EP1259227A1

EP1259227A1 - Method for producing pharmaceutical dosage forms

Info

Publication number: EP1259227A1
Application number: EP01907526A
Authority: EP
Inventors: Tobias Laich; Carola PÖRTNER; Jan-Olav Henck
Original assignee: Bayer AG; Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2000-02-24
Filing date: 2001-02-13
Publication date: 2002-11-27
Also published as: AU3547001A; WO2001062230A1; DE10008506A1

Abstract

The invention relates to a method for producing a granulate while using spray-dried D-mannitol and to the production of pharmaceutical dosage forms comprised of granulates of this type. The invention additionally relates to granulates obtained by using this method and to pharmaceutical dosage forms, which contain statins, especially cerivastatin, and which can be produced from said granulates.

Description

Process for the preparation of pharmaceutical dosage forms

The present invention relates to a process for the production of granules using spray-dried D-mannitol and the production of pharmaceutical dosage forms from such granules. The invention further relates to granules obtainable by this process and pharmaceutical dosage forms which can be produced therefrom and contain pharmaceutical active substances, in particular statins.

WO 97/38960 describes D-mannitol which has good properties as a filler for the production of pharmaceutical preparations, in particular tablets. The D-mannitol described there consists of a mixture of crystals in the δ-form (modification III) and the ß-form (modification I). It also describes that this D-mannitol is suitable, inter alia, for the production of solid pharmaceutical preparations of cerivastatin.

WO 98/57917 describes a process for the production of medicaments containing HMG-CoA reductase inhibitors. As a preferred embodiment, the production of cerivastatin-containing granules by wet granulation with mannitol is described.

It is also known that spray-dried mannitol can be used as a filler in direct tableting. No. 3,145,146 describes the production of spray-dried D-mannitol and its use for direct tableting. Furthermore, US Pat. No. 5,958,471, for example, describes preparations and compacted articles which contain a mixture of spray-dried polyols, including mannitol.

Surprisingly, it has now been found in a further development of the method described in WO 98/57917 that excellent results are obtained. if you use spray-dried D-mannitol in the granulation. This finding is particularly surprising because spray-dried D-mannitol is usually used as a filler for direct tableting, ie all components of the tablets in question are mixed dry and then pressed into tablets. When processing spray-dried mannitol under moist

Those skilled in the art would expect conditions to lose the beneficial properties of spray dried mannitol. Unexpectedly, however, this is not the case with the method according to the invention.

The invention relates to a method for producing a granulate, in which

(a) a solution or suspension containing an active pharmaceutical ingredient, which optionally contains other binders and / or auxiliaries, is granulated with spray-dried mannitol and optionally further binders and / or auxiliaries and

(b) the granules obtained dry.

The invention further relates to granules containing a statin and spray-dried D-mannitol.

The invention further relates to a process for producing a pharmaceutical dosage form, in which the granules described above are converted into the desired dosage form, if appropriate with the addition of further auxiliaries.

The invention further relates to a pharmaceutical dosage form containing a statin and spray-dried D-mannitol.

The invention further relates to the use of spray-dried mannitol for the production of pharmaceutical dosage forms containing a statin. In the process according to the invention for producing a granulate, water, alcohols such as methanol, ethanol, isopropanol, n-propanol and other volatile solvents such as dichloromethane, acetone, ethyl acetate or other pharmaceutically acceptable solvents are suitable as solvents for the solution or suspension containing the active pharmaceutical ingredient. Mixtures of the abovementioned solvents can also be used. Water-containing solvents or solvent mixtures are preferred; water is particularly preferred.

Other customary binders for the solution or suspension containing the active pharmaceutical ingredient are all customary pharmaceutically acceptable binders, examples are polyvinylpyrrolidones, gelatin, starch and cellulose derivatives (natural or synthetic) such as e.g. Hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose, methyl starch, pregelatinized starch, dextrins, and also dextrans, alginates or their derivatives.

Preferred are polyvinyl pyrrolidones, e.g. Kollidon® 25.

All conventional pharmaceutical auxiliaries can be used as further auxiliaries, e.g. as fillers, apart from spray-dried D-mannitol, celluloses and derivatives (e.g. microcrystalline cellulose, native cellulose,

Hydroxypropyl cellulose, hydropropyl methyl cellulose, methyl cellulose), sugar

(e.g. lactose, fructose, sucrose, glucose, maltose), other sugar alcohols (e.g.

