RU2537242C1 - Rectal suppositories with nicotinic acid and propolis extract - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to an agent for treating haemorrhoid. The agent in the form of rectal suppositories for treating haemorrhoid containing 10% ethanolic extract of propolis, nicotinic acid, polyethylene glycol 1500 (PEG 1500), polyethylene glycol 4000 (PEG 4000), emulsifier T-2, Lutrol F68 and Cremophore CO-40 in certain proportions.

EFFECT: presented suppositories for treating haemorrhoid possess a wide spectrum of biological and therapeutic activities: they have the vasodilation action at the level of small vessels, improve microcirculation, promote the weak anticoagulant action, have the antioxidant, anti-edematous, spasmolytic, anti-inflammatory, regenerative and antibacterial action with the uniform release of active substances and the manifested prolonged action; they are easy to administrate with no assistance.

2 cl, 1 dwg, 2 tbl, 7 ex

Description

The present invention relates to medicine, namely to pharmacy, and for the development of medical suppositories containing nicotinic acid, and can be used in the complex treatment of hemorrhoids.

Known pharmaceutical preparation made for external use in the form of suppositories or capsules for rectal administration, containing an active substance, a target additive and a base, and as an active substance it contains stefaglabrin in the form of a physiologically acceptable compound, for example stefaglabrin sulfate, and as a target additive may contain nicotinic acid as vitamin in the amount of 0.005-1.0 wt.% [application RU 2007140812, published 05/20/2009].

Known rectal suppositories containing propolis, dimexide, distilled monoglycerides, a mixture of H-15 and W-35 vitepsols in a ratio of 50-70: 30-50 in sufficient quantities to obtain a suppository mass of 1.4-2.0 [patent RU 2207138, 2003 g.].

Rectal suppositories "Olestesin" are known, which contain a medicinal substance - sea buckthorn oil in the form of a concentrate and additionally anestezin and ethazole sodium, as a base - polyethylene oxide-1500, and also additionally contain tween-80 and purified water at a certain ratio of components per 1 suppository weight 2.23-2.47 g [patent RU 2212882, 2003].

A complex natural preparation is known in the form of suppositories, in particular for the treatment of hemorrhoids and prostatitis, containing natural polyfler honey, royal jelly milk, propolis, flower pollen (dressing), a base additionally containing dried bee bread, beeswax, anhydrous lanolin, while pollen flower (pollen) collected by bees from different species of plants, propolis native and concentrate, and the base contains anhydrous lanolin, beeswax and cocoa butter, or solid fat, or supporin-M, or massupol, or vitepsol during the following m ratio of components per 1 suppository weight 2.9 g, g:

Polyfler natural honey - 0.12 (4.0%)

Royal jelly milk - 0.10 (3.5%)

Propolis native and concentrate - 0.31 (10.5%)

Dried salmon - 0.15 (5.2%)

Flower pollen (pollen) - 0.08 (2.8%)

Beeswax - 0.06 (2.0%)

Anhydrous lanolin - 0.12 (4.0%)

Cocoa butter, or solid fat, or supporin-M, or massupol, or vitepsol - 97 (68.0%), (RF patent No. 2146920, publ. 2000.03.27).

The well-known drug "Mipropol" (Romania), which is a suppository containing 0.4 g of polyfler honey, 0.25 g of propolis extract (thick extract), 0.15 g of pollen, 0.15 g of royal jelly and cocoa butter (T .V. Vakhonina "Bee Pharmacy", 1992, p.180).

Known suppositories for the treatment of hemorrhoids and prostatitis, having a wound-healing effect, containing beekeeping products - royal jelly, perga, natural honey, propolis, beeswax, base, anhydrous lanolin, additionally contain drone brood homogenate, calendula tincture, solid fat or viteps as a base , or cocoa butter in the following ratio, g:

Drone brood homogenate 0.05-0.06 (or drone brood lyophilisate) 0.03-0.04 Royal jelly 0.05-0.06 Perga 0.11-0.13 Natural honey 0.09-0.11 Propolis 0.23-0.25 Tincture of calendula 0.6 ml Beeswax 0.05-0.07 Anhydrous lanolin 0.09-0.11

Solid fat or vitepsol or cocoa butter is a sufficient amount for the preparation of a suppository weighing 2.2-2.5 g (RF patent No. 2225213, publ. 10.03.2004).

