Method and compositions for early detection of endomitriosis, adenomyosis and uterine cancer

Abstract

A method for the early diagnosis of endometriosis in a patient, the method comprising: applying a quantity of a thixotropic gel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an endometrial-myometrial junction (EMJ); and enhancing visualization of the morphological characteristics of an endometrium and a myometrium in the uterus of the patient.

Description

METHOD AND COMPOSITIONS FOR EARLY DETECTION OFENDOMITRIOSIS, ADENOMYOSIS AND UTERINE CANCERREFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No, 63 / 525,330, filed July 6, 2023, which is incorporated herein by reference in its entirety.BACKGROUNDIELD

[0002] The present disclosure relates to a method and compositions useful for the early diagnosis of endometriosis, adenomyosis, and uterine cancer. ESCRIPTION OF THE RELATED ART

[0003] Endometriosis is classically defined as the presence of endometrial glands and stroma in ectopic locations, primarily the pelvic peritoneum, ovaries, and rectovaginal septum. Affecting 6-10% of women of reproductive age, endometriosis is characterized by dysmenorrhea, dyspareunia, chronic pelvic pain, irregular uterine bleeding, and / or infertility. The prevalence of this condition in women experiencing pain, infertility, or both can be as high as 35-50%.

[0004] According to the most convincing model, the retrograde menstruation hypothesis, endometrial fragments reach the pelvis via trans tubal retrograde flow,implant onto the peritoneum and abdominal organs, proliferate, and cause chronic inflammation with formation of adhesions. The number and amount of menstrual flows together with genetic and environmental factors determines the degree of phenotypic expression of the disease. Endometriosis is estrogen-dependent, manifests during reproductive years and is associated with pain and infertility. Dysmenorrhea, deep dyspareunia, dysphasia, and dysuria are the most frequently reported symptoms.

[0005] Standard diagnosis is carried out by direct visualization and histologic examination of lesions. Pain can be treated by excising peritoneal implants, deep nodules, and ovarian cysts, or inducing lesion suppression by abolishing ovulation and menstruation through hormonal manipulation with progestins, oral contraceptives, and gonadotropin-releasing hormone agonists or antagonists. Medical therapy is symptomatic, not cytoreductive; surgery is associated with high recurrence rates. Although lesion eradication is considered a fertility-enhancing procedure, the benefit on reproductive performance is moderate. Assisted reproductive technologies constitute a valid alternative. Endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer.

[0006] Thus, there exists a need to develop additional methods for the diagnosis of endometriosis.SUMMARY

[0007] The present subject matter relates to a method for the early diagnosis of endometriosis in a patient, the method comprising: applying a quantity of a thixotropicgel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an endometrial-myometrial junction (EMJ); and enhancing visualization of morphological characteristics of an endometrium and a myometrium of the uterus of the patient. In certain embodiments in this regard, the present methods can be used to determine whether the patient has developed or is developing endometriosis. In certain further embodiments, the present methods can comprise applying an early treatment for the endometriosis once the endometriosis is detected, particularly when the endometriosis is detected early, before full onset of the endometriosis.

[0008] The present subject matter also relates to a thixotropic composition used in a method of diagnosing endometriosis, wherein the thixotropic composition provides black contrast for use as media with medical imaging procedures selected from the group consisting of an ultrasound, a CT scan, and an MRI for purposes such as examination, evaluation, and diagnosis of one or more of endometriosis, uterine polyps, submucosal fibroids, synechiae, uterine cancer, and adenomyosis.

[0009] The present subject matter also relates to a method for the early diagnosis of a condition of the uterus, the method including applying a quantity of a thixotropic gel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an endometrial- myometrial junction (EMJ); enhancing visualization of morphological characteristics of an endometrium and a myometrium of the uterus of the patient; and enhancing three-dimensional (3D) imaging ultrasound, CT scans, and MRI to examine, evaluate, and diagnose a condition of the uterus selected from the group consisting ofendometriosis, uterine polyps, submucosal fibroids, synechiae, uterine cancer, adenomyosis and a combination thereof in the early stages of the condition.

