WO2006089561A1 - Pharmaceutical compositions containing organic acids useful for softening and ripening uterine cervix. - Google Patents
Pharmaceutical compositions containing organic acids useful for softening and ripening uterine cervix. Download PDFInfo
- Publication number
- WO2006089561A1 WO2006089561A1 PCT/EG2005/000006 EG2005000006W WO2006089561A1 WO 2006089561 A1 WO2006089561 A1 WO 2006089561A1 EG 2005000006 W EG2005000006 W EG 2005000006W WO 2006089561 A1 WO2006089561 A1 WO 2006089561A1
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- WIPO (PCT)
- Prior art keywords
- acid
- organic acid
- cervical
- ripening
- cervix
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
Definitions
- compositions containing organic acids useful for softening and ripening uterine cervix are provided.
- the present invention relates generally to pharmaceutical compositions entailing organic acid compounds to lower the vaginal pH. More specifically, the invention relates to pharmaceutical compositions for cervical soften/ripening, thus fastening and easing its further dilatation by natural or induced uterine contractions and by mechanical means in mammals in need thereof.
- the cervix in contrast to the uterine corpus, is essentially a fibrous connective tissue organ.
- the cervix contains approximately 10% to 15% smooth muscle, with decreasing content of smooth muscle from the upper to the lower segment of the cervix.
- the underlying stroma is mainly connective tissue made of collagen bundles with glycosaminoglycans and proteoglycan molecules between the collagen fibers. [Granstr ⁇ m L. et al. Br J Obstet Gynaecol 1989; 96(10):1198- 202; and Leppert PC. Clin Obstet Gynecol 1995; 38:267-79].
- the general descriptions of fibrous connective tissue components, along with their presence in the non-pregnant cervix are generally reviewed [UIdbjerg N. Acta Obstet Gynecol Scand 1989; S(148):ll-19].
- the cervical canal In the non-pregnant state, the cervical canal is very narrow, and the cervix resists mechanical force to open it.
- the role of the cervix shifts between two opposing functions during pregnancy.
- the uterine cervix acts as a connective tissue-rich sphincter that resists tension and remains closed and rigid throughout most of gestation.
- a drastic change in cervical function is required in order to accommodate stretch and delivery [Leppert PC. J Matern Fetal Med 1992, 1:213-223, and Thomson AJ et al. The cervix.
- MMPs matrix metalloproteinases
- MMP-I, MMP-3, MMP-8, and MMP-9 are fibrillar and nonfibrillar collagens.
- MMP-I, MMP-3, MMP-8, and MMP-9 are increased during cervical ripening and are critically important to extracellualr matrix remodeling at this time [Curry TEJR. & Osteen KG. Endocrine Reviews 2003, 24(4):428-465].
- Cervical collagen degradation contributes to the ripening process.
- Collagenase (MMP-I) and other proteolytic enzymes play an essential role in the degradation of collagen fibers and subsequent dissolution of cervical connective tissue.
- Neutrophil accumulation in the cervical tissue is one of the main histological features which have been observed during ripening [Junqueira LCU.
- Type I collagen-degrading enzyme is thought to be produced by the cervical stromal cells themselves [Rajabi MR. & Singh A. Biol Reprod 1995;
- cytokines such as interleukin-I [EL-Maradney E et al. Eur J
- hyaluronic acid participates in the degradation of cervical collagen as it has been shown to stimulate the synthesis of proteolytic enizymes, including collagenase, by cervical fibroblasts [Hiro D et al. Res Commun 1986; 140:715-
- hyaluronic acid is suggested -through mutual interaction with cytokines- to stimulate migration and function of neutrophils, being the main source of collagenolytic enzymes during ripening [El-Maradny E. et al. Hum Reprod 1997; 12(5):1080-1088], an effect that is upregulated by dehydroepiandrosterone sulphate [Belayet HM et al. Hum Reprod 1999; 14(5):1361-1367].
- Epidural analgesia appears to be very effective in reducing pain during labor, although there appear to be some potential adverse effects. Further research is needed to investigate adverse effects and to evaluate the different techniques used in epidural analgesia [Howell CJ. Epidural versus non-epidural analgesia for pain relief in labor (Cochrane Review). In: The Cochrane Library, Issue 4, 2004].
- a second example is continuous electronic intrapartum monitoring, which is of great value in high risk cases [Umstat MP. Aust N Z J Obstet Gynaecol 1993; 33:145-9, and Kulkarni
- Every individual has the right to safe, satisfying health care with respect for human and cultural variations, and further it is believed that the normal processes of pregnancy and birth can be enhanced through education, health care and supportive intervention.
- the practice of midwifery advocates non-intervention in normal processes.
- appropriate technological interventions can be used where the benefits of such technology outweigh the risks. Avoiding unnecessary interventions should result in reduction in complications of the intervention and less use of resources. The problem comes in deciding at which point the desires of the mother conflict with any risks to mother and child.
- a pharmaceutical agent locally-acting on the cervix without inducing uterine contractions
- cervical softening/ripening would lower cervical resistance, thus enhances and shortens the duration of normal labor with less need for analgesia, monitoring, operative delivery, patient's stress, and health care facilities.
- Cervical ripening before induction of abortion, is needed to increase the success of induction, to reduce complications and to diminish the rate of operative interventions and duration of abortion.
- Pharmacological manipulation of cervical connective tissue is now firmly established in clinical practice in the context of induction of labor and induced abortion. A means of reversal of ripening process may ultimately hold the key to the prevention of preterm labor and delivery
- Induction of labor is common in obstetric practice. According to the most current studies, the rate varies from 9.5 to 33.7 percent of all pregnancies annually. Induction of labor refers to the process whereby uterine contractions are initiated by medical or surgical means before the onset of spontaneous labor. Following the introduction of Bishop Score in 1964 [Bishop EH. Obstet Gynecol 1964; 24:266- 268], there has been an increasing awareness that if the cervix is . unfavorable, a successful vaginal birth is less likely. This scoring system attempts to predict success of induction by assessing five factors: position of the cervix in relation to the vagina, cervical consistency, dilation, effacement and station of the presenting part.
- a score less than six indicates an unfavorable cervix for induction.
- a cervical ripening agent be used before labor induction.
- Nonpharmacologic approaches to cervical ripening and labor induction have included herbal compounds, castor oil, hot baths, enemas, sexual intercourse, breast stimulation, acupuncture, acupressure, transcutaneous nerve stimulation, and mechanical and surgical modalities.
- these nonpharmacologic methods only the mechanical (hygroscopic and balloon dilators) and surgical (stripping of the membranes and amniotomy) methods have proven efficacy for cervical ripening or induction of labor.
- the potential risks associated with mechanical methods include infection, bleeding, membrane rupture, and placental disruption.
- Stripping of the membranes promotes onset of labor but does not seem to produce important benefits on maternal and neonatal outcomes, and thus must be weighed against patient discomfort and other adverse effects such as bleeding, accidental rupture of membranes, infection, and uterine irritability.
- Risks associated with this amniotomy include umbilical cord prolapse or compression, maternal or neonatal infection, fetal heart rate deceleration, bleeding from placenta previa or low-lying placenta, and possible fetal injury.
- Pharmacologic agents available for cervical ripening and labor induction include prostaglandins, misoprostol, mifepristone, and relaxin. When the score is favorable, the preferred pharmacologic agent is oxytocin.
- prostaglandin When compared with oxytocin for labor induction, prostaglandin reduces the likelihood of operative delivery and failed induction yet with higher rates of uterine hyperstimulation, accompanying fetal heart rate changes, and maternal side effects whether gastrointestinal side effects (nausea and vomiting) and fever.
- Evidence supports the conclusion that vaginal use of misoprostol safely lowers the cesarean delivery rate among women undergoing labor induction compared with those receiving alternative induction regimens. Based on several randomized trials, there seems to be no increase in adverse maternal or perinatal outcomes. Other potential benefit of misoprostol lie in the fact that it is much cheaper than currently available induction agents and is easily stored and stable at room temperature.
- misoprostol is shown to be safe and effective.
- misoprostol may provoke excessive uterine activity leading to hyperstimulation.
- uterine rupture in women with previous cesarean section is also a possible complication, limiting its use to women who do not have a uterine scar.
- the ideal route, dose, and frequency of misoprostol for cervical ripening have yet to be determined [Royal College of Obstetricians and Gynaecologists. Induction of labor: Evidence-based Clinical Guideline
- PG may cause uterine hyperstimulation with potential adverse effects in patients with a previous uterine scar or in those at risk of fetal distress [Egarter CH. et al. Am J Obstet Gynecol 1990; 163:794-796].
- an attractive alternative method would be one that leads to cervical ripening without stimulating myometrial contractility.
- Vacuum aspiration is considered to be a safe and effective method of surgical abortion, but has been associated with major morbidity in up to 1% of women and minor morbidity in 10% [Joint Study of the Royal College of General Practitioners and the Royal College of Obstetricians and Gynaecologists. Induced abortion operations and their early sequelae. J R Coll Gen Pract 1985; 35:175-180], the major determinants of morbidity being gestational age and the procedure used to terminate the pregnancy.
- the complication rate is lowest at 7-8 weeks of gestation (0.26 per 100 abortions) and increases progressively to 1.37 per 100 abortions at 13 weeks [Grimes DA & Cates W. Obstet Gynaecol Surv 1979; 34:177-191].
- the incidence of cervical trauma and uterine perforation is related to the degree of forcible mechanical dilatation required [Schultz KF et al. Lancet 1983, i:1182- 1185, and Grimes DA et al. JAMA 1984; 251:2108-2111]. Traumatic complications may jeopardize future fertility, and have been associated with increased risk of miscarriage and preterm labor in subsequent pregnancies [Harlap S et al.
- Prostaglandins produce more effective cervical ripening than laminaria [Helm CW et al. Br J Obstet Gynaecol 1988; 95:911-915], but are associated with several side effects such as abdominal pain, gastrointestinal upset and vaginal bleeding [Task Force on Prostaglandins for Fertility Regulation. Vaginal administration of 15-methyl-PGF2 ⁇ methyl ester for preoperative cervical ripening. Contraception 1981; 23:251-259].
- Misoprostol a synthetic 15-deoxy- 16-hydroxy-16-methyl analogue of naturally occurring prostaglandin El (PGEl) has been shown to represent a stable, easily stored, inexpensive and effective alternative, being comparable with gemeprost in terms of efficacy [EI-Refaey H et al. Lancet 1994, 343:1207-1209, and Baird DT et al. Hum Reprod 1995; 95:1521-1527]. Furthermore, misoprostol is associated with fewer side effects than gemeprost [Henry AM & Haukkamaa M. Br J Obstet Gynaecol 1999; 106:540- 543].
- Cervical dilatation along with hysteroscopy or endometrial curettage, is one of the most common procedures in gynecological practice.
- difficulty in passing the internal cervical os may be encountered, especially in nulliparous women.
- the complications encountered during the procedure are mainly related to the difficulty of cervical dilatation, including cervical damage, creation of false tract and uterine perforation [Loffer FD. Obstet Gynecol 1989; 73:16-20].
- the incidence of these complications may be reduced if the cervix is primed beforehand. Therefore, there is a need for an effective cervical priming agent which can be used in non-pregnant women in general gynecological practice.
- misoprostol facilitates cervical dilation before surgical abortion
- researchers began to investigate whether the medication would ease dilation in nonpregnant patients.
- Misoprostol has been shown to be effective in priming the cervix prior to cervical dilatation in non-pregnant patients [Ngai SW et al. Obstet Gynecol 1999; 94(3):427-30, and Preutthipan S & Herabutya Y Obstet Gynecol 2000; 96(6):890-4, and Thomas JA et al. Am J Obstet Gynecol
- vaginal pH (using a pH meter with connected glass electrode) was found to be between 3.8 and 4.0 at the introitus, mid-vaginal, and at the anterior and posterior fornices; while cervical pH ranged between 6.5 and 7.0 [Riedewald S.
- glycogen which is deposited in large amounts in the vaginal epithelium during times of high estrogen availability could be metabolized to lactic acid by vaginal bacteria and/or the epithelium itself, with the former being the primary source of lactic acid in the vagina [Boskey ER et al. Hum Reprod 2001; 16(9): 1809-1813].
- concentrations of the many organic acids in the vaginal fluid are shown to be governed by the hormonal status of the woman [Bauman JE et al. Fertil Steril 1982; 38:572-579, and Owen DH & Katz DF. Contraception 1999; 59:91-95, and Boskey ER et al.
- the innate tendency of corneal stroma to imbibe fluid and swell is an unusual property of connective tissue.
- the swelling pressure is due primarily to glycosaminoglycans (GAGs) that make up the carbohydrate moiety of the proteoglycans (PGs) [Huang Y & Meek KM. Biophysical Journal 1999; 77:1655-1665].
- GAGs glycosaminoglycans
- PGs proteoglycans
- the corneal stroma or sclera can be considered as a polyelectrolyte gel.
- electrovalent attractive forces are produced between the equal numbers of positive and negative charges (i.e., zwitterion pairs), which results in tighter, less swollen tissue [Elliott GF et al. J. Physiol (Lond.) 1980; 298:453- 470, and Huang Y & Meek KM. Biophysical Journal 1999; 77:1655-
- the net charge will be positive below the isoelectric point and will affect the swelling in two ways.
- the fixed charge will require more counterions in the stroma to maintain electrical neutrality, resulting in the accumulation of small permeant ions. This will cause an excess internal osmotic pressure and will increase the swelling (Donnan effect).
- the reduction in the number of attractive zwitterions pairs will cause a reduction in the attractive forces and thus will loosen the stroma, again causing increased swelling [Elliott GF et al. J Physiol (Lond.) 1980; 298:453- 470]. It was also found that at lower pH (3, 4), the correlation between the interfibrillar spacing and the hydration is poor.
- Vaginal absorption of misoprostol is inconsistent with large individual variations. Sometimes remnants of tablets can be obtained from the vagina hours after its administration. Therefore, although used widely, the vaginal route may not be the ideal route of administration for clinical practice [Saxena P et al. Hum Reprod 2004; 19:77-80]. In some studies, the misoprostol tablets used were wetted only with water before introduction into the posterior vaginal fornix [Fong YF et al. Br J Obstet Gynaecol 1998, 105:413-417, and Singh K et al. Obstet Gynecol 1998, 92:795-798].
- such pharmacological treatment instead of or in addition to mechanical dilatation, offers several advantages to many gynecologic procedures including dilatation of the cervix, hysteroscopy, intrauterine contraceptive device application and removal, office endometrial sampling procedures, intra-uterine dye injection on hysterography, and introduction of intra-uterine catheter on insemination or embryo transfer.
- the induction of parturition at any gestational age, including term would be easier if one removes the cervical resistance factor, without inducing inappropriate contractions as the case is with prostaglandins.
- even the process of normal labor will be faster and shorter with less need for prolonged monitoring, analgesia, or operative intervention.
- the present invention was conceived based upon the above stated facts.
- the present invention is directed to a method for cervical softening/ripening in mammals in need thereof.
- the inventors of the present invention have completed the present invention by controlling the pH of the vagina, which is clinically easy to apply, that is, by acidifying the vagina, thereby leading to cervical softening/ripening process which is similar to that of a pregnant female approaching labor and confirming that the cervical connective tissue is remodeled.