Homeopathic suppositories for the treatment of hemorrhoids and prostatitis are known, containing propolis, sea buckthorn oil, homeopathic oil extract, oils and homeopathic essences (RF patent No. 2308964, publ. March 27, 2007).

The following drugs are known. Relief - suppository contains shark liver oil 75 mg (3%), phenylephrine hydrochloride 6.25 mg (0.25%), cocoa butter 2.137 g (base) and ReliefAdvance - suppository contains shark liver oil 3%, benzocaine 10.3% . Suppositories are used to eliminate exudation, swelling, serous secretions, as well as to provide local calming, anti-inflammatory, wound healing, hemostatic, immunomodulating effects in diseases of the rectum (http://amt.allergist.ru/relif_b.html).

Relief and ReliefAdvance are limited in use due to the high cost of the drug, and in cases of increased individual sensitivity to the ingredients of the drug, skin hyperemia, skin rash, or itching in the area of application may occur.

Known rectal suppositories "Aproxide" for the treatment of inflammatory diseases of the rectum, containing, g per suppository: propolis - not less than 0.09, as excipients - polyethylene oxide with a molecular weight of 400 0.3-0.5 and a preservative of 0.008-0 , 01, as well as a water-soluble base - the rest. As a water-soluble base, suppositories contain a polyethylene oxide base, in particular polyethylene oxide with a molecular weight of 4000 or a mixture of polyethylene oxides with a molecular weight of 1500 and 4000 [patent RU 2137468, 1999].

The closest analogue of the invention are rectal suppositories for the treatment of hemorrhoids containing 10% propolis alcohol extract as the active substance, pig fat, cocoa butter, butter as the basis (http://your-healthylife.com/rektalnye-svechi-s -propolisom /).

The objective of the invention is to expand the arsenal of funds in the form of rectal suppositories for the treatment of hemorrhoids and inflammation of the rectum.

EFFECT: obtaining a new domestic drug in the form of suppositories, which have a wide range of biological and therapeutic activity: they have a vasodilating effect at the level of small vessels, improve microcirculation, have a weak anticoagulant effect (increase fibrinolytic activity of the blood), have antioxidant, decongestant, antispasmodic anti-inflammatory regenerating and antibacterial action, with uniform release substances and their pronounced prolonged action.

The specified technical result is achieved by the fact that the tool in the form of rectal suppositories containing 10% alcohol extract of propolis as an active substance and a base, according to the invention additionally contains nicotinic acid as an active substance, and as a base it contains polyethylene glycol 1500 (PEG 1500), polyethylene glycol 4000 (PEG 4000), emulsifier T-2, lutrol F68 and cremophor CO-40 in the following ratio of components, g per 1 suppository weighing 4 g:

Nicotinic Acid 0.5 Propolis Extract 10% Alcohol 0.4 PEG 1500 0.3 PEG 4000 0.7 Emulsifier T-2 0.1 Cremophor CO-40 1.25 Loutrol F-68 0.75

The invention is illustrated by the following materials: the figure shows the effect of excipients PEG 4000, emulsifier T-2, lutrol F68, cremophor CO-40 and a combination of PEG 1500 and PEG 4000, emulsifier T-2, lutrol F68, cremophor CO-40 on the release of active substances on the example of nicotinic acid in dynamics; table 1 - the results of the determination of pharmaceutical availability by diffusion into agar using bromothymol blue in an amount of 5%; table 2 - determination of the time of complete dissolution of suppositories.

All components that are part of the suppository are approved for medical use.

Polyoxyethylene glycol (PEG) 4000 TU 2483-166-05757587-2000. In the pharmaceutical industry it is used as an auxiliary substance in the manufacture of medicines. It is used as a thickener, softener, binder, sliding and facilitating the casting agent, and also as a solubilizer, it does not have an emulsifying effect.

