CN100463675C - A kind of soluble sustained-release contraceptive for external use - Google Patents

Abstract

The invention discloses a soluble slow-release contraceptive for external use, which is prepared from 1.2-2.0 parts of nonoxynol ether, 10-20 parts of chitosan, 5-20 parts of moisturizing agent, 200-500 parts of water and other ingredients. Because the nonoxynol ether is encapsulated in the degradable material chitosan to make a suitable contraceptive, along with the dissolution of the contraceptive, the medicine is continuously released. After the drug is released, the carrier chitosan is slowly degraded in the body and absorbed by the body. It does not need to be taken out after sex, which makes up for the defects of the existing contraceptive tools in terms of placement and removal. This contraceptive is better than the existing nonoxynol film The duration of action of the drug was prolonged. Long-term use has no effect on liver function, has no effect on vaginal mucosa cells and cervical cells, does not affect the growth of vaginal bacilli, and does not interfere with women's endocrine. It is simple to make, easy to use, and stable in effect. It has good spermicidal and contraceptive effects and can Killing pathogenic microorganisms is beneficial to the promotion of reproductive health and family planning.

Description

A kind of soluble sustained-release contraceptive for external use

technical field

The invention relates to medical hygiene, in particular to a contraceptive for external use.

Background technique

The implementation of the basic national policy of family planning has continuously played an important and positive role in improving the quality of our population, improving the level of reproductive health, and improving the overall strength of the nation. In this context, the research and development of related birth control technology and related contraceptives have developed rapidly, and various contraceptives have been launched one after another. For example, the common physical barrier contraceptives for women include vaginal diaphragms and contraceptive cervical caps. Before use, a gynecological examination is required. According to the size of the vagina, an appropriate type of vaginal diaphragm should be selected for trial insertion, and then learn how to put it in and out under the guidance of a doctor until you can fully master the use. However, women need a vaginal diaphragm after giving birth. The size of the model may be different from before, and it often needs to be reconfigured, so the method of use is more cumbersome. In addition, there are various external contraceptives mainly made of the contraceptive drug nonoxynol with strong spermicidal effect. At present, nonoxynol preparations include suppositories, jelly, film, external tablets, and sponges. Drugs, etc., such as Lelemi contraceptive film and Lelemi cream produced by China Pharmaceutical University Pharmaceutical Co., Ltd., Ren Romance film produced by Tianjin Pharmaceutical Co., Ltd., and Albiscus Nonoxynol contraceptive film produced by Shandong Jintai Pharmaceutical Factory And nonoxynol suppository, nonoxynol gel, nonoxynol topical tablets, nonoxynol sponge, etc. The currently accepted dosage form is mainly nonoxynol film, which is prepared from polyethylene glycol as a matrix. Although the cost is low and the preparation method is simple, it is not completely satisfactory in use, such as: Since the film is thin and easily becomes sticky and deformed when exposed to water, it is required to pull out the finger quickly when placing it, otherwise the film will stick to the finger after encountering the vaginal fluid, and cannot be placed deep in the vagina, resulting in insufficient dosage. cause contraceptive failure.

Contents of the invention

The invention aims to provide a nonoxynol slow-release external contraceptive film to overcome the defects in the prior art.

For realizing the purpose of the present invention, the present invention is characterized in that it comprises the raw material of following weight portion to make:

Main drug: Nonoxynol 1.2～2.0,

Excipients: Chitosan 10-20, Humectant 5-20, Water 200-500.

The auxiliary material also includes 0.1-3 parts by weight of plasticizer.

The best parts by weight of each component described in the present invention are:

Main ingredient: nonoxynol 1.5, excipients: chitosan 15, humectant 15, water 375.

The medicinal specification of the water-soluble chitosan has a degree of deacetylation greater than or equal to 90%. The moisturizing agent is preferably selected from glycerol, propylene glycol or xylitol, preferably glycerol.

The plasticizer can be selected from gelatin, polyethylene glycol (molecular weight: 300-6000), poloxamer (poloxamer, specification: 188 or 407), carbomer 940GE, sodium hyaluronate (sodium hyaluronate), A kind of in povidone (polyvinylpyrrolidone, specification is k15 or k30), wherein preferably adopting molecular weight is the polyethylene glycol of 400.

