MXPA01003407A - Process for the preparation of oral pharmaceutical compositions comprising biphosphonates - Google Patents

Abstract

The invention relates to a process for the preparation of bisphonate-containing pharmaceutical compositions for oral application, wherein the active substance is wet-granulated in manner known per se in a fluidised-bed granulator using adjuvants which have no abrasive action and wherein the wet granulate is then dried in the fluidised bed, screened through a screen having a suitable mesh width and further processed by techniques known per se to form pharmaceutical compositions.

Description

PROCESS FOR THE PREPARATION OF ORAL PHARMACEUTICAL COMPOSITIONS COMPRISING BIFOSPHONATES Field of Invention The invention relates to a process for the preparation of pharmaceutical compositions for oral application containing, as active substance, aminoalkyl 1, 1 -diphosphonic acid derivatives or physiologically safe salts thereof (hereinafter referred to by the general term bisphosphonates). ).

Background of the Invention Bisphosphonates are important in the treatment of bone diseases and some disorders of calcium metabolism such as hypercalcemia, osoporosis, tumor osteolysis, Peget's disease, etc.

Pharmaceutical preparations in general must meet the requirements of accuracy with regard to content, uniformity of content and purity, special properties of substances Ref: 127953 active can adversely influence the content, uniformity and purity of the form of administration. It is known that bisphosphonates are a group of substances with a strong tendency to form complexes with polyvalent metal ions. Conventional pharmaceutical preparations for oral application are usually produced in facilities and apparatuses with metal surfaces and accordingly when processing the biosphosphonates, the highly active complex-forming substance comes into contact with the complexing material. This happens particularly in the case that water or an aqueous medium is used in the processing. A remedy consists of the principle of dry processing. Particularly in the direct formation of pellets, because in this case wet granulation is avoided. The formation, direct of pills is a very appropriate method to produce pills for high doses. It is known, however, that high dosage forms of bisphosphine cough for oral administration are particularly subject to compatibility problems, which makes oral treatment difficult. Aminobiphosphonic acids in particular produce irritation of the upper gastrointestinal tract (H: Fleish, Berme, 1993, pages 126-131). In the direct formation of pellets further, such as in the case where a non-granulated powder is introduced into gelatin capsules, there is a risk of content fluctuations particularly for active substances of low or very low dosage. For this reason, wet granulation is indispensable despite the mentioned risk of complex formation. When high-speed mixers are used, the active substance is mixed with coadjuvants and wet granulated with water or an aqueous binder solution. In the process the active substance is brought into very intense contact with the metal surfaces of the apparatus. The risk of complex formation can be further increased by the abrasive effect of certain pharmaceutical adjuvants.

Description of the invention The object of the invention is therefore to develop a process for the preparation of bisphosphonate-containing pharmaceutical compositions for oral application, preferably containing up to 50 mg of active substance per unit dose, in order to reduce the loss of active substance in the preparation of the compositions.

For this purpose according to the invention, bisphosphonates are converted by granulation of the known fluidized bed (Liebermann et al., "Pharmaceutical Dosage Forms", 2nd edition 1990, Marcel Dekker, New York, Basle, Pietsch: "Size Enlargements by Agglomeration ", John Wiley &Sons, Chichester) in formulations suitable for oral application. Fluidized bed granulation is a conventional method of wet granulation. Unexpectedly, however, this method can reduce the loss of active substance or decrease in the content of the active substance in the formulation to less than 6% by weight, preferably to less than 4% by weight.

The invention therefore relates to a process for the preparation of pharmaceutical compositions for oral application of bisphosphonates wherein the bisphosphonate is wet granulated in a manner known per se in a fluidized bed granulator using coadjuvants having no abrasive action and where the Wet granulation is dried in the fluidized bed, sieved through a screen having an appropriate mesh width and further processed by techniques known per se to form the pharmaceutical compositions.

Said disadvantage of complex formation during wet granulation is therefore not a problem at present when preparing low dose preparations of bisphosphonate. The pharmaceutical compositions preferably are produced with a content of up to 50 mg, particularly up to 10 mg of bisphosphonate per unit dose. The term "unit dose" denotes the discrete form of administration, ie, the capsule, or individual tablet.

