RU2177789C2 - Drug favoring ripening of cervix of the uterus, method for accelerating ripening of cervix of the uterus, and device for transportation of drug to the cervix of the uterus - Google Patents

Abstract

FIELD: obstetrics and gynecology. SUBSTANCE: sodium hyaluronate is used as agent favoring ripening of cervix of the uterus in cases of induction of delivery and abortion caused by different indications. In particular, vaginal portion of cervix is at least once treated by the drug for 3 to 8 h. Drug-transportation device comprises a mechanical carrier and drug with sodium hyaluronate as active principle. EFFECT: reduced probability of complications. 10 cl, 3 ex

Description

 The invention relates to medicine, in particular to obstetrics and gynecology, and can be used in the induction of labor and termination of pregnancy for various reasons.

 Currently, drugs that promote cervical ripening are used to induce labor and terminate pregnancy. These are prostaglandins, estrogens, oxytocin, relaxin / Guide to effective care during pregnancy and childbirth. M. Enkin, M. Keyrs, M. Renfrew, D. Neilson. // Ed. E. Enkin. SPB - 1999, pp. 389-397 / and other less common - interleukins and dehydroepiandrosterones.

Among prostagdandin preparations, Dinoprostone (PGE ₂ ) or Dinoprost (PGF _2α ) should be noted, which contribute to the maturation and opening of the cervix, as well as increase the tone and contractile activity of the myometrium / VIDAL Reference Book. Medicines in Russia: A Handbook. M.: AstraPharmService, 1998, p. E-73 /.

 However, there are a number of reasons, and first of all, economic (high cost of drugs), for which the mentioned drugs have not been widely used in medical practice, although the need for them or similar drugs is very high.

 The problem solved by the present invention is to expand the arsenal of tools that provide the ability to accelerate the maturation of the cervix by using a new tool according to a certain technique, including using a set of special devices for its delivery to the destination.

 The technical result is to reduce the likelihood of complications during the induction of labor and termination of pregnancy for various reasons.

To solve this problem, it is proposed to use the sodium salt of hyaluronic acid - sodium hyaluronate as a means of promoting the maturation of the cervix. The empirical formula is [(C ₁₄ H ₂₀ NO ₁₁ ) Na] _n , where n = 1000-3750; molecular weight 400000-1500000 daltons; the content of the main active substance is not less than 97%.

 Hyaluronic acid is a naturally occurring linear polysaccharide that is part of the extracellular basic substance of the connective tissue of vertebrates. It is contained in the vitreous body of the eye, umbilical cord, articular fluid, etc. Hyaluronic acid in the tissues of the body almost immediately takes part in complex, including insufficiently studied, physiological processes, for example, on the first day of normal healing of uncomplicated wounds, in the latter there is increased concentration hyaluronic acid / Goa KI, Benfield R. Hyaluronic acid. A review of its pharmacology and use as a surgical aid in ophtalmology and its therapeutic potential in joint disease and wound healing. // Drugs. - 1994. - V. 47, 3. - p. 536-566 /.

 It should be noted that in the body hyaluronic acid exists in the form of its sodium salt - sodium hyaluronate.

 In medical practice, preparations based on hyaluronic acid have found application as prolongators of the action of traditional drugs to increase the absorption of drugs by body tissues, as well as in the field of viscous surgery, viscous filling and wound healing / Prestwich GD, Vercruysse K. R. Therapeutic application of hyaluronic acid and hyaluronan derivatives. // PSTT. - 1998. - V. 1, 1. - p. 42-43 /.

 In domestic medical practice, the drug Healon was widely used, in particular, for topical use in ophthalmology, the active principle of which is sodium hyaluronate / VIDAL Handbook. Medicines in Russia: A Handbook. M.: AstraPharmService, 1998, p. B-736 /. The use of sodium hyaluronate as a means of promoting maturation of the cervix is unknown to the authors.

 There are various methods of induction of labor and surgical delivery / Guide to effective care during pregnancy and childbirth. M. Enkin, M. Keyrs, M. Renfew, D. Neilson. // Ed. E. Enkin. SPB - 1999, pp. 389-397 /, the elements of which are an assessment of the condition of the cervix and the introduction of drugs into the body that affect the connective tissue of the neck. As a means of promoting the maturation of the cervix, prostaglandins (with various options for the introduction into the body), estrogens, oxytocin, mechanical devices or relaxin are used. In addition, the acceleration of cervical maturation can be achieved by stimulating the mammary gland.