Polyethylene glycol with a molecular weight of 400 is liquid, non-toxic, non-irritating, and has excellent water solubility, compatibility, lubricity, adhesion and thermal stability. Therefore, it can be used as a lubricant, dispersant, adhesive, excipient, etc. Gelatin has neither smell nor taste, swells and softens in water, and can gradually absorb 5 to 10 times its own weight in water. In hot water, its solubility increases. When cooled to 35-40°C, the protein forms a gel or jelly. It exists in the form of sol when it is higher than 40°C. In the pharmaceutical industry, gelatin can be widely used in the preparation of solutions, syrups, tablets, sugar-coated tablets, inhalants and dental, vaginal, topical and injection solutions. Other applications include the preparation of pastes, lozenges, suppositories. Poloxamer

(Poloxamer) is a polyoxyethylene polyoxypropylene ether block copolymer, and its trade name is Pluronic. This is a new type of polymer nonionic surfactant. Its general formula is HO(C ₂ H ₄₀ )a(C ₃ H ₆₀ )b(C ₂ H ₄₀ )CH. Wherein, a and c are 2-130, and b is 15-67. The content of polyoxyethylene is 81.8±1.9%. It has the unique property of being liquid at low temperature (4-5°C) and gel at body temperature. Using this feature, the residence time of the drug can be prolonged, and the drug can be released slowly from it. To achieve the purpose of sustained release. Carbomer (Carboxgpolmethylene) is a polymer cross-linked with acrylic acid and allyl sucrose. Carbomer is soluble in water, ethanol, and glycerin, and its common concentration is 0.1% to 3.0%. As an auxiliary material, it has been recorded in the British and American Pharmacopoeia and has been widely used in pharmaceutical industry, daily chemical industry and other related industrial fields. It is mainly used as thickener, suspending agent and binder in pharmacy. Carbomer 940GE in pharmaceutical specification can be used as emulsifying and stabilizing agent for transdermal external preparations and gels with high transparency and low viscosity. Sodium hyaluronate is a naturally occurring biopolymer that has played an important role in many parts of the human body. It is composed of repeating disaccharide units composed of N-acetylglucosamine and sodium D-glucuronate. The mucopolysaccharide, hyaluronic acid shows a variety of physiological functions with its unique molecular structure and physical and chemical properties. Povidone is widely used in medicine and is one of the three major new pharmaceutical excipients in the world. Povidone with specifications of k15 or k30 is easily soluble in water and various organic solvents, and has good hygroscopicity and film-forming properties. sex, complexation and physiological compatibility. These excipients have good water solubility and water absorption. Adding a small amount in the prescription can play a good film-forming and emulsifying effect, and can also play a viscosity-increasing and stabilizing effect.

According to needs, adjust the consumption of water-soluble chitosan and humectant or plasticizer in the above-mentioned formula, can obtain the product of the present invention with different flexibility, water content.

The preparation method of the present invention is as follows: after dissolving each component in water, mixing and stirring evenly, injecting into a mold to make a cap-shaped external contraceptive film containing 30-100 mg of nonoxynol, and then drying and removing the film. Package. The component nonoxynol ether [nonoxynol-9, C ₉ H ₁₉ C ₆ H ₄ (OCH ₂ CH ₂ ) nOH (the average value of n in the formula is 9)] contained in the present invention is a spermicide. It is an anhydrous mixture formed by polycondensation of phenol and ethylene oxide, which was synthesized in the United States in 1969 and used for vaginal contraception. Nonoxynol ether is a highly stable compound, a colorless liquid at room temperature, easily soluble in water, ethanol, dichloroethane, xylene, corn oil, etc. After nonoxynol interacts with the lipoprotein membrane of sperm cells entering the vagina, it can reduce its surface tension, change the osmotic pressure of sperm cells, expose or overflow organelles, and kill sperm or prevent sperm from swimming, making sperm Can not enter the cervix, can not make eggs fertilized, so as to achieve the purpose of contraception. The in vitro effective spermicidal concentration of nonoxynol is 0.04%. After contact with sperm, it can inactivate and kill sperm within a few minutes, and can also kill microorganisms infected by sexual intercourse, including gonorrhea, trichomonas, and herpes virus , Chlamydia, etc. Long-term use of this product has no effect on liver function; has no effect on vaginal mucosa cells and cervical cells; does not affect the growth of vaginal bacilli; does not interfere with women's endocrine, so it is harmless to the human body.

