AU2011273595B2

AU2011273595B2 - Compositions with a high active ingredient fraction of a mixture of chondroitin sulphate and glucosamine

Info

Publication number: AU2011273595B2
Application number: AU2011273595A
Authority: AU
Inventors: Simon Ensslin
Original assignee: Mepha Schweiz AG
Current assignee: Mepha Schweiz AG
Priority date: 2010-06-29
Filing date: 2011-06-28
Publication date: 2015-08-20
Anticipated expiration: 2031-06-28
Also published as: CH703348A1; WO2012000971A3; EP2588087A2; EA201390033A1; EA025130B1; WO2012000971A2; AU2011273595A1

Abstract

The present invention relates to a composition comprising: a) at least 70% by weight of at least one pharmaceutically active substance which is a mixture of chondroitin sulphate and glucosamine or pharmaceutically acceptable salts thereof; b) 5 to 25% by weight of at least one binder, where at least 30% by weight of the binder has a particle size less than 70 µm; c) 0.1 to 0.75% by weight of at least one filler, where at least 90% by weight of the filler has a particle size less than 1.5 µm; and d) optionally further additives, where the total fraction of constituents in the composition is 100% by weight, and also to an oral administration form comprising the composition.

Description

AA-P2287_ATD -1 Compositions having high active substance content of pharmaceutically active substances The present invention relates to a composition containing a mixture of chondroitin sulfate and glucosamine, and an oral administration form containing the above-mentioned composition. Pharmaceutically active substances may be formulated as single-dose solid drugs in the form of tablets, which represent a common oral administration form. The tablets have various shapes, and biconvex shapes (round, oblong, upwardly and downwardly convex) have become prevalent for oral administration. Tablets may be produced by compressing powders or granules by means of tablet presses. A very large number of active substances may be processed into tablets. Various binders are often added to a composition containing a pharmaceutically active substance in order to obtain a tablet with sufficient hardness after pressing. The powdered or granulated compositions which are processed into tablets in a tablet press must also have sufficient flowability. In addition, it may be desired to have a high proportion by weight of pharmaceutically active substance per tablet. On the one hand, there are often therapeutic reasons for administering high daily dosages. This is simplified when a few, or only one, tablet(s) must be taken orally each day, in which case the tablets necessarily have a high active substance content. On the other hand, it may be desired for the tablet to be as small as possible in order to simplify oral administration, for example for children or the elderly. Here as well, a high 6/28/11 AA-P2287_ATD -2 active substance content in the tablet is required. However, high active substance contents adversely affect the hardness of the tablet, which must be avoided. In addition, with high active substance contents the flowability of the composition within a tablet press is often adversely affected. This inevitably results in production disturbances. The determination of the angle of repose a of a loosely piled sample, for example, is a measure of the flowability of a composition. In this process, the angle a between the base surface and the conically loosely piled sample of the composition to be investigated is determined. The smaller the angle of repose a of a loosely piled composition, the better the flowability. In particular, the angle of repose a is correlated with the processability of a composition within a tablet press. Fairly small angles of repose a of a loosely piled sample indicate improved processability within a tablet press. This reduces the likelihood of production disturbances within a tablet press. Thus, in the prior art there is a need for compositions containing a high proportion of pharmaceutically active substance, and from which tablets having sufficient hardness may be obtained. In addition, the composition must be flowable within a tablet press so that efficient pressing of the composition into tablets is ensured. This results in particular in the technical task of providing compositions having a small angle of repose a of a loosely piled sample. Correspondingly, the task in the prior art is to provide a composition containing a high proportion of chondroitin sulfate and glucosamine or the pharmaceutically acceptable salts thereof. The technical object of the present invention is achieved by a composition containing a) at least 70% by weight of at least one pharmaceutically active substance which is a mixture of chondroitin sulfate and glucosamine or the pharmaceutically acceptable salts thereof, 6/28/11 AA-P2287_ATD -3 b) 5 to 25% by weight of at least one binder, at least 30% by weight of the binder having a particle size less than 70 pm, c) 0.1 to 0.75% by weight of at least one filler, at least 90% by weight of the filler having