MXPA00005712A - Pharmaceutical compositions - Google Patents

Abstract

A layering process for preparing pharmaceutical compositions of the leukotriene antagonist zafirlukast.The process forms coated beads suitable for sprinkling onto food and drink.

Description

lUB PHARMACEUTICAL COMPOSITIONS DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions and in particular to pharmaceutical compositions containing the leukotriene zafiriukast antagonist. The invention also relates to processes for preparing such compositions and their use in the treatment of disease conditions mediated by leukotriene antagonists. Zafiriukast is an orally administered leukotriene antagonist sold under the trademark "ACCOLATE". Zafiriukast is marketed for the treatment, including prophylactic treatment, of asthma and is presented as a tablet formulation containing 20 mg or 40 mg of active ingredient. Asthma and related conditions are of particular importance in children and the elderly. However, these groups of patients have particular difficulties in swallowing the medications in tablet form. The present invention provides a formulation of zafiriukast that allows for easier administration and in particular may be of special benefit for pediatric and geriatric patients. - The zafiriukast, which has the chemical name N- [4- [5- (cyclopentyloxycarbonyl) amino-l-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzene, is known in a number of physical forms. USP 4859692 describes this compound as Example 105. USP 5319097 discloses that it is compiles. it can exist in more than one physical form which is: physical forms have stabilities - which differ and bioavailability '- s. Form A sc describes amorphous chromium and may have good bioavailability. That is, it is also known that the i "> Rma A tends to become_the Form E in the pi • -.serrcia of jgúa and • this was disadvantageous. Est. Is unattractive to develop a formulation containing a mixture of physical fibers with unattractive bioavailability, especially where a form is physically incitable, due to it; Effective dose of the compound that can not be adequately controlled Form B is described as a crystalline monomer with a diffraction pattern of Δlvo of ra > s X and a defined infrared spectrum. Form X is described as crystalline with an X-ray powder diffraction pattern. USP 5294636 describes iormuláciones. p: i: Lares of the form X. Example 4 describes a tablet formulation prepared by a wet gnawing process followed by drying, grinding, m - ': side and-ruching. ras-ió :? . Examples 2 - 3 describe pharmaceutical compositions of Form X which are suitable for metered dose inhaler administration. Examples 5 der- < -ribe the micronization of Form X to produce a poi, - ~ > which was extruded 1 to form bolira = soft; These pellets, which were free from dust and free from dust, were returned to the original particle size distribution indicating that the pellets were suitable for inhalation use. USP 5319097 describes particular formulations of Form A. Example 3 discloses a tablet formulation prepared by a wet granulation process followed by drying, grinding, mixing and compression. A particular feature of this Example is the presence of polyvinylpyrrolidone (also known as povidone). Example 5 describes a capsule formulation, an aperol formulation (spheroid) and a powder formulation. The pearlescent formulation is prepared by spraying an aqueous dispersion of polyvinylpyrrolidone and zafiri ukas t (in equal amounts) into sugar spheres. This is an example of a suspension stratification process, such as zafiriukast, at the exemplified concentration it could be partially soe in the dispersion. The pellet (also known as pearls, spheroids, coated "non -pareils", coated beads, coated seeds or granules) where a central core is surrounded by a drug-containing layer that can be prepared in a number of different ways. One method is to spray a solution of the drug that optionally contains pharmaceutically acceptable ingredients in the core material. Another method is to spray a suspension of the drug optionally containing pharmaceutically acceptable ingredients in the core or seed material as described in USP 5319097. A third method is to apply the drug and other pharmaceutically acceptable ingredients in the dry state. This third method is known as "dry powder stratification". Usually the stratification of dry powder requires the presence of water only, or water with a binder or other solvent to facilitate the attachment of the drug layer to the core material. As stated earlier in the present, zafiriukast exists in a number of physical forms and is known not to desire interconversion between certain forms that may occur, especially in the presence of water. The three stratification methods outlined above usually require water (as a solvent, as the suspending medium, or to facilitate bonding). Therefore, a problem was observed in preparing beads containing zafiriukast in particular in the amorphous form as none of the three methods was especially prominent for preparing layered beads suitable for pharmaceutical use. Unexpectedly, however, it was found that the pellets prepared by the dry powder stratification method were stable and the physical forms of zafiriukast are not interconverted during the preparation and processing (including high temperature and humidity conditions) of the formulation. The preferred pellets of this invention are stable, non-friable and wear-resistant. In particular, there is a tendency for any amorphous material (eg Form A) to convert to a crystalline form during processing conditions - as crystalline forms are generally the most stable forms. As stated hereinabove, its unattractive to develop a formulation containing a mixture of physical forms with different bioavailabilities, especially where a form is physically unstable, due to the effective dose of the compound that can not be adequately controlled. Accordingly, the present invention provides a process for preparing a pharmaceutical composition comprising applying amorphous zafiriukast and a binding agent and optionally other pharmaceutically acceptable ingredients to a plurality of cores to form layered beads wherein zafiriukast is present in essentially "amorphous" form. Amorphous zafiriukast is in dry form, suitable for stratification of dry powder, immediately before the composition process Preferably, the binding agent is an aqueous binding agent and in particular is water only or water with other solvents.

