EP2170296A2 - Procédé de fabrication d'un médicament contenant du trihydrate d'hydrochlorure de vardénafil - Google Patents

Procédé de fabrication d'un médicament contenant du trihydrate d'hydrochlorure de vardénafil

Info

Publication number
EP2170296A2
EP2170296A2 EP08759223A EP08759223A EP2170296A2 EP 2170296 A2 EP2170296 A2 EP 2170296A2 EP 08759223 A EP08759223 A EP 08759223A EP 08759223 A EP08759223 A EP 08759223A EP 2170296 A2 EP2170296 A2 EP 2170296A2
Authority
EP
European Patent Office
Prior art keywords
cellulose
starch
hydrochloride trihydrate
film
suitable pharmaceutical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08759223A
Other languages
German (de)
English (en)
Inventor
Sandra BRÜCK
Julia Schulze Nahrup
Birgit Schnitter
Yogesh S. Deshpande
Ganesh Gat
Javed Hussain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ratiopharm GmbH
Original Assignee
Ratiopharm GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of EP2170296A2 publication Critical patent/EP2170296A2/fr
Withdrawn legal-status Critical Current

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present invention relates to a method for producing a medicament comprising Vardenafii hydrochloride trihydrate in solid form, in which Vardenafii hydrochloride trihydrate is processed with suitable pharmaceutical excipients at a temperature of about 20 0 C to about 45 ° C.
  • Vardenafii (IUPAC name: ⁇ 2-ethoxy-5 - [(4-ethyl-1-piperazinyl) sulfonyl] phenyl ⁇ -5-methyl-7-propylimidazo [5, l- / j [l, 2, 4] triazine -4 (3H) on) belongs to the group of PDE-V
  • Vardenafii can be prepared, for example, according to M. Lögers ("Vardenafii.
  • Vardenafii hydrochloride trihydrate is problematic in that the trihydrate is not stable in any of the processing steps or coating of the tablets. There is a loss of hydrate, with the result that the active ingredient in the tablets is not in a uniform form. That's why it is z. B. necessary to treat the tablets after filing for several hours with humidity. Moisture absorption causes the trihydrate to form again. This process can take several hours depending on the humidity and therefore leads to a disadvantageous process delay (see WO2004 / 006894).
  • the water content of an active ingredient can influence its release from the formulation, which is also disadvantageous.
  • the solvent-free drugs have much higher dissolution rates than the corresponding hydrates. In this respect, fluctuations in the water content should be avoided.
  • mechanical processes such as grinding and compression can affect the reactivity of the active ingredient to water vapor or to the moisture content.
  • the object of the present invention was therefore to provide a process for the preparation of tablets with vardenafil hydrochloride trihydrate, in which a loss of hydrate (overdrying) is substantially avoided from the outset, and thus the additional rehydration step necessary according to WO2004 / 006894 can be dispensed with.
  • the present invention therefore provides a process for the preparation of a medicament containing vardenafil hydrochloride trihydrate in solid form, in which the vardenafil hydrochloride trihydrate with suitable pharmaceutical excipients at a temperature of about 20 ° C to about 45 ° C, preferably of about 20 ° C to about 40 0 C, in particular from about 20 ° C to about 35 ° C, especially from about 20 ° to about 30 ° C and particularly preferably at about 23 ° C is processed. Accordingly, the processing temperature according to the present invention should not exceed about 45 ° C.
  • temperature or “processing temperature” is understood to mean the product temperature, that is, unless stated otherwise. the temperature of the drug formulation during processing.
  • the relative humidity of the processing atmosphere at about 30% to about 90%, preferably at about 30% to about 50%, in particular at about 30% to about 40%, before Everything is at about 33% to about 35%.
  • the inventive method should be at a processing temperature of about 23 ° C and a processing atmosphere of about 33% to about 35% relative humidity.
  • the tablet production generally takes place in several steps.
  • the vardenafil hydrochloride trihydrate is in a first Step mixed with suitable pharmaceutical excipients, then pressed and optionally coated with a film.
  • the processed drug with a film at a temperature of about 40 ° C to about 55 ° C, preferably at about 40 ° C to about 50 ° C, in particular at ca 45 ° C is coated.