a particle size less than 1.5 pm, and d) optional further additives, in which the total proportion of constituents in the composition is 100% by weight. In one preferred embodiment, the composition contains at least 80% by weight of at least one pharmaceutically active substance which is a mixture of chondroitin sulfate and glucosamine or the pharmaceutically acceptable salts thereof, and 5 to 19.9% by weight of at least one binder, at least 30% by weight of the binder having a particle size less than 70 pm. The compositions of the present invention surprisingly show an increase in the efficiency of a tablet press when oral administration forms are produced. The angles of repose a of a loosely piled sample are smaller, which indicates improved flowability. In addition, it is surprising that the tablet hardness of an oral administration form containing the above mentioned composition is sufficient. In one preferred embodiment, the at least one pharmaceutically active substance a) has a particle size, relative to the total content of pharmaceutically active substance, for which at least 50% by weight is greater than 50 pm. The particle size distribution may be determined by sieve analysis or laser diffraction. In one preferred embodiment, the at least one pharmaceutically active substance a) preferably contains at least 30% by weight chondroitin sulfate sodium and at least 50% by weight glucosamine HCI. At least 30% by weight of the at least one binder b) contained in the composition has a 6/28/11 AA-P2287_ATD -4 particle size less than 70 pm. The particle size distribution may be determined by sieve analysis or laser diffraction. In another preferred embodiment, the at least one binder b) has a particle size for which at least 40% by weight is less than 70 pm, and more preferably, has a particle size for which 50% by weight is less than 70 pm. It is further preferred that the at least one binder b) is a dry binder. The binder b) is preferably selected from the group composed of starch, cellulose, modified cellulose, copolymers of polyvinylpyrollidone with polyvinyl acetate, or mixtures thereof. In another preferred embodiment, the binder b) is selected from the group composed of hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof. At least 90% by weight of the at least one filler c) contained in the composition has a particle size of less than 1 pm. The particle size distribution may be determined by sieve analysis or laser diffraction. In another preferred embodiment, the at least one filler has a particle size for which at least 90% by weight is less than 0.5 pm. In another preferred embodiment, the filler c) contains primary particles having a particle size, relative to the total content of filler, for which at least 90% by weight is less than 1 pm, more preferably, for which at least 90% by weight is less than 0.75 pm, and most preferably, for which at least 90% by weight is less than 0.5 pm. The content of the at least one filler c) in the composition is preferably 0.1 to 0.6% by weight, more preferably 0.1 to 0.5% by weight, and most preferably 0.2 to 0.5% by weight. The at least one filler c) is preferably an inorganic or organic filler. The filler c) is more preferably selected from the group composed of silicic acid, fumed silica, precipitated silica, kaolin, calcium carbonate, zinc oxide, alumina, titanium dioxide, silica, aluminum 6/28/11 AA-P2287-ATD hydroxide, colloidal silica, or mixtures thereof. The filler c) preferably has a specific surface (BET) of greater than 100 m 2 /g. The composition preferably contains further additives d), for example microcrystalline cellulose, lactose, disintegrants, lubricants such as magnesium stearate, and/or antioxidants. A further subject matter of the present invention is an oral administration form containing the above-mentioned composition. The oral administration form is preferably a tablet. The oral administration form is preferably used in the treatment of degenerative joint diseases. The degenerative joint disease is preferably arthrosis, coxarthrosis, finger joint arthrosis, and/or polyarthrosis. A further subject matter is the above-mentioned composition for use in the treatment of degenerative joint diseases. The degenerative joint disease is preferably arthrosis, coxarthrosis, finger joint arthrosis, and/or polyarthrosis. Production examples Production of compositions by mixing the active substances with magnesium stearate, various binders, and a filler. The quantities of the constituents are constant in Examples 1 through 3. Example 1 A composition was produced having high proportions of chondroitin sulfate sodium and glucosamine HCI, and using Kollidon* as binder. 