Definitions

• This invention covers novel methods of treating several conditions of women by changing the constitutive and stimulated secretions of the local reproductive system including the uterine, uterine cervix, fallopian tubular secretions and vaginal secretions, secretions of the Bartholin or vestibular glands and urethral secretions.
• This invention also covers agents which can influence the function of the mucus genes found in the reproductive system, including, but not limited to the cervix, uterus, and Bartholin' s glands and other parts of the reproductive system with mucus secreting cells. Both squamous epithelium of the lower genital tract (vagina, for example) and epithelial cells of the upper reproductive tract (the various parts of the uterus, for example) are included in this invention.
• Changing the hydration, viscosity or other properties or stimulating the secretions can have potential uses in a variety of conditions and disorders, including, but not limited to contraception, infertility, menopause, dyspareunia, infections, and others related and unrelated conditions. Description of the function and anatomy of these organs can be found in Novak' s Gynecology, 12 th edition, eds. Berek, Adashi and Hillard, Williams and Wilkins, Baltimore, MD, 1996.
• this invention will in particular, discuss the development of non-steroidal factors that may control the reproductive system. These products could potentially act on the cells of the reproductive system to augment steroid action or act in the absence of steroid action, as the case may be.
• Some of the approaches proposed in the invention are derived from research conducted on the actions of mucin genes and other cell systems in non-reproductive arenas. The invention will apply these new discoveries to the reproductive system to develop a new series of non-steroidal products targeted toward condition of the female reproductive system such as atrophic vaginitis and could also function as a contraceptive. There are two aspects to this invention.
• the first concept is the use of an agent or agents to increase the viscosity and nature of mucus of the reproductive organs, with such an action being utilized as a potential contraceptive.
• a specific agent, ebrotidine, is described in more detail later.
• the second concept is the use of agents to increase the amount and/or the water content of secretions of the reproductive organs including mucus and transudative secretions.
• agents described in this invention include purinergic agents that are known to increase water content of secretions in systems such as the lung. This concept will be used for the invention to generally increase the lubrication of the reproductive system.
• mucus secretion include, but not limited to content of mucin elements such as sulfo and sialomucins, changes in viscosity, hydrogen ion retardation, hydrophobicity, changes in phospholipid content, glycosylation and sulfation, macromolecular assembly. Also included are potential changes in growth factors such as, but not limited to tumor necrosis factor alpha and epidermal and platelet derived growth factors, effect on agents such as integrins, and other agents of the inflammatory and healing processes and agents that influence proteinases and other agents related to mucin breakdown.
• Influences of the covered agents on mucus properties such as but not limited to surface tension and adhesivity, transport properties and Theological properties such as but not limited to viscosity, elastic modulus, tensile properties, rigidity factors, recoil factors, spinnhus, sperm penetration qualities, consistency, cellularity, ferning, etc. are also included in this patent.
• Theological properties such as but not limited to viscosity, elastic modulus, tensile properties, rigidity factors, recoil factors, spinnhus, sperm penetration qualities, consistency, cellularity, ferning, etc. are also included in this patent.
• a variety of products, which can influence the mucosal gene and/or mucosal epithelium in the presence or absence of estrogens, progestogens, their natural and synthetic derivatives and other sex steroid hormones are described.
• Cervical mucus changes in quality and quantity throughout the menstrual cycle. Under the influence of rising estrogen levels, cervical mucus becomes thin, allows the passage of spermatazoa and has a characteristic quality called spinnbarkeit- it can be stretched into a thin, adhesive strand. Under the influence of progesterone later in the menstrual cycle, the mucus becomes thick and hostile to sperm penetration, closing the window of fertility. In fact, thickening of cervical mucus is thought to be one of the primary modes of contraceptive action for progestin-only contraceptives.
• cervical mucus becomes scant and highly viscous, contributing to vaginal dryness and lack of lubrication. Stimulation of cervical mucus production at this time, along with changes in vaginal mucosa should help alleviate vaginal dryness, and can also augment the action of exogenously administered estrogen's effect on this condition.
• cervical epithelia express at least five of the many known mucin genes.
• the epithelium of the mucosal surface of the endocervix expresses genes designated as MUC 1 ; 4; 5 AC; 5B and 6 while the vaginal epithelium expresses MUC 1 and 4 (Gipson DC, Ho SB, et al. Mucin Genes expressed by human female reproductive tract epithelia. Bio. Reprod. 1997:56:999-1011).
