WO2002053145A1 - Use of polidocanol for the treatment of the uterine and the fallopian tubes - Google Patents
Use of polidocanol for the treatment of the uterine and the fallopian tubes Download PDFInfo
- Publication number
- WO2002053145A1 WO2002053145A1 PCT/US2001/049572 US0149572W WO02053145A1 WO 2002053145 A1 WO2002053145 A1 WO 2002053145A1 US 0149572 W US0149572 W US 0149572W WO 02053145 A1 WO02053145 A1 WO 02053145A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polidocanol
- treatment
- preparation
- pharmaceutical composition
- fallopian tubes
- Prior art date
Links
- 229920001363 Polidocanol Polymers 0.000 title claims abstract description 47
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960002226 polidocanol Drugs 0.000 title claims abstract description 47
- 238000011282 treatment Methods 0.000 title claims abstract description 31
- 210000003101 oviduct Anatomy 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 241000124008 Mammalia Species 0.000 claims abstract description 6
- 210000004291 uterus Anatomy 0.000 claims description 13
- 208000025661 ovarian cyst Diseases 0.000 claims description 9
- 208000023664 Bartholin cyst Diseases 0.000 claims description 8
- 208000027029 Bartholin duct cyst Diseases 0.000 claims description 8
- 230000000740 bleeding effect Effects 0.000 claims description 7
- 239000000872 buffer Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 239000000644 isotonic solution Substances 0.000 claims description 2
- 239000003182 parenteral nutrition solution Substances 0.000 claims description 2
- 241001441724 Tetraodontidae Species 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000008247 solid mixture Substances 0.000 claims 1
- 208000031513 cyst Diseases 0.000 abstract description 15
- 206010046788 Uterine haemorrhage Diseases 0.000 abstract description 11
- 238000012148 non-surgical treatment Methods 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 13
- 210000003679 cervix uteri Anatomy 0.000 description 13
- 230000000306 recurrent effect Effects 0.000 description 9
- 210000001215 vagina Anatomy 0.000 description 8
- 229960000901 mepacrine Drugs 0.000 description 7
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 7
- 206010011732 Cyst Diseases 0.000 description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 5
- 206010003694 Atrophy Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000002421 anti-septic effect Effects 0.000 description 4
- 230000037444 atrophy Effects 0.000 description 4
- 230000002357 endometrial effect Effects 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 238000002679 ablation Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 210000004696 endometrium Anatomy 0.000 description 3
- 210000003038 endothelium Anatomy 0.000 description 3
- 229960003276 erythromycin Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002350 laparotomy Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 description 2
- 241000521257 Hydrops Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010027514 Metrorrhagia Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010000269 abscess Diseases 0.000 description 2
- 238000001949 anaesthesia Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000004392 genitalia Anatomy 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002357 laparoscopic surgery Methods 0.000 description 2
- 238000002504 lithotomy Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 206010057165 Venous varices Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000002947 bartholin's gland Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 230000000025 haemostatic effect Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000009802 hysterectomy Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000000608 laser ablation Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000002632 myometrial effect Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000002956 necrotizing effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000026234 pro-estrus Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
Definitions
- the invention concerns the use of polidocanol for the preparation of a pharmaceutical composition for the treatment of the uterus, the gynaecologic cysts and for the fallopian tubes of a female mammal, including human. More specifically, the invention concerns the use of polidocanol for the occlusion of the fallopian tubes and/or for the treatment of functional endometrial bleeding and cysts of fore-mentioned subjects and patients. The invention includes the methods of said non-surgical treatments.
- Polidocanol [alfa-dodecyl-omega-hydroxypoly(oxy-l,2-ethanediyl)] is acknowledged in the surgical praxis and in the medical literature for the sclerotization of venous varices. It is also known as Pistocaine and Hydroxy- polyethoxydodecane. It is commercially available in the form of isotonic solutions of 0.5, 1.0 or 2.0% by weight strength buffered with a phosphate buffer (distributed under the brand name Aethoxysklerol by Kreussler Pharma) . It has analgesic effect; therefore its application is seemingly painless.
- D+C dilatation and curettage
- Recurrent uterine bleeding poses a complicated dilemma, because it either necessitates repeated D+C, or after several repeated curettages the removal of the uterus.