Optionally, an additional binding agent may be present in the drug layer to aid in the bonding of the core material and to improve the strength of the beads. Such additional binding agents can be any known to the person skilled in the art for this purpose. The preferred binding agents sorr-polyvinylpyrrolidone and hydroxypropylmethylcellulose; of these, polyvinylpyrrolidone is the most preferred. The cores are typically rotated or tumbled in a container to which the amorphous zafiriukast and the binding agent, optionally with other pharmaceutically acceptable ingredients are added. The zafiriukast and the binding agent are typically kept separate until they are added to the container; they are added to the container in a common feed or preferably in separate feeds. The separate feeds are generally simultaneous although the binding agent feed may start slightly earlier than the "zafiriukast" feed and may end slightly after the zafiriukast feed.As set forth here, the function of the binding agent is to facilitate the binding of zafiriukast (and any pharmaceutically acceptable ingredients) to the nucleus The pharmaceutical ingredients can be introduced into the container with the zafiriukast feed or binder feed or they can be divided selectively into both feeds as the skilled person would understand. , the powders are fed into the container together and the aqueous ingredients for example water are fed separately.It is preferred that any aqueous feed is water 07 if the aqueous feed contains other ingredients, are in the form of a solution and not in the form of a suspension n. The nature of the central core of each pellet is not critical provided that it dissolves in aqueous media. Typically the core core material is a sugar sphere or untrimmed where the main ingredients are sugar, such as sucrose and starch. Such sugar spheres or untrimmed spheres are commercially available in a number of diameters under the trademarks "Nu-core 'and xNu-pareil' Available diameters include 35-40 mesh (425-500 microns), 30-35 mesh (500-600 microns), mesh of 25-3T) "(6O0-725 microns), mesh of 20-25 (710-850 microns), mesh of 18-20 (850-1000 microns), mesh of 16- 20 (850-1180 microns) and 14-18 mesh (1000-1400 microns). " These are prepared from crystalline sucrose that is coated using sugar syrup and starch powder. In an alternative the core is a sugar-free material, for example sorbitol or microcrystalline cellulose; such nuclei are prepared in a manner analogous to sugar spheres. The nuclei could not usually contain zafiriukast but this is a possibility. The person skilled in the art will select the particle diameter that is most appropriate considering the depth of the surrounding layer that is intended and the desired diameter of the final pellet. The use of sugar spheres of 50~-850 microns for example 30-35 mesh or 25-30 mesh is preferred. Conventional pharmaceutical ingredients can be included in the processes of this invention. Examples of such pharmaceutical ingredients include bulky agents such as sugar, sorbitol and starch; binding agents such as polyvinylpyrrolidone and hydroxypropylmethylcellulose; disintegrants such as starch, sodium croscaramellose, sodium starch glycolate (A and B) and crospovidone; dyes such as titanium dioxide; flavoring agents; flavor improvers; sweeteners such as aspartame; conservatives; antioxidants; chelating agents; and surfactants. The binding agents are useful to help bind the core, to improve the strength of the pellet, and to assist the coating of the pellets with an additional layer; if this is desired. Polyvinylpyrrolidone is available in various grades, known to those skilled in the art as K-values the use of Grades 29-32 is preferred.

