WO2003022278A1 - Contraceptives - Google Patents

Abstract

It is intended to provide nicotinamide-containing compositions which inhibit the mobility of sperm to thereby achieve a contraceptive effect.

Description

Technical field

 The present invention relates to a contraceptive composition containing nicotinamides.

 Light

Landscape technology

 In the past, spermicides, such as nonoxynol 9 or octoxinol 9, have been widely used as suppositories, creams and foams, mainly for contraception, alone and in conjunction with various contraceptive devices. It has been reported in the prior art that nonoxynol 9, in addition to sperm, has at least some bactericidal action in some in vitro tests and can also kill the human immunodeficiency virus (HIV).

 However, when nonoxynol 9 (or octoxynol 9) and other spermicides are used in vaginal suppositories, creams, foams (foam formulations), etc., these drug components may be irritating to the mucosal lining of the vagina. Yes, the tendency to reduce or destroy healthy and useful flora in the vagina has been identified, which has the potential to make women more susceptible to yeast infections (ligandiosis). With the increased risk of such vaginal irritation, the use of spermicides is reduced and the risk of sexually transmitted bacterial, fungal or viral diseases such as HIV and herpes is increased. May increase.

 Therefore, a contraceptive composition that has low irritation to the inner layer of the mucous membrane of the vagina, has no side effects, and can easily perform contraception is desired. Disclosure of the invention

An object of the present invention is to produce a sperm using a contraceptive composition containing nicotinamides. Inhibiting motor skills and obtaining a contraceptive effect.

 In order to solve the above-mentioned problems, the present inventors have studied a wide variety of chemical substances.As a result, unexpectedly, nicotinamides, which conventionally belong to the category of the vitamin B group, use piyumin as a raw material, and therefore have toxicity. The present inventors have found that they have an excellent spermicidal activity, and as a result of further study, they have completed the present invention.

 That is, the present invention

 (1) a contraceptive composition comprising nicotinamides,

(2) The nicotinamides are nicotinamide, nicotinic acid, pyrazine, pyrazinamide, pyrazine—2-rubilic acid, pyridoxine, pyridoxal, pyridoxamine, methylnicotinic acid, pyridine-3—virurubonic acid, hydrazine isonicotinate , 3-methylpyridine, NAD ⁺ , NAD H, NAD P ⁺ , NAD PH and at least one selected from the group consisting of salts thereof, the contraceptive composition according to (1),

 (3) The contraceptive composition according to (2), wherein the nicotinamide is nicotinamide,

 (4) The contraceptive composition according to (1), wherein the contraceptive composition is a vaginal effervescent tablet, jelly, or a film-form preparation.

 (5) a spermicidal or contraceptive method, which comprises contacting nicotinamides with sperm;

About. BEST MODE FOR CARRYING OUT THE INVENTION

The nicotinamides used in the contraceptive composition of the present invention can be produced and obtained by a known method. For example, nicotinamide can be produced and produced by passing ammonia gas through an ethanol solution of methyl nicotinate, or by partially hydrolyzing cyanopyridine. Also, Nicochi Commercially available amides may be used. Examples of such commercially available products include nicotinamide (manufactured by Nakaraitex), nicotinic acid (manufactured by Nakaraitex), pyrazine (manufactured by Nakaraitex), and pyrazineamide (manufactured by Nakaraitex).

 The active ingredient of the contraceptive composition according to the present invention includes, for example, nicotinamide, nicotinic acid, pyrazine, pyrazinamide, pyrazine-2-pyruvic acid, pyridoxine, pyridoxal, pyridoxamine, methylnicotinic acid, and pyridine-13-carboxylic acid. Hydrazine isonicotinate, 3-methylpyridine, NAD + (nicotinamide adenine dinucleotide), NADH (nicotinamide adenine dinucleotide reduced form), NAD P + (nicotinamide adenine dinucleotide phosphate), NAD PH (reduced form of nicotinamide adenine dinucleotide phosphate) and the like, and preferably, nicotinamide, pyrazinamide, nicotinic acid, methyl nicotinate, pyrazine-12-carboxylic acid and the like. These active ingredients may be used alone or in combination of two or more.

