DE3241765A1 - Stable compositions for injection, containing hydrochlorothiazide - Google Patents
Stable compositions for injection, containing hydrochlorothiazideInfo
- Publication number
- DE3241765A1 DE3241765A1 DE19823241765 DE3241765A DE3241765A1 DE 3241765 A1 DE3241765 A1 DE 3241765A1 DE 19823241765 DE19823241765 DE 19823241765 DE 3241765 A DE3241765 A DE 3241765A DE 3241765 A1 DE3241765 A1 DE 3241765A1
- Authority
- DE
- Germany
- Prior art keywords
- hydrochlorothiazide
- freeze
- stable
- preparations
- potassium canrenoate
- 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- Withdrawn
Links
- JZUFKLXOESDKRF-UHFFFAOYSA-N Dichlothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960002003 hydrochlorothiazide Drugs 0.000 title claims abstract description 24
- 239000007924 injection Substances 0.000 title claims abstract description 16
- 239000000203 mixture Substances 0.000 title claims abstract description 9
- 238000002347 injection Methods 0.000 title claims description 9
- 239000000243 solution Substances 0.000 claims abstract description 23
- JTZQCHFUGHIPDF-RYVBEKKQSA-M Potassium canrenoate Chemical compound [K+].O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)CCC([O-])=O)[C@@H]4[C@@H]3C=CC2=C1 JTZQCHFUGHIPDF-RYVBEKKQSA-M 0.000 claims abstract description 13
- 229960000206 potassium canrenoate Drugs 0.000 claims abstract description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000908 ammonium hydroxide Substances 0.000 claims abstract description 10
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 239000004471 Glycine Substances 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 abstract description 7
- 238000004090 dissolution Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IHJCXVZDYSXXFT-UHFFFAOYSA-N chloraminophenamide Chemical compound NC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O IHJCXVZDYSXXFT-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-Butylamine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N Propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 230000000894 saliuretic Effects 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000002110 toxicologic Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
Abstract
Description
Die vorliegende Erfindung betrifft stabile ZubereitungenThe present invention relates to stable preparations
für Injektionszwecke, welche Hydrochlorothiazid und zusätzlich Kaliumcanrenoat enthalten, sowie ein Verfahren zur Herstellung derselben. Weiterhin betrifft die Erfindung die Verwendung dieser Zubereitungen für die Herstellung von spritzfertigen injizierbaren Lösungen.for injections, which contains hydrochlorothiazide and additionally potassium canrenoate included, and a method for making the same. Furthermore, the Invention the use of these preparations for the production of ready-to-use injectable solutions.
Hydrochlorothiazid ist ein bekanntes und bewährtes Saluretikum; vgl. The Merck Index 9.Auflage, Seite 628, Nr. 4668.Hydrochlorothiazide is a well-known and proven saluretic; see. The Merck Index 9th Edition, page 628, item 4668.
l Hydrochlorothiazid ist bisher jedoch nicht in Form von stabilen Injektionslösungen auf den Markt gekommen, da es einerseits in Wasser sehr schwer löslich ist und andererseits sowohl durch Säuren wie durch Alkalien unter Bildung von 4-Amino-6-chlorbenzol-1,3-disulfonamid zersetzt wird. l Hydrochlorothiazide is so far not in the form of stable Injection solutions come onto the market because it is very difficult to put in water is soluble and on the other hand both acids and alkalis with formation is decomposed by 4-amino-6-chlorobenzene-1,3-disulfonamide.
Es wird deshalb beispielsweise von der USP XX und der BP 80 gefordert, daß Hydrochlorothiazid-Tabletten auf das oben erwähnte Zersetzungsprodukt untersucht werden. Auch das Zentral laboratorium der Deutschen Apotheker überprüft den Gehalt an diesem Zersetzungsprodukt; vgl. D. Steinbach und H. Möller, Pharmazeut.Zeitg. 123 (1978), S. 123.It is therefore required by USP XX and BP 80, for example, that examined hydrochlorothiazide tablets for the above-mentioned decomposition product will. The central laboratory of the German pharmacists also checks the salary on this decomposition product; see D. Steinbach and H. Möller, Pharmazeut.Zeitg. 123 (1978), p. 123.
