WO2006032386A1 - Lyophilisat enthaltend n-diaminomethylen-2-methyl-4,5-di-(methylsulfonyl)-benzamid - Google Patents
Lyophilisat enthaltend n-diaminomethylen-2-methyl-4,5-di-(methylsulfonyl)-benzamid Download PDFInfo
- Publication number
- WO2006032386A1 WO2006032386A1 PCT/EP2005/009741 EP2005009741W WO2006032386A1 WO 2006032386 A1 WO2006032386 A1 WO 2006032386A1 EP 2005009741 W EP2005009741 W EP 2005009741W WO 2006032386 A1 WO2006032386 A1 WO 2006032386A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lyophilisate
- methyl
- benzamide
- diaminomethylene
- methylsulfonyl
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Definitions
- the present invention relates to a stable lyophilizate containing N-diaminomethylene-2-methyl-4,5-di (methylsulfonyl) benzamide as the active ingredient and to the preparation of the lyophilisate.
- N-diaminomethylene-2-methyl-4,5-di (methylsulfonyl) benzamide is a potent and selective inhibitor of the sodium proton exchanger (NHE-1) with cardioprotective activity
- the drug will initially be used for pre-, peri- and postoperative myocardial protection in operations of high-risk patients.
- the lyophilizates obtained by lyophilization should be reconstitutable by adding an aqueous solvent to a parenterally administrable drug solution so that it can be made available promptly and easily when needed.
- Extensive tests with the active ingredient alone and with various excipients / scaffold builders such as mannitol, glucose, sodium acetate, glycine, dextran, lactose, sucrose, calcium gluconate and urea gave physically and chemically unstable products, if the parameters of the invention were not taken into account. Regularly unstable, poorly reconstitutable product cakes were obtained, which also often on reconstitution led to solutions with particles.
- the solutions obtained from the lyophilizates contained decomposition products of diaminomethylene-2-methyl-4,5-di- (methylsulfonyl) benzamide, so that overall no stabilization of the active ingredient could be achieved.
- the preparation should contain no toxicologically questionable excipients, be stable under prolonged stress conditions, such as elevated temperature and humidity, stable for a long time and be reconstituted with an aqueous solvent to a parenterally administrable solution.
- a preparation corresponding to these requirements could be made available by freeze-drying an aqueous, optionally buffered solution which contains diaminomethyl-2-methyl-4,5-di- (methylsulfonyl) -benzamide and a scaffold-forming agent and which has a pH Value of 1 to 3.8.
- the present invention therefore provides a lyophilisate obtainable by freeze-drying an aqueous solution which contains at least N-diaminomethylene-2-methyl-4,5-dihydroxypropylamine.
- aqueous solution used for freeze drying has a pH of 2.5 to 3.5, particularly preferably a pH of about 3.
- the preparation of the invention is physiologically well tolerated, easy to prepare, precisely metered and stable over the duration of storage and also after multiple freezing and thawing processes in terms of content, decomposition products and aggregates. It can at refrigerator temperature (2-8 ° C) and at room temperature (23-27 0 C, 60% relative humidity (RH) over a period of 2 years can be stably stored.
- the present invention Preparing storable stable even at higher temperatures and humidities, for example, at a temperature of 4O 0 C and 75% RH over the period indicated.
- the lyophilisate can be easily prepared by adding an aqueous
- Solvent for example, water for injection or an isotonic aqueous solution to be reconstituted to an application-ready, particle-free solution.
- the reconstituted solution is stable for a period of about 7 days, but is more preferably applied within 24 hours.
- Diaminomethylene-2-methyl-4,5-di- (methylsulfonyl) -benzamide-containing solutions having a pH of from 1 to 3.8, preferably having a pH of can advantageously be prepared from the preparation according to the invention by reconstitution with aqueous solvents 2.5 to 3.5, more preferably having a pH of 3 and an osmolality of 50-500 m ⁇ smol / kg.
- the reconstituted preparation can then be administered largely painlessly intravenously, intraarterially and also subcutaneously directly.
- the preparation can also infusion solutions, such.
- Glucose solution, isotonic saline or Ringer's solution, which may also contain other active ingredients, are added, so that even larger amounts of active ingredient can be applied.