 The active ingredient of the contraceptive composition according to the present invention may be a salt. For example, pharmacologically acceptable salts of the above compounds that form salts are preferred. Examples of such salts include salts with organic or inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and citric acid, and salts with bases such as ammonia, dimethylamine, and getylamine. .

 The contraceptive composition of the present invention can be obtained by formulating an effective amount of a nicotinamide in combination with a suitable pharmaceutical carrier or other adjuvant by a conventional method. The term “effective amount” as used herein means that sperm present in the mammal's vagina is brought into contact with nicotinamide to cut the flagella of the sperm and immobilize it to make fertilization impossible. The amount that can be done. In addition, an amount that produces the desired effect with few side effects is preferable.

Although it cannot be said unconditionally because it differs depending on the type of active ingredient, form of use, etc. The concentration of the active ingredient is usually about 0.5 mM to 10 mM, preferably about 1 mM to 3 mM. Contraception can be achieved by vaginal administration 10 to 60 minutes before sexual intercourse.

 Examples of the form of the contraceptive composition of the present invention include, for example, ointments, dispersions, creams, vaginal effervescent tablets, jellies, film-form preparations, and the like. Examples include effervescent tablets, jellies, and film-form preparations, which are used alone when administered intravaginally or when applied to the vagina using a finger or an applicator.

 The form of the effervescent tablet in the vagina according to the present invention includes, for example, a circle, a rectangle, an ellipse, and a donut, but the form is not particularly limited and may be composed of several layers. Intravaginal effervescent tablets disintegrate rapidly in the vagina, producing a thick suspension.

 The intravaginal effervescent tablet according to the present invention is characterized in that nicotinamides include, for example, glucose, saccharides, sorbitol, mannitol, an inert diluent such as polyvinylpyrrolidone, cellulose, a cellulose derivative exhibiting adhesiveness when contacted with a mucous membrane, A substance such as a lipoxyvinyl polymer, a derivative of a carboxyvinyl polymer, a lectin or a natural substance, or a mixture thereof, for example, lipoxyl polymethylene, carboxymethylcellulose, or acetic acid furic acid, which produces a storage effect. It is manufactured by a generally well-known method by mixing with materials such as polyethylene and polyvinyl acetate.

The vaginal effervescent tablet according to the present invention may be formulated, if necessary, in addition to the above-mentioned drugs, for example, excipients, binders, disintegrants, lubricants, coloring agents, humectants, thickeners, preservatives It may be carried out by adding an agent, a flavoring agent, an antioxidant, an antibacterial preservative, a pH adjuster and the like. Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, and the like.Examples of the binder include, for example, starch, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, and methyl cellulose. , Arabic gum, tragacanth, gelatin, shellac, hydroxy Propylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin and the like. Disintegrants include, for example, starch, hydroxypropyl starch, Q! Maize starch, alginic acid, and lubricating agents, for example, talc powder, magnesium stearate, talc, polyethylene glycol, silica, hardened Vegetable oils and the like. Colorants that are permitted to be added to pharmaceuticals are used. Examples of humectants include glycerin, polyglycerin, 1,3_butylene glycol, sorby] ^ il, xylitol, mulch! ^ Mucopolysaccharides, hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, mucopolysaccharides such as heparin and keratan sulfate and their salts, collagen, elastin, keratin, etc. proteins and their derivatives, and Thickeners, such as carboxymethyl cellulose, agarose, methylcellulose, ethylcellulose, gum arabic, polyvinyl chloride, and the like, such as carboxymethyl cellulose, sorbyl, inositol, trehalose, urea, pyrrolidonecarboxylic acid and salts thereof. Examples of preservatives such as alcohol, montmorillonite, and labonite are, for example, ethyl ethyl parahydroxybenzoate (ethylparaben) and methyl paraoxybenzoate (methyl paraben). Examples of aromatic agents are menthols, fruit juice and other flavors. And essential oils. Examples of antioxidants include vitamin A, such as vitamin A acetate and vitamin A palmitate, and their derivatives and their salts, vitamin B and their derivatives, their salts, and monophosphate phosphate. Vitamin C and its derivatives such as virmagnesium, sodium L-ascorbate sulfate, and vitamin C dipalmitate, and their salts, vitamins D and their derivatives, and their salts; and vitamin E and its salts such as vitamin E acetate Derivatives and their salts, daryuthione and its derivatives and their salts, butylated hydroxytoluene (BHT), and butylated hydroxyazole (BHA). You. Examples of the pH adjuster include bases such as sodium hydroxide, sodium carbonate and sodium hydrogen carbonate, and acids such as hydrochloric acid.

