MXPA97010305A - Procedure for preparing the composition of prolonged action of granules containing 4-nitro-2-fenoximetanosulfonanil - Google Patents

Abstract

The invention comprises a composition formulated by a sustained release granule association that maintains the therapeutic action of 4-nitro-2 phenoxymethanesulfonanilide and with decreased oscillations of plasma concentrations. The invention also comprises a process for obtaining the composition. The active principle is micronized together with a disintegrant and adhered by means of binding polymers from a solution to neutral granules composed of sugar, forming granules of fast, conventional or immediate action. A fraction of the granules adhered and coated with the active ingredient is incorporated with polymers from a solution that give a controlled and prolonged action of the active ingredient and is associated or mixed with the remaining granules containing the active principle (granules of immediate action), to prepare and administer different dosages

Description

Preparation Process of the Composition of Prolonged Action of Granules Containing 4-Nitro-2-Phenoxymethanesulfonanilide Sphere of the invention: The present invention relates to a process for forming a sustained and prolonged release composition in granules that maintains the therapeutic action of 4-nitro-2-phenoxymethanesulfonanilide and with decreasing oscillations of plasma concentrations. This active principle - 4-nitro-2-phenoxymethanesulfonanilide - is currently used in a remedy sold under the brand name "NIMESULIDE".

It is a non-steroidal anti-inflammatory agent with anti-inflammatory, analgesic and antipyretic properties indicated in (osteoarthritis, rheumatoid arthritis, chronic inflammatory states of the upper respiratory tract, inflammation in the otorhinolaryngologic area, soft tissues, genitourinary tract, dysmenorrhea, thrombophlebitis, phlebitis, odontalgia ) with adverse effects of the digestive type. Background: Nimesulide, or 4-nitro-2-phenoxymethanesulfonanilide, has been known since 1974 from Belgian patents No. 801,812 and from the USA. of America No. 3,840,897. Both patents define Nimesulide in its preparation and its anti-inflammatory activity. The current presentation of the product is in tablets of 100 mg and 200 mg of fast or conventional action. There are other non-steroidal anti-inflammatories in the world market, with which it was demonstrated that the sustained and sustained release forms of action, compared to the administration of the same product in its conventional form have a lower incidence of side effects, as examples we have Diclofenac Sodium, Ketoprofen, Indomethacin, etc., being in many cases sustained forms in controlled release granules those of greater safety, efficacy and maintenance of plasma levels within the therapeutic bands. Synthesis of the Invention: The present invention, according to its statement, is a procedure related to a controlled release preparation of 4-nitro-2-phenoxymethanesulfonanilide (active ingredient) in granules multiple granules that gradually release the active principle and maintains plasma concentrations stable The objective of the present invention is to achieve an association of this active principle that allows having more stable plasma concentrations and minimizing digestive side effects. This invention of granules or microgranules containing 4-nitro-2-phenoxy-methanesulfonanilide comprises:. Neutral granules or neutral microgranules composed of sugar and starch. 2. Incorporation and adhesion of the active micronized powder that adheres to the neutral microgranules by means of binding polymers coming from the solution, resulting in granules commonly known as fast acting, conventional or immediate granules. 2 \ _ Adherence of polymers that form a film from a solution that contains them with which a fraction of the product of the previous stage is coated obtaining granules of sustained and controlled action of active principle. __. Association or mixture of the granules not coated in 2 with the granules of 3.

The neutral granules have a size of 0.2 mm to 1.8 mm, preferably 0.4 mm to 1.4 mm. According to preferred features of the invention, the active principle is associated with a mixed disintegrant as a step prior to micronization. The disintegrant may be croscarmellose sodium or crospovidone or others.

The solvents used in 2 for the adherent solution may be acetone, isopropyl alcohol, water or mixtures thereof. The binder polymers can be different types of polyvinyl pyrrolidones or polyethylene glycols, gelatins or mixtures thereof. Once all the active ingredient has been incorporated and the granules are dried, a part of them is added with a solution with polymers that configure a controlled and sustained action to the active principle and that form a coating on the granules once they are dry. The solvents used can be acetone, isopropyl alcohol, water or mixtures between them. The polymers used can be different types of methylcelluloses, different types of hydroxypropylmethylcelluloses, different types of hydroxypropylmethylcelluloses phthalate, different types of acrylic polymers (which can be different types of Eudragit L, Eudragit S, Eudragit RL or Eudragit RS or combinations between yes) different types of rubber lacquers and different types of ethylcelluloses; these polymers can be combined in different proportions with each other. To this solution it is possible to incorporate plasticizers of the type diethyl phthalate, di-butiftalate, polyethylene glycol, triethyl citrate, triacetin, triglycerides of fatty acids, or others.

