Antihistaminics tool and method thereof


(57) Abstract:

The invention can be used in medicine for the treatment of seasonal and perennial allergic rhinitis, conjunctivitis, hay fever, urticaria and other allergic diseases. The tool is made in the form of solid dosage forms, particularly tablets. The tool contains, wt%: loratadine is 0.5 to 20.0, lactose 53,8-98,3, microcrystalline cellulose 1,0-25,0, salt stearic acid 0.2 to 1.2. To obtain the mix loratadine and these excipients and the mixture is molded. The tool is intended for oral administration and rapidly releases the active principle. This ensures a high speed of absorption loratidine, which accelerates the onset of their therapeutic effects of the drug. 2 S. and 3 C.p. f-crystals, 4 PL.

The invention relates to the field of medicine and is suitable for the treatment of seasonal and perennial allergic rhinitis, conjunctivitis, hay fever, urticaria, including chronic idiopathic urticaria, angioedema, psevdoallergicakie reactions caused by the release of histamine, itching dermatoses, allergic reactions to insect bites and itching of various etiologies.

Loratadine (or aetsa one of the most effective anti-histamine funds [Mashkovsky M. D. Medicines, T. 1, ed. 13th, Kharkov: Torsing, 1997, S. 283]. The connection blocks histamine H-1 receptors, which determines its antiallergic, antipruritic and protivoekssudativnoe action.

Loratadine has a relatively long therapeutic effect that gives you the ability to use the drug 1 time a day, unlike other antihistamines, such as bicarbona.

In U.S. patent N 4659716, 1987, describes a pharmaceutical composition comprising the following ingredients, wt.%:

Active substance - 33,3,

Corn starch - 25,0

Including in the composition of the humidifier - 10,0

Lactose - 40,7

Magnesium stearate - 1,0

However, as the active connection is not used loratadine and its decarboxylating similar or 8-fluoro-substituted latest.

The composition is produced by hydration of a mixture of active compounds with lactose, wet granulation, drying and subsequent screening, the introduction of the rest of starch and magnesium stearate and pelletizing.

In U.S. patent N 4282233, 1981, described antihistaminics means in the form of solid dosage forms containing the active substance and excipients. Nepal - 10,6

Lactose, wet 84,8

Polyvinylpyrrolidone - 4,0

Salt of stearic acid - 0,2

As the active substance, the tool may contain 11-((1-substituted carboxy/ or sulfonyl)-4-piperidylidene)-5H - benzo[5,6]cyclohepta[1,2-b] pyridine and their dehydrogenated or chlorine substituted analogues, including loratadine. However, the qualitative and quantitative composition of ingredients allows you to get a solid dosage form of loratidine with satisfactory results of release of the active substance.

To obtain this antihistaminics means the mixture of the active substance, water, lactose, polyvinylpyrrolidone, part of the starch (56.6 per cent of the total) and water is dried by spraying method. To dry the material a salt of stearic acid (stearate) and another part of the starch and pressed received tabletow mass.

However, this method, like the above, the method according to U.S. patent N 4659716, when you receive a new antihistaminics means involves the operations of wetting/drying, which complicates the process. In addition, it increases process losses, which leads to additional RA is oblama create an anti-histamine drug on the basis of loratidine, intended for oral administration in the form of solid dosage forms quick release of the active principle, which, of course, necessary to replenish the register of medicines.

The technical result obtained by implementing the present invention, is that the new anti-histamine agent in the form of solid dosage forms easily releases the active substance that provides a high absorption rate of loratidine and, consequently, accelerates the onset of their therapeutic effects of the drug, and thus stable for a sufficiently long period (at least 2 years), and the sequence of operations and their technological options that allow you to produce a dosage form of the required quality, in particular with satisfactory strength, and at the same time to simplify the manufacturing process.

This technical result is achieved by the fact that the proposed antihistaminics tool contains as active ingredient loratadine and as excipients lactose, microcrystalline cellulose and a salt of stearic acid in the following ratio of ingredients, wt.%:

Loratadine is 0.5 to 20, Declare that the ratio of ingredients is optimal, found experimentally and ensures compliance of the composition requirements of the global Fund XI.

Introduction to composition based on loratadin as the target additive microcrystalline cellulose along with application in prescribed limits of lactose and salts of stearic acid provides a high rate of release of the active substance. So, after 45 minutes on Wednesday dissolution of the drug moves not less than 95,0% loratidine. In addition, the use of the above-mentioned auxiliary substances in the claimed proportions allows to obtain a satisfactory quality of solid dosage forms and stability of its parameters during storage.

The preferred content of the microcrystalline cellulose in the dosage form is 3.0 to 15.0 wt.%.

As a salt of stearic acid can be used stearates of calcium, magnesium, zinc or other metals.

The proposed pharmaceutical composition is in the form of solid dosage forms, preferably in tablet form that provides maximum adaptability subsequent packaging and precision dosing of the active substance.