- the lyophilisate is preferably taken up in about 5% glucose solution, 0.9% sodium chloride solution or Ringer's lactate solution.
- a physiologically acceptable organic or inorganic acid for this purpose, suitable acids are, for example, citric acid, phosphoric acid, sulfuric acid, acetic acid,
- Formic acid and hydrochloric acid Preferably, the pH is adjusted with hydrochloric acid.
- the lyophilisate according to the invention may contain, as a scaffold-forming agent, sugar alcohols, sugar, urea, glutamic acid and / or the substance class of ectoines and hydroxyectoins, ie preferably substances which in the freeze-drying process are amorphous substances with a
- the lyophilisate contains as a scaffold sugar and / or sugar alcohol / e.
- Mono-, di- or trisaccharides can be used as sugars. These sugars can be used alone or in admixture with sugar alcohols. As examples may be mentioned as monosaccharides
- Glucose, mannose, galactose, fructose and sorbose as disaccharides sucrose, lactose, maltose or trehalose and as trisaccharide raffinose.
- Sugar alcohols which can be used according to the invention are, for example, mannitol and sorbitol.
- sucrose, lactose, maltose, trehalose mannitol and / or sorbitol particularly preferred are mannitol and / or lactose.
- scaffold formers are contained in the aqueous solution to be freeze-dried generally in a concentration of 0.01 to 0.20 mmol / L, preferably in a concentration of 0.03 to 0.12 mmol / L. After reconstitution with the intended volume of solvent, the scaffold former is present in the resulting solution in a concentration of 0.005 to 0.23 mmol / L.
- the skeleton former preferably lies in the reconstituted solution in a concentration of 0.03 to 0.12 mmol / L.
- the lyophilisate according to the invention may contain one or more buffers. Basically, all physiologically compatible substances which are suitable for setting the desired pH can be used as buffers.
- the amount of buffer substance is chosen so that after reconstitution of the lyophilisate, for example with water for injection, the resulting aqueous solution has a buffer concentration of 5 mmol / l to 50 mmol / l, preferably 10 to 20 mmol / l. Citrate buffers and / or phosphate buffers are preferred as buffers.
- suitable Phosphate buffers are solutions of the mono- and / or di-sodium and potassium salts of phosphoric acid, such as disodium hydrogen phosphate or potassium dihydrogen phosphate, and mixtures of the sodium and potassium salts, such as mixtures of disodium hydrogen phosphate and potassium dihydrogen phosphate.
- the lyophilizates according to the invention may contain further physiologically acceptable auxiliaries, such as Antioxidants such as ascorbic acid or glutathione, preservatives such as phenol, m-cresol, methyl or propylparaben, chlorobutanol, thiomersal or
- Benzalkonium chloride stabilizers, scaffolding agents, e.g. Sucrose, lactose, maltose, trehalose, mannitol and / or sorbitol, mannitol and / or lactose and solubilizers such as polyethylene glycols (PEG), e.g. PEG 3000, 3350, 4000 or 6000 or cyclodextrins, e.g. Hydroxypropyl- ⁇ -cyclodextrin, sulfobutylethyl- ⁇ -cyclodextrin or ⁇ -cyclodextrin or
- PEG polyethylene glycols
- PEG polyethylene glycols
- cyclodextrins e.g. Hydroxypropyl- ⁇ -cyclodextrin, sulfobutylethyl- ⁇ -cyclodextrin or ⁇ -cyclodextrin or
- the lyophilisate according to the invention contains one or more physiologically compatible excipients selected from the group consisting of antioxidants, preservatives and / or solubilizers.
- the preparation according to the invention can be prepared by preparing an aqueous preparation containing at least N-diaminomethylene-2-methyl-4,5-di- (methylsulfonyl) -benzamide and a scaffold-forming agent, optionally the resulting solution with an acid Adjust a pH of 1 to 3.8 and then lyophilized.
- the active and adjuvant / e-containing aqueous solution is sterile filtered before freeze-drying.
- the lyophilizate obtained can be reconstituted by adding an aqueous solvent to an aqueous preparation which can be applied directly, in particular parenterally.