The component chitosan contained in the present invention is prepared from chitin present in shrimp, crab shells, insects, fungi, and bacterial cell membranes, and chitin is made into deacetylated chitosan with relatively large solubility through deacetylation and other processes The element reacts with the amino group to form a salt, and the positive charge increases its water solubility, which is called chitosan [ie β, (1,4)-2-acetylamino-D-glucose unit and β-(1,4)- The copolymer of 2-amino-D-glucose unit], chitosan has two kinds of water-soluble and acid-soluble as pharmaceutical excipient, and the present invention adopts water-soluble chitosan. Research data show that chitosan is non-toxic, subcutaneous administration to rats for 3×30 days, subacute toxicity test, no physiological, biochemical and pathological changes were found, the acute toxicity test of chitosan showed that the mouse LD50 was 5.3g·kg ^-1 , rat LD50 is 3.0g·kg ^-1 ; no allergy and irritation in skin test. Chitosan is widely used in many industries such as environmental engineering, food, agriculture, biotechnology, cosmetics and medicine. The clinical effect of using chitosan and other drugs to make a film is very good, and it has a good sustained release effect. The biological activity and pharmacological action of chitosan are as follows: it has broad-spectrum antibacterial activity, and has obvious antibacterial effect on Gram-positive bacteria, negative bacteria and Candida albicans. Chitosan has the advantages of rich resources, low price, safety and non-toxicity, good biocompatibility, and can increase the dissolution rate of drugs. It also has good film-forming properties, flexibility, and air permeability. Absorbing poisoning, anti-inflammatory, antibacterial, hemostatic and pain relief, etc., can also promote wound healing and prevent scar formation. According to reports, the bioavailability of prednisolone, indomethacin and other drugs mixed with chitosan can be more than three times higher than that of the original drug powder. Preparations made of chitosan, nitrendipine, indomethacin, aspirin, etc. can achieve the purpose of sustained release and controlled release. In recent years, with the development of new drug delivery systems, the application of chitosan and its derivatives in pharmaceutical preparations has become a research hotspot, especially in the research of slow and controlled release preparations. Physicochemical and biological properties have attracted the attention of formulation researchers from all over the world.

The present invention and other related dosage form contraceptive comparative experiment situation are as follows:

Two kinds of commercially available external contraceptive Lelemi Contraceptive Diaphragm 50 and the raw material nonoxynol liquid were tested in vitro with the present invention (containing nonoxynol 50mg/piece), referring to the in vitro research requirements of external spermicidal contraceptives in China And method, using the Sander-Ceamer method recommended by WHO, dilute the three preparations into a series of concentrations with normal saline, choose 6 healthy and fertile men, masturbation method to collect semen in a clean cup, according to WHO After the specified standard test, semen samples with a sperm density ≥ 20.0×10 ⁶ /ml, a motility rate ≥ 60%, and a deformity rate ≤ 25% are selected for use.

Experimental procedure: Add the semen samples to the above three drug solutions diluted to serial concentrations of 2mg/ml, 1mg/ml, and 0.5mg/ml of nonoxynol in a ratio of 10:2, and mix quickly. Take one drop on a glass slide and immediately observe 10 high-power fields of view continuously. Within 20 seconds, there is no motile sperm in 10 high-power fields of view. Motile sperm exists, and the recorded results are shown in the table below.

Lelemi contraceptive film 50, nonoxynol ether solution and the product of the present invention in vitro spermicidal effect comparison table

In the above table, "—" means that all spermatozoa were killed within 20 seconds; "+" means that all spermatozoa were not killed within 20 seconds.

As can be seen from the results in the table above, compared with the commercially available nonoxynol film and nonoxynol raw materials, the product of the present invention contains 2mg/ml and 1mg/ml nonoxynol dilutions and the two have the same spermicidal effect .