Polyoxyethylene glycol (PEG) 1500 TU 2483-167-05757587-2000. Waxy scales or a dense mass of white. Used in the cosmetic industry and pharmaceuticals as a binder. Polyethylene glycol is part of many cutting fluids and hydraulic fluids. It is also used as an emulsifier, detergent, dispersant, antistatic agent in the textile and leather industries. Quite often, polyethylene glycol is used in the production of polyurethane foams, in ceramics and powder metallurgy. PEG 1500 is used as a base ingredient in the development of medicines, as a hydrophilic base for creams, toothpastes, a component of lotions, deodorants, shampoos.

Emulsifier T-2 (Russia) TU 18-17-05-76. Gives the mass sufficient elasticity, is used as a stabilizer, plasticizer and emulsifier.

Lutrol F 68 BASF (Germany) 9003-11-6. Lutrol® F 68 is a hydrophilic polymer, a block copolymer of polyoxyethylene polyoxypropylene, available in granular form with an average particle size of about 1000 microns, while non-crystalline active ingredients have a particle size in the range of 20-200 microns. One of the physical ways to increase the solubility of the active ingredient is to increase its surface area by micronization. Another method is the use of solubilizers, such as surfactant polymers - poloxamers.

Cremophor CO-40 BASF (Germany). Raw materials for the production of cosmetic products. Cremophor CO 40 (input to formulations up to 3.0% of the final product). Nonionic surfactant - castor oil (hydrogenated, ethoxylated, viscous liquid). It is used as a solubilizer, it has the ability to enhance the pharmacological effect of drugs, which allows to reduce their dose, can eliminate the incompatibility of the ingredients in the compositions. It has absolute resistance in hard water, mostly selective emulsifying, wetting and solubilizing ability, relatively low toxicity, etc.

Niacin (TU 6-68-183-01) has lipoproteinemic (lowering the level of lipoproteins in the blood) activity, has fairly extensive indications for use. This drug can be taken both for medicinal purposes and for the prevention of many diseases, in particular, for treatment with the following diseases and conditions:

- osteochondrosis of the spinal column of various departments;

- ischemic stroke;

- violation of cerebral circulation;

- noise in ears;

- atherosclerosis;

- pellagra;

- impaired glucose tolerance;

- circulatory disorders in the lower extremities;

- hemorrhoids;

- lipid metabolism disorders and obesity;

- liver disease;

- alcohol intoxication;

- drug intoxication;

- professional intoxication;

- trophic ulcers of the lower extremities;

- decrease in visual acuity.

For the prevention of nicotinic acid use:

- to reduce the risk of cancer;

- to quickly break down fats and reduce the level of intake of fatty acids in the human body;

- with gastritis with low acidity;

- to eliminate the symptoms of hemorrhoids;

- to improve memory and vision;

- to speed up the process of splitting fats during weight loss.

Propolis TU GOST 28886-90. The introduction of alcohol propolis extract in combination with nicotinic acid into the suppository composition of the drug increases antimicrobial activity, tissue regeneration, and contributes to the manifestation of the analgesic, hemostatic, immunomodulating, reparative effect of the dosage form.

In the available scientific, medical and patent literature, information about the popularity of rectal suppositories containing nicotinic acid and propolis alcohol extract as an active ingredient in a certain ratio of components was not found. Thus, the claimed invention meets the criterion of "novelty."

As a result of experimental studies, it was found that the proposed suppositories have high bioavailability and a number of advantages: they have a satisfactory appearance, are homogeneous, the therapeutic effect of the active substances appears 5 minutes after administration; complete dissolution after 11 minutes. Suppositories are very promising for use in coloproctology. The composition of the suppository base contributes to the rapid and further prolonged release of the active substances of nicotinic acid and propolis extract. Giving the drug the form of suppositories provides convenience and hygiene of use, storage stability. Due to the introduction of nicotinic acid in combination with propolis extract, suppositories have a wide range of biological and therapeutic activity: they have a vasodilating effect at the level of small vessels, improve microcirculation, have a weak anticoagulant effect (increase fibrinolytic activity of the blood), have antioxidant, decongestant, antispasmodic, anti-inflammatory regenerating and antibacterial action, and the optimal composition of the suppository base sp Property uniform release of the active substances expressed and prolonged action. In addition, suppositories are convenient for use by patients on their own. In addition to the manifestation of known properties, each component of the claimed composition in the aggregate enhances its effect, which is explained, obviously, by the effect of their synergism. Thus, the claimed invention meets the criterion of "inventive step".