• MUC 4 was most intensely expressed using in-situ hybridization, conducted predominantly during the luteal phase. The expression of this particular gene appears to be dependent partly on the estrogen/progesterone ratio (Audie JP, Tetaert D.
• Cervical mucus is a mixture of mucin secreted by the mucus cells and transudation of capillary exudates, which include water (85-98%), electrolytes, serum and locally derived proteins.
• the mucins are responsible for the rheological properties of mucus, but comprise less than 1% in volume.
• estrogens stimulate the stromal cells, which in turn stimulate the mucus cells.
• the mucus produced during this time has a higher water content, accounting for part of the rheological changes such as ferning.
• the human cervix secretes a profuse, clear and thin mucus, and about 600 mg of mucus a day, in the pre-ovulatory and ovulatory phases of the menstrual cycle. Under the influence of progestins, this decreases to 20-60 mg/day and the mucus is thick and viscous (Moghissi, KS. The function of the cervix in fertility. Fert. Steril. 1972 23:295-306).
• estrogen dependEnt tissue will start to involute and take on the characteristic appearance of estrogen deprivation.
• human cervical mucus becomes scanty. In vitro, this mucus has been shown to be impenetrable to sperm. (Chretien FC. Ultrastructure and variations of human cervical mucus during pregnancy and the menopause. Acta. Obstet. Gynecol. Scand. 1978 57:337-348).
• vaginal mucosa also regresses during menopause. With aging, the vagina becomes shortened, ruggae disappear, and elasticity is lost. Vaginal secretion becomes scanty. When estrogen is provided, some of these effects are reversed: the cervix starts to secrete some mucus and the vaginal mucosa regains its lost layers, but often the symptoms do not disappear completely partly because the amount of estrogen provided for hormone replacement is lower than circulating estrogen levels during a normal menstrual cycle.
• Cervical mucus its rheological properties and role in reproduction
• Cervical mucus contains 98% water at mid cycle and 90% at other times (Kopito L et al. Water and electrolytes in human cervical mucus. Fertil. Steril. 1973; 24:499-506). Cervical mucus is also rich in metallic ions, enzymes (such as alkaline phosphatase, etc.), soluble proteins and salts (Fordney-Settlage, D. A review of cervical mucus and sperm interactions in humans. Int. J. Fertil.
• the gel phase of cervical mucus contains primarily a form of mucin, a high molecular weight glycoprotein. Mucin micelles cross-link by disulfide bridges. Estrogen and progestogens control the arrangement of these micelles. These micellar arrangements influence the rheological properties of mucus.
• mucus and its properties are defined by chemical, physical and biological properties.
• Rheological or flow properties of mucus include viscosity, rate of flow, shear index, spinnhus or stretch of mucus due to increased viscoelasticity and ferning (crystallization) parameters.
• Ebrotidine for use as a contraceptive
• Systemic contraceptives such as oral contraceptives and implants have many side effects, which can result in poor compliance or lack of usage. For instance, irregular bleeding and weight gain are some of the minor side effects, while major side effects such as venous and pulmonary thromboemobolism are also found. Local contraceptives such as diaphragms are not as effective. These problems lead to poor compliance or to lack of use altogether, as evidenced by the large number of unintended pregnancies in spite of the availability of many types of contraceptives. There is a great need for innovative and safe new contraceptive products.
• the focus of this aspect of this invention is in the area of contraception is to develop a safe, non-steroidal, locally active product that will change the nature of cervical mucus, rendering it hostile to sperm penetration.
• the aspect of the invention could potentially develop as a product that will not dynamically disturb the woman's reproductive system, but will provide contraceptive efficacy. It is anticipated that the drug may be given either locally or systemically.
• This invention pertains to a novel use of the known influence of a new drug, ebrotidine, (benzene su l fo namide N- [ [ [ 2 - [ [ [ [2 - [ (aminoiminomethyl)amino] -4- thiazolylmethyl0thio]ethyl]amino]methylene]-4-bromo[CAS]) [CAS- 100981-43-9] a H2 receptor blocker with profound effect on gastric mucus, as a potential contraceptive.
• This product is being developed for gastric ulcer healing, as described in EP Patent Number 159012, priority date ES8404418.
• ebrotidine Of particular interest to this aspect of the invention are ebrotidine' s unique actions on the functionality of gastric mucosa as shown below. It is known that the mucous secretion of the gastric mucous cells parallels in several respects (mucus genes post-translational processing) that of the cervical mucus cell of the reproductive system.