It is preferable to add a lubricant before the drying process, commonly silicon dioxide. According to other features of the invention, the following proportions are preferable for 2. The proportion of Active Principle with respect to the rest of excipients must be between 20% and 90% and that of binding polymers with respect to the rest of excipients between 0.2% and 5% disintegrants between 0.5% and 7%.

It is also preferable that the final concentration of active principle granules be between 20% and 80% and that the granule size be between 0.6 mm and 2 mm, preferably between 0.8 mm and 1.7 mm. mm. The proportion of acrylic polymers with respect to the rest of polymers can be between 0% and 100%. The solvents used in phases 2 and 3 can be 0% to 100% organic or 0% to 100% aqueous. The final proportion of granules coming from 2 with respect to the final mixture can be from 0 to 50%. The granules containing 4-nitro-2-phenoxymethanesulfonanilide make it possible to prepare and administer different doses, for this reason they can be dosed in hard gelatin capsules in different concentrations. This association in granules of Active Principle has a system of programmed and sustained dissolution that can be checked with the Dissolution Equipment type USP XXIII page 1791 Apparatus 1 of the basket type at 100 r.p.m. and each glass with 500 ml of digestive solution, making a change in pH in the different hourly fractions. The dissolution profile is as follows: read. Hour 20% - 50% 4th. Hour 55% - 85% 8th. Time > 80% With this invention, dosage forms of sustained and prolonged action of 4-nitro-2-phenoxymethane-sulfonanilide with stable hematic concentrations are achieved. Examples: The invention is further defined with the following examples: Example 1 Neutral 120 g Croscaramellose sodium 8 g Polyvinylpyrrolidone 4 g Hydroxypropylmethylcellulose phthalate 85 g Eudragit RL 50 g Shellac 95 g Triethyl citrate 16 g Active principle 615 g JL In a double cone mixer, the active principle and sodium croscarmellose are mixed; this association is micronized to a size below 40 microns. 2_ The powder resulting from 1 is slowly incorporated into a stainless steel pan that rotates at a speed between 8 and 30 r.p.m. in which the neutral granules have already been incorporated. The aggregate of the micronized material is simultaneous to the atomization of a solution over the neutrals; said solution is polyvinylpyrrolidone in isopropyl alcohol. (4 g solute - 36 g solvent) Once the process is finished, let the product dry. 2 * The resulting product is separated by weight 35% 2 and the remaining 65% covered in a pail that operates at a speed between 8 and 30 rpm, atomizing on the granules in order to cover a solution containing solutes (hydroxypropylmethylcellulose phthalate, Eudragit RL, shellac, triethylcitrate) (246 g) dissolved in (1,400 g) of solvent with the proportion of 50% isopropyl alcohol, 40% acetone and 10% water. __ The resulting product of 3 is dried before silicon dioxide is added and mixed with the granules coming from 2.

Example 2 Neutral 120 g Crospovidone l l g Polyethylene glycol 3 g Hydroxypropylmethylcellulose phthalate 45 g Hydroxypropylmethylcellulose 52 g Eudragit RS 27 g Ethylcellulose 50 g Triacetin 10 g Silicon dioxide 4 g Active principle 675 g X_ In a double-cone mixer, active ingredient and crospovidone are mixed; this association is micronized to a size below 40 microns. 2_ The resulting dust of 1 slowly uncoils to a stainless steel pan that rotates at a speed between 8 and 30 r.p.m. in which the neutral granules have already been incoforated. The aggregate of the micronized material is simultaneous to the atomization of a solution over the neutrals; said solution is polyethylene glycol in water. (3 g solute - 10 g solvent) Once the process is finished, let the product dry. 2_ Of the resulting product is separated by weight 30% of 2 and the remaining 70% is covered in a paila that operates at a speed between 8 and 30 r.p.m., atomizing on the granules in order to coat them with a solution containing solutes (hydroxypropylmethylcellulose, phthalate, hydroxypropylmethylcellulose, Eudragit RS, ethylcellulose, triacetin) (184 g) dissolved in (1,200 g) of solvent with the proportion of 70% alcohol isopropyl, 25% acetone and 50% water.

