PROCESS FOR THE PREPARATION OF EASY-TO-TAKE TABLETS CONTAINING DRY EXTRACT OF GINKGO BILOBA LEAVES

Abstract

A process prepares a rapidly disintegrating tablet with a disintegration time of at most 15 minutes for the peroral administration of a dry extract of the leaves of Ginkgo biloba, and with a total weight of the tablet of between 150 mg and 300 mg per 100 mg of ginkgo extract contained. Rapidly disintegrating tablets containing dry extract of the leaves of Ginkgo biloba can be prepared, which, due to their smaller dimensions, are easier to take than the tablets used hitherto. In a preferred form, the tablets do not contain lactose and are therefore also well tolerated.

Claims

1-17. (canceled)

18: A process for the preparation of a rapidly disintegrating tablet having a disintegration time of at most 15 minutes for the peroral administration of a dry extract of leaves of Ginkgo biloba and having a total tablet weight of between 150 mg and 300 mg per 100 mg of ginkgo extract, the process comprising: (a) mixing ginkgo extract with 6.94 mg to 27.78 mg of a binder per 100 mg of ginkgo extract, with 5.56 mg to 22.22 mg of a disintegration accelerator per 100 mg of ginkgo extract, with 1.11 mg to 4.44 mg of a flow regulating agent per 100 mg of ginkgo extract, and with 0.28 mg to 1.11 mg of a mould release agent per 100 mg of ginkgo extract, to obtain a first mixture, and then compacting and comminuting the first mixture to obtain a concentrated granulate, and (b) mixing the concentrated granulate obtained in (a) with 22.78 mg to 91.11 mg of a further binder per 100 mg of ginkgo extract, with 11.11 mg to 44.44 mg of a further disintegration accelerator per 100 mg of ginkgo extract, with 0.56 mg to 2.22 mg of a further flow regulating agent per 100 mg of ginkgo extract, and with 1.67 mg to 6.67 mg of a further mould release agent per 100 mg of ginkgo extract, to obtain a second mixture, and pressing the second mixture into a tablet, wherein a total amount of excipients in (a) is from 13.89 mg to 55.56 mg per 100 mg of ginkgo extract and in (b) is from 36.11 mg to 144.44 mg per 100 mg of ginkgo extract; and wherein the binder in (a) and the further binder in (b) is microcrystalline cellulose, wherein the disintegration accelerator in (a) and the further disintegration accelerator in (b) is independently selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone, and sodium starch glycolate, wherein the flow regulating agent in (a) and the further flow regulating agent in (b) is independently selected from the group consisting of highly dispersed silica and precipitated silica, and wherein the mould release agent in (a) and the further mould release agent in (b) is independently selected from the group consisting of magnesium stearate, stearic acid, behenic acid, sodium stearyl fumarate, glycerol dibehenate, calcium behenate, and fumaric acid.

19: ne process according to claim 18, wherein the total tablet weight is between 160 mg and 200 mg per 100 mg of ginkgo extract, wherein in (a), the ginkgo extract is mixed with 8.33 mg to 13.89 mg of the binder per 100 mg of ginkgo extract, with 6.67 mg to 11.11 mg of the disintegration accelerator per 100 mg of ginkgo extract, with 1.33 mg to 2.22 mg of the flow regulating agent per 100 mg of ginkgo extract, and with 0.33 mg to 0.56 mg of the mould release agent per 100 mg of ginkgo extract, wherein in (b), the concentrated granulate obtained in (a) is mixed with 27.33 mg to 45.56 mg of the further binder per 100 mg of ginkgo extract, with 13.33 mg to 22.22 mg of the further disintegration accelerator per 100 mg of ginkgo extract, with 0.67 mg to 1.11 mg of the further flow regulating agent per 100 mg of ginkgo extract, and with 2.00 mg to 3.33 mg of the further mould release agent per 100 mg of ginkgo extract, and wherein the total amount of excipients in (a) is 16.67 mg to 27.78 mg per 100 mg of ginkgo extract and in (b) is 43.33 mg to 72.22 mg per 100 mg of ginkgo extract.

20: The process according to claim 18, wherein the disintegration accelerator in (a) and the further disintegration accelerator in (b) is croscarmellose sodium, wherein the flow regulating agent in (a) and the further flow regulating agent in (b) is precipitated silica, and wherein the mould release agent in (a) and the further mould release agent in (b) is magnesium stearate.

21: The process according to claim 18, wherein the compacting in (a) is performed by roller compacting.

22: The process according to claim 18, wherein, apart from the ginkgo extract, no further plant extracts or other active ingredients are used, and, apart from the excipients mentioned, no further excipients are used.

