EP0697890A1

EP0697890A1 - More easily biologically absorbed tablet containing dichloromethylene diphosphonic acid as the active agent

Info

Publication number: EP0697890A1
Application number: EP93917636A
Authority: EP
Inventors: Walter Preis; Bernd Müsel; Günter Neugebauer; Rolf-Dieter Gabel
Original assignee: Roche Diagnostics GmbH; Boehringer Mannheim GmbH
Current assignee: HESTIA PHARMA GmbH
Priority date: 1993-05-15
Filing date: 1993-07-24
Publication date: 1996-02-28
Also published as: TW350772B; CA2162470A1; GR940300095T1; CA2162470C; WO1994026310A1; GR3017547T3; BR9307859A; KR100263284B1; ES2065313T3; PL307133A1; CN1041797C; NO944405L; DK0625355T3; RU2134103C1; UA39884C2; SK281193B6; HU9403160D0; NO307548B1; CZ287984B6; HU220872B1

Abstract

The invention relates to tablets in which the active agent dichloromethylene diphosphonic acid or a physiologically acceptable salt thereof is more easily absorbed and a proportion of microcrystalline cellulose as a pharmaceutical auxiliary, medicament packages containing said tablets, the use of the active agent dichloromethylene diphosphonic acid together with microcrystalline cellulose for the production of a more easily biologically absorbed tablet and the process for producing said tablet.

Description

Tablet with improved bioavailability containing dichloromethylene diphosphonic acid as an active ingredient

The invention relates to tablets with improved bioavailability of the active substance dichloromethylene diphosphonic acid (clodronic acid) or a physiologically tolerable salt thereof and an addition of microcrystalline cellulose as a pharmaceutical auxiliary, medicament packs containing these tablets, the use of dichloromethylene diphosphonic acid together with microcrystalline cellulose for the production a tablet with improved bioavailability and the process for producing this tablet.

It is known that the active substance dichloromethylene diphosphonic acid, also known under the name clodronate, is used in medicaments for the treatment of osteolysis due to bone metastases of solid tumors and for the treatment of hypercalcaemia (cf., for example, DE-18 13 659 ). In the meantime it has also been shown that biphosphonates such as e.g. B. clodronic acid or its physiologically acceptable salts can be used successfully in the treatment of osteoporosis and osteoporosis pain.

To treat osteolysis, the compound must be administered in relatively high doses over a long period of time in order to be effective. The preparation Ostac ^(R) capsules contains the active ingredient in the form of its sodium salt (clodronic acid, disodium salt x 4 H2O; MW = 360 g / mol) in an amount of 500 mg per capsule. Based on the active ingredient clodronic acid (MW = 244.9 g / mol) this corresponds to an amount of about 340 mg. The treatment requires four capsules a day, in severe cases up to eight capsules a day. This corresponds to a daily dose of 1360 - 2720 mg clodronic acid.

Because of the required high dosage of the active ingredient, dosage forms were first developed which contain the active ingredient with the highest possible content in order to make the size of the individual dosage form as small as possible. EP 0 275 468 describes such formulations with an active ingredient content of 80-95%. The preparation Ostac ^(R) has a percentage content of the active substance disodium clodronate tetrahydrate of about 500 mg (corresponding to 91%) with a total weight of the capsule filling mass of about 550 mg.

For some patients, it is problematic due to their state of health to swallow capsules of such a size between 550-570 mg filling mass several times a day over a longer period of time.

On the other hand, for reasons of better adherence to the intake mode by the patient, it would be desirable to reduce the daily intake of four to eight capsules, since experience shows that e.g. B. a one or two ingestion is followed more consistently than a multiple application. In view of the required total dose of approximately 1400 mg, in severe cases of approximately 2700 mg clodronate, which must be administered daily, two relatively large capsules with a total weight of at least 1100 mg each would be required. However, such capsules are disadvantageous because of their size.

The object of the invention was to provide a dosage form with increased bioavailability of the active ingredient clodronic acid to provide, whereby the total daily dose to be administered to the patient can be reduced and thus the number of dosage forms to be taken daily can be reduced or smaller dosage forms, such as tablets, can be used with the same frequency of ingestion.