Of all the methods, the use of prostaglandins is considered the most promising. In domestic practice, prostaglandin preparations are used for these purposes: Dinoprost (PGF _2α ) - intraamnial or intravenous drip, Dinoproston (PGF ₂ ) - oral or intravenous administration and in the form of a vaginal gel for insertion into the posterior vaginal fornix.

 A method of accelerating cervical ripening using prostaglandins has medical contraindications - this is, first of all, hypersensitivity to these drugs, which cause nausea, vomiting, hyperactivity and hypertonicity of the uterus, etc. In addition, the high cost of drugs limits the widespread use of the said method in practice.

A known method of accelerating childbirth in women with pathology of contractile function of the uterus, including the introduction into the body of an agent that affects the connective tissue of the cervix and promotes its maturation (in this case, estrogen) in addition to a complex of pharmacological agents that combine antispasmodic, analgesic and psychoenergetic effects / Description of the invention to the patent of the Russian Federation 2108756, IPC ⁶ A 61 B 17/42, publ. 04/20/98 Bul. eleven/.

 To use the known method, a sufficiently accurate and complex diagnosis of the state of the woman in labor is required in order to prescribe a course of treatment that is characteristic only for this patient. In addition, clinical trials of various estrogen preparations did not reveal their beneficial effect on the cervical maturation process (see the Guide for Effective Care during Pregnancy and Childbirth - p. 393). All this speaks of the problematic use of the known method in practice.

 The problem solved by the present invention is to create a simple and affordable way to accelerate the maturation of the cervix.

 The technical result is to reduce the likelihood of complications during the induction of labor and termination of pregnancy for various reasons.

 To solve the problem in a method of accelerating the maturation of the cervix, including the introduction into the body of an agent that acts on the connective tissue of the cervix, sodium hyaluronic acid is used as such by at least once treating the vaginal part of the cervix with it for 3-8 hours.

Besides:
- treatment of the vaginal part of the cervix provide it with application and / or intravaginal administration of the drug;
- additionally, a prostaglandin preparation PGE ₂ or PGE _2α is introduced into the body in a ratio of 1: 0.1-1.0 separately or in the form of a composition.

 Known swab for stopping or preventing uterine bleeding, made of a polyurethane foam impregnated with hemostatic, vasoconstrictor or uterine drugs / Description of the invention a. from. USSR 192344, IPC A 61 M 29/00, publ. 04/11/67, Bull. 5/.

 The scope of the swab is limited to the prevention or stopping of uterine bleeding. Its use for delivery to the cervix of drugs that contribute to its maturation is not provided for by the purpose of the invention.

 Known intrauterine device made in the form of a frame made of hydrophobic highly elastic polymer containing hydrophilic inclusions from polymerizable grafted compounds, including various actively active water-soluble substances, for example prostaglandins / Description of the invention to the USSR patent 656471, MKl. A 61 F 13/20, publ. 04/05/79. Bull. thirteen/.

 The scope of the intrauterine device is limited to use as a means to prevent pregnancy, including when prostaglandin is used as the active substance.

A device for delivering a drug to the cervix (cervical diaphragm) is known, containing a sterile mechanical carrier, on the inner surface of which there is a layer of drug substance / Description of the invention to RF patent 2033120, IPC ⁶ A 61 F 06/10, publ. 04/20/95. Bull. eleven/.

 The potential capabilities of the known device are very wide. However, its use for delivery to the cervix of drugs that contribute to its maturation is only implied as one of the many possible uses of the invention. In addition, with this design of the diaphragm, there is a high probability of penetration of drugs into the cervical canal under pressure, and this in some cases is fraught with complications for the fetus during the induction of labor.

 The problem solved by this invention is to expand the range of devices for delivery to the cervix of the drug, contributing to its maturation.

 The technical result will be the creation of a device that minimizes the likelihood of complications during the induction of labor and termination of pregnancy for various reasons.

 To solve the problem in a device for delivering a drug to the cervix, including a mechanical carrier and a drug with an active principle, the latter is made in the form of the sodium salt of hyaluronic acid.