Typical pharmaceutical ingredients added in the processes of this invention include confectionery sugar, starch and polyvinylpyrrolidone. The ratio of ingredients can be varied, with respect to the desired dose, size and weight, also known to the expert. Suitably the layer to core ratio is in the range 1: 0.3 to 1: 3.0 (w / w), more suitably in the range of 1: 1 to 1: 2 (w / w). The ratio of zafiriukast to other ingredients in the layer is suitably in the range of 1: 1 to 1:10 (w / w), more suitably in the range of 1: 1 to 1: 6.

(P / p) • The dry powder stratification process of this invention can be conveniently performed on any machine known to be suitable by those skilled in the art. For example the process can be performed in a rotary granulator, such as those sold by Glatt under the trade names Glatt GPCG-1, Glatt GPCG-5 and Glatt GPCG-60 [Handbook of Pharmaceutical Granulation Technology, ed. Dilip M. Parikh, published by Marcel Dekker Inc. 1997, page 291]. These granulators essentially consist of a fluidized bed dryer with the bottom of the bowl product consisting of a movable and rotatable disk. The bowl contains ports from which the powder and aqueous binder are fed to the material in the bowl. The typical processing temperature / conditions for the stratification phase, for the GPCG-60 devices are as follows: air inlet temperature: 30-40 ° C; Air outlet temperature: 25-40 ° C; rotor speed 390"rpm, flow rate of povidone solution, 100 gmin-1, powder flow rate: 400-gmin-1, processing time: 100 minutes, the layered pellets are then dried at an elevated temperature, for example 30-60 ° C, "preferably approximately 45 ° C in the container. These balls comprise zafiriukast, essentially in an amorphous form: that; ~~ is substantially free of other physical forms of zafiriukast (for example as determined by X-ray diffraction data) preferably at least 90% by weight of zafiriukast is amorphous, more preferably 95% by way of example at least 96%, "97%, 98% ~ or 99% is amorphous." In another aspect, the present invention provides a pharmaceutical composition comprising a plurality of pellets, each pellet comprising: a) a core, and b) a layer surrounding the pellet. nucleus in which the layer "contains amorphous zafiriukast substantially free of other physical forms. c) and optionally other pharmaceutically acceptable ingredients.

