MXPA00001713A - New pharmaceutical compositions of meloxicam with improved solubility and bioavailability - Google Patents

Abstract

Pharmaceutical compositions containing enolic carboxamide type antiinflammatory agent meloxicam that exhibit improved wettability, aqueous solubility, dissolution behaviour over a broad range of pH, and that are prepared by crystal structure modification of the drug through dry or wet mechanical homogenization with two further components - one of them is selected from a group of oligo - and dissolution improving, or alkalizing agent. The application of the formulations according to the present invention results in an improved biovailability and effectiveness of meloxicam.

Description

NEW MELOXICAM PHARMACEUTICAL COMPOSITIONS WITH IMPROVED SOLUBILITY AND BIOAVAILABILITY FIELD OF THE INVENTION La. present invention relates to novel meloxicam pharmaceutical compositions having improved solubility and biosavailability, and to pharmaceutical formulations.

BACKGROUND X > E XNVENTION Non-steroidal anti-inflammatory croqas (DAINE) are widely used for the long-term treatment of chronic rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. The target for the action of DAINE is the cyclooxygenase (COXJ, the enzyme ümit-an ± e of IB, the speed of the prostaglandin synthesis, the meloxicam [2H-l ^ -l3er? _zo ± ia ^ in-3 -caj: Qa ??? id - 4-hydroxy-2-methyl-lü- (5-methyl-2-thiazolyl) -1, 1-dioxide] is a new anti-inflammatory drug ± oia ÜO spheroidal of enolic-acid type ^ with high anti-inflammatory potency and low ulcerogenic activity and low renal toxicity In addition to anti-inflammatory, antipyretic and analgesic activity, effective (inhibitor ia with selectivity relative to COX-2) meloxicam has been shown to prevent the development of colorectal cancer. It is known that meloxicam is crystallized in four different prototropic forms, the anion, the acid enol, the zwitterion, and the cationic form and depending on the pH value of the solution.The meloxicam has a low solubility in an acidic or neutral medium. therefore the preparation of pharmaceutical formulations results in complicated and difficult production processes. In addition, the low solubility of meloxicam gives rise to irregular resorption, and consequently ea.te. a_ with non-uniform plasma concentrations and in vivo. JP 04321624 discloses the improvement of the biodispersibility of numerous non-spheroidal anti-inflammatory agents (for example indomethacin, fentanyl, flurbiprofen, piroxicam, lornoxicam and eloxicamj formulating the drugs with a block polymer of is tyro-isoprene-is tyrolean and with crotamiton. An improved transdermal supply of the drug is thus achieved WO 93/01814 describes ophthalmic compositions containing meloxicam for treating ocular inflammation and microbial infections Describes medium viscosity instillable ophthalmic compositions containing an anti-inflammatory oxicam as an active ingredient, together with a polymer of acrylic acid gelling agent and a base, in such a way that the resulting aqueous solution has the desired fluidity and a pH between 6.5 and 8. IT 01,? -FLl-5¿0 de-scri7be a complex d in- meloxicam cyclodextrin cyclodextrin The molar ratio of meloxicam to cyclodextrin is 1: 2.5, claiming a real inclusion complex. The methods described in the patent application are traditional techniques that consume energy and time to complex meloxicam.

BRIEF DESCRIPTION OF THE INVENTION. The main object of the present invention is to provide new compositions of meloxicam with improved solubility and bioavailability. Surprisingly it has now been found that the solubility and bioavailability of meloxicam can be improved by mixing meloxicam with special additives, using different production processes (co-grinding, co-pulverizing, co-kneading, etc.).

