WO2001062230A1 - Method for producing pharmaceutical dosage forms - Google Patents
Method for producing pharmaceutical dosage forms Download PDFInfo
- Publication number
- WO2001062230A1 WO2001062230A1 PCT/EP2001/001565 EP0101565W WO0162230A1 WO 2001062230 A1 WO2001062230 A1 WO 2001062230A1 EP 0101565 W EP0101565 W EP 0101565W WO 0162230 A1 WO0162230 A1 WO 0162230A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dried
- mannitol
- spray
- granules
- cerivastatin
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
Definitions
- 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 ⁇ -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.
- the production of cerivastatin-containing granules by wet granulation with mannitol is described.
- the invention relates to a method for producing a granulate, in which
- 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.
- 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.
- 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.
- 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.
- 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,
- Sorbitol, xylitol, lactitol inorganic fillers (e.g. calcium phosphates, calcium sulphates), starches and derivatives (corn starch, potato starch, wheat starch,
- lubricants for example magnesium stearate, calcium stearate, calcium behenate, sodium stearyl fumarate
- disintegrants for example crosslinked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, starches
- wetting agents for example sodium lauryl
- alkaline additives for example sodium hydroxide, potassium hydroxide, amines, ammonia, calcium hydroxide, magnesium hydroxide
- stabilizers antioxidants such as for example ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), pherols, BHA), Citric acid, EDTA sodium
- flavors for example color pigments or
- 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).
- 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 can preferably be carried out, for example, in an intensive shear mixer.
- 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 ( ⁇ -form) and II ( ⁇ -form). Furthermore, the modifications I ( ⁇ -form) and II ( ⁇ -form). Furthermore, the modifications I ( ⁇ -form) and II ( ⁇ -form). Furthermore, the modifications I ( ⁇ -form) and II ( ⁇ -form). Furthermore, the
- Amount of modification III ( ⁇ -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 ⁇ m, preferably 50 to 350 ⁇ m, particularly preferably 100 to 250 ⁇ m.
- 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
- 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.
- medicinally active substances (“pharmaceuticals, drugs”) are to be understood, which are suitable for the prophylaxis, healing or alleviation of diseases.
- tartment is used as active pharmaceutical ingredients.
- Statins are a class of HMG-CoA reductase inhibitors with the following formula
- M is a physiologically acceptable cation, for example from the series of alkali cations, preferably sodium or potassium and also an ammonium ion.
- Statins can also be used in the form of their ⁇ -lactone.
- statins are particularly preferred.
- Atorvastatin commercially available under the name Lipitor® from Parke-Davis
- 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);
- Itavastatin also called "Nisvastatin”; NK-104; systematic name: [S- [R *, S * - (E)]] - 7- [2-Cyclo ⁇ ropyl-4- (4-fluorophenyl) -3-quinolinyl ] -3,5-dihydroxy-6-heptenoic acid);
- Cerivastatin and atorvastatin and their respective salts, hydrates, alcoholates, esters, lactones and tautomers are very particularly preferred.
- salts 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, ethyldiisopropy
- Statins which are in the form of their salts are preferably used in the context of this invention.
- 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-fluo ⁇ henyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine-5- yl) -3,5-dihydroxy-6 (e) heptenoic acid
- 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.
- 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).
- 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).
- statins in open-chain salt form in particular for cerivastatin sodium
- a suitable active ingredient precursor the ester or in particular the lactone
- aqueous base in particular with a essentially equivalent molar amount to produce the actual active ingredient
- add the binder preferably, for example, PVP
- 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.
- 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 are Suitable excipients such as e.g. the fillers, lubricants, disintegrants, wetting agents, flavors, colorants, stabilizers etc. given above are added.
- the tablets obtained can be provided with a suitable coating in the customary manner.
- 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
- cerivastatin sodium from cerivastatin lactone
- cerivastatin lactone 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,
- cerivastatin sodium from cerivastatin lactone
- cerivastatin lactone 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.
- another minute is granulated.
