HK1080714B - High dose ibandronate formulation - Google Patents

Description

High dose ibandronic acid formulations

The present invention relates to a pharmaceutical composition for oral use comprising a high dose of a bisphosphonate or a pharmaceutically acceptable salt thereof as an active ingredient and a process for preparing such a composition.

Aminoalkyl-1, 1-diphosphonic acid derivatives (hereinafter referred to by the term "bisphosphonates") are important drugs in the treatment of bone diseases and certain calcium metabolism disorders, such as hypercalcemia, osteoporosis, tumor osteolysis, paget's disease, and the like.

In the processes described in, for example, EP-A-170,228, EP-A-197,478, EP-A-22,751; bisphosphonates as pharmaceuticals are described in EP-A-252,504, EP-A-252,505, EP-A-258,618, EP-A-350,002, EP-A-273,190, WO-A-90/00798, which are each incorporated herein by reference.

The pharmaceutical forms of the bisphosphonates currently marketed are oral formulations (tablets or capsules) or solutions for intravenous injection or infusion. They are well tolerated systemically when administered at therapeutic doses. However, bisphosphonates are irritating to the skin and mucosa and may cause gastrointestinal side effects when administered continuously orally, such as esophageal adverse events or gastrointestinal disorders. For this reason and because of their low oral bioavailability, the oral route of administration has to date been used according to usage recommendations which are inconvenient for the patient.

As described, bisphosphonates have gained acceptance as providing strong efficacy in the control of osteoporosis. However, since there are dosing limitations related to low oral bioavailability and possible gastrointestinal side effects, this is clearly an opportunity for a regimen that may provide improved convenience and flexibility, and thus may provide a higher level of compliance and superior patient management/satisfaction.

Furthermore, it has been found during clinical development of ibandronate that ibandronate exhibits efficacy in reducing bone fractures at non-dosing intervals beyond daily dosing. It is quite unexpected that the benefits of reducing bone fractures can be achieved by weekly or monthly oral administration of bisphosphonates using a single or multiple tablet dosing regimen.

For this purpose, it is necessary to prepare a new composition comprising a high dose, i.e. up to 250mg, preferably comprising 150mg or 100mg, of a bisphosphonate derivative, especially ibandronic acid or physiologically safe salts thereof, which on the one hand has an increased ratio of active substance to excipients and on the other hand meets the stability requirements.

It has been found that the stability of such high dosage formulations can be greatly increased by adding the disintegrant with the active substance and a portion of the filler material just during the granulation step. Such compositions are readily soluble and have increased stability in storage with respect to temperature and humidity.

The pharmaceutical composition of the invention comprises up to 250mg, preferably up to 200mg, especially comprises 150mg or 100mg of a bisphosphonic acid (salt), especially ibandronic acid or a physiologically safe salt thereof, as active substance.

The following bisphosphonates are active substances which can be used in the pharmaceutical compositions according to the invention in the form of the free acids or physiologically safe salts or hydrates, in particular sodium salts:

(4-amino-1-hydroxybutylidene) bis-phosphonic acid (alendronic acid),

(dichloromethylene) di-phosphonic acid (chlorophosphonic acid),

[ 1-hydroxy-3- (1-pyrrolidinyl) -propylidene ] di-phosphonic acid (EB-1053),

(1-hydroxyethylidene) di-phosphonic acid (etidronic acid),

[ 1-hydroxy-3- (methylpentylamino) propylidene ] di-phosphonic acid (ibandronic acid),

[ cycloheptylamino ] -methylene ] bis-phosphonic acid (incadronic acid),

(6-amino-1-hydroxyhexylidene) di-phosphonic acid (neridronic acid),

[3- (dimethylamino) -1-hydroxypropylene ] di-phosphonic acid (olpadronic acid),

(3-amino-1-hydroxypropylene) di-phosphonic acid (pamidronic acid),

[ 1-hydroxy-2- (3-pyridyl) ethylidene ] di-phosphonic acid (risedronic acid),

[ [ (4-chlorophenyl) thio ] -methylene ] bis-phosphonic acid (tiludronic acid),

[ 1-hydroxy-2-imidazo (1, 2-a) pyridin-3-ylethylene ] di-phosphonic acid (YH 529),

[ 1-hydroxy-2- (1H-imidazol-1-yl) ethylene ] di-phosphonic acid (zoledronic acid); in particular [ 1-hydroxy-3- (methylpentylamino) propylidene ] di-phosphonic acid (ibandronic acid).

