MX2007005985A - Process for the manufacture of thermal-adhesion coated cores. - Google Patents

Abstract

The present invention is related to a process for the manufacture of microspheres or cores coated with pharmaceutically acceptable active principles and excipients by means of thermal adhesion using pharmaceutically acceptable melting agents, wherein a melting agent carries the components of a formulation in order to be adhered to the cores. Said process is performed without solvents, in a single stage, in a closed system and in a single coating processor. The final micro-sphere formulation may be a finished product or may be subjected to further manufacturing processes; the product thus obtained may be of immediate or modified release.

Description

PROCESS OF MANUFACTURE OF COATED NUCLEI BY THERMO-ACCESSION FIELD OF THE INVENTION The present invention relates to a process for manufacturing microspheres or cores coated with pharmaceutically acceptable active ingredients and excipients, by means of a new manufacturing process called thermo-adhesion. For said procedure, the fluxing agent functions as a carrier vehicle for the components of the formulation to adhere them to the cores. This coating process is carried out without the use of solvents, in a single stage, in a closed system, in a single coating processor, with better content uniformity. The final formulation of microspheres can be finished product or they can be subjected or other manufacturing processes. The product obtained can be immediate release or modified release.

BACKGROUND OF THE INVENTION The demand for new pharmaceutical products creates in the pharmaceutical industry the need to develop and innovate technologies for obtaining various pharmaceutical forms to meet the needs of the population, with oral dosage forms being of special interest.

The oral route offers advantages over other pharmaceutical forms, these are its easy and convenient administration, allow the administration of high doses of the active principle and are easy to store and transport.

Of the oral compositions, the tablets, dragees, capsules with powder, capsules with granules or microspheres (coated cores), are the most frequently used formulations for pharmaceutical development.

In recent years, special interest has been placed on the design of pharmaceutical compositions presented in capsules containing microspheres or coated cores, that is, for the advantages offered by their manufacturing methods and for their industrial and therapeutic applications.

The present invention relates to the novel manufacture of cores coated in a single container where the process of mixing, melting and cooling the microspheres in a single stage is presented. The manufacturing process of the microspheres is carried out without the use of solution sprinklers, with a minimum use of excipient and vehicles, the use of solvents of any kind is omitted, with this the manufacturing times are reduced significantly by eliminating stages such as the preparation of the cover and the drying of the composition.

There are several methods for the manufacture of microspheres, such as thin-layer coating processes, which are traditionally carried out in fluid bed equipment, or, spheres coated with active can be obtained by means of high-cut feronization, direct spheronization. or extrusion-spheronization, when it is desired that the active principle be within the matrix of the sphere.

The conventionally manufactured microspheres are made by fluidized bed; the cores sprayed by fluid bed spray can be obtained with equipment where a liquid stream sprayed in microdrops is directed on the cores to be coated, the liquid spray called as a cover contains dissolved solids or in suspension, which will be adhered on the surface of the nuclei to evaporate the liquid that drives them.

In the fluidized bed, the active principle is dissolved or suspended in a solvent, then it is sprinkled on the nuclei. In these systems, aqueous or non-aqueous solvents are used, according to the characteristics of the assets used. In aqueous systems, water is the most used, which is potentially inconvenient for formulations of oxidizable or moisture sensitive active ingredients since polymorphism phenomena can occur when experimenting operations of solution-recrystallization or also migration of color, fragility of the cover or other related to the interaction of the active with the excipients of the formulation.

Another system for the manufacture of microspheres or coated cores is by centrifugal equipment with rotating discs or also called spheronization. Some of these are also considered as fluid bed but construction and operation somewhat different because it uses tangential spray and rotating disk, which allows intensive centrifugal mixing with the efficiency of the fluid bed. Spheronization can be carried out by different alternatives, among which we have direct spheronization and spheronization by gradual growth of nuclei (Layering).

The problems that can arise in the manufacture of microspheres by the conventional fluidized bed system or by rotary disk are similar since both processes employ solvents, which can be aqueous or non-aqueous.

Another disadvantage that can occur when manufacturing microspheres by these methods is the time factor, since the composition must be passed through a drying step, where the objective is to eliminate moisture from the microsphere. Depending of the system of solvents and equipment used, will vary the time it will take the composition in the drying stage.

There is another process of manufacturing microspheres, known as thermo granules. In this process, the active principle, a wax and excipients are mixed and processed in high-cut mixing equipment.