It has also been found that it is possible to produce special dosage forms containing meloxicara resulting from the improved solubility. Thus, the fundamental problem of the invention is solved by a pharmaceutically acceptable composition comprising meloxicam as active ingredient, a cyclodextrin, an optional oligosaccharide different from cyclodextrinat an optional polysaccharide, one or more pharmaceutically acceptable additives selected from the group consisting of: - surfactants - hydrotropic agents - alkalizing agents = - hydroco-loides and - polymers and optional excipients .., carriers and / or auxiliary agents, wherein the pharmaceutical composition is available by co-grinding, co-pulverizing or co-melting meloxicam in the presence of a pharmaceutically acceptable additive. By -COJ Following in a fashion 1 of the invention, meloxicam is mixed with additives such as surfactants and / or co-solvents and / or hydrotropic agents and / or alkalizing agents and / or cyclodextrins and / or hydrocolloids and / or pharmaceutically acceptable polymers. . In one embodiment of the invention meloxicam is mixed with surfactants, especially mono-polyoxyethylene sorbitan fatty acids, diethylene glycol monoethyl ether, and nonionic tetraethylene glycol ether. In a further embodiment of the invention the solubility and bioavailability of meloxicam can be improved by micronization of the substance in the presence of suitable co-solvents such as propylene glycol ... glyceoxol polyethylene glycol and ethanol. The addition of hydrotropic agents to meloxicam during micronization may also improve solubility and bioavailability. Preferred hydrotropic agents are, for example, glycinate of sodium dioxycoumarin, methylqiuc mine or a combination thereof. The use of cyclodextrin in combination with meloxicam. it can improve the solubility and bioavailability without forming an actual inclusion complex of cyclodextrin and meloxicam. Suitable cyclodextrins are for example β-cyclodextrin hydrate (BCDx), 6-monoamino-beta-cyclodextrin (ambcdX.) _, Β-cyclodextrin hydrate (GCDx), branched β-cyclodextrin (of the glucosyl-maltosyl substituted type) , derivative of β-cyclodextrin hydrate modified by enzyme) and hydroxypropyl-β-cyclodextrin (with a degree of hydroxyajLylation between 4.0-5.0). the cyclodextrins are preferably used in an amount of eloxica: cyclodextrin = 1: 99 and especially 30:70 (w / w) • The combination of the cyclodextrin-meloxicam product with the additives mentioned above results in a further improvement of the solubility and bio-discrimination. Suitable additives are suxfactants, cosolvents, hydrotropic components, alkalizing additives, hydrocolloids and pharmaceutically acceptable polymers, especially propylene glycol methyl cellulose ether, trl-Jahydroxy st.1.1-aminomethane 2,6-diamino-hexanoic acid, (D, L-lysine), mannitol, polyethylene glycol, propylene glycol, diethanolamine, ethyleneamine, monoethanolamine, triethanolamine, diisopropylamine, dibutylamine, pentylamine, sodium carbonate, sodium dodecyl sulfate, ammonium carbonate, powdered sodium hydroxide, sodium phosphate , methylglucamine, polyvinylpyrrolidone, cellulose ether, polyoxyethylene-polyoxypropylene block copolymers and / or nicotinamide. Another object of the present invention is to provide pharmaceutical compositions containing meloxicam with the mentioned additives, which have an improved solubility for oral, rectal, transdermal, ophthalmic and parenteral administration. Another object of the present invention is to provide a controlled release oral pharmaceutical composition consisting of a two-p tablet. The first layer contains an initial rapid release dose of meloxicam, together with at least one additive mentioned above. The second layer consists of meloxicam with usual pharmaceutical excipients, respectively controlled release agents. The auxiliary agents known in the state of the art are used for the preparation of these two-layer tablets. Other pharmaceutical compositions of the present invention provide an effervescent tablet, flavored effervescent sachets, tablets, tablets. hydrogelt ophthalmic ointments, ophthalmic hydrogels and rectal suppositories, Figure 1J Thermal flow curves of free meloxicam (A) the physical mixture of meloxicam with β-cyclodextrin hydrate (B) and the composition according to example IV / 1 CC). Figure 2: Thermal flow curves of free meloxicam (A) the physical mixture of meloxicam with β-cyclodextrin hydrate (B) and the composition according to example IV / 2 (C) _ Figure 3: Thermal flow curves of free meloxicam i A) the physical mixture of meloxicam with β-cyclodextrin hydrate (B) and the composition according to example IV / 3 (C). Figure 4 __ Heat flow curves of free meloxicam (a) the physical mixture of meloxicam with β-cyclodextrin hydrate (B) and the composition according to example IV / 4 (C). To describe the invention more specifically but without attempting to limit the scope of the invention in any way, the following examples are presented: Example 1/1. 10 g of meloxicam and 90 g of microcrystalline cellulose (AVICEL) were intensively co-milled for 6 hours at room temperature in a ball mill of r.erárni.r.a. presence of. 0 -2.5_% (w / w) of the following surfactants: TWEEN-80 and Solutol HS 15, The co-ground system was then dried at constant weight, and passed through a 0.075 mm sieve. The in vitro dissolution test showed that the composition according to Example 1/1 has a significantly improved solution (Table 1), The control composition consisted of cellulose and meloxicam, and was prepared under identical conditions as the surfactant compositions. meloxicam-cellulose.