Surprisingly, it was found that tablets with an addition of microcrystalline cellulose as dosage forms bring about a higher bioavailability of the active ingredient in comparison with the capsules when administered to humans. This makes it possible to reduce the daily dose of clodronic acid to be reduced. In particular, it has been found that the tablets according to the invention enable the total daily dose of clodronic acid to be reduced to values of up to 60%. This means that, for example, instead of the usual amount of 1360 mg of clodronic acid, a daily total dose of about 820 mg of clodronic acid has a comparable therapeutic effect.

Provided that a patient normally had to take four capsules of the preparation Ostac ^(R) with a single dose of about 340 mg clodronic acid (corresponding to a total daily dose of 1360 mg clodronic acid), the tablets according to the invention lead to a reduction in the total daily dose to about 800 - 1100 mg. On the one hand, this means a reduction in the active substance content per individual dose to approximately 200-270 mg of clodronic acid and a reduction in the total weight of the tablet to approximately 350-500 mg if the intake of four tablets per day is to be maintained. This is particularly important for those patients who have difficulty swallowing larger tablets. By reducing the active substance content, there is the possibility of reducing the total weight of the tablet, so that relatively small tablets result. On the other hand, in order to reduce the frequency of ingestion, tablets can be produced that replace the usual intake of four Ostac ( ^R ) capsules. The excellent bioavailability achieved with the formulation according to the invention makes it possible, depending on the desired daily frequency of ingestion, to vary the active substance content per tablet and thus the tablet size as desired within certain limits.

For example, if one assumes a total daily dose of 1360 mg of clodronic acid, which was previously administered through four Ostac ^(R) capsules, and the higher bioavailability of the active ingredient found in human experiments in the tablets according to the invention is used, which is a reduction in the total dose of clodronic acid to about 65% (corresponding to 884 mg clodronic acid), this daily dose can be administered by two, three or four tablets according to the invention with an active ingredient content of 442 mg, 295 mg or 221 mg clodronic acid. The tablet size can thus be adapted to the respective requirements. The larger tablets are particularly advantageous when there is a fear that the patient will not consistently follow the intake required several times a day and will prefer to take them once or twice a day. The smaller tablets are advantageous in such cases when the patient has difficulty swallowing the larger tablets and thus prefers to take smaller tablets several times a day. With a higher or lower daily dose than the dose of 1360 mg clodronic acid described here by way of example, the active substance content per tablet is determined in an analogous manner, depending on the desired requirements with regard to the frequency and size of the tablets.

The following examples illustrate some preferred embodiments of the invention: a) A conventional Ostac ( ^R ) capsule (340 mg clodronic acid) can be replaced by a tablet according to the invention with an active ingredient content of approximately 220 mg. In the event that the active ingredient is used in the form of the tetrahydrate of the sodium salt, this means a reduction in the amount of active ingredient in the dosage form from 500 mg to about 325 mg.

b) Two conventional Ostac ( ^R ) capsules (total dose 680 mg clodronic acid) can be replaced by a tablet according to the invention with an active ingredient content of approximately 440 mg. According to the information under point a), this means a reduction in the amount of active substance from 1000 mg to 650 mg of the tetrahydrate of disodium clodronate, or in relation to the anhydrous form from 800 mg to 520 mg.

c) Three conventional Ostac ( ^R ) capsules (total dose 1020 mg clodronic acid) can be replaced by a tablet according to the invention with an active ingredient content of approximately 660 mg or by two tablets each with 330 mg.

d) Four customary Ostac ( ^R ) capsules (total dose 1360 mg clodronic acid) can be given by a tablet according to the invention with an active ingredient content of approximately 880 mg, or by two tablets each with approximately 440 mg, or three tablets each with approximately 300 mg clodronic acid be replaced.

The above calculation of the active substance content of the tablet according to the invention was based on the results from bioequivalence studies in humans, from which it emerged that the intake of a tablet with an active substance content of 520 mg (based on the anhydrous form of sodium clodronate) is bioequivalent for taking two common Ostac ( ^R ) capsules, each with an active substance content of 400 mg. The measurement of serum Concentration of clodronic acid in the blood of several patients gave largely comparable values over a period of 16 hours.

The tablets according to the invention can be used in particular for the treatment of osteoporosis. Since it is often long-term therapy in these cases, the advantageous reduction in the daily dose of clodronic acid and thus the minimization of possible side effects is of particular importance.

