RU2253453C1 - Antiinflammatory and antiallergic composition - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: composition contains steroid as active principle, in particular 11-β,16-α,17-α,21-tetrahydroxy-9-α-fluoro-1,4-pregnadiene-3,20-dione or pharmaceutically acceptable salt thereof and special-destination additives including microcrystalline cellulose, crospovidone, and magnesium stearate.

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

3 cl, 1 tbl

Description

The invention relates to the field of the pharmaceutical industry and medicine, and relates to compositions based on glucocorticosteroids exhibiting anti-inflammatory and anti-allergic effects.

Glucocorticosteroids are among the most effective drugs that can be used to treat inflammatory processes, allergic or immunological diseases of the skin, respiratory tract. The drugs of this group are of particular importance, since they can be used to treat such a serious illness as asthma.

In the pathophysiological mechanisms of the development of bronchial asthma, a central place is given to chronic inflammation of the respiratory tract with the development of bronchial hyperreactivity. Inhaled glucocorticosteroids are currently first-line drugs in the treatment of patients with persistent asthma. The drugs not only improve lung function, but also prevent the development of exacerbations and irreversible airway obstruction. And therefore, they can be prescribed in the early stages.

In recent decades, new agents have also been introduced with a high affinity for glucocorticosteroid receptors and more pronounced anti-inflammatory activity, produced not only in the form of ointments, aerosols, but also in the form of other dosage forms, including preparations of prednisone, dexamethasone, etc. for oral administration.

One such preparation is a 1,4-pregnadiene-triamcinolone or 11-beta derivative, 16-alpha, 17-alpha, 21-tetrahydroxy-9-alpha-fluoro-1,4-pregnadiene-3,20-dione.

The chemical structure and action of triamcinolone is close to dexamethasone. It differs from it by the presence of an OH group instead of CH ₃ at position C ₁₆ . In some cases, it is better tolerated than other glucocorticosteroid analogues. The presence of a fluorine atom in the molecule affects the activity, enhancing the anti-inflammatory and anti-allergic effect.

It is known that the drug activates specific receptors located in the cytoplasm of target organ cells, induces mRNA synthesis and the formation of a special class of proteins — lipocortins, one of which lipomodulin inhibits the activity of phospholipase A ₂ ; regulates all types of metabolism, has anti-anabolic and catabolic effects; reduces glucose utilization by insulin-dependent tissues, causes hyperglycemia, increases the amount of glycogen in the liver (activates gluconeogenesis), enhances the breakdown of fats, delays sodium and water ions, promotes the excretion of potassium ions, reduces the absorption of calcium ions, induces the secretion of parathyroid hormone that mobilizes calcium from bone tissue. Its anti-inflammatory properties are due to the stabilization of cell membranes, including fat, and organelles (lysosomes), inhibition of phospholipase A ₂ activity (lipomodulin), cessation of arachidonic acid liberalization from phospholipids of cell membranes and a decrease in the level of metabolic products (PG, Tx, leukotrienes). In addition, it inhibits hyaluronidase, prevents the splitting of the main substance of connective tissue, inhibits the division of mast cells and reduces their degranulation (with the release of histamine, serotonin, bradykinin), inhibits the synthesis of platelet activating factor and proliferation of connective tissue; reduces the number of T- and B-lymphocytes, disrupts their interaction, stops the migration of B-lymphocytes (immunosuppressive and anti-allergic effect); reduces the concentration of immunoglobulins in blood serum, inhibits the cooperation of phagocytes and lymphocytes; it has an antishock and antitoxic effect, which is associated with an increase in blood pressure (due to an increase in the concentration of circulating catecholamines and restoration of the sensitivity of adrenoreceptors to them, as well as vasoconstriction), a decrease in the permeability of the vascular wall, membrane-protective properties, and activation of liver enzymes involved in the metabolism of endo - and xenobiotics.

Polyhedral properties of the drug are responsible for a wide range of applications: adrenal insufficiency, autoimmune thyroiditis, hypercalcemia of malignancy, psoriatic arthritis, gout and rheumatoid arthritis (including juvenile), ankylosing spondylitis, bursitis, tenosynovitis, post-traumatic osteoarthritis, epicondylitis, systemic lupus erythematosus, rheumatic carditis, pemphigus , Stevens-Johnson syndrome, erythema multiforme, dermatitis (exfoliative, herpetiform, bullous, seborrheic, contact , atonic), psoriasis, allergic rhinitis, bronchial asthma, serum or drug disease, allergic conjunctivitis, keratitis, iridocyclitis, sarcoidosis, Leffler’s syndrome, borreliosis, aspiration pneumonia, adult idiopathic thrombocytopenic purulent hemoplastic hematocytoma, hematopenia, thrombocytopenia, hematocytoma, hematopenia ), erythroblastopenia, acute or chronic lymphoblastic leukemia, lymphogranulomatosis, non-Hodgkin's lymphomas, breast cancer, prostate cancer, m cell disease, tuberculous meningitis, acute lymphoid leukemia in children, nephrotic syndrome, ulcerative colitis, Crohn's disease, celiac disease, hyperthermia in malignant neoplasms.

Anti-inflammatory compositions for oral administration are known, including an anti-inflammatory enzyme and a steroid, for example triamcinolone, in a mixture with excipients such as magnesium stearate and lactose and / or polyethylene glycol or sorbitol. The tablets may be enteric coated (patent GB 1005985 A, published September 29, 1965).

Known anti-inflammatory compositions for oral administration based on corticosteroids, including triamcinolone or its acceptable salts. A tablet may contain triamcinolone, 3-methylsalicylic acid, corn starch, methyl cellulose, aerosil and aluminum stearate (GB patent 1076425 A, published July 19, 1967).