The product resulting from 3 is dried before silicon dioxide is added and mixed with the granules from 2. Example 3 Neutral 120 g Croscaramellose sodium 4 g Crospovidone 5 g Polyvinylpyrrolidone 5 g Hydroxypropylmethylcellulose phthalate 30 g Eudragit RL 30 g Eudragit L 29 g Gum Lacquer 110 g Dibutylphalate 8 g Silicon dioxide 2 g Active principle 608 g. In a double cone mixer, the active ingredient, croscarmellose sodium and crospovidone is mixed; this association is micronized to a size below 40 microns. 2_ The resulting dust of 1 slowly uncoils to a stainless steel pan that rotates at a speed between 8 and 30 r.p.m. in which the neutral granules have already been incoforated. The aggregate of the micronized material is simultaneous to the atomization of a solution over the neutrals; said solution is polyvinylpyrrolidone in isopropyl alcohol. (5 g solute - 40 g solvent) Once the process is finished, let the product dry. __, Of the resulting product, 42% is separated by weight from 2 and the remaining 58% is covered in a pan operating at a speed between 8 and 30 rpm, atomizing on the granules in order to coat them with a solution containing solutes. (hydroxypropylmethylcellulose phthalate, Eudragit RL, Eudragit L, shellac, dibutylphthalate) (207 g) dissolved in (1,500 g) of solvent with the proportion of 75% isopropyl alcohol, 20% acetone and 5% water. The product resulting from 3 is dried before silicon dioxide is added and mixed with the granules from 2. Example 4 Neutral 120 g Croscaramellose sodium 10 g Polyvinylpyrrolidone 3 g Eudragit RS 25 g Eudragit L 60 g Eudragit S 10 g Gum lacquer 70 g Ethylcellulose 15 g Triacetin 3 g Triethyl citrate 14 g Silicon dioxide 3 g Active principle 620 g. In a double cone mixer, active principle and sodium croscarmellose are mixed; this association is micronized to a size below 40 microns. __, The resulting powder of 1 slowly uncoils to a stainless steel pan that rotates at a speed between 8 and 30 r.p.m. in which the neutral granules have already been incoforated. The aggregate of the micronized material is simultaneous to the atomization of a solution over the neutrals; said solution is polyvinylpyrrolidone in isopropyl alcohol and acetone. (5 g solute - 40 g solvent 95% isopropyl alcohol and 5% acetone) Once the process is finished, let the product dry. __, Of the resulting product, 33% is separated by weight from 2 and the remaining 67% is covered in a pan operating at a speed between 8 and 30 rpm, atomizing on the granules in order to coat them with a solution containing solutes (Eudragit RS, Eudragit L, Eudragit S, shellac, ethylcellulose, triacetin, triethyl citrate) (197 g) dissolved in (1,500 g) of solvent with the proportion of 50% isopropyl alcohol, 40% acetone and 10% water . The resulting product of 3 is dried before silicon dioxide is added and mixed with the granules coming from 2. Example 5 Neutral 120 g Croscaramellose sodium 10 g Polyvinylpyrrolidone 4 g Hydroxypropylmethylcellulose phthalate 95 g Eudragit RL 60 g Gum Lacquer 87 g Triethylcitrate 14 g Silicon dioxide 5 g Active principle 608 g. In a double cone mixer, active principle and sodium croscarmellose are mixed; this association is micronized to a size below 40 microns. 2t The resulting powder of 1 slowly uncoils to a stainless steel pan that rotates at a speed between 8 and 30 r.p.m. in which the neutral granules have already been incoforated. The aggregate of the micronized material is simultaneous to the atomization of a solution over the neutrals; said solution is polyvinylpyrrolidone in isopropyl alcohol. (4 g solute - 14 g solvent) Once the process is finished, let the product dry. _. { The resulting product is separated by weight 40% of 2 and the remaining 60% is covered in a pan that operates at a speed between 8 and 30 r.p.m., atomizing on the granules in order to coat them with a solution containing solutes (hydroxypropylmethylcellulose phthalate, Eudragit RL, shellac, triethylcitrate) (256 g) dissolved in (2,300 g) of solvent with the proportion of 85% isopropyl alcohol, 11% of acetone and 4% water. The resulting product of 3 is dried before silicon dioxide is added and mixed with the granules coming from 2. The Granules Release Test was carried out according to U.S.P. XXIII, basket method with 500 ml glass making pH changes in hourly fractions obtaining the following results.

Pharmacokinetic Studies: Taking into account what has been described above and the examples presented, capsules with granules or microgranules of 200 mg of controlled action 4-nitro-2-phenoxy-methanesulfonanilide were generated and comparative pharmacokinetic studies were carried out with the conventional action products commercialized with a posology of 100 mg and 200 mg. As significant parameters, the maximum plasma concentration (Cmax), the time to reach the maximum concentration (Tmax) and the area under the curve (AUC) of each of the products were calculated.

The studies were carried out with 6 individuals for each of the 3 products that were administered with an oral dose and extractions at different times, analyzing the plasma concentrations and performing the statistical study of the calculated parameters. Throughout the evaluation the products are defined as follows: LP3: They are microgranules of prolonged or controlled action of 4-nitro-2-phenoxy-methanesulfonanilide in hard gelatine capsules with a dose of 200 mg. 100 mg: Dosage of 100 mg of Nimesulide in conventional action 200 mg tablets: Dosage of 200 mg of Nimesulide in conventional action tablets.

