New anti-allergic anti-inflammatory composition and method of reception

 

(57) Abstract:

The composition includes, in particular, non-steroidal anti-inflammatory of sulfonanilide - nimesulide and its salts 1-53, antihistamine drug of the second generation, which is a receptor blocker N1-cetirizine, 0.3 to 3.3 and a suitable pharmaceutical base and fillers 44-98,5. The composition may be prepared in the form of a preparation for injection, local delivery systems, suspension for children, capsules or tablets, double-layered tablets, tablets with delayed release of active ingredients of gel for topical application, the composition for the reception of once a day dosing inhaler. A novel composition useful in the treatment of allergic diseases such as rhinitis, bronchitis, asthma, urticaria. The combination of nimesulide and cetirizine provides synergistic pharmacological action. 5 s and 5 C.p. f-crystals, 3 tables.

The invention relates to a new antileukotriene, antihistaminic, anti-allergic and anti-inflammatory compositions of non-steroidal anti-inflammatory sulfonanilide and its salts with antihistamine drugs of the second generation (receptor blockers H1).

B is whitesky acceptable combination in a suitable pharmaceutically acceptable base and fillers.

More specifically, this invention relates to compositions for use in allergic diseases, namely, rhinitis, bronchitis, asthma, urticaria, etc.

The background to the invention

Clinical symptoms that occur when allergic reactions are the result of early-specific immune response and late inflammatory response. Inhaled allergens (e.g. pollen, dust mites) mediate the early phase by stimulating high-affinity receptors of the immunoglobulin (IgE), for example, mast cells and basophils, which, in turn, release histamine and cytokines. This early stage lasts about 30 minutes. Cytokines released by mast cells and basophils, and then mediate the late phase by attracting cells of inflammation in the nasal and upper respiratory tract (Serafin, WE, in Goodman and Gillmans "The Pharmacological Basis or Tnerapeutics", Hardmen, Ja; Limbird, L,E eds. MC Graw - Hill, New York, 1996, 659-682). The influx of eosinophils, macrophages, lymphocytes, neutrophils and platelets leads to inflammation. This late phase, the ongoing 8-48 hours, amplifies the initial immune response, which, in turn, causes even greater release of cells of inflammation (Townley RG is receiving allergens in the nasal mucosa, that leads to the development of hypersensitivity reactions of immediate type. If allergens (eg, dust mites) reach the lower respiratory tract (i.e., bronchioles), in sensitive individuals, the result is bronchoconstriction (i.e. asthma). Induced by allergen release of leukotrienes, products of arachidonic acid metabolism, formed with the participation of 5-lipoxygenase, in the activated cells of the respiratory tract is the main point of the pathophysiology of asthma. Leukotrienes are produced by mast cells, eosinophils, neutrophils and alveolar macrophages. The use of specific antagonists leukotriene receptor inhibitors or path 5-lipoxygenase leads to an increase of the airway and alleviating symptoms in patients with asthma (Henderson WR, Jr., Annals of Allergy, 12, 1994, 272-277). Immunological concepts of asthma and related allergic diseases currently undergoing fundamental changes. Now assume that all types of asthma have an allergic basis, and all chronic allergic diseases are based on continuous inflammation, which is never eliminated completely. At the annual conference Heb the axis of the clinical significance of minimal persistent inflammation (IPOs). The presence of small amounts of cells and inflammatory receptors ICAM-1 on epithelial cells in patients suffering from allergies, was shown even during asymptomatic periods. Thus, the correct treatment of allergic diseases should be directed to allergic inflammation, not its symptoms. This annual conference was paid special attention to the revision of the definition of allergic diseases. Rhinitis and asthma were United as inflammatory mechanisms of mutual unified concept of the pathogenesis of allergic diseases. Allergic rhinitis and asthma often co-exist. Up to 40% of persons suffering from rhinitis, as concomitant diseases are asthma, and up to 80% of people with asthma, as an accompanying disease also have rhinitis. Persons suffering from rhinitis, have the risk of developing asthma, exceeding three times the risk of healthy individuals as mediators of inflammation that are constantly released in the respiratory tract, may cause damage to the epithelium of the respiratory tract, resulting in a person who suffers from allergies, it becomes prone to the appearance of asthma attacks (Wenzel, S. E., Annals of Allergy, 72, 1994, 261-271). Thus, it was VistaTM to control asthma. It was concluded that we should engage in the approach to the development of therapeutic strategies for the prevention of respiratory allergies than a strategy to treat emergency conditions when asthma.