This process has the disadvantage of generating amorphous granules having a too large particle size distribution. The product obtained is very sensitive to small changes in the processing conditions and can give rise to a final product with high variability regarding its qualities in the dissolution profiles, rheological characteristics and granulometry. In addition, these thermosealing processes have a significantly higher amount of flux compared to the present invention.

US Pat. No. 5,569,467 describes a dry particle manufacturing process involving the use of a polymeric solvent-free gel support phase on which a biocompatible polymer and an active ingredient adhere. The polymer phase and the active ingredient are immiscible with the support phase. The polymer phase and the active ingredient are premixed before joining it to the phase of polymeric support. To produce the particles an ultrasonic generator is used that also provides the heating, or a mixer of Kinematica gmbH from Luzern, Switzerland of Polytron, after obtaining the spherical particles they are washed and filtered for their recovery. In this composition substantially no active ingredient is found on its formed sphere surface.

Unlike the spherical particles obtained by the process described by this patent, the one described by the present invention preferably uses Glatt type granulator-coating equipment, it is not necessary to premix the flux and the active principle to adhere them to the inert nuclei, it is not necessary to carry out a subsequent washing process, no type of solvents is used and additionally the microspheres may contain, if necessary, the active principle in its outer layer.

Patent document WO 2004/058137 A2 mentions a process in which the active ingredient is mixed with a fatty acid (glyceryl ester) at a temperature above its melting point, making a fluid liquid dispersion for subsequent spraying in a medium with temperature lower than the melting temperature of the flux, causing a phase change and the formation of drug-flux particles, the mixture contains from 60% to 80% of flux in the composition; this process is carried out in a fluidized bed equipment.

The present invention differs from the process described above, since it does not employ a liquid aspersion of the flux in solution or dispersion with the active principle. The present invention uses a granulator equipment and its operating conditions are used to perform the thermo-melting of the inert core with the active and the excipients that are required.

As described, there are various processes for the manufacture of microspheres with active principles. However, conventional manufacturing processes employ operating conditions and process steps that represent a high percentage in time and resources for the manufacture of a pharmaceutical composition.

The present invention describes a novel process for coating inert cores that differs from conventional processes such as fluidized bed processes, since manufacturing times are reduced significantly by eliminating steps such as preparation of the cover and drying of the composition. the whole process of mixing, melting and cooling the microspheres in a single stage and in a single processor, without the use of solution sprinklers and with a minimum use of excipient and vehicles; The use of solvents of any kind, whether aqueous, non-aqueous or organic, is also eliminated.

With this manufacturing process the coating can be carried out without requiring a spray system, the manipulation of the active ingredient (s) does not involve dissolution-recrystallization steps, preventing any change in the structure and / or the morphology of the crystals, having as consequence a potentially better stability in the finished product.

The present invention offers the advantage of substantially reducing operating times, for example, up to 50% of the time spent by the conventional process for manufacturing fluid-bed coated cores.

Additionally, it offers other advantages since no aqueous, non-aqueous or organic solvents are used for the carry and adhesion of the flux with the active principle.

The spheres obtained by the process of this invention reduce the use of excipients, since no carriers, lubricants, solvents or others are required; additionally, the microspheres obtained meet and satisfy the needs for uniformity of the active ingredient content in the microsphere.

The obtained microspheres can be finished product or they can even be used in subsequent processes for formulations of tablets or capsules since the amounts of flux used are relatively low, which allows to obtain coated cores of small size that can be coated again by a cover of one or more active ingredients or mixture thereof, which allows the manufacture of pharmaceutical compositions containing active ingredients that are incompatible with each other or sensitive to light or environment.

The product obtained is spherical, complies with the tests of particle size and uniformity of content, dissolution profiles described for each formulation and optimizes its rheological characteristics.

DESCRIPTION OF THE INVENTION.

The present invention relates to a process for manufacturing coated cores called microspheres by means of thermo-adhesion of one or more active substances with one or more fluxing agents on inert cores.

The fabricated microspheres can have a total weight of the adhered material representing between 1% and up to 30% of the total weight of the microsphere.

The manufacturing process of the present invention is particularly applicable and advantageous for pharmaceutical compositions where the drug is low dose. That is to say, the active principle or the active principles can be contained between 1% and up to 15% of the total- of the mass of the microsphere.

The cores can be constituted of prefabricated inert substances, pharmaceutically acceptable as for example: sucrose, starch, cellulose, among others that will be chosen depending on the characteristics of the active principle to be worked. The process can also start from spheres covered by a fluidized bed process or other, these spheres can contain one or more active principles.