[0010] These and other features of the present subject matter will become readily apparent upon further review of the following specification.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows an ultrasound image showing an enlarged uterus associated with Adenomyosis.

[0012] FIG. 2 shows an ultrasound image of an EMI in a uterus.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The following definitions are provided for the purpose of understanding the present subject matter and for construing the appended patent claims.Definitions

[0014] Throughout the application, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings can also consist essentially of, or consist of, the recited components, and that the processes of the present teachings can also consist essentially of, or consist of, the recited process steps.

[0015] It is noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

[0016] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components. Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present teachings, whether explicit or implicit herein.

[0017] The use of the terms “include,” “includes,” “including,” “have,” “has,” or “having” should be generally understood as open-ended and non-limiting unless specifically stated otherwise.

[0018] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently described subject matter pertains.

[0020] Where a range of values is provided, for example, concentration ranges, percentage ranges, or ratio ranges, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in thatstated range, is encompassed within the described subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and such embodiments are also encompassed within the described subject matter, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the described subject matter.

[0021] Throughout the application, descriptions of various embodiments use ‘‘comprising” language. However, it will be understood by one of skill in the art, that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of’ or “consisting of’.

[0022] “Subject" as used herein refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, and pct companion animals such as household pets and other domesticated animals such as, but not limited to, cattle, sheep, ferrets, swine, horses, poultry, rabbits, goats, dogs, cats, and the like.

[0023] "Patient" as used herein refers to a subject in need of treatment of a condition, disorder, or disease, such as but not limited to endometriosis, adenomyosis and uterine cancer.

[0024] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that mayvary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0025] Endometriosis is driven by relatively low levels of prenatal and postnatal testosterone. Testosterone affects the developing hypothalamic-pituitary-ovarian (HPO) axis, and at low levels, it can result in an altered trajectory of reproductive and physiological phenotypes that can mediate the symptoms of endometriosis. Women with endometriosis exhibit, relative to controls: shorter Anogenital Distance AGDs, indicative of lower prenatal testosterone lower luteinizing hormone (LH) relative to follicle stimulating hormone (FSH), higher Sex Hormone Binding Globulin (SHBG), higher serum oxytocin, lower ovarian and serum testosterone, lower Anti Mullerian Hormone (AMH), lower Waist to Hip Ratio (WHR) and body mass index (BMI), lower P-endorphin and a wider endometrial-myometrial junction (EMJ).

[0026] The endometrial-myometrial junction (EMJ) is related to peristaltic-like movements in the non-pregnant uterus. Hyperperistalsis and dysperistalsis of a uterus may underlie many important disorders such as dysmenorrhea, infertility, endometriosis, implantation failure, and preterm birth. The maximum thickness of EMJ in patients with endometriosis is often significantly greater (6.5 ± 1.9 mm) than in patients without endometriosis (4.8 ± 1.0 mm). The features of EMJ can appear similar at different stages, whereas they may be statistically different if correlated with patients without endometriosis.

[0027] The major proteins for uterine contraction of the non-pregnant uterus are Oxytocin (OT) and the oxytocin receptor (OTR). The expression level of OTR in the fundusregion of the EMJ is positively associated with the severity of dysmenorrhea in an endometriosis group (r = 0.870, p < 0.05). Comparing to normal uteri, the expression of OTR in the secretory phase can be significantly higher in the endometriosis uteri (p < 0.05). In the fundus of endometriosis uteri, OTR expression can be significantly higher in both the proliferative and secretory phases (p = 0.045 and 0.028, respectively).

[0028] Women with endometriosis can show higher serum OT levels, PGF2a levels, and uterine contractions. Atosiban treatment before embryo transfer (ET ) in endometriosis is effective in the priming of the uterus, suitable for embryo implantation.