- the objective of the present invention is to provide an agent for acidifying the vagina, which induces extensive remodeling of the cervical connective tissue, reduces the cervical collagen content and thus softening the cervix and easing its further dilatation by natural or induced uterine contractions and by mechanical means.
- vaginal pharmaceutical compositions comprising organic acid, homologues, or analogs thereof that possess pharmaceutical activity suitable for softening and ripening the cervix with fewer adverse effects, if any.
- Collagen degradation is known to play an important role in the cervical softening/ripening process.
- the vagina should be acidified.
- different organic acids, homologues, or analogs, solely or in different combinations and regimens thereof the therapeutically effective amount of the active ingredient(s) is administered into the vagina to directly control pH, thereby inducing cervical softening and ripening.
- the present invention provides compounds, compositions, and methods for softening and ripening of the cervix and for treating or preventing cervical rigidity in mammals -including humans- and the complications thereof.
- the invention provides methods for softening and ripening of the cervix and for treating or preventing cervical rigidity by administration of pharmaceutical compositions comprising organic acids, homologues, or analogs in a therapeutically effective amount sufficient to soften and ripen the cervix or prevent cervical rigidity.
- the invention is drawn to the organic acids, homologues, analogs; and their pharmaceutical compositions and such methods of use.
- the organic acid is a free organic acid or as a prodrug, In some embodiments, it is produced or released through a chemical process or biological means.
- the organic acid, homologues, or analogs structure is aliphatic (straight chained, acyclic), ring chain (cyclic), heterocyclic (aliphatic ring structure, but including at least one atom which is not carbon), or aromatic (containing a benzene ring).
- the organic acid, homologues, or analogs structure may have a branched chain of carbon atoms.
- the organic acid, homologues, or analogs structure may be saturated or unsaturated, and if unsaturated may be monounsaturated or polyunsaturated.
- Other embodiments are provided by varying the structure of the organic acids, homologues, or analogs. These embodiments include the presence of one or more of the following: an alkyl group, an aryl group, an amino group, an imino group, a sulphar atom, a carboxylic group (di- or polycarboxylic acid), a halogen (acylated acid), a hydroxyl group (hydroxy- or polyhydroxy acid), a ketone group (ketoacid) or an aldehyde group (aldehyde-acid).
- the carboxylate group of the organic acid is bound to other compounds to form an ester or salt.
- Other embodiments include the extraction of water (anhydride acid).
- the organic acid is an acid sugar, glucuronic or iduronic acid.
- the acid sugar is attached to another group, as N- acetylgalactoseamine or N-acetylglucosamine.
- the acid moiety of the organic acids, homologues, or analogs is a structural isomer, a cis- or trans- stereo(geo)isomer, and D- or L- stereo(optical) isomer.
- the organic acid, homologues, or analogs is selected from a list, but are not limited to, those compounds specifically listed in the examples presented herein, such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, butyric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, hydroxybenzoic acid, para-aminobenzoic acid, citric acid, mandelic acid, malonic acid, oxalic acid, salicylic acid, succinic acid, imino acid, tartaric acid, ascorbic acid, retionic acid, glucuronic acid, iduronic acid, hyaluronic acid, amino acids as valeric acid and arginine, fatty acids as oleic, linoleic and linolenic.
- the suitable active acidic organic compounds are preferred.
- the suitable active acidic organic compounds are known in the art to be those compounds that produce the desired pharmacologically acceptable vaginal pH, being ⁇ 5, preferably 1.5-3.5, still preferably 2-2.5. Any organic acid, homologues, or analogs, that are presently known, or that may be developed in the future, are within the contemplation of the invention for use as the active component in new formulations to induce cervical ripening and/or softening.
- the methods and compositions employ organic acids, homologues, or analogs for cervical softening/ripening in which the compounds, homologs and analogs cause cervical softening/ripening when administered to test animals or human volunteers.
- Still other aspects of the invention address methods of using and administering the subject compounds and compositions for cervical softening/ripening or reducing cervical rigidity or causing easier and faster cervical dilatation in mammals, including humans.
- the subject compositions may be administered vaginally in a variety of forms.
- FIG.l. is a photomicrograph of control section of human uterine cervix (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.2. is a photomicrograph of control section of human uterine cervix (dyeing: Mallory's triple stain, magnification: 400X).
- FIG.3. is a photomicrograph of section of human uterine cervix after 1 day of immersion in 3.5% lactic acid solution (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.4. is a photomicrograph of section of human uterine cervix after 1 day of immersion in 5% lactic acid solution (dyeing: Mallory's triple stain, magnification: 400X).
- FIG.5. is a photomicrograph of section of human uterine cervix after 2 day of immersion in 4% acetic acid solution (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.6 is a photomicrograph of section of human uterine cervix after 4 days of immersion in 4% citric acid solution (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.7. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.8. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.9. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: Mallory's triple stain, magnification: 400X).
- FIG.10. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- FIG.ll. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 1000X).
- FIG.12. is a photomicrograph of section of human cervical punch biopsy from a nulligravida after with acetic acid vaginal tablets for 5 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
- the present invention is directed to a method for cervical softening/ripening in mammals in need thereof.
- the inventors of the present invention have completed the present invention by controlling the pH of the vagina, which is clinically easy to apply, that is, by acidifying the vagina, thereby leading the cervical softening/ripening process which is similar to that of a pregnant female approaching labor and confirming that the cervical connective tissue is remodeled.
- the objective of the present invention is to provide an agent for acidifying the vagina, which induces extensive remodeling of the cervical connective tissue, reduces the cervical collagen content and thus softening the cervix and easing its further dilatation by natural or induced uterine contractions and by mechanical means.
- This invention relates to the discovery that organic acid compounds act to induce cervical softening and ripening processes. It has been surprisingly discovered that lactic acid and acetic acid, natural acids present in vaginal fluid in mammals, are actively-effective agents in inducing cervical softening/ripening when applied to cervical tissue in vitro and when administered to human volunteers.
- an organic acid compound includes a single organic acid compound as well as two or more organic acid compounds.
- active agent drug
- drug pharmacologically
- active agent drug
- pharmaceutically pharmacologically
- active agent drug
- pharmaceutically pharmacologically
- organic acid compounds organic acid compounds
- composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions of the present invention encompass any composition made by admixture of a compound of the present invention and a pharmaceutically acceptable carrier.
- the term "functional group” shall mean the carboxyl (COOH) group on the organic acid compound, which is implicated in the therapeutic (pharmacological) effects associated with organic acid compounds for inducing softening/ripening of the uterine cervix.
- organic acid compounds, homologues, and analogs thereof, hereinafter collectively referred to as "organic acids”, shall mean any organic acid compound, and derivatives thereof.
- the present invention includes organic acid compounds of all types that are effective for inducing softening/ripening of the uterine cervix because the presence of structural variation does not materially affect the beneficial activity of the acidic effect of the carboxylic group of the organic acid compound.
- organic acid compounds examples include acetic acid, glycolic acid, priopionic acid, lactic acid, pyruvic acid, butyric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, hydroxybenzoic acid, para- aminobenzoic acid, citric acid, mandelic acid, malonic acid, oxalic acid, salicylic acid, succinic acid, cinnamic, adipic acid, tartaric acid, ascorbic acid, retionic acid, glucuronic acid, iduronic acid, hyaluronic acid, nicotinic acid, pentanoic acid, amino acids as valeric acid and arginine, fatty acids as oleic, linoleic, linolenic and arachidonic.
- useful organic acid compounds are not limited to the compounds already mentioned or those to be specifically listed in the examples presented herein. Any organic acid might be used alone or in a mixture (formed of ingredients) of more than one
- prodrug is meant to include an organic acid ester, or preferably an organic acid salt. It also includes bacteria as Lactobacillus, whether live or lyophilized killed, producing or releasing organic acids that are at least minimally effective in inducing softening/ripening of the uterine cervix.
- analog is intended to mean any somewhat modified version of a natural product, in this case an organic acid, or a related synthetic analog, wherein a number of atoms such as carbon, hydrogen, oxygen or heteroatoms such as nitrogen, sulfur or halide have been added or deleted from the parent structure, so as to yield a new molecular compound.
- softening/ripening means to induce changes in the cervix including softening only, or along with shortening (effacement) and dilatation.
- the term "rigid cervix” refers to the tough cervix that does not show appropriate effacement and dilatation in response to good uterine contractions.
- a “pharmaceutically acceptable carrier” is meant a material that is suitable for vaginal drug administration to an individual female with an active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical formulation in which it is contained.
- Preferred pharmaceutical carriers depend upon the intended mode of administration of the active agent. Typical modes of administration are described below.
- a "pharmacologically acceptable" salt, ester, isomer or other derivative of an active agent as provided herein is a salt, ester, solvate, isomer or other derivative that is not biologically or otherwise undesirable.
- an effective amount and “therapeutically effective amount” of an active agent as provided herein is meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect.
- the exact amount required will vary from subject to subject, depending on the age, weight, and condition of the subject, the condition being treated, the judgment of the clinician, and the like. Thus, it is not possible to specify an exact "effective amount”. However, an appropriate
- the desired result comprise an objective improvement in the recipient of the dosage, which may be increased ripening and/or softening of the cervix on examination, more rapid cervical effacement and dilatation on the start of uterine contractions in a pregnant female, or more easily performed gynecologic procedure entailing the cervix as mechanical dilatation, IUD insertion or removal, office endometrial biopsy, hysteroscopy, injection of the dye on hystreography, and introduction of intra-uterine catheter on insemination or embryo transfer.
- a "prophylactic treatment” as used herein refer to a treatment administered to a subject who does not exhibit signs of a disease, wherein treatment is administered for the purpose of decreasing the risk of developing a pathology associated with unwanted cervical rigidity or decreased cervical softening/ripening.
- a "therapeutic treatment” is a treatment administered to a subject who exhibits signs of pathology, wherein treatment is administered for the purpose of diminishing or eliminating those pathological signs of cervical rigidity.
- the compounds are organic acids; a carboxylic acid (containing the functional group COOH) whether mono- or poly-carboxylic.
- the structure of the compounds may be aliphatic (straight chained, acyclic), ring chain (cyclic), heterocyclic (aliphatic ring structure, but including at least one atom which is not carbon), or aromatic (containing a benzene ring). Certain compounds may have a branched chain of carbon atoms. Some of the compounds are saturated, monounsaturated, or polyunsaturated.
- Certain compounds of the present invention may be in the anhydride acid, oxyacid, ketoacid, acylated acid or aldehyde-acid form. Others may have an attached (one or more) alkyl group, aryl group, amino group, imino group, a halogen, or sulfur atom. Other may be sugar acids.
- Certain compounds of the present invention may possess asymmetric carbon atoms or double bonds; the structural, optical and geometric isomers are all intended to be encompassed within the scope of the present invention.
- the compounds of the present invention may have unnatural ratios of atomic isotopes at one or more of their atoms. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.
- the instant compounds may be isolated in the form of their pharmaceutically acceptable salts or esters, such as those in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
- pharmaceutically acceptable salts or ester refers to those prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
- the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
- prodrugs will be derivatives of the present compounds that are readily convertible in vivo into a functional compound of the invention.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Bundgaard, H., ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam, which is hereby incorporated by reference.
- the invention also encompasses active metabolites of the present compounds.
- the invention encompasses the production and/or the release of these compounds through a biological means, such as the use of bacteria.
- the organic acid compounds are active in lowering the vaginal pH in humans and other animals and are therefore useful in inducing cervical softening/ripening and avoiding cervical rigidity. Therefore, in a method of use aspect of the invention, a therapeutically effective amount of at least one organic acid compound is administered into the vagina to induce cervical softening/ripening in a vaginal formulation.
- the compounds, compositions and methods of the invention are used in mammals, including human, to induce cervical softening and ripening to decrease the complications and hasten the course of different obstetric conditions, including induction of labor, first- and second-trimester abortion, whether spontaneous (missed or incomplete) or induced. They can be used also in normal pregnant women near term aiming at a faster and shorter labor with less need for monitoring, analgesia, or operative intervention.
- the individuals to be treated are non-pregnant females.
- the compounds, compositions, and methods of the invention are used as a preparatory step to facilitate gynecologic processes entailing the cervix, such as mechanical dilatation, hysteroscopy, intrauterine contraceptive device application and removal, office endometrial sampling procedures, intra-uterine dye injection on hysterography, and introduction of intra-uterine catheter on insemination or embryo transfer.
- compositions which comprise compounds of the invention and a pharmaceutically acceptable carrier. Preparation of each of the formulations described herein would be within the ambit of the person of skill in the art, although reference is made to Remington's Pharmaceutical Sciences, 18th Edition (1990), Philadelphia College of
- a topical vaginal composition or formulation in accordance with the present invention, broadly comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the organic acids.
- the carrier for the active agent(s) would be a neutral medium.
- the amount of organic acid compound(s) in the composition is an amount which is safe and therapeutically effective and varies depending on the active ingredient(s), the nature of the composition, the medical condition being treated. Such an amount is determinable by a person of skill in the art.
- Such compositions and preparations can contain 0.1 percent or less of the active compound(s). The percentage of active compound(s) in these compositions may, of course, be varied and may conveniently be between about 0.1 percent to about 60 percent of the weight of the unit.
- acetic acid preferably comprises about 0.1% to 10.0% by weight of the composition, more preferably 2.0-5.0% by weight of the composition.
- These compositions for topical vaginal administration are formed to yield a pH ⁇ 5, preferably 2-3.5, still preferably 2-2.4; as is known in the art.
- the composition is active, independent of pH, in the presence of blood or vaginal secretions, one particular advantage in combining two or more acids is that the pH of the composition may be readily adjusted to allow therapeutic amounts of each component while maintaining the pH at a level that is most effective for the treatment.
- the composition of the present invention may also be pH balanced by the addition of a base, such as triethanolamine or sodium hydroxide, to adjust the pH to a level compatible with the desired therapeutic pH value.
- the pH is approximately between 3.8 and 4.4.
- the pH is adjusted to a point where the irritation is minimal or nonexistent, while still being effective in inducing cervical softening and ripening.
- compositions of the present invention comprise a compound(s) of the instant invention as an active ingredient or a pharmaceutically acceptable salt/ester thereof, and may also contain a pharmaceutically acceptable carrier or coatings and optionally other therapeutic ingredients to modify the physical form of the dosage unit.
- the compositions include different forms suitable for vaginal administration, although the most suitable form in any given case will depend in part on the condition of the patient being treated and on the nature of the active ingredient.
- the compositions may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
- the compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier constituents are to be neutral.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e. g., ovule, gels, or cream.
- any of the usual pharmaceutical media may be employed, such as, for example, suspensions, and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of vaginal solid preparations such as, for example, powders, hard and soft tablets.
- composition is applied as a suppository
- the active ingredients are combined with inert suppository bases, depending on the nature of the suppository, such as cocoa butter, glycerinated gelatin, hydrogenated vegetables oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- inert suppository bases depending on the nature of the suppository, such as cocoa butter, glycerinated gelatin, hydrogenated vegetables oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- inert suppository bases depending on the nature of the suppository, such as cocoa butter, glycerinated gelatin, hydrogenated vegetables oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- Means of creating these suppository bases are known to those skilled in the art.