- This operation is deeply controversial in itself, as a healthy organ (the uterus) is removed because of a recurrent functional problem (bleeding).
- There- fore surgical methods for the removal of the source of bleeding endometrial resection or ablation were used during the 1980-ies [Lewis, B.V., Magos, A.L., Eds.
- Polidocanol can also serve as a destructive agent preventing the recurrence of ovarian cysts and simplifying the treatment of such cysts. Moreover, polidocanol is a promising agent for the nonsurgical treatment of Bartholin's cysts.
- the object of this invention is the use of polidocanol for the preparation of a pharmaceutical composition suitable for the treatment of the uterus and the fallopian tubes of a female mammal, including human.
- the object of this invention is the use of polidocanol for the preparation of a pharmaceutical composition for the occlusion of the fallopian tubes (sterilization) and for the treatment of functional endometrial bleeding and ovarian cysts and Bartholin's cysts.
- Another object of this invention is to provide methods for the above- mentioned non-surgical treatments.
- polidocanol is used for the preparation of a pharmaceutical composition for tubal sclerotization.
- the pharmaceutical composition is a 0.01 to 10% by weight polidocanol solution, which is injected into the fallopian tubes through the uterine cervix.
- the outer genitals and the vagina are cleansed with antiseptic solution.
- a speculum is entered into the vagina and the uterine cervix exposed. Then the vagina and the cervix are cleansed with antiseptic again.
- the cervix is grasped with a forceps and a cannula introduced into the cervix.
- a 5 ml syringe filled with polidocanol solution is attached to the cannula and the fluid is injected under pressure into the fallopian tubes. To maintain prolonged sclerotizing effect and avoid flow-back of the solution, the cannula and syringe are kept in place for 5 minutes.
- the woman can leave the clinic.
- the occlusion of the tubes has to be checked by a method commonly used for the examination of fallopian tubes (e.g. hysterosalpingography, perflation etc.). If the closure is not complete, the procedure can be repeated.
- polidocanol is used for the preparation of a pharmaceutical composition suitable for the treatment of recurrent functional uterine bleeding.
- uterine bleeding recurs after histological diagnosis has been obtained within one year, it is feasible to treat the recurrent bleeding non-surgically.
- haemostasis a polidocanol solution of 0.01 to 10%o by weight strength is injected into the uterine cavity through the uterine cervix.
- haemostasis a polidocanol solution of 0.01 to 10%o by weight strength is injected into the uterine cavity through the uterine cervix.
- the women assume the usual gynaecologic (lithotomy) position.
- the outer genitals and the vagina are cleansed with antiseptic solution.
- a speculum is entered into the vagina and the uterine cervix exposed.
- vagina and the cervix are cleansed with antiseptic again.
- the cervix is grasped with a forceps and a cannula introduced into the cervix.
- a 5 ml syringe filled with 2 ml polidocanol solution is attached to the cannula and the fluid is injected with minimum pressure into the uterine cavity.
- the cannula and syringe are kept in place for 5 minutes. Thereafter the bleeding stops and the woman can leave the clinic.
- this inventipn polidocanol is used for the preparation of a pharmaceutical composition suitable for the treatment of ovarian cysts.
- the most important point of this treatment is the conservation of ovarian tissue of the patient being in fertile age.
- Fenestration of a simple cyst or removal of the inner layer of endometriotic cysts is a common procedure.
- the operation can be simplified by destroying the inner layer by polidocanol. This operation can be performed by laporoscopy or under ultrasound guidance, which further simplifies the procedure. After puncturing the cyst and removing its content a polidocanol solution of
- polidocanol is used for the preparation of a pharmaceutical composition suitable for the treatment of Bartholin's cysts.
- Bartholin's cyst could be punctured under direct manual guidance in local anaesthesia. After puncturing the cyst and removing its content a polidocanol solution of 0.01 to 10% by weight strength is injected into the cavity and left in place. The cyst would collapse and its wall sclerotize with a possible minimum of recurrence. The procedure is performed on ambulatory or day-care basis.