Thus, it is obvious that despite the fact that antihistamines (receptor blockers H1second generation) are the most common agents for the treatment of allergic conditions (Gong, H, Tashkin, D. P., Dauphinee, W. et al., J. Allergy. Clin. Immunol., 85, 1990, 632-641), NSAIDs (nonsteroidal anti-inflammatory drugs) can also be very useful as anti-inflammatory medicines. To date NSAIDs, such as aspirin, its analogy or even unrelated chemical parts cannot be used in allergic diseases due to occurrence psevdoallergicakie reactions in patients with intolerance to aspirin. Despite their anti-inflammatory effects, almost all NSAIDs increase the release of histamine from mast cells and basophils, IgE mediated, what causes vasomotor rhinitis, urticaria, and asthma in these patients (Bianco, S, Robuschi, M, Petrigrni, G. et al., Drugs, 46, 1993, 115-120).

All of the above studies only meant the possible spread of the anti-inflammatory action of nimesulide on the control of inflammation of the upper respiratory tract. However, on the application of nimesulide as an anti-asthmatic drug because of its anti-allergic and inhibiting leukotrienes activity are still not reported, and after careful experimentation and use of scientific logic, the authors of the invention have joined nimesulide with cetirizine in different ratios and conducted a series of experiments to assess the suitability of this combination for use as an Antiasthmatic agent is zwyczajna useful in the treatment of asthma.

Other anti-inflammatory drugs used in chronic rhinitis, chronic bronchitis and bronchial asthma are kromolin sodium, nedocromil and glucocorticoids. Treatment with glucocorticoids is not without attendant risk of many side effects (Serafin, WE, 1996). Kromolin-sodium and nedocromil can enter only through inhalation, only 1% of the dose cromolyn absorbed when administered orally. Even inhalation kromolin-sodium must be entered 4 times a day due to a short half-life existence, constituting 45-100 minutes. It is reported that nedocromil leaves a nasty taste in the mouth. Evaluated several other anti-inflammatory agents, mainly as agents, without steroids. These agents include methotrexate, gold, troleandomycin, hydroxychloroquine, Dapsone, and cyclosporine. However, their efficacy is not clearly established (Szefler, S., Antiinflammatory drugs in the treatment of allergic diseases., Medical Clinics of North America, 76, 1992, 953-975).

U.S. patent 5658948 issued by ALLERGAN INC., discloses a composition and method that includes an acceptable drug, such as prostaglandins, flurbiprofen, Ketorolac, tromethamine, cetirizine is rvant, forming a precipitate, and the amino acid having sufficient positive charge at the pH of the composition and/or tromethamine is present in a quantity sufficient to inhibit the interaction of drugs with benzalkonium chloride and, thus, to maintain the activity of benzalkonium chloride as preservative. Further, the use of lysine, L-arginine or histidine is also useful for reducing the cytotoxicity of the composition.

U.S. patent 5627183 issued by SEPRACOR INC., reveals ways of using optically pure (+) cetirizine to treat hives in people, while supporting the propensity for side effects associated with the racemic mixture of cetirizine, is avoided.

U.S. patent 5419898 issued by SENJU PHARMACEUTICAL Co., LTD., reveals the antiallergic composition for ophthalmic and nasal application, comprising cetirizine or its salt as an active ingredient. This antiallergic composition may further comprise cyclodextrine compound, and a surfactant and/or water-soluble polymer.

Patent WO 9406429 issued by SEPRACOR INC., discloses methods and compositions using optically pure (-) cetirizine to treat with the effects associated with the racemic mixture of cetirizine, is eliminated. This optically pure (-) isomer is also suitable for the treatment of allergic asthma and chronic and physical urticaria. (-) cetirizine is an inhibitor of chemotaxis of eosinophils and therefore suitable for treatment of other conditions associated with eosinophilia, such as allergic asthma, seasonal allergic rhinitis, atopic dermatitis, some parasitic diseases, some chronic obstructive pulmonary disease and certain gastrointestinal and genitourinary disease.

