MXPA01010717A - Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix - Google Patents

Abstract

The invention relates to a method for producing pharmaceutical forms or preliminary stages thereof by means of extrusion. The pharmaceutical form has a matrix in which the active agent is contained essentially, and whose essential characteristics are determined by the extrusion process and which comprises a polysaccharide and/or a derivative thereof and/or a complex thereof and/or any mixture of the aforementioned substances with other substances and/or saccharides and/or derivatives thereof as an essential constituent, and at least one pharmaceutically active substance. The invention also relates to a pharmaceutical form which has a matrix in which the active agent is contained essentially, and whose essential characteristics are determined by the extrusion process, and which comprises a polysaccharide and/or a derivative thereof and/or a complex thereof and/or any mixture of the aforementioned substances with other substances and/or saccharides and/or derivatives thereof as an essential constituent, and at least one pharmaceutically active substance. Finally, the invention also relates to the use of said pharmaceutical form for producing granulates for tabletting and filling capsules, for further processing using injection moulding techniques and as an auxiliary material for direct tabletting and/or for producing monobloc pharmaceutical forms.

Description

METHOD TO PRODUCE A MATRIX OF CONTROLLED RELEASE, AMORFA OR PARTIALLY LOVE AND INSOLUBLE IN WATER FIELD OF THE INVENTION The invention relates to a method for producing pharmaceutical dosage forms or precursors thereof by means of extrusion processes. The invention further relates to a pharmaceutical dosage form that can be produced by extrusion methods.

BACKGROUND OF THE INVENTION Extrusion is a widely generalized process, especially in the adhesives industry or in plastics that are processed to purify polysaccharides, in particular, starches. Extrusion is known within the food technology for the production of starch-containing compositions, such as noodles, so-called pralines or various sweets. However, the production conditions of all these products are selected in such a way that foamed products, called inflated, are obtained. Within the pharmaceutical technology, extrusion is used for the processing of waxes, fatty alcohols, fats and various thermoplastics and duroplastic.

Pl377 For example, extruded matrices of various polymeric compounds are disclosed in EP-A2 0 240 904, EP-A2 0 240 906 and EP-A2 0 358 105. Processing of mixtures containing starch in pharmaceutical products (capsules ) by means of an injection molding technique are described in EP-B2 0 118 240. Within the context of the present, it is not well known how the polysaccharides that are used change during extrusion processes. Extrusion methods for producing solid dispersions of an active agent in a polymeric carrier are known from EP-A 0 580 860. Among the raw material that can be used, is the starch and the starch derivatives that are mentioned in general . However, the method described there is not suitable for preparations containing starch as the main ingredient. In pharmaceutical technology, dosage forms that are administered orally, for example, tablets, dragees or capsules, are by far the most important. These also include so-called controlled release (delayed) forms, which contain a relatively high dose of the active agent and release it in a controlled manner for a longer period of time. For the patient, this means that the frequency of medication can be significantly reduced. From a medical-pharmacological point of view, the advantage of the controlled release dosage forms is to achieve a very uniform concentration of the active agent in the blood, which produces a long-lasting effect with fewer side effects. When formulating the controlled release dosage forms, said matrix form is of fundamental importance. The term "matrix" means a shaped body, for example, a tablet or dragee, which is made of inert adjuvants, which release the active agents in the gastrointestinal tract in a controlled manner. The release of the active agent generally occurs partly through diffusion, and partly through slow degradation of the matrix. In pharmaceutical technology, these matrices are produced from synthetic polymers, such as polyacrylate or polyethylene. In the context of the present, extrusion methods for the production of controlled release forms from synthetic raw material are also known. A fundamental disadvantage of the dosage forms that are produced up to now by means of extrusion methods is the use of excipients such as plastics, wax and even fatty alcohols. These adjuvants, which are not biologically degradable and are in part environmentally harmful, such as the residual monomers in the polymers used, are even indispensable for dosage forms that are produced by extrusion methods and that allow slow and controlled release of the active agent. Even more, there is no known extrusion method for the production of dosage forms that allows a rapid release of the active agent. Therefore, there is a great need to provide an extrusion method for the production of dosage forms that have a regulated release, ie that is delayed by selection or even more rapid release of the active agent, which overcomes the disadvantages of the prior art and which in particular avoids the use of biologically non-degradable excipients and to some extent even environmentally toxic. Other objects can be gathered from the following description of the invention. The solution of the objectives that relate to the method are in the combination of the characteristics of claim 1.