The size of the cores coated by the process described can have a diameter between 20 microns and up to 2500 microns, preferably between 400 and 1500 microns.

Pharmaceutical formulations containing a low dose active ingredient, when designing the composition, present the difficulty of complying with the content uniformity. The manufacturing process described in this invention achieves optimizing the homogeneity of the content of the active in the microsphere.

The use of microspheres in pharmaceutical formulations can reduce the incidence and severity of side effects of drugs because it is possible to apply a protective film on the spheres that give protection to the environment and the passage through the gastrointestinal tract until the microspheres reach the absorption site.

The present invention uses a flux substance whose function is to carry and fix the active principle to the surface of the cores or pellets, which must have properties such as melting point of 40 ° C to 150 ° C, be compatible with the active principle to formulate and that is pharmaceutically acceptable. Both lipophilic and hydrophilic excipients can be used as fluxes, these can be selected from those described later in the manufacturing process.

The fluxes can be contained between 0.5% and up to 15% of the total mass of the microsphere.

The operation of the process is carried out in systems known as rotary processors, which to date has not been reported to be used to generate microspheres by wax melting. For the development of the present invention, Glatt GPCG 1.1 granulator-coating equipment equipped with a rotary disk was used.

The process known as thermo-adhesion consists in mixing an active principle with a flux that at the same time adhere to nuclei and other excipients if required; The components of the formulation must be compatible with the other ingredients of the formulation.

The mixture of nuclei, active principle, flux and other excipients, if applicable, is introduced into the rotoprocessor equipment; After the inclusion of the components, the mixture is heated by an air flow at a temperature higher than the melting temperature of the flux. Simultaneously, the disk on which the product to be processed is placed is rotated.

The flow of air and the speed of rotation imparted to the cores depend on the scale of manufacture. In general, an air flow of 20 and up to 300m3 / h can be used for each kilogram of product to be processed; as well as, generally, a rotation speed between 0.5 and up to 10 m / s can be used.

When the temperature of the mixture reaches the melting temperature of the flux or above it (called the cutting temperature), the flux goes into a liquid state and adheres to the surface of the nuclei, carrying the active principle. The process temperature for adhesion of the components of the formulation is between 1 ° C and up to 20 ° C above the melting point of the flux.

Once the microspheres are formed in the rotoprocessor during the operation time determined by each formulation, the temperature and the rotation speed of the disc are gradually decreased, the flux solidifies and as a result, coated nuclei, also called microspheres, are obtained which have an excellent Spherical physical appearance and comply with content uniformity.

The resulting coated microspheres can be used as a finished product or are capable of being subjected to other conventional manufacturing operations, such as thin bed coatings in fluidized bed, spheronization, extrusion among others in order to improve the aesthetics or functionality of the Final product.

The obtained coated microspheres are stable and robust and can be encapsulated or subjected to a compression process. As a product, it can be immediate release or prolonged release, this will depend on the excipients used and the characteristics of each active ingredient used as well as the formulation that is intended.

The release profiles depend on the characteristics of the fluxing substance. If, for example, soluble fluxes such as polyethylene glycol or ethylene polyoxide are used, very rapid solutions can be obtained, greater than 75% in 5 minutes.

If water-insoluble fluxes such as glyceryl palmito-stearate having hydrophobic characteristics are used, the release time is prolonged. Additionally, mixtures of fluxes can be made for the case of designing release profiles in particular.

The time used in the present process is significantly less than that used in film coating by fluidized bed that can be up to eight hours. The process by the system proposed in this invention can be up to one third of the time occupied by the system hitherto known. This was demonstrated in tests carried out on a laboratory scale. This is due to the fact that a solution or dispersion of the active principle is not prepared with the fluxing agent previously, no solvents are used that must evaporate during the process, as well as the time allocated in the conventional processes to dry the microspheres is eliminated.

The proposed coating technique may contain an active principle or the combination of more than two in turn, this technique can be used in a unique way to generate a pharmaceutical composition in tablets or capsules, it is also possible to use the microspheres obtained by thermo-adhesion with other operations of manufacturing processes or coatings of pharmaceutical compositions.

The equipment to carry out this process must have a heating system and a system to promote the movement of the cores and the material to be covered; there is no limitation on the type, manufacturer, or size of this equipment; for this novel invention, Glatt GPCG 1.1 granulator-coating equipment equipped with a rotating disc was used.