Eigene Untersuchungen der Anmelderin haben ergeben, daß der zulässige Höchstwert von 1,0% 4-Amino-6-chlorbenzol-1,3-disulfonamid in wäßrigen Natrium-oder Kaliumhydroxidlösungen bereits innerhalb von 24 Stunden bei Raumtemperatur überschritten wird. Versuche, derartige Lösungen gefrierzutrocknen,führten zu dem Ergebnis, daß die so erhaltenen Produkte bereits unmittelbar nach der Herstellung etwa 0,5% Zersetzungsprodukt aufweisen. Im Laufe der Lagerung bei Raumtemperatur steigen die Werte kontinuierlich an. Sie überschreiten nach kurzer Lagerzeit bereits die zulässige Grenze von 1%.The applicant's own investigations have shown that the permissible Maximum value of 1.0% 4-amino-6-chlorobenzene-1,3-disulfonamide in aqueous sodium or Potassium hydroxide solutions exceeded within 24 hours at room temperature will. Attempts to freeze-dry such solutions have led to the result that the products obtained in this way already have about 0.5% decomposition product immediately after manufacture exhibit. The values increase continuously during storage at room temperature at. After a short storage period, they already exceed the permissible limit of 1%.
Die Erfindung hat sich die Aufgabe gestellt, trotz-dieser bekannten Instabilität, stabile, rasch lösliche Zubereitungen für Injektionszwecke enthaltend Hydrochlorothiazid zu entwickeln. Ggf. sollen diese Zubereitungen zusätzlich Kaliumcanrenoat enthalten.The invention has set itself the task, in spite of these known ones Instability, containing stable, rapidly dissolving preparations for injection purposes Hydrochlorothiazide to develop. If necessary, these preparations should additionally contain potassium canrenoate.
Es wurde gefunden, daß überraschenderweise Hydrochlorothiazid gefriergetrocknet werden kann und dabei stabile, rasch lösliche Zubereitungen für Injektionszwecke ergibt, wenn man das Hydrochlorothiazid in wäßriger Ammoniumhydroxidlösung oder der wäßrigen Lösung eines leicht flüchtigen Amins auflöst, sterilfiltriert und danach in üblicher Weise gefriertrocknet. Es wurde weiter gefunden, daß diese Zubereitungen ggf. auch zusätzlich Kaliumcanrenoat enthalten können, ohne daß hierdurch die Stabilität negativ beeinflußt wird.It has been found that, surprisingly, hydrochlorothiazide is freeze-dried and thereby stable, rapidly soluble preparations for injection purposes results when the hydrochlorothiazide in aqueous ammonium hydroxide solution or the aqueous solution of a volatile amine dissolves, sterile-filtered and then freeze-dried in the usual way. It was further found that these preparations may optionally also contain potassium canrenoate without impairing the stability is negatively affected.
Gegenstand der vorliegenden Erfindung sind somit stabile, rasch lösliche, gefriergetrocknete Zubereitungen für Injektionszwecke enthaltend Hydrochlorothiazid und ggf.The present invention thus relates to stable, rapidly soluble, Freeze-dried preparations for injection purposes containing hydrochlorothiazide and possibly
zusätzlich Kaliumcanrenoat.additionally potassium canrenoate.
Das Verfahren zur Herstellung dieser Zubereitungen ist dadurch gekennzeichnet, daß man Hydrochlorothiazid und ggf.The process for the production of these preparations is characterized by that one hydrochlorothiazide and possibly
Kaliumcanrenoat in wäßriger Ammoniumhydroxidlösung oder der wäßrigen Lösung eines leicht flüchtigen Amins auflöst, sterilfiltriert und in üblicher Weise gefriertrocknet.Potassium canrenoate in aqueous ammonium hydroxide solution or the aqueous Solution of a volatile amine dissolves, sterile-filtered and in the usual way freeze dried.
I Diese Zubereitungen können zur Herstellung von spritzfertigen injizierbaren Lösungen verwendet werden durch Wieder-i auflösen mit Hilfe eines sterilen, physiologisch verträglichen Lösungsmittels zu einem pH-Wert von 9-11 bei geringer Pufferkapazität. Vorzugsweise wird hierfür ein KOH-Glycin-Puffergemisch vom pH-Wert von ca. 10 verwendet. I These preparations can be used to make ready-to-use injectables Solutions are used by re-i-dissolve with the help of a sterile, physiological compatible solvent to a pH value of 9-11 with low buffer capacity. A KOH-glycine buffer mixture with a pH of approx. 10 is preferably used for this.
Untersuchungen der Haltbarkeit des Lyophilisats haben ergeben, daß »loch nach mehreren Monaten Lagerung bei 8"C, 20"C und 35"C die Werte für 4-Amino-6-ehlorbenzol-1,3-disulfonamid deutlich unter 1% liegen.Studies of the shelf life of the lyophilizate have shown that »After several months of storage at 8" C, 20 "C and 35" C, I found the values for 4-amino-6-chlorobenzene-1,3-disulfonamide are well below 1%.
Zur Durchführung des erfindungsgemäßen Verfahrens wird Hydrochlorothiazid alleine oder ggf. zusammen mit Kaliumcanrenoat in wäßriger Ammoniumhydroxidlösung aufgelöst.Hydrochlorothiazide is used to carry out the process according to the invention alone or possibly together with potassium canrenoate in aqueous ammonium hydroxide solution dissolved.