23: A rapidly disintegrating tablet having a disintegration time of at most 15 minutes for peroral administration of a dry extract of leaves of Ginkgo biloba and having a total weight of the tablet between 150 mg and 300 mg per 100 mg of Ginkgo extract, prepared by the process according to claim 18.

24: The rapidly disintegrating tablet according to claim 23, wherein the tablet comprises, in addition to the ginkgo extract, microcrystalline cellulose as the binder in (a) and the further binder in (b): the disintegration accelerator in (a) and the further disintegration accelerator in (b) are independently selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone, and sodium starch glycolate; the flow regulating agent in (a) and the further flow regulating agent in (b) are independently selected from the group consisting of highly dispersed silica and precipitated silica; and the mould release agent in (a) and the further mould release agent in (b) are independently selected from the group consisting of magnesium stearate, stearic acid, behenic acid, sodium stearyl fumarate, glycerol dibehenate, calcium behenate, and fumaric acid, wherein no lactose is contained in the tablet, and wherein apart from the ginkgo extract, no other plant extracts or other active ingredients are contained in the tablet and, apart from the excipients mentioned, no other excipients are contained in the tablet.

25: A rapidly disintegrating tablet having a disintegration time of at most 15 minutes for peroral administration of a dry extract of leaves of Ginkgo biloba, wherein a total weight of the tablet is between 150 mg and 30) mg per 100 mg of ginkgo extract, wherein the tablet comprises, in addition to the ginkgo extract, microcrystalline cellulose as a binder; a disintegration accelerator selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone and sodium starch glycolate; a flow regulating agent selected from the group consisting of highly dispersed silica and precipitated silica, and a mould release agent selected from the group consisting of magnesium stearate, stearic acid, behenic acid, sodium stearyl fumarate, glycerol dibehenate, calcium behenate, and fumaric acid; wherein no lactose is contained in the tablet, and wherein apart from the ginkgo extract, no other plant extracts or other active ingredients are contained in the tablet and, apart from excipients mentioned, no other excipients are contained in the tablet.

26: The tablet according to claim 23, wherein the total weight of the tablet is between 160 mg and 200 mg per 100 mg of ginkgo extract.

27: The tablet according to claim 23, wherein the total weight of the tablet is 175 mg per 100 mg of ginkgo extract.

28: The tablet according to claim 23, comprising 80 to 360 mg of the dry extract of leaves of Ginkgo biloba.

29: The tablet according to claim 23, comprising 220 to 260 mg of the dry extract of leaves of Ginkgo biloba.

30: The tablet according to claim 23, comprising 240 mg of the dry extract of leaves of Ginkgo biloba.

31: The tablet according to claim 23, wherein the dry extract of leaves of Ginkgo biloba comprises, by weight, 22.0 to 27.0% of flavonoids calculated as flavone glycosides, 2.6 to 3.2% of bilobalide, and 2.8 to 3.4% of ginkgolides A, B and C; and at most ppm of ginkgolic acids.

32: The tablet according to claim 23, wherein no lactose is contained in the tablet.

33: The tablet according to claim 23, wherein, apart from the ginkgo extract, no other plant extracts or other active ingredients are contained in the tablet, and, apart from the excipients mentioned, no other excipients are contained in the tablet.

34: The tablet according to claim 24, wherein the binder is microcrystalline cellulose, the disintegration accelerator is croscarmellose sodium, the flow regulating agent is precipitated silica, and the mould release agent is magnesium stearate.

35: The tablet according to claim 23, wherein the tablet is additionally coated with a film and has a disintegration time of at most 30 minutes.

Description

EXAMPLE 1 ACCORDING TO THE INVENTION

[0047] Compact, Lactose-Free Tablets without Coating Containing 240 mg Dry Extract of Ginkgo biloba Leaves with a Ratio of Tablet Mass to Active Ingredient Mass Contained of 1.5

TABLE-US-00002 Calculated on 100 mg of the Amount contained per tablet ginkgo extract Component [mg] [mg]. 1. Ginkgo leaf extract (EGb ® 761) 240.00 100.00 2. Cellulose, microcrystalline 16.67 6.94 3. Croscarmellose sodium 13.33 5.56 4. Silica, precipitated 2.67 1.11 5. Magnesium stearate 0.67 0.28 2.-5. Sum of excipients in step (a) 33.34 13.89 1.-5. Compactate 273.34 113.89 6. Cellulose, microcrystalline 54.66 22.78 7. Croscarmellose sodium 26.67 11.11 8. Silica, precipitated 1.33 0.56 9. Magnesium stearate 4.00 1.67 6.-9. Sum of excipients in step (b) 86.66 36.11 1.-9. Tablet 360.00 150.00

[0048] For the preparation of the tablets according to the invention as described in Example 1, 480 g of ginkgo leaf extract are mixed with 33.34 g of microcrystalline cellulose, 26.66 g of croscarmellose sodium, 5.34 g of precipitated silica and 1.34 g of magnesium stearate and processed with a roller compactor to a concentrated granulate (compactate) (step (a)). To produce 1600 tablets, 437.34 g of the granulate thus obtained are mixed with 87.46 g of microcrystalline cellulose, 42.67 g of croscarmellose sodium, 2.13 g of precipitated silica and 6.40 g of magnesium stearate and compressed on a rotary tablet press to form tablets with a mass of 360 mg each (step (b)).