Said substances and their preparation are known and described, for example, in the following references:

US 4,705,651 (alendronic acid), US 4,927,814 (ibandronic acid), US 3,468,935, 3,400,147, 3,475,486 (etidronic acid), o.t.quinby et al, j.org.chem.324111(1967) (clodronic acid) and US 4,505,321 (risedronic acid) and US 4,134,969 and 3,962,432 (pamidronic acid), US 5,130,304(EB-1053), US 4,970,335 (incadronic acid), belgian patent 885139 (neridronic acid), US 4,054,598 (olpadronic acid), US 4,746,654, 4,876,248 and 4,980,171 (tiludronic acid), US 4,990,503(YH 529) and US 4,939,130 (zoledronic acid).

Preference is given to compositions comprising as active substance an amount of bisphosphonate corresponding to 150mg or a physiologically safe salt thereof and compositions comprising as active substance an amount of bisphosphonate corresponding to 100mg or a physiologically safe salt thereof. Ibandronic acid or a physiologically safe salt thereof is a particularly preferred active substance, in particular ibandronic acid-Na monohydrate.

The composition further comprises an adjuvant such as a binder, e.g., polyvinylpyrrolidone (e.g., Povidone)) Or hydroxypropyl methylcellulose (e.g., Pharmacoat)) Fillers such as lactose in the form of hydrates or anhydrates, cellulose in the form of microcrystals or fibers (e.g. Avicel) Or starch, disintegrating agents such as cross-linked polyvinylpyrrolidone (e.g. Crospovidone)USPNF) or croscarmellose (carmelose), lubricating agents such as stearic acid or magnesium stearate, and flow control agents such as colloidal silicon dioxide.

The preferred form of the composition is a tablet, preferably a tablet coated with a film coating mixture and a plasticizer. Such film coating mixtures and plasticizers are well known to those skilled in the art.

According to the invention, the tablet core consists of:

30.0 to 36.0, preferably 33.3% active substance;

4.0 to 6.0, preferably 4.8 to 5.2% by weight of a binder;

39.6 to 59.4, preferably 47.0 to 52.0% by weight of a filler;

4.5 to 5.5, preferably 4.8 to 5.2% by weight of a disintegrant;

1.8 to 2.2, preferably 1.9 to 2.1% by weight of a lubricant; and

0.9 to 1.1, preferably 0.95 to 1.05% by weight of a flow regulator.

Preferred active substances are ibandronic acid or physiologically safe salts thereof; preferred binders are polyvinylpyrrolidone; preferred fillers are lactose in the form of a hydrate or anhydrate, or cellulose in the form of microcrystals or fibers; a preferred disintegrant is crosslinked polyvinylpyrrolidone. Preferred are compositions wherein a disintegrant is added as early as in the granulation, together with the active substance and a portion of the filler material.

Furthermore, the present invention relates to a method for preparing a pharmaceutical composition for oral administration comprising a high dose of bisphosphonate, in particular ibandronic acid or physiologically safe salts thereof. According to the invention, the pharmaceutical composition is prepared by the following method:

-wet granulation of the bisphosphonate or pharmaceutically acceptable salt thereof in the presence of an auxiliary agent such as a binder as described above and a portion of the filler, characterised in that a disintegrant is added to the granulation mixture;

-subjecting the mixture of particles to a fluidization in a manner known per se;

-subsequently, drying the wet granulate and sieving the dried granulate with a sieve having a suitable mesh width;

the remaining auxiliaries, such as the abovementioned fillers, lubricants and flow regulators, are added and the mixture is mixed and then processed in a manner known per se to form the pharmaceutical composition.

In a preferred form of the invention, the active substance in dry powder form, a portion of the filler and the disintegrant are granulated by spraying an aqueous solution of the binder onto the powder mixture. The process is preferably carried out at a temperature of 60 to 80 c, preferably at a temperature of about 70 c.

The spray granulated material is then preferably dried at a temperature of 60 to 80 ℃, preferably about 70 ℃, and subsequently sieved with a fine sieve; the dried granules are mixed with the remaining amount of filler, lubricant and flow modifier that has been previously sieved with a fine sieve. The final mixture is then compressed into tablet cores, which are coated with a coating suspension of purified water and a film coating mixture.