 The effervescent tablet in the vagina according to the present invention may be, for example, sugar-coated, gelatin-coated, or optionally coated as needed.

 The above-mentioned additives are appropriately selected by those skilled in the art, and the mixing ratio with the active ingredient of the present invention can be appropriately adjusted according to known methods depending on the type and amount of the additives.

 The contraceptive jelly according to the present invention is manufactured by an ordinary method. The base material of the contraceptive jelly according to the present invention is not particularly limited as long as it is a commonly used base, and includes, for example, gelatin, pectin, xanthan gum, carrageenan, mouth-to-mouth bean gum, mannan, and cyclodextrin. One or more selected ones can be mentioned. The contraceptive jelly according to the present invention contains, for example, a pharmacologically acceptable carrier, a water-soluble polymer base material, and a solubilizing component.

Pharmaceutically acceptable carriers include, for example, water, ethanol, glycerin, alcohols such as propylene glycol, or mixtures thereof. The water-soluble polymer matrix is preferably, for example, a polyethoxylate compound or a cellulose derivative, and most preferably a hydroxyalkyl cellulose containing a lower alkyl (c _{2 to} c ₆ ) component such as ethyl, propyl, or butyl. . The contraceptive jelly according to the present invention comprises, for example, adding nicotinamides to a water-soluble polymer such as a cellulose derivative, adding a predetermined amount of a solubilizing agent to the obtained mixed solution, stirring and dissolving the mixture, and adding a predetermined amount of purified water. Stir and mix. The obtained contraceptive jelly preferably has a pH of about 3.0 to 5.5 for compatibility with vaginal mucosa. Formulation of the contraceptive jelly according to the present invention may be further performed, if necessary, similarly to the above-mentioned effervescent tablets, for example, excipients, binders, disintegrants, lubricants, coloring agents, humectants, thickeners, Preservatives, fragrances, antioxidants, antibacterial preservatives, pH adjusters, etc. may be added. The above additives are appropriately selected by those skilled in the art, and the mixing ratio with the active ingredient of the present invention can be appropriately adjusted according to a known method depending on the kind and amount of the additives. In addition, the contraceptive jelly according to the present invention uses a finger or an applicator to form, for example, a contraceptive device for a child (IUD), a condom for males, a condom for females, and a contraceptive besser. And nicotine in the manufacture of thin films by applying them to Z or surfaces or by processing the constituents of the thin films, such as polyethylene, nylon, latex and other similar elastic materials. Amides can also be used by kneading.

 The film-form preparation according to the present invention can be produced by a known method. For example, it can be produced by dissolving nicotinamides, a water-soluble polymer and a polyhydric alcohol in water, drying and solidifying a plurality of times at a predetermined temperature to form a film. Examples of the water-soluble polymer that constitutes the film layer of the film-form preparation include polyvinyl alcohol, polyethylene oxide, polyacrylamide, cellulose ether, polysaccharide, and soluble starch. As a raw material for producing the film layer of the preparation, a partially saponified polyvinyl alcohol having a degree of polymerization of about 300 to 500 is preferable. The lower the degree of polymerization, the lower the strength of the film, and the higher the degree of polymerization, the slower the dissolution rate in the vagina.

 When forming a film layer of a film-form preparation by mixing a water-soluble polymer and nicotinamides, it is preferable to use a polyhydric alcohol as a humectant and a plasticizer, such as glycerin and ethylene glycol. , Polyethylene glycol and the like are used.

 Formulation of the film-form preparation according to the present invention may further include, if necessary, as in the case of the effervescent tablet, for example, excipients, binders, disintegrants, lubricants, coloring agents, humectants, thickeners, Preservatives, fragrances, antioxidants, antibacterial preservatives, PH regulators, etc. may be added. The above additives are appropriately selected by those skilled in the art, and the mixing ratio with the active ingredient of the present invention can be appropriately adjusted according to a known method depending on the type and number of the additives.