EXAMPLE 2 ACCORDING TO THE INVENTION

[0049] Compact, Lactose-Free Tablets without Coating Containing 240 mg Dry Extract of Ginkgo biloba Leaves with a Ratio of Tablet Mass to Active Ingredient Mass Contained of 1.75

TABLE-US-00003 Calculated on 100 mg of the Amount contained per tablet ginkgo extract Component [mg] [mg]. 1. Ginkgo leaf extract (EGb ® 761) 240.00 100.00 2. Cellulose, microcrystalline 25.00 10.42 3. Croscarmellose sodium 20.00 3.33 4. Silica, precipitated 4.00 1.67 5. Magnesium stearate 1.00 0.42 2.-5. Sum of excipients in step (a) 50.00 20.83 1.-5. Compactate 290.00 120.83 6. Cellulose, microcrystalline 82.00 34.17 7. Croscarmellose sodium 40.00 16.67 8. Silica, precipitated 2.00 0.83 9. Magnesium stearate 6.00 2.50 6.-9. Sum of excipients in step (b) 130.00 54.17 1.-9. Tablet 420.00 175.00

[0050] To produce 100,000 tablets of the invention according to Example 2, 24.00 kg of ginkgo leaf extract is mixed with 2.50 kg of microcrystalline cellulose, 2.00 kg of croscarmellose sodium, 0.40 kg of precipitated silica and 0.10 kg of magnesium stearate and processed with a roller compactor to form a concentrated granulate (compactate) (step (a)). The granulate is mixed with 8.20 kg microcrystalline cellulose, 4.00 kg croscarmellose sodium, 0.20 kg precipitated silica and 0.60 kg magnesium stearate and compressed on a rotary tablet press to form tablets with a mass of 420 mg each (step (b)).

EXAMPLE 3 ACCORDING TO THE INVENTION

[0051] Compact, Lactose-Free Tablets without Coating Containing 240 mg Dry Extract of Ginkgo biloba Leaves with a Ratio of Tablet Mass to Active Ingredient Mass Contained of 3.0

TABLE-US-00004 Calculated on 100 mg of the Amount contained per tablet ginkgo extract Component [mg] [mg]. 1. Ginkgo leaf extract (EGb ® 761) 240.00 100.00 2. Cellulose, microcrystalline 66.67 27.78 3. Croscarrnellose sodium 53.33 22.22 4. Silica, precipitated 10.67 4.44 5. Magnesium stearate 2.67 1.11 2.-5. Sum of excipients in step (a) 133.34 55.56 1.-5. Compactate 373.34 155.56 6. Cellulose, microcrystalline 218.66 91.11 7. Croscarmellose sodium 106.67 44.44 8. Silica, precipitated 5.33 2.22 9. Magnesium stearate 16.00 6.67 6.-9. Sum of excipients in step (b) 346.66 144.44 1.-9. Tablet 720.00 300.00

[0052] For the preparation of the tablets according to the invention as in Example 3, 480 g of ginkgo leaf extract are mixed with 133.34 g of microcrystalline cellulose, 106.66 g of croscarmellose sodium, 21.34 g of precipitated silica and 5.34 g of magnesium stearate and processed with a roller compactor to a concentrated granulate (compactate) (step (a)). To produce 1600 tablets, 597.34 g of the granulate thus obtained are mixed with 349.66 g of microcrystalline cellulose, 170.67 g of croscarmellose sodium, 8.53 g of precipitated silica and 25.60 g of magnesium stearate and compressed on a rotary tablet press to form tablets with a mass of 720 mg each (step (b)).

EXAMPLE 4 ACCORDING TO THE INVENTION

[0053] Compact, Lactose-Free Tablet with Coating Containing 240 mg Dry Extract of Ginkgo biloba Leaves

[0054] The lactose-free, compact tablets of Example 2 according to the invention can be provided with a thin coloured coating which hardly delays the disintegration of the tablets and thus the release of the active ingredient (cf. Table 2).