- Subject of the present invention therefore also provides an aqueous pharmaceutical preparation of N-diaminomethylene-2-methyl-4,5-di- (methylsulfonyl) -benzamide obtainable by reconstitution of the lyophilisate according to the invention with an aqueous solvent.
- the reconstituted aqueous pharmaceutical preparation preferably has a pH of from 1 to 3.8, preferably a pH of from 2.5 to 3.5, particularly preferably a pH of about 3.
- the reconstitution can be carried out in 5 to 100 ml reconstitution agent, more preferably in 10 to 20 ml with e.g.
- the ingredients are dissolved in any order in water for injections.
- the resulting solution is adjusted to the desired pH with 1N hydrochloric acid, sterile filtered, filled under low-germ conditions in vials and provided with plugs.
- the vials stoppered be placed in the lyophilizer and frozen for 3 hours at -5o C 0.
- the frozen solutions are then subjected to a lyophilization process according to the following table:
- the vacuum is removed while simultaneously introducing nitrogen, the vials are closed by lowering the stopper, removed from the lyophilizer after its opening under low-germ conditions and crimped.
- Example 4 The preparation and reconstitution of the lyophilisate is carried out analogously to Example 1.
- Example 4 The preparation and reconstitution of the lyophilisate is carried out analogously to Example 1.
- the stability of the preparations according to the invention is tested in shelf life studies.
- the lyophilisates prepared are stored at different temperatures, outsourced at certain times and investigated by suitable analytical methods.
- climatic conditions 25 ° C and a relative humidity (RH) of 60% and 40 0 C can be selected with one of RH of 75%.
- RH relative humidity
- the latter condition is selected as a stress condition to quickly reach differences in stability in the various formulations.
- Possible instabilities manifest in N-diaminomethylene-2-methyl-4,5-di- (methylsulfonyl) benzamide mainly in the formation of degradation products.
- the prepared lyophilisates are assessed visually for the appearance of the lyophilisate cake.
- the reconstitution time is also examined.
- the prepared formulations are visually examined for particles with the aid of a cold light source and for the occurrence of a possible haze.
- the lyophilisates obtained according to Examples 1 and 2 are reconstituted by addition of 5 to 100 ml, more preferably 10 to 20 ml of water for injection or 5% glucose solution and with respect to their contents of N-diaminomethylene-2-methyl-4, 5-di (methylsulfonyl) benzamide and the resulting decomposition products.
- the results obtained are shown in Figures 1 to 3.
- Figure 1 shows the change in the proportions of N-diaminomethylene-2-methyl-4,5-di- (methylsulfonyl) benzamide normalized to 100% in the reconstituted solutions as a function of the storage time in the various climatic conditions (25 ° C / 60% RH and 40 ° C / 75% RH).
- Figure 2 shows the increase indicates the decomposition product hydrolytically formed 2-methyl-4,5-dimethylsulfonylbenzoeklare in the reconstituted solutions as a function of storage time at different environmental conditions (25 0 C / 60% RH and 40 0 C / 75% RH).
- Figure 3 shows the increase in the sum of unknown decomposition products in the reconstituted solutions as a function of the storage time in the different climatic conditions (25 0 C / 60% RH and 40 0 C / 75% RH).
- the number of unknown decomposition products on which the measurement points are based is given as a number.
- the reconstituted from the lyophilizate according to Example 1 solution compared to the reconstituted from the lyophilizate solution to a significantly higher chemical stability.
- the teaching according to the invention thus not only results in a surprisingly higher physical but also in a surprisingly higher chemical stability of the lyophilizate.
