DE102012009057A1 - Rotational pessary made from a polymer comprises an active substance against premature births - Google Patents

Abstract

Rotational pessary (20) made from a polymer comprises at least one active substance against premature births.

Description

Every year, 13 million children are born prematurely worldwide, of which approximately 1 million die as a result of preterm birth and many survive with severe disabilities. The object of this invention is the further development of a rotational pessary which, in addition to the previously known effect, can prevent premature births even more efficiently.

excipient

In gynecological patients pessaries and vaginal rings are used for a long time, which are provided with pharmaceutical agents. These include pessaries, which secrete daily a small amount of progestogens and estrogens, which are either as contraception or as substitution therapy - for example, after the removal of the ovaries because of a carcinoma - are thought. Such an application is z. B. in the DE10151365A1 described. In contrast to the innovation submitted here, these pessaries have only the function of a drug carrier.

EP1646378B1 describes the use of ascorbic acid or a physiologically acceptable salt thereof for the preparation of a formulation for topical application for the prevention and treatment of vaginal fungal infections, e.g. A pessary, which is provided in a delayed melt application form for the release of active principle.

EP1478352B1 describes a process in which a copolymer is processed in combination with pharmaceutically customary additives into moldings and therein a pharmaceutical active substance such as from the class of antibiotics, antirheumatics, antiallergic drugs, chemotherapeutic lipid-lowering agents, urologics, etc, is included. The application is carried out as a transdermal therapy system z. In the form of suppositories, vaginalia or implants.

The applications described have in common that they allow only a short to medium term delivery of the active ingredients. The applications described are not comparable with the subject invention, since even with vaginal application of drug carriers is quickly replaced by the user.

EP1620060B1 describes processes and thermoplastic materials that can be used to release drugs with a delay. The application for progesterone, z. In contraception and hormone replacement therapy. In the EP1620060B1 Although the delayed release of the active ingredients is provided, there are no indications of an application in a shaped body which is comparable to the subject invention.

EP1317304B1 describes a pharmaceutical implant for the sustained release of drugs over a longer period of at least 3 months. The active ingredients are enclosed in microcapsules in biodegradable polymers, optionally the microcapsules are also pressed into tablets. Also, the applications described in this publication have the disadvantages described above, namely an irregular supply by the patients themselves, which may be limited by the compliance.

Prevention of premature birth

A summary of pessary therapy for preventing preterm birth is included Dharan VB and Ludmir J: Alternative Treatment for a Short Cervix: The Cervical Pessary (Semin Perinatol 2009; 33: 338-42) ,

As a support pessary used in pregnancy, the pessary according to Hamann, which has never been tested in randomized trials and in which no rotation of the cervix was detected. This pessary is among others on the website http://www.viomed.de/de/cerclagepessar_hamann and the application is described as follows: "In the sense of" bloodless cerclage "the cerclage & supporting pessary curbs the pressure on the cervix in case of cervical insufficiency. The pessary is made of a physiologically harmless elastomer. "

The mechanism of action of arabin pessary, found at www.drarabin.de, is not based solely on the fact that the cervical canal is closed. The cervix uteri is picked up from the central opening in the pessary and turned backwards. The rotation and broad support of the pessary on the pelvic floor relieve the cervix. The intrauterine pressure on the uterine anterior wall is displaced as a result of dorsoventral pessary obliquity and sacrum position of the uterine cervix. The application is also described in Arabin B et al .: Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? (J Perinat Med 2003; 31: 122-133) ,

The term rotational pessary is understood below to mean any pessary that exhibits the effect named here.

First, evidence level III studies have shown that treatment with the arabin pessary reduces the number of premature births in critically pregnant pregnancies in both single and multiple pregnancies can be significantly reduced: Quaas L et al: The Arabin Cerclage Pessary-to alternative to surgery (Geburtsh Frauenheilk 1990; 50: 429-33) ; Arabin B et al: Is treatment with vaginal pessaries option in patients with a sonographically detected short cervix (J Perinat Med 2003; 31: 122-133) . Archayra G et al: Noninvasive cerclage for the management of cervical incompetence: a prospective study (Arch. Gynecol. Obstet 2006; 273: 283-287) ,

Up to now, only the Arabin pessary has been able to show that the latest nuclear spider recordings showed that the cervix rotates sacrally after treatment and in many cases even becomes longer ( Jani J et al , not yet published).