Sorbitol, xylitol, lactitol), inorganic fillers (e.g. calcium phosphates, calcium sulphates), starches and derivatives (corn starch, potato starch, wheat starch,

Dextrins, pre-gelatinized starches) and all other auxiliaries that are used for

Production of pharmaceutical formulations of the desired properties are required, for example lubricants (for example magnesium stearate, calcium stearate, calcium behenate, sodium stearyl fumarate), for example disintegrants ("disintegrants" for example crosslinked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, starches), for example wetting agents (for example sodium lauryl) , Polyoxy ethylene sorbitan fatty acid esters, sorbitan fatty acid esters, stearic acid, lecithins), for example alkaline additives (for example sodium hydroxide, potassium hydroxide, amines, ammonia, calcium hydroxide, magnesium hydroxide), for example stabilizers (antioxidants such as for example ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), pherols, BHA), Citric acid, EDTA sodium), for example flavors, for example color pigments or

Dyes.

The proportion of binder in the overall mixture is preferably 0 to 20% (m / m). The proportion of fillers and auxiliaries in the overall mixture is 20 to 99%, preferably 50 to 99%, particularly preferably 70 to 99% (m / m).

If the proportion of fillers and auxiliaries is considered to be 100%, the proportion of spray-dried D-mannitol is 50 to 100%, preferably 60 to 100%, particularly preferably 70 to 100% (m / m).

The drying temperature of the solvent-containing granules is generally 40 to 120 ° C, preferably 60 to 100 ° C (temperature of the drying medium).

Step (a) of the method according to the invention (granulation) can preferably be carried out, for example, in an intensive shear mixer.

According to the invention, spray-dried D-mannitol is used as an essential filler. Spray-dried D-mannitol is characterized by the fact that D-mannitol is present in the modifications I (β-form) and II (α-form). Furthermore, the

Amount of modification III (δ-form) in spray-dried mannitol is usually less than 5% (mm). The D-mannitol used according to the invention has an average particle size of 5 to 400 μm, preferably 50 to 350 μm, particularly preferably 100 to 250 μm. The individual particles of the spray-dried mannitol (granules) have a particle size distribution, the mean value (x50) of which lies in the specified intervals. A volume distribution is assumed and all particles are assumed to be spherical.

Such a measured value can be determined by laser light diffraction, e.g. using Sympatec HELOS laser diffraction device at focal length R5 (500 mm) using the SUCELL wet dispersion unit with integrated ultrasound bath (35 kHz, 50 W) (Baysilon oil M 10 is used as the dispersion medium), the sample is treated with ultrasound for 3 min before measurement. The measurement is evaluated at

Use of the Sympatec software WTNDOX.

In contrast to the spray-dried mannitol, the D-mannitol described in WO 97/38960 is present in modifications I and III. Modification II can practically not be detected in this mannitol (proportion <5% (m / m)).

The method according to the invention is suitable in principle for all active pharmaceutical ingredients which do not change undesirably under the process conditions. “Pharmaceutical active ingredients” are to be understood here as substances that occur in relatively small quantities or can have a great physiological effect. In particular, medicinally active substances ("pharmaceuticals, drugs") are to be understood, which are suitable for the prophylaxis, healing or alleviation of diseases. In particular, amazement is used as active pharmaceutical ingredients. Statins are a class of HMG-CoA reductase inhibitors with the following formula

OH OH

R-X-CH-CH CH-CH COOM (I)

embedded image in which R represents an organic radical,

X for a group -CH2-CH2- or -CH = CH-; stands especially in the (E) form and

M is a physiologically acceptable cation, for example from the series of alkali cations, preferably sodium or potassium and also an ammonium ion.

Apart from the open chain salt form shown in formula (I), the

Statins can also be used in the form of their δ-lactone.