Table 1. Meloxicam in vitro dissolution (at pH 7.6, 37 ° C) of compositions based on solid cellulose after a mechanical treatment of 6 hours.

Similar effects of the mentioned additives were observed at melting rates of meloxicam at pH 6.6 in distilled water and at pH 1.2 in hydrochloric acid.

Example Il / l. 25 g of meloxicam were completely ground in a ceramic ball mill at 25 ° C for 6 hours with 75 g of microcrystalline cellulose, in the presence of 5% (v / p) of propylene glycol, polyethylene glycol 400 (PEG-400 ) and glycerol, respectively. The composition was dried at 457 * C at constant weight to provide 102 g of a slightly yellow solid with a meloxicam content of 24.6%. The dissolution rates were determined in aqueous solution with pH 7.6 at 37 ° C. The improvement in the rate of meloxicam dissolution due to mechanical treatment is shown in Table 2. (The control composition was prepared under an identical mechanical treatment of 25 g of meloxicam _ and 75 g of microcrystalline cellulose without co-solvents).

Table 2. Effect of co-solvents on meloxicam solution in buffer solution 7.6- to 3-7 ° C Example III / 1 25 g of meloxicam and 75 g of lactose were milled intensively in a ball mill for 4 hours without (control) and in the presence of 20% (by weight) of nicotinamide and 20% of sodium glycinate, respectively. Solid compositions were sieved through a 0.071 mm sieve and tested for meloxicam solution at pH = 1.2 at 37 ° C. The results are listed in Table 3.

Table 3, Effect of hydrotropic additives on the melonic dissolution rate in buffer solution d-e-pH 1.2 at 3-7 ° C.

Example IV / 1. The co-spraying of the S-component meloxicam bolides and beta-cyclodextrin hydrate (BCDx) in a ceramic ball mill for a sufficient time resulted at room temperature in a novel solid state structure of these solids, as proved by X-ray diffractometry and also by microscopy. The composition after a milling process also exhibited an improved dissolution profile, compared to meloxicam, milled only under the same conditions. Thus, 11.35 g of beta-cyclodextrin hydrate (Crystalline BCDxl with a water content of 13.8% and 1.76 g of crystalline meloxicam were milled in a ball mill intensively for 6 hours at 25 ° C to reach the amorphous state. Metastable, The resulting solid composition was passed through a 250 μm sieve Characteristics of the meloxicam composition according to Example IV. / I .: The product appears as a slightly yellow, free-flowing, xxo hygroscopic powder, as indicated by the investigations of high differential calorimetry and scanning. resolution this co-operation -auustra do-s most distinct ß - related to meloxicam - on the thermal flow curve at 255 ° C, and 280 ° C. This phenomenon is attributed more probably to the co-existence of different Prototropic forms in the solid state of the drug, which are generated by mechanical manipulation in the presence of hydrated beta-cyclodextrin The CBD of pure meloxicam showed an endothermic thermal flow of fus ion at 267-270 ° C which is in good agreement with literature data meloxicam melting point (_268 ° C) • (See Figure 1). The content of eloxicam of the composition according to Example IV / 1. It is 13.1%, and the product has a weight loss between 5.9-6.6% after drying. The X-ray diffraction analysis of powders of the co-ground system in a ball mill according to Example IV / 1. He indicated that the micronization treatment resulted in the decrease of crystallinity, but without the complete amorphization of the system. The dissolution characteristics of the melQxicam composition according to Example IV / 1. They are shown in Table 4. The s} The standard method was used to determine the dissolution rate of the drug compositions: the in vitro dissolution properties of the meloxicam compositions based on oiolodextrin were studied. non-sedimentation conditions in two different buffer systems, pH 1.3 and 7.6, respectively, and in deionized water (pH = 6.6) at 37 ° C. The agitation speed was 160 rpm. To ensure a comparable particle size distribution, the samples were passed through an 80 mesh screen before the dissolution test. The sampling time intervals were 5, 10, 15, 30, 45 and 60 minutes.