- the mixer is over a 4 mm grater
- 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,
- cerivastatin sodium from cerivastatin lactone
- cerivastatin lactone 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,
- 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
- cerivastatin sodium from cerivastatin lactone
- sodium hydroxide approximately 1.97 g remain in the granules
- polyvinylpyrolidone Keldon 25, from BASF, Germany
- cerivastatin lactone 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,
- 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
- the addition time of granulation liquid is 3 min.
- the addition time of granulation liquid is 5 min.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01907526A EP1259227A1 (en) | 2000-02-24 | 2001-02-13 | Method for producing pharmaceutical dosage forms |
AU35470/01A AU3547001A (en) | 2000-02-24 | 2001-02-13 | Method for producing pharmaceutical dosage forms |
US10/204,837 US20030031720A1 (en) | 2000-02-24 | 2001-02-13 | Method for producing pharmaceutical dosage forms |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2000108506 DE10008506A1 (en) | 2000-02-24 | 2000-02-24 | Process for the preparation of pharmaceutical dosage forms |
DE10008506.7 | 2000-02-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001062230A1 true WO2001062230A1 (en) | 2001-08-30 |
Family
ID=7632144
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2001/001565 WO2001062230A1 (en) | 2000-02-24 | 2001-02-13 | Method for producing pharmaceutical dosage forms |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1259227A1 (en) |
AU (1) | AU3547001A (en) |
DE (1) | DE10008506A1 (en) |
WO (1) | WO2001062230A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003086387A1 (en) * | 2002-04-09 | 2003-10-23 | Bernard Charles Sherman | Stable tablets comprising simvastatin |
DE102007052070A1 (en) | 2007-10-30 | 2009-05-07 | Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg | candesartancilexetil |
EP2138165A1 (en) | 2008-06-27 | 2009-12-30 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising a statin |
RU2606592C1 (en) * | 2015-10-07 | 2017-01-10 | Открытое Акционерное Общество "Татхимфармпрепараты" | Pharmaceutical composition containing rosuvastatin calcium salt (versions) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3145146A (en) * | 1961-10-31 | 1964-08-18 | Warner Lambert Pharmaceutical | Modified mannitol for pharmaceutical tablets |
WO1994000111A1 (en) * | 1992-06-26 | 1994-01-06 | Merck & Co., Inc. | Spheronization process using charged resins |
WO1997038960A1 (en) * | 1996-04-16 | 1997-10-23 | Takeda Chemical Industries, Ltd. | D-mannitol and its preparation |
-
2000
- 2000-02-24 DE DE2000108506 patent/DE10008506A1/en not_active Ceased
-
2001
- 2001-02-13 WO PCT/EP2001/001565 patent/WO2001062230A1/en not_active Application Discontinuation
- 2001-02-13 AU AU35470/01A patent/AU3547001A/en not_active Abandoned
- 2001-02-13 EP EP01907526A patent/EP1259227A1/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3145146A (en) * | 1961-10-31 | 1964-08-18 | Warner Lambert Pharmaceutical | Modified mannitol for pharmaceutical tablets |
WO1994000111A1 (en) * | 1992-06-26 | 1994-01-06 | Merck & Co., Inc. | Spheronization process using charged resins |
WO1997038960A1 (en) * | 1996-04-16 | 1997-10-23 | Takeda Chemical Industries, Ltd. | D-mannitol and its preparation |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003086387A1 (en) * | 2002-04-09 | 2003-10-23 | Bernard Charles Sherman | Stable tablets comprising simvastatin |
DE102007052070A1 (en) | 2007-10-30 | 2009-05-07 | Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg | candesartancilexetil |
US8193226B2 (en) | 2007-10-30 | 2012-06-05 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Candesartan cilexetil |
EP2138165A1 (en) | 2008-06-27 | 2009-12-30 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising a statin |
RU2606592C1 (en) * | 2015-10-07 | 2017-01-10 | Открытое Акционерное Общество "Татхимфармпрепараты" | Pharmaceutical composition containing rosuvastatin calcium salt (versions) |
Also Published As
Publication number | Publication date |
---|---|
EP1259227A1 (en) | 2002-11-27 |
DE10008506A1 (en) | 2001-09-13 |
AU3547001A (en) | 2001-09-03 |
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