The pharmaceutical compositions are prepared according to the invention by a fluidized bed granulator known per se, using adjuvants which have no abrasive effect during the process in the conventional pharmaceutical production of plants, for example, as is the case with dioxide silicon.

Preferably the active substance in solution or in suspension, together with an aqueous binder solution, is sprayed on or with other suitable coadjuvants and is granulated, or said active substance and coadjuvants in dry powder form are placed in a fluidized bed granulator and granulated by spraying an aqueous binder solution into the powder mixture; alternatively, water can also be sprayed into the powder mixture, which in this case contains a binder.

The resulting wet granulate is then dried in the fluidized bed granulator until the material has an acceptable residual moisture content for further processing in a pharmaceutical composition in other machines. The dried granulate is passed through a screen having an appropriate mesh width and then processed by known techniques mixing with other additives if necessary.

The following bisphosphonates are active substances which can be used according to the invention in the form of free acids or pharmaceutically compatible salts or hydrates, particularly sodium salts: (4-amino-l-l-hydroxybutylidene) bis-phonate (alendronate). (Dichloromethylene) bis-phosphonate (chlorodonate), [l-hydroxy-3- (1-pyrrolidinyl) -propylidene] bis-phosphonate (EB-1053), (1-hydroxyethylidene) bis-fos-fonate (etidronate), [l-hydroxy-3- (methyl pentylamino) propyl ideno] bis-phosphonate (ibandronate), [Cyclopentylamino) -met iyl] bis -phosphonate (incadronate), (6-amino-l-hydroxyhexyl idene) bis- phosphonate (neridronate), [3- (dimethylamino) -l-hydroxypropylidene] bis-phosphonate (olpadronat o), (3-amino-1-hydroxypropyl idene) bis-phosphonate (pamidronate), [l-hydroxy-2- (3 -pyridinyl) ethylene] bis-phosphonate (risedronate), [[(4-chlorophenyl) thiol)] -methylene] is-phosphonate (t-ilundronate), [l-hydroxy-2-imidazo- (1, 2-a) pyridin-3-yl ethylidene] bis- phosphonate (YH 529), [l-hydroxy-2- (lH-imidazol-1-yl) ethylidene] bis-phosphonate (zoledronate).

Said substances and their preparation are known and have been described, for example, in the following references. U.S. Patent No. 4,705,651, (Alendronate), U.S. Patent No. 4,927,814 (Ibandronate), U.S. Patent No. 3,468,935, 3,400,147, 3,475,486, (Editorial), O.T. Quinby et al., Org. Chem. 32, 111 (1967) (Clodronate) and U.S. Patent No. 4,505,321 (Ri zendronate), and U.S. Patent Nos. 4,134,969 and 3,962,432, (Pamidronate), U.S. Patent No. 5,130,304 (EB-1053), U.S. Patent No. 4,970,335 (Incadronate), Belgian Patent No. 885139 (Neridronate), U.S. Patent No. 4,054,598 (olapadronate), U.S. Patent No. 4,746,654, 4,876,248, and 4,980,171 (ilundrona to), US Patent No. 4,990,503 (YH 529) and Patent Nort eame ri cana N 4,939,130 (Zolendronate The invention is preferably used to produce pharmaceutical preparations containing the active substance in a proportion of up to 50 mg per unit dose, preferably up to 10 mg and particularly preferably 0.1 to 5 mg and 0.1 to 2.5 mg. Ibandronate is a particularly preferred active substance, particularly in the form of Ibandronate (Na) monohydrate.

The adjuvants which do not have an abrasive effect during the granulation, can be, according to the invention fillers, such as lactose in the form of hydrate or anhydrate, sugar alcohols, such as mannitol, adjuvants for tablets such as cellulose in fibrous form or microcrystalline, and binders such as polyvinylpyrrolidone (Povidone USP) or cellulose ethers such as methylhydroxypropylcellulose. At least one coadjuvant is used that acts as a binder.

Preferably at least one of the adjuvants is lactose, microcrystalline cellulose such or polyvinylpyrrolidone. In a preferred embodiment, 1-99% by weight of lactose, 1-99% by weight of microcrystalline cellulose are used, 0.1-20% by weight, and particularly preferably 25-75% by weight are used of lactose, 10-20% by weight of microcrystalline cellulose and 2-3% by weight of polyvinyl pyrrolidone.