6/28/11 AA-P2287_ATD -6 Example 2 A composition was produced having the same proportions of chondroitin sulfate sodium and glucosamine HCI as in Example 1, but using Klucel* as binder. Example 3 A composition was produced having the same proportions of chondroitin sulfate sodium and glucosamine HCI as in Example 1, but using Ceolus® as binder. Compositions 1 through 3 are listed in Table 1. Table 1 Example No. 1 2 3 %by %by %by weight weight weight Chondroitin sulfate sodium 32.35 32.35 32.35 Glucosamine HCI 53.9 53.9 53.9 Magnesium stearate 1 1 1 Kollidon* VA64 Fine 12.5 Klucel* EXF 12.5 Ceolus* UF-711 12.5 Aerosil* 200 0.25 0.25 0.25 According to sieve analysis (using a sieve in accordance with DIN ISO 3310-1), the chondroitin sulfate sodium used has a particle size with d( 50 ) = 75 pm and d(9o) = 244 pm. According to sieve analysis (using a sieve in accordance with DIN ISO 3310-1), the glucosamine HCI used has a particle size with d(so) = 271 pm and d(go) = 552 pm. The Kollidon* VA64 Fine used is a binder containing copolymers of polyvinylpyrollidone with polyvinyl acetate, and according to laser diffraction has a particle size with d(so) = 40.2 pm and d(go) = 84.8 pm. 6/28/11 AA-P2287-ATD -7 The Klucel* EXF used is a binder containing hydroxypropyl cellulose, and according to laser diffraction has a particle size with d( 50 ) = 26.5 pm and d(go = 92.5 pm. The Ceolus* UF-711 used is a binder containing microcrystalline cellulose, and according to laser diffraction has a particle size with d(so) = 64.2 pm and d(go) = 128.1 pm. The Aerosil® 200 used is a filler (fumed silica) having a particle size with d(go) < 0.5 pm. Comparative examples In comparative examples A through E, compositions containing either no filler or 4 times the quantity of filler were produced by mixing. An overview of the compositions is provided in Table 2. Table 2 Comparative example A B C D E %by %by %by %by %by weight weight weight weight weight Chondroitin sulfate sodium 32.5 32.1 32.5 32.1 32.5 Glucosamine HCI 54.0 53.4 54.0 53.4 54.0 Magnesium stearate 1 1 1 1 1 Kollidon* VA64 Fine 12.5 12.5 Klucel* EXF 12.5 12.5 Ceolus* UF-711 12.5 Aerosil* 200 1.0 1.0 6/28/11 AA-P2287_ATD -8 Testing of the application-related properties of the compositions Example 4 The flowability of the compositions in Examples 1 through 3 and of comparative examples A through E was determined by measuring the angle of repose a in degrees. The steeper (larger) the angle of repose of a loosely piled sample, the less the flowability. In each case, 50 g of the composition was poured through a flow opening 10 mm in diameter onto a base plate having a diameter of 10 cm. The angle of repose was measured by laser (ERWEKA GTB*, ERWEKA GmbH). The results are summarized in Table 3. Table 3 Example No. 1 2 3 A B C 0 E Angle of repose [0] 33.5 33.4 31.2 40.7 37.0 38.5 38.8 36.4 It was surprisingly shown that the compositions in Examples 1 through 3 of the present invention, containing 0.25% by weight filler, had the smallest angle of repose, and thus, the best flowability. The flowability decreases with a higher proportion of filler. The same is true for no filler content in the compositions. Example 5 In addition, the tablettability of the compositions in Examples 1 through 3 and in comparative examples A through E was assessed in a tablet press. The measurement of the angle of repose and the flowability derived therefrom was verified by visual checking the flowability and the tablettability within a tablet press. A numerical rating system was used, as defined below: - 1: Very good flow, best tablettability - 2: Good flow, good tablettability 6/28/11 AA-P2287 ATD - 3: Moderate flow, average tablettability The flowability and the tablettability of the above compositions were visually assessed, and evaluated according to the described rating system. The results are shown in Table 4. Table 4 Example No. 1 2 3 A B C D E Flowability 2 2 1 3 3 3 3 3 I Tablettability 2 2 2 3 3 3 3 3 It was surprisingly shown that the compositions in Examples 1 through 3 of the present invention, containing 0.25% by weight filler, had the best flowability and tablettability. The flowability and tablettability decrease with a higher proportion of filler. The same is true for no filler content in the compositions. Example 6 The tablet hardness of tablets produced from the above-mentioned compositions in Examples 1 through 3 and in comparative examples A through E was determined. For this purpose, the compositions were pressed into tablets in an eccentric press with 20 kN pressing force, and the tablet hardness in [N] was determined. A higher value corresponds to a greater hardness. The results are shown in Table 5. Table 5 Example No. 1 2 3 A B c D E Tablet hardness [N] 156 178 150 111 198 144 214 78 It was surprisingly shown that the compositions in Examples 1 through 3 of the present invention, containing 0.25% by weight filler, had sufficient tablet hardness after pressing. 6/28/11 C:\Users\ACG\AppData\Lcal\Temp\7f51a519687f4014af8;4bdd850f155ad.8145058117785E4.docx-31/07/2015 - 10 In summary, it has been shown that the compositions in Examples 1 through 3 of the present invention and tablets produced therefrom have an advantageous combination of flowability, tablettability, and tablet hardness. This result is unexpected by one skilled in the art. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