For the manufacture of the microspheres can be used two types of fluxes: those insoluble in water and water soluble. The use of these fluxes is determined by the formulation that is developed since the selected flux will give the formulation the particularity of the modified release. Here are some of the fluxes that can be used. Insoluble fluxes: - Glycerol esters such as: or glyceryl palmito-stearate (precirol), melting point 52-55 ° C or glyceryl behenate (compritol), melting point 65-77 ° C or glyceryl monostearate, melting point 55-60 ° C Fatty esters of cetyl, melting point 43-55 ° C Stearyl alcohol, melting point 59.4-59.8 ° C Wax, microcrystalline, melting point 54-102 ° C Stearic acid, melting point higher than 64 ° C - Cetyl alcohol , melting point 47-53 ° C Vegetable fat, melting point 61-66 ° C Yellow wax, melting point 61-65 ° C Carnauba wax, melting point 80-88 ° C White wax, melting point 62- 65 ° C - Paraffin, melting point 47-65 ° C Soluble fluxes: Ethylene polyoxide, melting point 65-70 ° C Polyethylene glycol, melting point 42-57 ° C Sorbitan monostearate (emulsifier).

Eg emplos For the development of the present invention, two formulation examples are described.

Example 1 In accordance with the invention described, the following process is enunciated as an illustrative but not limitative example, in which uses corn starch as a model to replace active ingredients with a particle size of less than 30 microns with poor flow properties and with a tendency to agglomerate as a raw material.

Composition of example 1.

The previous example, describes a laboratory level lot of 750 g total, made in a Glatt GPCG 1.1 granulator-coating equipment with rotoprocessing accessories, 30 cm diameter smooth disc, without spray nozzles, without continuous feeding accessories. solid Development of the process 1. The physical mixture of corn starch with polyethylene glycol is made. 2. It is sifted through 30 mesh and incorporated into the inert nuclei.

The total mixture is introduced into the equipment chamber rotoprocessor and the mixture is heated, with a current of air at 80 ° C, with a flow of '100 m3 / h, with a rotation speed of 500 rpm, with disk opening 3 mm and the powder mixture is heated until it have a product temperature of 60 ° C to 65 ° C.

The mixture is cooled by decreasing 5 ° C every 10 minutes and, when the product temperature reaches 35 ° C, the product is discharged which is made up of the nuclei coated with starch and polyethylene glycol.

Control records are made.

Next, the table that shows some processing characteristics with respect to a composition manufactured by a traditional coating process and the process by termoadhesion.

Description Conventional process Proposed process by fluidized bed by thermo-adhesion Amount of 35. Og 35. Og active substance Amount of 52.5g 14. Og binder required Amount of water of 875 mL 0 mL process Time of 45 min. 0 min. coverage preparation Application time 4.5 hours 1 hour of coating including drying Total time of 5.25 hours 1 hour process Example 2 In accordance with the invention described, the following process as illustrative but not limitative example, in which is used piroxicam as active principle, with a size particle size less than 30 microns, with poor flow properties and tendency to agglomeration.

Composition of example 2.

The previous example describes a laboratory-level batch of 1250g total, performed in a granulator-coater brand Glatt GPCG 1.1 with rotoprocessing accessories, disc ribbed 30cm in diameter, without spray nozzles, without continuous solids feed accessories.

Development of the process 1. The physical mixture of piroxicam with stearyl glyceryl palmitate is performed. 2. It is sifted through 30 mesh, and incorporated into the inert nuclei. 3. The total mixture is introduced into the chamber of the described equipment and the mixture is heated, with an air current at 90 ° C, with a flow of 150 m3 / h, with a rotation speed of 1000 rpm, with an opening of 3 mm disc. 4. The powder mixture is heated until it has a product temperature of 70 ° C to 80 ° C. 5. The mixture is cooled by decreasing 7 ° C every 10 minutes and when the product temperature reaches 45 ° C. 6. The product is discharged, which is made up of the cores coated with Piroxicam and stearyl glyceryl palmitate. 7. Control records are made.

Next, a table with the comparison of the characteristics of process that shows the same formulation is presented manufactured by a traditional thermo adhesion process coating process of the invention.

Additionally, as illustrative but not limitative examples of active principles susceptible to be used in this system we have: Piroxicam, chlorpheniramine, loratadine, ambroxol, estradiol, diazepam, prednisolone, ramipril, glimepiride, tropisetron, salbutamol or any stable active at the temperatures of melting of the flux used and preferably the amount of active ingredient of the formulation is low dose.