• the invention involves the use of ebrotidine to influence the mucous secretion of the cervix, thereby rendering the mucous thick and viscous and hostile to sperm and acting as a potential contraceptive in pre-menopausal women.
• ebrotidine may be successful as a non-steroidal locally acting product for contraception.
• a recent publication has reviewed ebrotidine' s gastric and biochemical properties (Slomiany, BL, Piotrowski, J and Slomiany, A. Gastroprotective Properties of Ebrotidine. A review. Arzneim- Forsch Drug Research 1997. 47:459-467).
• Ebrotidine has been extensively studied in experimental animal models evaluating its effect on gastric mucus (Slomiany, BL et al. Enhancement in the protective quality of gastric mucus by ebrotidine during duodenal ulcer healing. Gen. Pharmacol. 1995, 26: 1039-1044). Moreover, a complete package of preclinical toxicology studies has been conducted, including acute and chronic toxicology, reproductive, genotoxicity, reproductive toxicity, and carcinogenicity studies conducted up to 24 months of exposure. Overall, no serious adverse effects were seen with ebrotidine in these pre-clinical studies. Specifically, no effects were found on reproductive or genotoxicity screens and no hyperplastic and/or dysplastic changes were seen in carcinogenicity studies.
• Ebrotidine More than 500 patients with gastric ulcers have been treated with ebrotidine, with drug exposures up to 8 weeks, in doses up to 800 mg per day given orally. No serious adverse effects were noted with the drug in this large database. Ebrotidine was well tolerated. Ebrotidine, in comparative clinical studies was found to be as effective as ranitidine (Zantac) and in some studies, was shown to have a better ulcer healing property
• Ebrotidine' s effect on the physical properties of gastric mucus was evaluated in experimental studies. 12 ⁇ 13 Ebrotidine was found to change the physicochemical nature of gastric mucus. Mucus gel became thicker with the gel dimension found to be 290 ⁇ m in animals treated with ebrotidine and 223.5 ⁇ m in control. Furthermore, this effect was seen even when ebrotidine was given with indomethacin, a prostaglandin inhibitor known to cause gastric mucosal injury. Ebrotidine evoked a 65% greater increase in hydrophobicity of mucus, a 1.4 fold increase in mucus viscosity and 16% increase in hydrogen ion retardation capacity. Improvements in the mucus gel properties are probably related to ebrotidine's ability to raise the content of mucin and phospholipids in mucus.
• ebrotidine could demonstrate similar effects on cervical mucus, it is believed to be useful during the follicular phase by changing the local mucus quality, rendering it hostile to sperm penetration and potentially providing an effective contraceptive.
• systemic dosage is contemplated to a preferred dosage range between 200 to 1600 mg per day.
• lower amounts are contemplated with a target of achieving local tissue exposure in the range of 50 to 250 uMol/L.
• the second aspect of the invention relates to the development of a new treatment for a bothersome and potentially problematic symptom of menopause, namely vaginal dryness, by stimulating the secretion of cervical mucus and vaginal transudative secretions.
• the approach outlined here has been successfully utilized to change the mucus quality and increase transudative secretion in the respiratory system, namely, the stimulation of purinergic receptors.
• vaginal dryness is caused by inadequate mucus secretion and atrophy of the vaginal mucosa, the end result of falling estrogen levels. It is one of the more common side effects of menopause, and leads to quality of life issues along with a propensity for greater incidence of infections.
• vaginal mucosa and the cervical mucosal gland become atrophic.
• estrogen is not used in this population. Another important segment of the population represents younger women undergoing estrogen withdrawal for treating diseases such as endometriosis or even in the late luteal phase of a normal menstrual cycle. These women may actually constitute a unique cohort in which to test the concept. We believe that our application, as discussed below, may indeed help many menopausal women.
• Purinergic receptors or receptors responsive to external stimulation by nucleotides such as ATP are now the focus of research in the respiratory and nervous system. In the respiratory system, these agents have been shown to increase the secretions of the respiratory epithelium thereby thinning the mucus. This finding is now being utilized to develop products for cystic fibrosis, a disease characterized by the disabling accumulation of viscid thick inspissated mucus. It has been shown that purinergic stimulation can lead to a thin watery secretion. The novel purinergic stimulants have been identified as part of a discovery effort. This approach can be found in US patent numbers 4,501729, 5,292,498, and 5,635,160 the entire disclosure of which is incorporated by reference herein.
