onset, or prior thereto at a time when menopausal onset normally occurs, and either is caused by menopausal onset or has a greater than random coincidence therewith.
• Peri-menopausal conditions include, for example, hot flashes and reduction of bone mass.
• Post-menopausal condition refers to a condition that occurs after menopausal onset, and either is caused by menopause or has a greater than random coincidence therewith.
• Post-menopausal conditions include, for example, vasomotor symptoms, osteopenia, osteoporosis, cardiovascular disease and cognitive dysfunction.
• a "menopause disorder effect" or “menopause disorder effective amount” is intended to qualify the amount of a sex hormone binding globulin synthesis inhibiting agent and a steroid, including for example androgen and/or estrogen, required to treat or prevent a menopause disorder or relieve to some extent one or more of the symptoms of a menopause disorder, including, but not limited to, normalizing hypogonadism, improving sexual or erectile dysfunction, increasing libido, lowering blood cholesterol levels; normalizing abnormal electrocardiograms of patients and improving vasomotor symptoms; improving diabetic retinopathy as well as lowering the insulin requirements of diabetic patients; decreasing the percentage of body fat; decreasing the risk factors for heart attack, hypertension, and obesity; preventing osteoporosis, osteopenia, vaginal dryness, and thinning of the vaginal wall; relieving menopausal symptoms and hot flashes; improving cognitive dysfunction; treating or reducing the onset of cardiovascular disease, Alzheimer's disease, dementia, and cataracts; and
• non oral or “non orally deliverable” refers to percutaneous, transmucosal, implantation, inhalation spray, rectal, vaginal, topical, buccal (for example, sublingual), or parenteral (for example, subcutaneous, intramuscular, intravenous, intramedullary and intradermal injections, or infusion techniques) formulations and administrations.
• buccal for example, sublingual
• parenteral for example, subcutaneous, intramuscular, intravenous, intramedullary and intradermal injections, or infusion techniques
• pharmaceutically acceptable is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product.
• Pharmaceutically acceptable cautions include metallic ions and organic iohs. More preferred metallic ions include, but are not limited to appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.
• Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
• Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
• penetration enhancer refers to an agent known to accelerate the delivery of the drug through the skin.
• These agents also have been referred to as accelerants, adjuvants, and sorption promoters, and are collectively referred to herein as “enhancers.”
• This class of agents includes those with diverse mechanisms of action including those which have the function of improving the solubility and diffusibility of the drug, and those which improve percutaneous absorption by changing the ability of the stratum corneum to retain moisture, softening the skin, improving the skin's permeability, acting as penetration assistants or hair-follicle openers or changing the state of the skin such as the boundary layer.
• the penetration enhancer of the present invention is a functional derivative of a fatty acid, which includes isosteric modifications of fatty acids or non-acidic derivatives of the carboxylic functional group of a fatty acid or isosteric modifications thereof.
• the functional derivative of a fatty acid is an unsaturated alkanoic acid in which the — COOH group is substituted with a functional derivative thereof, such as alcohols, polyols, amides and substituted derivatives thereof.
• fatty acid means a fatty acid that has four (4) to twenty-four (24) carbon atoms.
• Non-limiting examples of penetration enhancers include Cg-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; Cg-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of Cg-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C22 diacids such as diisopropyl adipate; monoglycerides of C -C 2 2 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2- ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl
• the thickeners used herein may include anionic polymers such as polyacrylic acid (CARBOPOL® by B.F. Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxymethylcellulose and the like. Additional thickeners, enhancers and adjuvants may generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co. United States Pharmacopeia/National Formulary.
• anionic polymers such as polyacrylic acid (CARBOPOL® by B.F. Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxymethylcellulose and the like. Additional thickeners, enhancers and adjuvants may generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co. United States Pharmacopeia/National Formulary.
• the term "lower alcohol,” along or in combination, means a straight-chain or branched-chain alcohol moiety containing one to about six carbon atoms. In one embodiment, the lower alcohol contains one to about 4 carbon atoms, and in another embodiment the lower alcohol contains two to about 3 carbon atoms. Examples of such alcohol moieties include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.
• lower alkyl means a straight-chain or branched-chain alkyl radical containing one to about six carbon atoms. In one embodiment, the lower alkyl contains one to about four carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
• compositions of the present invention are used in a "pharmacologically effective amount.”