Example 1. Composition per 1 suppository, weighing 4 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 4000 - 1.0 g; emulsifier T-2 - 0.1 g; Lutrol F68 - 0.75 g; Cremophor CO-40 - 1.25 g.

In a beaker, PEG 4000, T-2 emulsifier, Lutrol F68 and Cremophor CO-40 are melted in a water bath at a temperature of not more than 70 ° C. To remove air without stirring, incubated for 30 minutes at a temperature of 45 ° C. Nicotinic acid and propolis alcohol extract are introduced into a suppository mass, continuously stirring with a glass rod. The metal suppository forms are wiped with a gauze swab moistened with liquid paraffin, cooled in the refrigerator at a temperature of 3-5 ° C for 5-6 minutes and the prepared suppository mass is poured at a temperature of 38-40 ° C for 1-2 seconds. The forms are placed in the refrigerator for 7-10 minutes, after which the frozen suppositories are removed. The quality of suppositories is evaluated by appearance, elasticity, uniformity, solubility. The resulting suppositories are of regular shape, solid and uniform. The total dissolution time is 6 minutes (Table 2), the prolongation effect is noted (Figure).

Example 2. Composition per 1 suppository, weighing 3.9 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 1500 - 0.5 g; PEG 4000 - 0.5 g; Lutrol F68 - 0.75 g; Cremophor CO-40 - 1.25 g.

In a beaker, PEG 1500, PEG 4000, Lutrol F68 and Cremophor CO-40 are melted in a water bath at a temperature of no more than 70 ° C. To remove air without stirring, incubated for 30 minutes at a temperature of 45 ° C. Nicotinic acid and propolis alcohol extract are introduced into a suppository mass, continuously stirring with a glass rod. The metal suppository forms are wiped with a gauze swab moistened with liquid paraffin, cooled in the refrigerator at a temperature of 3-5 ° C for 5-6 minutes and the prepared suppository mass is poured at a temperature of 38-40 ° C for 1-2 seconds. The forms are placed in the refrigerator for 7-10 minutes, after which the frozen suppositories are removed. The quality of suppositories is evaluated by appearance, elasticity, uniformity, solubility. The resulting suppositories are of regular shape, solid and uniform. The total dissolution time is 9 minutes (table 2).

Example 3. Composition per 1 suppository, weighing 4 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 1500 - 0.3 g; PEG 4000 - 0.7 g; emulsifier T-2 - 0.1 g; Lutrol F68 - 0.75 g; Cremophor CO-40 - 1.25 g.

In a beaker, PEG 1500, PEG 4000, T-2 emulsifier, Lutrol F68, and Cremophor CO-40 are melted in a water bath at a temperature of no more than 70 ° C. To remove air without stirring, incubated for 30 minutes at a temperature of 45 ° C. Nicotinic acid and propolis alcohol extract are introduced into a suppository mass, continuously stirring with a glass rod. The metal suppository forms are wiped with a gauze swab moistened with liquid paraffin, cooled in the refrigerator at a temperature of 3-5 ° C for 5-6 minutes and the prepared suppository mass is poured at a temperature of 38-40 ° C for 1-2 seconds. The forms are placed in the refrigerator for 7-10 minutes, after which the frozen suppositories are removed. The quality of suppositories is evaluated by appearance, elasticity, uniformity, solubility. The resulting suppositories are of regular shape, solid and uniform. The total dissolution time is 11 minutes (table 2). They have a pronounced prolonged effect, due to the optimal composition of the base, that is, the active substances nicotinic acid and propolis extract enter the body immediately, and then are held on the mucous surface for a certain period of time, provide a long-term effect of drugs with rectal administration to the patient. The determination of pharmaceutical availability was carried out by agar diffusion using bromothymol blue in an amount of 5% (Table 1). High pharmaceutical availability on the example of nicotinic acid was noted (Figure 1). Suppositories are convenient and hygienic to use, which is explained by the proposed composition of the ingredients.

