RU2253451C1 - Antiallergic drug - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: drug composition includes antihistamine agent as active principle, in particular 1-(p-chlorophenyl)-1-(pyrid-2-yl)-3-N,N-dimethylpropylamine or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier including microcrystalline cellulose, lactose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

6 cl, 5 ex

Description

The invention relates to the field of the pharmaceutical industry and medicine, and relates to antiallergic and antihistamines.

Allergic diseases are one of the urgent problems of modern medicine. Thus, according to the World Health Organization, allergic diseases currently occupy the third place in prevalence.

An unprecedented increase in the growth of these diseases has been noted. According to some reports, on average, about 10% of the world's population suffers from various forms of allergic pathology. The prevalence of allergic diseases in different regions of Russia is 15-30%, and in some environmentally disadvantaged areas it reaches 40-50% (P.M. Khaitov, 1998).

Many researchers attribute this phenomenon to the influence of a significant complex of adverse factors, such as pollution of the environment, air, food, water, as well as various factors of a physical, chemical or biological nature.

One of the first reactions after the action of a damaging agent, resulting in increased vascular permeability, is the release of a histamine mediator. It is rapidly destroyed, the action ceases, and changes in microcirculation are already supported by other mediators.

Histamine is 4- (2-aminoethyl) -imidazole, first synthesized in 1907 by A. Vindaus and V. Vogt from imidazolpropionic acid. Various exogenous and endogenous factors, such as bacterial endotoxins, hormones, chemical compounds can induce an increase in histidine decarboxylase activity and increase histamine synthesis.

Currently, three types of histamine receptors (H1, H2, H3) are differentiated. Histamine H1 receptors are involved in the formation of allergic inflammation, and they directly determine the main clinical manifestations of almost all the symptoms of allergic pathology.

Therefore, in the pharmacotherapy of allergic diseases, an important role is played by the use of drugs with antihistamine action, which are used as anti-allergic drugs as first aid, mainly for stopping the effects of histamine. More precisely, they should be called HI receptor antagonists.

The first antihistamine used in the clinic was phenbenzamine (suprastin), proposed in 1942 by B. Halpern.

Then a number of compounds of a similar action were synthesized.

Chlorpheniramine (1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-dimethylpropylamine) is one of the most potent histamine H ₁ receptor blockers. The main area of its purpose: symptomatic treatment of allergic reactions, including urticaria, angioedema, allergic and seasonal rhinitis, conjunctivitis; diseases accompanied by skin itching; as part of combination therapy for cough and colds. Colds and allergies have different etiologies, and as a means of monotherapy, chlorpheniramine is not effective for both symptomatic and pathogenetic treatment of colds.

Known tablets for buccal action, which may contain chlorpheniramine as an active substance, and as excipients sugar, agar, mannitol, aspartame (RF patent 2109509 C1, publ. 04/27/1998). The tablets quickly disintegrate in the oral cavity. However, for a number of pathologies, a very rapid release of the active principle is undesirable.

A known preparation for the oral release of an active agent, for example, chlorpheniramine, comprising a solid matrix of lipid and colloidal silicon, such as cabosil, as well as other auxiliary substances, for example, water-soluble polymers such as microcrystalline cellulose, stearic acid (GB 1113860 A, publ. 15.05 .1968). The composition is not stable enough during storage.

As the closest analogue, a therapeutic composition containing an antihistamine may be indicated, including chlorpheniramine maleate, 4-8% disintegrant, 20-70% dispersion medium, 10-50% binder, other components, such as flavoring and flavoring, if necessary agents (patent RO 118563 B1, publ. 30.07.2003). Compositions contain a large number of silicon-containing fillers as a dispersion medium and require additional introduction of components that correct organoleptic properties.

The present invention is to develop a pharmaceutical composition suitable for tabletting, with a high content of active substance, its optimal bioavailability, stable during storage, with good organoleptic properties.

The problem is solved in that the proposed anti-allergic composition contains as an active principle 1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-dimethylpropylamine or a pharmaceutically acceptable salt thereof, for example maleate, succinate, hydrochloride, citrate, etc., and as excipients, lactose, microcrystalline cellulose, crospovidone, magnesium stearate in the following ingredients, wt.%:

1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-dimethylpropylamine

or its pharmaceutically acceptable salt

(in terms of base) 3.5-4.5

Microcrystalline cellulose 14.0-16.0

Crospovidone 4.0-6.0

Magnesium Stearate 0.5-1.0

Lactose rest

The composition is in the form of a tablet, optionally coated. The average weight of the uncoated tablet is preferably 200 mg.

The particle size distribution of the active principle will be critical for uniformity of content and should be uniformly small. Ideally, it should be obtained as a very fine powder with an average particle size of less than 10 microns.

Lactose is used in the form of a dry spray, and not in the form of crystals, as is the practice in most tablet forms. Alpha-lactose monohydrate is preferred.

Microcrystalline cellulose is preferably used in the form of coarse particles, for example, Avicel PH 200 [FMC Corp.], although PH 102 will also be suitable. Microcrystalline cellulose serves as a sliding material and also provides optimal dispersibility conditions for the tablet.

The composition may additionally contain 0.1-0.4% colloidal silica to improve the fluidity of the mixture and / or up to 0.5% surfactant sodium lauryl sulfate to improve wettability.

Magnesium stearate is used as a traditional lubricant.

The particles of the active substance have a small adhesive force and high pressure is required for tabletting, which leads to poor-quality tablets.

It was found that the inclusion of the indicated amounts of cross-linked polyvinylpyrrolidone - crospovidone allows to obtain the required cohesive ability. The fragility of the resulting tablets corresponds to 8-12 cr.