Table 4: In vitro dissolution rates of free meloxicam and of the composition according to Example IV / 1 to p? T 1.3- and 7.6 to 3-7 ° C.

The improvement in solubility at gastric pH was about 5 times.

Example TV / 2. 1.0 g of meloxicam, 9.0 g of beta-CD hydrate (BCDx), 0.01 g of Methocel ™ and 5 ml of deionized water were added to a ceramic mortar and they were kneaded intensively for 45 minutes at room temperature. The wet homogenized material was passed through a 2 m screen, and dried at 40 ° C to provide a hard, yellowish solid. The dried product was sieved through a 0.25 mm sieve (.9.53 g, meloxicam content: 8.7% by weight). The investigation of the solid state of the product according to Example IV / 2. by CBD revealed the existence of a new type of structure of the active ingredient, which is characterized by thermal flow curves of CBD in the temperature range of 160-320 ° C. This indicates the co-existence of two different allotropic forms of the meloxicam, evidenced by changes in negative enthalpy fusion), at around 250 and 293 ° C respectively. None of these enthalpy strands are identical to the defined melting thermal flux of meloxicam itself, which appears at 254-266 ° C. The simple mechanical blending of meloxicam with beta-CD hydrate resulted in a composition that had a CBD pattern. with a melting range (255-265 ° C) near the meloxicam melting point (See Figure 2). The dissolution characteristics of the product according to Example IV / 2 are shown in Table 5.

Table 5: In vitro dissolution rates of free meloxicam (130 mg) and of the composition according to Example IV / 2. (1500 mg) at pH 1.3- and 7.6 at 37 ° C.

Example TV / 3. 1.0 g of meloxicam, 9.0 g of beta-a-CD hydrate (BCDx), 0.01 g of tris-hydroxymethyl aminomethane and 5 ml of deionized water were added to a double-screw kneading apparatus, and intensively co-kneaded for 45 minutes at room temperature. The wet humid material was passed through a 2 mm screen, and dried at 40 ° C to provide a hard, yellowish extruded material. The solid and dry product was sieved through a 0.25 mm sieve (Yield: 10.03 g of yellow powder, meloxicam content: 8.2% by weight). The CBD pattern of the product according to Example IV / 3. showed the existence of two different allotropic forms of meloxicam, with enthalpy-negative changes characteristic of 256 and 294 ° C (See Figure 3). The dissolution characteristics of the product according to Example IV / 3 are shown in Table 6.

Table 6: In vitro dissolution rates of free meloxicam (, 130 mg) and of the composition according to Example IV / 3-. (1500 mg) at pH 1.3- and 7.6 at 37 ° C.

Example IV / 4 1.0 g of meloxicam, 9.0 g of beta-CD hydrate (BCDx), 0.01 g of 2,6-diamino-hexanoic acid (DL-lysine) and 5 ml of deionized water were added to a double-kneading machine. screw, and co-kneaded intensively for 45 minutes at room temperature. The wet mixture was dried at 40 ° C to provide a hard, yellowish solid. The solid and dry product was sieved C, through a 0.25 mm sieve (yield: 9.9 g of yellow powder, with a meloxicam content of 9.8% by weight). The thermoanalytical study proved the existence of two different types of solid forms of meloxicam, with curves of thermal flow of fusion in about., 256 and 292 ° C respectively. (See Figure 4). The improvement of the dissolution characteristics of the product according to Example IV / 4. In comparison with free meloxicam are shown in Table 7.

Table 7: In vitro dissolution rates of free meloxicam (130 mg) and of the composition according to Example IV / 4. (1300 mg) at pH 1.3- and 7.6 at 37 ° C.