- the use of soluble or dispersible bases
- suppository compositions include well known techniques of rolling (hand shaping), molding ' (fusion) and cold compression. Suppositories are usually globular or oviform and weigh about 5 gram.
- the composition may include a water soluble base.
- a water soluble base lowers the surface tension of the composition aiding in a more thorough distribution of the composition.
- a water soluble base also decreases the risk of secondary infection.
- Illustrative water soluble bases are corn starch, aloe, cocoa butter and the like.
- compositions of the invention may include propylene glycol.
- Propylene glycol acts as a surfactant and assists in penetration, contact, and absorption of the active ingredients. Propylene glycol also serves as a preservative and as a microbial agent.
- compositions of the invention may also include a non-ionic surfactant, such as polysorbate.
- a non-ionic surfactant such as polysorbate.
- Such a surfactant provides better surface contact of the composition with the epithelium by further reducing surface tension.
- compositions of the invention may also be used as a carrier material for and/or in combination with other medicines useful in cervical softening/ripening, such as prostaglandins and their analogues or nitric oxide donors, thereby further broadening the compositions medical efficacy.
- solid (tablet, ovule, pessary, suppository, and capsule) and semisolid (gel, cream, ointment, foam) forms represent the most advantageous vaginal form.
- the composition is preferably administered in the solid form of a suppository or a tablet although other dosage forms are also advantageously envisioned.
- Advantages to administering the composition as a solid form include convenience, ease of application, increased safety and neatness.
- the semisolid forms are preferred for ease of dispersion and lacking dissolution problems associated with the solid forms.
- Administering the composition as a cream having a low surface tension is advantageous as it provides a uniform wetting action that assists in composition penetration into cervical tissue.
- Other dosage forms include solutions and douches for douching and the like.
- compositions in the form of a solution, which may initially be provided in a concentrated liquid form, or as a dissolvable powder, tablet or the like requiring the addition of water, or other suitable diluents, prior to use, enables the composition to be administered as a vaginal douche.
- a vaginal douche the composition can also be used in non-pregnant females only.
- the compounds of the invention are administered vaginally.
- the pharmaceutical forms must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the compounds of the invention can be effective over a wide dosage range, depending on the condition, and the type of mammal. For example, in the treatment of adult humans, dosages from about 10 to about 1000 mg, about 100 to about 500 mg or about 1 to about 100 mg may be needed. Doses of the 0.05 to about 100 mg, and more preferably from about 0.00001 to about 100 mg, per day may be used. An appropriate amount or dose of the candidate compound may be determined empirically as is known by those skilled in the art.
- An appropriate or therapeutic amount is an amount sufficient to effect cervical softening/ripening over time.
- the candidate form can be administered as often as required to effect cervical softening/ripening, for example, every four, six, eight, twelve, or eighteen hours, or daily.
- the exact dosage and duration of treatment will depend on the therapy desired, form in which it is administered, the subject to be treated and the preference and experience of the physician or veterinarian in charge. While the precise regimen is left to the discretion of the clinician, it is recommended that the resulting formulation be vaginally applied one or two times a day.
- Compounds of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in cervical softening/ripening. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention.
- a pharmaceutical composition in unit dosage form containing such other drugs and the compound is preferred.
- the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
- the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds disclosed above.
- Samples from each group were then collected daily (from day 1 to day 6) from each solution, processed for preparation of paraffin sections (4-5 ⁇ m thick), and stained with either Mallory's triple stain for collagen fibers or haematoxylin and eosin stain.
- Fig.2 which is the typical cervical collagen appearance in non-pregnant state. Histological examination of all of the specimens immersed in acids revealed collagen degradation that was subdivided into three grades: (1) Decreased density of the collagenous network: There is loosening of collagen bundles that appear less compact (Fig.3). Collagen fibers are decreased and loosely arranged, yet they are still organized regularly in bundles (Fig.4). (2) Decreased density and organization of the collagenous network: Destruction of collagen bundles is noticed with loss of their wavy arrangement. The collagen bundles appear much thinner, pale in staining in some areas, and separated by small clear empty spaces resulting from dissolution of some fibers.
- vaginal tablet for inducing cervical softening/ripening is given as follows:
- Each vaginal tablet contains:
- the vaginal tablet comprising the above formulation is prepared in accordance with well known techniques in the art.
- the disintegration rate of the tablet is 4.5 minutes. It is soluble in water totally in 25 minutes.
- These tablets were inserted vaginally twice daily for 3 days postmenstrually in two human volunteers (regularly menstruating, muciparous women) scheduled for total abdominal hysterectomy operation. The subjects were asked to insert the moistened tablet high up in the vagina, and to lie in bed for few hours afterwards. From each patient, two biopsies were taken from the vaginal portion of the cervix. The first one was a punch biopsy taken before the beginning of treatment, and served as a control. The second biopsy was taken just after hysterectomy.
- Example 2 The procedure of Example 2 was repeated except that these tablets were inserted vaginally twice daily for 5 days postmenstrually in one nulligravida human volunteer complaining of primary infertility and scheduled for laparoscopy combined with hysteroscopy.
- Initial assessment prior to the start of therapy revealed a normal uterus and a normal cervix with failure to pass a uterine sound (4 mm in diameter).
- the collagen fibers appeared pale in staining, loosely arranged in some sections (Refer to Fig.5) or completely destroyed with marked increase in the extracellualr ground substance in other sections (Fig.12), being associated with mononuclear cellular infiltration of the cervical stroma (Refer to Fig.11).
- a suitable formulation for a composition in the form of a vaginal lotion for inducing cervical softening/ripening is 5% lactic acid in oil in water emulsion. This lotion was inserted vaginally twice daily (3 ml) for 4 days postmenstrually in a human volunteer (regularly menstruating, nulliparous woman) scheduled for cervical dilatation.
- Initial assessment prior to the start of therapy revealed a normal uterus and a normal cervix with the uterine sound (4 mm in diameter) hardly passed through the cervix.
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Abstract
The present invention relates to pharmaceutical compositions containing organic acids useful for softening/ripening uterine cervix. The composition is applied vaginally. It contains about 0.1 wt. % to about 50 wt. % of the active agent.
Description
Description
Pharmaceutical compositions containing organic acids useful for softening and ripening uterine cervix.
TECHNICAL FIELD [1] The present invention relates generally to pharmaceutical compositions entailing organic acid compounds to lower the vaginal pH. More specifically, the invention relates to pharmaceutical compositions for cervical soften/ripening, thus fastening and easing its further dilatation by natural or induced uterine contractions and by mechanical means in mammals in need thereof. BACKGROUND ART:
[2] The cervix, in contrast to the uterine corpus, is essentially a fibrous connective tissue organ. The cervix contains approximately 10% to 15% smooth muscle, with decreasing content of smooth muscle from the upper to the lower segment of the cervix. The underlying stroma is mainly connective tissue made of collagen bundles with glycosaminoglycans and proteoglycan molecules between the collagen fibers. [Granstrδm L. et al. Br J Obstet Gynaecol 1989; 96(10):1198- 202; and Leppert PC. Clin Obstet Gynecol 1995; 38:267-79]. The general descriptions of fibrous connective tissue components, along with their presence in the non-pregnant cervix are generally reviewed [UIdbjerg N. Acta Obstet Gynecol Scand 1989; S(148):ll-19].
[3] In obstetric practice, it is well known that an extensive remodeling of the connective tissue prior to parturition, i.e., cervical ripening, is necessary for a harmless and successful delivery of the fetus. The idea of the cervix as a passive, inert, connective tissue structure is no longer tenable. The cervix is in fact a dynamic structure, which undergoes marked changes during pregnancy and labor.
In the non-pregnant state, the cervical canal is very narrow, and the cervix resists mechanical force to open it. The role of the cervix shifts between two opposing functions during pregnancy. In order to hold the products of conception inside the uterus during pregnancy, the uterine cervix acts as a connective tissue-rich sphincter that resists tension and remains closed and rigid throughout most of gestation. At term, however, a drastic change in cervical function is required in
order to accommodate stretch and delivery [Leppert PC. J Matern Fetal Med 1992, 1:213-223, and Thomson AJ et al. The cervix. In: Elder MG, Romero R, Lamont RF (eds.), Preterm Labor, New York: Churchill Livingstone; 1997: 445-455, and Ludmir J & Sehdev HM. Clin Obstet Gynecol 2000; 43:433-439]. Towards the end of pregnancy, the cervix softens to become more pliable or distensible, dilates and effaces in a process known as cervical ripening. These changes occur in humans, as well as in all other mammals [Cabrol D. Semin Perinatol 1991; 2:133-139, and Kokenyesi R et al. Biol Reprod 1990; 42:87-97, and Hafez ESE. Anatomy of female reproduction. In: Hafez ESE (ed.), Reproduction in Farm Animals. Philadelphia: Lea and Febiger; 1993:20-55, and Kaga N et al. Am J Obstet Gynecol 1996; 175:713-718]. Though cervical ripening —characterized by softening, effacement and eventually by early dilatation- becomes especially obvious during the last six weeks of pregnancy ( Hen d ricks CH et al. Am J Obstet Gynecol 1970; 106:1065-82], cervical softening starts early in pregnancy. Softening of the cervix (Goodell's sign) and especially of the isthmus (Hegar's sign) are early signs of pregnancy which can be observed about 6 weeks after the last menstrual period. This increased compliance has also been demonstrated more objectively by a system of cervical dilators attached to a force measuring instrument [Fisher J et al. J of Medical Engineering & Technology 1981; 5(4): 194-195].
[4] Histological examination of the non-pregnant state showed that the collagen fibrils are uniform and assembled in compact bundles which form collagen fibers traversing the tissues of the cervix in all directions [Junqueira LCU et al. Am J Obstet Gynecol 1980; 138:273-81]. The histological appearance of cervical collagen is changed already after 9-14 weeks of gestation. The collagen fibers become less densely packed and the waves are broader and deeper [Theobald PW et al. Arch Gynecol 1982; 231:241-5, and Minamoto T et al. Am J Obstet Gynecol 1987; 82:61-7]. In the last weeks of pregnancy and by delivery, these changes are still more marked. On histological examination, the individual collagen fibers are separated by clear spaces and the fibrillar components appear to be dissociated, being much thinner and more spread out [Minamoto T et al. Am J Obstet Gynecol 1987; 82:61-7]. Furthermore, the collagen fibers appear irregular,
express lack of continuity, and have variable thickness, suggesting that they have been corroded [Junqueira LCU et al. Am J Obstet Gynecol 1980; 138:273-81].
[5] During the extensive remodeling of the connective tissue prior to parturition, i.e. cervical ripening, marked biochemical changes take place in the cervix, causing it to become soft and dilatable at the time of parturition [Uldbjerg N et al. Clin
Obstet Gynecol 1995; 38:267-79]. The most striking changes are the decreases in concentrations of collagen and glycosaminoglycans, estimated to be about 50-70% [Uldbjerg N et al. Am J Obstet Gynecol 1983; 147:662-666, and Granstrδm L et al. Br J Obstet Gynaecol 1989; 96(10):1198-202] together with a marked increase in hyaluronic acid (HA) concentration [von Maillot K & Zimmermann
BK. Arch Gynaekol 1976; 220: 275- 80, and Leppert PC. Clin Obstet Gynecol 1995; 38:267-79]. The decrease in collagen was shown to correspond well with increased softening of the cervix [Uldbjerg N et al. Am J Obstet Gynecol 1983; 147:662-6]. Not only quantitative but also qualitative changes have been demonstrated in several studies, as the solubility or extractability of hydroxyproline
- in pepsin and/or acetic acid- is markedly raised during pregnancy. A shift from "old" mature crosslinks to "young" reducible crosslinks might explain increased extractability of collagen during pregnancy [Uldbjerg N. Acta Obstet Gynecol Scand 1989; S(148): 11-19]. In fact, the decrease in dermatan sulfate concentration causes a decrease in its bridges between collagen fibrils. The net effect is rearrangement of the collagen fibers into a looser and more disorganized network. [Leppert PC. Clin Obstet Gynecol 1995; 38:267-79].
[6] The exact mechanisms that regulate cervical softening or ripening during pregnancy are not completely understood. Major events in the female reproductive tract, including ovulation, menstruation, implantation, and parturition, require extensive remodeling of extracellular matrix. Matrix metalloproteinases (MMPs) are known to play a central role in breakdown of ECM components and are important in reorganization of extracellualr matrix. The MMP family consists of 20 members with broad substrate specificities, which can be partly explained by the presence of specific structural domains. Main substrates for collagenases (MMP-I,
-8, and r 13) are fibrillar and nonfibrillar collagens. In particular, MMP-I, MMP-3, MMP-8, and MMP-9 are increased during cervical ripening and are critically
important to extracellualr matrix remodeling at this time [Curry TEJR. & Osteen KG. Endocrine Reviews 2003, 24(4):428-465]. Cervical collagen degradation contributes to the ripening process. Collagenase (MMP-I) and other proteolytic enzymes play an essential role in the degradation of collagen fibers and subsequent dissolution of cervical connective tissue. Neutrophil accumulation in the cervical tissue is one of the main histological features which have been observed during ripening [Junqueira LCU. Am J Obstet Gynecol 1980; 138:273-81]. These neutrophils were found to be the main source of collagenolytic enzymes during ripening [Osmers R et al. Am J Obstet Gynecol 1992; 166:1455-1460]. Most probably, the high cervical collagenolytic activity would destroy all cervical collagen long before term pregnancy if the rate of synthesis of collagen was unchanged. Thus there are reasons to believe that the turnover of cervical collagen is markedly increased during pregnancy. If true, this explains the shift from "old collagen" -with nonreducible or mature crosslinks- to "young collagen" -with reducible crosslinks-suggested by the increase in hydroxyproline extractability during pregnancy [UIdbjerg N. Acta Obstet Gynecol Scand 1989; S(148): 11- 19]. Considering these reduced cervical levels of type I collagen - the main niacromolecular component of the extracellualr matrix of the cervix- in the process of cervical softening, a recent study suggests at least two possible mechanisms for regulation of the turnover of this collagen. First, the synthesis of type I collagen by cervical stromal cells might be reduced at the gene level in the process of cervical softening. Second, the degradation of cervical type I collagen might be intensified in the process of cervical softening [Iwahashi M. J Clin Endoc Metab 2003, 88(5):2231-2235]. Type I collagen-degrading enzyme is thought to be produced by the cervical stromal cells themselves [Rajabi MR. & Singh A. Biol Reprod 1995;
52:516-523, and Watari M et al. Am J Pathol 1999; 154:1755-1762] or by neutrophil [Osmers R et al. Am J Obstet Gynecol 1992;166:1455-1460] accumulated in the cervical tissues during ripening. It is suggested that during pregnancy, collagenase in the cervical connective tissues might be controlled by estrogen [Rajabi MR. et al. Endocrinology 1991; 128:371-378, and Stjernholm
Y et al. Obstet Gynecol 1997; 90:375-380], progesterone [Wallis RM. et al. J Reprod Fertil 1981; 62:55-61, and Radestad A et al. Contraception 1990, 41:283-292, and Sato T et al. Biochem J. 1991; 275:645-650],
dehydroepiandrosterone [Mochizuki M et al. Acta Obstet Gynecol Scand 1978; 57:397-401, and Belayet HM. et al. Hum Reprod 1999; 14(5):1361-1367], and prostaglandins [Calder A & Embrey MP. Lancet 1973, ii, 1322-3(Letter), and Ulmsten U et al. Obstet Gynecol. 1982; 59:336-9, and Kelly RW. Endocr Rev 1994; 15:684-706], cytokines such as interleukin-I [EL-Maradney E et al. Eur J
Obstet Gynecol Reprod Biol 1995; 60:75-80], interleukin-8 [Barclay CG. et al. Am J Obstet Gynecol 1993; 169:625-632, and Chwalisz K et al. Hum Reprod 1994; 11:2173-2181, and El-Maradney E et al. Am J Obstet Gynecol 1994; 171:77-83, and Osmers R et al. Obstet Gynecol 1995; 86:223-229, and Winkler M et al. Obstet Gynecol 1998; 91:945-9], interleukin-6, and granulocyte colony-stimulating factor [Sennstrδm MB et al. Molec Hum Reprod 2000, 6(4):375-381], and nitric oxide [Thomson AJ et al. Br J Obstet Gynaecol 1997; 104:1054-1057, and Calder A. Hum Reprod 1998; 13:250-251, and Chwalisz K & Garfield R. Hum Reprod 1998; 13:245-248, and Norman L et al. Hum Reprod 1998; 13:251-252, and Romero R. Hum Reprod 1998; 13:248-250, and
Tschugguel W et al. Biol Reprod 1999; 60:1367-1372]. These data demonstrate that cervical ripening is similar to an inflammatory process [Sennstrδm MB et al. Molec Hum Reprod 2000, 6(4):375-381].