  • the tolerance limits (approx. Ranges) in the method according to the invention are generally +/- 2 ° C.
  • the method according to the invention comprises the following steps:
  • the process according to the invention does not comprise precompacting the active ingredient vardenafil hydrochloride trihydrate in the presence of suitable pharmaceutical excipients, i. the active ingredient is merely mixed with suitable pharmaceutical excipients, pressed and optionally coated with a film.
  • the abovementioned pharmaceutical auxiliaries are preferably selected in the process according to the invention from binders, flow regulators and / or lubricants and optionally also from fillers and / or disintegrants (disintegrants) and optionally a film former.
  • Step (a) of the process according to the invention is preferably carried out in the presence of at least one binder.
  • Step (b) of the process is preferably carried out with at least one flow regulator and at least one lubricant.
  • Step (d) of the process (coating) is preferably carried out with at least one film former.
  • the binder used is especially cellulose, in particular microcrystalline cellulose or microfine cellulose, one or more cellulose derivatives, in particular hydroxypropylmethylcellulose or hydroxypropylcellulose, polyvinylpyrrolidone and / or starch.
  • microcrystalline cellulose is used as the binder.
  • silica As flow control agent is mainly silica or a Glycerinfettklarester, z. B. Boeson ® VP (Baker Mark Germany GmbH), a mixture of mono-, di- and triglycerides added.
  • silica is used as a flow regulator.
  • the flow regulator is colloidal silica (SiO 2; silica) or Syloid ® 244 FP (Grace GmbH, Germany; trade name for a synthethische porous and amorphous silica having a content of 99.7 to 99.8% SiO 2, max 0.009% iron and 0.1% SO 4 max.).
  • the lubricants used are above all magnesium stearate, calcium stearate, fumaric acid, sodium stearyl fumarate, stearic acid, talc, starch and / or solid polyethylene glycols.
  • the lubricant magnesium stearate is used.
  • Crosslinked polyvinylpyrrolidone, starch, sodium carboxymethyl starch (synonym: sodium starch glycolate), carboxymethyl cellulose (synonym: carmellose), alginic acid, calcium alginate, pectic acid, formaldehyde gelatin and / or amylose are used as additional disintegrants.
  • the disintegrant crosslinked polyvinylpyrrolidone (synonymous name: crospovidone) is used.
  • the disintegrant is cross-linked carboxymethycellulose (synonymous term: croscarmellose), cross-linked sodium carboxymethylcellulose (synonymous term: croscarmellose sodium) or corn starch.
  • microcrystalline cellulose starch, mono- and disaccharides, especially lactose, glucose and sucrose, sugar alcohols, especially mannitol and sorbitol, dicalcium phosphate and / or calcium carbonate is used.
  • the filler microcrystalline cellulose is used.
  • the filler is modified starch (1500 gauge).
  • Water-soluble cellulose derivatives especially methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,
  • Hydroxyethylcellulose and sodium carboxymethylcellulose water-insoluble Cellulose derivatives, in particular ethylcellulose, cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, polyacrylates, polymethacrylates,
  • the film may also contain one or more pigments, for example an iron oxide, alumina and / or titanium dioxide.
  • the film former Opadry II ® (Colorcon FD Enterprise Corp./Pharma Dynamics, Inc.) based on HPMC (Hydroxyprophyl- methyl cellulose) or based on PVA (polyvinyl alcohol).
  • Opadry II ® indicates a commercially available tablet coating agent, which contains a mixture of lactose, Methocel HPCM copolymer, polyethylene glycol and desired pigments.
  • Some film formers that can be used at a relatively low temperature are listed in the following table as examples.
  • iron oxide and titanium dioxide pigments e.g. B. Sicovit ® yellow (BASF AG) and Sicovit ® red (BASF AG).
  • the room temperature is preferably about 23 0 C and the relative humidity at 33-35%.
  • lacquered tablets can be prepared as described, for example, in Examples 3 and 6 of WO 2004/006894.
  • the dose of active substance advantageously ranges from about 1-100 mg, especially about 2-50 mg.
  • Figure 1 Raman spectra of the samples vardenafil hydrochloride trihydrate, vardenafil hydrochloride, tablets of Examples 1 to 4