DETAILED DESCRIPTION OF THE INVENTION Advantageous embodiments of the inventive method are defined in the method of the dependent claims. According to the invention, a method is suggested for producing dosage forms or precursors thereof by means of extrusion, characterized in that the dosage form has a matrix comprising essentially the content of the active agent, the essential characteristics of the matrix being formed by extrusion and comprises a biologically degradable polysaccharide and / or a derivative thereof and / or a complex thereof and / or a mixture of the aforementioned substances with other substances and / or saccharides and / or derivatives thereof, by way of a constituent of the matrix, and at least one pharmaceutically effective substance. According to a preferred embodiment, the release of the active agent from the dosage form is regulated by the addition of adjuvants and / or by variation of the parameters in the extrusion processes, such as the temperature, geometry of the dies and / or the speed of extrusion. In another preferred embodiment, the matrix of the dosage form which is made according to the invention is amorphous or partially amorphous. Furthermore, in a preferred embodiment, the invention relates to a method, wherein the dosage form according to the invention comprises, in the matrix, a starch or a derivative thereof, in particular an amorphous or partially amorphous starch or a derivative thereof. this one, like the polysaccharide. In another preferred embodiment, the invention relates to a production method wherein the dosage form comprises a water-insoluble matrix and preferably a matrix with dilation ability. According to an especially preferred embodiment, the dosage form according to the invention is a controlled release matrix. Other preferred embodiments include a dosage form according to the invention, which shows a release of the active agent which follows, essentially, the function of lapidus and which especially shows a release of the active agent which can be adjusted over a period of 24 hours or plus . Another essential objective of the invention is the provision of a dosage form that can function essentially without biologically degradable ingredients. According to the invention, this object is solved by a dosage form comprising a matrix in which the active agent is essentially contained and whose essential properties are determined by the extrusion processes and which comprises a polysaccharide and / or a derivative thereof and / or a complex thereof and / or any mixture of the aforementioned substances with other substances and / or saccharides and / or derivatives thereof, in the manner of an essential constituent of the matrix, and at least one pharmaceutically effective substance. Moreover, the invention relates to the use of the inventive dosage form as an adjuvant for the direct formation of tablets, to produce granules to produce tablets and the filling of the capsules, for further processing, using the techniques of injection molding and / or to produce pharmaceutical dosage forms in monoblocks. During the extrusion processes, that is to say while using or applying heat, cutting forces and pressure, an amorphous or partially amorphous matrix is generated from the crystalline or partially crystalline polysaccharides, in particular from the starch or derivatives thereof. or mixtures of these components. For the reproducible production of dosage forms based on the extrusion of polysaccharides and derivatives thereof, the extrusion conditions, such as temperature, die geometry and extrusion rate, are very important. For example, the natural starch can be fully plasticized or vitrified under suitable extrusion conditions, so that homogeneous bodies of a plastic-like conformation can be obtained. When the starch is extruded, heating is only necessary at the beginning of the process. During the course of the process, the heat generated by the shear stress and friction is preferably removed by cooling, in order to maintain a constant temperature. The formulations which are used in the inventive method comprise a mixture of polysaccharides and / or derivatives thereof, preferably a mixture of starch and / or starch derivatives, having various types of starch which are suitable. Moreover, the mixture contains at least one pharmaceutically effective substance in an amount of up to 50% and preferably up to 30%, based on the total weight of the formulation, and may additionally comprise other different substances. The water, at concentrations that cover up to 15%, must be added to the dry formulation and completely mixed. When a forced transport extruder is used, a water content of less than 15% is sufficient. After mixing thoroughly and adding water, the premix obtained must be passed through the sieve so that it is free of lumps, in order to ensure a perfect transport through the advance by the worm. The start-up and cleaning of the extruder can be carried out, for example, using a mill. When a matrix is generated according to the inventive method, the temperature in the orifice of the extruder must not exceed 100 ° C under normal pressure, since at temperatures above 100 ° C the formation of a matrix that is free of porosities is hardly possible. The total energy that is provided in the process, in the form of cutting forces, temperature, heat or pressure, should be as constant as possible and should be enough to achieve the vitreous transition. The optimum spindle speed and the geometry of the dies can be adjusted to the mixture comprised of an inventive carrier and water. At extrusion temperatures below 100 ° C and at suitable spindle speeds, transparent and completely amorphous products are obtained in most cases. The degree of plasticization of the active agent / polysaccharide mixture, preferably of the active agent / starch mixtures, is closely related to the spindle speed. While extrusion is not possible below the lower speed, a spindle speed that is too high causes the dosage form to "burst or float". By varying the parameters of the extrusion process, the production of