• concentration of the therapeutic agents of the present invention are such that in the composition it results in a therapeutic level of drug delivered over the term that the drugs are to be used.
• delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the flux rate of the therapeutic agent, for example, testosterone or estradiol, from the gel, surface area of application site, etc.
• the amount of therapeutic agent, for example, testosterone or estradiol, necessary can be experimentally determined based on the flux rate of the drug through the gel, and through the skin when used with and without enhancers.
• Treatment dosages generally may be titrated to optimize safety and efficacy.
• dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration.
• Studies in animal models generally may be used for guidance regarding effective dosages for treatment of menopause in accordance with the present invention.
• the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered the condition of the particular patient, etc. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Thus, where an compound is found to demonstrate in vitro activity at, for example, 10 ng/ml, one will desire to administer an amount of the drug that is effective to provide about a 10 ng/ml concentration in vivo. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.
• a therapeutically effective amount of methyltestosterone per daily dose for use in the present invention is typically about 0.2 mg to about 5.0 mg; a therapeutically effective amount of testosterone per daily unit for use in the present invention is typically about 0.1 mg to about 10 mg; and a therapeutically effective amount of estradiol per daily dose for use in the present invention is typically about 0.1 mg to about 10 mg.
• the present invention includes compounds that inhibit the synthesis of the sex hormone binding globulin. Sex hormone binding globulin is a serum protein, and is known to bind to testosterone and estradiol, effecting the biological activity of these hormones.
• Specific compounds of interest that inhibit the synthesis the sex hormone binding globulin include but are not limited to methyltestosterone and fluoxymesterone, and all salts, esters, amides, enantiomers, isomers, tautomers, prodrugs and derivatives of these compounds.
• Methyltestosterone is currently available in various formulations including those available orally, for example ANDROID® and TESTRED® ICN.
• Fluoxymesterone is also currently available in various formulations including those available orally, for example HALOSTESTIN®. Combinations of the above mentioned compounds can be used.
• methyltestosterone decreases hepatic synthesis of endogenous proteins like sex hormone binding globulin. This decrease in synthesis produces a decline in blood concentrations of sex hormone binding globulin, which is the primary means of endogenous hormone transport. The decrease in sex hormone binding globulin subsequently causes an increase in free-hormone concentration for binding at the receptor.
• Transdermal application of an androgen, for example, testosterone, or an estrogen, for example, estradiol bypasses first-pass metabolism and can provide a means of increasing hormone concentrations in the bloodstream.
• methyltestosterone and percutaneously administered testosterone and/or estradiol produce a greater therapeutic effect and provide a means of increasing hormone concentrations in the bloodstream.
• Methyltestosterone and testosterone and/or estradiol produce a greater therapeutic effect than either entity alone because the decrease in hormone binding ability is coupled with an increased hormone bioavailability, producing higher free-hormone concentrations that would be produced by methyltestosterone alone, or testosterone alone, or estradiol alone.
• formulations of the invention will contain from about 0.2 mg to about 50.0 mg methyltestosterone or the equivalent per dosage unit.
• the formulations may contain for example, about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 10.0, 20.0, 30.0, 40.0 or 50.0 mg methyltestosterone per dosage unit.
• a class of androgens useful in the methods, combinations and compositions of the present invention include steroids in the testosterone anabolic or catabolic pathway.
• the active ingredients employed in the composition may include anabolic steroids such as androisoxazole, bolasterone, clostebol, ethylestrenol, formyldienolone, 4- hydroxy-19-nortestosterone, methenolone, methyltrienolone, nandrolone, oxymesterone, quinbolone, stenbolone, trenbolone; androgenic steroids such as boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17 alpha-methyl- testosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymetholone, prasterone, stanlolone, stanozolol, dihydrotestosterone, testosterone; and progestogens such as anagestone, chlormadinone acetate, delmadinone
• Testosterone is currently available in various formulations including, but not limited to those available as an injectable, for example DEPO-TESTOSTERONE® (testosterone cypionate), and DELATESTRYL BTG® (testosterone enanthate), as a transdermal, for example TESTODERM® (testosterone), TESTODERM® TTS (testosterone), and ANDRODERM®, or as a gel.
• One such testosterone gel that may be used in the methods, combinations and compositions of the present invention has only recently been made available in the United States under the trademark ANDROGEL ® by Unimed Pharmaceuticals, Inc., Deerfield, Illinois, a wholly owned subsidiary of Solvay Pharmaceuticals, Inc.