TABLE-US-00005 Mass fraction in mg Component per film-coated tablet 1. Ginkgo leaf extract (EGb ® 761) 240.00 2. Cellulose, microcrystalline 107.00 3. Croscarmellose sodium 60.00 4. Silica, precipitated 6.00 5. Magnesium stearate 7.00 Subtotal tablet weight without coating 420.00 6. Hypromellose 4.80 7. Microcrystalline cellulose 2.00 8. Glycerol, anhydrous 0.70 9. Iron oxide E172 3.00 10. Talc 1.50 Subtotal film coating weight 12.00 Total film-coated tablet weight 434.00

NON-INVENTIVE COMPARATIVE EXAMPLES

Comparative Example 1 from EP 2072054A1

[0055] EP2072054A1 describes the use of an extract from leaves of Ginkgo biloba in the preferred embodiment of a tablet with a mass of 800 mg, of which 160 mg is lactose monohydrate. For the production (paragraph [0033]) of the tablet according to Example 3 of EP 2072054A1 according to the invention, the extract is mixed with the excipients mentioned in the following table and pressed directly into tablets without further process steps. The tablet described is a tablet with rapid release of the active ingredient (EP2072054A1, claim 15 and table for Example 1 according to the invention). This embodiment is significantly larger and heavier than the tablet according to the invention and contains lactose monohydrate.

TABLE-US-00006 Calculated on 100 mg of the Amount contained per tablet ginkgo extract Component [mg] [mg]. 1. Ginkgo leaf extract EGb ® 761 240.00 100.00 2. Cellulose, microcrystalline 290.00 120.83 3. Lactose monohydrate 160.00 66.67 4. Maize starch 50.00 20.83 5. Croscarrnellose sodium 40.00 16.67 6. Silica, highly dispersed 10.00 4.17 7. Magnesium stearate 10.00 4.17 Tablet weight 800.00 333.33

Comparative Example 2 from EP 2701688B1

[0056] WO2012/146592A1 (granted as EP2701688B1) describes a tablet containing 240 mg of controlled release dry extract of Ginkgo biloba leaves and its preparation. The tablet is prepared as described in Example 1 of WO2012/146592A1 according to the invention. In this regard, the composition is shown in the table below. This tablet is lactose-free, contains very few excipients and is thus very compact. However, according to the definition of the European Pharmacopoeia, this embodiment is a tablet with modified release of the active ingredient, in this case a so-called retard tablet, in which the disintegration of the tablet is deliberately slowed down and the active ingredient is released in a controlled manner over a period of more than six hours (see table for Example 1 according to the invention).

TABLE-US-00007 Calculated on 100 mg of the Amount contained per tablet ginkgo extract Component [mg] [mg]. 1. Ginkgo leaf extract EGb ® 761 240.00 100.00 2. Ethyl cellulose 170.00 70.83 3. Silica, highly dispersed 2.00 0.83 4. Magnesium stearate 6.00 3.33 Tablet weight 420.00 175.00

Comparison of Disintegration Times and Dimensions

[0057] According to the specifications of the European Pharmacopoeia Ph.Eur. 2.9.1, the disintegration times of the compact tablets according to the invention according to Examples 1 to 4 and the tablets of Comparative Example 1 (large, fast-disintegrating tablet with lactose) and Comparative Example 2 (compact retard tablet) were determined.

TABLE-US-00008 TABLE 2 Disintegration times and dimensions of the tablets from Examples 1 to 4 according to the invention and Comparative Examples 1 and 2. Disintegration Dimensions Batch time, Length/Width/Thickness Embodiment designation TM/WM* n = 6 [min] [mm] Compact tablet according 201804 1.50 5:14-7:00 14.46/7.56/4.13 to the invention (without coating) according to example 1 Compact tablet according P201602 1.75 7:18-9:32 14.08/7.07/5.18 to the invention (without coating) according to example 2 Compact tablet according 201805 3.00 4:12-5:04 17.14/8.08/6.97 to the invention (without coating) according to example 3 Compact film-coated tablet P201602 1.75  9:14-11:16 14.06/7.09/5.28 according to the invention (without (with coating) according to coating) example 4 Tablet (without coating) P201301 3.33 10:20-13:00 19.15/8.07/5.82 according to comparative example 1 Retard tablet (without 201401 1.75 >30 min round tablet coating) according to (11 mm) comparative example 2 *TM/WM = ratio tablet mass/active ingredient mass

[0058] The tablets according to the invention have a short disintegration time of less than 15 minutes (without coating, examples 1 to 3) or of less than 30 minutes (with coating, example 4) despite a high active ingredient content or the low tablet mass in relation to the active ingredient mass contained and thus comply with the specifications of the European Pharmacopoeia.

[0059] Thereby, the tablets of examples 1 to 4 according to the invention are smaller than the tablets of comparative example 1 with the same active ingredient content.