The tablets may be coated in the form of a water-soluble or enteric coating.

The presence of a shell gives stability to the drug during storage, reduces the irritating effect on the mucous membranes and improves the appearance, forming a smooth, shiny surface. An example of a water-soluble coating is a polyvinylpyrrolidone film. The enteric coating may be formed from natural substances such as shellac, wax, ceresin, polymers such as acetylphthalyl cellulose, polyvinyl alcohol, acetylphthalyl cellulose, additives such as lactose, stearic acid, dextrin, etc. For example, a quantity of a mixture of cellulose acetate and PVP may be coated. 20-30% of the weight of the tablet.

Production Method:

Make a weight of the active principle and place it in a mixer with a rotating body (or similar).

Weigh out the amount of lactose equivalent to the weight of the active principle and place in the mixer. Stir for 5 minutes or more, until the mixture is completely homogeneous.

Weigh additionally the lactose equivalent to the weight of the material already in the mixer and add to it. Stir for 5 minutes.

Add the rest of the lactose specified in the recipe to the mixer and mix for 10 minutes.

Weigh microcrystalline cellulose, then crospovidone and add them to the mixture. Stir for 15 minutes.

Weigh magnesium stearate and add it through a fine sieve for dispersion. Stir for another 3 minutes.

Pour the contents of the mixer into suitable lined containers and place them on the tableting surface. If the tabletting process is delayed, the containers should be closed to prevent contact with the atmosphere.

Equip the press with a normal round 7-8 mm concave tool and place part of the final mixture to the hopper of the machine.

Manually adjust the press to obtain the planned weight and then adjust the pressure force to obtain tablets in the range from 80 to 120 N hardness. Additionally, if the tablets are coated, the degree of fragility must be taken into account. Successful coverage requires a value significantly less than 0.5%.

During manufacture, control the product by weight and hardness at short intervals.

In the case of coating using methods traditional in pharmacy.

Examples of compositions.

Example 1:

1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-

dimethylpropylamine 3.5%

Microcrystalline cellulose 16.0%

Crospovidone 4.0%

Magnesium Stearate 0.5%

Lactose 76.0%

Example 2:

Core:

1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-

dimethylpropylamine maleate 4.5%

Microcrystalline cellulose 14.5%

Crospovidone 6.0%

Magnesium Stearate 0.5%

Alpha-Lactose Monohydrate 74.5%

Shell: from polyvinylpyrrolidone taken in an amount of 30% of the total weight of the composition.

Example 3:

Core:

1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-

dimethylpropylamine 4.0%

Microcrystalline cellulose 15.0%

Crospovidone 5.0%

Magnesium Stearate 1.0%

Lactose 75.0%

Shell: a mixture of acetylphthalyl cellulose and castor oil 2: 1, taken in an amount of 5% by weight of the tablet.

Example 4

Core:

1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-

dimethylpropylamine 3.5%

Microcrystalline cellulose 16.0%

Crospovidone 4.0%

Magnesium Stearate 0.5%

Lactose 75.9%

Colloidal Silica 0.1%

Shell: cellulose acetate in an amount of 10% by weight of the tablet

Example 5

1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-

dimethylpropylamine 4.0%

Microcrystalline cellulose 14.5%

Crospovidone 4.0%

Magnesium Stearate 0.5%

Lactose 76.4%

Colloidal Silica 0.1%

Lauryl Sulfate 0.5%

The resulting tablets were evaluated by dissolution rate. The experiments were performed on an Erweka DT instrument (type “rotating basket”). The tablet is placed in a solution of 0.1 N. Hcl, dissolution occurs at a basket rotation speed of 100 rpm at a temperature of 37 ° C. At standard time intervals, 15 ml of solution were taken. Filtered by discarding the first 5 ml of filtrate. The content of the active principle was determined by UV spectrometry. The percentage of the substance transferred to the solution was calculated.

The average tablet dissolution time is 6 minutes. After 45 minutes, about 90% of the active principle passed into solution.

The claimed composition meets the requirements of the Global Fund XI in appearance, disintegration, dissolution, uniformity of dosage and other requirements. It has improved organoleptic properties, stable during storage.

The invention can be recommended for implementation in pharmaceutical practice.

Claims (6)

1. An antiallergic composition for oral administration in the form of a tablet containing an antihistamine as an active principle and a pharmaceutically acceptable carrier, characterized in that it contains 1- (para-chlorophenyl) -1- (2-pyridyl) - as an antihistamine 3-N, N-dimethylpropylamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier includes lactose, microcrystalline cellulose, crospovidone, magnesium stearate in the following ingredients, wt.%: 1- (para-chlorophenyl) -1- (2-pyridyl) -3-N, N-dimethylpropylamine or its pharmaceutically acceptable salt (in terms of base) 3.5-4.5 Microcrystalline cellulose 14.0-16.0 Crospovidone 4.0-6.0 Magnesium Stearate 0.5-1.0 Lactose rest. 2. The composition according to claim 1, characterized in that it contains an active principle in the form of finely ground particles with an average size of less than 10 microns. 3. The composition according to claim 1 or 2, characterized in that it further comprises a coating in the form of a water-soluble shell. 4. The composition according to claim 1 or 2, characterized in that it further comprises a coating in the form of an enteric coating. 5. The composition according to claim 1 or 2, characterized in that as lactose contains alpha-lactose monohydrate. 6. The composition according to claim 1 or 2, characterized in that it further comprises 0.1-0.4% colloidal silica and / or up to 0.5% sodium lauryl sulfate.