The contraceptive composition of the present invention is prepared by passing nicotinamide, which is an essential component, according to a conventional method. It can be prepared by blending with various additives known as ordinary external compositions. Although the amount of the additive varies depending on the kind or the form of use of the contraceptive composition of the present invention, it cannot be determined unconditionally, but is prepared by an ordinary method.

 The contraceptive composition of the present invention contains nicotinamides as an active ingredient, and is preferably administered parenterally as a dosage form.For example, vaginal effervescent tablets, jellies, films, vaginal suppositories, ointments, Dosage forms such as solutions, application solutions, and vaginal drops.

 The preferred dose of the contraceptive composition of the present invention cannot be said unconditionally because it differs depending on, for example, the method of administration, the type and activity of the formulated composition, the frequency of use, and the like. Is about 1 to 10 Omg Zkg per day. Example

 Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.

 (Test Example 1)

Fresh sperm was obtained from four healthy volunteers. Using this as a sample, lm1 of each sample is dispensed into a 5 ml volume centrifuge tube, and 1.61 nicotinamide solution is added so that the final concentration becomes 5 mM and 25 mM, respectively. did. After incubation for 1 or 2 hours, the detachment of the flagella was observed at a magnification of 600 times using a phase contrast microscope. Nicotinamide compounds 16 types are shown below. Nicotinamide, nicotinic acid, pyrazine, pyrazinamide, pyrazine-2-pyruvonic acid, pyridoxine, pyridoxal, pyridoxamine, methylnicotinic acid, pyridin-13-carboxylic acid, hydrazine isonicotinic acid hydrazine, 3-methylpyridine, NAD ⁺ , NAD H, NAD P ⁺ , NAD PH (all purchased from Nakarai Techs). In each case, the sperm flagella of all four volunteers was severed or lost motility, and sperm movement stopped.

(Example 1)

 To prepare the contraceptive jelly according to the present invention, nicotinamide (manufactured by Nacalai Tex Co.) 92.20 g and commercially available from BSF (BASF) under the trade name of "Cremophor RH-60" Pre-mix 2.0 g of the polyethoxylated castor oil at 50 ° C. Then, in a separate beaker from the beaker relating to this mixing, 35 g of propylene glycol was taken, and 0.20 g of methylparaben and 0.20 g of sorbic acid were added thereto. The solution was heated to 80 ° C and stirred with a stir bar until the solution became clear. This solution was added to 76.08 g of water taken in another beaker. The pH of this solution was adjusted with 0.02 g of sodium hydroxide (10% solution) to be 3.59. This solution was stirred at high speed until it diffused and then added to the first aqueous solution prepared. The resulting solution was then mixed at an intermediate speed for 3 hours to obtain the contraceptive jelly of the present invention. Industrial applicability

 The nicotinamides of the present invention can cut sperm flagella or inhibit sperm motility by contact with sperm. The sperm whose flagella have been severed cannot swim up the uterus and cannot be fertilized to obtain a contraceptive effect. In addition, the contraceptive composition of the present invention does not need to be taken daily like a pill, so it can be used easily, and has no toxicity because it is made of biquinamine, which originally belongs to the vitamin B group. It is safe to use because of its low irritation to the vaginal mucosal lining.

Claims

The scope of the claims 1. A contraceptive composition comprising nicotinamides. 2. When the nicotinamides are nicotinamide, nicotinic acid, pyrazine, pyrazinamide, pyrazine-2-carboxylic acid, pyridoxine, pyridoxal, pyridoxamine, methylnicotinic acid, pyridine-3-butyronic acid, hydrazine isonicotinate, 3 — The contraceptive composition according to claim 1, wherein the composition is one or more selected from the group consisting of methylpyridine, NAD +, NADH, NADP +, NADPH, and salts thereof. 3. The contraceptive composition according to claim 2, wherein the nicotinamide is nicotinamide. 4. The contraceptive composition according to claim 1, wherein the contraceptive composition is a vaginal effervescent tablet, jelly, or film-form preparation. 5. A spermicidal or contraceptive method comprising contacting nicotinamides with sperm.