• the testosterone gel is comprised of the following substances in approximate amounts:
• compositions may contain about 0.1 to about 10.0 g of testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl myristate, and about 30.0 to about 98.0 g ethanol.
• a therapeutically effective amount of the gel is rubbed onto a given area of skin by the user.
• the combination of the lipophilic testosterone with the hydroalcoholic gel helps drive the testosterone in to the outer layers of the skin where it is absorbed and then slowly released into the blood stream.
• the administration of the gel of the present invention has a sustained effect.
• the androgen is testosterone and is formulated for percutaneous administration comprising testosterone in a hydroalcoholic gel.
• the gel comprises one or more lower alcohols, a penetration enhancing agent, a thickener, and water.
• the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
• formulations of the invention will contain from about 0.1 mg to about 100 mg testosterone or the equivalent per dosage unit.
• the formulations may contain for example, about 0.1, 0.25, 0.5, 0.625, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 20.0, 30.0, 40.0, 50.0 or 100.0 mg testosterone per dosage unit.
• estrogenic hormones are useful in the methods, combinations and compositions of the present invention.
• the estrogenic hormone is the naturally occurring estrogen 17 beta-estradiol (beta-estradiol; 1, 3, 5(10)-estratriene-3, 17 beta-diol).
• Other estrogenic steroid hormones can be used in partial or complete replacement of 17 beta-estradiol, for example, an ester which is biologically compatible and can be absorbed effectively transdermally.
• the estradiol esters can be, illustratively estradiol-3,17-diacetate; estradiol-3-acetate; estradiol- 17-acetate; estradiol-3,17-divalerate; estradiol-3-valerate; estradiol- 17-valerate; 3-mono, 17-mono and 3,17-dipropionate esters, corresponding cypionate, heptanoate, benzoate and the like esters; ethynil estradiol; estrone and other estrogenic steroids and salts, enantiomers, isomers, tautomers, prodrugs and derivatives thereof that are possible to administer by transdermal route.
• estrogen-related compounds that may be used in the methods, combinations and compositions of the present invention include, but are not limited to conjugated estrogens (including estrone sulfate, equilin, and 17-.alpha.-dihydroequilin), estradiol valerate, estriol, estrone, estrone sulfate, estropipate, ethinyl estradiol, mestranol, and all salts, esters, amides, enantiomers, isomers, tautomers, prodrugs and derivatives of these compounds.
• conjugated estrogens including estrone sulfate, equilin, and 17-.alpha.-dihydroequilin
• estradiol valerate estriol
• estrone, estrone sulfate estropipate
• ethinyl estradiol mestranol
• esters amides, enantiomers, isomers, t
• Estrogenic hormones are currently available in various formulations including, but not limited to those available as a cream, pessary, vaginal ring, vaginal tablet, transdermal preparation, gel, and oral tablet.
• vaginal creams include PREMARIN® (conjugated estrogen), ORTHO DIENOSTEROL® (dienosterol), and OVESTIN® (estriol).
• Available pessary formulations include ORTHO-GYNEST® (estriol), and TAMPOVAGAN® (stilbestrol).
• An example of a vaginal ring formulation is ESTRING® (estradiol)
• an example of a vaginal tablet is VAGIFEM® (estradiol).
• estradiol available transdermal estrogen preparations containing estradiol include ERC ALORA®, CLIMARA®, DERMESTRIL®, ESTRADERM®, ESTRADERM® TTS, ESTRADERM® MX, EVOREL®, FEMATRIX®, FEMPATCH®,
• estradiol available estrogen gels containing estradiol include ESTROGEL®, and SANDRENA®. Estradiol is also available formulated as an implant pellet, for example, ESTRADIOL IMPLANT®.
• Tablet formulations include PREMARIN® (conjugated estrogen), ESTRATAB® (esterified estrogen), ESTRATEST® (esterified estrogen, methyltestosterone), MENEST® (esterified estrogen), CLIMAGEST®, (estradiol), CLIMAVAL® (estradiol), ELLESTE SOLO® (estradiol), ESTRACE® (estradiol), PROGYNOVA® (estradiol), ZUMENON® (estradiol), HORMONIN® (estradiol, estrone, estriol), HARMOEN® (estrone), OGEN® (estropipate), and ORTHO-EST® (estropipate).