In the literature there are no reports of pharmacological compositions, as well as in the sale of the product, which was used nimesulide and its salts in combination with antihistamine drugs of the second generation. Combinations of drugs with a fixed dose now again rapidly introduced into clinical practice after several years of ostracism, because they have the potential synergistic and predictable actions.

The aim of the present invention is to provide a new antileukotriene, antihistaminic, anti-allergic and anti-inflammatory composition containing nimesulide and its salts, and takiwa antileukotriene, antihistaminic, anti-allergic and anti-inflammatory composition containing nimesulide and its salts, and cetirizine.

Another objective of the present invention is the creation of a new delivery system of the above-mentioned composition in the form of a dosing nasal inhaler.

Another objective of the present invention is the creation of a new delivery system of the above-mentioned composition in the form of a device for injection.

Another objective of the present invention is the creation of a new local delivery system of the above-mentioned composition.

Another objective of the present invention is the provision of opportunities for oral administration of the above-mentioned composition in the form of pedriatic suspension/capsules/tablets.

A brief description of the nature of the invention

The present invention relates to a new composition of nimesulide and its salts and cetirizine with antileukotriene, antihistamines, anti-inflammatory and antiallergic effect.

This composition is suitable for treatment of allergic diseases such as rhinitis, bronchitis, asthma, urticaria, etc.

Detailed description of the invention

The following unique soust">

1) Nimesulide is a powerful stabilizer of mast cells and basophils. Thus, it prevents the release of histamine, proteases, TNF-, prostaglandins, leukotrienes, VEILS and other cytokines from activated mast cells.

2) Nimesulide inhibits indirectly the flow of eosinophils in asthmatic attacks due to its ability to stabilize mast cells and basophils. Mast cells and basophils release factor chemotaxis of eosinophils, which causes eosinophils to migrate in the direction of inflamed allergic tissue. It was also reported that nimesulide inhibits chemotaxis and synthesis of platelet activating factor and leukotrienes by human eosinophils.

3) Nimesulide powerfully inhibits phosphodiesterase type IV in neutrophilic leukocytes. Following this, the increase in the concentration camp responsible for the pronounced weakening of chemotaxis, degranulation and production of free radicals. Currently, inhibitors of PDE-IV are used as anti-asthmatic drugs.

4) Nimesulide inhibits neutrophil respiratory burst and, therefore, the release of free radicals, cytokines, eicosanoids, prostaglandins, etc.

5) is palenia by maintaining the natural defense systems of the body.

The second generation histamine antagonists (H1receptor) (e.g., cetirizine, Fexofenadine, acrivastine, astemizole, loratadine, etc.,) is the drug of choice for the treatment of allergic rhinitis because they are long and not have a sedative and anticholinergic effects. In addition, second generation antihistamines has the following unusual and potentially favorable properties:

1) These nnegative antihistamines showed dose-dependent protection against induced histamine of bronchoconstriction.

2) it Was shown that they protect from bronchoconstriction caused by physical stress, sprayed ultrasound, distilled water and cold air.

3) They cause a modest but statistically significant fast bronchodilatation asthma from mild to moderate severity.

4) it was Reported that cetirizine has anti-inflammatory properties in addition to its action as an antagonist of H1-receptors. Cetirizine inhibits the migration of cells inflammation through strong suppression of the influx of eosinophils and their degranulation.

5) Expression of ICAM-1 is a sensitive mouse human who are the cause of more than 80% of asthma attacks in children. It was reported that cetirizine is able to modulate and regulate in the direction of reducing the expression of SAM-1 in the epithelial cells.

6) Cetirizine very effectively inhibits skin with the phase of "early & late responses through the inhibition of VEILS and influx of eosinophils in the skin. Recently it was reported that almost 70% of patients with chronic urticaria have shown excellent results in the treatment of cetirizine daily dose of 10 mg In comparison with other antihistamines treatment with cetirizine caused a faster, more powerful and longer-lasting relief in the presence of blisters and inflammatory hyperemia.