- composition according to the invention can be prepared in any pharmaceutical dosage form suitable for the above-mentioned treatments.
- Said composition can comprise an effective amount of polidocanol composed with pharmaceutically acceptable additives and/or vehicles, such as buffers, solvents, co-solvents etc.
- suitable forms of administration include solutions, gels, emulsions, suspensions and a powder of polidocanol to be dissolved before use and powders or premixes to be reconstituted with a suitable solvent before use.
- the proposed total dose is 0.250 mg to 250 mg of polidocanol depending on the body weight of the subj ect.
- Step 1 Preparation of phosphate buffer pH 7.45.
- Solution A 9.073 g KH2P04 dissolved to 1000 ml water.
- Solution B 11.87 g Na2HP04.2H20 dissolved to 1000 ml water.
- Polidocanol 1 g is dissolved in 96%> ethyl alcohol 5 ml and filled up to 100 ml with phosphate buffer pH 7.45. The 1% polidocanol solution is sterilized and filled into ampoulles.
- Example 2 Description of the preparation of 1% polidocanol parenteral gel. Step 1. Methylcellulose 3 g is dissolved in phosphat buffer pH 7.45 and replenished with buffer to 100 ml, which is a viscous gel. Step 2. Polidocanol 1 g is dissolved in 96% ethyl alcohol 5 ml and filled up to 100 ml with the viscous gel prepared in step 1. The 1% polidocanol in 3%> methylcellulose gel is sterilized and filled into ampoulles.
- Example 3 For purposes of longer shelf life polidocanol is dispensed in separate ampoulles and dissolved before application with a solution of 5% ethyl alcohol in phosphate buffer pH 7.45 provided in rubber capped ampoulles separately.
- Macroscopic and microscopic examinations There were no animals lost during the following 30 days.
- the weight of treated animals increased to 286-333 g, that of control animals to 298-331 g.
- Animals were anesthetised with ether and sacrificed. Lower laparotomy was performed and the upper third of the vagina, the cervix, both uterine horns with oviducts and ovaries were excised in toto.
- the specimen was fixed in 4% buffered formaldehyde solution. Macroscopic changes were recorded.
- the fixed specimen were transferred to the laboratory of pathologist Dr. J. Liechtenstein-Zabrak. Specimen were embedded in paraffin and cut at the uterine- cervical junction, at the mid-portion and at the distal portion of the uterine horn. Specimen were stained with hematoxyllin-eosine and examined under 40x magnification.
- Acute inflammation 7 Dilated lumen 6 Vilous projections 6 Fibrosis 6 Atrophy 5
Abstract
The invention concerns Th. use of polidocanol for the preparation of a pharmaceutical composition for the treatment of the uterine and the fallopian tube of a female mammal, including human. More specifically, the invention concerns the use of polidocanol for the occlusion of the fallopian tubes and/or for the treatment of functional endometrial bleeding and cysts of said subjects and patients. The invention includes the methods of said non-surgical treatments.
Description
USE OF POLIDOCANOL FOR THE TREATMENT OF THE UTERINE AND THE FALLOPIAN TUBES The invention concerns the use of polidocanol for the preparation of a pharmaceutical composition for the treatment of the uterus, the gynaecologic cysts and for the fallopian tubes of a female mammal, including human. More specifically, the invention concerns the use of polidocanol for the occlusion of the fallopian tubes and/or for the treatment of functional endometrial bleeding and cysts of fore-mentioned subjects and patients. The invention includes the methods of said non-surgical treatments. Polidocanol [alfa-dodecyl-omega-hydroxypoly(oxy-l,2-ethanediyl)] is acknowledged in the surgical praxis and in the medical literature for the sclerotization of venous varices. It is also known as Pistocaine and Hydroxy- polyethoxydodecane. It is commercially available in the form of isotonic solutions of 0.5, 1.0 or 2.0% by weight strength buffered with a phosphate buffer (distributed under the brand name Aethoxysklerol by Kreussler Pharma) . It has analgesic effect; therefore its application is seemingly painless. Earlier practices for the occlusion of fallopian tubes: The traditional methods of tubal sterilization are surgical, which involves entering the peritoneal cavity either by open surgery (laparotomy) or by laparoscopy. Both methods are dangerous and necessitate surgical and anaesthetic facilities, hospital stay and technical skills on the part of the operateur. Non- surgical methods were initiated during the 1970-ies. The quinacrine method was first published and practiced [Zipper, J. et al.: "The clinical efficacy of the repeated transcervical instillation of quinacrine for female sterilization", Int. J. Gynaecol. Obstet. 14 499-502 (1976); Hieu, D. T. et al.: "31,781 cases of non- surgical female sterilization with quinacrine pellets in Vietnam", Lancet 342, 213-7 (1993)] until safety issues prohibited its further application [Kessel, E.: Quinacrine sterilization revisited. Commentary. Lancet 344, 689 (1994)].