• the estrogenic hormone is formulated for percutaneous administration in a hydroalcoholic gel.
• the gel comprises one or more lower alcohols; a penetration enhancing agent; a thickener; and water.
• the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
• the estrogenic gel is comprised of the following substances in approximate amounts:
• composition may contain about 0.1 to about 10.0 g of estradiol, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g triethanolamine, and about 30.0 to about 98.0 g ethanol.
• a therapeutically effective amount of the gel is rubbed onto a given area of skin by the user.
• the combination of the lipophilic estradiol with the hydroalcoholic gel helps drive the estradiol in to the outer layers of the skin where it is absorbed and then slowly released into the blood stream. It is contemplated that the administration of the gel of the present invention has a sustained effect.
• formulations of the invention will contain from about 0.1 mg to about lOOmg estradiol or the equivalent per dosage unit.
• the formulations may contain for example, about 0.1 , 0.25, 0.5, 0.625, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 20.0, 30.0, 40.0, 50.0 or 100.0 mg estradiol per dosage unit.
• compositions containing estrogen-related compounds or androgen-related compounds that may be used in the methods, combinations and compositions of the present invention, see for example, Sturdee, D. W., et al. Br. J. Obstet. Gynecol. (1997) 104:109-115.
• Toxicity and therapeutic efficacy of the therapeutic agents of the present invention can be determined by standard pharmaceutical procedures, for example, for determining LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
• Compounds which exhibit large therapeutic induces are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
• combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients, such as, but not limited to, agents for improving sexual performance or impotence, and include agents to treat erectile dysfunction, or increasing libido by increasing testosterone levels in men, such as VIAGRA®.
• Other pharmaceuticals useful for treating erectile dysfunction include any agent that is effective to inhibit the activity of a phosphodiesterase.
• Suitable phosphodiesterase inhibitors include, but are not limited to, inhibitors of the type III phosphodiesterase (cAMP-specif ⁇ c-cGMP inhibitable form), the type IV phospodiesterase (high affinity-high specificity cAMP form) and the type V phosphodiesterase (the cGMP specific form). Additional inhibitors that may be used in conjunction with the present invention are cGMP-specific phosphodiesterase inhibitors other than type V inhibitors.
• type III phospodiesterase inhibitors that may be administered include, but are not limited to, bypyridines such as milrinone and amirinone, imidazolones such as piroximone and enoximone, dihydropyridazinones such as imazodan, 5-methyl-imazodan, indolidan and ICI1118233, quinolinone compounds such as cilostamide, cilostazol and vesnarinone, and other molecules such as bemoradan, anergrelide, siguazodan, trequinsin, pimobendan, SKF-94120, SKF-95654, lixazinone and isomazole. ,
• type IV phosphodiesterase inhibitors suitable herein include, but are not limited to, rolipram and rolipram derivatives such as RO20-1724, nitraquazone and nitraquazone derivatives such as CP-77059 and RS-25344-00, xanthine derivatives such as denbufylline and ICI63197, and other compounds such as EMD54622, LAS-31025 and etazolate.
• type V phosphodiesterase inhibitors include, but are not limited to, zaprinast, MY5445, dipyridamole, and sildenafil.
• Other type V phosphodiesterase inhibitors are disclosed in PCT Publication Nos. WO 94/28902 and WO 96/16644.
• an inhibitor of phosphodiesterase type 5 (“PDE5"), such as VIAGRA ® (sildenafil citrate USP) is used.
• Other compounds useful for treating erectile dysfunction may also be used. These include: (a) pentoxifylline (TRENTAL ® ); (b) yohimbine hydrocholoride (ACTIBINE ® , YOCON ® , YOHIMEX ® ); (c) apomorphine (UPRIMA ® ); (d) alprostadil (the MUSE ® system, TOPIGLAN ® , CAVERJECT ® ); (e) papavaerine (PAVABID ® , CERESPAN ® ); (f) phentolamine (VASOMAX ® , REGITINE ® ), and combinations, salts, prodrugs, isomers, amides, esters, tautomers, derivatives and enantiomers of all of the above.
• the compounds described in PCT Publication No. WO 94/28902 are pyrazolopyrimidinones.