Preferred pharmaceutical compositions of this invention are those described hereinabove with reference to the process of this invention. Preferably the layer surrounding the core comprising polyvinylpyrrolidone, more preferably wherein the amount of polyvinylpyrrolidone is not more than 50% by weight of the amount of zafiriukast, more preferably even where the amount of polyvinylpyrrolidone is in the range of 5-30T -T by weight of the amount of zafiriukast and in particular is approximately 10% by weight. In a preferred aspect, the process of the invention comprises separate feeds, one including amorphous zafiriukast and the other not including, for example "including aqueous polyvinylpyrrolidone." Food without zafiriukast, for example including aqueous polyvinylpyrrolidone, "may be continued after feeding. zafiriukast to provide a coated layer in the balls. This coated layer acts as a seal (a "coated seal") and protects the beads against wear and friability, thereby maintaining the integrity of the formulation. Thus, in a further aspect the present invention provides a pharmaceutical composition comprising a plurality of beads each of the beads comprises: a) a core; b) a first layer surrounding such core whose layer contains amorphous zafiriukast substantially free of other physical forms, preferably containing polyvinyl pyrrolidone and optionally containing other pharmaceutically acceptable ingredients; and c) a second coated layer that does not contain zafiriukast. In a further aspect, the pharmaceutical compositions of the present invention may be coated with a conventional coating layer for protection of the beads or to provide sustained release beads for application of a conventional sustained release coating such as "Surelease" (a trademark). commercial trademark of Colorcon), Aquacoat '(a trademark of FMC ~) or' Eudragit '(a trademark of Huís) which, in general, are cellulose derivatives such as hydroxypropylmethylcellulose or ethylcellulose or' are polymers of methacrylic acid. sustained release can be applied using the apparatus described hereinabove or can be applied in a rotary granulator.The sustained release coating provides a generally uniform and constant release rate over an extended period of time achieving a blood level (plasma ) Stable and desired from -zafiriukast. They may be substantially uniform or may vary in thickness and composition of the coating layer as well as in diameter. Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a plurality of pellets, each of said pellets comprising: a) a core; b) a first layer surrounding the core that the amorphous zafiriukast containing layer substantially free of other physical forms, preferably contains polyvinyl pyrrolidone and optionally contains other pharmaceutically acceptable ingredients; and c) a second coating layer which does not contain zafiriukast and which provides sustained release zafírlukast. ~ In one embodiment, the food that does not contain zafiriukast can be finished simultaneously with the zafiriukast that contains food and the sustained release layer is applied subsequently. In another embodiment, the food that does not contain zafiriukast is continued after the "zafiriukast food" provides a "seal cover" and the sustained release coating is applied subsequently. Thus, a further aspect of this invention provides a pharmaceutical composition comprising a plurality of pellets, each of the pellets comprising: a) a core; b) a first layer surrounding the core _ containing amorphous zafiriukast, polyvinylpyrrolidone and optionally other pharmaceutically acceptable ingredients; c) a second layer that does not contain zafiriukast; and d) an additional layer that does not contain zafiriukast and that provides sustained release. The pellets of the present invention typically range in size from 100 microns to 2 mm. rably, it varies in size from 200-1500 microns and preferably they are in the range of 400-1200 microns. Preferably the pellets are approximately of uniform size and shape. The pellets are normally sprinkled on or inside food or drinks for easy consumption by the patient, but need not be taken with food or drink. The dose to be administered to the patient will depend on the condition to be treated, the severity of that condition, the patient's age and weight, and personal physical preferences. In general, the dose to be administered will be in the range of 0.1 mg / Kg to 10 mg / Kg, for example 0.2 mg / Kg to 5 mg / Kg, more particularly 0.5 m / Kg to 2 mg / Kg. In another aspect, the present invention provides a method of treating patients in need thereof with a pharmaceutical composition according to the present invention whose composition contains an effective amount of zafiriukast. _ The pellets are packed so a defined dose of zafiriukast is administered, for example the bolit-as can be packed in a sachet, in a capsule or in a measured delivery device. In one aspect a sachet is preferred wherein the patient tears the opening of the pouch and sprinkles the pellets in their food or drink. In another aspect, a capsule is preferred; an example of such a capsule is that in which the capsules are consumable and dissolved / opened which has been taken orally by the patient. Another more preferred example of a capsule is where the capsule does not intend to be consumed and the patient opens the capsule and sprinkles the pellets in their food or drink. Examples of suitable sachets, consumable capsules (such as gelatin capsules) and non-consumable capsules (such as plastic) are known to persons skilled in the art. The dose of zafiriukast delivered in a sachet, capsule or metered delivery device can be varied as desired. Typically, 540 mg of zafiriukast is supplied in each dose unit, for example, 10 mg, 20 mg or 40 mg of zafiriukast per capsule. The amount (by weight) of zafiriukast in the pellets can also be varied as desired; for example, 100 mg per weight of pellets may contain either 10 mg, 20 mg or 40 mg of zafiriukast. The following examples and data serve to illustrate the invention: Example 1 A solution of 5% w / w polyvinylpyrrolidone (150 g) in purified USP water (2850 ml) was made in a stainless steel vessel and mixed until dissolved. The sugar spheres (1000 g, 20-25 mesh size) were placed in a rotor processor product container (I.E. Glatt GPCG-1) and the temperature was taken at 37 ° C. The polyvinylpyrrolidone solution was sprayed into the container at approximately 10 gmin -1 to 37 ° C. Simultaneously, zafírlukast (100 g) was manually fed through an entry in the product container at a ratio of 10 gmin -1. addition of the polyvinylpyrrolidone solution was continued for 6 minutes, then the addition of zafiriukast was terminated to provide a "seal" cover. The resulting pellets were dried in the product container by raising the air temperature inlet to 45 ° C. The pellets were encapsulated in size # 2 hard gelatin capsules using an automatic encapsulator (I.E. Zanasi AZ / 5) at a target filling weight of approximately 100 mg with 10% loading of zafiriukast.