The tablet according to the invention contains the active substance dichloromethylene diphosphonic acid in an amount of 50-900 mg, preferably 200-700 mg, based on the content of clodronic acid. The physiologically tolerable salts of clodronic acid, in particular the alkali salts, preferably the disodium salt, are preferably used, which can be used either as tetrahydrate or in anhydrous form. Of course, other physiologically acceptable salts, such as. B. the lithium, potassium, ammonium or calcium salt or their hydrates can be used. The percentage content of the active ingredient (based on clodronic acid) is 10-65% by weight, preferably 50-60% by weight, in particular approximately 55% by weight, based on the total weight of the tablet core. When using the sodium clodronate tetrahydrate as a reference, the amount of active ingredient is preferably 74-88%, in particular about 80% of the total weight of the tablet.

The addition of microcrystalline cellulose according to the invention is 1 to 20% by weight, based on the total weight of the tablet core, in particular 5 to 15% by weight or 8 to 12% by weight. The microcrystalline cellulose content is particularly preferably about 10% by weight. The microcrystalline cellulose is preferably used as Avicel ^(R) . Instead of microcrystalline cellulose, other equivalent ones can also be used Agents such as other modified cellulose derivatives or polyethylene glycol (PEG) 4000-6000 can be used.

The tablet also contains one or more pharmaceutically customary auxiliaries or carriers, such as e.g. Fillers, lubricants, disintegrants, binders or mold release agents. Starch (potato, wheat and corn starch), lactose, glucose, mannitol, calcium carbonate, calcium phosphate, cellulose, talc or other products known in the art for this purpose are suitable as such. The proportion of pharmaceutical auxiliaries and carriers can vary within wide limits depending on the active ingredient content of the tablet and is in each case 0.1-20% by weight.

The proportion of the fillers is about 3-10%, preferably 5-7% by weight, based on the total weight of the tablet. Particularly suitable fillers are corn starch, talc and / or lactose. The proportion of talc is preferably approximately 3.5-5%, the proportion of corn starch approximately 2-5%, in particular approximately 2.5% by weight.

The tablet can contain common lubricants. As such, preference is given to silicon dioxide, talc and / or stearic acid or their salts, in particular their magnesium or calcium salts. The total content of lubricants is up to 6% by weight based on the total weight of the tablet. One or more lubricants can be used in the same or different amounts. The content is preferably up to 3% by weight, in particular 0.1-2% by weight. Magnesium stearate and / or talc is preferably used in the range of 0.2-2% by weight.

In addition to the excipients mentioned above, the tablet can also be added with tablet disintegrants, which disintegrate the tablet more quickly when it comes into contact with the stomach. effect liquid. Such disintegrants are, for example, sodium carboxyethyl starch, crosscar ellose, crospovidone and other similar agents, which can be present in amounts of up to 10% by weight, preferably up to 3% by weight, based on the total weight of the tablet. Sodium carboxymethyl starch in the range of 1-5% by weight, preferably 1-2% by weight, is preferably used as the disintegrant.

The tablet core, which serves as a reference variable for calculating the weight ratios mentioned above, can be provided with a coating. The coating can serve on the one hand to avoid the unpleasant taste of the tablet as such. In this case, flavors are added during the production of the tablet coating. On the other hand, the coating can also delay the release of the active ingredient. For this purpose, substances are used which, in the form of an applied diffusion film, contribute to a delayed release of the active substance.

Bioavailability studies have shown that, for example, a tablet according to the invention with an active substance content of approximately 420-460 mg of clodronic acid has a bioavailability of the active substance that corresponds to that of two conventional capsules, each with approximately 340 mg of clodronic acid. The total weight of this tablet according to the invention, which therefore contains twice the usual dose, is between 750-850 mg, preferably 790-810 mg, when using the tetrahydrate of sodium clodronate. When using the anhydrous clodronate, the lower total weight of the active ingredient results in a lower total weight of the tablet. In these cases, it may be expedient to reduce the proportion of pharmaceutical auxiliaries and carriers accordingly to the lower amount of active substance in the same ratio in the manufacture of the tablet. Likewise, tablets with an active ingredient content of 500-530 mg and a maximum total weight (based on sodium clodronate tetrahydrate) of 870-970, preferably 900-950 mg, can be produced according to the recipe according to the invention. Thus tablets according to the invention can be made available with single and double doses, which are smaller and thus can be administered orally better than would be the case according to the formulations known to date. For a previous capsule with 340 mg active ingredient content of clodronic acid (corresponding to about 500 mg disodium clodronate tetrahydrate or 400 mg anhydrous disodium clodronate), only about 220 mg active ingredient are required according to the formulation according to the invention, whereby the total weight of the tablet is generally between 395 - 410 mg.