According to the invention, statins are particularly preferred

• Atorvastatin (commercially available under the name Lipitor® from Parke-Davis);

• Cerivastatin (commercially available under the name Lipobay® or Baycol® from Bayer);

• fluvastatin (commercially available under the name Lescol® from Novartis);

Lovastatin (commercially available under the name Mevacor® from Merck); • Pravastatin (commercially available under the name Lipostat® from Bristol-Myers Squibb);

• Simvastatin (commercially available under the name Zocor® from Merck);

• Itavastatin (also called "Nisvastatin"; NK-104; systematic name: [S- [R *, S * - (E)]] - 7- [2-Cycloρropyl-4- (4-fluorophenyl) -3-quinolinyl ] -3,5-dihydroxy-6-heptenoic acid);

• Dalvastatin;

• mevastatin;

• dihydrocompactin;

• Compactin; and S-4522; systematic name (+) - (3R, 5S) -Bis- (7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) -pyrimidin-5-yl) -3 , 5-dihydroxy-6 (E) - heptenoic acid; and their respective salts, hydrates, alcoholates, esters, lactones and tautomers, including very particularly preferably atorvastatin, cerivastatin, fluvastatin,

Lovastatin, Pravastatin, Itavastatin, Simvastatin and (+) - (3R, 5S) -Bis- (7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine) 5-yl) -3,5-dihydroxy-6 (E) -heptenic acid and their respective salts, hydrates, alcoholates, esters, lactones and tautomers.

Cerivastatin and atorvastatin and their respective salts, hydrates, alcoholates, esters, lactones and tautomers are very particularly preferred.

For further details on the aforementioned statins, reference is made to the

Treatises in Drugs of the Future 1994, 19 (6), pages 537 - 541 and 1995, 20 (6), page 611 and 1996, 21 (6), page 642, the respective contents of which are incorporated in their entirety by reference.

The term "salt" in the sense of the present invention means physiologically acceptable salts of the respective compounds: These can be, for example, salts with mineral acids, carboxylic acids or sulfonic acids, in particular with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, Naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid or mixed salts thereof, but they can also be salts with conventional bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts ) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methyl morpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine and mixed salts thereof.

Statins which are in the form of their salts are preferably used in the context of this invention.

Examples of statin salts which can be used according to the invention are the monosodium salt of fluvastatin; the monopotassium salt and the calcium salt of itavastatin; and the calcium salt of (+) - (3R, 5S) -Bis- (7- (4- (4-fluoφhenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine-5- yl) -3,5-dihydroxy-6 (e) heptenoic acid

("ZD 4522" or "S 4522" from Shionogi or AstraZeneca). Further examples of statin salts which can be used according to the invention are the monosodium and monopotassium salts and the magnesium and calcium salts of cerivastatin, atorvastatin and pravastatin. The cerivastatin salts, particularly the sodium salt (also referred to as cerivastatin sodium), are particularly preferably used.

Further preferred HMG-CoA reductase inhibitors are described in EP-A-0 325 130 and in EP-A-0-491 226, both in the name of Bayer AG, the content of which is hereby incorporated by reference. Subject of

EP-A-0 325 130 are substituted pyridines, and EP-A-0-491 226 describes substituted pyridyldihydroxyheptenoic acid derivatives and their salts, including in particular the cerivastatin particularly preferred according to the invention (claim 6 of EP-A-0 491 226).

Likewise preferred according to the invention are the HMG-CoA reductase inhibitors, which are described in Bioorganic & Medicinal Chemistry, Vol. 2, pages 437-444 (1997), the disclosure of which is hereby fully incorporated by reference. A further overview of HMG-CoA reductase inhibitors can be found in pharmacy in our time, 28th year, No. 3, pages 147-152 (1999).

In the case of statins in open-chain salt form, in particular for cerivastatin sodium, it proves to be favorable for the preparation of the active ingredient-containing solution or suspension, first of all from a suitable active ingredient precursor, the ester or in particular the lactone, by treatment with aqueous base, in particular with a essentially equivalent molar amount to produce the actual active ingredient, add the binder (preferably, for example, PVP) to this so-called hydrolysis solution in the form of an aqueous solution and, if appropriate, add a further solution containing auxiliaries, in particular, for example, an aqueous solution of a base (for example sodium hydroxide) to this mixture admix. The mixture obtained in this way can then first be granulated with spray-dried mannitol by the process according to the invention and then dried.

"Granules" is to be understood here as an accumulation of granules; a granulate is an aggregate of powder particles (whole crystals, crystal fragments, etc.). Granules typically have an irregular surface and a porous structure. "Granulating" means the transfer of powder particles into granules.

The granules according to the invention containing a statin and spray-dried mannitol are preferably produced by the process according to the invention. They are characterized by advantageous properties: they show excellent flowability, which leads to better meterability of the granules and easier processing in the manufacture of pharmaceutical dosage forms, for example when tableting. The granules according to the invention also have good compacting properties. Finally, the fine fraction of the granules according to the invention is significantly reduced, which means less dust conditionally. This has advantages in terms of safety (less dust contamination of the person performing the work) and leads to less cleaning effort.