The procedure involves the introduction of solid pellets of quinacrine into the uterine cavity, where these are dissolved and the resulting concentrated
solution enters the fallopian tubes, causes necrosis and sclerotization resulting in permanent occlusion [Zipper, J. at al., ibid]. A similar method of introducing solid pellets of erythromycin was disclosed in U.S. Patent No. 5,885,601.
Earlier practices of treatment of recurrent dysfunctional endometrial bleeding:
Recurrent endometrial bleeding is a very common disease which is presently treated with surgical methods. The standard treatment of endometrial bleeding is dilatation and curettage (D+C), which is an invasive procedure with the danger of injury or perforation of the uterine wall. It also involves local or more commonly general anaesthesia with its inherent additional dangers.
Recurrent uterine bleeding poses a complicated dilemma, because it either necessitates repeated D+C, or after several repeated curettages the removal of the uterus. This operation is deeply controversial in itself, as a healthy organ (the uterus) is removed because of a recurrent functional problem (bleeding). There- fore surgical methods for the removal of the source of bleeding (endometrial resection or ablation) were used during the 1980-ies [Lewis, B.V., Magos, A.L., Eds. "Endometrial ablation", Edinburgh Churchill-Livingstone (1993)], but none of them secures the permanent and reliable destruction of the endometrium and bleeding may return in some 30-40% of the patients [Seeras, R.C., Gilliland, G.B.: "Resumption of menstruation after amenorrhoea in women treated by endometrial ablation and myometrial resection", J. Am. Assoc. Gynecol. Laparosc. 4:305-9 (1997)], plus the procedure has its own inherent dangers [Pinion, I.T. et al.: "Randomized trial of hysterectomy, endometrial laser ablation and transcervical resection for dysfunctional uterine bleeding", BMJ 309:979-83 (1994)]. Therefore non-surgical methods for the treatment of recurrent dysfunctional uterine bleeding would be an important addition to the surgical armamentarium. Earlier practices for the treatment of ovarian cysts: Ovarian cysts can be treated either expectantly or surgically. There is no clear-cut borderline between the two approaches. The treatment of recurrent ovarian cysts is another problem and it usually requires surgery. Although
laparoscopy is taking over the place of laparotomy, total removal of ovarian cysts is sometimes impossible and recurrent cysts would necessitate some additional treatment, which could destruct the inner layer of the cyst wall. Earlier practices for the treatment of Bartholin's cysts: Abscesses and cysts are commonly encountered in the Bartholin's gland.
Abscesses are usually marsupialized, cysts are either marsupialized or excised in toto, and still they tend to recur in many patients. The surgical treatment of Bartholin's cysts is a hospital procedure involving either local or general anaesthaesia. It has been found that polidocanol can be used for the non-surgical treatment of the uterus and the fallopian tube, which type of treatment does not necessitate surgical/anesthetic facilities nor hospitality care. Polidocanol is a promising agent for the occlusion of the fallopian tube. Polidocanol can also be used for the temporary treatment of functional uterine bleeding after histological exclusion of malignant laesions. Polidocanol can also serve as a destructive agent preventing the recurrence of ovarian cysts and simplifying the treatment of such cysts. Moreover, polidocanol is a promising agent for the nonsurgical treatment of Bartholin's cysts.