[0029] Women with endometriosis can be more prone to have medically indicated preterm births before 37 gestational weeks and spontaneous preterm births before 32 gestational weeks compared with women without endometriosis.

[0030] Adcnomyosis is a common disorder of the uterus and is associated with an enlarged uterus (FIG. 1), heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. Such theories include intrinsic or induced microtrauma of the endometrial-myometrial interface; enhanced invasion of endometrium into myometrium; metaplasia of stem cells in myometrium; infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and abnormal uterine development in response to genetic and epigenetic modifications.Dysmenorrhea, HMB, and infertility arc likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components.

[0031] Adenomyosis is most often found in women between 40 and 50 years of age. This age range may be explained by the more common performance of hysterectomies in this age group but may also be attributed to prolonged life-time exposure to hormones. The most commonly reported associated symptoms are abnormal uterine bleeding and dysmenorrhea that occur in approximately 65% of patients. Adenomyosis often coexists with deep endometriosis. The association between adenomyosis, endometriosis, and infertility is still under debate and the mechanism is poorly understood. Patients with coexisting deep infiltrating endometriosis and uterine adenomyosis may constitute a subgroup with a particularly poor reproductive prognosis. A recent mcta-analysis described a 68% reduction in the likelihood of pregnancy in women seeking conception after surgery for rectovaginal and colorectal endometriosis.

[0032] Uterine cancer (endometrial cancer and uterine sarcomas) will affect approximately 66,200 women and about 13,000 will die from the disease in the US alone, per the American Cancer Society.

[0033] Tumor size, depth of myometrial invasion and cervical stromal involvement cannot be determined by clinical examination. Therefore, ultrasound and magnetic resonance imaging (MRI) are being used increasingly to improve preoperative evaluation, i.e. to identify women in need of more extensive surgery including pelvic- and para-aortic lymph node dissection. According to the European Society of Gynecological Oncology (ESGO), the European Society for Medical Oncology (ESMO) and the EuropeanSociety of Radiotherapy and Oncology (ESTRO), the preoperative workup should include pelvic examination, transvaginal or transrectal ultrasonography, and pathological assessment of an endometrial biopsy (histological type and grade). To optimize the sonographic assessment of endometrial tumors, a better understanding of the association between sonographic features and tumor stage, grade and histological type is needed.

[0034] The EMJ is the transitional zone between the mucous membrane that is the endometrium and the outer smooth- muscle layer of the myometrium. The inner layer of myometrium that encircles the endometrium has been variously termed the uterine junctional zone, the endometrial - sub endometrial, the sub endometrial unit or stratum sub-vascular, myometrium, the archimetra or archimyometrium and the inner myometrium. While these terms arc often used interchangeably, it is not always clear whether they are referring to exactly the same entity. The EMJ is structurally distinct from other mucosal - muscle interfaces within the human body in that it lacks a submucosal layer. Most tissues with a mucosa have a histologically recognizable submucosa that protects the underlying tissue from mucosal invasion (e.g. stomach, intestine, trachea and bronchi).

[0035] As illustrated in FIG. 2, the EMJ is seen as consisting of two distinctive structures: basal endometrium and inner myometrium. In normal uteri, the basal endometrium is seen as a continuous uninterrupted hyperechoic line and in practical terms it represents the endometrial - myometrial interface.

[0036] EMJ thickness and its alterations are different in patients with endometriosis compared with those women without endometriosis but are not correlated withAmerican Society of Reproductive Medicine staging methods. Noninvasive evaluation of the EMJ may be useful in the identification of those women who are affected by endometriosis at an early stage of the disease when there are no other sonographic signs of pelvic endometriosis.