7) Cetirizine does not cause cardiac arrhythmias reported using some other antihistamines.

8) it was Reported that long-term treatment with cetirizine effective compared with treatment needs rhinitis caused by sensitivity to the pollen.

Our research, as described in this patent application show that sulfonanilide NSAIDs, for example, nimesulide and its salts, when combined with cetirizine, provide an excellent synergistic omashu careful experiments, the authors present invention installed, despite the fact that nimesulide is not blocking introduced exogenous histamine, he very effectively blocks the release of histamine by stabilizing mast cells and basophils, as evidenced by the experiment with egg albumin described in this invention.

Released histamine, if such release occurred, will be blocked by cetirizine. Unexpectedly, we also found that nimesulide, as well as cetirizine, is effective on leukotrienes, and this effect is synergistic, when drugs are combined, as evidenced by table 3.

According to the present invention, describes a new composition of nimesulide and its salts and cetirizine with antileukotriene, antihistamines, anti-inflammatory and antiallergic effect.

According to a preferred variant implementation of the present invention, the composition comprises nimesulide in an amount of from 1 to 53 parts, cetirizine in the amount of from 0.3 to 3.3 parts and pharmaceutical base and fillers in an amount of from 44 to 98.5 parts.

Anti-inflammatory, antileukotriene, antihistaminic and antiallergic composition of the present invention may be in the application, capsules, tablets with delayed release of active ingredient, etc.

Anti-inflammatory, antileukotriene, antihistaminic and antiallergic composition of the present invention is produced by a method which includes the following steps.

Nimesulide and cetirizine mix until smooth and pass through a fine sieve to reduce the size of particles in the form of fine powder, and then perform any of the following steps to obtain the product in the desired form:

1. Indicated homogeneous powder is mixed with fillers at a temperature of 25 2oC and a relative humidity of 50 5% and fill with this mixture, empty gelatin capsules to obtain a dosage form in the form of capsules.

2. A homogeneous mixture granularit using a granulating liquid at room temperature and dried at a temperature not exceeding 60oWith over a period of time sufficient to obtain a moisture content of about 1%. After size reduction and lubricative granules pressed into tablets at a temperature of 25 2oC and a relative humidity of 50 5%.

3. A homogeneous mixture is dissolved in suitable solvent and adding a gelling agent DK dissolved in a solvent, suitable for parenteral administration. The solution is made at a temperature of from 25 to 35oSince under normal conditions of mixing. This solution is then filtered, sterilized and filled them ampoules under aseptic conditions. Alternatively, the sealed autoclave at a temperature of approximately 121oWith over a period of time of about 30 minutes.

Preferably, the composition comprises nimesulide and cetirizine in the ratio from 1:5 to 1:40.

Preferably, granulating liquid for granulating finely ground mixture of nimesulide and cetirizine is corn starch and/or polyvinylpyrrolidone.

Preferably, the solvent and gelling agent for dissolving finely ground mixture of nimesulide and cetirizine order to obtain gel for local and percutaneous application are the sulfoxide and/or dimethylacetamide and carbopol and/or hydroxypropylcellulose.

Preferably, the solvent for dissolving a homogeneous mixture of nimesulide and cetirizine order to obtain for injecting water and/or dimethylacetamide.

EXPERIMENT FOR THE STUDY OF ANTI-ASTHMATIC ACTIVITY OF NIMESULIDE AND CETIRIZINE
induced by egg albumin and induced leukotriene D4bronchoconstriction in Guinea pigs in vivo.

Materials and methods:

Animals

Used Guinea pigs weighing 300-350 g of the same sex, grown in the Central vivarium company Panacea Biotec Ltd., Lalru and kept in standard laboratory conditions.

Procedure:

Used Guinea pigs weighing 300-350 g after 18-hour fast under urethane anesthesia. To prevent spontaneous respiratory movements were administered d-tubocurarine (3 mg/kg intravenously). Guinea pigs was carried out by artificial ventilation through a tracheal cannula with injection speed of 60 movements per minute and the injection volume of 1 ml/100 g, with the use of the device for ventilation UGO Basile Rodent ventilator. The insufflation pressure was measured by connecting the pressure transducer (UGO Basile) to dual Registrar Gemini (UGO Basile). For intravenous administration of drugs into the left jugular vein was placed a polyethylene catheter. The animals were stabilized for 10 minutes.