The granulate is further processed by known methods using if necessary additional adjuvants, for tablets, chewable tablets, effervescent tablets, film pellets, dragees and granules or fillers for capsules or hard gelatine pads. The adjuvants used for further processing are conventional lubricants for example stearic acid, disintegrants, for example cross-linked polyvinylpyrrolidone.

(Crospovidone USPNF), flow regulators, for example colloidal silicon dioxide, coadjuvants for tablets, etc. In a preferred embodiment, the additional granulation process is carried out by the addition of stearic acid as a lubricant in amounts of less than 5% by weight with reference to the total weight of administration, particularly 0.05 to 3% by weight of stearic acid.

The preparation of pharmaceutical compositions according to the invention by fluidized-bed granulation, particularly by the fluidized-bed granulator drying process, results in less intense contact between the material and the surface of the apparatus, which surprisingly reduces the loss of active substance. This is particularly advantageous when the content of active substance of the unit dose is small. This substantially avoids the disadvantages previously described in the conventional production of forms for oral administration.

The invention will now be explained in more detail with reference to the examples, without being limited thereto.

Example 1 (Comparative example Production of 2.5 mg capsules Ibandronate after granulation in a high speed granulator / blender (batch size for 45,000 capsules).

Constituents g Ibandronate of Na 120.24 Lactose 7934, 76 Polyvinyl pyrrolidone 202, 50 Polyvinyl pyrrolidone, crosslinked (disintegrant) 562.50 Stearic acid (lubricant) 180.00 The amount of active substance per capsule is equivalent to 2.5 mg of free acid.

Lactose, ibandronate and polyvinylpyrrolidone were mixed for two minutes with a 50% fill factor in a high speed mixer / granulator (Diosna type), and then granulated with water for 8 minutes. The wet granulation was dried in a fluidized bed (Aeromatic type apparatus) was passed through a 0.8 mm sieve, mixed with disintegrant and lubricant (Rhoenrad type mixer, and with a mixing time of 10 minutes) and they were encapsulated in uncompressed size 2 hard gelatin capsules in a capsule machine (type MG2 / G36) having a capacity of 20,000 capsules per hour.

Weight established for filling 200.0 mg Actual fill weight according to the control in process 200.9 mg Content of active substance found in capsules produced in this way: 94.8% + _ 5.2% (n = 10 individual measurements).

Example 2 (comparative example) Production of 1.0 mg capsules Ibandronate after granulation in a high speed mixer / blender (batch size for 5000 capsules).

Constituents Ibandronate of Na 5.345 Lactose 999.655 Polyvinyl pyrrolidone 22,500 Polyvinyl pyrrolidone, crosslinked (disintegrant) 62,500 Stearic acid (lubricant) 10,000 The amount of active substance per capsule is equivalent to 1.0 mg of free acid.

Lactose, ibandronate and polyvinylpyrrolidone were mixed for two minutes in a high speed mixer / granulator (Diosna type), and then granulated with water for ten minutes. The wet granulation was dried in a fluidized bed (Aeromatic type apparatus) was passed through a 0.8 mm screen, mixed with disintegrant and lubricant (Rhoenrad type mixer, and with a mixing time of 10 minutes) and they were encapsulated in size 2 hard gelatin capsules by an encapsulating machine (type KFM Harro Hdflinger).

Weight established for filling 200.0 mg Actual filling weight according to the control in process 220.5 mg Active substance content found in capsules produced in this way: 94.9% + 1.9% (n = 10 individual measurements).

Example 3 Production of 1.0 mg tablet of Ibandronate after granulation in a fluidized bed (batch size for 60,000).

Constituents Ibandronate of Na 64.14 Lactose 4405.86 Polyvinyl pyrrolidone 150.00 Polyvinyl pyrrolidone, crosslinked (disintegrant) 300.00 Stearic acid (lubricant) 120.00 Microcrystalline cellulose 900.00 Si2 colloidal (flow agent) 60.0 The amount of active substance per capsule is equivalent to 1.0 mg of free acid.