Comparison between the present invention and existing other contraceptive preparations or tools:

1. Nonoxynol suppositories are made of cocoa butter and other suppository bases, which have high preparation costs, low clinical utilization rate, and poor acceptance among the population.

2. Nonoxynol jelly needs to squeeze the drug into the injector before sex, lie on your back, then slowly push the injector deep into the vagina, and then push in the drug. The method of use is complicated and the preparation cost is higher. high.

3. The sponge should be soaked with water before use, squeeze out excess water, and put it deep in the vagina. It cannot be taken out immediately after intercourse. The time to take it out should not be less than 8 hours or more than 30 hours after intercourse.

4. The nonoxynol film produced by China Pharmaceutical University Pharmaceutical Co., Ltd. and Tianjin Pharmaceutical Co., Ltd. is thin and easily sticky and deformed when exposed to water. The film is easy to stick to fingers after encountering vaginal fluid On, so that the drug film can not be placed deep in the vagina, so that the dosage is insufficient to cause contraceptive failure.

The technical progress achieved by the present invention: because the nonoxynol drug is wrapped in the degradable material water-soluble chitosan to make a contraceptive film that is not easy to stick to the hand, along with the dissolution of the contraceptive, the drug is continuously released. It is slowly degraded and absorbed in the internal environment. When the drug is released, the carrier chitosan disintegrates and is absorbed by the body at the same time. It does not need to be taken out after sexual life. The dosage form suitable for placement in the present invention can make up for the placement and removal of existing contraceptive tools. At the same time, using the uniform and sustained release effect of chitosan, it can prolong the action time compared with the existing nonoxynol film, and the use method does not need special guidance; compared with other nonoxynol film on the market, this product has the same Spermicidal effect, and long-term use has no effect on liver function, has no effect on vaginal mucosa cells and cervical cells, does not affect the growth of vaginal bacilli, does not interfere with women's endocrine, and is simple to make, easy to use, and stable in effect. The spermicidal and contraceptive effect can also kill some pathogenic microorganisms, which is beneficial to the promotion of reproductive health and family planning.

Detailed ways

For further illustrating the present invention, below in conjunction with specific embodiment is further described:

Embodiment 1: take by weighing nonoxynol ether 1.5kg earlier, degree of deacetylation is 92% water-soluble chitosan 15kg, glycerol (glycerol) 15kg, then each component that takes by weighing is mixed at normal temperature Add 375kg of distilled water, stir, pour into the mold after dissolving, and make a circular or semi-elliptical shell containing 30-100 mg of nonoxynol each, that is, a cap-shaped contraceptive film for external use, and then dry and remove the film , packaging, and finished products.

Other embodiment each component and consumption thereof are different from embodiment 1 and see the table below:

Appropriately increasing the proportion of plasticizer and film-forming agent in the formula of the present invention can enhance the water content and flexibility of the contraceptive of the present invention; increasing the proportion of chitosan can strengthen the hardness of the product of the present invention, but neither Affect the contraceptive effect.

The present invention can also be made into other various suitable shapes or dosage forms as required, such as ring-shaped, condom-shaped contraceptives, etc. or dosage forms such as tablets and suppositories.

Claims (5)

1. A soluble slow-release contraceptive for external use, characterized in that it comprises the following raw materials by weight: Main drug: Nonoxynol 1.2～2.0, Excipients: chitosan 10-20, humectant 5-20, water 200-500. 2. The soluble sustained-release contraceptive for external use according to claim 1, characterized in that the auxiliary material also includes 0.1-3 parts by weight of a plasticizer. 3. The soluble slow-release contraceptive for external use according to claim 1, characterized in that the parts by weight of each component are: Main drug: Nonoxynol 1.5, Excipients: Chitosan 15 Humectant 15 Water 375. 4. The soluble sustained-release contraceptive for external use according to claim 1, 2 or 3, wherein the humectant is selected from one of glycerol, propylene glycol or xylitol. 5. The soluble slow-release external contraceptive according to claim 2 is characterized in that said plasticizer is selected from one of gelatin, polyethylene glycol, poloxamer, carbomer, hyaluronic acid, povidone kind.