% the insufflation pressure was calculated as % increase of pressure due to konstruktsii respiratory tract from the source of pressure. Less % pressure insufflation meant less bronchoconstriction caused by the influence of ispytuemykh and the cetirizine dihydrochloride (Panacea Biotec Ltd., India), histamine, leukotriene D4and urethane (all from Sigma, USA), d-tubocurarine chloride (Diosynth, the Netherlands), egg albumin (Qualigens Fine Chemicals, Mumbai). Cetirizine was dissolved in deionized water. Nimesulide suspended in a 0.25% solution of xanthan gum. Histamine and d-tubocurarine chloride was dissolved in physiological solution, and leukotrien D4was diluted with methanol and buffer of ammonium acetate in the ratio of 70:30 at pH of 5.4.

Statistical analysis

Used unpaired t-student test and was considered significant value p<0.05 and above.

The Protocol of the experiment

Group 1 the Effects of histamine

The animal spent provocation with histamine (5 g/kg and 10 g/kg intravenously), and in the control group noted increased pressure insufflation (table 1).

In the experimental group compound (nimesulide, cetirizine, nimesulide + cetirizine) was given 2 hours before the provocation with histamine. Noted any decrease in pressure insufflation (table 1).

Group II the Impact of egg albumin

Guinea pigs were senzibilizirani injections of 100 mg of egg protein administered intraperitoneally and 100 mg of egg protein subcutaneously in saline. Guinea pigs zadiel increasing pressure insufflation (table 2).

Group III the Impact of leukotriene D4< / BR>
Animals were carried out provocation 1 μg/kg and 2 mg/kg leukotriene D4and noted increased pressure insufflation in the control group (table 3).

In the experimental group two hours to provocations by leukotriene D4gave compound (nimesulide, cetirizine, nimesulide + cetirizine). Noted any decrease in pressure insufflation compared with the control group (table 3).

The results:

Cetirizine (of 1.66 mg/kg) significantly decreased induced by histamine (5 and 10 g/kg) increased pressure insufflation. Nimesulide (single dose, S, 11,66 mg/kg and a double dose, D, 23,32 mg/kg) had no significant inhibitory effect on the pressure insufflation.

The combination of nimesulide (single dose, S) and cetirizine showed no significant effect, while nimesulide (double dose. D) and cetirizine had a powerful antihistamine effect.

Nimesulide (11,66 mg/kg) significantly reduced induced by egg albumin (1 mg/kg, 2 mg/kg) pressure insufflation, the effect of nimesulide was 92,0 to 94,0%. Cetirizine (of 1.66 mg/kg) also reduced the pressure insufflation, but a little less than nimesulide. In combination Nimnul ulid (11,66 mg/kg) had no effect on the pressure insufflation, while cetirizine (1,16 mg/kg) significantly blocked the reduction (bronchi), induced leukotriene D4. The combination of nimesulide (11,66 mg/kg) and cetirizine (1,16 mg/kg) potently blocked the reduction (bronchi), induced leukotriene. A double dose of nimesulide (23,32 mg/kg) by itself had a strong inhibitory effect on the contraction of the bronchi), induced leukotriene D4. The combination of nimesulide (23,32 mg/kg) and cetirizine (1,16 mg/kg) had the maximum ( 90%) inhibitory effect on the contraction of the bronchi), induced leukotriene D4(table 3).

Discussion

It is cetirizine and not nimesulide acts as a powerful antihistaminic agent in an experimental model of bronchoconstriction in Guinea pigs. A double dose of nimesulide in combination with cetirizine demonstrates a powerful antihistamine effect, which is probably due to the same cetirizine.

Thus, the nimesulide possesses antihistaminic action, if histamine is already freed and took their receptors. However, nimesulide may have an inhibitory effect on the already formed mediators of Allergy, showing, thus, indirect antihistamine effect.