The tablet according to the invention also shows good dissolution behavior. The dissolution rate of the 440 mg dosage according to the invention (determined according to the USP paddle method) is already at least 60% after 15 minutes and at least 75% after 30 minutes.

The invention also relates to pharmaceutical packs containing 30-400 tablets according to the invention for administration in a daily dose of one to three, preferably two tablets (active ingredient content 420-460 or 500-530 mg) or four to eight, preferably four, tablets ( Active ingredient content 200 - 270 mg).

The invention furthermore relates to the use of the active substance dichloromethylene diphosphonic acid or a physiologically tolerable salt thereof together with microcrystalline cellulose as a pharmaceutical auxiliary for the production of a tablet with improved bioavailability, preferably a tablet of conventional size with twice the effectiveness compared to a conventional capsule. The tablets according to the invention are produced in a customary manner in that the tablet mass is brought into a suitable granular form by granulation (dry, wet or spray granulation) before compression. As a rule, the desired amount of the active ingredient for the dosage form to be produced is dry-mixed with about 4 to 8% by weight of the fillers and granulated with a conventional binder, for example corn starch, or even only with water. In addition, other methods such as that of compacting can also be used. The granules obtained in this way are then mixed and mixed in a commercial mixing apparatus with 5-15% by weight of microcrystalline cellulose, up to 6% by weight of lubricant and up to 3% by weight of disintegrant. After the mixing process, the granules are tabletted or, if necessary, previously sprayed with an aroma solution and stored for penetration. The finished tablet can also be covered with a film to improve the taste.

The dosage details in the following exemplary embodiments relate to the clodronic acid content (MW = 244.9). To convert to the content of disodium clodronate, anhydrous (MW = 288.9), the conversion factor is around 1.18, in the case of tetrahydrate (MW = 360.9) around 1.47.

Example 1:

Tablets with an active ingredient content of 440 mg clodronic acid

a) The following is the preparation of a batch size of

200,000 tablets with an active ingredient content of 440 mg of clodronic acid (corresponding to 520 mg of sodium clodronate, anhydrous; or 650 mg of sodium clodronate tetrahydrate) are described. Pos. 1: Clodronic acid

Disodium tetrahydrate 129945.4 g

Pos. 2: corn starch 3900.0 g

Pos. 3: talc 5980.0 g

Pos. 4: sodium carboxymethyl starch 2654.6 g

Pos. 5: Magnesium stearate 520.0 g

Pos. 6: microcrystalline cellulose 15600.0 g

Neck weight: 158600.0 g

The feed materials from items 1-3 are granulated. The additives from items 4-6 are then mixed into the granulate. The mass produced in this way is then compressed into tablets on suitable machines. The yield of optically perfect tablets is 177,215 (88.6%).

When using the anhydrous form of sodium clodronate, the following composition of the pharmaceutical mixture results analogously to example la):

Pos. 1: Clodronic acid

Disodium salt, anhydrous 104000.0 g

Pos. 2: corn starch 3121.3 g

Pos. 3: talc 4786.0 g

Pos. 4: sodium carboxymethyl starch 2124.6 g

Pos. 5: Magnesium stearate 416.2 g

Pos. 6: microcrystalline cellulose 12485.3 g

Neck weight: 126,933.4 g

The granules and the tablet mass are produced analogously to example la). The following table shows the composition of the tablet core:

440 mg - dosage

Sodium clodronate x 4 H ₂ 0 649.727

Talc 29.90

Corn starch 19.50

Microcrystalline cellulose 78.00

Sodium carboxymethyl starch 13,273

Magnesium stearate 2.6

Tablet weight / mg 793

The tablets are particularly suitable for the application of 2 tablets per day and thus replace 4 conventional Ostac capsules.