The present use of polidocanol is genuinely new and do not follow from its earlier use, i.e. from venous sclerotization. The latter is based on the necrotizing effect of polidocanol exerted on the endothelium. Contrarily, the proposed new use of polidocanol is based on its effect produced on the fallopian tube and the uterus, which are not covered by endothelium. The inner lining of the uterus is endometrium. The inner linings of cysts are not endothelium either. Accordingly, the object of this invention is the use of polidocanol for the preparation of a pharmaceutical composition suitable for the treatment of the uterus and the fallopian tubes of a female mammal, including human.
More specifically, the object of this invention is the use of polidocanol for the preparation of a pharmaceutical composition for the occlusion of the fallopian tubes (sterilization) and for the treatment of functional endometrial bleeding and
ovarian cysts and Bartholin's cysts.
Another object of this invention is to provide methods for the above- mentioned non-surgical treatments.
According to the first embodiment of this invention polidocanol is used for the preparation of a pharmaceutical composition for tubal sclerotization. In this embodiment the pharmaceutical composition is a 0.01 to 10% by weight polidocanol solution, which is injected into the fallopian tubes through the uterine cervix. During the treatment women assume the usual gynaecologic (lithotomy) position. The outer genitals and the vagina are cleansed with antiseptic solution. A speculum is entered into the vagina and the uterine cervix exposed. Then the vagina and the cervix are cleansed with antiseptic again. The cervix is grasped with a forceps and a cannula introduced into the cervix. A 5 ml syringe filled with polidocanol solution is attached to the cannula and the fluid is injected under pressure into the fallopian tubes. To maintain prolonged sclerotizing effect and avoid flow-back of the solution, the cannula and syringe are kept in place for 5 minutes.
Thereafter the woman can leave the clinic. After 6 weeks the occlusion of the tubes has to be checked by a method commonly used for the examination of fallopian tubes (e.g. hysterosalpingography, perflation etc.). If the closure is not complete, the procedure can be repeated.
According to another embodiment of this invention polidocanol is used for the preparation of a pharmaceutical composition suitable for the treatment of recurrent functional uterine bleeding. When uterine bleeding recurs after histological diagnosis has been obtained within one year, it is feasible to treat the recurrent bleeding non-surgically. For haemostasis a polidocanol solution of 0.01 to 10%o by weight strength is injected into the uterine cavity through the uterine cervix. For this the women assume the usual gynaecologic (lithotomy) position. The outer genitals and the vagina are cleansed with antiseptic solution. A speculum is entered into the vagina and the uterine cervix exposed. Then the vagina and the cervix are cleansed with antiseptic again. The cervix is grasped
with a forceps and a cannula introduced into the cervix. A 5 ml syringe filled with 2 ml polidocanol solution is attached to the cannula and the fluid is injected with minimum pressure into the uterine cavity. To maintain prolonged haemostatic effect and avoid flow-back of the solution, the cannula and syringe are kept in place for 5 minutes. Thereafter the bleeding stops and the woman can leave the clinic.
According to a further embodiment of this inventipn polidocanol is used for the preparation of a pharmaceutical composition suitable for the treatment of ovarian cysts. The most important point of this treatment is the conservation of ovarian tissue of the patient being in fertile age.
Fenestration of a simple cyst or removal of the inner layer of endometriotic cysts is a common procedure. The operation can be simplified by destroying the inner layer by polidocanol. This operation can be performed by laporoscopy or under ultrasound guidance, which further simplifies the procedure. After puncturing the cyst and removing its content a polidocanol solution of
0.01 to 10% by weight strength is injected into the cavity and left in place. The cyst would collapse and its wall sclerotize with a possible minimum of recurrence. The procedure is feasible on day-care basis.
According to another embodiment of this invention polidocanol is used for the preparation of a pharmaceutical composition suitable for the treatment of Bartholin's cysts. Bartholin's cyst could be punctured under direct manual guidance in local anaesthesia. After puncturing the cyst and removing its content a polidocanol solution of 0.01 to 10% by weight strength is injected into the cavity and left in place. The cyst would collapse and its wall sclerotize with a possible minimum of recurrence. The procedure is performed on ambulatory or day-care basis.