[7] The striking biochemical change that needs elaboration is the marked increase in hyaluronic acid concentration. There is sudden and marked increase in hyaluronic acid during cervical ripening [Osmers RG et al. Obstet Gynecol 1993;
81(l):88-92]. It has been also shown that interleukin-8 stimulates hyaluronic acid production [El-Maradny E et al. Hum Reprod 1997; 12(5): 1080-1088]. This suggests an important role for hyaluronic acid in ripening process through different mechanisms. Firstly, hyaluronic acid is hydrophilic, and by attracting water molecules, it makes the cervix softer [Leppert PC. Clin Obstet Gynecol 1995;
38:267-79] by increasing its water content, a change well-known to occur during cervical ripening [Uldbjerg N. Acta Obstet Gynecol Scand 1989; S(148): 11-19].
Secondly, hyaluronic acid participates in the degradation of cervical collagen as it has been shown to stimulate the synthesis of proteolytic enizymes, including collagenase, by cervical fibroblasts [Hiro D et al. Res Commun 1986; 140:715-
722]. Thirdly, hyaluronic acid is suggested -through mutual interaction with cytokines- to stimulate migration and function of neutrophils, being the main
source of collagenolytic enzymes during ripening [El-Maradny E. et al. Hum Reprod 1997; 12(5):1080-1088], an effect that is upregulated by dehydroepiandrosterone sulphate [Belayet HM et al. Hum Reprod 1999; 14(5):1361-1367].
[8] Recent decades have seen a rapid expansion in the development and use of a range of practices designed to start, augment, accelerate, regulate or monitor the physiological process of labor, with the aim of improving outcomes for mothers and babies, and sometimes of rationalizing work patterns in institutional birth. In developed countries where such activity has become generalized, questions are increasingly raised as to the value or desirability of such high levels of intervention. In the mean time, developing countries are seeking to make safe, affordable delivery care accessible to all women. In normal birth there should be a valid reason to interfere with the natural process. There are many examples of the medicalization of normal birth, transforming a physiological event into a medical procedure. [Care in normal birth: report of a technical working group.
WHO/FRH/MSM/96.24]. These include pharmacological methods of pain relief [Dickersin K. Pharmacological control of pain during labor. In: Chalmers et al (eds). Effective care in pregnancy and childbirth. Oxford, Oxford University Press 1989; and Thorp JA et al. Am J of Obstet Gynaecol 1993; 169(4):851-858, and Dewan DM & Cohen SE. Anesthesiology 1994;
80(6):1189-1192; and Morton SC et al. Obstet Gynecol 1994; 83(6): 1045-1052, and Miller AC. International Journal of Obstetric Anesthesia 1997; 6:2-18, and Leeman L et al. Am Fam Physician 2003; 68:1115-22]. Epidural analgesia appears to be very effective in reducing pain during labor, although there appear to be some potential adverse effects. Further research is needed to investigate adverse effects and to evaluate the different techniques used in epidural analgesia [Howell CJ. Epidural versus non-epidural analgesia for pain relief in labor (Cochrane Review). In: The Cochrane Library, Issue 4, 2004]. A second example is continuous electronic intrapartum monitoring, which is of great value in high risk cases [Umstat MP. Aust N Z J Obstet Gynaecol 1993; 33:145-9, and Kulkarni
AA & Shotri AN. J Obstet Gynaecol Res 1998; 24:255-9], yet not in low risk ones [Mires G et al. Br Med J 2001; 322:1435-1498]. The relationship between prolonged labor and adverse maternal and fetal outcome is the reason why it is so
important to monitor the progress of labor accurately. The third are the several measures used to prevent delay in the progress of labor; with the most active interventions being early amniotomy and early oxytocin infusion [Care in normal birth: report of a technical working group. WHO/FRH/MSM/96.24], or a combination of the two, often called "active management of labor", and as such it was first advocated in Ireland [O'Driscoll K et al. Br Med J 1969; 2:447-80; O'Driscoll K et al. Br Med J 1973; 3:135-137]. A policy of early amniotomy in normal spontaneous labor reduces the length of labor (by an average of 1-2 hours) and is associated with less use of oxytocin but has no effect on the use of analgesia, forceps or Caesarean section [Brisson-Carroll G et al. Obstet Gynecol 1996;
87:891-896]. However, others suggested a minimal increase in the Caesarean section rate [Johnson N et al. Br J Obstet and Gynaecol 1997; 104:340-346]. Active management of labor, by the liberal use of both amniotomy and oxytocin in more or less modified form, has been widely adopted across the world. It is suggested to be instrumental in reducing Caesarean section rates [O'Driscoll K et al. Br Med J 1973; 3:135-137, and Chalmers I, Enkin M, Keirse MJNC. Effective care in pregnancy and childbirth. Oxford: Oxford University Press, 1989 p. 958]. The practice has been investigated in a number of randomized trials and it is not clear from the available data that liberal use of oxytocin augmentation ("active management of labor") is of benefit to women and babies. Of course this does not mean that oxytocin is useless in the therapy of prolonged labor. However, there is no evidence that the prevention of prolonged labor by the liberal use of oxytocin in normal labor is beneficial. Oxytocin augmentation is a major intervention and should only be implemented on a valid indication [Care in normal birth: report of a technical working group. WHO/FRH/MSM/96.24].
Every individual has the right to safe, satisfying health care with respect for human and cultural variations, and further it is believed that the normal processes of pregnancy and birth can be enhanced through education, health care and supportive intervention. The practice of midwifery advocates non-intervention in normal processes. In order to achieve the optimal outcome for the mother and/or infant at risk for conditions that deviate from the normal, appropriate technological interventions can be used where the benefits of such technology outweigh the risks. Avoiding unnecessary interventions should result in reduction in complications of
the intervention and less use of resources. The problem comes in deciding at which point the desires of the mother conflict with any risks to mother and child. In this regard, the use of a pharmaceutical agent (locally-acting on the cervix without inducing uterine contractions) that increases cervical softening/ripening would lower cervical resistance, thus enhances and shortens the duration of normal labor with less need for analgesia, monitoring, operative delivery, patient's stress, and health care facilities.
[9] It is also known that termination of pregnancy by medical or surgical methods, especially in the presence of unfavorable cervix may lead to additional difficulties and complications. Cervical ripening, before induction of abortion, is needed to increase the success of induction, to reduce complications and to diminish the rate of operative interventions and duration of abortion. Pharmacological manipulation of cervical connective tissue is now firmly established in clinical practice in the context of induction of labor and induced abortion. A means of reversal of ripening process may ultimately hold the key to the prevention of preterm labor and delivery
[Olah KS & Gee H. Br J Obstet Gynaecol 1992; 99:278-280].
[10] Induction of labor is common in obstetric practice. According to the most current studies, the rate varies from 9.5 to 33.7 percent of all pregnancies annually. Induction of labor refers to the process whereby uterine contractions are initiated by medical or surgical means before the onset of spontaneous labor. Following the introduction of Bishop Score in 1964 [Bishop EH. Obstet Gynecol 1964; 24:266- 268], there has been an increasing awareness that if the cervix is. unfavorable, a successful vaginal birth is less likely. This scoring system attempts to predict success of induction by assessing five factors: position of the cervix in relation to the vagina, cervical consistency, dilation, effacement and station of the presenting part. A score less than six indicates an unfavorable cervix for induction. In this condition, it is recommended that a cervical ripening agent be used before labor induction. Nonpharmacologic approaches to cervical ripening and labor induction have included herbal compounds, castor oil, hot baths, enemas, sexual intercourse, breast stimulation, acupuncture, acupressure, transcutaneous nerve stimulation, and mechanical and surgical modalities. Of these nonpharmacologic methods, only the mechanical (hygroscopic and balloon dilators) and surgical (stripping of the
membranes and amniotomy) methods have proven efficacy for cervical ripening or induction of labor. The potential risks associated with mechanical methods include infection, bleeding, membrane rupture, and placental disruption. Stripping of the membranes promotes onset of labor but does not seem to produce important benefits on maternal and neonatal outcomes, and thus must be weighed against patient discomfort and other adverse effects such as bleeding, accidental rupture of membranes, infection, and uterine irritability. Risks associated with this amniotomy include umbilical cord prolapse or compression, maternal or neonatal infection, fetal heart rate deceleration, bleeding from placenta previa or low-lying placenta, and possible fetal injury. Pharmacologic agents available for cervical ripening and labor induction include prostaglandins, misoprostol, mifepristone, and relaxin. When the score is favorable, the preferred pharmacologic agent is oxytocin. In the presence of a favorable cervix, the use of oxytocin from the time of amniotomy results in a higher rate of delivery in 12 and 24 hours and a lower rate of operative delivery, compared with amniotomy alone. Evidence supports that prostaglandins are effective cervical ripening and labor induction agents that lowers the incidence of failure to achieve vaginal delivery in 24 hours and the need for oxytocin augmentation. Compared with placebo/no treatment, the use of prostaglandins has been reported to be associated with similar rates of caesarean section, epidural anesthesia, instrumental delivery, postpartum hemorrhage, and adverse maternal or perinatal outcome measures. When compared with oxytocin for labor induction, prostaglandin reduces the likelihood of operative delivery and failed induction yet with higher rates of uterine hyperstimulation, accompanying fetal heart rate changes, and maternal side effects whether gastrointestinal side effects (nausea and vomiting) and fever. Evidence supports the conclusion that vaginal use of misoprostol safely lowers the cesarean delivery rate among women undergoing labor induction compared with those receiving alternative induction regimens. Based on several randomized trials, there seems to be no increase in adverse maternal or perinatal outcomes. Other potential benefit of misoprostol lie in the fact that it is much cheaper than currently available induction agents and is easily stored and stable at room temperature. Its ease of administration may also be of benefit if oral misoprostol is shown to be safe and effective. However, there is some concern that the use of misoprostol may provoke excessive uterine activity
leading to hyperstimulation. Finally, uterine rupture in women with previous cesarean section is also a possible complication, limiting its use to women who do not have a uterine scar. The ideal route, dose, and frequency of misoprostol for cervical ripening have yet to be determined [Royal College of Obstetricians and Gynaecologists. Induction of labor: Evidence-based Clinical Guideline
Number 9. Published by the RCOG Press at the Royal College of Obstetricians and Gynaecologists, London, UK, 2001, p.1-90, and Crane J, Leduc L, Farine D, Hodges S, Reid GJ, Van Aerde J. Induction of labor at term: Guideline. JOGC August 2001; 107:1-12, and Sanchez-Ramos L & Hsieh E. Current Women's Health Reports 2003, 3:55-60, and Tenore JL. Am
Fam Physician 2003; 67:2123-8]. Currently, the gold standard for inducing cervical ripening in human pregnancy is local application of prostaglandins (PG), notably PGE2 [Calder AA & Greer IA. Cervical physiology and induction of labor. In: Bonnar J (ed.), Recent Advances in Obstetrics and Gynaecology. Edinburgh: Churchill Livingstone, 1992; 17:33-56]. Unfortunately, a clear and unequivocal reduction in the rate of cesarean section after PG treatment has not been demonstrated [Keirse MN. Therapeutic use of prostaglandins. Bailliere's Clin Obstet Gynecol 1992; 6:787-809]. Moreover, the effects of PG, even when used to ripen the cervix, are not confined to the cervix. PG may cause uterine hyperstimulation with potential adverse effects in patients with a previous uterine scar or in those at risk of fetal distress [Egarter CH. et al. Am J Obstet Gynecol 1990; 163:794-796]. In this regard, an attractive alternative method would be one that leads to cervical ripening without stimulating myometrial contractility.
[11] In practice, mid-trimester termination of pregnancy (TOP) is a problematic procedure. Currently, though, the use of laminaria tents [Jain JK & Mishell DR.
Am J Obstet Gynecol 1996; 175:173-7] and cervical Foley's catheter [Khadem N
& Khadivzadeh T. Iran J Med Sci (IJMS) 2003; 28(3): 119-122] have been investigated, termination of second trimester pregnancy is frequently performed by administration of prostaglandins or their analogues by various routes. Patients usually receive misoprostol therapy alone and this may result in protracted induction-to-abortion intervals and failure of medical therapy. This is distressing to both patients and health care staff and further prejudices the implementation of safe obstetric service. Optimal regimens for mid-trimester TOP are essential if the
morbidity and mortality of unsafe abortion are to be reduced. Many studies have been performed aiming at minimizing the dose required, and hence side effects and expense [Jain JK. & Mishell DR. N Eng J Med 1994; 331:290-3, and Nuutila M et al. Obstet Gynecol 1997; 90(6): 896-900, and Wong KS. et al. Hum Reprod 2000; 15(3):709-712]. Side effects of misoprostol therapy include fever, nausea, vomiting, diarrhea, dizziness, fatigue, headache, and breast tenderness. More frequent administration of the drug was proved to be more effacious in women with previous pregnancy -and not in primigravidae- with increased incidence of fever [Wong KS et al. Hum Reprod 2000; 15(3):709-712]. Other studies addressed the use of adjuvant therapies: such as mifepristone [Webster D et al. Br J Obstet
Gynaecol 1996; 103:706-709, and Ngai SW et al. Hum Reprod 2000; 15(10):2205-2208.] and trilostane [Le Roux PA et al. Hum Reprod 2002; 17(6):1483-1489].