• the inhibitor compounds include 5-(2-ethoxy-5- morpholinoacetylphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7H-p yrazolo[4,3-d]pyrimidin-7-one, 5-(5-morpholinoacetyl-2-n- ⁇ ropoxyphenyl)-l -methyl-3-n-propyl-l ,6-dihydro-7 -H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-l -piperazinylsulfonyl)-phenyl] 1 -methyl-3 -n-propyl - 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-allyloxy-5-(4-methyl-
• the phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644 include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives, fused and condensed pyrimidines, pyrimidopyrimidine derivatives, purine compounds, quinazoline compounds, phenylpyrimidinone derivative, imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone derivatives, and others.
• phosphodiesterase inhibitors disclosed in WO 96/16644 include l,3-dimethyl-5- benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)- l,2-dihydro-2-oxypyridine-3-carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)- one, 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidi ne, 6- hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide, 1 -ethyl-3- methylirnidazo[l ,5a]quinoxalin-4(5H)-one, 4-phenylmethylamino-6-chloro-2-(l - imidazoloy
• Still other type V phosphodiesterase inhibitors useful in conjunction with the present invention include: IC-351 (ICOS); 4-bromo-5-(pyridylmethylamino)-6-[3-(4- chlorophenyl)propoxy]-3(2H)pyridazi none; l-[4-[(l ,3-benzodioxol-5-ylmethyl)amiono]-6- chloro-2-quinazolinyl]-4-piper idine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a- hexahydro-2-[4-(trifluoromethyl)-phenymmethyl-5-meth yl-cyclopent-4,5]imidazo[2, 1 -b]purin- 4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3 ,4,5,6a,7,8,9,9a- octa
• phosphodiesterase inhibitors that may be used in the method of this invention include nonspecific phosphodiesterase inhibitors such as theophylline, IBMX, pentoxifylline and papaverine, and direct vasodilators such as hydralazine.
• a testosterone containing gel such as AndroGel® is administered to increase and enhance the therapeutic effectiveness of drugs effective at inhibiting the activity of a phosphodiesterase, in either hypogonadal or eugonadal men having erectile dysfunction.
• pharmaceuticals such as VIAGRA® work principally by various physiological mechanisms of erection initiation and maintenance
• the testosterone gel used in accordance with the present invention plays a beneficial role physiologically, and stimulates both sexual motivation (that is, libido) and sexual performance.
• Testosterone controls the expression of the nitric oxide synthase gene. See Reilly et al., Androgenic Regulation of NO Availability in Rat Penile Erection, 18 J. ANDROLOGY 110 (1997); Park et al., Effects of Androgens on the Expression of Nitric Oxide
• VIAGRA® is generally taken 20-40 minutes before sexual intercourse in 50 mg doses. This combination of therapy is particularly useful in hypogonadal men who need increased testosterone levels in order to optimize the effects of VIAGRA® and the sexual experience as a whole. In essence, a synergistic effect is obtained.
• AndroGel® is preferably applied to the body for a sufficient number of days so that the steady-state levels of testosterone are achieved.
• the active agents of the present invention may be administered, if desired, in the form of salts, esters, amides, enantiomers, isomers, tautomers, prodrugs, derivatives and the like, provided the salt, ester, amide, enantiomer, isomer, tautomer, prodrug, or derivative is suitable pharmacologically, that is, effective in the present methods, combinations and compositions.
• Salts, esters, amides, enantiomers, isomers, tautomers, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed.
• acid addition salts are prepared from the free base using conventional methodology, and involves reaction with a suitable acid.
• a suitable acid such as methanol or ethanol
• the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto.
• the resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent.
• Suitable acids for preparing acid addition salts include both organic acids, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• organic acids for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid
• An acid addition salt may be reconverted to the free base by treatment with a suitable base.
• Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids.
• preparation of basic salts of acid moieties which may be present on a phosphodiesterase inhibitor molecule are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
• Particularly preferred basic salts herein are alkali metal salts, for example, the sodium salt, and copper salts.
• Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug.
• esters are typically acyl -substituted derivatives of free alcohol groups, that is, moieties that are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
• Amides and prodrugs may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
• Prodrugs are typically prepared by covalent attachment of a moiety, which results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
• compositions according to the present invention include those suitable for oral, percutaneous, transmucosal, implantation, inhalation spray, rectal, vaginal, topical, buccal (for example, sublingual), or parenteral (for example, subcutaneous, intramuscular, intravenous, intramedullary and intradermal injections, or infusion techniques) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used.