[0037] Routine ultrasound examination of the uterus includes a detailed assessment of the morphological characteristics of the myometrium and endometrium. These two main functional components of the uterus display different acoustic properties, which facilitates their differentiation on ultrasound imaging. The majority of pathological entities that affect the myometrium differ in their pathogenesis and clinical significance from those that affect the endometrium, and they tend to be analyzed separately on ultrasound examination. However, it is well known that, due to their anatomical proximity, some endometrial abnormalities tend to extend into the myometrium and vice versa. This can be documented only by a careful examination of the interface between the endometrium and myometrium, which is often referred to as the endometrial-myometrial junction (EMJ).

[0038] Traditionally, assessment of the EMJ has been part of the magnetic resonance imaging (MRI) evaluation of the uterus, with changes in this area being a key component of the diagnosis of adenomyosis. Although the EMJ is visible on ultrasound, it has not played a major part in the sonographic evaluation of uterine pathology. In order to obtain clear images of the EMJ, high-resolution ultrasound equipment with three-dimensional (3D) imaging capability is often required. In one study on 3D reconstructed coronal images of the uterine cavity, the 2 mm Volume Contrast Imaging(VCI) slices gave the best quality images of the EMJ.

[0039] This has limited its usefulness in the early diagnosis of endometriosis where the differences are relatively small, as the maximum thickness of EMJ in patients with endometriosis is significantly greater than in patients without endometriosis (6.5 ± 1.9 mm vs 4.8 ± 1.0 mm), but still relatively small.

[0040] The present subject matter relates to a method of administering a small quantity of a thixotropic gel, e.g., about 6 mL or less, where a non-zero amount of at least 0.1 mL thixotropic gel is applied to the uterus through the cervical os. The opening in the center of the cervix is called the os. The thixotropic gel is administered via a standard catheter to enhance contrast and make accurate measurement of the endometrial-myometrial junction (EMJ). The thixotropic gel may also help to make accurate measurements of the morphological characteristics of the endometrium and myometrium with high- resolution ultrasound equipment. In certain embodiments, the high-rcsolution ultrasound equipment can have three-dimensional (3D) imaging capability for the early diagnosis of endometriosis adenomyosis and uterine cancer.

[0041] The present subject matter may also make noninvasive evaluation of the EMJ possible for those women who are affected by endometriosis at an early stage of the disease when there are no other sonographic signs of pelvic endometriosis. The present methods may help in identifying women with endometriosis who are at risk of implantation failure and / or preterm labor. In addition to the endometriosis, the present methods may also improve visualization of uterine polyps, submucosal fibroids, synechiae uterine cancer, and adenomyosis, as well as combinations thereof.

[0042] The present subject matter also demonstrates that Endometrial thickness can be positively associated with optimal EMJ visualization, and the procedure is bestconducted in the luteal phase for accurate early diagnosis of endometriosis adenomyosis and uterine cancer.

[0043] In an embodiment, the present subject matter relates to a method for the early diagnosis of endometriosis in a patient, the method comprising: applying a quantity of a thixotropic gel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an endometrial-myometrial junction (EMJ); and enhancing visualization of morphological characteristics of an endometrium and a myometrium of the uterus of the patient. In certain embodiments in this regard, the present methods can be used to determine whether the patient has developed or is developing endometriosis. In certain further embodiments, the present methods can comprise applying an early treatment for the endometriosis once the endometriosis is detected, particularly when the endometriosis is detected early, before full onset of the endometriosis.

[0044] In various embodiments, the thixotropic gel compositions may be designed to remain in a gel form in the uterus after application thereto and can distend the cavity for at least about 3 to about 30 minutes, at least 3 minutes, at least 30 minutes, 3 to 30 minutes, or a sufficient time for the examination and measurement of critical parameters to be made via one or more of ultrasound, CT scan, and MRI. At the end of an examination, body temperature (37°C) and the natural contractility of the uterus can cause the viscosity of the thixotropic gel to decrease and be naturally expelled through the cervical os.

[0045] In some embodiments, the quantity of the thixotropic gel may be about 6 mL, or6 mL, or less. In various embodiments, the quantity of thixotropic gel may be about 6 mL to about 0.1 mL, or 6mL to 0.1 mL.