[12] Medical termination of first trimester pregnancy using mifepristone in combination with misoprostol has proven to be a safe and effective alternative to vacuum aspiration [El-Refaey H & Templeton A. Contraception 1994; 49:111-
114, and El-Refaey H et al. N Eng J Med 1995; 332:893-987, and Ashok PW et al. Lancet 1998, 352:542-543, and Ashok PW et al. Hum Reprod 1998;
13:2962-2965]. Randomized controlled trials comparing first trimester medical abortion with vacuum aspiration showed that although both methods were highly acceptable to women, medical abortion was more painful and seemingly less effective with advancing gestation [Henshaw RC et al. Br Med J 1993; 307:714-
717, and Henshaw RC et al. Hum Reprod 1994; 9:2167-2172, and Ashok PW et al. Hum Reprod 2002, 17(l):92-98]. Despite the increased incidence of side effects (gastrointestinal upset, abdominal pain, hot flashes, dizziness, headache, and tiredness), medical abortion is safe and effective at 10-13 weeks gestation and should be considered an option for those women who wish to avoid surgery and anesthesia [Ashok PW et al. Hum Reprod 2002, 17(l):92-98].
[13] Surgical termination of pregnancy is associated with complications such as uterine perforation, cervical laceration and incomplete evacuation of the uterus
[Beric BM & Kuperesanin M. Br J Obstet Gynaecol 1972; 2:619-621, and
Wright CSW et al. Lancet 1972; 1:1278-1279]. Vacuum aspiration is considered
to be a safe and effective method of surgical abortion, but has been associated with major morbidity in up to 1% of women and minor morbidity in 10% [Joint Study of the Royal College of General Practitioners and the Royal College of Obstetricians and Gynaecologists. Induced abortion operations and their early sequelae. J R Coll Gen Pract 1985; 35:175-180], the major determinants of morbidity being gestational age and the procedure used to terminate the pregnancy. In the first trimester, the complication rate is lowest at 7-8 weeks of gestation (0.26 per 100 abortions) and increases progressively to 1.37 per 100 abortions at 13 weeks [Grimes DA & Cates W. Obstet Gynaecol Surv 1979; 34:177-191]. The incidence of cervical trauma and uterine perforation is related to the degree of forcible mechanical dilatation required [Schultz KF et al. Lancet 1983, i:1182- 1185, and Grimes DA et al. JAMA 1984; 251:2108-2111]. Traumatic complications may jeopardize future fertility, and have been associated with increased risk of miscarriage and preterm labor in subsequent pregnancies [Harlap S et al. N Eng J Med 1979; 301:677-681]. Difficult or inadequate cervical dilatation may increase the risk of hemorrhage and incomplete uterine evacuation [Mackenzie IZ & Fry A. Br J Obstet Gynaecol 1981; 88:1033-1037]. As first trimester vacuum aspiration is widely performed on an outpatient or day surgery basis, there has been considerable interest in establishing the optimal dosage and administration route for rapid and effective cervical priming with minimum side effects. Pre-operative treatment with a priming agent, to ripen i.e. soften and dilate the cervix, has been shown to decrease the morbidity associated with pregnancy termination by vacuum aspiration [Mackenzie IZ & Fry A. Br J Obstet Gynaecol 1981; 88:1033-1037, and Schultz KF et al. Lancet 1983; i:1182-1184, and Grimes D et al. JAMA 1984; 251:2108-2111]. The use of preoperative cervical preparation agents prior to termination of pregnancy by vacuum aspiration has been well established in gynecological practice as it reduces the risk of cervical injury and uterine perforation [Schultz KF et al. Lancet 1983, i, 1182-1185, and Grimes DA et al. JAMA 1984; 251:2108-2111]. Agents commonly employed for pre-operative cervical ripening include mifepristone [Henshaw RC & Templeton
AA. Br J Obstet Gynaecol 1991; 98:1025-1030], laminaria and prostaglandin analogues. The efficacy of prostaglandins for such purposes has been clearly demonstrated [Christensen NJ & Bygdeman M. Contraception 1984; 29:457-
464, and Fisher PR & Taylor JH. Br J Obstet Gynaecol 1984; 91:1141-1144].
Prostaglandins produce more effective cervical ripening than laminaria [Helm CW et al. Br J Obstet Gynaecol 1988; 95:911-915], but are associated with several side effects such as abdominal pain, gastrointestinal upset and vaginal bleeding [Task Force on Prostaglandins for Fertility Regulation. Vaginal administration of 15-methyl-PGF2α methyl ester for preoperative cervical ripening. Contraception 1981; 23:251-259]. Misoprostol, a synthetic 15-deoxy- 16-hydroxy-16-methyl analogue of naturally occurring prostaglandin El (PGEl) has been shown to represent a stable, easily stored, inexpensive and effective alternative, being comparable with gemeprost in terms of efficacy [EI-Refaey H et al. Lancet 1994, 343:1207-1209, and Baird DT et al. Hum Reprod 1995; 95:1521-1527]. Furthermore, misoprostol is associated with fewer side effects than gemeprost [Henry AM & Haukkamaa M. Br J Obstet Gynaecol 1999; 106:540- 543]. Randomized controlled trials have shown different results as to whether the oral or the vaginal administration route is most effective and what is the optimal dose [El-Refaey H et al. N Eng J Med 1995; 332:983-987, and Lawrie A et al. Br J Obstet Gynaecol 1996; 103:1117-1119, and Singh K et al. Obstet Gynecol 1998; 92:795-798, and Saxena P et al. Hum Reprod 2004; 19:77-80, and Oppegaard KS et al. BJOG 2004; 111:154-159]. It is suggested to be administered vaginally at least 3 hours prior to operation [Singh K et al. Obstet
Gynecol 1999; 94:431-434]. The efficacy of vaginal misoprostol for cervical priming is both dose and time dependent, however, with increasing the dose from 400 μgm to 600 μgm more side effects -fever, abdominal pain, and vaginal bleeding- were noted [Singh K & Prasad RN. Br J Obstet Gynaecol 1999; 106:266-269]. Misoprostol, a prostaglandin El analogue, binds to myometrial cells causing strong myometrial contractions leading to softening and dilation of the cervix. This results in separation of the conceptus from the uterine wall, thereby initiating the abortion process before surgical evacuation [Saxena P et al. Hum Reprod 2004; 19:77-80]. Though the occurrence of gastro-intestinal upset seems less, misoprostol use still appears to be associated with abdominal pain, above- average vaginal bleeding [Henry AM & Haukkamaa M. Br J Obstet Gynaecol 1999; 106:540-543, and Ngai SK et al. Hum Reprod 1999; 14(8):2139-2142] and fever [Saxena P et al. Hum Reprod 2004; 19:77-80].
[14] Cervical dilatation, along with hysteroscopy or endometrial curettage, is one of the most common procedures in gynecological practice. However, difficulty in passing the internal cervical os may be encountered, especially in nulliparous women. The complications encountered during the procedure are mainly related to the difficulty of cervical dilatation, including cervical damage, creation of false tract and uterine perforation [Loffer FD. Obstet Gynecol 1989; 73:16-20]. The incidence of these complications may be reduced if the cervix is primed beforehand. Therefore, there is a need for an effective cervical priming agent which can be used in non-pregnant women in general gynecological practice. With consistent evidence that misoprostol facilitates cervical dilation before surgical abortion, researchers began to investigate whether the medication would ease dilation in nonpregnant patients. Misoprostol has been shown to be effective in priming the cervix prior to cervical dilatation in non-pregnant patients [Ngai SW et al. Obstet Gynecol 1999; 94(3):427-30, and Preutthipan S & Herabutya Y Obstet Gynecol 2000; 96(6):890-4, and Thomas JA et al. Am J Obstet Gynecol
2002; 186(5):876-9]. Yet, other investigators claim no effect overall [Perrone JF et al. Obstet Gynecol 2002; 99(3):439-44, and Bunnasathiansri S et al. J Obstet Gynaecol Res 2004; 30(3):221-5, and Fernandez H et al. Hum Reprod 2004, 19(7):1618-1621] or in postmenopausal [Ngai SW et al. Hum Reprod 2001, 16(7): 1486-1488, and Fung TM et al. BJOG 2002; 109(5):561-5] or hypo- estrogenic women [Bisharah M et al. J Am Assoc Gynecol Laparosc 2003; 10(3):390-l]. On the other hand, others demonstrated effectiveness in all patients [Thomas JA et al. Am J Obstet Gynecol 2002; 186(5) -.876-9]. In this study, subjects received either placebo or 400 μg of oral misoprostol at 24 hours and again at 12 hours before the procedure. This observed benefit might be due to the extended dosing regimen used. The discrepancy in these findings can be partially explained by the fact that endogenous estrogen may be essential for the cervical priming induced by prostaglandin, and therefore women in hypo-estrogenic state would show no response to prostaglandins [Ngai SW et al. Hum Reprod 2001, 16(7):1486-1488].
[15] The effect of acidity on connective tissue remodeling and softening of the cervix needs elaboration as it seems to play a vital role. It was reported that the solubility of collagen undergoes a huge increase at full dilatation with no
significant change in the water content [von Maillot K et al. Am J Obstet Gynecol 1979; 135:503-506]. The same authors demonstrated in the course of pregnancy that the fractions of collagen which are acid-soluble increased in relation to the total collagen content and dry weight, with the highest value found during labor at full cervical dilatation and also immediately postpartum. In fact, acids have been used in in vitro studies to extract the newly cross-linked collagen [Bank RA et al. Ann Rheum Dis 1999; 58:35-41, and Zhao L et al. Biol Reprod 2000; 63:697-703]. A unique in vitro study demonstrated that the degradation of cervical collagen can be manipulated by drugs. Studying in vitro cervical cultures from nonpregnant premenopausal women showed that PGE2 and PGF2α did not affect the collagen dissolution whereas low concentrations of arachidonic acid doubled the amount of hydroxyproline in the culture, reflecting a collagenolytic activity. This stimulant effect was not inhibited by indomethacin (an inhibitor of cyclooxygenase and prostaglandin synthesis) and the mechanism behind the action of arachidonic acid was not explained [Wallis RM & Hillier K. Prostaglandins
1982; 24:377-85]. The direct exogenous application of hyaluronic acid on the cervix was shown to induce cervical ripening in both non-pregnant and pregnant rabbits, and it was suggested to be involved in the regulation of cervical tissue water content, collagenolytic enzymes and cytokines [El-Maradny E et al. Hum Reprod 1997, 12(5): 1080-1088]. This effect of acidity on collagen is not limited to the cervix, but it rather seems to be a universal phenomenon. It has been shown that acidity enhances bone resorption by decreasing the collagen through suppressing the osteoblastic activity along with stimulating the osteoclastic activity [Krieger NS et al. Am J Physiol 1992; 262:F442-F448, and Bushinsky DA. Am J Physiol 1995; 268:C80-C88], an effect that appears to be mediated by prostaglandins
(PGE2) synthesis [Krieger NS et al. Am J Physiol Renal Physiol 2000; 279:F1077-F1082]. In a recent study, it was shown that both the increased acidity and the elevated lactate concentration act, independently, to depress osteoblast elaboration of vascular endothelial growth factor (VEGF) [Spector JA et al. Am J Physiol Cell Physiol 280:C72-C80, 2000]. Moreover, pH is suggested to play a role in modulating the function of matrix metalloproteinases (MMPs) [Davis GE. Arch Biochem Biophys 1991; 286(2):551-4, and Dung SZ et al. Caries Res 1995; 29(6):483-9, and Fasciglione GF et al. Biophysical Journal 2000;
79:2138-2149, and Johnson LL et al. J Biol Chem 2000; 275(15): 11026-11033, and Murphy KA et al. J Biol Chem 2004; 279(24):25284-93, and Zhang X. Invest Ophthalmol Vis Sci 2004; 45(7):2374-83]. In normal pregnancy vaginal pH (using a pH meter with connected glass electrode) was found to be between 3.8 and 4.0 at the introitus, mid-vaginal, and at the anterior and posterior fornices; while cervical pH ranged between 6.5 and 7.0 [Riedewald S. J Perinat Med 1990; 18(3):181-6]. During pregnancy, the systemic concentrations of estrogens and progesterone increase up to 100-fold until parturition [Speroff L, Galss R and Kase N (eds.) Clinical Gynecologic Endocrinology and Fertility. Williams & Wilkins, USA, 1989, 4th edition, pp. 317-350]. However, in contrast to other species the serum concentrations of neither estrogen nor progesterone are abruptly changed immediately before parturition in humans [Csapo AL et al. Am J Obstet Gynecol 1971; 110:630-633, and Turnbull AC et al. Lancet 1974; i:101-104]. So, there has been some debate about whether or not estrogens stimulate cervical ripening. It has been recently shown that the levels of both the estrogen receptor alpha (ERa) and the progesterone receptor (PR) in the cervix are significantly lower in term pregnant in comparison with non-pregnant women [Stjernholm Y et al. Am J Obstet Gynecol 1996; 174:1065-1071; Stjernholm Y. et al. Obstet Gynecol 1997; 90:375-380]. On the other hand, other investigators reported an increased level of ERβ in the myometrium of term pregnant women, and a down- regulation in the expression of labor-associated genes in the uterine smooth muscle cells, suggesting that ERβ may play an important biological role during term pregnancy [Wu JJ et al. Eur J Endocrinol 2000; 142:92-99]. Also, it was reported that ERβ concentrations were significantly increased in term pregnancy [Wang H et al. Molec Hum Reprod 2001; 7(3):293-300]. This might be associated with increased glycogen deposition in epithelium, lactic acid concentration and vaginal acidity that might play a role in cervical ripening. It is known that glycogen, which is deposited in large amounts in the vaginal epithelium during times of high estrogen availability could be metabolized to lactic acid by vaginal bacteria and/or the epithelium itself, with the former being the primary source of lactic acid in the vagina [Boskey ER et al. Hum Reprod 2001; 16(9): 1809-1813]. In fact, the concentrations of the many organic acids in the vaginal fluid are shown to be governed by the hormonal status of the woman
[Bauman JE et al. Fertil Steril 1982; 38:572-579, and Owen DH & Katz DF. Contraception 1999; 59:91-95, and Boskey ER et al. Hum Reprod 2001; 16(9):1809-1813]. This might explain the lack of cervical ripening benefit observed with misoprostol in postmenopausal [Ngai SW et al. Hum Reprod 2001, 16(7): 1486-1488, and Fung TM et al. BJOG 2002; 109(5):561-5] or hypo- estrogenic women [Bisharah M. J Am Assoc Gynecol Laparosc 2003; 10(3):390-l].