Example 2

Tablets with an active ingredient content of 509 mg clodronic acid

The preparation is carried out analogously to Example 1 for a batch size of 200,000 tablets with an active substance content of clodronic acid of 509 mg (corresponding to 600 mg sodium clodronate, anhydrous; or 750 mg sodium clodronate tetrahydrate) per tablet.

Pos. 1: Clodronic acid

Disodium tetrahydrate 150,000 g Pos. 2: Corn starch 4500 g Pos. 3: talc 6900 g

Pos. 4: sodium carboxymethyl starch 3063 g

Pos. 5: Magnesium stearate 600 g

Pos. 6: microcrystalline cellulose 18000 g

Neck weight: 183063

The following table shows the composition per tablet core:

509 mg - dosage

Sodium clodronate x 4 H ₂ 0 749.685 mg

Talc 34.50 mg

Corn starch 22.50 mg

Microcrystalline cellulose 90.00 mg

Sodium carboxymethyl starch 15,315 mg

Magnesium stearate 3.0 mg

Tablet weight / mg 915 mg

Example 3

Tablet with an active ingredient content of 678 mg clodronic acid

The preparation is carried out analogously to Example 1 for a batch large of 100,000 tablets with an active ingredient content of clodronic acid of 678 mg (corresponding to 800 mg sodium clodronate, anhydrous; or 1000 mg sodium clodronate tetrahydrate) per tablet.

Pos. 1: Clodronic acid

Disodium tetrahydrate 99958 g

Pos. 2: corn starch 3000 g

Pos. 3: talc 4600 g

Pos. 4: sodium carboxymethyl starch 2042 g

Pos. 5: Magnesium stearate 400 g

Pos. 6: microcrystalline cellulose 12000 g

Neck weight: 22000.0 g

The following table shows the composition per tablet core:

678 g dosage

Sodium clodronate x 4 H ₂ 0 1000.0

Talc 46.0

Corn starch 30.0

Microcrystals Cellulose 120.0

Sodium carboxymethyl starch 20.42

Magnesium stearate 4.0

Tablet weight / mg 1220

The above tablet replaces approximately three conventional Ostac ^(R) capsules. Example 4

Tablet with an active ingredient content of 220 mg clodronic acid

The preparation is carried out analogously to Example 1 for a batch size of 300,000 tablets with an active ingredient content of clodronic acid of 220 mg (corresponding to 260 mg sodium clodronate, anhydrous; or 325 mg sodium clodronate tetrahydrate) per tablet.

Pos. 1: Clodronic acid

Disodium tetrahydrate 97459 g

Pos. 2: corn starch 2925 g

Pos. 3: talc 4485 g

Pos. 4: sodium carboxymethyl starch 1992 g

Pos. 5: Magnesium stearate 390 g

Pos. 6: microcrystalline cellulose 11700 g

Neck weight: 118951

The following table shows the composition per tablet core:

220 mg dosage

Sodium clodronate x 4 H 0 324.864

Talc 14.95

Corn starch 9.75

Microcrystalline cellulose 39.0

Sodium carboxymethyl starch 6.64

Magnesium stearate 1.30

Tablet weight / mg 396.5 The tablets are particularly suitable for the administration of 4 tablets per day, in severe cases 8 tablets per day. They replace the conventional Ostac ^(R) capsules, the total weight of which is 550 mg when using sodium chlorodronate tetrahydrate.

Example 5

Tablet with an active ingredient content of 254 mg clodronic acid

The preparation is carried out analogously to Example 1 for a batch size of 300,000 tablets with an active ingredient content of clodronic acid of 254 mg (corresponding to 300 mg sodium clodronate, anhydrous; or 375 mg sodium clodronate tetrahydrate) per tablet.