For the first time ever, however, a prospective randomized study (evidence level I) has succeeded in demonstrating the effect of arabin pessary on a drastic reduction in prematurity, with a clear improvement in the outcome of the children, namely Goya et al: Cervical pessary in pregnant women with a short cervix (PECEP): open-label randomized controlled trial (www.thelancet.com, published online April, 3, 2012) ,

Regardless of the studies on the effects of pessaries in the prevention of premature birth, it has previously been reported that treatment with progesterone, the most important of the luteal hormones produced in the corpus luteum, may reduce premature birth in patients with premature cervical shortening ,

In early pregnancy, the effect of progesterone is to prepare the lining of the uterus to receive the fertilized egg and to help maintain the pregnancy. This effect of treatment with progesterone is described in a variety of papers, summarized at Wahabi HA et al .: Progestogen in treating threatened miscarriage (Review). (Cochrane Collaboration, The Cochrane Libary 2011: Issue 12) ,

In advanced pregnancy, however, premature shortening of the cervix may occur with cervical tissue loosening and disorganization of the collagenous connective tissue of the cervix. This tissue remodeling can be prevented, if not completely prevented, by the addition of progesterone. In addition, the progesterone should have an antiphlogistic effect.

There are several studies from the past years to date that demonstrate the early-birth-prevention effect of progesterone in clinical trials. Here are just the most important to be listed: Fonseca EB et al: Progesterone and the risk of preterm birth among women with a short cervix (New Engl J Med 2007; 377: 462-9) ; Romero R: Prevention of spontaneous preterm birth: the role of cervical length in identifying patients who may benefit from progesterone treatment (Ultrasound Obstet Gynecol 2007; 30: 675-686) ; Hassan SS et al: Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial (Ultrasound Obstet Gynecol 2011, 38: 18-31) , also published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002 / uog.9017 and Romero R et al: Vaginal progesterone in women with asymptomatic sonographic short cervix in the mid-trimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data (Am J Obstet Gynecol 2012; 124: .e1-19) ,

Progesterone has such. In WO2010065936A1 described several functions related to the development of the fetus, the nervous system, the immune system and other systems. It can be anti-inflammatory and regulate immune responses. ENDOMETRIN vaginal suppositories (100 mg) received FDA approval in June 2007 to support embryo implantation and early pregnancy. Other products include CRINONE and PROCHIEVE bioadhesive progesterone vaginal gels approved by the FDA for use in infertility and during pregnancy to prevent miscarriage and premature birth.

Oral administration of these progestagens has the disadvantage that the active ingredients are not accurately delivered at the site of need, but they are distributed over the woman's body and even metabolized. Better effects are achieved by intramuscular administration (17-alpha hydroxy-progesterone caproate has been used to date) and the use of suppositories in the pregnant woman's vagina. However, there is also the disadvantage here that the active ingredients parenterally or distributed over the entire vaginal mucous membrane are supplied to the body of pregnant women and therefore relatively large amounts of active substance must be supplied in order to develop the intended effect in the area of the cervix uteri.

Description of the invention

According to the invention it is therefore provided that in the hitherto mainly mechanically acting rotational pessaries in addition active ingredients are introduced or the active ingredients are contained in biodegradable layers, which are applied in the effective partial areas on the surface of the pessary. The so provided Drugs are released over a 1-5 month period, depending on the time of pregnancy when the pessary is applied. Due to their pharmacological action, these active ingredients support the antiinflammatory action and stability of the internal cervical os, the opening of which represents a first stage in the preterm birth syndrome. Since it is often unknown whether the biochemical processes or the mechanical stress on the cervix are the cause of the shortening of the cervix and then of prematurity, a potentiating effect can be achieved by the combination according to the invention of the rotational pessaries with the progestins. Of inestimable advantage is that no active ingredient is lost by the pressure of the pessary in the upper vaginal pole, as well as the drug is delivered specifically targeted to the desired site of action.

In the variant of the order on the pessary, the active ingredients can be applied to the rotational or support pessary in one or more layers, from which they are given over the intended period in a retarding manner. Due to the number of layers, the use of the active ingredients can be adapted to the temporal active substance requirement (short application time = one shift, etc.). Suitable carrier substances of the application layer are, in particular, water-insoluble polymers of synthetic, semi-synthetic and natural origin. These include cellulose derivatives, eg. Cellulose acetate, ethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, acrylate derivatives, e.g. As Eudragite, poly (methyl methacrylate) and especially also biocompatible and biodegradable polymers such as polyanhydrides, polyesters, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes and polyacetals. Important here are polyesters such as polylactide, polyglycolide, polycaprolactone, polyhydroxybutyrate or valerate. It is also possible to use copolymers or terpolymers or else combinations of the carrier substances.

The solvents in which the carrier is incorporated include water, ethanol, citrate esters (eg, triethyl citrate), triacetin, propylene glycol, glycerol, polyethylene glycol, acetone, ethyl acetate, methyl acetate, dimethylformamide, dimethylsulfoxide, dimethylacetamide, 2-pyrrolidone, N -methyl-2-pyrrolidone. It can also be used solvent mixtures selected z. As to the solvent quality for the polymer or miscibility with aqueous and oily phases. The choice of solvent can influence the miscibility of the carrier fluid with body fluids, the outer phase and the solidification of the carrier phase. The viscosity of the carrier phase can be influenced by the carrier (eg molecular weight, concentration, etc.) and also by the solvent.