The method of the present invention is carried out as follows:

a) an adhesive, preferably Povidone K25Dissolving in purified water;

b) bisphosphonates, preferably the monosodium salt (1H) of ibandronic acid₂O), a portion of the filler, preferably lactose monohydrate and up to a total of 60% by weight of microcrystalline cellulose, and a disintegrant are fed to a dryer, preferably a fluid bed dryer;

c) spray granulating the starting material of step b) with the granulation liquid of step a) at a temperature of 60 to 80 ℃, preferably about 70 ℃,

e) drying the spray granulated material of step c) at 60 to 80 ℃, preferably about 70 ℃ (set value of inlet air temperature), and then sieving the dried intermediate with a fine sieve;

f) mixing the granulate of step e) with the remaining amount of filler, e.g. microcrystalline cellulose, lubricant, preferably stearic acid, previously sieved with a fine sieve (e.g. 1mm), and flow modifier, e.g. anhydrous colloidal silica;

g) compressing the final mixture of step f) into tablet cores; coating mixtures (which are commercially available, e.g., Opadry) with purified water and a film comprising, e.g., hydroxypropylmethylcellulose, titanium dioxide and talc00A28646) and Macrogol 6000Coating suspension of (a) coating the tablet.

These auxiliaries are known and commercially available.

The present invention will now be described in more detail with reference to examples, but the present invention is not limited by these examples.

Example 1:

a film coated tablet containing 150mg of active substance was prepared as follows:

1. povidone K25Dissolving in purified water.

2. The monosodium salt (1H) of ibandronic acid₂O), lactose monohydrate, crospovidone, and microcrystalline cellulose were charged to a fluid bed dryer. The crospovidone and microcrystalline cellulose have been sieved with a fine sieve (e.g. 1mm) prior to mixing.

3. The raw material of step 2 was spray granulated with the granulation liquid of step 1 at 70 ℃ (inlet air temperature setpoint).

4. The spray granulated material of step 3 was finally dried at 70 ℃ (inlet air temperature setpoint).

5. The dried intermediate granules are sieved with a fine sieve (e.g. 2mm openings) and

6. repeating steps 1-5 as necessary to obtain the desired final batch.

7. The granules of step 6 are mixed with microcrystalline cellulose, stearic acid and anhydrous colloidal silicon dioxide in a container mixer. The microcrystalline cellulose, stearic acid and anhydrous colloidal silica are sieved through a fine sieve (e.g. 1mm) prior to mixing.

8. The final blend of step 7 was compressed into tablet cores using a rotary tablet press.

9. A mixture of film coatings with purified water, containing hydroxypropyl methylcellulose (60.5%), titanium dioxide (29%) and talc (10.5%), which is commercially available, for example, Opadry00A28646) and Macrogol 6000A coating suspension is prepared.

10. The coating suspension of step 9 is sprayed onto the core tablet with a coating apparatus. The composition of the tablet is as follows:

tablet core

Ibandronic acid 150.0mg

Is the monosodium salt of ibandronic acid (1H)₂O) form 168.75mg

Povidone K25 22.5mg

Lactose, monohydrate 162.75mg

Microcrystalline cellulose 60.0mg

Crospovidone 22.5mg

Stearic acid 959.0mg

Anhydrous colloidal silica 4.5mg

Film coating

Film coating mixture^＊ 12.75mg

Macrogol 6000 2.25mg

^＊This film coating mixture comprises: hydroxypropyl methylcellulose (60.5%), titanium dioxide (29%) and talc (10.5%); the mixture is commercially available (e.g., Opadry)00A28646)

The tablet core weighs 450mg, the total tablet weight is 465mg, and the amount of active substance per tablet is equivalent to 150mg of free ibandronic acid.

Example 1 a: 110000 pieces in batches

1. 14.850kg of demineralized water are introduced into a suitable container and 2.475kg of Povidone K25 are added thereto with constant stirringThe addition time was about 15 minutes.

2. 18.563kg of the monosodium salt of ibandronic acid, 17.903kg of lactose monohydrate 100, 4.125kg of Avicel PH-102 were addedAnd 2.475kg of Croospovidone CLFed to a fluidized bed dryer.

3. These components were mixed and used with Povi prepared abovedone K25The spray granulation was carried out at 70 ℃ with an aqueous solution which was added at a rate of 300 g/min with a pressure of 2.5 bar.

4. Then, the granules were dried in a fluid bed dryer at 70 ℃;

5. followed by sieving (2.0mm mesh) to obtain 44.540kg of dry granular material.

6. 2.426kg of AVICEL PH-102 was added0.970kg of stearic acid and 0.4850kg of silicic acid AEROSIL 200Sieving and adding it to dry granular material (44.650kg) and mixing

Mixing the components;

7. the final blend was compressed into tablets to give 103244 tablet cores.