[16] The innate tendency of corneal stroma to imbibe fluid and swell is an unusual property of connective tissue. At the molecular level, the swelling pressure is due primarily to glycosaminoglycans (GAGs) that make up the carbohydrate moiety of the proteoglycans (PGs) [Huang Y & Meek KM. Biophysical Journal 1999; 77:1655-1665]. The swelling of corneal stroma was observed to be a function of time and ionic strength at various pH levels, with minimum swelling near pH 4. The explanation of this swelling behavior was that the isoelectric point is close to pH 4 and that the net fixed electric charge is zero at this point. The corneal stroma or sclera can be considered as a polyelectrolyte gel. When the tissue is equilibrated at the isoelectric point, electrovalent attractive forces are produced between the equal numbers of positive and negative charges (i.e., zwitterion pairs), which results in tighter, less swollen tissue [Elliott GF et al. J. Physiol (Lond.) 1980; 298:453- 470, and Huang Y & Meek KM. Biophysical Journal 1999; 77:1655-
1665]. Hydration at pH away from the isoelectric point was found to be higher, especially with lower pH (pH3) [Huang Y & Meek KM. Biophysical Journal 1999; 77:1655-1665]. Extent of swelling is, in such a system, inversely dependent on the number of crosslinks. It was supposed that no effective cross-links exist in the cornea and that the swelling pressure is due entirely to the Donnan-osmotic pressure between the stroma and the external solution [Hodson SA. J Theor Biol 1971; 33:419-427]. Hydrations at pH away from the isoelectric point are higher because of the reduction in the number of zwitterions pairs and the increase in net fixed charges in the tissue. The net charge will be positive below the isoelectric point and will affect the swelling in two ways. First, the fixed charge will require more counterions in the stroma to maintain electrical neutrality, resulting in the accumulation of small permeant ions. This will cause an excess internal osmotic pressure and will increase the swelling (Donnan effect). Second, the reduction in
the number of attractive zwitterions pairs will cause a reduction in the attractive forces and thus will loosen the stroma, again causing increased swelling [Elliott GF et al. J Physiol (Lond.) 1980; 298:453- 470]. It was also found that at lower pH (3, 4), the correlation between the interfibrillar spacing and the hydration is poor. This suggests either that a larger portion of the water goes not into interfibrillar space but into another space, such as lakes (regions devoid of collagen fibrils), or that a larger change in the packing arrangement of the fibrils leads to some fibrils being so disorganized [Huang Y & Meek KM. Biophysical Journal 1999; 77:1655-1665].
[17] Vaginal absorption of misoprostol is inconsistent with large individual variations. Sometimes remnants of tablets can be obtained from the vagina hours after its administration. Therefore, although used widely, the vaginal route may not be the ideal route of administration for clinical practice [Saxena P et al. Hum Reprod 2004; 19:77-80]. In some studies, the misoprostol tablets used were wetted only with water before introduction into the posterior vaginal fornix [Fong YF et al. Br J Obstet Gynaecol 1998, 105:413-417, and Singh K et al. Obstet Gynecol 1998, 92:795-798]. However, at the time of vacuum aspiration it was quite common to identify particulate remnants of the tablets, albeit in varying proportions. This finding of incomplete dissolution of misoprostol tablets in the vagina has also been reported by other investigators [Zieman M et al. Obstet
Gynecol 1997, 90:88-92]. Since it is desirable to achieve a constant plasma profile, it is important to develop a preparation or medium that would ensure more complete dissolution of the vaginal misoprostol tablets to achieve optimal efficacy. Misoprostol is said to liquefy better in an acidic medium [American Hospital Formulary Service Drug Information. Gastrointestinal drugs. American
Society of Health System Pharmacists Publication 1998, 56:2445-2450]. In one study investigating vaginal misoprostol use for cervical softening in pregnancy interruption before ten weeks of gestation, Gynoflor vaginal tablet was used in addition to create an acidic milieu in order to increase the absorption of misoprostol [Ficicioglu C et al. Acta Obstet Gynecol Scannd 1996; 75(l):54-56]. However, the data of one study showed that the use of acetic acid (pH 2) to dissolve vaginal misoprostol does not improve the efficacy in achieving successful cervical dilatation for pre-abortion cervical priming [Singh K et al. Hum Reprod 1999;
14(6): 1635-1637]. On the other hand, other investigators examined the efficacy of intravaginally administered misoprostol for cervical ripening and labor induction, in relation to vaginal acidity. The presence of a vaginal pH <5 was found not to be related to the efficacy of the drug in one study entailing a small number (37) of women [Ramsey PS et al. Am J Obstet Gynecol. 2000; 182(6):1616-9]. However in a larger number of women (103), others reported increased efficacy of the drug and suggested that acidity affect the pharmacokinetics of vaginally administered misoprostol, and increase the efficacy of the drug markedly [Gunalp S & Bildirici I. Acta Obstet Gynecol Scand 2000; 79(4):283-5]. The findings in the latter study concur with the newly suggested concept. In these women, the cervical collagen is already affected by the increased vaginal acidity, and hence the cervix is more readily responsive to misoprostol.
[18] From this review, it is clear that there is a need in the art for effective compounds for cervical softening and ripening to decrease the complications and hasten the course of different obstetric and gynecologic conditions. First- and second-trimester terminations of pregnancy could be done more effectively since the cervix represents the main obstacle, often being insensitive to prostaglandins. Moreover, in spontaneous miscarriage, either incomplete or missed, chemical ripening could allow uterine evacuation with fewer, if any, use of anesthetic agents. Also, such pharmacological treatment, instead of or in addition to mechanical dilatation, offers several advantages to many gynecologic procedures including dilatation of the cervix, hysteroscopy, intrauterine contraceptive device application and removal, office endometrial sampling procedures, intra-uterine dye injection on hysterography, and introduction of intra-uterine catheter on insemination or embryo transfer. The induction of parturition at any gestational age, including term, would be easier if one removes the cervical resistance factor, without inducing inappropriate contractions as the case is with prostaglandins. Finally, even the process of normal labor will be faster and shorter with less need for prolonged monitoring, analgesia, or operative intervention. It would therefore be a significant advance in the art of drug therapy as it will satisfy the ideal criteria for achieving cervical softening/ripening in mammals including humans, i.e. being inexpensive; easy; simple to use; locally-acting on the cervix without inducing uterine contractions or other systemic effects and safe for the fetus/newborn and/or the
patient. It would also be advantageous to provide pharmaceutical compositions that cause these cervical changes in a physiologic manner so that cervical dilatation can proceed more rapidly in an easy and smooth way. The benefits of such pharmaceutical compositions would extend beyond improved patient safety, comfort and acceptance, to involve societal economical benefits, eventually helping to improve medical practice.
DISCLOSURE AND SUMMARY OF THE INVENTION
[19] The present invention was conceived based upon the above stated facts. The present invention is directed to a method for cervical softening/ripening in mammals in need thereof. The inventors of the present invention have completed the present invention by controlling the pH of the vagina, which is clinically easy to apply, that is, by acidifying the vagina, thereby leading to cervical softening/ripening process which is similar to that of a pregnant female approaching labor and confirming that the cervical connective tissue is remodeled. Accordingly, the objective of the present invention is to provide an agent for acidifying the vagina, which induces extensive remodeling of the cervical connective tissue, reduces the cervical collagen content and thus softening the cervix and easing its further dilatation by natural or induced uterine contractions and by mechanical means. It is an object of this invention to provide improved vaginal pharmaceutical compositions comprising organic acid, homologues, or analogs thereof that possess pharmaceutical activity suitable for softening and ripening the cervix with fewer adverse effects, if any. Collagen degradation is known to play an important role in the cervical softening/ripening process. To induce this extensive remodeling of the cervical connective tissue, the vagina should be acidified. To easily acidify the vagina, different organic acids, homologues, or analogs, solely or in different combinations and regimens thereof, the therapeutically effective amount of the active ingredient(s) is administered into the vagina to directly control pH, thereby inducing cervical softening and ripening.
[20] The present invention provides compounds, compositions, and methods for softening and ripening of the cervix and for treating or preventing cervical rigidity in mammals -including humans- and the complications thereof. In one aspect, the
invention provides methods for softening and ripening of the cervix and for treating or preventing cervical rigidity by administration of pharmaceutical compositions comprising organic acids, homologues, or analogs in a therapeutically effective amount sufficient to soften and ripen the cervix or prevent cervical rigidity. In other aspects, the invention is drawn to the organic acids, homologues, analogs; and their pharmaceutical compositions and such methods of use.
[21] In some embodiments, the organic acid is a free organic acid or as a prodrug, In some embodiments, it is produced or released through a chemical process or biological means.
[22] In other embodiments, the organic acid, homologues, or analogs structure is aliphatic (straight chained, acyclic), ring chain (cyclic), heterocyclic (aliphatic ring structure, but including at least one atom which is not carbon), or aromatic (containing a benzene ring). In some embodiments, the organic acid, homologues, or analogs structure may have a branched chain of carbon atoms.
[23] In some embodiments, the organic acid, homologues, or analogs structure may be saturated or unsaturated, and if unsaturated may be monounsaturated or polyunsaturated.
[24] Other embodiments are provided by varying the structure of the organic acids, homologues, or analogs. These embodiments include the presence of one or more of the following: an alkyl group, an aryl group, an amino group, an imino group, a sulphar atom, a carboxylic group (di- or polycarboxylic acid), a halogen (acylated acid), a hydroxyl group (hydroxy- or polyhydroxy acid), a ketone group (ketoacid) or an aldehyde group (aldehyde-acid). In another embodiment, the carboxylate group of the organic acid is bound to other compounds to form an ester or salt. Other embodiments include the extraction of water (anhydride acid).
[25] In some embodiments, the organic acid is an acid sugar, glucuronic or iduronic acid. In other embodiments, the acid sugar is attached to another group, as N- acetylgalactoseamine or N-acetylglucosamine.
[26] In some embodiments, the acid moiety of the organic acids, homologues, or analogs is a structural isomer, a cis- or trans- stereo(geo)isomer, and D- or L- stereo(optical) isomer.
[27] In some embodiments, the organic acid, homologues, or analogs is selected from a list, but are not limited to, those compounds specifically listed in the examples presented herein, such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, butyric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, hydroxybenzoic acid, para-aminobenzoic acid, citric acid, mandelic acid, malonic acid, oxalic acid, salicylic acid, succinic acid, imino acid, tartaric acid, ascorbic acid, retionic acid, glucuronic acid, iduronic acid, hyaluronic acid, amino acids as valeric acid and arginine, fatty acids as oleic, linoleic and linolenic.
[28] It is to be understood that, irrespective of whether specifically designated herein, the most suitable active acidic organic compounds are preferred. Typically, the suitable active acidic organic compounds are known in the art to be those compounds that produce the desired pharmacologically acceptable vaginal pH, being <5, preferably 1.5-3.5, still preferably 2-2.5. Any organic acid, homologues, or analogs, that are presently known, or that may be developed in the future, are within the contemplation of the invention for use as the active component in new formulations to induce cervical ripening and/or softening.
[29] In other aspects of the invention, the methods and compositions employ organic acids, homologues, or analogs for cervical softening/ripening in which the compounds, homologs and analogs cause cervical softening/ripening when administered to test animals or human volunteers.
[30] Still other aspects of the invention address methods of using and administering the subject compounds and compositions for cervical softening/ripening or reducing cervical rigidity or causing easier and faster cervical dilatation in mammals, including humans. The subject compositions may be administered vaginally in a variety of forms.
DESCRIPTION OF THE DRAWINGS
[31] FIG.l. is a photomicrograph of control section of human uterine cervix (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[32] FIG.2. is a photomicrograph of control section of human uterine cervix (dyeing: Mallory's triple stain, magnification: 400X).
[33] FIG.3. is a photomicrograph of section of human uterine cervix after 1 day of immersion in 3.5% lactic acid solution (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[34] FIG.4. is a photomicrograph of section of human uterine cervix after 1 day of immersion in 5% lactic acid solution (dyeing: Mallory's triple stain, magnification: 400X).
[35] FIG.5. is a photomicrograph of section of human uterine cervix after 2 day of immersion in 4% acetic acid solution (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[36] FIG.6. is a photomicrograph of section of human uterine cervix after 4 days of immersion in 4% citric acid solution (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[37] FIG.7. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[38] FIG.8. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[39] FIG.9. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: Mallory's triple stain, magnification: 400X).
[40] FIG.10. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
[41] FIG.ll. is a photomicrograph of section of human uterine cervix removed on total hysterectomy after therapy with acetic acid vaginal tablets for 3 days (dyeing: hematoxylin-eosin dyeing, magnification: 1000X).
[42] FIG.12. is a photomicrograph of section of human cervical punch biopsy from a nulligravida after with acetic acid vaginal tablets for 5 days (dyeing: hematoxylin-eosin dyeing, magnification: 400X).
DETAILED DESCRIPTION OF THE INVENTION
[43] The present invention is directed to a method for cervical softening/ripening in mammals in need thereof. The inventors of the present invention have completed the present invention by controlling the pH of the vagina, which is clinically easy to apply, that is, by acidifying the vagina, thereby leading the cervical softening/ripening process which is similar to that of a pregnant female approaching labor and confirming that the cervical connective tissue is remodeled. Accordingly, the objective of the present invention is to provide an agent for acidifying the vagina, which induces extensive remodeling of the cervical connective tissue, reduces the cervical collagen content and thus softening the cervix and easing its further dilatation by natural or induced uterine contractions and by mechanical means.
[44] This invention relates to the discovery that organic acid compounds act to induce cervical softening and ripening processes. It has been surprisingly discovered that lactic acid and acetic acid, natural acids present in vaginal fluid in mammals, are actively-effective agents in inducing cervical softening/ripening when applied to cervical tissue in vitro and when administered to human volunteers.
BEST MODE
[45] Acetic acid and lactic acid are the best mode for carrying out the invention.
Upon The discovery that lactic and acetic acid administration acts to induce cervical softening/ripening and to reduce cervical rigidity, other organic acid compounds, derivatives, and analogs were also found to be active. This invention provides such other compounds as disclosed below.
DEFINITIONS AND NOMENCLATURE
[46] Before describing the present invention in detail, it is to be understood that unless otherwise indicated this invention is not limited to specific organic acid compounds, carrier or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
[47] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an organic acid compound" includes a single organic acid compound as well as two or more organic acid compounds.
[48] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below. They mostly have their conventional meaning within the chemical and biological arts unless otherwise stated.
[49] The terms "active agent", "drug", and "pharmacologically , " are used interchangeably herein to refer to a chemical material or compound that, when administered to a patient (human or animal) induces a desired pharmacologic effect. Included are derivatives and analogs of those compounds or classes of compounds specifically mentioned that also induce the desired pharmacologic effect. Unless the context clearly dictates otherwise, the active agents referred to herein are organic acid compounds.
[50] The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any
composition made by admixture of a compound of the present invention and a pharmaceutically acceptable carrier.
[51] As used herein, the term "functional group" shall mean the carboxyl (COOH) group on the organic acid compound, which is implicated in the therapeutic (pharmacological) effects associated with organic acid compounds for inducing softening/ripening of the uterine cervix.
[52] For the purposes of this patent, the term "derivative" is intended to mean all compounds which have a chemical affinity, resemblance, or structural character which clearly associates them with the organic acids.