As an alternative to the application of active ingredient-containing layers, the active ingredients are incorporated directly into the materials of the rotational or supporting pessary, so that the active ingredient is released substantially directly from the pessary via the contact surfaces between pessary and cervix.

Likewise, drug delivery occurs from the pessary surface to the vaginal secretions and from there to the surface of the vaginal mucosa. The active ingredients are dosed in the carrier materials described above so that the regular delivery in a daily dose of 10 mg to 100 mg, but preferably takes place in a dose of 30 mg to 50 mg.

Depending on the medium, the course of drug delivery may vary over time due to the effect of solubilization between vaginal secretions or diffusing cell fluid between the cervical surface and the pessary. To keep the delivery over the course of time to a sufficiently high level, the order of the active ingredients can be carried out in several layers, wherein the layers are successively resolved, so that it after dissolution of each topmost layer to a renewed increase in drug delivery from the subsequent Shift is coming.

Basically, it is not excluded that a pessary after delivery of the drug progesterone is replaced by a new one.

Description of the pictures

1 shows the application of the rotational pessary on the cervix uteri.

2 shows a cross section through the pessary invention with one or more layers containing the active ingredients in the important for the direct transition of the active ingredients surface area.

3 shows a cross section through the pessary according to the invention in the application.

LIST OF REFERENCE NUMBERS

10

Cervix uteri

15

uterus

20

Rotationspessar

21

Inner diameter of the pessary = central opening

22

Outer diameter of the pessary

23

Active substance layer (s)

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• DE 10151365 A1 [0002]
• EP 1646378 B1 [0003]
• EP 1478352 B1 [0004]
• EP 1620060 B1 [0006, 0006]
• EP 1317304 B1 [0007]
• WO 2010065936 A1 [0019]

Cited non-patent literature

• Dharan VB and Ludmir J: Alternative Treatment for a Short Cervix: The Cervical Pessary (Semin Perinatol 2009; 33: 338-42) [0008]
• http://www.viomed.de/en/cerclagepessar_hamann [0009]
• Arabin B et al .: Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? (J Perinat Med 2003; 31: 122-133) [0010]
• Quaas L et al: The Arabin Cerclage Pessary-alternative to surgery (Geburtsh Frauenheilk 1990; 50: 429-33) [0012]
• Arabin B et al: Is treatment with vaginal pessaries option in patients with a sonographically detected short cervix (J Perinat Med 2003; 31: 122-133). [0012]
• Archayra G et al: Noninvasive cerclage for the management of cervical incompetence: a prospective study (Arch. Gynecol. Obstet 2006; 273: 283-287). [0012]
• Jani J et al [0013]
• Goya et al: Cervical pessary in pregnant women with a short cervix (PECEP): open-label randomized controlled trial (www.thelancet.com, published online April, 3, 2012) [0014]
• Wahabi HA et al .: Progestogen in treating threatened miscarriage (Review). (Cochrane Collaboration, The Cochrane Libary 2011: Issue 12) [0016]
• Fonseca EB et al: Progesterone and the risk of preterm birth among women with a short cervix (New Engl J Med 2007; 377: 462-9) [0018]
• Romero R: Prevention of spontaneous preterm birth: the role of cervical length in identifying patients who may benefit from progesterone treatment (Ultrasound Obstet Gynecol 2007; 30: 675-686) [0018]
• Hassan SS et al: Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial (Ultrasound Obstet Gynecol 2011; 38: 18-31) [0018]
• Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002 / uog.9017 [0018]
• Romero R et al: Vaginal progesterone in women with asymptomatic sonographic short cervix in the mid-trimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data (Am J Obstet Gynecol 2012, 124: 1-1-19) [0018 ]

Claims (9)

Rotary pessary of a polymer, characterized in that the pessary contains at least one pharmacologically active substance which acts against premature birth. Pessary according to claim 1, characterized in that this active ingredient is dispensed over a prolonged period of time, in particular of at least 1 month. Pessary according to claim 1 or 2, characterized in that the active ingredient is selected from the group of gestagens and is preferably progesterone. Pessary according to claim 2 or 3, characterized in that the delivery of the substance over a period of 1 month to 5 months, preferably 2 to 4 months, takes place. Pessary according to any one of the preceding claims, characterized in that the active substance is present in at least one biodegradable layer on at least part of the surface of the supporting pessary. Pessary according to any one of claims 1 to 4, characterized in that the substance is distributed in the polymer of the rotational support pessary and delivered in a delayed manner, in particular to the body fluid in contact with it. Pessary according to claim 6, characterized in that the delivery of the substance takes place from at least one chamber which is disposed within the Stützpessars, and is preferably refilled through an opening on the surface of the Stützpessars or can be refilled. Pessary according to claim 5, characterized in that the thickness of the layer on the Stützpessar 0.01 mm to 2 mm, preferably 0.1 mm to 1 mm. Pessary according to one of the preceding claims, characterized in that the amount of the substance to be applied is 10 mg to 100 mg, preferably 30 mg to 50 mg.

Images