  • FIG. 2 Raman spectra of the tablets from Examples 1 to 4 (enlarged)
  • FIG. 3 TGA curve of the vardenafil hydrochloride trihydrate
  • Vardenafil hydrochloride trihydrate was prepared according to Example 336 from WO99 / 24433.
  • thermogravimetric analysis of the vardenafil hydrochloride trihydrate showed a significant weight loss at approx. 50 - 100 ° C. This suggests that this is the loss of adsorbed water. A slight weight loss occurred at about 190 0 C, which points to water of crystallization ( Figure 3).
  • Vardenafil hydrochloride trihydrate and anhydrate can be identified or distinguished from one another by Raman spectroscopy, for example.
  • Vardenafil hydrochloride trihydrate shows in the Raman spectrum a maximum at about 1702 cm ⁇ ⁇
  • Vardenafil HCl anhydrate has a maximum at about 1694 cm "1 .
  • example 1
  • Kollidon ® CL 17.7 g Kollidon ® CL was first passed through a 250 micron sieve. A first amount of Avicel ® (115.9 g) and Kollidon ® CL (8.6 g) was treated with the active substance (47.7 g) together for 10 minutes in the Turbula mixed. A second amount of Kollidon ® Cl (9.1 g) and Avicel ® (167.7 g) was added and further mixed for 10 minutes in a Turbula. The mixture was precompacted with a 20 mm punch with various press forces.
  • Tablets weighing 177 mg and 8 mm in diameter were pressed at 4 or 9 kN.
  • the room temperature was at all manufacturing steps at about 23 ° C and the rel. Humidity at 33 - 35%.
  • Sample No. 1 compacted with 9 kN
  • Sample No. 2 compacted with 12 kN
  • Sample No. 3 compacted with 6 kN
  • Sample No. 5 compressed with 4 kN
  • Sample No. 6 compressed with 9 kN
  • Example 1 The tablets of Example 1 were coated with an aqueous solution and dried. The temperature and drying time was varied.
  • Methocel ® E5 LV hypermethylcellulose
  • the tablets were preheated to 45 ° C (product temperature). Volume flow: 60% (corresponds to approx. 70 m 3 / h) Supply temp .: 45 ° C
  • the tablets were preheated to 60 ° C for 5 min.
  • Raman spectra were recorded after the precompacting, post-mixing, pressing and coating steps (FIGS. 1 and 2). The film was previously scraped off the film-coated tablets. For comparison, the Raman spectra of the pure vardenafil hydrochloride trihydrate and the anhydrate are shown.
  • Example 1 In the relevant range 1694-1702 cm -1 , the excipients used in Example 1 had no influence on the bands of the vardenafil (measurement on a placebo tablet is not shown). All tablets of Examples 1 to 3 showed a maximum in the Raman spectrum at about 1702 cm -1 , just like the vardenafil hydrochloride trihydrate. Thus, under the processing conditions used, the vardenafil hydrochloride is stable, ie it does not dehydrate.
  • Example 4 the maximum of the tablet of Example 4 was about 1694 cm -1 , as with vardenafil hydrochloride anhydrate These tablets were sprayed at a higher feed temperature than the other tablets At a supply air temperature of 60-65 ° C, the vardenafil dehydrated Hydrochloride trihydrate.
  • the mixture from Step I is sieved with the remaining amount of lactose and dibasic calcium phosphate through a 40 mesh sieve (ASTM).
  • Step II The mixture from Step II is sieved through a 40 mesh sieve (ASTM) to ensure uniform distribution of the active ingredient.
  • Silica is screened through a 40 mesh sieve (ASTM) and added to the mixture from Step III.
  • Magnesium stearate is passed through a 40 mesh sieve and mixed with the mixture from step 4.
  • Core tablets were film coated using Opadry II® (based on HPMC) and the fabrication temperature was maintained below 42 ° C.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de fabrication d'un médicament qui contient du trihydrate d'hydrochlorure de vardénafil sous forme solide, selon lequel le trihydrate d'hydrochlorure de vardénafil est traité avec des adjuvants pharmaceutiques appropriés à une température d'environ 20 °C à environ 45 °C.
EP08759223A 2007-06-12 2008-06-12 Procédé de fabrication d'un médicament contenant du trihydrate d'hydrochlorure de vardénafil Withdrawn EP2170296A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007027067A DE102007027067A1 (de) 2007-06-12 2007-06-12 Verfahren zur Herstellung eines Arzneimittels enthaltend Vardenafil Hydrochlorid Trihydrat
PCT/EP2008/004755 WO2008151811A2 (fr) 2007-06-12 2008-06-12 Procédé de fabrication d'un médicament contenant du trihydrate d'hydrochlorure de vardénafil