[0046] In another embodiment, the thixotropic gel has a pH in a range between 6 to 8, or about 6 to about 8.

[0047] In a further embodiment, the present methods of applying the thixotropic gel to the uterus of the patient can comprise entering the uterus through a cervical os.

[0048] In another embodiment, the present methods can also include one or more of enhancing visualization of a uterine polyp, a submucosal fibroid, and a synechiae. In various embodiments, the method may provide a convenient contrast enhancing composition for use as media with medical imaging procedures such as ultrasound, CT scans, and MRI for purposes such as examination, evaluation, and diagnosis of one or more of endometriosis, uterine polyps, submucosal fibroids, synechiae uterine cancer, and adenomyosis. The contrast agent may permit clear visualization and accurate measurement of the endometrial-myometrial junction (EMJ) for early diagnosis of endometriosis, adenomyosis, and / or uterine cancer.

[0049] In an embodiment of the present methods, the measurement of the EMJ is conducted by applying about 6 mL or less of the thixotropic gel in a luteal phase of the patient when the patient menstrual cycle is at its maximum endometrial thickness. The luteal phase is the last stage of the menstrual cycle during which the uterus thickens to prepare for possible pregnancy. It starts after ovulation (when the ovaries release an egg) and lasts until the first day of a period. The luteal phase is usually 10 to 14 days long but can range from 10 to 17 days. During the luteal phase, the corpus luteum (theempty follicle left in the ovary after an egg has been released) produces hormones, mainly progesterone and some estrogen, to keep the uterine lining thick and ready for a fertilized egg to implant. During this phase, the endometrium begins to thicken and may measure between 10-16 mm, about 10 to about 16 mm, or 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15, mm, or 16mm. The endometrium is the lining of the uterus. The body prepares the endometrium to host an embryo during the menstrual cycle. Depending on what stage of the cycle a person is in, endometrial thickness can vary from 1-18 mm, or about 1 mm to about 18 mm, for a woman without endometriosis. The typical thickness of the endometrium changes throughout a person’s life, from childhood to puberty, through reproductive years, and after menopause. The endometrium is at its thinnest during menstruation, typically measuring between 1-4 mm, or about 1 to about 4 mm, in thickness.

[0050] In another embodiment of the present method, a thixotropic gel may be administered to the uterus of the patient via the cervical os from a syringe through a standard catheter.

[0051] In a further embodiment of the present method, a diagnosis of endometriosis, adenomyosis and uterine cancer can be made with no sonographic signs of endometriosis, adenomyosis and uterine cancer. The current method specifically enhances three-dimensional (3D) imaging ultrasound, CT scans and MRI for the purposes such as examination, evaluation, diagnosis of endometriosis, uterine polyps, submucosal fibroids, synechiae uterine cancer and adenomyosis especially in the early stages.

[0052] The present subject matter also relates to a thixotropic composition, wherein the thixotropic composition provides black contrast for use as media with medical imaging procedures selected from the group consisting of an ultrasound, a CT scan, an MRI, and combinations thereof for purposes such as examination, evaluation, and diagnosis of endometriosis, uterine polyps, submucosal fibroids, synechiae, uterine cancer and / or adenomyosis. The thixotropic composition may facilitate a clear visualization and accurate measurement of the endometrial-myometrial junction (EMJ) for early diagnosis of endometriosis, adenomyosis and uterine cancer.

[0053] In a further embodiment of the method, the thixotropic composition may remain a gel in the uterus and distends the cavity for at least about 3 to about 30 minutes, at least 3 minutes, at least 30 minutes, or at least 3 to 30 minutes.