[53] The term "organic acid compounds, homologues, and analogs" thereof, hereinafter collectively referred to as "organic acids", shall mean any organic acid compound, and derivatives thereof. The present invention includes organic acid compounds of all types that are effective for inducing softening/ripening of the uterine cervix because the presence of structural variation does not materially affect the beneficial activity of the acidic effect of the carboxylic group of the organic acid compound. Examples of organic acid compounds that are useful include acetic acid, glycolic acid, priopionic acid, lactic acid, pyruvic acid, butyric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, hydroxybenzoic acid, para- aminobenzoic acid, citric acid, mandelic acid, malonic acid, oxalic acid, salicylic acid, succinic acid, cinnamic, adipic acid, tartaric acid, ascorbic acid, retionic acid, glucuronic acid, iduronic acid, hyaluronic acid, nicotinic acid, pentanoic acid, amino acids as valeric acid and arginine, fatty acids as oleic, linoleic, linolenic and arachidonic. However, useful organic acid compounds are not limited to the compounds already mentioned or those to be specifically listed in the examples presented herein. Any organic acid might be used alone or in a mixture (formed of ingredients) of more than one acid.
[54] The term "prodrug" is meant to include an organic acid ester, or preferably an organic acid salt. It also includes bacteria as Lactobacillus, whether live or lyophilized killed, producing or releasing organic acids that are at least minimally effective in inducing softening/ripening of the uterine cervix.
[55] The term "analog" is intended to mean any somewhat modified version of a natural product, in this case an organic acid, or a related synthetic analog, wherein a number of atoms such as carbon, hydrogen, oxygen or heteroatoms such as nitrogen, sulfur or halide have been added or deleted from the parent structure, so as to yield a new molecular compound.
[56] The term "softening/ripening" means to induce changes in the cervix including softening only, or along with shortening (effacement) and dilatation.
[57] The term "rigid cervix" refers to the tough cervix that does not show appropriate effacement and dilatation in response to good uterine contractions.
[58] By a "pharmaceutically acceptable carrier" is meant a material that is suitable for vaginal drug administration to an individual female with an active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical formulation in which it is contained. Preferred pharmaceutical carriers depend upon the intended mode of administration of the active agent. Typical modes of administration are described below.
[59] Similarly, a "pharmacologically acceptable" salt, ester, isomer or other derivative of an active agent as provided herein is a salt, ester, solvate, isomer or other derivative that is not biologically or otherwise undesirable.
[60] By the terms "effective amount" and "therapeutically effective amount" of an active agent as provided herein is meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the age, weight, and condition of the subject, the condition being treated, the judgment of the clinician, and the like. Thus, it is not possible to specify an exact "effective amount". However, an appropriate
"effective amount" in any individual case may be determined by one of ordinary skill in the art. The desired result comprise an objective improvement in the recipient of the dosage, which may be increased ripening and/or softening of the cervix on examination, more rapid cervical effacement and dilatation on the start of uterine contractions in a pregnant female, or more easily performed gynecologic
procedure entailing the cervix as mechanical dilatation, IUD insertion or removal, office endometrial biopsy, hysteroscopy, injection of the dye on hystreography, and introduction of intra-uterine catheter on insemination or embryo transfer.
[61] A "prophylactic treatment" as used herein refer to a treatment administered to a subject who does not exhibit signs of a disease, wherein treatment is administered for the purpose of decreasing the risk of developing a pathology associated with unwanted cervical rigidity or decreased cervical softening/ripening.
[62] A "therapeutic treatment" is a treatment administered to a subject who exhibits signs of pathology, wherein treatment is administered for the purpose of diminishing or eliminating those pathological signs of cervical rigidity.
COMPOUNDS OF THE INVENTION
[63] All organic acids, homologues, analogs or derivatives, are the active ingredient(s) which lowers the pH of the vagina when administered herein, and which are at least minimally effective in inducing softening/ripening of the uterine cervix in mammals including humans.
[64] The compounds are organic acids; a carboxylic acid (containing the functional group COOH) whether mono- or poly-carboxylic. The structure of the compounds may be aliphatic (straight chained, acyclic), ring chain (cyclic), heterocyclic (aliphatic ring structure, but including at least one atom which is not carbon), or aromatic (containing a benzene ring). Certain compounds may have a branched chain of carbon atoms. Some of the compounds are saturated, monounsaturated, or polyunsaturated.
[65] Certain compounds of the present invention may be in the anhydride acid, oxyacid, ketoacid, acylated acid or aldehyde-acid form. Others may have an attached (one or more) alkyl group, aryl group, amino group, imino group, a halogen, or sulfur atom. Other may be sugar acids.
[66] Certain compounds of the present invention may possess asymmetric carbon atoms or double bonds; the structural, optical and geometric isomers are all intended to be encompassed within the scope of the present invention.
[67] The compounds of the present invention may have unnatural ratios of atomic isotopes at one or more of their atoms. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.
[68] The instant compounds may be isolated in the form of their pharmaceutically acceptable salts or esters, such as those in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases. The term "pharmaceutically acceptable salts or ester" refers to those prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
[69] The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be derivatives of the present compounds that are readily convertible in vivo into a functional compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Bundgaard, H., ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam, which is hereby incorporated by reference. The invention also encompasses active metabolites of the present compounds. Moreover, the invention encompasses the production and/or the release of these compounds through a biological means, such as the use of bacteria.
PHARMACEUTICAL UTILITY, COMPOSITIONS and
ADMINISTRATION
[70] The organic acid compounds are active in lowering the vaginal pH in humans and other animals and are therefore useful in inducing cervical softening/ripening and avoiding cervical rigidity. Therefore, in a method of use aspect of the invention, a therapeutically effective amount of at least one organic acid compound is administered into the vagina to induce cervical softening/ripening in a vaginal formulation.
UTILITY
[71] The compounds, compositions and methods of the invention are used in mammals, including human, to induce cervical softening and ripening to decrease the complications and hasten the course of different obstetric conditions, including induction of labor, first- and second-trimester abortion, whether spontaneous (missed or incomplete) or induced. They can be used also in normal pregnant women near term aiming at a faster and shorter labor with less need for monitoring, analgesia, or operative intervention.
[72] In some embodiments, the individuals to be treated are non-pregnant females. The compounds, compositions, and methods of the invention are used as a preparatory step to facilitate gynecologic processes entailing the cervix, such as mechanical dilatation, hysteroscopy, intrauterine contraceptive device application and removal, office endometrial sampling procedures, intra-uterine dye injection on hysterography, and introduction of intra-uterine catheter on insemination or embryo transfer.
PHAMACEUTICAL COMPOSITIONS
[73] The practice of the invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical formulating and the like, which are within the skill of the art. Such techniques are fully explained in the literature. See for, example, Remington: The Science and Practice of Pharmacy, Twentieth Edition (Easton, PA: Mack Publishing Co., 2000).
[74] Another aspect of the present invention provides pharmaceutical compositions which comprise compounds of the invention and a pharmaceutically acceptable carrier. Preparation of each of the formulations described herein would be within the ambit of the person of skill in the art, although reference is made to Remington's Pharmaceutical Sciences, 18th Edition (1990), Philadelphia College of
Pharmaceutical Sciences, the disclosure of which is expressly incorporated herein by reference.
[75] A topical vaginal composition or formulation, in accordance with the present invention, broadly comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the organic acids. In typical
formulations, the carrier for the active agent(s) would be a neutral medium. The amount of organic acid compound(s) in the composition is an amount which is safe and therapeutically effective and varies depending on the active ingredient(s), the nature of the composition, the medical condition being treated. Such an amount is determinable by a person of skill in the art. Such compositions and preparations can contain 0.1 percent or less of the active compound(s). The percentage of active compound(s) in these compositions may, of course, be varied and may conveniently be between about 0.1 percent to about 60 percent of the weight of the unit. For example, acetic acid preferably comprises about 0.1% to 10.0% by weight of the composition, more preferably 2.0-5.0% by weight of the composition. These compositions for topical vaginal administration are formed to yield a pH <5, preferably 2-3.5, still preferably 2-2.4; as is known in the art. Although, the composition is active, independent of pH, in the presence of blood or vaginal secretions, one particular advantage in combining two or more acids is that the pH of the composition may be readily adjusted to allow therapeutic amounts of each component while maintaining the pH at a level that is most effective for the treatment. The composition of the present invention may also be pH balanced by the addition of a base, such as triethanolamine or sodium hydroxide, to adjust the pH to a level compatible with the desired therapeutic pH value. In the normal vagina, the pH is approximately between 3.8 and 4.4. In order to prevent irritation of the vagina from a composition that is too acidic, the pH is adjusted to a point where the irritation is minimal or nonexistent, while still being effective in inducing cervical softening and ripening.
[76] The pharmaceutical compositions of the present invention comprise a compound(s) of the instant invention as an active ingredient or a pharmaceutically acceptable salt/ester thereof, and may also contain a pharmaceutically acceptable carrier or coatings and optionally other therapeutic ingredients to modify the physical form of the dosage unit. The compositions include different forms suitable for vaginal administration, although the most suitable form in any given case will depend in part on the condition of the patient being treated and on the nature of the active ingredient. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
[77] In practical use, the compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier constituents are to be neutral. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e. g., ovule, gels, or cream.
[78] In preparing the compositions for any dosage form, any of the usual pharmaceutical media may be employed, such as, for example, suspensions, and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of vaginal solid preparations such as, for example, powders, hard and soft tablets.
[79] Where the composition is applied as a suppository, the active ingredients are combined with inert suppository bases, depending on the nature of the suppository, such as cocoa butter, glycerinated gelatin, hydrogenated vegetables oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. Means of creating these suppository bases are known to those skilled in the art. The use of soluble or dispersible bases such as polyethylene glycols or glycol surfactant combinations has the substantial advantage of lack of dependence on melting point approximating body temperature. Moreover, handling, storage and shipping are considerably simplified.
[80] The preparation of such suppository compositions includes well known techniques of rolling (hand shaping), molding ' (fusion) and cold compression. Suppositories are usually globular or oviform and weigh about 5 gram.
[81] The composition may include a water soluble base. A water soluble base lowers the surface tension of the composition aiding in a more thorough distribution of the composition. A water soluble base also decreases the risk of secondary infection. Illustrative water soluble bases are corn starch, aloe, cocoa butter and the like.
[82] The compositions of the invention may include propylene glycol. Propylene glycol acts as a surfactant and assists in penetration, contact, and absorption of the
active ingredients. Propylene glycol also serves as a preservative and as a microbial agent.
[83] The compositions of the invention may also include a non-ionic surfactant, such as polysorbate. Such a surfactant provides better surface contact of the composition with the epithelium by further reducing surface tension.
[84] The compositions of the invention may also be used as a carrier material for and/or in combination with other medicines useful in cervical softening/ripening, such as prostaglandins and their analogues or nitric oxide donors, thereby further broadening the compositions medical efficacy.
[85] Because of their ease of administration, solid (tablet, ovule, pessary, suppository, and capsule) and semisolid (gel, cream, ointment, foam) forms represent the most advantageous vaginal form. The composition is preferably administered in the solid form of a suppository or a tablet although other dosage forms are also advantageously envisioned. Advantages to administering the composition as a solid form include convenience, ease of application, increased safety and neatness. The semisolid forms are preferred for ease of dispersion and lacking dissolution problems associated with the solid forms. Administering the composition as a cream having a low surface tension is advantageous as it provides a uniform wetting action that assists in composition penetration into cervical tissue. Other dosage forms include solutions and douches for douching and the like.
Providing the composition in the form of a solution, which may initially be provided in a concentrated liquid form, or as a dissolvable powder, tablet or the like requiring the addition of water, or other suitable diluents, prior to use, enables the composition to be administered as a vaginal douche. As a vaginal douche, the composition can also be used in non-pregnant females only.
ADMINISTRATION
[86] The compounds of the invention are administered vaginally. The pharmaceutical forms must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
[87] The compounds of the invention can be effective over a wide dosage range, depending on the condition, and the type of mammal. For example, in the treatment of adult humans, dosages from about 10 to about 1000 mg, about 100 to about 500 mg or about 1 to about 100 mg may be needed. Doses of the 0.05 to about 100 mg, and more preferably from about 0.00001 to about 100 mg, per day may be used. An appropriate amount or dose of the candidate compound may be determined empirically as is known by those skilled in the art. An appropriate or therapeutic amount is an amount sufficient to effect cervical softening/ripening over time. The candidate form can be administered as often as required to effect cervical softening/ripening, for example, every four, six, eight, twelve, or eighteen hours, or daily. In choosing a regimen for patients, the exact dosage and duration of treatment will depend on the therapy desired, form in which it is administered, the subject to be treated and the preference and experience of the physician or veterinarian in charge. While the precise regimen is left to the discretion of the clinician, it is recommended that the resulting formulation be vaginally applied one or two times a day.
[88] Compounds of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in cervical softening/ripening. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound is preferred. When used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds disclosed above.
EXAMPLES
[89] The present examples disclose the present invention in more detail. They are representative of the method and type of pharmaceutical preparations or
formulations in accordance with the principles of the invention and that are contemplated for vaginal application in inducing cervical softening/ripening. The following examples are provided by way of illustration only and not by way of limitation of the scope of the invention. Those of skill will readily recognize a variety of non-critical parameters which could be changed or modified to yield essentially similar results.
[90] EXAMPLE 1:
1) Purpose: To determine the effect of acidity on the uterine cervix in vitro.
2) Materials and Methods: The cervical tissues, taken from the hysterectomy specimens of five patients undergoing hysterectomy, were fixed in 10% formol saline for 10 days. Then, each cervix was cut transversely into small pieces of nearly equal thickness (4-5 mm). Six samples from each cervix were immersed into one of the following four solutions: 5% lactic acid, 3.5% lactic acid, 4% acetic acid, and 4% citric acid. Control specimens were immersed in distilled water. Samples from each group were then collected daily (from day 1 to day 6) from each solution, processed for preparation of paraffin sections (4-5 μm thick), and stained with either Mallory's triple stain for collagen fibers or haematoxylin and eosin stain.
3) Results: Histological examination of the control specimens revealed preservation of the collagen in dense bundles in-between cervical glands (G) (Fig.1) with the normal well organized, dense, and wavy arrangement of blue-dyed collagen fibrils
(Fig.2), which is the typical cervical collagen appearance in non-pregnant state. Histological examination of all of the specimens immersed in acids revealed collagen degradation that was subdivided into three grades: (1) Decreased density of the collagenous network: There is loosening of collagen bundles that appear less compact (Fig.3). Collagen fibers are decreased and loosely arranged, yet they are still organized regularly in bundles (Fig.4). (2) Decreased density and organization of the collagenous network: Destruction of collagen bundles is noticed with loss of their wavy arrangement. The collagen bundles appear much thinner, pale in staining in some areas, and separated by small clear empty spaces resulting from dissolution of some fibers. There is dissociation of the collagen fibers into their fibrillar components that appear broken and fragmented (Fig.5). (3) Marked decreased
density and organization of the collagenous network: There is marked destruction of collagen fibers, with fragmentation and separation of the collagen bundles. There is marked complete dissolution of great amount of collagen fibers leaving empty spaces, bounded by thin collagen fibers (Fig.6). The occurrence of these changes was time-related in different acidic solutions. The most marked effect was noticed to occur with 5% lactic acid solution, where grade 3 changes were observed 2 days after immersion. With 3.5% lactic acid and 4% acetic acid solutions, the changes started after one day and reached its maximum on the third day. With 4% citric acid solution, the changes started to be observed on the second day of immersion and reached its maximum on the fourth day.