Way to get a new leee molding the resulting mixture. The use of the claimed quantitative and qualitative composition of ingredients allows to exclude from the process flowsheet stage wet granulation and drying, which significantly simplifies the manufacture of the dosage form and reduces losses. Mix ingredients in specified proportions also provides satisfactory strength tablets (5 - 6.5 kg, the abrasion resistance of not less than 99.8 per cent).

The obtained pharmaceutical composition complies with the requirements of the global Fund XI (in appearance, raspadaemosti, dissolution, uniformity of dosage and other factors), stable in storage and has a shelf life of at least 2 years.

Pharmacokinetic studies of the proposed drug was carried out on rabbits male breed chinchilla weighing 2,650,15 kg after a single injection of the drug per os at a dose of 18.75 mg/kg was Found that the bioavailability of the new antihistaminics means did not differ significantly from the known (pill claritin firm Schering-plough (Belgium), the active ingredient is loratadine), and the concentration of loratidine in the blood 15 minutes after administration of equivalent doses of the active substances was proposed composition is 18% more than the drug the efficacy and tolerability in the treatment of patients with perennial allergic rhinitis. Tests were carried out on 10 patients, including women - 8, men - 2, ranging in age from 17 to 45 years. The disease duration ranged from 1 to 10 years. The study included patients with perennial allergic rhinitis confirmed by the results of allergological anamnesis, skin testing with atopic allergens and the presence of specific IgE atopic allergens in the serum. All patients had clinical manifestations in the form of rinorea and/or swelling of the lining of the nose, sneezing, itching in the nose. The intensity of the symptoms was not less than 2 points. All the patients prior to the appointment of the preparation was carried out clinical and allergological examination, including:

- collection allergic, pharmacological and dietary history,

skin tests with atopic allergens: domestic (home, library dust), epidermal (feather, fur animals and birds), pollen (pollen of trees, grasses and Compositae), food,

- identification of specific IgE-antibodies to atopic allergens,

clinical and biochemical analysis of blood.

The proposed remedy was prescribed 1 tablet (10 mg), 1 time per day, directly before Breakfast, for 4 weeks. The severity of the clinical symptomes, but do not bother him;

2 points - moderate symptoms, and there are definitely observed, disturb the patient for some time;

3 points - severe symptoms, pronounced and disturb the patient most of the time.

Among the examined patients at 4 noted the average degree of severity of the disease and at 6 - easy. All patients confirmed allergic nature of the disease, and table 1 presents the results of Allergy tests.

All patients noted improvement of nasal breathing by the end of the first day of application of the proposed drug. Table 2 presents the assessment of symptoms of allergic rhinitis in scores at admission and their dynamics during the 4-week observation.

Table 3 presents the clinical effectiveness scores in patients receiving the new drug. 8 (80%) of 10 patients by the end of the second week there was total absence of symptoms of allergic rhinitis. 1 (10%) disappearance of symptoms was noted only to the 4th week of taking the drug, and only one minor symptoms persisted for 4 week new tools.

Thus, 90% of patients with allergic rhinitis mild and moderate group of patients had a satisfactory clinical effect of a new drug. All patients showed good tolerance of the drug. Therefore, all patients demonstrated positive clinical effect of the proposed drug and it can be recommended for medical use.

The invention is illustrated by the following examples (see table 4):

Example 1. To and 91.2 g of lactose (76,0 wt.%) add successively the mixture loratidine (12.0 g, 10.0 wt.%) with microcrystalline cellulose (15.6 g, 13,0 wt. %) and stearinovokisly calcium (1.2 g, 1.0 wt.%), stirred until a homogeneous mass. Ready tabletow mixture tabletirujut on a tablet press "Erweka (Germany). Get tablets with an average weight of 0.2 g that satisfy the requirements of the pharmaceutical agent. Raspadaemost tablets - 3 min (GF XI - not more than 15 min), dissolution for 45 min in 0.1 M p-d HCl - 100,0% (GF XI - not less than 75%), strength - 6.5 kg, abrasion - owner of 99.87%.

Examples 2, 3 perform similarly (table 4). The obtained tablets meet the requirements of the pharmaceutical agent.

1. Antihistaminics means in the form of a solid dosage form comprising as active ingredient loratadine and as excipients lactose and salt stearic the following ingredients, wt.%:

Loratadine is 0.5 to 20.0

Lactose - 53,8 - 98,3

Microcrystalline cellulose - 1,0 - 25,0

Salt of stearic acid - 0,2 - 1,2

2. Antihistaminics tool under item 1, characterized in that it contains from 3.0 to 15.0 wt.% microcrystalline cellulose.

3. Antihistaminics tool under item 1 or 2, characterized in that it contains as a salt of stearic acid, calcium stearate or magnesium.

4. Antihistaminics tool according to any one of paragraphs.1, 2 or 3, characterized in that it is made in the form of tablets.

5. The method of obtaining antihistaminics means, characterized in PP. 1 to 4, which comprises mixing the specified active substance and excipients and then molding the resulting mixture.


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