Example 4. Composition per 1 suppository, weighing 4 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 1500 - 0.7 g; PEG 4000 - 0.3 g; emulsifier T-2 - 0.1 g; Lutrol F68 - 0.75 g; Cremophor CO-40 - 1.25 g.

Medical suppositories are made in a similar manner. The resulting suppositories are homogeneous, regular in shape, the dissolution time is 9 minutes (table 2).

Example 5. Composition per 1 suppository, weighing 4 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 1500 - 0.4 g; PEG 4000 - 0.6 g; emulsifier T-2 - 0.1 g; Lutrol F68 - 0.75 g; Cremophor CO-40 - 1.25 g.

Medical suppositories are made in a similar manner. The resulting suppositories are homogeneous, regular in shape, the dissolution time is 9 minutes (table 2).

Example 6. Composition per 1 suppository, weighing 4 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 1500 - 0.2 g; PEG 4000 - 0.8 g; emulsifier T-2 - 0.1 g; Lutrol F68 - 0.75 g; Cremophor CO-40 - 1.25 g.

Medical suppositories are made in a similar manner. The resulting suppositories are homogeneous, regular in shape, the dissolution time of 10 minutes (table 2).

Example 7. Composition per 1 suppository, weighing 3.5 g: nicotinic acid 0.5 g; propolis extract 10% alcohol 0.4 g; PEG 4000 - 0.5 g; emulsifier T-2 - 0.1 g; Lutrol F68 - 1.0 g; Cremophor CO-40 - 1.0 g.

Medical suppositories are made in a similar manner. The resulting suppositories of irregular shape, unsatisfactorily removed from the forms and heterogeneous.

From the above examples it is seen that the composition described in example 3 is optimal from the point of view of ease of use, high release of active substances and at the same time the effect of prolongation.

Obtaining the proposed suppositories is easily feasible, and when using them, the specified technical result is achieved. Thus, the claimed invention meets the criterion of "industrial applicability".

Clinical trials have shown that the number of released drugs with a given ratio of components in one suppository is the same in the studied patients. This enables the doctor in practical medicine, depending on the form and severity of the disease, to recommend to patients the necessary number of suppositories for self-treatment, which makes the claimed suppositories a promising dosage form in coloproctology.

Table 1 Determination of the pharmaceutical availability of suppositories in examples 1-6 Time min Diameter of the painted zone, mm composition 1 composition 2 composition 3 composition 4 composition 5 composition 6 fifteen 13 eleven fifteen fifteen fifteen fifteen thirty fifteen 13 eighteen 17 17 17 45 16 fourteen 19 eighteen eighteen eighteen 60 eighteen fifteen 21 19 19 19 120 21 eighteen 22 21 21 21 180 23 twenty 24 22 21 21 table 2 Determination of the time of complete dissolution of suppositories in examples 1-6 Composition number The time of complete dissolution, minutes one 6 ± 0.5 2 9 ± 0.2 3 11 ± 0.2 four 9 ± 0.5 5 9 ± 0.5 6 10 ± 0.2

Claims (2)

1. A tool in the form of rectal suppositories for the treatment of hemorrhoids, containing 10% alcohol extract of propolis as an active substance and a base, characterized in that it additionally contains nicotinic acid as an active substance, and as a base contains polyethylene glycol 1500 (PEG 1500), polyethylene glycol 4000 (PEG 4000), emulsifier T-2, lutrol F68 and cremophor CO-40 in the following ratio of components, g per 1 suppository weighing 4 g:
Nicotinic Acid 0.5 Propolis Extract 10% Alcohol 0.4 PEG 1500 0.3 PEG 4000 0.7 Emulsifier T-2 0.1 Cremophor CO-40 1.25 Loutrol F-68 0.75 2. The tool according to claim 1, characterized in that as a solvent to obtain an extract of propolis alcohol 10%, ethyl alcohol 70% is used.

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