forms of P1377 dosage, according to the inventive method, showing a regulated release of the active agent. Within the meaning of the present invention, the term "regulated" means that the dosage forms with a rapid release as well as the dosage forms with a delayed release, called controlled release dosage forms can be produced by the inventive extrusion method. , with release periods of up to 24 hours or more. Apart from the process parameters already mentioned, also the processing temperature is of a major importance in relation to the regulation of the release of the active agent. Dosage forms with rapid release can be obtained, for example, by extrusion below the gelatinization temperature of the polysaccharides which are used in each case. Taking into account that, among other things, the density of the matrix influences the release of the incorporated active agents, the corresponding dosage forms with a controlled release can be produced by a partial or complete vitrification, that is, by the transition of the amorphous state of the mixture containing the polysaccharide under suitable extrusion conditions. Unlike the previously described systems, such an amorphous or partially amorphous matrix according to the inventive method, Pl377 is preferably made of amorphous or partially amorphous starch or derivatives thereof or mixtures of these components, which is essentially not soluble in water, but instead preferably has the ability to expand and is insoluble in water. or pharmaceutically effective substances may be present in the matrix in dissolved, solid or liquid form. Examples of starches that can be used in the inventive method of production are tapioca starch, wheat starch, potato starch, starch 1500® (partially pregelatinized cornstarch, available from Colorcon), Waxylis® (corn starch, paraffinose Roquette), Eurylon 7® (corn starch starch available from Roquette), corn starch, acetyl starch. In addition, the dosage forms can be obtained according to the inventive method of extrusion, which have a regulated release of the active agent due to the addition of adjuvants. To accelerate the release of the active agent by forming pores in the matrix, the following substances can be added, for example: hydrophilic or amphiphilic solids, water-soluble substances, such as sodium chloride, lactose, surfactants, for example sodium lauryl sulfate. , silica (colloidally dispersed and / or by way of xerogel), Pl377 hydrophilic or amphiphilic liquids, polyglycols, for example glycerol, polyethylene glycol, surfactants, for example polysorbate, gases, for example nitrogen, carbon dioxide. For example, a reduction in the release of the active agent can be effected by inhibiting diffusion by the addition of the following adjuvants: lipophilic or amphiphilic adjuvants of natural, synthetic and / or partially synthetic origin, for example fats, fatty acids, wax in solid or liquid state, saturated and unsaturated hydrocarbons, metal soaps, for example magnesium stearate. In addition, a reduction in the release of the active agent can be achieved by the formation of stoichiometric or non-stoichiometric complexes, for example an iodine-starch complex and a miltefosine-amylose complex. Moreover, the release of the incorporated active agents can be influenced by the use of suitable mixtures of the components of the matrix, preferably by using mixtures of different starches and / or derivatives thereof. Other factors that may also influence the release of the active agent are the external surface of the shaped body of the dosage form and its particle size, or the distribution of the active agents within the particle. An examination of the pathway of active agent release shows that the release of the active agent is preferably controlled by diffusion and the so-called Lapidus rule., as shown in the analyzes described below. The path of the release does not change, even after storage of the dosage forms for several months. Dosage forms that are produced according to the inventive method can be used to produce granules for tabletting and capsule filling, can be used as an adjuvant for direct tablet formation, for further processing of extrusion molding techniques and / or in the form of dosage forms in monoblocks, wherein the extruded product is formed by means of a suitable configuration in the extrusion die, similar to the case of the production of soaps. The inventive method allows the production and use of monobloc shapes, in which process an extruded product is created that vitrifies only on the surface and includes the active substance / carrier mixture in a state without changes therein. TO Pl 77 In order to achieve the desired biopharmaceutical properties of the dosage form, they can be used. use all known adjuvants to produce solid forms. The drying of the dosage form can be carried out merely by the friction heat that is generated, so that a final drying step is not necessary. In a production extruder, preferably in a twin-screw extruder, especially preferred in a forced-drive double-screw extruder, all process steps, such as dosing, wetting, mixing, extrusion and forming, can be carried out continuously . The inventive method, therefore, is able to combine the process of mixing, granulation and drying, for which no additional energy should be spent in a single piece of equipment. According to the invention, the number of possible incompatibilities is also reduced, since the dosage form comprises, for example, only one excipient, preferably of starch or a derivative thereof and a pharmaceutically effective substance. The matrix that is made according to the inventive method also prevents a possible unintentional separation. The following examples show that the degree of retardation of the active agent is best regulated by the process or process parameters, the type of polysaccharide or the addition of other adjuvants. The examples serve only to illustrate the invention and do not represent any limitation to certain embodiments or applications. Rather, other embodiments may be conceived within the scope defined by the appended claims.