Both drugs, and cetirizine, and nimesulide in double dose, can block bronchoconstriction induced by leukotriene D4, in Guinea pigs. The combination of cetirizine nimesulide is a very powerful blocker of bronchoconstriction induced leukotriene D4. This effect might be due to selective inhibition of phosphodiesterase (PDE) isoforms III and IV. Such inhibition has demonstrated significant anti-inflammatory effects in vivo. Inhibitors of PDE IV act by the induction of increased intracellular camp levels, which, in turn, inhibits the activity of cells of inflammation and causes the relaxation of smooth muscles of the respiratory tract. It is reported that nimesulide is a potent inhibitor of PDE IV in vitro under IC5040 microns. What this combination effectively blocks exogenously introduced leukotriene D4implies that namesco nimesulide/cetirizine act as receptor antagonists leukotriene D4.

Inhibition of this combination of antigen-induced (egg albumin) bronchoconstriction can also occur due to its ability to act as an inhibitor of PDE III/IV.

These preclinical results suggest the potential therapeutic effectiveness of the combination of nimesulide and cetirizine for the treatment of allergic inflammatory diseases of the Airways such as asthma.

Conclusion

As currently asthma is treated primarily as a chronic allergic disease with underlying inflammatory activity, an ideal anti-asthmatic drug must possess the following three properties:

Antiallergic activity

Antileukotriene action

Antigistaminny action

Nimesulide and cetirizine together with a have all three properties that clearly follows from the following observations:

1. Cetirizine (1,16 mg/kg orally) causes a decrease in % pressure insufflation on 42,86%, nimesulide (23,32 mg/kg orally) on 61,0%, while nimesulide + cetirizine synergistically reduce this pressure on 80,21% if bronchoconstriction, induserve reduction % pressure insufflation on 70,52%, nimesulide (11,66 mg/kg orally) on 90,24%, while nimesulide + cetirizine synergistically reduce this pressure on 96,57% if bronchoconstriction induced by egg albumin, Guinea pigs (table 2).

3. If bronchoconstriction induced by histamine, cetirizine (1,16 mg/kg orally) causes a decrease in % pressure insufflation on 62,71%, while nimesulide has no antihistamine actions.

Thus, to obtain a synergistic action in cases 1 and 2 require the combination of these two drugs, as described above. In case 3, histamine, who escaped stabilizing mast cells actions of nimesulide and freed, will be blocked cetirizine, will not reach the receptor sites, and bronchoconstrictive will be prevented.

These preclinical results suggest the presence of anti-asthmatic action of a combination of nimesulide and cetirizine in three directions.

The inflammation associated with asthma, will be reduced by nimesulide by selective inhibitory activity against SOH-2.

Thus, the present invention should, for the treatment of asthma will be useful combination of NSAID nimesulide and an is, is going to be useful in the elimination of symptoms of asthma and related to asthma conditions much more effectively than known medicines when they are applied separately.

The present invention will be further described by the accompanying examples, which serve the purpose of illustration only and should not be construed as limiting the scope of the present invention.

Example I: Tablets

1. Nimesulide 200 mg

2. Of the cetirizine dihydrochloride 10 mg

3. Microcrystalline cellulose 100 mg

4. Corn starch 40 mg

5. PVP K-30 4 mg

6 Lauryl sulfate 1 mg

7. Magnesium stearate 4 mg

8. Colloidal silicon dioxide 6 mg

9. The glycolate sodium starch 10 mg

10. Purified water - -

Mix 1, 2, 3 and 4. Dissolve 5 and 6 in 10 and pelletize this mixture and stir. Dried, soften and mix 7, 8 and 9. Extruding tablets.

Example II: Tablets

1. Nimesulide 200 mg

2. Of the cetirizine dihydrochloride 5 mg

3. Microcrystalline cellulose - 81 mg

4. Corn starch 30 mg

5. Castor oil, gidrirovannoe polyoxyl 40 - 1 mg

6. PVP K-30 2 mg

7. Magnesium stearate 2 mg

8. Colloidal silicon dioxide 4 mg

9. the W ith this mixture and stir. Dried, soften and mix with 7, 8 and 9. Extruding tablets.