The pharmaceutical dosage forms according to the invention, containing a statin and spray-dried D-mannitol, can be prepared by methods known per se. The granules according to the invention are preferably used for their production.

Suitable pharmaceutical dosage forms are known to the person skilled in the art. Examples include sacchets, capsules and tablets. The are preferred

Granules processed into tablets. Suitable excipients such as e.g. the fillers, lubricants, disintegrants, wetting agents, flavors, colorants, stabilizers etc. given above are added. If desired, the tablets obtained can be provided with a suitable coating in the customary manner. The process steps required for this are known to the person skilled in the art. As coatings come e.g. Consider natural, synthetic or partially synthetic polymers (shellac, hydroxypropylmethyl cellulose, polymethacrylates, cellulose acetate) or starch syrups in combination with sugars (sucrose, glucose, fructose etc.) together with dyes or pigments. Hydroxpropylmethylcellulose in is preferred

Combination with iron oxides and / or titanium dioxide used.

The processes described above for the production of granules or pharmaceutical dosage forms are particularly suitable if the active ingredient is used in only very small amounts, for example less than 5%, preferably less than 1% (weight fraction in the final formulation). By further processing the active ingredient solution or suspension to form the granulation liquid and then coating or granulating the filler or filler mixture, pharmaceutical preparations can be produced which are distinguished by excellent uniformity of the active ingredient distribution. The well-known problems that arise with conventional (dry) mixing of components with widely different Proportions in an overall mixture are thus avoided in a simple manner.

Examples

example 1

Dosage 0.4 mg cerivastatin

5228.13 g of D-mannitol spray-dried (Pearlitol 200 SD, Roquette, France)

25.00 g cerivastatin sodium (from cerivastatin lactone)

8.12 g sodium hydroxide (approx. 5.97 g remain in the granules) 112.50 g polyvinylpyrolidone (Kollidon 25, from BASF, Germany)

437.50 g water

22.92 g of cerivastatin lactone are reacted with 233.91 g of water and 2.12 g of NaOH to give cerivastatin sodium solution (hydrolysis solution). A solution is prepared from PVP, the remaining amount of water and the remaining amount of NaOH. This is mixed with the hydrolysis solution and used as a liquid for the granulation. The spray-dried D-mannitol is placed in an intensive mixer (MGT 30, Lödige, Germany) and premixed at 200 rpm (chopper stage 1) for 1 min. The granulation liquid is added uniformly in 7 min. Then another minute is granulated. The mixer is about a 4 mm

Friction chips (Alexanderwerk, Germany) emptied. The granules obtained are dried in a fluidized bed (Glatt, Switzerland) at a supply air temperature of 70 ° C. to a product temperature of 41.5 ° C.

The dry granulate is cross-linked with 3% (m / m) PVP (Polyplasdone XL,

BASF, Germany) and 2% (m / m) magnesium stearate (Greven, Germany) mixed for 5 min. Then round tablets are pressed into 90 mg tablets (format 6 mm WR 9 mm).

The tablets thus obtained can also be coated. Example 2

Dosage 0.8 mg cerivastatin

5228.13 g of D-mannitol spray-dried (Pearlitol 200 SD, Roquette, France)

25.00 g cerivastatin sodium (from cerivastatin lactone)

8.12 g sodium hydroxide (approx. 5.97 g remain in the granulate)

112.50 g polyvinylpyrolidone (Kollidon 25, BASF, Germany)

437.50 g water

22.92 g of cerivastatin lactone are reacted with 233.91 g of water and 2.12 g of NaOH to give cerivastatin sodium solution (hydrolysis solution). Another solution is made from PVP and 178.60 g of water. This is mixed with the hydrolysis solution. A solution is prepared from the remaining amount of water and the remaining amount of NaOH. This is mixed with the previously prepared mixture of hydrolysis solution and PVP solution and used as a liquid for the granulation. The spray-dried mannitol is placed in an intensive mixer (MGT 30, Lödige, Germany) and premixed at 200 rpm (chopper stage 1) for 1 min. The granulation liquid is added uniformly in 7 min. Then another minute is granulated. The mixer is over a 4 mm grater

(Alexanderwerk, Germany) emptied. The granules obtained are dried in a fluidized bed (Glatt, Switzerland) at a supply air temperature of 70 ° C. to a product temperature of 41.5 ° C.