Lactose was granulated, and 600 g of microcrystalline cellulose with an aqueous solution of polyvinyl pyrrolidone and ibandronate in a fluidized bed granulator (Aeromatic type). The wet granulate was dried in a fluidized bed (Aeromatic type), passed through a 1.0 mm sieve, mixed with disintegrant, lubricant, flow regulator and 300 g of microcrystalline cellulose (Turbula type mixer, mixture of 5 minutes) and was converted into tablets by means of a tablet-forming press (Korsch type) having a capacity of 25,000 tablets per hour.

Set weight of the tablets 100.0 mg Actual weight of the tablets according to weight control 101.3 mg Content of active substance found per tablet produced in this way: 98.3% + 4.2% (n = 10 individual).

The active substance content of the tablets was within the limits of acceptance.

Example 4 Production of 0.1 mg tablets of Ibandronate after granulation in a fluidized bed (batch size for 150,000 tablets).

Constituents Ibandronate monohydrate Na 16.95 Lactose 11158.05 Polyvinyl pyrrolidone 375.00 Polyvinyl pyrrolidone, crosslinked (disintegrant) 750.00 Stearic acid (lubricant) 300.00 Microcrystalline cellulose 2250.00 Si? 2 colloidal (flow agent) 150.00 The amount of active substance per capsule is equivalent to 1.0 mg of free acid.

Lactose, and 1500 g of microcrystalline cellulose were granulated with a solution of polyvinylpyrrolidone and ibandronate in a fluidized bed granulator (Aeromatic type). The wet granulate was dried in the fluidized bed (Aeromatic type), passed through a 1.0 mm sieve. It was mixed with disintegrant, lubricant, flow regulator and 750 microcrystalline cellulose (Turbula type mixer, mixing time of 10 minutes) and converted into tablets by a tablet press (Korsch type) having a capacity of 60,000 tablets per hour.

Set weight of the tablets: 100.0 mg Actual weight of the tablets according to weight control 101.3 mg Content of active substance found per tablet produced in this way: 98.5% + 2.4% (n = 10 individual measurements).

The active substance content of the tablets was within the limits of acceptance.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

Claims Having described the invention as above, the content of the following is claimed as property.

1. A process for the preparation of pharmaceutical compositions for the oral application of bisphosphonates, characterized in that the bisphosphonate is wet granulated in a manner known per se in a fluidized bed granulator using coadjuvants having no abrasive action and wherein the granulate The moisture is then dried in the fluidized bed, sieved through a screen having a suitable mesh width and further processed by techniques known per se to form pharmaceutical compositions containing up to 50 mg of active substance per unit dose.

2. The process according to claim 1, characterized in that the bisphosphonate in solution or suspension and together with an aqueous binder is sprayed on the other coadjuvants and granulated.

3. The process according to claim 1, characterized in that the bisphosphonate and the adjuvants in dry powder form are placed in a fluidized bed reactor and granulated by spraying water into the powder mixture, which in this case contains a binder. , or the powder containing the active substance is granulated by spraying in an aqueous binder solution.

4. The process according to any of claims 1 to 3, characterized in that the bisphosphonate used is alendronate, clodronate, EB-1053, etidronate, ibandronate, incadrojiate, neridronate, olpadronate, pamidronate, residronate, tiludronate, YH 529 or zoledronate in free acid form or a pharmaceutically compatible salt or hydrate, particularly the sodium salt.

5. The method according to claim 4, characterized in that the bisphosphonate used is ibandronate.

6. The process according to any of claims 1 to 5, characterized in that at least one of the adjuvants is lactose, microcrystalline cellulose or polyvinylpyrrolidone. The process according to claim 6, characterized in that the adjuvants are 1-99% by weight of lactose, 1-99% by weight of microcrystalline cellulose, and 0.1-20% by weight of polyvinylpyrrolidone. The process according to claim 7, characterized in that 25-75% by weight of lactose, 10-20% by weight of microcrystalline cellulose and 2-3% by weight of polyvinylpyrrolidone are used. 9. The process according to any of claims 1 to 8, characterized in that further processing is carried out tablets, capsules, tablets with film, dragees, granules, effervescent tablets, chewable tablets or pellets in pads. The process according to claim 9, characterized in that an additional process is carried out with the addition of 0.05-3% by weight of stearic acid to the mixture.