Example III: topical Gel

1. Nimesulide - 1%

2. Cetirizine (suitable pharmaceutical form) - 0,5%

3. The carbopol - 1%

4. Hydroxypropylcellulose is 1.5%

5. PEG 400 - 25%

6. Dimethyl sulfoxide - 15%

7. Isopropyl alcohol - 40%

8. Hydrochloric acid - q.s. to adjust pH 9

Propylene glycol - 5%

10. Purified water - 10%

Dispersing 1 in 5, 6 and 9 separately. Dissolve 2 80% 10. Dispersing 3 and 4 in 7 under vigorous stirring. Add these two solutions to the dispersion. Dilute 8 in the remaining 10 and to bring the pH to within 2-6.

Example IV: Capsules

1. Nimesulide 200 mg

2. Of the cetirizine dihydrochloride 10 mg

3. Corn starch 80 mg

4. Sodium lauryl sulphate 1.5 mg

5. Colloidal silicon dioxide is 3.5

Empty hard gelatin capsules. Sift 1, 3 and 5 through a sieve mesh 30, and 2 and 4 through a sieve of 60 mesh. Stir until smooth and fill the empty hard gelatin capsules of this blend in the amount of 295 mg.

Example V: Tablets with delayed release of active ingredients

AND

1. Nimesulide 200 mg

2. Lactose 100 mg

3. Hydroxypropylmethyl magnesium - 2 mg

7. Colloidal silicon dioxide 2 mg

8. Isopropyl alcohol 2 mg

Mix 1, 2 and 3. Dissolve 4 and 5 8 and pelletize this mixture and stir. Dried, soften and mix with 6 and 7.

Century

1. Of cetirizine hydrochloride 10 mg

2. Lactose - 225 mg

3. Corn starch - 55 mg

4. PVP K-30 3 mg

5. Magnesium stearate 3 mg

6. The glycolate sodium starch 4 mg

10. Purified water - -

Mix 1, 2 and 3. Dissolve 4 in 10 and pelletize this mixture and stir. Dried, soften and mix with 5 and 6. Extruding the granules a and b in a two-layer tablet.

Example VI: Tablets of nimesulide (emotions.com pump) + cetirizine

I Drug layer

Nimesulide 200 mg

Sodium chloride 15 mg

The carbopol 934 P 100 mg

Magnesium stearate 1 mg

Osmotic layer

Plastic oil 100 mg

The carbopol 934 P - 150 mg

Sodium chloride 10 mg

Magnesium stearate 1 mg

Red iron oxide 0.5 mg

Two layers to mix separately and extruded in a double-layer tablet.

II Covering layer

The cellulose acetate - 4%

PEG 600 - 4%

Purified water - 10%

Acetone - 82%

Dissolve the cellulose acetate in a solvent is pouring hole to the drug layer.

III Cetirizine floor

Of cetirizine hydrochloride 10 mg

The hypromellose - 7 mg

PEG 400 - 0.5 mg

Isopropyl alcohol. Purified water. Red iron oxide is 0.05 mg

To prepare the covering solution and apply a coating on the tablets of phase II to obtain 10 mg/tablet of cetirizine hydrochloride.

Example VII: Dosing inhaler

1. Nimesulide (ranging from 1 to 5 microns) - 33%

2. Of cetirizine hydrochloride (ranging from 1 to 5 microns) and 3.3%

3. Lactose - 2%

4. Sorbitan trioleate - 0,5%

5. The propellant 114 - 30,60%

6. Propellant 12 - 30,60%

Suspended 1, 2 and 3 in a mixture of 4, 5 and 6 and to fill the device for metered dose inhalation with the help of cold filling, well-known to experienced professionals.

Example VIII: Preparation for injections

1. Potassium salt of nimesulide - 2%

2. Of cetirizine hydrochloride - 0,33%

3. Benzyl alcohol - 2%

4. Donativa salt of ethylenediaminetetraacetate - 0,002%

5. Water for injection q.s. up to 100%

Dissolve 4 90% 5 by heating up to 80oC. Add 3 and mix. Then add 1 and 2 and mix until obtaining a clear solution. To bring the volume to 100% with 5. Filtered through nylone the Nimesulide - 0.1 wt.%

2. Of the cetirizine dihydrochloride is 0.33 wt.%

3. Oligobrachia acid and 0.5 wt.%

4. Alerby alcohol to 4.0 wt.%

5. 1,1,2-Tetrafluoroethane (HFC-134a) - q.s. to 100 wt.%

Mix 1 and 2 with 3, then 4. Dispersing this mixture in 5 at a temperature below 20oC. Placed in a can or bottle inhalation and clogging the valve with pump dispenser.