The dry granulate is cross-linked with 3% (m / m) PVP (Polyplasdone XL,

BASF, Germany) and 2% (m / m) magnesium stearate (Greven, Germany) mixed for 5 min. Then 180 mg tablets (format 8 mm WR 12 mm) round tablets are pressed.

The tablets thus obtained can also be coated. Example 3

Dosage 0.2 mg cerivastatin

5240.63 g D-mannitol spray-dried (Pearlitol 200 SD, Roquette, France)

12.50 g cerivastatin sodium (from cerivastatin lactone)

7.06 g sodium hydroxide (approx. 5.97 g remain in the granulate)

112.50 g polyvinylpyrolidone (Kollidon 25, BASF, Germany)

437.50 g water

1. 1.46 g of cerivastatin lactone are reacted with 116.95 g of water and 1.06 g of NaOH to give cerivastatin sodium solution (hydrolysis solution). A solution is prepared from PVP, the remaining amount of water and the remaining amount of NaOH. This is mixed with the hydrolysis solution and used as a liquid for the granulation. The spray-dried mannitol is in an intensive mixer (MGT 30, Fa Lödige,

Germany) and premixed at 200 rpm (chopper stage 1) for 1 min. The granulation liquid is added uniformly in 7 min. Then another minute is granulated. The mixer is emptied using a 4 mm grater (Alexanderwerk, Germany). The granules obtained are dried in a fluidized bed (Glatt, Switzerland) at a supply air temperature of 70 ° C. to a product temperature of 41.5 ° C.

The dry granules are mixed with 3% (m / m) cross-linked PVP (Polyplasdone XL, from BASF, Germany) and 2% (m / m) magnesium stearate (from Greven, Germany) for 5 minutes. Then 90 mg tablets (format 6 mm WR

9 mm) round tablets pressed.

The tablets thus obtained can also be coated. Example 4

Dosage 0.1 mg cerivastatin

5246.88 g D-mannitol spray-dried (Pearlitol 200 SD, Roquette, France)

6.25 g of cerivastatin sodium (from cerivastatin lactone) 6.53 g of sodium hydroxide (approx. 5.97 g remain in the granules) 112.50 g of polyvinylpyrolidone (Kollidon 25, from BASF, Germany) 437.50 g of water

5.73 g of cerivastatin lactone are reacted with 58.47 g of water and 0.53 g of NaOH to give cerivastatin sodium solution (hydrolysis solution). A solution is prepared from PVP, the remaining amount of water and the remaining amount of NaOH. This is mixed with the hydrolysis solution and used as a liquid for the granulation. The spray-dried mannitol is in an intensive mixer (MGT 30, Fa Lödige,

9 mm) round tablets pressed.

The tablets thus obtained can also be coated. Example 5

As in example 1, granulation liquid addition time only 2 min.

Example 6

As in example 1, the addition time of granulation liquid is 3 min.

Example 7

As in example 1, the addition time of granulation liquid is 5 min.

Claims

claims

1. A process for producing a granulate, in which one

(a) a solution containing an active pharmaceutical ingredient or

Suspension, which optionally contains other binders and / or auxiliaries, is granulated with spray-dried D-mannitol and optionally further binders and / or auxiliaries and

(b) the granules obtained dry.

2. The method according to claim 1, wherein the active pharmaceutical ingredient is a statin.

3. The method according to claim 2, wherein the statin lovastatin, simvastatin,

Pravastatin, Fluvastatin, Atorvastatin, Cerivastatin, Itavastatin or S-4522.

4. Granules containing a statin and spray-dried D-mannitol

5. Granules containing cerivastatin and spray-dried D-mannitol

6. A process for the preparation of a pharmaceutical dosage form, in which the granules according to one of claims 4 or 5, optionally with the addition of further auxiliaries, are converted into the desired dosage form.

7. The method according to claim 6, in which the granules are prepared according to claim 1.

8. The method according to any one of claims 6 or 7, in which a tablet is produced from the dried granules.

9. Pharmaceutical dosage form, containing a statin and spray-dried D-mannitol.

10. Pharmaceutical dosage form, containing cerivastatin and spray-dried D-mannitol.

11. Pharmaceutical dosage form according to claim 9 or 10 in the form of

tablets

12. Use of spray-dried D-mannitol for the production of pharmaceutical dosage forms containing a statin.

13. Use according to claim 12, wherein the statin is cerivastatin.