• methyltestosterone is administration orally, and testosterone and estradiol are administered percutaneously.
• the pharmaceutical composition of methyltestosterone may be in the form of, for example, a tablet, capsule, cachet, lozenge, dispensable powder, granule, solution, suspension, emulsion or liquid.
• Capsules, tablets, etc. can be prepared by conventional methods well known in the art.
• Oral formulations can contain excipients such as binders (for example, hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (for example, lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (for example, starch polymers and cellulosic materials) and lubricating agents (for example, stearates and talc).
• binders for example, hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch
• diluents for example, lactose and other sugars, starch, dicalcium phosphate and cellulosic materials
• disintegrating agents for example, starch polymers and cellulosic materials
• lubricating agents for example, stearates and talc
• Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (for example, gums, zanthans, cellulosics and sugars), humectants (for example, sorbitol), solubilizers (for example, ethanol, water, PEG and propylene glycol), surfactants (for example, sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and antioxidants (for example, parabens, vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents (for example, EDTA).
• suspending agents for example, gums, zanthans, cellulosics and sugars
• humectants for example, sorbitol
• solubilizers for example, ethanol, water, PEG and propylene glycol
• surfactants for example, sodium lauryl sulfate, Spans, Twe
• Percutaneous administration includes transdermal delivery systems that include patches, gels, tapes and creams, and can contain excipients such as alcohols, penetration enhancers, and thickeners, as well as solubilizers (for example propylene glycol, bile salts, and amino acids), hydrophilic polymers (for example, polycarbophil and polyvinylpyrolidone), and adhesives and tackifiers (for example, polyisobutylenes, silicone-based adhesives, acrylates and polybutene).
• excipients such as alcohols, penetration enhancers, and thickeners, as well as solubilizers (for example propylene glycol, bile salts, and amino acids), hydrophilic polymers (for example, polycarbophil and polyvinylpyrolidone), and adhesives and tackifiers (for example, polyisobutylenes, silicone-based adhesives, acrylates and polybutene).
• solubilizers for example propylene glycol, bil
• Transmucosal formulations or delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and permeation enhancers (for example, propylene glycol, bile salts and amino acids), and other vehicles (for example, polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid).
• solubilizers and permeation enhancers for example, propylene glycol, bile salts and amino acids
• other vehicles for example, polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid.
• Injectable drug formulations include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (for example, ethanol, propylene glycol and sucrose) and polymers (for example, polycaprylactones and PLGA's).
• solubility-altering agents for example, ethanol, propylene glycol and sucrose
• polymers for example, polycaprylactones and PLGA's.
• Implantable formulations or systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone.
• the therapeutic agents of the present invention can then be administered orally, percutaneously, transmucosally, by implantation, by inhalation spray, rectally, vaginally, topically, buccally or parenterally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
• the compounds of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.
• compositions of the present invention can be administered for the prophylaxis or treatment of a menopause disorder by any means that produce contact of these compounds with their site of action in the body, for example in the ileum, the plasma, or the liver of a mammal.
• compositions of the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
• the therapeutic agents come in the form of kits or packages containing a sex hormone binding globulin synthesis inhibiting agent, and one or more steroids, including for example, androgen and/or estrogen.
• the kits or packages contain methyltestosterone and testosterone, or methyltestosterone and estradiol, or methyltestosterone and testosterone and estradiol, or methyltestosterone and testosterone and a pharmaceutical suitable for treating erectile dysfunction, or methyltestosterone and estradiol and a pharmaceutical suitable for treating erectile dysfunction, or methyltestosterone and testosterone and estradiol and a pharmaceutical suitable for treating erectile dysfunction, in amounts sufficient for the proper dosing of the drugs.
• kits contain methyltestosterone in a dosage form suitable for oral administration, for example, a tablet, and testosterone and/or estradiol in a dosage form suitable for percutaneous administration, for example, a gel or a patch.
• the therapeutic agents of the present invention can be packaged in the form of kits or packages in which the daily (or other periodic) dosages are arranged for proper sequential or simultaneous administration.
• the present invention further provides a kit or package containing a plurality of dosage units, adapted for successive daily administration, each dosage unit comprising at least one of the therapeutic agents of the present invention. This drug delivery system can be used to facilitate administering any of the various embodiments of the therapeutic compositions.