Example TV / 5. 15.2 g of 6-monoamino-beta-cyclodextrin (AMBCDx), 3 ml of water and 1.8 g of crystalline meloxicam were intensively mixed for 60 minutes at 25 ° C. The resulting wet mixture was passed through a 2 mm screen, and dried at 40 ° C at constant weight. The resulting yellowish solid was ground to a fine powder, and sieved through a 0.25 mm screen. Yield, - 16.6 g of powder with a meloxicam content of 10.4% by weight, The meloxicam solid composition according to Example IV / 5. showed a significantly increased dissolution. The increased dissolution of the meloxicam composition of aphenium. a_7L Example IV / 5 is shown in Table 9. Table 9. The in vitro dissolution rate of the meloxicam composition according to Example IV / 5 (pH: 1.2, at 37 ° C) * controj .: meloxicam showed a dissolution rate of 0.8 μg / ml in 60 minutes.

Example IV / 6. 113.5 g of dry and solid beta cyclodextrin hydrate (BCDx) were mixed thoroughly with 35.14 g crystalline meloxicam at 25 ° C in a high speed twin screw kneading apparatus for 10 minutes. 7.43 g of polyethylene glycol (PEG-400J were added to the kneading machine.) The reaction mixture was completely kneaded for 0.5 hours at 60 ° C, then for 2 hours at 25 ° C. The resulting composition was directly transferred to a machine of granulation, and the granulation process was carried out in the presence of 10 ml of a 0.1% aqueous solution of sodium carboxymethylcellulose.The granules were dried at 40 ° C at constant weight.The resulting granules, slightly yellowish and flow Free can be used directly for tablet formation Yield: 155 g of granules, with a meloxicam content of 22.0%.

Eg IV / 7, 129.7 g of crystalline gamma-cyclodextrin hydrate (GCDX) were co-milled intensively at room temperature in a ceramic ball mill with 17.57 g of solid meloxicam for 3 hours at 25 ° C. Yield: 146.2 g of slightly yellow powder were obtained. The solid composition appears as an almost amorphous powder with a meloxicam content of 11.8% by weight, and exhibited an increased solution in water.

Example IV / 8 16 g of branched beta-cyclodextrin (an enzyme-modified CDX beta-derivative, of the glycosyl-malt_psyl-substituted type) were kneaded intensively in a double-screw kneading apparatus with 1.8 g of meloxicam in the presence of 2.0 ml of propylene glycol for 30 minutes at 40 ° C until a thick creamy paste was obtained. The paste was further kneaded for an additional 3 hours at 25 ° C, and dried at room temperature to constant weight. The dried product appeared as a hard, slightly yellowish solid, which was further ground to give a fine powder, and passed through a 250 μm sieve. Yield: 17.5 g of yellow amorphous powder, slightly hygroscopic, with a meloxicam content of 10.0%, The weight loss by drying of the sample according to Example 8 is 6.0%.

Example IV / 9. 16 g of hydroxypropyl-beta-cyclodextrin (with a degree of hydroxyalkylation between 4.0-5.0) were mixed intensively in powder form in a ceramic ball mill with 1.8 g of meloxicam. The mixture was then co-milled further for 3 hours at 25 ° C to achieve the desired metastable physical state. Yield: 17.2 g yellowish amorphous powder, meloxicam content: 10.0%. The drying loss of the product according to Example IV / 9 was 4.3%, and the sample appeared to be amorphous by powder X-ray diffraction.

Example IV / 10. 4.54 g of beta-cyclodextrin hydrate (BCDx) were moistened with 1 ml of water, and kneaded in a ceramic mortar with 0.702 g of crystalline meloxicam at 25 ° C for 15 minutes. Then 0.24 g of solid nicotinamide was added to the mixture, and the solid three-component system was further kneaded for 30 minutes at 25 ° C. The mixture was dried at 45 ° C at constant weight. Yields 5.1 g of slightly yellow powder, with a meloxicam content of 11.9% by weight. The composition according to Example IV / 10 showed significantly improved dissolution rates in a buffer solution of pH 7.6 at 25 ° C compared to meloxicam. See Table 11).

Table 11. In vitro dissolution rates of free meloxicam and composition according to Example IV / 10. at pH 1.3 and 7.6 at 37 ° C.

Example TV / 11. 10.5 g of beta-cyclodextrin hydrate were mechanically treated by intense co-grinding with 1.6 g of solid meloxicam and 1.5 g of diethanolamine for 30 minutes at 40 ° C, and for 2 hours at 25 ° C. The resulting slightly yellow mixture dried at 45 ° C to constant weight, and passed through a 0.071 mm sieve. The solid composition obtained had a meloxicam content of 11.9% by weight. The rate of dissolution of the composition according to Example IV / 12 is shown in Table 13.