Besides:
- the carrier is made in the form of an elastic cap or tampon reinforced with an elastic cap;
- the carrier is equipped with a flexible bond, made in the form of a sterile or processed with antiseptic substance threads;
- the carrier is made in the form of a syringe tube;
- the carrier is in the form of a capsule with a soluble shell or suppository, or tablet;
- the drug includes a preparation of prostaglandin PGE ₂ or PGE _2α .
We illustrate the possibility of implementing inventions.

 The use of hyaluronic acid in the form of its most stable form, sodium hyaluronate for its new purpose, was, among other useful qualities, its ability to bind interstitial water in intercellular spaces due to its high hydrophilicity, as a result of which the resistance of tissues to compression increases sharply. In practice, this looks like the acquisition of superelasticity by the tissues of the body. For example, the presence of hyaluronic acid in the synovial fluid determines its high structural viscosity, which allows the joints to withstand significant mechanical stress.

 It has been experimentally established that one of the mechanisms by which prostaglandins realize their effects is the accumulation of hyaluronic acid in the tissues of the cervix / Rath W., Osmers R., Adelmann-Grill BC, Stuhlsatz HW, Szevereny M., Kuhn W. Biohemical changes in human cervical application of prostaglandin E2. // Prostaglandins 1993. - Vol. 45, pp. 375-384 /.

 To increase the concentration of hyaluronic acid in the cervix, the natural ability of its sodium salt to penetrate deep into the tissues with external use was used. Compared with artificial stimulation of the body to synthesize its own acid, this method of increasing the concentration is the most acceptable and preferred. The only contraindication to the use of sodium hyaluronate can only be an allergic reaction of the body to the protein that is part of the drug. For example, if the drug was obtained from cocks, then when prescribing it, one should proceed from the individual tolerance of poultry meat, eggs by patients, as well as from the absence of allergy to chicken fluff, etc.

 A method of accelerating cervical ripening during induction of labor and vaginal delivery or termination of pregnancy for various indications includes exposure to its connective tissue with sodium salt of hyaluronic acid by at least once treating the vaginal part of the cervix with it for 3-8 hours. The ability of the sodium salt of hyaluronic acid to bind water (solvent) is very high. For this reason, its 2% solution is used as a medicine, for the preparation of a standard dose of 1-2 ml, 20-40 mg of dry matter is required. The drug, penetrating the neck tissue, initiates the process of its maturation. It is very important that the treatment of the fetal membrane and the fetus itself does not occur. It is for this reason that the vaginal part of the cervix is processed, but not the cervical canal, and especially not the internal pharynx of the cervix.

 The desired effect is ensured by the application of the cervix uteri with sodium hyaluronate or its intravaginal administration by using a special device that has various options for implementation and which includes a mechanical carrier made in the form of an elastic cap, for example rubber, on the inside of which a layer of the drug is applied, the active principle of which is made in in the form of sodium salt of hyaluronic acid. Thus, the directed action of the drug is ensured.

 In addition, the application can be provided with a swab impregnated with sodium hyaluronate. In this case, processing takes place on only the cervix, but also on the vagina, the muscles of which also acquire superelasticity.

 If the tampon is reinforced with an elastic cap, then it will be possible to avoid saturation with the drug, in addition to the neck, surrounding tissues. In its effect, such a device will be similar to a cap, except that the tampon transfers the drug to the tissues for a longer time.

 The installation of these devices is carried out traditionally - by the doctor, or, which is permissible in some cases, by the patient independently. For more convenient removal of the device, the mechanical carrier may be provided with a flexible connection, for example a specially processed thread, such as feminine hygienic tampons Tampax or O. b.

 In cases where the drug is in the form of a gel, it is recommended that the mechanical carrier be in the form of a syringe-tube or capsule with a membrane soluble under the action of the vaginal microflora.

 In addition to these cases, the drug carrier can be made in the form of a certain form of suppository, for example, made on the basis of cocoa butter or in the form of a vaginal tablet.

Pharmacological enterprises have mastered the production of dosage forms of this type. An example is Pharmatex - vaginal tampons, Prostin E ₂ - vaginal gel in syringes, Polygynax - vaginal capsules, Contracetin T - vaginal suppositories, Klion-D and Prostin E ₂ - vaginal tablets, etc. / VIDAL Handbook. Medicines in Russia: A Handbook. M.: AstraPharmService, 1997, ss. B-615, B-468, B-453, B-279, B-269 and other editions of this reference book.