Examples 2-8 In a manner similar to that of Example 1, the following Examples were prepared. In these examples zafiriukast, starch and confectionery sugar were loaded into a mixer (mixer I.E. PK V), mixing and adding by means of a powder feeder (instead of being fed manually). The pellets were dried in the range of 37-55 ° C. ~~ In some Examples, Glatt GPCG-1 was replaced by a Glatt GPCG-5 or Glatt GPCG-60 rotor processor container and the encapsulator was an H &K encapsulator. Example 7 Zafiriukast 10.00 10.00 10.00 10.00 10.0 10.00 ro.oo " Starch, NF 10.00 4.20 7.20 7.20"7.20 7X720 T.20 Sugar of 46.67 19.13 32.80 32.80 32.80 32.80 32.8U Confectionery Polyvinylpyrrolidone 2.99 0.96 1.39 1.2Í 0.67 0".67 0.67 USP Sugar Spheres (30/35 mesh) 66.67 50.00 41 ¡6 50.00 49.33 49.33 Sugar Spheres (20/25 mesh) 99.50 0.00 0.00 0.00 - O.U0 0V00 0.00 Purified Water, USP 56.72 23.04 33.38 33.38 16.57 16.67 13.84 Dissolution Studies Initial dissolution studies, using 1% sodium dodecylsulfate, in rapid, satisfactory dissolution of the beads shown unencapsulated.

Stability Studies The non-encapsulated and encapsulated beads of Example 7 were studied for 180 days at 25 ° C, 50 ° C and 40 ° C "(Relative Humidity 80%). X-ray diffraction data showed no peaks - this indicates amorphous material without change with any observable conversion to the crystalline material This compares favorably with the results of the tablets of Example 4, Table 1 of USP 5319097. In that Table, 87%, 91% and 82% conversion for the Form B (monohydrate) was recorded at 40 ° C (Relative Humidity 80%) over 1, 2 and 3 months respectively Examples 9-24 Pellets coated with Sustained Release Magnesium talc or stearate was dispersed in purified water using a homogenizer. The dispersion was added to a stirred suspension of Eudragit.The Eudragit suspension was stirred using a mixer.Additional purified water was added to provide the coated composition. It can be used instead of the Eudragit mixture with talc or magnesium stearate. The Zafiriukast beads [Example 7] (400 g) were heated to 24-35 ° C in the product container of a fluidized bed dryer equipped with a urster column or rotor insert.