1. Composition, which is suitable for the production of tablets and has improved flowability properties, containing: a) at least 70% by weight of at least one pharmaceutically active substance which is a mixture of chondroitin sulfate and glucosamine or the pharmaceutically acceptable salts thereof; b) 5 to 25% by weight of at least one binder, at least 30% by weight of the binder having a particle size less than 70 pm wherein said at least one binder is a dry binder selected from the group composed of starch, cellulose, modified cellulose, copolymers of polyvinylpyrollidone with polyvinyl acetate, or mixtures thereof; c) 0.1 to 0.75% by weight of at least one filler, said filler containing primary particles of at least 90% by weight, calculated to the total weight of the filler, having a particle size of less than 1 pm, wherein said at least one filler is selected from the group composed of silicic acid, fumed silica, precipitated silica, kaolin, calcium carbonate, zinc oxide, alumina, titanium dioxide, silica, aluminum hydroxide, colloidal silica, or mixtures thereof; and d) optional further additives, in which the total proportion of constituents in the composition is 100% by weight.

2. A composition according to Claim 1, wherein that the composition contains at least 30% by weight chondroitin sulfate sodium and at least 50% by weight glucosamine HCI.

3. A composition according to claim 1 or 2, wherein that the at least one pharmaceutically active substance a) has a particle size, relative to the total content of pharmaceutically active substance, for which at least 50% by weight is greater than 50 pm. H:\ACG\ntfovn\NRPortbl\DCC\ACG\8179688_1.doc-5/082015 - 12

4. A composition according to any one of claims 1 to 3, wherein that the binder b) has a particle size, relative to the total content of binder, for which at least 40% by weight is less than 70 pm.

5. A composition according to any one of claims 1 to 4, wherein that the binder b) has a particle size, relative to the total content of binder, for which at least 50% by weight is less than 70 pm.

6. A composition according to any one of claims 1 to 5, wherein that the at least one binder b) is a dry binder.

7. A composition according to any one of claims 1 to 6, wherein that the binder b) is selected from the group composed of hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.

8. A composition according to any one of claims 1 to 7, wherein that the at least one filler c) is an inorganic or organic filler.

9. A composition according to any one of claims 1 to 8, wherein that the filler c) has a specific surface (BET) of greater than 100 m 2 Ig

10. A composition according to any one of claims 1 to 9, wherein that the filler c) contains primary particles having a particle size, relative to the total content of filler, for which at least 90% by weight is less than 0.75 pm.

11. A composition according to any one of claims 1 to 10, wherein that the filler c) has a specific surface (BET) of greater than 100 m 2 Ig.

12. A composition according to any one of claims 1 to 11, wherein that the composition contains further additives d) such as microcrystalline cellulose, H:\ACG\ntovv,\RPortbl\DCCACG\8179688 1.docx-5/08/2015 - 13 lactose, disintegrants, lubricants, and/or antioxidants.

13. A use of the composition according to any one of claims 1 to 12 for producing an oral administration form.

14. Oral administration form containing the composition according to any one of claims 1 to 12.

15. A composition according to any one of claims 1 to 12 for use in the treatment of degenerative joint diseases.

16. A method of treating a degenerative joint disease including the step of administering an effective amount of a composition according to any one of claims 1 to 12.

17. Use of a composition according to any one of claims 1 to 12, in the manufacture of a medicament for treating a degenerative joint disease.

18. A use according to claim 17, wherein the medicament is an orally administrable medicament.