Table 13. In vitro dissolution of free meloxicam and composition according to Example IV / 12. at pH 1.3 and in deionized water (pH = 6.6- at 37 ° C).

The use of other pharmaceutically acceptable amines with a high boiling point (such as ethylenediamine, monoethanolamine, triethanolamine, diisopropylamine, dibutylamine, pentylamine, etc.) and other pharmaceutically acceptable solid alkalizing agents (such as sodium carbonate, ammonium carbonate) , powdered sodium hydroxide, sodium phosphate, etc.) resulted in increased solubility and bioavailability.

Example IV / 12 113.5 q of solid 7-cyclodextrin hydrate LBCTQx) were co-milled intensively in a high-energy ceramic ball mill with 35.14 g of crystalline melQxicam and 0.5 g of sodium carbonate at 25 ° C for 30 minutes . Performance; 147.6 g of slightly yellowish, free-flowing powder with a meloxicam content of 22.0%. The solid composition appeared to be almost amorphous by X-ray powder diffraction.

Example V / l Formulation of flavored sachets equivalent to 7.5 mg of meloxicam as an active ingredient. Meloxicam composition according to Example IV / 1 58 mg Sucrose 788 mg Granulated orange flavor 14.5 mg Ascorbic acid 7.25 mg Methylglucamine 2.0 mg Example V / 2 .Preparation of an immediate release tablet containing 7.5 mg of meloxicam per tablet.

Meloxicam composition according to Example IV / 1 58 mg Lactose • 1H20 531 mg Corn starch 251 mg PVP XX 100 mg Aerosil 200 50 mg Magnesium stearate 10 mg Example VJ3 A formulation of 10 mg / g of meloxicam in hydrogel was prepared as follows. Micronized composition of meloxicam according to Example IV / 9, equivalent to 10 mg of meloxicam 100.0 mg Hydroxpylmethylcellulose 215.0 mg Propylene glycol 2500.0 mg PEG-7-glyceryl-CQConatQ 300.0 mg Isopropyl alcohol 500.0 mg Deionized water 6385.0 mg EXAMPLE V / 4 Ophthalmic Ointment: In a Diosna cream homogenizer, a meloxicam composition was thoroughly mixed according to Example IV / 12 previously sterilized for 60 minutes with an ophthalmic cream base at 25 ° C having the following ingredients: Distilled water 29.0 g Flax wax 16.0 g Paraffin subliquid 48.0 g Calcium stearate 4.5 g Meloxicam composition according to Example IV / 13 2.5 g Example V / 5 Preparation of an ophthalmic hydrogel. The ophthalmic hydrogel formulation was prepared by dispersing meloxicam composition according to Example pv / 4. Water with 0.002% of ihlomersal 95 g CarbopolMR 940 0.9 g Diisopropanolamine 1.0 g Meloxicam composition according to Example IV / 4 3.1 g Example V / 6 Preparation of a rectal suppository. The rectal suppository was prepared by mixing the meloxicam composition according to Example IV / 7 at 40 ° C with a previously melted hydrophilic suppository base which consisted of Massa polyoxaetheni base. The composition of the suppositories was 15 mg of meloxicam per suppository. Thus, 127 mg of meloxicam composition according to Example IV / 7 were mixed with 1873 mg of Massa polyoxaetheni base, resulting in a 2 g suppository.

Example V / 7 Preparation of a two-layer tablet. In a first stage the dough for tabletting was prepared for the initial dose. The components of the initial dose are: Meloxicam-cyclodextrin 19.1 g (equivalent to 2.5 mg of meloxicam) Lactose- 1H20 11.5 mg Hydrogen and calcium phosphate • 2H¿0 15.3 mg Microcrystalline cellulose 18.7 mg Corn starch 7.6 mg Sodium and sodium glycolate 3.0 mg Silica. Colloidal hydride 0.4 mg Magnesium stearate 0.8 mg Red ferric oxide 0.04 mg They were sieved through a 0.8 mm sieve, and homogenized in a mixing vessel for 20 minutes / 5 rpm.