There are known pharmaceutical compositions for the treatment of allergic and inflammatory diseases, for example, in the form of capsules containing glucocorticosteroid as an active principle, and sugar, polysorbate, eudragit, talc, triethyl citrate and others as auxiliary substances (Patent RU 2111212 C1, published 05.20.1998 )

As the closest analogue, a pharmaceutical composition may be indicated containing a steroid in microcrystalline form as an active ingredient, and collidone, Avicel, PEG, Aerosil, polyplazdone, Precirol, lactose as a carrier (RF patent 2126013 C1, published on 02.10.1999).

The bioavailability of the active principle when taking known tablets is not great, and the duration of action is on average 2.5 days. In addition, the doses of the active ingredients are small enough, which requires uniformity in the content of a single form. And this problem is not fully solved by the existing forms of the drug.

Triamcinolone and its salts are insoluble or slightly water soluble powders. Like most drug substances, they do not have the ability to direct tabletting.

As you know, the effectiveness of a drug depends on its bioavailability, stability and safety. Therefore, when developing new forms, the influence of such factors as the physical state of the substance, the method of their preparation, especially the selection of excipients, packaging is taken into account.

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-inflammatory and anti-allergic composition contains as an active principle 11-beta, 16-alpha, 17-alpha, 21-tetrahydroxy-9-alpha-fluoro-1,4-pregnadien-3,20-dione or its pharmaceutically acceptable salt, and as target additives, lactose, microcrystalline cellulose, crospovidone, magnesium stearate in the following components in wt.%:

11-beta, 16-alpha, 17-alpha, 21-tetrahydroxy-

9-alpha-fluoro-1,4-pregnadien-3,20-dione

or its salt 2.0-3.0

Microcrystalline cellulose 14.5-15.5

Crospovidone 4.0-6.0

Magnesium Stearate 0.5-1

Lactose rest

The pharmaceutical composition is in the form of tablets, which ensures maximum manufacturability of the subsequent packaging and the accuracy of the dosage of the active principle.

As the active principle, both 11-beta, 16-alpha, 17-alpha, 21-tetrahydroxy-9-alpha-fluoro-1,4-pregnadiene-3,20-dione in the form of a base can be used, as well as its pharmaceutically acceptable salts such as acetonide.

The composition may further comprise 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.

Lactose should be 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 large particles, for example, Avicel PH 200 [FMC Corp.], although pH 102 will also be suitable. The introduction of cellulose provides optimal dispersibility conditions for the form. And also gives good fluidity to the tableted mass.

Magnesium stearate is used as a traditional lubricant. Unlike stearic acid and its other salts, magnesium stearate affects the stability of the active principle to a lesser extent.

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.

In addition, the introduction of crospovidone improves the appearance of the tablets.

Disintegration of tablets significantly affects the release of active substances. However, this does not provide a direct connection with their bioavailability. So, microcrystalline cellulose contribute to the rapid disintegration of the tablets. However, it has the property of adsorbing active substances on itself. The formulation according to the invention allowed to obtain the optimal combination of disintegration and release of the active component.

A specially selected ratio of ingredients also provides improved organoleptic properties of the composition.

Production Method:

1. Dissolve the active principle in a suitable small volume of a selected solvent, such as methanol or ethyl acetate.

2. Weigh the amount of lactose equivalent to 20-25% of the total, and place in a closed mixing mixer.

3. Slowly add the active ingredient solution to the mixer with the stirrer working. Stirred for 5 minutes or more until the solution of the active principle is completely distributed in lactose.

4. Remove the solvent.

5. The remaining lactose is added to the dried mixture according to the recipe. Stirred for 10 minutes.

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

7. Weigh the magnesium stearate and add it to the mixture through a fine sieve for dispersion and mixing.

8. Transfer the tabletting mixture. If the tabletting process is delayed, the containers should be closed to prevent contact with the atmosphere. During manufacture, the product is controlled by weight and hardness at short intervals.

The possibility of carrying out the invention is illustrated by the following examples of pharmaceutical compositions (see table).

Table Composition, wt.% Example 1 Example 2 Example 3 Active start 2.0 2,5 3.0 lactose 78.0 78.0 74.0 microcrystalline cellulose 14.5 15.0 15,5 crospovidone 5,0 4.0 6.0 magnesium stearate 0.5 0.5 1,0 colloidal silica - - 0.3 sodium lauryl sulfate - - 0.2

The claimed pharmaceutical composition meets the requirements of GF XI in appearance, disintegration, solubility, uniformity of dosage, etc., does not have a bitter taste, is stable during storage.

The invention can be recommended for implementation in pharmaceutical practice.

Claims (3)

1. Anti-inflammatory and anti-allergic composition, made in the form of a tablet containing a steroid as an active principle and targeted additives, including microcrystalline cellulose and lactose, characterized in that the steroid is 11-beta, 16-alpha, 17-alpha, 21- tetrahydroxy-9-alpha-fluoro-1,4-pregnadien-3,20-dione or a pharmaceutically acceptable salt thereof, and additionally contains crospovidone, magnesium stearate as target additives in the following components, wt.%: 11-beta, 16-alpha, 17-alpha, 21-tetrahydroxy- 9-alpha-fluoro-1,4-pregnadien-3,20-dione or its salt is 2.0-3.0 Microcrystalline cellulose 14.5-15.5 Crospovidone 4.0-6.0 Magnesium Stearate 0.5-1 Lactose rest 2. The composition according to claim 1, characterized in that as lactose contains alpha-lactose monohydrate. 3. 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.