[91] EXAMPLE 2
1) Purpose: To determine the effect of vaginal acidification, using acetic acid, on the cervix in human volunteers.
2) Materials and methods: A suitable formulation for a composition in the form of a vaginal tablet for inducing cervical softening/ripening is given as follows: Each vaginal tablet contains:
The vaginal tablet comprising the above formulation is prepared in accordance with well known techniques in the art. The disintegration rate of the tablet is 4.5 minutes. It is soluble in water totally in 25 minutes. These tablets were inserted vaginally twice
daily for 3 days postmenstrually in two human volunteers (regularly menstruating, muciparous women) scheduled for total abdominal hysterectomy operation. The subjects were asked to insert the moistened tablet high up in the vagina, and to lie in bed for few hours afterwards. From each patient, two biopsies were taken from the vaginal portion of the cervix. The first one was a punch biopsy taken before the beginning of treatment, and served as a control. The second biopsy was taken just after hysterectomy. All of the four specimens were fixed in 10% formol saline for 6 days. Then, they were processed for preparation of paraffin sections (4-5 μm thick) and stained with both Mallory's triple stain for collagen fibers or haematoxylin and eosin stain.
3) Results: Histological examination of a cervical punch biopsy taken prior to the start of therapy showed tightly packed collagen bundles in both of them (Refer to Fig.l and Fig.2). After hysterectomy, histological examination of cervical specimen in both of them revealed marked structural changes, consistent with those occurring in cervical ripening in pregnancy. The collagen fibers were markedly decreased, loosely arranged lying in-between cervical glands (G) (Fig.7). In other sections, the collagen fibers appeared destroyed, fragmented, and dispersed randomly with complete loss of orientation of the fibers (Fig.8 and Fig.9). Also, there was congested blood vessels (Fig.10) and mononuclear cellular infiltration of the cervical stroma (marked with an arrow in Fig.10 and highly magnified in Fig.11).
[92] EXAMPLE 3:
1) Purpose: To determine the effect of vaginal acidification using acetic acid, on cervical resistance during dilatation of the cervix in a human volunteer.
2) Method: The procedure of Example 2 was repeated except that these tablets were inserted vaginally twice daily for 5 days postmenstrually in one nulligravida human volunteer complaining of primary infertility and scheduled for laparoscopy combined with hysteroscopy. Initial assessment prior to the start of therapy revealed a normal uterus and a normal cervix with failure to pass a uterine sound (4 mm in diameter).
3) Results: By the end of therapy, reversed Hegar's dilators application method (prior to cervical dilatation during hysteroscopy) revealed easy passage of Hegar's 8 dilator (diameter: 8 mm). Histological examination of a cervical punch biopsy revealed marked structural changes. The collagen fibers appeared pale in staining, loosely arranged in some sections (Refer to Fig.5) or completely destroyed with marked increase in the extracellualr ground substance in other sections (Fig.12), being associated with mononuclear cellular infiltration of the cervical stroma (Refer to Fig.11).
[93] EXAMPLE 4
1) Purpose: To determine the effect of vaginal acidification, using acetic acid, on the degree of cervical ripening and progress of induced labor in pregnant human volunteers.
2) Materials and methods: Two pregnant females were included. The first was a 27 years old woman, with a previous normal delivery, vaginal examination at 38 weeks in her second pregnancy revealed a well- formed, and closed cervix, with cephalic presentation, station -2. The second was a 30 years old woman, para 1+1, with previous IUFD at 28 weeks, and midtrimesteric missed abortion due to anti- phospholipid (APL) syndrome. In the third pregnancy, the patient received low-dose aspirin and heparin therapy and managed to reach the 37th gestation week. By this time, vaginal examination showed a well- formed, and closed cervix, with cephalic presentation, station -1. Both women received acetic acid vaginal tablet - already described in example 2- once daily for 7 days. The subjects were asked to insert the moistened tablet high up in the vagina, and to lie in bed for few hours afterwards. Repeat vaginal examination was then done to assess the condition of the cervix.
3) Results: On repeat examination at 39 weeks in the first woman, the cervix was found to be 0.5 cm long and 3-cm dilated. Induction of labor was performed for social reasons. Artificial rupture of membranes (ARM) with immediate installation of IV syntocinon drip resulted in the occurrence of 4 strong contractions with delivery of the fetus within about 15 minutes only. There were neither postpartum nor postnatal complications. On repeat examination at 38 weeks in the second woman, the cervix was found to be 0.5 cm long and 4-cm dilated. Induction of labor
was performed. Artificial rupture of membranes (ARM) with immediate installation of IV syntocinon drip resulted in the delivery of the fetus within 30 minutes only. There were neither postpartum nor postnatal complications.
[94] EXAMPLE 5
1) Purpose: To determine the effect of vaginal acidification, using lactic acid, on cervical resistance during dilatation of the cervix in a human volunteer.
2) Materials and methods: A suitable formulation for a composition in the form of a vaginal lotion for inducing cervical softening/ripening is 5% lactic acid in oil in water emulsion. This lotion was inserted vaginally twice daily (3 ml) for 4 days postmenstrually in a human volunteer (regularly menstruating, nulliparous woman) scheduled for cervical dilatation. Initial assessment prior to the start of therapy revealed a normal uterus and a normal cervix with the uterine sound (4 mm in diameter) hardly passed through the cervix.
3) Results: By the end of therapy, reversed Hegar's dilators application method (prior to cervical dilatation) revealed easy passage of Hegar's 7 dilator (diameter: 7 mm).
[95] These results reveal an unexpected role for organic acid compounds in inducing cervical softening/ripening, and provide a framework to develop novel medicines for reducing cervical rigidity or inducing cervical softening/ripening. These medicines would include not only organic acid compounds, analogues, homologues, and derivatives thereof, but also agents which control vaginal organic acid levels by acting upon their formation and release herein.
[96] Although the foregoing invention has been described in some detail by way of illustration and example and in terms of specific embodiments and applications for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention which is defined by appended claims. Accordingly, it is to be understood that the figures and descriptions in this disclosure are proffered to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Claims
[1] A method for preventing cervical rigidity and/or inducing softening and ripening of the uterine cervix in a mammal in need thereof, said method comprising the step of administering a vaginal pharmaceutical composition comprising a therapeutically effective amount of active ingredient(s) and a pharmaceutically acceptable carrier to said mammal, said active ingredient(s) being an organic acid compound(s), said organic acid compound(s) being provided over sufficient time to lower the pH of the vagina of said mammal, said lowering of vaginal pH induces softening and ripening of the cervix of said mammal.
[2] The pharmaceutical combination of claim 1, wherein said organic acid compound is selected from the group including (but not limited to) acetic acid, glycolic acid, priopionic acid, lactic acid, pyruvic acid, butyric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, hydroxybenzoic acid, para-aminobenzoic acid, citric acid, mandelic acid, malonic acid, oxalic acid, salicylic acid, succinic acid, cinnamic, adipic acid, tartaric acid, ascorbic acid, retionic acid, glucuronic acid, iduronic acid, hyaluronic acid, nicotinic acid, pentanoic acid, amino acids as valeric acid and arginine, fatty acids as oleic, linoleic, linolenic and arachidonic, and the like and combinations thereof.
[3] The method according to claim 1, wherein the organic acid compound is supplied as a free organic acid or as a prodrug, being produced or released through a chemical process or biological means.
[4] The method according to claims 1 to 3, wherein the acidifying agent is organic acid, a carboxylic acid containing the functional group COOH.
[5] The method according to claims 1 to 3, wherein the organic acid is monocarboxylic or polycarboxylic (mono- or polybasic acid).
[6] The method according to claims 1 to 3, wherein the organic acid structure is aliphatic (straight chained, acyclic), ring chain (cyclic), heterocyclic (aliphatic ring
structure, but including at least one atom which is not carbon), or aromatic (containing a benzene ring).
[7] The method according to claims 1 to 3, wherein organic acid structure has a branched chain of carbon atoms.
[8] The method according to claims 1 to 3, wherein organic acid structure is saturated, monounsaturated or polyunsaturated.
[9] The method according to claims 1 to 3, wherein organic acid structure has an attached alkyl group.
[10] The method according to claims 1 to 3, wherein organic acid structure has an attached aryl group.
[11] The method according to claims 1 to 3, wherein the organic acid structure is in the anhydride form.
[12] The method according to claims 1 to 3, wherein the organic acid structure is in the halogenated (acylated) form.
[13] The method according to claims 1 to 3, wherein the organic acid structure is in the oxy- or polyoxy-acid form (contains one or more hydroxyl group).
[14] The method according to claims 1 to 3, wherein the organic acid structure is in the keto-acid form (contains a ketone group).
[15] The method according to claims 1 to 3, wherein the organic acid structure is in the aldehyde-acid form (contains an aldehyde group).
[16] The method according to claims 1 to 3, wherein the organic acid structure contains one or more amino group.
[17] The method according to claims 1 to 3, wherein the organic acid structure contains one or more imino group.
[18] The method according to claims 1 to 3, wherein the organic acid structure contains one or more sulfur atom.
[19] The method according to claims 1 to 3, wherein the organic acid structure is a sugar acid.
[20] The method according to claims 1 to 3, wherein the organic acid moiety is a structural isomer or stereoisomer; whether geometrical (trans- or cis-) or optical (D or L) isomer.
[21] The method according to claims 1 to 3, wherein the organic acid moiety is radiolabeled.
[22] The method according to claims 1 to 3, wherein the organic acid moiety is in an ester form.
[23] The method according to claims 1 to 3, wherein the organic acid moiety is in a salt form.
[24] The method according to claim 1, wherein the composition comprises a pharmaceutically acceptable excipient.
[25] The method according to claim 24, wherein the excipient is selected from the group consisting of stabilizers, surfactants, solvents, preservatives, pH regulators, softeners, colorants and combinations thereof.
[26] The method according to claim 1 , wherein the mammal is human.
[27] The method according to claim 1 wherein the composition is administered in a form selected from the group consisting of a vaginal pessary, suppository, ovule, capsule, tablet, cream, ointment, gel, foam, lotion, douche, and solution whether supplied in ready-made or dissolvable powder or tablet form.
[28] The method according to claim 1, wherein the amount of the organic acid compound(s) represents in the range of about 0.1 wt. % to about 50 wt. % of the composition.
[29] The method according to claim 1, wherein the amount of the organic acid compound(s) represents in the range of about 0.1 wt. % to about 30 wt. % of the composition.
[30] The method according to claim 1, wherein the amount of the organic acid comρound(s) represents in the range of about 0.1 wt. % to about 10 wt. % of the composition.
[31] The method according to claims 1 to 3, wherein the pharmaceutical composition include the comρound(s) of the invention in combination with other drugs that may also be useful in cervical softening/ripening, whether sequentially or contemporaneously, in the latter case a pharmaceutical composition in unit dosage form containing such other drugs and the compound is preferred.
[32] The method according to claim 1, wherein the composition comprises an additional active agent.
[33] The method according to claim 32, wherein the additional active agent is selected from the group consisting of prostaglandins compounds, prostaglandin derivatives or analogues, nitric acid donors, cytokines, and combinations thereof.
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102010015350A1 (en) | 2010-04-16 | 2011-10-20 | Michael Zimmermann | vaginal applicator |
WO2011156812A3 (en) * | 2010-06-11 | 2012-04-19 | Controlled Therapeutics (Scotland) Ltd. | Intravaginal administration of misoprostol |
ITMI20120757A1 (en) * | 2012-05-07 | 2013-11-08 | Berardino Luigi Di | POST COITAL VAGINAL WASHING SYSTEM |
US20150174139A1 (en) * | 2012-07-26 | 2015-06-25 | Ferring B.V. | Misoprostol Composition |
US20150238414A1 (en) * | 2012-07-26 | 2015-08-27 | Ferring B.V. | Misoprostol Formulation |
US10105445B2 (en) | 2006-07-05 | 2018-10-23 | Ferring B.V. | Hydrophilic polyurethane compositions |
US20200030365A1 (en) * | 2013-11-26 | 2020-01-30 | Fidia Farmaceutici S.P.A. | Pharmaceutical compositions with hydrating and lubricating activity |
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EP0380036A2 (en) * | 1989-01-23 | 1990-08-01 | Kanebo Ltd. | Vaginal suppository |
JPH04193831A (en) * | 1990-11-22 | 1992-07-13 | Kanebo Ltd | Pessary |
WO1996028145A1 (en) * | 1995-03-14 | 1996-09-19 | Schering Aktiengesellschaft | Use of nitric oxide donors or nitric oxide inhibitors for regulating cervical dilatation and extensibility |
EP0867452A1 (en) * | 1996-10-15 | 1998-09-30 | Toray Industries, Inc. | Cervical canal maturing agent |
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EP0380036A2 (en) * | 1989-01-23 | 1990-08-01 | Kanebo Ltd. | Vaginal suppository |
JPH04193831A (en) * | 1990-11-22 | 1992-07-13 | Kanebo Ltd | Pessary |
WO1996028145A1 (en) * | 1995-03-14 | 1996-09-19 | Schering Aktiengesellschaft | Use of nitric oxide donors or nitric oxide inhibitors for regulating cervical dilatation and extensibility |
EP0867452A1 (en) * | 1996-10-15 | 1998-09-30 | Toray Industries, Inc. | Cervical canal maturing agent |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
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US10105445B2 (en) | 2006-07-05 | 2018-10-23 | Ferring B.V. | Hydrophilic polyurethane compositions |
EP2389940A2 (en) | 2010-04-16 | 2011-11-30 | Michael Zimmermann | Vaginal applicator with two openings |
EP2389940A3 (en) * | 2010-04-16 | 2012-01-18 | Michael Zimmermann | Vaginal applicator with two openings |
DE102010015350A1 (en) | 2010-04-16 | 2011-10-20 | Michael Zimmermann | vaginal applicator |
JP2016164167A (en) * | 2010-06-11 | 2016-09-08 | フェリング ベスローテン フェンノートシャップ | Intravaginal administration of misoprostol |
WO2011156812A3 (en) * | 2010-06-11 | 2012-04-19 | Controlled Therapeutics (Scotland) Ltd. | Intravaginal administration of misoprostol |
JP2013528231A (en) * | 2010-06-11 | 2013-07-08 | フェリング ベスローテン フェンノートシャップ | Intravaginal administration of misoprostol |
ITMI20120757A1 (en) * | 2012-05-07 | 2013-11-08 | Berardino Luigi Di | POST COITAL VAGINAL WASHING SYSTEM |
US20150174139A1 (en) * | 2012-07-26 | 2015-06-25 | Ferring B.V. | Misoprostol Composition |
US20170112854A1 (en) * | 2012-07-26 | 2017-04-27 | Ferring B.V. | Misoprostol Composition |
US20150238414A1 (en) * | 2012-07-26 | 2015-08-27 | Ferring B.V. | Misoprostol Formulation |
US20200030365A1 (en) * | 2013-11-26 | 2020-01-30 | Fidia Farmaceutici S.P.A. | Pharmaceutical compositions with hydrating and lubricating activity |
US11197886B2 (en) * | 2013-11-26 | 2021-12-14 | Fidia Farmaceutici S.P.A. | Pharmaceutical compositions with hydrating and lubricating activity |
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