In a second step, the granules were prepared for the controlled release layer. Meloxicam (5 mg, lactose-1H20 (56.3 mg), methylhydroxy-propylcellulose (12.5 mg) was granulated, Crospovidone (2 mg) with purified water in a fluid bed granulator. Magnesium stearate (0.375 mg), colloidal anhydrous silica (0.25 mg) and sodium lauryl sulfate (0.125 mg) were added. The mixture was sieved through a 1.0 mm sieve, and mixed in a mixing vessel for 20 minutes / 6 rpm. The slow release granules above were compressed in a first run, and the granules of the initial dose were added onto the controlled release layer. and they were compressed as a second layer.

Example V / 8 Preparation of an effervescent tablet containing 7.5 mg of meloxicam per tablet. Meloxicam composition according to Example IV / 1 58 mg Methylglucamine 2 mg Hydrogen carbonate and sodium 260 mg Sodium Hydrogen Tartrate 320 mg Aspartame 35 mg Flavoring Substances 77 mg Example V / 9 Preparation of an effervescent tablet containing 7.5 mg of meloxicam per tablet (.3142 g). Meloxicam composition according to Example IV / 1 58 mg Lactose-1H20 1102 mg Sodium Docusate 5.8 mg Polydimethylsiloxane 16.24 mg Polyvinylpyrrolidine 37.7 mg Citric acid 942.5 mg Sodium hydrogen carbonate 333.5 mg Sodium sulfate 348 mg sodium saccharin 8.7 mg Aspartame 58 mg Flavoring agents 87 mg Example V / IO Preparation of a tablet containing 7.5 mg of meloxicam per tablet. Meloxicam composition according to Example IV / 1 58 mg Lactose • lfí20 490.1 mg Microcrystalline cellulose 145 mg Crospovidone 23.2 mg Magnesium stearate 4.35 mg Colloidal anhydrous silica 2.5 mg Sodium lauryl sulfate 1.45 mg The description also includes that of the appended application EP 97 114 816.8.

Claims (22)