 Each of the above devices has its own advantages. Thus, taking into account the individual physiological characteristics of the patients, as well as sexual experience and the presence of children, it is possible to recommend a device of a specific design for the delivery of sodium hyaluronate to the cervix. For example, the application of a swab can be shown to a nulliparous woman, which will ensure the elasticity of not only the neck, but also the vagina. Women who have given birth can be shown any of the above devices. Women with deviations from normal physiology may be shown targeted action of the drug or some other options.

 In some cases, a single treatment may not be enough, so the doctor may decide on the additional exposure of the drug to the organ, including through the use of a combination of devices, such as a tampon plus a cap, etc.

 A sufficiently large selection of devices for delivering the drug to the cervix allows to optimize their cost, when the potential use of several types of devices can be stopped at the most affordable price. This differentiation in cost of various versions of the device allows you to make the drug more accessible to the general population.

Sodium hyaluronate can be introduced into the body either separately or in the form of compositions (mixtures) with other medicinal substances, for example, prostaglandin preparations PGE ₂ or PGE _2α . In this case, as the cervix ripens, the contractile activity of the uterus increases, which further stimulates the expulsion of the fetus. In addition to the fact that the positive effect of the use of both drugs is summarized, they require a significantly smaller amount compared to a single application, including due to the fact that sodium hyaluronate helps to prolong the action of other drugs.

 Consider examples of the use of inventions.

 Example 1. Ch. A. N. 18 years old, the first pregnant, primiparous. Sent to the gynecological department for termination of pregnancy for social reasons.

 Somatically healthy.

 Menses from 12 years, 5 days, after 28 days, moderate, painless. Pregnancy is 19-20 weeks.

 Upon admission, vaginal examination data: vaginal nulliparous, cervix posterior, 4 cm long, dense throughout. The external pharynx is closed.

 Diagnosis: 20 weeks pregnancy. Termination of pregnancy for social reasons.

 Hormonal background started: Sinestrol solution 2% - 0.2 ml intramuscularly after 12 hours. In order to prepare the cervix, a tampon with 1 ml of a 2% sodium hyaluronate solution was brought to its vaginal part. After 6 hours, the tampon was removed by the patient on her own.

 In the morning, a vaginal examination: the cervix in the center 4 cm long is softened by 1/3. The external pharynx passes the tip of the examining finger.

 A day later, a swab with 1 ml of a 2% sodium hyaluronate solution was reconnected to the cervix for 6 hours.

 In the morning, vaginal examination data: the cervix in the center, 3 cm long, is completely softened, the canal passes for one transverse finger beyond the internal pharynx. The fetal bladder is intact.

 The next day, intraemnional administration of a 10% sodium chloride solution was made. After 6 hours, independent labor activity developed and after 9 hours, a miscarriage occurred.

 Discharged on the 6th day.

 Example 2. E. N. A. 23 years old, the first pregnant, primiparous.

 Sent to the department of pathology of pregnant women for treatment and preparation for childbirth. The gestational age is 37-38 weeks. The course of pregnancy was complicated by pathological weight gain in terms of 32-34 and 37 weeks. Mild proteinuria was noted. Blood pressure level 140/90 mm RT. Art.

 Vaginal examination data: vaginal nulliparous. The cervix in the center, 3 cm long, is dense throughout. The external pharynx passes the tip of the examining finger. The internal pharynx is closed. Through the arches is determined by the head. Cape is not reached. There are no exastoses in the pelvis.

 Diagnosis: pregnancy 37-38 weeks. Late toxicosis of pregnant women. Nephropathy 1-2 degrees. Immature cervix.

 Gestosis is being treated. In order to prepare the cervix for childbirth, a hormonal background was prescribed: Sinestrol 2% - 0.2 ml intramuscularly, papaverine - 2% - 2 ml intramuscularly after 12 hours 5.

 After 5 days of treatment, the data of the vaginal examination are the same.

 It was decided to use a solution of sodium hyaluronate. A swab with 1 ml of a 2% solution is brought to the vaginal part of the cervix. After 6 hours, the tampon was removed by the pregnant woman on her own.