Publications (1)

Publication Number Publication Date
EP2170296A2 true EP2170296A2 (fr) 2010-04-07

Family

ID=39986037

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08759223A Withdrawn EP2170296A2 (fr) 2007-06-12 2008-06-12 Procédé de fabrication d'un médicament contenant du trihydrate d'hydrochlorure de vardénafil

Country Status (6)

Country Link
US (1) US8772292B2 (fr)
EP (1) EP2170296A2 (fr)
CA (1) CA2687500A1 (fr)
DE (1) DE102007027067A1 (fr)
RU (1) RU2493849C2 (fr)
WO (1) WO2008151811A2 (fr)

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Publication number Priority date Publication date Assignee Title
AR074689A1 (es) * 2008-12-19 2011-02-02 Solvay Pharm Bv Formulaciones farmaceuticas de desintegracion rapida pre-compactadas de compuestos con baja biodisponibilidad oral. proceso de preparacion
DE102009020888A1 (de) 2009-05-12 2010-11-18 Ratiopharm Gmbh Schmelztablette, enthaltend ein Vardenafil-Salz
CZ2011767A3 (cs) 2011-11-24 2013-06-05 Zentiva, K.S. Zpusob prípravy a izolace solí vardenafilu s kyselinami
CZ307091B6 (cs) * 2012-09-14 2018-01-10 Zentiva, K.S. Stabilní farmaceutický přípravek obsahující Vardenafil hydrochlorid
US20160317542A1 (en) 2013-12-09 2016-11-03 Respira Therapeutics, Inc. Pde5 inhibitor powder formulations and methods relating thereto
US20200330470A1 (en) 2017-12-20 2020-10-22 Klaria Pharma Holding Ab Film formulation comprising vardenafil, method for its preparation, and use thereof
JP7336241B2 (ja) * 2019-04-02 2023-08-31 富士化学工業株式会社 バルデナフィル含有錠剤の製造方法
CN114246835A (zh) * 2022-01-05 2022-03-29 河北龙海药业有限公司 一种枸橼酸西地那非口腔崩解片的制备方法
CN115737581B (zh) * 2022-12-13 2024-03-12 上海普康药业有限公司 一种盐酸伐地那非口崩片及其制备方法

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IL135462A0 (en) 1997-11-12 2001-05-20 Bayer Ag 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US6569461B1 (en) * 1999-03-08 2003-05-27 Merck & Co., Inc. Dihydroxy open-acid and salts of HMG-CoA reductase inhibitors
DE19944161A1 (de) * 1999-09-15 2001-03-22 Bayer Ag Neue Kombination zur Behandlung von sexueller Dysfunktion
DE10232113A1 (de) * 2002-07-16 2004-01-29 Bayer Ag Vardenafil Hydrochlorid Trihydrat enthaltende Arzneimittel
DE102004023069A1 (de) 2004-05-11 2005-12-08 Bayer Healthcare Ag Neue Darreichungsformen des PDE 5-Inhibitors Vardenafil
DE102005009241A1 (de) 2005-03-01 2006-09-07 Bayer Healthcare Ag Arzneiformen mit kontrollierter Bioverfügbarkeit
DE102005009240A1 (de) * 2005-03-01 2006-09-07 Bayer Healthcare Ag Arzneiformen mit verbesserten pharmakokinetischen Eigenschaften
PL1928427T3 (pl) * 2005-09-23 2010-06-30 Hoffmann La Roche Nowa postać dawkowana

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Also Published As

Publication number Publication date
CA2687500A1 (fr) 2008-12-18
US8772292B2 (en) 2014-07-08
US20100159003A1 (en) 2010-06-24
RU2010100819A (ru) 2011-07-20
WO2008151811A3 (fr) 2009-03-26
WO2008151811A2 (fr) 2008-12-18
RU2493849C2 (ru) 2013-09-27
DE102007027067A1 (de) 2008-12-18

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