8. By mixing 0.290kg of PEG 6000(MACROGOL 6000) Dissolved in 7.743kg of demineralized water and 1.645kg of OPADRY 00A28646Dispersed into this solution to make a coating suspension.

9. The tablet cores are coated with the coating suspension under standard conditions.

These tablets have the composition and weight given in example 1.

Example 2:

film-coated tablets containing 100mg of active substance were prepared as described in example 1:

tablet core

Ibandronic acid 100.0mg

Is ibandronic acid monosodium salt (1H)₂O) form 112.50mg

Povidone K2515.0 mg

Lactose, monohydrate 108.50mg

Microcrystalline cellulose 40.0mg

Crospovidone 15.0mg

Stearic acid 956.0mg

Anhydrous colloidal silica 3.0mg

Film coating

Film coating mixture^＊ 10.20mg

Macrogol 6000 1.80mg

^＊The composition was as described in example 1

The tablet core weighs 300mg, the total tablet weight is 312mg, and the content of active substance in each tablet is equivalent to 100mg of free ibandronic acid.

Claims (10)

1. Tablet for oral use containing 150mg of ibandronic acid or a physiologically safe salt thereof as active substance, characterized in that a disintegrant is added in the granulation together with the active substance and a part of the filling material, wherein the disintegrant is crosslinked polyvinylpyrrolidone or crosslinked carboxymethylcellulose.

2. A tablet according to claim 1 wherein the core consists of:

30.0 to 36.0% of active substance

4.0 to 6.0% by weight of a binder;

39.6 to 59.4% by weight of a filler;

4.5 to 5.5% by weight of a disintegrant;

1.8 to 2.2% by weight of a lubricant; and

0.9 to 1.1% by weight of a flow regulator.

3. A tablet according to claim 1 wherein the core consists of:

33.3% active substance;

4.8 to 5.2% by weight of a binder;

47.0 to 52.0% by weight of a filler;

4.8 to 5.2% by weight of a disintegrant;

1.9 to 2.1% by weight of a lubricant; and

0.95 to 1.05% by weight of a flow modifier.

4. The tablet according to claim 1, comprising

5. A process for preparing a tablet as claimed in any one of claims 1 to 4, said process comprising

(a) Dissolving the adhesive in purified water;

(b) feeding ibandronic acid monosodium salt monohydrate, a portion of the filler, and the disintegrant onto a dryer;

(c) spray granulating the raw material of step (b) with the granulation liquid of step (a) at a temperature of 60 to 80 ℃,

(d) drying the spray granulated material of step (c) at an inlet air temperature setpoint of 60 to 80 ℃ and then sieving the dried intermediate with a fine sieve;

(e) mixing the granules of step (d) with the remaining amount of filler, lubricant and flow modifier previously sieved with a fine sieve;

(f) compressing the final mixture of step (e) into tablet cores; the tablets were coated with purified water and a film coating mixture containing hydroxypropyl methylcellulose, titanium dioxide and talc and a coating suspension of Macrogol 6000.

6. A method according to claim 5, said method comprising

(a) Dissolving polyvinylpyrrolidone in purified water;

(b) feeding ibandronic acid monosodium salt monohydrate, a portion of lactose monohydrate and up to a total of 60% microcrystalline cellulose and crospovidone onto a dryer;

(c) spray granulating the raw material of step (b) with the granulation liquid of step (a) at a temperature of 60 to 80 ℃,

(d) drying the spray granulated material of step (c) at a set value of inlet air temperature of 60 to 80 ℃ and then sieving the dried intermediate with a fine sieve;

(e) mixing the granules of step (d) with the remaining amount of microcrystalline cellulose, stearic acid and anhydrous colloidal silicon dioxide previously sieved with a fine sieve;

(f) compressing the final mixture of step (e) into tablet cores; the tablets were coated with purified water and a film coating mixture containing hydroxypropyl methylcellulose, titanium dioxide and talc and a coating suspension of Macrogol 6000.

7. The process according to claim 5 or 6, wherein the dryer in step (b) is a fluid bed dryer.

8. The process according to claim 5 or 6, wherein the temperature in step (c) is 70 ℃.

9. The process according to claim 5 or 6, wherein the temperature in step (d) is 70 ℃.

10. Pharmaceutical composition in the form of a tablet obtained by the process of claim 5 or 6.