 The next day, the pregnant woman's condition worsened: proteinuria was observed up to 1 g / l, A / D level up to 150/100 mm RT. Art. Given the increasing severity of gestosis, it was decided to produce premature birth by prenatal amniotomy.

 With vaginal examination: the cervix is shortened to 2 cm, completely softened, the channel is freely passable for 1 transverse finger for the internal pharynx. The fetal bladder is intact. Slated to be head, pressed to the entrance to the small pelvis. Cape is not reached. An amniotomy was performed - 150 ml of clear water was poured. Next, delivery is prescribed by intravenous drip of 0.5 mg enzaprost with 6 drops in 1 minute. Against the background of the introduction of the drug, effective generic activity has developed. The total duration of labor is 9 hours. A boy was born with a body weight of 3150 g. An Apgar score of 8–9 points. Discharged on the 7th day after the normalization of hemodynamic parameters.

 Example 3. V. N. G. 29 years old, re-pregnant, primiparous. Sent to the department of pathology of pregnant women to prepare for childbirth. The gestational age is 39-40 weeks. The dimensions of the pelvis are 23-27-30-18.

 A history of 1 spontaneous miscarriage during pregnancy is 9 weeks, followed by curettage of the uterine cavity.

 Vaginal examination data: vagina of a nulliparous woman. The cervix is located in the center, 3 cm long, dense throughout. The external pharynx is closed. Through the arches is determined by the head. Cape is not achieved, bone pelvis without pathology.

 Diagnosis: pregnancy 39-40 weeks. Uniformly narrowed pelvis of the 1st degree of narrowing. Immature cervix.

 A course of harmonious preparation was held. Sinestrol 2% solution of 0.2 ml intramuscularly after 12 hours 5. No effect. The cervix was prepared by bringing to the vaginal part of the neck of the swab with 1 ml of 2% sodium hyaluronate solution. The tampon is removed after 6 hours.

 The data of the vaginal examination the next day. The cervix is shortened to 2 cm, soft to the internal pharynx. The cervical canal pass for 1 transverse finger for the internal pharynx. In view of the prolongation of pregnancy, it was decided to perform birth by prenatal amniotomy.

 After an amniotomy, an independent labor activity developed after 2 hours. About the threat of rupture of the perineum - episiotomy. A girl was born with a body weight of 3300 g. An Apgar score of 7-8 points. The duration of labor is 11 hours. Blood loss 250 ml. The postpartum period in the mother and the neonatal period in the newborn proceeded without complications. Discharged home on the 6th day.

 The domestic industry has widely mastered the production of sodium hyaluronate, the raw materials for which are cocks and bull eyes. The presence of various forms of implementation of a device for delivering this drug to the cervix suggests that medical institutions and practitioners will receive a drug that is so necessary for practical health care, the use of which will reduce the risk of complications during the induction of labor and termination of pregnancy for various reasons.

Claims (10)

 1. The use of sodium salt of hyaluronic acid as a means of promoting maturation of the cervix.  2. A method of accelerating the maturation of the cervix, comprising introducing into the body an agent acting on the connective tissue of the cervix, characterized in that the sodium salt of hyaluronic acid is used as an agent acting on the connective tissue of the cervix by at least one treatment of the vaginal part with it cervix for 3-8 hours  3. The method according to p. 2, characterized in that the treatment of the vaginal part of the cervix is provided by its application and / or intravaginal administration of the agent. 4. The method according to p. 2 or 3, characterized in that the prostaglandin drug PGE ₂ or PGE _2α is additionally introduced into the body in a ratio of 1: 0.1-1.0 separately or in the form of a composition.  5. A device for delivering a drug to the cervix, including a sterile mechanical carrier and a drug with an active principle, characterized in that the active principle of the drug is made in the form of the sodium salt of hyaluronic acid.  6. The device according to p. 5, characterized in that the carrier is made in the form of an elastic cap or tampon reinforced with an elastic cap.  7. The device according to p. 5, characterized in that the carrier is equipped with a flexible bond, made in the form of a sterile or processed with antiseptic substance threads.  8. The device according to p. 5, characterized in that the carrier is made in the form of a syringe tube.  9. The device according to p. 5, characterized in that the carrier is in the form of a capsule with a soluble shell, or suppository, or tablet. 10. The device according to any one of paragraphs. 5-9, characterized in that the drug further comprises a prostaglandin drug PGE ₂ or PGE _2α .