The composition according to the invention can be prepared in any pharmaceutical dosage form suitable for the above-mentioned treatments. Said composition can comprise an effective amount of polidocanol composed with pharmaceutically acceptable additives and/or vehicles, such as buffers, solvents,
co-solvents etc. The suitable forms of administration include solutions, gels, emulsions, suspensions and a powder of polidocanol to be dissolved before use and powders or premixes to be reconstituted with a suitable solvent before use. The proposed total dose is 0.250 mg to 250 mg of polidocanol depending on the body weight of the subj ect.
The following Examples illustrate the invention but do not limit it any way. All the materials and procedures are in accordance with the prescriptions of the Pharmacopoea Hungarica VII edition i.e. correspond to the requirements of parenteral preparations. Example 1
Description of the preparation of 1% polidocanol parenteral solution. Step 1. Preparation of phosphate buffer pH 7.45.
Solution A: 9.073 g KH2P04 dissolved to 1000 ml water. Solution B: 11.87 g Na2HP04.2H20 dissolved to 1000 ml water.
19.7 ml of solution A is mixed with 80.3 ml of solution B (final volume 100 ml) which has a pH of 7.45. Step 2. Polidocanol 1 g is dissolved in 96%> ethyl alcohol 5 ml and filled up to 100 ml with phosphate buffer pH 7.45. The 1% polidocanol solution is sterilized and filled into ampoulles.
Example 2 Description of the preparation of 1% polidocanol parenteral gel. Step 1. Methylcellulose 3 g is dissolved in phosphat buffer pH 7.45 and replenished with buffer to 100 ml, which is a viscous gel. Step 2. Polidocanol 1 g is dissolved in 96% ethyl alcohol 5 ml and filled up to 100 ml with the viscous gel prepared in step 1. The 1% polidocanol in 3%> methylcellulose gel is sterilized and filled into ampoulles. Example 3 For purposes of longer shelf life polidocanol is dispensed in separate
ampoulles and dissolved before application with a solution of 5% ethyl alcohol in phosphate buffer pH 7.45 provided in rubber capped ampoulles separately.
Pharmaceutical experiments To prove the efficacy of polidocanol a time validated rat uterine model was selected. This model is widely accepted to test different substances, such as quinacrine, oxytetracyclin or erythromycin to cause damage to uterine horns [Chwalisz, K. et al.: "A nonsurgical technique for the transcervical administration of physiological and pharmacological agents into rat uteri", Acta Endocrin. 103:131-7 (1983)]. Animals
Twenty female Wistar rats, weighing 238-265 g, eight weeks of age were kept under controlled light and temperature. They were fed rat chow and tap water ad libitum.
Methods In proestrus, animals were weighed and anesthetised with ether. Animals were put in supine position. Under visual control an otoscope of 3 mm diameter was introduced into the vagina and the cervix visualized. A tuberculin syringe equipped with a plastic cannula was filled either with a 1% solution of polidocanol or physiologic saline. The cannula was introduced into the uterine cervix and 0.3 ml fluid filled under pressure into the uterus. There was no special effort to cannulate either uterine horn. To avoid flow-back of the fluid, the cannula was kept in place for two minutes.
After waking up, animals were put into marked cages according to treatment group and transferred back to the animal husbandry and kept under controlled conditions for another 30 days.
Macroscopic and microscopic examinations There were no animals lost during the following 30 days. The weight of treated animals increased to 286-333 g, that of control animals to 298-331 g. Animals were anesthetised with ether and sacrificed. Lower laparotomy was performed and the upper third of the vagina, the cervix, both uterine horns with
oviducts and ovaries were excised in toto. The specimen was fixed in 4% buffered formaldehyde solution. Macroscopic changes were recorded.
The fixed specimen were transferred to the laboratory of pathologist Dr. J. Liechtenstein-Zabrak. Specimen were embedded in paraffin and cut at the uterine- cervical junction, at the mid-portion and at the distal portion of the uterine horn. Specimen were stained with hematoxyllin-eosine and examined under 40x magnification.