EXAMPLES In the following examples, which have been carried out according to the inventive method, various polysaccharides are used with the addition of caffeine as an active agent model. The extrusion experiments are carried out with a Brabusder single-screw extruder type 811201. This device has three segments, which can be independently tuned to each other, the feeding area, the spindle area and the die. A spindle conveyor is used without compression, having a spindle length of 22 cm, a spindle diameter of 19 mm, a center diameter of 16 mm and an inclination of 15 mm. Dies with different diameters between 2.5 and 7 mm are used. The lot size in the experiments is between 350 and 600 grams. The active agent and the starch are completely mixed in a Stephan mixer, wetted with 15% water; this premix is passed through a sieve Pl377 until it is free of lumps. Temperatures of about 65 ° C in the extruder feed area, about 80 ° C in the spindle area and about 98 ° C in the die, have been shown to be a suitable temperature choice to carry out the inventive method . The test of the transition of the crystalline or partially crystalline structures of the polysaccharides into amorphous or partially amorphous structures can be carried out with the aid of different techniques. By means of differential scanning colorimetry (DSC), the transition from crystalline or partially crystalline starch to its amorphous state can be detected. Under suitable extrusion conditions, the starch becomes completely vitrified, ie it changes to the amorphous state. By way of example, an analysis with tapioca starch as the polysaccharide and caffeine as the active agent was carried out. The thermogram of the premix is shown in Figure IA and consists of 90% tapioca starch and 10% caffeine with the addition of water, and shows the typical endothermic peaks in the range of about 65 ° C. After the extrusion is carried out according to the invention, no peaks can be detected in the decisive temperature range. It has to be concluded that starch P1377 has been completely vitrified, which means that it has been converted to its amorphous state (see Figure lb). The transition from the crystalline or partially crystalline state to the amorphous or partially amorphous state can also be expressed by the aid of X-ray diffraction. In the following exemplary analysis, a sample consisting of 80% potato starch and 20% caffeine is used. The X-ray diffraction pattern of the potato-caffeine starch premix shown in Figure 2 shows the signals of the crystalline part of the starch in the range of about 20 ° C. After the application of the inventive method, the X-ray diffraction pattern of the corresponding extruded product no longer has any signals, which indicates a crystalline portion of the starch. In the context of the present, it is once again noted that the degree of de-structuring to the vitreous state is decisive for the kinetics of the release of the active agents. The verification of the release of the active agent is carried out in a stirrer of blades according to USP in the liquids: of hydrochloric acid 0.1 N (artificial gastric fluid having a pH value of 1) and in a phosphate buffer pH 7.2 (fluid artificial intestinal). In the context of this, once again it should be noted that extruded products do not Pl377 dissolve in the analysis, but merely a dilation of the extruded products is observed. In the following exemplary analysis to determine the quantitative release of the active agent, a sample consisting of commercially available starch Eurylon 7® (amylose corn starch available from Roquette) and a 30% portion of caffeine is used. The diagram in Figure 3 shows the quantitative path of active agent release. For comparative purposes, the release of caffeine in its pure, non-retarded state and filled in a capsule has also been drawn inside. It can be seen that the incorporation of caffeine in a polysaccharide matrix leads to a delay in the release, in the current case from about 15 min to about 8 to 10 h for the total dose of 25 mg. A plot of the amount released against the square root of the period according to the Lapidus rule shows an almost straight path of the curves, which indicates that the release of the active agent is controlled by diffusion (see Figure 4). As already described, the release rate of the active agent can also be relieved by the type of polysaccharide in the polysaccharide mixture. The following example, a premix consisting of starch from P1377 potato and 10% caffeine is used for a quantitative investigation of the release of the active agent. Changing the type of starch, together with a lower dose of the active agent, leads to a significant delay in the release of the active agent. The diagram shown in Figure 5 indicates that the extruded product prepared according to the inventive method provides a release of the active agent over a period of 24 hours. The graph shown in Figure 6 according to the Lapidus rule indicates that the release of the active agent is controlled by diffusion. As already described above, the duration and path of the total release of the active agent can be regulated. Very long periods of time for the release of the active agent, such as a period of 24 hours in the aforementioned example, are considered advantageous in view of the development of a new active principle of delay, since in this way they are obtained " reserves "for fairly good water-soluble active agents. The release of the active agent can be selectively influenced, as already described several times, by the polysaccharides or the corresponding derivatives and mixtures thereof, by the addition of corresponding adjuvants and / or by the P1377 parameters in extrusion processes. According to the inventive method, faster time periods for the release of active agents can also be achieved. The Table shown below shows, by way of example, that a change in the process parameter, which for example leads to incomplete vitrification, results in the possibility of regulating the periods of time of release of the active agent on a broad range.