[0054] In some embodiments, the thixotropic composition comprises at least one polymer and one copolymer. Ingredients useful in compositions of the thixotropic contrast medium include, but are not limited to, polymers (such as carbomers, including, but not limited to, Carbopol and polycarbophil) and copolymers (such as poloxamers). pH modifiers may also be incorporated to maintain a pH of 6 to 8, or about 6 to about 8. In various embodiments, the polymer may be selected from the group consisting of Carbopol 974P, 971P, 71G, 980, 981, 5984EP, 934, 934P, 940, 941, 1342, ETD 2020, Ultrez 10, Noveon (polycarbophil), Novion AA-1 (polycarbophil USP), and combinations thereof.

[0055] When extended uterine residence time is required for procedures such as MRI, thixotropic polycarbophil (Noveon AA-1) may be added to the present compositions.Polycarbophil is a lightly cross-linked polymer. Noveon® AA-1 Polycarbophil, USP isa high molecular weight acrylic acid polymer crosslinked with divinyl glycol. Polycarbophil is also a weak polyacid containing multiple carboxyl radicals (COO-), the source of its negative charges (Noveon is a registered trademark of Noveon Magnetics Inc. of San Marcos, TX). These acid radicals permit hydrogen bonding with the cell surface. Hydrogen bonds are weak, in the case of polycarbophil they are numerous and, therefore, tenacious. A water-insoluble polymer, polycarbophil stays attached to superficial cells until they turn over.

[0056] In further embodiments, the polymer may be a carbomer and the concentration of the carbomer may be between 0.1% and 10%, or about 0.1 % to about 10%, by weight. Carbomers used in the present compositions include but are not limited to synthetic high-molecular-weight polyacrylic acids cross-linked with allyl sucrose or allyl pcntacrythritol and can contain between 56 and 68% w / w carboxylic acid groups. The molecular weight of carbomer is estimated to be at about 7xl05to about 4xl09Da. As three-dimensionally cross-linked microgels, carbomers do not dissolve but swell to a remarkable extent in water after neutralization to form a gel. Carbomers can be used in liquid or semisolid pharmaceutical formulations as rheology modifiers that manifest thixotropic properties.

[0057] In some embodiments, the copolymer may be a poloxamer and the poloxamer may be selected from a group consisting of poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124. Poloxamers or Pluronics® (Pluronics is a registered trademark of BASF corporation of Ludwigshafen, Germany) used in the present formulations are a class of water-soluble nonionic triblock copolymers formed by polar (polyethylene oxide) and non-polar (poly propylene oxide) blocks which confer amphiphilic andsurface-active properties to the polymers. Aqueous solutions of poloxamers undergo sol-to-gel transition with increasing the temperature above a LCGT; moreover, the coexistence of hydrophilic and hydrophobic monomers into block copolymers allows the formation of ordered structures in solution, the most common of these being the micelles. The formation of micelles in solution is a reversible and a dynamic process. The concentration of the poloxamer may be between 1% and 50%.

[0058] In further embodiments, the thixotropic composition may be sterile. The composition may be sterilized using gamma irradiation.

[0059] The present subject matter may relate to a method for the early diagnosis of endometriosis, the method comprising: applying a quantity of a thixotropic gel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an cndomctrial-myomctrial junction (EMJ); enhancing visualization of the morphological characteristics of an endometrium and a myometrium of the uterus of the patient; and enhancing three- dimensional (3D) imaging ultrasound, CT scans, or MRI to examine, evaluate, and diagnose conditions of the uterus selected from the group consisting of endometriosis, uterine polyps, submucosal fibroids, synechiae, uterine cancer, adenomyosis and a combination thereof in the early stages of the condition. In various embodiments, the quantity of the thixotropic gel is about 6 mL or less. Said another way, the quantity of the thixotropic gel used may be between about 0.1 mL to about 6 mL.

[0060] It is to be understood that the method for early diagnosis of endometriosis, adenomyosis and uterine cancer is not limited to the specific embodiments described above, but encompasses any and all embodiments within the scope of the genericlanguage of the following claims enabled by the embodiments described herein, or otherwise shown in the drawings or described above in terms sufficient to enable one of ordinary skill in the art to make and use the claimed subject matter.