The present invention relates to the novel manufacture of coated cores, which are characterized by being manufactured in a single container where the process of mixing, melting and cooling the microspheres in a single stage is presented. The manufacturing process of the microspheres is carried out without the use of solution sprinklers, with a minimum use of excipient and vehicles, the use of solvents of any kind is omitted, with this the manufacturing times are reduced significantly by eliminating stages such as the preparation of the cover, and the drying of the composition.

The product obtained is spherical, complies with the tests of particle size, content uniformity and dissolution profiles described for each formulation. Likewise, its rheological characteristics are optimized.

The active principle or the active ingredients can be contained between 1% and up to 15% of the total mass of the microsphere.

The amounts of flux used are relatively low, which makes it possible to obtain coated cores of small size that can be compressed or coated again by one or more active ingredients, which allows the manufacture of pharmaceutical compositions containing active principles that are incompatible with each other, or sensitive to light or environment.

The invention has been sufficiently described so that a person with average knowledge in the field can reproduce and obtain the results mentioned in the present description. However, any person skilled in the art who is competent in the present invention may be able to make modifications not described in the present application. Therefore, if for the application of these modifications in a given composition the matter claimed in the following claims is required, said compositions should be included within the scope of the present invention.

Claims (1)

1. CLAIMS Having described the invention as above, it is claimed as property of what is contained in the following claims: 1. A manufacturing process of thermo-adhesion-coated cores called microspheres comprising the following steps: to. Mix the inert nuclei, one or more active principles, one or more fluxes and, where appropriate, pharmaceutically acceptable excipients in a granulator with rotoprocessor; b. With rotation speed, heat the mixture by air flow until reaching or exceeding the melting temperature (s) of the flux (s) to adhere it (s) to the surface of the cores carrying the (the) active principle (s) and, where appropriate, excipients; and c. Gradually decrease the temperature and speed of rotation so that the flux (s) solidify (n) and obtain the coated nuclei called microspheres. The process according to claim 1, wherein the rotational speed of the rotoprocessor, the air inlet temperature, the air flow and the operating time are a function of the characteristics of the active principle (s) (s), the flux (s) and, where appropriate, selected excipients. The process according to claim 1, wherein the process temperature for the adhesion of the components of the formulation is between 1 ° C and up to 20 ° C above the melting point of the flux. The process according to claim 1, wherein the selected flux has a melting point ranging from 40 ° C to 150 ° C, preferably between 40 ° C and 800 ° C. The process according to claim 1, wherein the required air flow is between 20 a 300 m3 / h for each kilogram of product to be processed. The process according to claim 1, wherein the flux (s) is (are) selected from soluble and / or insoluble fluxes and / or mixtures thereof. The process according to claim 1, wherein the flux (s) represent 0.5% and up to 15% of the total mass of the coated microsphere. 8. The process according to claim 6, wherein the insoluble flux (s) is (are) selected from glycerol esters such as: glyceryl palmito stearate-precirole, glyceryl behenate-compritol, glyceryl monostearate; microcrystalline wax-, paraffin, cetyl alcohol, stearyl alcohol, vegetable fat, stearic acid, white wax, yellow wax, carnauba wax, fatty esters of cetyl and / or mixtures thereof. 9. The process according to claim 6, wherein the soluble flux (s) is (are) selected from: polyethylene glycol, ethylene polyoxide, sorbitan monostearate and / or mixtures thereof. The process according to claim 1, wherein the inert cores are selected from sucrose, starch, cellulose and / or pharmaceutically acceptable substances or coated cores. 11. The process according to claim 1, wherein the coated cores have a diameter of between 20 and up to 2500 microns, preferably between 400 and 1500 microns. 12. The process according to claim 1, wherein the content of the active principle (s) is between 1% up to 15% of the total of the microsphere. 13. The process according to claim 1, wherein the active principle (s) can be any that is stable at the melting temperature of the flux used and the mixture with various excipients. The process according to claim 1, wherein the active principle can be selected from: piroxicam, chlorpheniramine, loratadine, ambroxol, estradiol, diazepam, prednisolone, ramipril, glimepiride, tropisetron, salbutamol, among others. 15. The process according to claim 1, wherein the total weight of the adhered material can represent between 1% and up to 30% of the total weight of the microsphere. 16. The process according to claim 1, wherein additional conventional manufacturing operations such as thin-bed coatings in fluidized bed, spheronization, extrusion, among others, can be performed on the coated microspheres to improve aesthetics or functionality. of the final product. 17. The process according to claim 1, wherein the coated microspheres can be compressed or encapsulated. 18. The process according to claim 1, wherein the coated microspheres can be immediate release or prolonged release.