Table As can be seen from this Table, P1377 for identical types of starch, relatively short release time periods for the active agent can be achieved as well as active agent release time periods that fall within the range of controlled release dosage forms only by varying the process parameters.

P1377

Claims (19)

1. CLAIMS; A method for producing pharmaceutical dosage forms or precursors thereof, by means of an extrusion process, wherein the dosage form has a matrix wherein the active agent is essentially included and which comprises a polysaccharide and / or a derivative thereof and / or a complex thereof and / or a mixture of the aforementioned substances with other substances and / or saccharides and / or derivatives thereof, as an essential constituent, and at least one pharmaceutically active agent, and which is formed in its essential properties, with respect to the release of the active agent, by a simultaneous extrusion with the active agent.
2. The method according to claim 1, wherein the release of the active agent from the dosage form is regulated by an addition of adjuvants and / or by variation of the parameters in the extrusion process, such as temperature, geometry of the dies and / or extrusion speed.
3. 3. The method according to claim 1 or claim 2, wherein the matrix is amorphous or partially amorphous.
4. 4. The method according to any of the preceding claims, wherein the polysaccharide is P1377 starch or a derivative thereof.
5. The method according to any of the preceding claims, wherein the matrix is soluble in water.
6. 6. The method according to any of the preceding claims, wherein the matrix is a controlled release matrix.
7. The method according to any of the preceding claims, wherein the release of the active agent from the dosage form substantially follows the function of Lapidus.
8. The method according to any of the preceding claims, wherein the release of the active agent from the dosage form can be adjusted for a period of time of 24 hours or more.
9. The method according to any of the preceding claims, wherein at least one pharmaceutically active agent is present in the matrix in dissolved, solid or liquid form.
10. 10. The pharmaceutical dosage form, comprising a matrix wherein the active agent is essentially included, comprising a polysaccharide and / or a derivative thereof and / or a complex thereof and / or any mixture of the aforementioned substances with other substances and / or saccharides and / or P1377 derivatives thereof, as the essential constituent of the matrix, and at least one pharmaceutically active agent, and which is formed, in its essential properties with respect to the release of the active agent, by a simultaneous extrusion with the active agent.
11. The dosage form according to claim 10, wherein the release of the active substance is regulated by the addition of adjuvants and / or by the variation of the parameters in the extrusion processes, such as temperature, geometry of the dies and / or extrusion speed.
12. 12. The dosage form according to claim 10 or claim 11, wherein the matrix is amorphous or partially amorphous.
13. 13. The dosage form according to any of claims 10 to 12, wherein the polysaccharide is starch or a derivative thereof.
14. 14. The dosage form according to any of claims 10 to 13, wherein the matrix is insoluble in water.
15. 15. The dosage form according to any of claims 10 to 14, wherein the matrix is a controlled release matrix.
16. 16. The dosage form according to any of claims 10 to 15, wherein the release of the P1377 active agent substantially continues the function of Lapidus.
17. 17. The dosage form according to any of claims 10 to 16, wherein the release of the active agent is adjusted for a period of time of up to 24 hours or more.
18. 18. The dosage form according to any of claims 10 to 17, wherein at least one pharmaceutically active agent is present in the matrix in dissolved, solid or liquid form.
19. 19. The use of a dosage form according to claim 10 to 18, for producing granules for tabletting and capsule filling, for further processing using injection molding techniques, as an adjuvant for direct formation of the tablets and / or to produce pharmaceutical dosage forms in monoblocks. P1377