Claims

CLAIMSWe claim:

1. A method for the early diagnosis of endometriosis in a patient, the method comprising: applying a quantity of a thixotropic gel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an endometrial-myometrial junction (EMJ); and enhancing visualization of the morphological characteristics of an endometrium and a myometrium of the uterus of the patient.

2. The method of claim 1, wherein the quantity of the thixotropic gel is about 6mL or less.

3. The method of claim 1, wherein the thixotropic gel has a pH in a range between about 6 and about 8.

4. The method of claim 1, wherein applying the thixotropic gel to the uterus of the patient comprises entering the uterus through a cervical os.

5. The method of claim 1, further comprising enhancing visualization of a uterine polyp, a submucosal fibroid, and a synechiae.

6. The method of claim 1, wherein the measurement of the EMJ is conducted by applying about 6 mL or less of the thixotropic gel in a luteal phase of the patient when the patient menstrual cycle is at its maximum endometrial thickness.

7. The method of claim 6, wherein the thixotropic gel is administered to the uterus of the patient via the cervical os from a syringe through a standard catheter.

8. The method of claim 6, wherein a diagnosis of endometriosis, adenomyosis and uterine cancer can be made with no sonographic signs of endometriosis, adenomyosis and uterine cancer.

9. The method of claim 1, further comprising applying an early treatment for the endometriosis once the endometriosis is detected early, before full onset of the endometriosis.

10. A thixotropic composition, comprising at least a polymer and a copolymer.

11. The thixotropic composition of claim 10, wherein the polymer is selected from the group consisting of Carbopol 974P, 971P, 71G, 980, 981, 5984EP, 934, 934P, 940, 941, 1342, ETD 2020, Ultrez 10, Noveon (polycarbophil), Novion AA-1 (polycarbophil USP), and a combination thereof.

12. The thixotropic composition of claim 11, wherein the copolymer is a poloxamer and the poloxamer is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 184, poloxamer 124, and a combination thereof.

13. The thixotropic composition of claim 12, wherein the polymer is a carbomer and a concentration of the carbomer is between about 0.1% and about 10% by weight.

14. The thixotropic composition of claim 13, wherein the concentration of the poloxamer is between about 1% and about 50% by weight.

15. The thixotropic composition of claim 10, wherein the thixotropic composition provides black contrast for use as media with medical imaging procedures selected from the group consisting of an ultrasound, a CT scan., an MRI, and a combination thereof for purposes such as examination, evaluation and diagnosis of one or more of endometriosis, uterine polyps, submucosal fibroids, synechiae, uterine cancer and adenomyosis.

16. The thixotropic composition of claim 15, wherein the thixotropic composition facilitates a clear visualization and accurate measurement of the endometrial-myometrial junction (EMJ) for early diagnosis of at least one of endometriosis, adenomyosis, and uterine cancer.

17. The thixotropic composition of claim 15, wherein the thixotropic composition remains as a gel in a uterus after application to the uterus and distends a cavity of the uterus for at least 3 to 30 minutes.

18. The thixotropic composition of claim 15, wherein the composition is sterilized using gamma irradiation.

19. A method for the early diagnosis of endometriosis in a patient, the method comprising: applying a quantity of a thixotropic gel to a uterus of a patient using a catheter; enhancing a contrast and a distend of the uterus using the thixotropic gel; facilitating measurement of an cndomctrial-myomctrial junction (EMJ); enhancing visualization of the morphological characteristics of an endometrium and a myometrium of the uterus of the patient; and enhancing three-dimensional (3D) imaging ultrasound, CT scans and MRI to examine, evaluate, and diagnose conditions of the uterus selected from the group consisting of endometriosis, uterine polyps, submucosal fibroids, synechiae, uterine cancer, adenomyosis and a combination thereof in the early stages of the condition.

20. The method of claim 19, wherein the quantity of the thixotropic gel is about 6 mL or less.

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