1. Antileukotriene, antihistamines, anti-inflammatory and antiallergic composition of non-steroidal anti-inflammatory sulfonanilide-of nimesulide and its salts and antihistamine drugs of the second generation, which is a receptor blocker N1-cetirizine, in a suitable pharmaceutical basis and fillers in the following ratio of these components, including:

Nimesulide - 1-53

Cetirizine - 0,3-3,3

Pharmaceutical basis and fillers - 44-98,5

2. The composition according to p. 1, characterized in that it is in the form of a preparation for injection, local delivery systems, suspension for children, capsules or tablets, double-layered tablets, tablets with delayed release of active ingredients of gel for topical application, the composition for the reception of once a day dosing inhaler.

3. FPIC is p. 1 non-steroidal anti-inflammatory sulfonanilide-of nimesulide and its salts and antihistamine drugs of the second generation, which receptor blocker N1-cetirizine, which involves mixing of nimesulide and cetirizine until smooth and pass the mixture through a fine sieve to reduce the particle size to obtain a fine powder, mixing the indicated homogeneous powder with fillers at a temperature of 252oC and relative humidity 505% and the content of this mixture is empty gelatin capsules to obtain a dosage form in the form of capsules.

4. The method of obtaining antileukotriene, antihistaminic, anti-allergic and anti-inflammatory compositions under item 1 of nonsteroidal anti-inflammatory sulfonanilide-of nimesulide and its salts and antihistamine drugs of the second generation, which is a receptor blocker N1-cetirizine, which involves mixing of nimesulide and cetirizine until smooth and pass the mixture through a fine sieve to reduce the particle size to obtain a fine powder, granulating the homogeneous mixture at room temperature and drying at a temperature not exceeding 60oWith over a period of time sufficient to obtain a moisture content of about 1%, the reduction of the dimensions of the resulting mixture in a conventional manner and l is about getting antileukotriene, antihistaminic, anti-allergic and anti-inflammatory compositions under item 1 of nonsteroidal anti-inflammatory sulfonanilide-of nimesulide and its salts and antihistamine drugs of the second generation, which is a receptor blocker N1-cetirizine, which involves mixing of nimesulide and cetirizine until smooth and pass the mixture through a fine sieve to reduce the particle size to obtain a fine powder, dissolve a homogeneous mixture in a suitable solvent and adding a gelling agent to gel formation for local use or gel for cutaneous injection.

6. The method of obtaining antileukotriene, antihistaminic, anti-allergic and anti-inflammatory compositions under item 1 of nonsteroidal anti-inflammatory sulfonanilide-of nimesulide and its salts and antihistamine drugs of the second generation, which is a receptor blocker N1-cetirizine, which involves mixing of nimesulide and cetirizine until smooth and pass the mixture through a fine sieve to reduce the particle size to obtain a fine powder, dissolve a homogeneous mixture in a solvent suitable for parenteral entered the obtained solution.

7. The method according to any of paragraphs.3-6, characterized in that the composition comprises nimesulide and cetirizine in the ratio of from 1:0.3 to 1:3,3.

8. The method according to p. 4, characterized in that for granulating finely ground powder mixture of nimesulide and cetirizine use corn starch and/or polyvinylpyrrolidone.

9. The method according to p. 5, characterized in that the diluent for dissolving finely ground mixture of nimesulide and cetirizine is the sulfoxide and/or dimethylacetamide, and gelling agent in the preparation of a gel for topical application and gel for cutaneous injection is the carbopol and/or hydroxypropylcellulose.

10. The method according to p. 6, characterized in that the solvent for dissolving a homogeneous mixture of nimesulide and cetirizine for injecting water and/or dimethylacetamide.

 

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