• the system contains a plurality of dosages to be taken daily via oral administration (as commonly practiced in the oral contraceptive art). In another embodiment, the system contains a plurality of dosages to be administered weekly via transdermal administration (as commonly practiced in the hormone replacement art). In yet another embodiment, the system contains a plurality of dosages to be administered daily, or weekly, or monthly, for example, with one or more therapeutic agents administered orally, and one or more therapeutic agents administered transdermally.
• ANDROGEL® administered at 5.0 g/day delivers 50 mg/day of testosterone to the skin of which about 10%, or 5 mg, is absorbed; and ANDROGEL® administered at 10.0 g/day, delivers 100 mg/day of testosterone to the skin of which about 10%, or 5 mg, is absorbed; and estradiol gel (Table 7) administered at 5.0 g/day, delivers 3 mg/day of estrogen to the skin of which about 10%, or 0.3 mg, is absorbed; and estradiol gel administered at 10.0 g/day, delivers 6 mg/day of estrogen to the skin of which about 10%, or 0.6 mg, is absorbed, for 30 days.
• the therapeutic combination or kit is comprised of an orally deliverable methyltestosterone and a non-orally deliverable testosterone.
• methyltestosterone is formulated as a capsule for oral administration and each dosage unit contains 5 mg of methyltestosterone.
• Testosterone is formulated as a gel for transdermal administration as described above in Table 6 (ANDROGEL®).
• 10 males and 10 females age 18 and older experiencing a menopausal disorder will be randomized to receive a daily dose of 5 mg or 20 mg methyltestosterone for 30 days, plus (a) 5.0 g/day ANDROGEL®, or (b) 10 g/day
• the therapeutic combination or kit is comprised of an orally deliverable methyltestosterone and a non-orally deliverable estrogen.
• methyltestosterone is formulated as a capsule for oral administration and each dosage unit contains 5 mg of methyltestosterone.
• Estrogen is formulated as a gel for transdermal administration as described above in Table 7.
• 10 males and 10 females age 18 and older experiencing a menopausal disorder will be randomized to receive a daily dose of 5 mg or 30 mg methyltestosterone for 30 days, plus (a) 5.0 g/day estradiol gel or (b) 10 g/day estradiol gel.
• the estrogen gel is rubbed daily onto a given area of skin.
• Menopausal disorders will be studied prior to treatment, during treatment and following treatment, by methods known in the art. Applicant expects the menopausal disorders will show improvement with the combinations.
• the therapeutic combination or kit is comprised of an orally deliverable methyltestosterone, a non-orally deliverable testosterone, and a non-orally deliverable estrogen.
• methyltestosterone is formulated as a capsule for oral administration and each dosage unit contains 10 mg of methyltestosterone.
• Testosterone is formulated as a gel for transdermal administration as described above in Table 6 (ANDROGEL®).
• Estrogen is formulated as a gel for transdermal administration as described above in Table 7.
• 10 males and 10 females age 18 and older experiencing a menopausal disorder will be randomized to receive a daily dose of 10 mg or 50 mg methyltestosterone for 30 days, plus (a) 5.0 g/day ANDROGEL® and 5.0 g/day estradiol gel or (b) 5.0 g/day ANDROGEL® and 10.0 g/day estradiol gel, or (c) 10.0 g/day ANDROGEL® and 5 g/day estradiol gel, or (d) 10.0 g/day ANDROGEL® and 10.0 g/day estradiol gel.
• the gels are rubbed daily onto a given area of skin. Menopausal disorders will be studied prior to treatment, during treatment and following treatment by methods known in the art. Applicant expects the menopausal disorders will show improvement with the combination.
• the therapeutic combination or kit is comprised of an orally deliverable methyltestosterone, a non-orally deliverable testosterone, and a pharmaceutical agent for treating erectile dysfunction.
• methyltestosterone is formulated as a capsule for oral administration and each dosage unit contains 10 mg of methyltestosterone.
• Testosterone is formulated as a gel for transdermal administration as described above in Table 6 (ANDROGEL®).
• the pharmaceutical agent for treating erectile dysfunction is VIAGRA® (citrate salt of sildenafil), an inhibitor of cyclic guanosine monophophate-specific phosphodiesterase type 5, and is formulated as a 50 mg tablet for oral administration.