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Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007532800A JP2008513526A (ja) | 2004-09-22 | 2005-09-10 | N−ジアミノメチレン−2−メチル−4,5−ジ(メチルスルホニル)ベンズアミドを含む冷結乾燥物 |
EP05779438A EP1791528A1 (de) | 2004-09-22 | 2005-09-10 | Lyophilisat enthaltend n-diaminomethylen-2-methyl-4,5-di-(methylsulfonyl)-benzamid |
CA002581081A CA2581081A1 (en) | 2004-09-22 | 2005-09-10 | Lyophilisate containing n-diaminomethylene-2-methyl-4,5-di-(methylsulfonyl)-benzamide |
AU2005287591A AU2005287591A1 (en) | 2004-09-22 | 2005-09-10 | Lyophilisate containing N-diaminomethylene-2-methyl-4,5-di-(methylsulfonyl)-benzamide |
US11/575,741 US20070299139A1 (en) | 2004-09-22 | 2005-09-10 | Lyophilisate Comprising N-Diaminomethylene-2-Methyl-4,5-Di(Methylsulfonyl)Benzamide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004045825.1 | 2004-09-22 | ||
DE102004045825A DE102004045825A1 (de) | 2004-09-22 | 2004-09-22 | Lyophilisat enthaltend N-Diaminomethylen-2-methyl-4,5-di-(methylsulfonyl)-benzamid |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006032386A1 true WO2006032386A1 (de) | 2006-03-30 |
Family
ID=35432481
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/009741 WO2006032386A1 (de) | 2004-09-22 | 2005-09-10 | Lyophilisat enthaltend n-diaminomethylen-2-methyl-4,5-di-(methylsulfonyl)-benzamid |
Country Status (7)
Country | Link |
---|---|
US (1) | US20070299139A1 (de) |
EP (1) | EP1791528A1 (de) |
JP (1) | JP2008513526A (de) |
AU (1) | AU2005287591A1 (de) |
CA (1) | CA2581081A1 (de) |
DE (1) | DE102004045825A1 (de) |
WO (1) | WO2006032386A1 (de) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0758644A1 (de) * | 1995-08-11 | 1997-02-19 | MERCK PATENT GmbH | Sulfonyl- oder Sulfinyl-benzoyl-guanidin-Derivate |
WO2000044354A1 (de) * | 1999-01-28 | 2000-08-03 | Merck Patent Gmbh | Lyophilisate mit verbesserter rekonstituierbarkeit |
WO2002064166A1 (en) * | 2001-02-13 | 2002-08-22 | Korea Institute Of Science And Technology | Formulation to enhance bioavailability of bioactive matrials and preparation method thereof |
-
2004
- 2004-09-22 DE DE102004045825A patent/DE102004045825A1/de not_active Withdrawn
-
2005
- 2005-09-10 US US11/575,741 patent/US20070299139A1/en not_active Abandoned
- 2005-09-10 EP EP05779438A patent/EP1791528A1/de not_active Withdrawn
- 2005-09-10 AU AU2005287591A patent/AU2005287591A1/en not_active Abandoned
- 2005-09-10 WO PCT/EP2005/009741 patent/WO2006032386A1/de not_active Application Discontinuation
- 2005-09-10 CA CA002581081A patent/CA2581081A1/en not_active Abandoned
- 2005-09-10 JP JP2007532800A patent/JP2008513526A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0758644A1 (de) * | 1995-08-11 | 1997-02-19 | MERCK PATENT GmbH | Sulfonyl- oder Sulfinyl-benzoyl-guanidin-Derivate |
WO2000044354A1 (de) * | 1999-01-28 | 2000-08-03 | Merck Patent Gmbh | Lyophilisate mit verbesserter rekonstituierbarkeit |
WO2002064166A1 (en) * | 2001-02-13 | 2002-08-22 | Korea Institute Of Science And Technology | Formulation to enhance bioavailability of bioactive matrials and preparation method thereof |
Non-Patent Citations (2)
Title |
---|
BOOK OF ABSTRACTS, 215TH ACS NATIONAL MEETING, DALLAS, MARCH 29-APRIL 2 , I&EC-127 PUBLISHER: AMERICAN CHEMICAL SOCIETY, WASHINGTON, D. C. CODEN: 65QTAA, 1998 * |
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MILLER, D. ET AL: "Fundamental studies of novel cryoprotectants for pharmaceutical applications", XP002361306, retrieved from STN Database accession no. 1998:141008 * |
Also Published As
Publication number | Publication date |
---|---|
CA2581081A1 (en) | 2006-03-30 |
JP2008513526A (ja) | 2008-05-01 |
US20070299139A1 (en) | 2007-12-27 |
AU2005287591A1 (en) | 2006-03-30 |
EP1791528A1 (de) | 2007-06-06 |
DE102004045825A1 (de) | 2006-03-23 |
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