Results There were only cyclic changes observed in control animals. There were 15 macroscopic and 37 microscopic changes in the 20 uterine horns of 10 animals. Macroscopic findings: Hydrops uteri 6 Atrophy 5
Inflammation 4 cases Microscopic findings: Q
Acute inflammation 7 Dilated lumen 6 Vilous projections 6 Fibrosis 6 Atrophy 5
Inflammation 3 Squamous metaplasia 2 Synechia 2 cases
Discussion Instillation of physiologic saline failed to cause any remarkable macroscopic or microscopic changes in the uteri of control animals. Polidocanol caused extensive damage in both uterine horns, although there was no special effort exerted to instill both of them. Nevertheless the substance reached both horns and proved to be effective in them. The macroscopic observations of hydrops and atrophy coincided with the microscopic findings of dilatation and atrophy.
This extent of changes is able to influence the fertility of animals, as it is supported by the observations disclosed in the literature concerning the damage caused by quinacrine and erythromycin [Zipper, J. et al.; Hien, D.T. et al.; U.S. Patent No. 5,885,601]. The results clearly show that polidocanol can be used for the occlusion of fallopian tubes and for treating functional endometrial bleeding and cysts of mammals, including human.
Claims
1. Use of polidocanol [alfa-dodecyl-omega-hydroxypoly(oxy-l,2-ethanediyl)] for the preparation of a pharmaceutical composition containing an effective amount of said compound for the treatment of the uterus and/or the fallopian tubes of a female mammal, including human.
2. The use according to claim 1 , for the preparation of a pharmaceutical composition for the occlusion of the fallopian tubes.
3. The use according to claim 1, for the preparation of a pharmaceutical composition for the treatment of functional endomentrial bleeding.
4. The use according to claim 1, for the preparation of a pharmaceutical composition for the treatment of ovarian cysts.
5. The use according to claim 1, for the preparation of a pharmaceutical composition for the treatment of Bartholin's cysts.
6. The use according to claim 1, for the preparation of a pharmaceutical composition containing 0.1 to 10% by weight polidocanol and optionally pharmaceutically acceptable additives and/or puffers in water.
7. The use according to claim 6, for the preparation of a pharmaceutical composition in the form of a parenteral solution, a parenteral gel composition or a solid composition to be dissolved before use.
8. Method for treating the uterus and/or the fallopian tubes of a female mammal, including human, comprising administering a therapeutically effective amount of polidocanol locally into the uterus and/or the fallopian tubes of said patients.
9. The method according to claim 8, for the occlusion of the fallopian tubes of said subjects.
10. The method according to claim 8, for the treatment of functional endomentrial bleeding of said patients.
11. The method according to claim 8, for the treatment of ovarian cysts of said patients.
12. The method according to claim 8, for the treatment of Bartholin's cysts of said patients.
13. The method according to claim 8, comprising administering the polidocanol in the form of an isotonic solution containing 0.1 to 5% by weight polidocanol in water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0005013A HUP0005013A2 (en) | 2000-12-28 | 2000-12-28 | Use of polidocanol for producing pharmaceutical compositions for treatment certain disorders of the uterus and closing of the oviduct |
| HUP0005013 | 2000-12-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002053145A1 true WO2002053145A1 (en) | 2002-07-11 |
Family
ID=89978883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2001/049572 WO2002053145A1 (en) | 2000-12-28 | 2001-12-27 | Use of polidocanol for the treatment of the uterine and the fallopian tubes |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HUP0005013A2 (en) |
| WO (1) | WO2002053145A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110015950A (en) * | 2010-06-10 | 2019-07-16 | 克施乐化学工厂两合公司 | Prepare the method and product of alcohol ethoxylate |