The characteristics to be considered in relation to the long-acting product with respect to the conventional products in 100 mg and 200 mg are the following: The LP3 product has plasma levels compared to the product of similar 100 mg during the first 3 hours but more stable and higher in the following hours. With respect to the 200 mg product has more stable and higher plasma concentrations during the first 5-6 hours maintaining similar levels in the following hours. The LP3 product with these characteristics is defined as controlled action and shown in Table I and attached Figures I and II, observing a significant displacement of Tmax, and Cmax and an AUC with no significant differences with respect to the 200 mg product and the time with stable concentrations throughout the hours.

Table I and Figures I and II show the parameters of 4-nitro-2-phenoxy-methanesulfonanilide granules, conventional Nimesulide 100 mg and conventional Nimesulide 200 mg (average values- of 6 individuals). In the accompanying graphs: Figure 1 shows the average concentrations over time of 4-nitro-2-phenoxymethanesulfonanilide granules and Nimesulide 100 mg (average values of 6 individuals), while Figure 2 shows average concentrations at over time of 4-nitro-2-phenoxymethanesulfonanilide granules, conventional Nimesulide 100 mg and conventional Nimesulide 200 mg (average values of 6 individuals) The present invention has been described above by way of example for per¬ mitir that the experts in the field can understand and reproduce the fundamentals of the invention, but there is no doubt that modifications can be made, without departing from the scope and the spirit of the invention.

Claims (1)

CLAIMS Having thus specially described and determined the nature of the present invention and the way in which it can be put into practice, it is declared that what is claimed, as invention and property and exclusive right, is: 1. Preparation procedure of a long-acting composition of granules containing 4-nitro-2-phenoxymethanesulfonanilide as active ingredient, characterized in that the steps of: (i) compounding neutral granules composed of sugar and starch; (ii) micronising the active principle together with a disintegrant and adhering them to the neutral granules by means of binding polymers from a solution; forming granules of fast, conventional or immediate action; (iii) adhering and coating a fraction of the granules with the active ingredient inciprorated with polymers from a solution that confer a controlled and prolonged action of the active principle; and (iv) associating or mixing the rest of the granules containing the active principle (immediate action granules) with the granules coated with the polymers of controlled and prolonged action to enable the preparation and administration of different dosages. Process according to claim 1, characterized in that the neutral cores have a size of 0.2 mm to 1.8 mm, preferably 0.4 mm to 1.4 mm. Process according to claim 1, characterized in that the active ingredient is mixed or associated with disintegrants of the croscarmellose sodium type, crospovidone, alone or in combination. Process according to claim 1, characterized in that: (A) the binding polymers that adhere the active principle are chosen from the group of polyvinylpyrrolidones and polyethylene glycols, gelatins, alone or in combination; Y (B) the polymers of the fraction that cover the active principle and that confer a controlled and prolonged action on the active principle are chosen from the group of different types of hydroxypropylmethylcellulose, hydroxypropylmethylcelluloses phthalate, ethylcelluloses, shellac, different types of methacrylates (Eudragit L , Eudragit S, Eudragit RL, Eudragit RS) or combinations with each other. Process according to claim 1, characterized in that the percentage of granules of immediate action in the mixture or association with the granules of controlled and prolonged action can be from 0% to 50%. Process according to claim 1, characterized in that the solvents used in (ii) and (iii) are chosen from the group of acetone, isopropyl alcohol, water, alone or in combination. Process according to claim 1, characterized in that in (iii) the solution contains plasticizers chosen from the group consisting of diethyl phthalate, polyethylene glycol, dibutyl phthalate, triacetin, triethyl citrate, triglycerides of fatty acids, alone or in combination. Process according to claim 2, characterized in that the proportion of active principle with respect to the rest of the excipients must be between 20% and 90%. Process according to claim 2, characterized in that the proportion of binding polymers with respect to the rest of excipients should be between 0.2% and 5%. Process according to claim 2, characterized in that the proportion of disintegrants must be between 0.5% and 7%. Process according to claim 2 and 3, characterized in that the percentage of methacrylates in proportion to the rest of the polymers is between 0% and 100%. Process according to claim 1, characterized in that the final size of the granules is from 0.6 mm to 2 mm, preferably between 0.8 and

1.7 mm. Process according to claim 1, characterized in that the granules maintain stable plasma concentrations and similar to the dosage of lower concentration for 3 hours and with no significant differences with the maximum concentration of active principle in the following hours.