Pos. 1: Clodronic acid

Disodium tetrahydrate 112452 g

Pos. 2: corn starch 3375 g

Pos. 3: talc 5175 g

Pos. 4: sodium carboxymethyl starch 2298 g

Pos. 5: Magnesium stearate 450 g

Pos. 6: microcrystalline cellulose 13500 g

Neck weight: 137337 g

The following table shows the composition per tablet core: 254 mg dosage

Sodium clodronate x 4 H ₂ 0 374.84

Talc 17.25

Corn starch 11.25

Microcrystals Cellulose 45.0

Sodium carboxymethyl starch 7.66

Magnesium stearate 1.50

Tablet weight / mg 457.5

The tablets are particularly suitable for the administration of 4 tablets per day, in severe cases 8 tablets per day. They replace the conventional Ostac ^(R) capsules, the total weight of which is 550 mg when using sodium chlorodronate tetrahydrate.

Example 6

24 patients received the usual dosage of two Ostac ^(R) capsules with an active substance content of 340 mg clodronic acid each. The serum concentration of clodronic acid was measured over a period of 16 hours using standard methods. The time course of the serum concentration is shown in Fig. 1 (curve +).

The same patient group received one tablet with an active substance content of 440 mg clodronic acid. Compared to the group treated with Ostac ^(R) , the course of the mean serum concentration of clodronic acid is largely identical, ie bioequivalent to the administration of two Ostac ^(R) capsules.

Claims

1. Tablet with improved bioavailability of the active ingredient clodronic acid or a physiologically tolerable salt thereof and containing microcrystalline cellulose as a pharmaceutical excipient.

2. Tablet according to claim 1 with a content of microcrystalline cellulose of 5-15% based on the total weight of the tablet.

3. Tablet according to claims 1 or 2 with an active ingredient content of clodronic acid of 200-700 mg.

4. Tablet according to claims 1-3 containing the active substance in the form of the disodium salt, preferably in the form of the tetrahydrate.

5. Tablet according to claims 1-4 additionally containing a filler, in particular corn starch or talc.

6. Tablet according to claims 1-5 additionally containing a lubricant and a disintegrant.

7. Tablet according to claim 6, wherein the lubricant is a physiologically acceptable salt of stearic acid, preferably magnesium stearate, and the disintegrant is sodium carboxymethyl starch.

8. Tablet according to claims 1-7 with an active ingredient clodronic acid content of 420-460 mg and a total weight of the tablet of 750-850 mg, preferably 790-810 mg.

9. Tablet according to claims 1-7 with an active ingredient content of clodronic acid of 500-530 mg and a total weight of the tablet of 870-970 mg, preferably 900-950 mg.

10. Tablet according to claims 1-7 with an active ingredient clodronic acid content of about 200-270 mg and a total weight of the tablet of 350-500 mg.

11. Medicament pack containing 30-400 tablets according to claims 8 or 9 for administration in a daily dose of one to three tablets, preferably two tablets.

12. Pharmaceutical package containing 30-400 tablets according to claim 10 for administration in a daily dose of four to eight tablets, preferably four tablets.

13. Use of the active ingredient clodronic acid or a physiologically compatible salt thereof and microcrystalline cellulose as a pharmaceutical auxiliary for the production of a tablet with improved bioavailability of the active ingredient.

14. Use according to claim 13 for the production of a tablet of usual size with double effectiveness.

15. A process for the preparation of a tablet with improved bioavailability of the active ingredient clodronic acid or a physiologically tolerable salt thereof, characterized in that the active ingredient is mixed together with microcrystalline cellulose and optionally other pharmaceutical auxiliaries or excipients by methods known per se and pressed into tablets.

16. The method according to claim 15, characterized in that mixing the active ingredient with about 4 - 8 wt .-% of the fillers, granulated with a conventional binder, the granules thus obtained in a conventional mixing apparatus 5 - 15 wt .-% microcrystalline Cellulose, up to 3% by weight of disintegrant and up to 6% by weight of lubricant are added, the granules are tabletted after the mixing process and, if necessary, the tablet core obtained is provided with a coating for improving the taste or for the sustained release of the active ingredient.

17. The method according to claim 16, characterized in that the active ingredient is granulated with 6-7% by weight of the fillers and the granules 8-12% by weight of microcrystalline cellulose, up to 2% by weight of disintegrant and up to

3% by weight of lubricant added.

18. The method according to any one of claims 16 or 17, characterized in that corn starch and / or talc are used as fillers.

19. The method according to any one of claims 16 - 18, characterized ge indicates that magnesium stearate is used as lubricant and sodium carboxymethyl starch is used as disintegrant.