• 10 males age 18 and older will be randomized to receive a daily dose of 10 mg or 50 mg methyltestosterone for 30 days, plus (a) 5.0 g/day of ANDROGEL® for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone and ANDROGEL® therapy; or (b) 10.0 g/day of ANDROGEL® for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone and ANDORGEL® therapy; or (c) 5.0 g/day of ANDROGEL® for 30 days and nothing before intercourse.
• the gel is rubbed daily onto a given area of skin. Libido, erections and sexual performance will be studied by methods known in the art. Applicant expects that all test parameters will show improvement with the combination.
• the therapeutic combination or kit is comprised of an orally deliverable methyltestosterone, a non-orally deliverable estrogen, and a pharmaceutical agent for treating erectile dysfunction.
• methyltestosterone is formulated as a capsule for oral administration and each dosage unit contains 10 mg of methyltestosterone.
• Estrogen is formulated as a gel for transdermal administration as described above in Table 7.
• the pharmaceutical agent for treating erectile dysfunction is VIAGRA® (citrate salt of sildenafil), an inhibitor of cyclic guanosine monophophate-specific phosphodiesterase type 5, and is formulated as a 50 mg tablet for oral administration.
• 10 males age 18 and older will be randomized to receive a daily dose of 10 mg or 50 mg methyltestosterone for 30 days, plus (a) 5.0 g/day of estradiol gel for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone and estradiol gel therapy; or (b) 10.0 g/day of estradiol gel for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone and t estradiol gel therapy; or (c) 5.0 g/day of estradiol gel for 30 days and nothing before intercourse.
• the gel is rubbed daily onto a given area of skin. Libido, erections and sexual performance will be studied by methods known in the art. Applicant expects that all test parameters will show improvement with the combination.
• the therapeutic combination or kit is comprised of an orally deliverable methyltestosterone, a non-orally deliverable testosterone, a non-orally deliverable estrogen and a pharmaceutical agent for treating erectile dysfunction.
• methyltestosterone is formulated as a capsule for oral administration and each dosage unit contains 10 mg of methyltestosterone.
• Testosterone is formulated as a gel for transdermal administration as described above in Table 6 (ANDROGEL®).
• Estrogen is formulated as a gel for transdermal administration as described above in Table 7.
• the pharmaceutical agent for treating erectile dysfunction is VIAGRA® (citrate salt of sildenafil), an inhibitor of cyclic guanosine monophophate-specific phosphodiesterase type 5, and is formulated as a 50 mg tablet for oral administration.
• 10 males age 18 and older will be randomized to receive a daily dose of 10 mg or 50 mg of methyltestosterone for 30 days, plus (a) 5.0 g/day ANDROGEL® and 5.0 g/day estradiol gel for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone, ANDROGEL® and estradiol gel therapy; or (b) 5.0 g/day ANDROGEL® and 10.0 g/day estradiol gel for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone and ANDORGEL® therapy; or (c) 10.0 g/day ANDROGEL® and 5.0 g/day estradiol gel for 30 days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1 day of methyltestosterone, ANDROGEL® and estradiol gel therapy; (d) 1

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Diabetes (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Epidemiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Physical Education & Sports Medicine (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Ophthalmology & Optometry (AREA)
• Gynecology & Obstetrics (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Rheumatology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Biomedical Technology (AREA)
• Psychiatry (AREA)
• Emergency Medicine (AREA)
• Vascular Medicine (AREA)
• Child & Adolescent Psychology (AREA)
• Urology & Nephrology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (2)

Family

ID=25400826

Family Applications (1)

Country Status (5)

Cited By (10)

Families Citing this family (24)

Family Cites Families (8)

• 2001
  • 2001-06-27 US US09/892,981 patent/US20030027804A1/en not_active Abandoned
• 2002
  • 2002-06-26 CA CA002451725A patent/CA2451725C/en not_active Expired - Lifetime
  • 2002-06-26 JP JP2003508362A patent/JP2005515964A/ja active Pending
  • 2002-06-26 WO PCT/US2002/020141 patent/WO2003002123A2/en not_active Ceased
  • 2002-06-26 EP EP02746682A patent/EP1404343A4/en not_active Withdrawn

Also Published As

Similar Documents

Legal Events