| US20210228503A1 (en) * | 2018-06-07 | 2021-07-29 | Paolo Casoni | Polidocanol for use as immunomodulating agent |
| WO2023227069A1 (en) * | 2022-05-25 | 2023-11-30 | 北京键凯科技股份有限公司 | Polidocanol with single molecular weight, and use thereof |
-
2000
- 2000-12-28 HU HU0005013A patent/HUP0005013A2/en unknown
-
2001
- 2001-12-27 WO PCT/US2001/049572 patent/WO2002053145A1/en not_active Application Discontinuation
Non-Patent Citations (4)
| Title |
|---|
| BR. J. UROL., vol. 80, no. 3, 1997, pages 468 - 471 * |
| DATABASE CAPLUS [online] DIV. OF UROLOGY, DEPART. OF SURG., HAUKELAND HOSPITAL, UNIVERSITY OF BERGEN (BERGEN, NORWAY); DAEHLIN ET AL.: "Comparison of polidocanol and tetracycline in the sclerotherapy of testicular hydrocele and epididymal cyst", XP002909222, accession no. STN Database accession no. 1997:669446 * |
| DATABASE SCISEARCH [online] ASLBORG HOSP. DEPT. SURG. GASTROENTEROL., (AALBORG, DENMARK); LUND ET AL.: "Treatment of hydrocele testis with aspiration and injection of polidocanol", XP002909223, accession no. STN Database accession no. 92:225703 * |
| JOURNAL OF UROLOGY, vol. 147, no. 4, April 1992 (1992-04-01), pages 1065 - 1066 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110015950A (en) * | 2010-06-10 | 2019-07-16 | 克施乐化学工厂两合公司 | Prepare the method and product of alcohol ethoxylate |
| US20210228503A1 (en) * | 2018-06-07 | 2021-07-29 | Paolo Casoni | Polidocanol for use as immunomodulating agent |
| WO2023227069A1 (en) * | 2022-05-25 | 2023-11-30 | 北京键凯科技股份有限公司 | Polidocanol with single molecular weight, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0005013A2 (en) | 2002-11-28 |
| HU0005013D0 (en) | 2001-03-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK1660009T3 (en) | METHODS OF TREATING ENDOMETRIOSIS | |
| EP1006964B1 (en) | Intrauterine chemical necrosing compositions and apparatus | |
| Morita et al. | Laparoscopic excision of myometrial adenomyomas in patients with adenomyosis uteri and main symptoms of severe dysmenorrhea and hypermenorrhea | |
| Fayrer-Hosken et al. | Follicular cystic ovaries and cystic endometrial hyperplasia in a bitch | |
| Mushambi et al. | Anaesthetic considerations for hysteroscopic surgery | |
| Exalto et al. | Safety aspects and side-effects of ExEm-gel and foam for uterine cavity distension and tubal patency testing | |
| Bachus et al. | Conservative management of cervical pregnancy with subsequent fertility | |
| Lin et al. | Three-contrasts method: An ultrasound technique for monitoring transcervical operations | |
| Kohli et al. | Pyometra following Le Fort colpocleisis | |
| WO2002053145A1 (en) | Use of polidocanol for the treatment of the uterine and the fallopian tubes | |
| WO2003022260B1 (en) | Use of methotrexate and l-arginine for the preparation of a medicament for treatment of uterine myoma | |
| Cocuzza et al. | Development of an animal model for endometrial ablation using trichloroacetic acid | |
| Karamanidis et al. | Two-year results of a new two-minute hot liquid balloon endometrial ablation system (Thermablate): a pilot study | |
| RU2224297C1 (en) | Method for modeling chronic uterine appendages inflammation | |
| Ugwu | UTERINE FIBROIDS-A COMPREHENSIVE REVIEW | |
| SPEIDEL et al. | Research approaches to new sterilization technology | |
| UA137276U (en) | METHOD OF MEDICINAL HEMOSTASIS IN CONSERVATIVE MYOMECTOMY | |
| Tan et al. | Treatment of tubal pregnancy using comprehensive interventional methods | |
| Gunasheela et al. | Use of Uterine Arterial Embolization in the Treatment of Leiomyomas | |
| ZA200602695B (en) | Methods for the treatment of endometriosis | |
| XV | It results also that marriage favours the development of organic changes | |
| TWEEDY et al. | PART IIL | |
| Morse | A Field of Experimental Investigation Intimately Allied to Obstetrics and Gynecology | |
| Patton et al. | Endometriosis—New Insights Into an Enigmatic Disorder | |
| Jackson | Annual Report of the Section on Obstetrics and Diseases of Women and Children of the Chicago Society of Physicians and Surgeons: Department of Gynæcology. Read before the Society December 8, 1873 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: JP |
|
| WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |