Set for stimulation of labor activity

 

The invention relates to medicine and pharmacy, namely, set for induction of labour. For extemporanea receiving the drug, enabling clan activities, proposed a set of ready-sterile form hydrophilic ointment bases and prostaglandin as an active ingredient. Rheological parameters of the finished product proved experimentally, meet rheological optimum extrusion capacity and provided a composition basis. Individually dosed quantity of prostaglandins dictated effective dose. Ointment base may be made of gels of sodium carboxymethyl cellulose, redkostej acrylic polymers (Aresol, Mars and others ) or oxides. The sealed container can be any appropriate goals and withstanding heat sterilization packaging with the possibility of aseptic entry. The resulting product has a high modestmouse activity without the side effects typical of prostaglandins, with individual dosing of the active substance. 2 C.p. f-crystals, 2 ill., table 1.

The invention relates to medicine and pharmacy, and it is ekologii is the development of drugs for stimulation of labor activity. In recent years, in obstetric practice for stimulation of labor activity most often used interannually, ekstraamnialny and intravaginal route intravenous injections of prostaglandin (PG) [1, 2]. Thus, there is a rapid destruction of GHGs, which necessitates re-introducing them. The use of a catheter, and aqueous solutions of GHGs leads to rapid absorption of substances that cause side effects typical of GHGs.

Known [13] imported drugs with prostaglandin E2: Prepidil - gel (USA) and Certipost (the Netherlands). Lack of drugs is a fixed concentration of the active substance, are insufficient to achieve the desired effect, for example, to interrupt the pathological pregnancy.

Of interest is the creation of the finished form of sterile hydrophilic ointment bases that allow turning it into a finished composition with the active substance at any point in time, for example immediately prior to use of the composition, through aseptic introduction of the active substance specified concentration in a sealed package ready on base.

The most promising group of ointment bases I have. The hydrophilic base is compatible with a large group of active substances, do not interfere with their absorption. The hydrophilic base capable of almost unlimited mixed with water or dissolve in it and enable technologically just get ointment with asked rheological properties [22].

In this group of foundations of special interest gels of sodium carboxymethyl cellulose (sodium CMC), oxides of different brands (PEO) and gels redkostej acrylic polymer (PMA).

Gels sodium CMC does not have the smell and taste and are characterized by neutral pH, stable in a wide range of pH (from 3.0 to 12.0). They are well tolerated by patients, to more fully give active substances. Numerous studies have shown that the gels sodium CMC harmless to the body, does not have a direct irritant or sensitizing effect. Sodium CMC is widely used in pharmacy and cosmetics [7, 22].

Among gels synthetic high-molecular compounds are widely used in pharmaceutical practice PEO of different molecular weight and gels RAP. The widespread introduction of these media in practice due to many positive qualities.

PEO p is bmenu skin, capable of dissolving many drugs and provide them with high biological availability. They have a high osmotic activity and bactericidal properties [9, 22].

RAP easily form a viscous and transparent gel. They are widely used as carriers of various medicinal substances, as they have several advantages over other ointment bases: provide high bioavailability, prolonging effect and easy to use, non-toxic, do not undergo hydrolysis and oxidation and resistant to environmental factors [3, 16, 20].

Hydrophilic ointment bases are used in many finished dosage forms and cosmetic compositions with a fixed system parameters: viscosity, the concentration of the active substance and the other At the same time, physico-chemical properties of hydrophilic bases, their compatibility with a large group of drugs allow to foresee the possibility of manufacturing (including extemporal) compositions with active substances on the basis of prepared sterile bases. Parameters such compositions may be dictated by the situation. Currently, however, sterile hydrophilic ointment bases as such in packages of one moment of time and in the required situation proportions.

Known sterile form the basis for eye ointments, representing a homogeneous alloy [19]. This base is hydrophobic, it is not enough releases medicinal substances, irritating effect, its packaging does not allow you to maintain sterility after the first use [7] .

Closest to the basis of the invention is to 8.6% gel sodium-CMC [1] . To obtain gel 0.6 g of powdered sodium carboxymethyl cellulose dissolved in 7 ml of water in a bottle with a capacity of 10 ml Vial sealed and sterilized with saturated steam for 20-25 minutes at a temperature of 120oC. However, the gel with the indicated concentration is too high value of effective viscosity that makes it difficult to mix with the drug substance and the introduction of the received medicine to the patient, and hard sterilization conditions significantly violate the rheological properties of the basis [15, 19]. In addition, the optimum sterilization time volume to 100 ml under GF-XI, V. 2. (S. 193) and the Ministry of health of the Russian Federation from 16.07.97, 214 "On the control of quality of drugs manufactured in pharmacies" is 8 minutes, and up to 1000 ml in 15 minutes.

A prototype of the proposed technical solution is the drug with PG on the basis of ointment bases is th introduction and affects the outcome of treatment.

The problem posed by the authors, was the creation of the drug from satisfactory for intravaginal introduction rheological properties of high modestmouse activity without the side effects typical of PG, with individual dosing of the active substance.

And to this end, the creation of prepared sterile hydrophilic ointment bases, characterized experimentally justified by the concentration of polymer that provides a uniform distribution therein of the active substance, efficiency and duration of the proposed composition with such a basis for the account specified the basis of the required rheological properties, as well as meeting the requirements of the GF-XI under the conditions of heat sterilization and healing rheological properties after cooling.

The objective of the invention is solved by the creation of the drug, consisting of finished sterile form hydrophilic ointment bases and prostaglandin E1or F2as the active substance.

Satisfactory rheological parameters of the drug substantiated experimentally, meet rheological optimum extrusion capacity and provide the my number prostaglandins dictated effective dose and is for PGE10,001-0,004 wt.%, for PG f2of 0.05-0.10 wt.%.

The problem is solved by creating a prepared sterile hydrophilic ointment bases, made in the form of a gel structure with experimentally justified rheological properties and is sealed air-tight container.

The sealed container can be any appropriate goals and withstanding heat sterilization packaging with the possibility of aseptic penetrate in particular sealed with a rubber stopper under breaking glass vial, bottle or plastic container.

The structure of ointment bases may be made of gels sodium CMC, RAP (Aresol, Mars and others) or PEO or other suitable natural or synthetic polymers having rheological characteristics within the rheological optimum extrusion ability hydrophilic bases [5].

Rheological optimum extrusion capacity of the foundations of limited quantities of the tangent shear stress from 30 to 420 PA at shear rates from 1 to 365-1respectively (Fig.1) and is provided by the composition, wt.%: Sodium-CMC - 4,5-6,0 purified Water or To 100.0 RAP - 0,4-1,7 Solution of NaOH or KOH in the s sterile ointment bases and the proposed drug is shown in Fig. 2, showing: 1 - tight tank, 2 - sterile hydrophilic ointment base, representing a homogeneous gel formed loose structural grid 3 and the dispersion medium 4. Prostaglandine 5 evenly distributed in sterile hydrophilic ointment base.

The invention is implemented as obrazom.

To obtain gel sodium CMC to 5,0 parts (accurately weighed) of sodium carboxymethyl cellulose add an equal amount of purified water and mix thoroughly. Then the parts add remaining water and mix until a homogeneous mass. The resulting gel was filtered, filled into vials for up to 1 liter and sealed with rubber stoppers under the test. The gel is sterilized by steam under pressure at 120oC for 8-15 minutes depending on volume.

Gels of various types of PMA was obtained as follows: RUP with stirring contribute to the calculated amount of purified water, then add alkaline agent, for example a solution of sodium or potassium hydroxide or triethanolamine, and mix to obtain a homogeneous transparent gel with a pH from 5.0 to 7.0. The resulting gel was filtered, filled into vials required capacity (from 5 ml to 1000 ml), ukuporivaniya of the volume.

The PEO gel was prepared as follows: a polyethylene oxide 1500 alloy with polyethylene oxide 400 in a water bath at a temperature of 605oC. the resulting mass is stirred while cooling to room temperature. Then the alloy is filtered, filled into bottles up to 1 liter, sealed with rubber stoppers under tested and sterilized by steam under pressure at 120oC for 8-15 minutes depending on volume.

As a result of mixing of the components of the hydrophilic ointment bases begins gelation, that is, the transition system in verdooren state. Due to the coupling of the particles of the gel in the fluid volume occurs spatial structural grid.

Liquid dispersion medium 4 is included in the cells loose spatial grid 3, reducing turnover basis up to specified composition rheological properties. Contacts between particles structure and easily reversible violated by the introduction of the gel in the tank and sterilized. After cooling the inside of the airtight container 1 sterile hydrophilic ointment base 2 restores its gel structure with retention of the original properties. The dispersion medium included in the cell spatial strukturbiologie composition of ointment bases allows to maintain the rheological properties and the proposed remedy.

The study of the rheological properties of the above-described gels showed that the latter possess thixotropic properties, and their rogramme fit into the rheological optimum extrusion for hydrophilic ointments (Fig.1), which allows to make a conclusion about their satisfactory extrusion ability, describing, for example, ease of intake of the drug into the syringe and vydavlivaete from it.

Explore the possibility of sterilization of the gels showed that the rheological properties of the gels are not changed.

All the gels are characterized by thermal stability at +45oWith and -(5-10)o[17].

Proposed hydrophilic base is compatible with a large group of medicinal substances and virtually unlimited mix them with water. The introduction of the desired substance in the base directly in front of the medical procedure can significantly extend the capabilities of the physician associated with the need for individual dosing of the active substance or the finished dosage form of the labile active substance or of a mixture of several active substances.

To get any song with the prepared sterile hydrophilic ointment bases active substance in sa And a) in an airtight container 1 (for example, in the form of a sterile solution by syringe through the rubber stopper of the vial or similar method). With the introduction of the active ingredient in the ointment base 2 uniform distribution in a structured weight is achieved by simple shaking, and thus the finished dosage form or any other ointment composition on the basis of (medicinal or cosmetic).

With the introduction of prostaglandins 5 into the container 1 with sterile hydrophilic ointment base 2 and the mixing by simple shaking of the molecules of the active substance is distributed in the dispersion medium 4, enclosed in a loose grid 3 structured gel systems.

The so-obtained drugs, the composition of which is given in the table.

At the time of introduction of the drug into the body loose spatial grid 3 gel base protects the active ingredient from 5 simultaneous destructible contact with the tissues of the body. Due to mechanical and thermal effects communication between the particles of the gel structure is destroyed and released active substance. The experimental basis of the rheological properties of the system determine the required conditions of contact of the active substance with the tissues and systems of the m PG f2in experiments in vitro model of isolated uterus and intestine [10] and in vivo in pregnant and non-pregnant rats showed that the gels have a high modestmouse activity.

Manufactured under aseptic conditions pharmacies Leningrad hospital (LRCH) in the form of a ready form of sterile gel sodium CMC and drug with PG on its basis was used in the Department of pathology of pregnancy LRCH on medical grounds for abortion in the second trimester, both independently and in combination with intravenous prostaglandins. Marked high rodosthenous activity of the proposed drug in comparison with the prototype and imported analogues (Prepidil-gel, Certipost). Allergic reactions, side effects, normal to increased doses of prostaglandins, and intolerance were observed. The use of prepared sterile hydrophilic ointment bases allowed the drug with the possibility of choosing the dose of prostaglandin and avoid side effects related to the same doses of PG input in aqueous solutions.

Literature 1. Abramenko Centuries , Bogdashkin N. G. Prostaglandins and the reproductive system is standard practice. - SPb.: Petropol, 1993. - 214 S.

3. Alekseev, K. C., Lee, C. N., Demichev Century. N. and other Reconstitue acrylic polymers in pharmacy.// Pharmacy. 1987. 5. C. 15-18.

4. Alekseev, K. C., Starodubova M. C., Sliusar O. I. Respol - new excipient in technology ointments. // VII Russian national Congress "Man and medicine": Abstracts. - M., 2000. S. 598.

5. Arkusha A. A. Evaluation and monitoring lubricating properties of ointments using reogram: Methodical recommendations. - Kharkov, 1986. - 12 S.

6. Astranova M. M. , Starodubova M. C., K. Alekseev Century, Elagina I. A. New drugs have anti-inflammatory actions for external use. // VI Congress "Man and medicine": Abstracts. - M., 1999. S. 383.

7. Walnut Century M the Basis for medical ointments. - M., 1975. S. 22-30.

8. Gunko Century,, Gun'ko A. A., Musienko N. M. The study of the osmotic activity of some ointment bases. // Pharmaceutical journal. 1982. 3. S. 345-346.

9. The Dashevskaya B. I., Gluzman M X, bodnia C. M. Oxides and their application in pharmacy. // General. INF.: Chemical-pharmaceutical industry. 1974. C. 2. C. 3-27.

10. Isaiah S. C., Ivankina, N. F., Kafanov T. C. Prostaglandins Sika deer antlers. // Pharmaceutical journal. 1994. 7. S. 23-26.

11. Kudryakov E. A., Moskitoo acrylic polymer "Aresol". // Sat. proceedings of the FIP. So 39. H. 1. S. 207-211.

12. Kuzin, M. I., Kostyuchenok B. M., Datsenko B. M. Local medical treatment of wounds: Methodical recommendations. - M., 1985. - 18 S.

13. Drugs in Russia: on the main page. - M.: Attraversare, 1995. - 1168 S.

14. Mayorov, A. C., K. Alekseev Century, Suslin S. N. Experience using Recoletos acrylic polymer Aresol as part of new dermatological preparations. // Mat. scient. are the practice. proc. "Topical issues of cosmetology".- St. Petersburg, 2000. S. 80.

15. Manufacture of sterile solutions in pharmacies: HOWTO. - M.: the Ministry of health, 1994. - 145 S.

16. Overview: Medicine and health care. Pharmacy and pharmacology. - 1982. 6. S. 39-46.

17. OST 18-304-76. Cosmetic creams. Acceptance rules and sampling. Testing methods. - M.: the Ministry of food industry of the USSR, 1976. - 47 S.

18. Peppers, I. M. , Datsenko B. M., Gunko Century, multi-component hydrophilic ointments on the basis of. // Pharmacy. 1990. 5. S. 73-77.

19. Order of the Ministry of health of the Russian Federation from 16.07.97, 214 "On the control of quality of drugs manufactured in pharmacies". - M.: the Ministry of health, 1997. - 70 S.

20. Avenue Carbopol. / B. F. Goodrich. - 1998. - 39 S.

21. Suslin S. N. , Sliusar O. I., Aref'eva N. In. Dosage forms for ndow. - M., 1999. S. 476.

22. ANCOVA A. I., Walnut C. M. Modern aspects of research and production of ointments. - M.: Medicine, 1980. - 153 C.

23. Chaldiran E. A. Alekseev, K. C. Experimental study of gels interferon. // Sat. scient. proceedings of Vnipitechnologia. T. 1. - M.: UNISANTE. S. 66-69.


Claims

1. Set for stimulation of labor activity, consisting of prepared sterile hydrophilic ointment bases, enclosed in a sealed container, and prostaglandin as an active ingredient, characterized in that the hydrophilic base is a gel containing sodium CMC and water in the following ratio, wt.%:

Sodium CMC 4,5 - 5,5

Purified water Up to 100.0

or gel RUP, including redkosty acrylic polymer aqueous solution Paon or CON or triethanolamine and purified water in the following ratio, wt.%:

RAP 0,4 - 1,7

An aqueous solution of NaOH or KOH,

or triethanolamine To a pH of 5.0 - 7.0

Purified water Up to 100.0

or alloy of polyethylene oxide 400 and polyethylene oxide 1500, in the following ratio, wt.%:

PEO 1500 5,0 - 25,0

PEO 400 To 100.0

the number of components provide the basis reologicheskih 30 - 420 PA at a shear rate of 1.0 - 365,0 with-1accordingly, the prostaglandin is selected from the group PGE1or PG f2Aand the number of prostaglandin - individually effective.

2. Set for stimulation of labor activity on p. 1, wherein the prostaglandin is a PGE1his concentration is (0,001-0,004)% of the total mass of prostaglandin and hydrophilic ointment bases.

3. Set for stimulation of labor activity on p. 1, wherein the prostaglandin is a F2and its concentration is 0,05-0,10)% of the total mass of prostaglandin and hydrophilic ointment bases.

 

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