• purinergic agents included but not limited to in this invention are duramycin and related lantibiotics, plus other agents that similarly raise the chloride secreting response; dinucleotides and pharmaceutically acceptable salts of Formula I (Patent 5,635,160), such as A 2 P 4 stimulating dinucleotides that enhance chloride secretion by increasing transcellular chloride ion transport or alter paracellular permeability, in either case leading to an altered hydration of the overlying or secreted mucus; amiloride and other agents, including but not limited to benzaril and phenamil that similarly hinder sodium ion uptake and lead to altered hydration of mucus; anion secretion inhibitors such as carbonic anhydrase inhibitors [e.g.
• acetazolamide and carbamide.
• Anion secretion inhibitors can find specific use in bacterial vaginosis and like conditions. Furthermore, all of the above products may be used singly or in combination, with or without estrogens, progestogens, androgens and their synthetic and natural derivatives and with or without the mucus secretion/stimulation of hypertonic saline and/or the addition of NaCl.
• Agents described above or their antagonists can also increase the secretion and/or enhance the properties of mucus in postmenopausal women, thereby become protective against localized infections and friability and conducive to normal health and normal sexual activity in these women. Similarly they could find use in pre-menopausal women lacking sufficient mucus for proper lubrication.
• Such products can be given with or without estrogen, progesterone or their synthetic derivatives to enhance or antagonize the effect of a product such as purinergic products. Potentially, these purinergic agents could also stimulate the uterine cervix and the vaginal mucosa.
• Amiloride and other agents that block Na 1" uptake, and/or P 2 Y 2 receptor agonists could be used to enhance cervical mucous secretion, to treat conditions such as dyspareunia and/or infertility. Such products may also potentially, be found to have activity against sexually transmitted diseases.
• Another use embodied in this invention are products that can influence purinergic receptors.
• P 2 Y 2 receptor agonists have been specifically cited, we incorporate by reference the entire classes of purinoceptor subtypes that are selective for nucleotides and agents that mimic the effects of nucleotides. Such an increase in secretion may be helpful in situations such as menopause, when there is much reduced or absent secretion of mucous causing vaginal dryness.
• All of these products may or may not be given with estrogen, progesterone or their synthetic derivatives and all new classes of estrogens and progestogens developed to provide differential effects based on binding to, but not limited to various receptors such as the alpha and beta estrogen receptors and A and B progesterone receptors.
• These compounds are sometimes called anti-estrogens, anti-progestogens or Selective Estrogen Receptor Modulators, or designer steroid molecules.
• These compounds can be sometimes associated with vaginal dryness; the current invention may help women who must take these drugs for the menopause or for the treatment or prevention of conditions such as, but not limited to, breast cancer, osteoporosis and cardiovascular disease.
• the dosage of therapeutic agents identified in this application as dinucleotides in suitable formulations for local application can contain active ingredients up to 40% w/w concentration but preferably below 20% w/w concentration.
• a carrier typically would be a pyrogen free water and/or an aqueous alcohol solution.
• Powder for insufflation can be placed in a metered dose applicator.
• active agents might range from 0.1 to 100 w/w concentration. Dosing by whatever means would likely fall in the range of 1-20 mg of active agent by weight daily.
• nucleotide concentrations can vary between 10 "3 and 10 "6 molar in creams, gels and/or solutions. Amiloride doses are anticipated at 5 mg/day when given systemically and local concentrations of 3xl0 '2 to 3X10 "4 molar in solutions are anticipated.
• Both aspects of the invention can be given orally, systemically, including but not limited to implants and transdermal patches, etc. or given locally, i.e., vaginally, including but not limited to foams, creams, rings, sprays, gels, tablets, films, all manner of solid and liquid dosage forms etc.
• the products may also be delivered with a variety of devices, including but not limited to tampons, sponges, spray devices, etc.
• Products insoluble in water such ebrotidine may be formulated after micronization or nanoization in water and a polymer such as carbopol or dissolved in mineral oil and formulated with carbopol.

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• 1999
  • 1999-07-07 JP JP2000558812A patent/JP2002520279A/ja not_active Withdrawn
  • 1999-07-07 AU AU49734/99A patent/AU4973499A/en not_active Abandoned
  • 1999-07-07 EP EP99933743A patent/EP1191928A1/en not_active Withdrawn

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