1. RE IV NDICATIONS 1. Pharmaceutical composition comprising meloxicam as an active ingredient, a cyclodextrin, an optional oligosaccharide other than cyclodextrin, an optional polysaccharide, one or more pharmaceutically acceptable additives selected from the group consisting of de-surfactants-agents, hydrotropic-agents alkali before - hydrocolloids and - polymers and excipients, carriers and / or auxiliary agents,. wherein the pharmaceutical composition is available by co-spewing, co-spraying or co-melting meloxicam in the presence of cyclodextrin or a pharmaceutically acceptable additive.
2. 2, Composition according to claim 1, available by micronising meloxicam in the presence of cyclodextrin as a pharmaceutically acceptable additive.
3. 3, Composition according to claim 1 or 2, obtainable by wet mechanical homogenization of its components in the presence of water, preferably in an amount of 5 to 50% by weight (based on the total weight of the composition).
4. 4_ "Composition according to any of the preceding claims, characterized by microcrystalline cellulose and / or lactose and / or starch as oligo- or polysaccharide.
5. 5. Composition according to any of the preceding claims, characterized by mono-fatty acids of polyoxyethylene sorbitan, diethylene glycol monoethyl ether, and / or nonyl phenoltetraethylene glycol ether as a surfactant.
6. 6. Composition according to any of the preceding claims, characterized by an amount of 1 to 99, and preferably about 20% by weight of a hydrotropic agent (based on the total weight of the composition).
7. 7. Composition according to any of the preceding claims, characterized by sodium glycinate, nicotinamide and / or methylglucamine as a hydrotropic agent.
8. 8. Composition according to any of the preceding claims, characterized by sodium carbonate, ammonium carbonate, sodium hydroxide, especially pulverized sodium hydroxide, and / or sodium phosphate as alkalizing agent.
9. 9. Composition according to any of the preceding claims, characterized by β-cyclodextrin hydrate (BCDx), 6-monoamino-beta-cyclodextrin (AMBCDX), β-cyclodextrin hydrate (GCDx), branched β-cyclodextrin especially a β-cyclodextrin of the glycosyl / maltosyl substituted type, or a β-cyclodextrin hydrate derivative, and / or hydroxypyryl-β-cyclodextrin as cyclodextrin ,. especially of a hydroxyalglylation degree in the range of 4.0-5.0.
10. 10. Composition according to any of the preceding claims, characterized by propylene glycol methyl cellulose ether ,. tris-hydroxymethyl aminomethane, 2,6-diamino-hexanoic acid, (D, L-lysine), mannitol, polyethylene glycol, propylene glycol, diethanolamine, ethyleneamine, monoethanolamine, triethanolamine, diisopropylamine, dibutylamine, pentylamine, sodium dodecyl sulfate, methylglucamine , polyvinylpyrrolidone, cellulose ether, polyoxyethylene-polyoxypropylene block copolymers and / or nicotinamide as a pharmaceutically acceptable additive.
11. 11. A pharmaceutical composition comprising meloxicam as an active ingredient, a cyclodextrin and an optional oligosaccharide or polysaccharide, water as an aqueous carrier, a co-solvent and optional auxiliary agents, wherein the pharmaceutical composition is available by micronising meloxicam in the presence of the cyclodextrin or the oligosaccharide or optional polysaccharide, water and a co-solvent as a pharmaceutically acceptable additive.
12. 12. A pharmaceutical composition comprising meloxicam as an active ingredient, a cyclodextrin and an optional oligosaccharide or polysaccharide-, water as an aqueous carrier, a co-solvent and optional auxiliary agents, obtainable by wet mechanical homogenization of its components in the presence of water, preferably in an amount from 5 to 50 § > by weight (based on the total weight of the composition).
13. 13. Composition according to claim 11 or 12, characterized by β-cyclodextrin hydrate (BCDx), 6-monoamino-beta-cyclodextrin (AMBCDX), β-cyclodextrin hydrate (GCDx), branched β-cyclodextrin especially a β- branched cyclodextrin of the glycosyl / maltosyl substituted type, or a hydrate derivative of β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin as cyclodextrin, especially of a degree of hydroxyalkylation in the range of 4.0-5.0.
14. 14. Composition in accordance with IB. claim 11 to 13, characterized by microcrystalline cellulose, lactose and / or starch as oligo- or polysaccharide.
15. 15. Composition according to any of claims 11 to 14, characterized by an amount of 0.1 to 25, and preferably about 5.0% by weight of co-solvent (based on the amount of water or on the total weight of the composition .).
16. 16. Composition according to any of claims 11 to 15, characterized by i-propanol, propylene glycol, glycerol, polyethylene glycol and / or ethanol as co-solvent.
17. 17. Composition according to any of claims 11 to 16, characterized by one or more additional pharmaceutically acceptable additives selected from the group consisting of surfactants, hydrotropic agents, alkalizing agents, hydrocolloids and polymers, preferably selected from the group consisting of propylene ether. Methyl cellulose glycol, tri-J-iid-oxoxymethyl-aminometa or, 2,6-diamino-hexanoic acid, (D, L-lysine), mannitol, polyethylene glycol, propylene glycol, diethanolamine, ethyleneamine, monoethanolamine, triethanolamine, diisopropylamine, dibethylamine, pentylamine, sodium carbonate, sodium dodecyl sulfate, ammonium carbonate, sodium hydroxide, especially powdered sodium hydroxide, sodium phosphate, methylglucane, polyvinylpyrrolidone, cellulose ether, polyoxyethylene-polyoxypropylene block copolymers and / or nicotinamide as pharmaceutically acceptable additive.
18. 18. Composition according to any of claims 11 to 17, characterized by an amount of 1 to 99, and preferably about 20% by weight of a hydrotropic agent (based on the total weight of the composition).
19. 19. Composition according to any of the preceding claims, for oral, rectal, transdermal, ophthalmic or parenteral administration.
20. 20. Composition according to any of the preceding claims, characterized in that it is provided as a tablet, effervescent tablet, sachets, effervescent sachet with flavor, tablet, hydrogel, ophthalmic ointment, ophthalmic hydrogel or rectal suppository.
21. 21. Composition according to any of the preceding claims, characterized in that it is provided as a controlled release tablet for oral application.
22. 22. Composition according to claim 20 or 21, characterized in that it is provided as a multilayer tablet, especially a two-layer tablet, wherein one of the layers comprises meloxicam together with at least one pharmaceutically acceptable additive for rapid release, and - another layer comprises meloxicam optionally with a usual controlled release agent