The pellets were coated with the coating composition [for example Eudragit NE30D (200 g) and talc (30 g with purified water (370 g)] and dried at 24-30 ° C to provide coated pellets TABLE Example: 10 11 12 13 14 15 16 Coating Suspension Composition: Eudragit NE30D 15% 10% 10% 10% 10% Talc 10% 5% 5% 5% Magnesium 5% Stearate, USP Surelease 15% 15% 15% Purified Water, USP 75% 85% 85% 85% 85% 85% 85% 85% Coating Quantity 120 g 55.6 g 135 g 188 g 55 g 55 g 134 g 188 g Applied Suspension Percentage Gain in 7.5% 2% 5% 7% 2% 2% 5% 7% Weight Example: 17 18 19 20 21 22 23 24 Coating Suspension Composition: Eudragit NE30D 5% 5% 2.5% 2.5% 5% 5% Talc 5% 5% 2.5% 2.5% 10% 10% Surelease 25.3% 25.3% Purified Water, USP 90.0% 90.0% 95.0% 95.0% 74.7% 74.7% 85.0% 85.0% Coating Quantity 80 g 200 g 160 g 400 g 34.5 g 83 g 60 g 140 g Applied Suspension Percentage Gain at 2% 5% 2% 5% 2% 5% 2% 5% Weight Example 25 Pellets coated with sustained release A composition was prepared in the same way as in Examples 2-8 with zafiriukast (19.74% ), starch (24.29%), confectionery sugar (5.37%), polyvinylpyrrolidone (1.28%) in sugar spheres (30/35 mesh) (49.36%) using purified water (62.17% of the weight of the powder). (5000 g) were coated, in a manner similar to that of Examples 9-23, with a coating suspension (35 g) [Surelease (25.0%) and purified water (75%)]. The coating provides, after heating, pellets coated with a weight gain of 2% In a further experiment, the coating suspension (82 g) [Surelease (25.0% in "purified" water (85 g)] provides a weight gain of 5%.

Claims (12)

1. CLAIMS 1. A process for preparing a pharmaceutical composition characterized in that it comprises applying zafiriukast and a binding agent and optionally other pharmaceutically acceptable ingredients to a plurality of cores to form layered beads wherein the zafiriukast is present essentially in an amorphous form.
2. 2. The process according to claim 1, characterized in that the zafiriukast is essentially amorphous and in dry form immediately before the composition process.
3. 3. The process according to claim 1 or claim 2, characterized in that the binding agent is water or water in admixture with other solvents.
4. 4. The process according to any of claims 1 to 3, further characterized in that it comprises applying polyvinylpyrrolidone.
5. The process according to any of claims 1 to 4, characterized in that zafiriukast and the binding agent are added to the plurality of nuclei in separate feeds and the feed contains the binding agent that starts slightly before the feed containing zafiriukast and ends slightly after feeding containing zafiriukast.
6. 6. A pharmaceutical composition characterized in that it comprises a plurality of pellets each of the pellets comprises: a) a core; b) a layer surrounding such a core whose layer contains amorphous zafiriukast substantially free of other physical forms; and _ c) optionally other pharmaceutically acceptable ingredients.
7. The pharmaceutical composition according to claim 6, characterized in that the layer surrounding the core further comprises polyvinylpyrrolidone in the range of 5-30% by weight of the amount of zafiriukast present.
8. 8. The pharmaceutical composition according to either claim 6 or claim 7, characterized in that it comprises: a) a core; b) a first layer surrounding such a core whose layer contains amorphous zafiriukast substantially free of other physical forms; and c) a second coating layer that does not contain zafiriukast.
9. 9. The pharmaceutical composition according to claim 8, characterized in that the second coating layer provides sustained release of zafixlukast.
10. 10. The pharmaceutical composition according to claim 8, characterized in that it comprises an additional layer that does not contain zafiriukast and provides sustained release.
11. 11. The pharmaceutical composition according to any of claims 6 to 10 packaged in sachet, capsule or metered delivery device. The method for treating patients in need thereof with a pharmaceutical composition according to any of claims 6 to 11, which composition contains an effective amount of zafiriukast.