Die Konzentration der Ammoniumhydroxidlösung ist nicht kritisch. Man kann daher Konzentrationen von 2-25% ein setzen. Niedrigere Konzentrationen führen zu unnötigen Kosten bei der anschließenden Gefriertrocknung.The concentration of the ammonium hydroxide solution is not critical. Man can therefore use concentrations of 2-25%. Lower concentrations result at unnecessary costs in the subsequent freeze-drying.
Konzentriertere Lösungen als 25%-ige sind schwer zu handhaben, daher auch weniger bevorzugt. Anstelle wäßriger Ammoniumhydroxidlösung können auch leicht wäßrige Lösungen leicht flüchtiger Amine verwendet werden, insbesondere kommen Methylamine und Ethylamine in Frage.Solutions more concentrated than 25% are difficult to handle, therefore also less preferred. Instead of aqueous ammonium hydroxide solution can also easily Aqueous solutions of volatile amines can be used, methylamines in particular and ethylamine in question.
Andere niedermolekulare Amine, wie Propylamin und Butylamin lassen sich aufgrund ihres höheren Siedepunktes schwieriger vollständig entfernen. Aus toxikologischen Gründen ist aber eine vollständige Entfernung dieser Amine auf weniger als 10 ppm erforderlich. Da Ammoniumhydroxid leicht und vollständig entfernt werden kann und auch aus den Abgasen der Gefriertrocknungsanlage leicht und preiswert entfernbar ist, wird es bevorzugt eingesetzt.Let other low molecular weight amines, such as propylamine and butylamine more difficult to remove completely due to their higher boiling point. the end For toxicological reasons, however, a complete removal of these amines is less than 10 ppm required. Because ammonium hydroxide can be easily and completely removed can and can also be easily and inexpensively removed from the exhaust gases of the freeze-drying system it is preferred.
Die erfindungsgemäßen stabilen, rasch löslichen und gefriergetrockneten Zubereitungen lassen sich durch Wiederauflösen zur Herstellung von spritzfertigen injizierbaren Lösungen verwenden. Die Wiederauf lösung erfolgt erfindungsgemäß mit Hilfe eines sterilen, physiologisch verträglichen Lösungsmittels zu einem pH-Wert von 9-11 bei geringer Pufferkapazität. Insbesondere hat sich die Wiederauflösung in einem KOH-Glycin-Puffergemisch vom pH-Wert von ca. 10 bewährt.The stable, rapidly soluble and freeze-dried according to the invention Preparations can be made ready for injection by re-dissolving for the production of use injectable solutions. The re-resolution takes place according to the invention with Help a sterile, physiologically compatible solvent to a pH value from 9-11 with low buffer capacity. In particular, the re-dissolution has Proven in a KOH-glycine buffer mixture with a pH of approx. 10.
Die erfindungsgemäßen Zubereitungen, das Verfahren zu ihrer Herstellung und ihrer Verwendung sind in den nachfolgenden Beispielen näher erläutert.The preparations according to the invention, the process for their production and their use are explained in more detail in the following examples.
Beispiel 1 60 g Hydrochlorothiazid werden in0,5 1 Wasser (für Injektionszwecke) mit 250 ml Ammoniumhydroxidlösung 25%-ig gelöst. Nach Auffüllen auf 1,01 mit Wasser wird sterilfiltriert, unter aseptischen Bedingungen in Mengen zu je 1 mol' in Lyophilisierflaschen abgefüllt und in bekannter Weise gefriergetrocknet. Die Wiederauflösung zu einer spritzfertigen Lösung erfolgt mit einem KOH-Glycin-Puffergemisch vom pH-Wert ca. 10. Example 1 60 g of hydrochlorothiazide are dissolved in 0.5 l of water (for injection purposes) dissolved with 250 ml of 25% ammonium hydroxide solution. After making up to 1.01 with water is sterile-filtered, under aseptic conditions in quantities of 1 mol 'each in lyophilization bottles bottled and freeze-dried in a known manner. The re-dissolution to one The ready-to-use solution is made with a KOH-glycine buffer mixture with a pH of approx. 10.
Beispiel 2 f 60 g Hydrochlorothiazid werden in 0,5 1 Wasser (für Injektionszwecke) mit 50 ml Diethylamin gelöst, auf 1 1 mit Wasser aufgefüllt, sterilfiltriert, unter aseptischen Bedingungen in Mengen zu je 1 ml in Lyophilisierflaschen abgefüllt und gefriertgetrocknet.Example 2 f 60 g of hydrochlorothiazide are dissolved in 0.5 1 of water (for injection purposes) dissolved with 50 ml of diethylamine, made up to 1 l with water, sterile-filtered, under aseptic conditions in quantities of 1 ml each in lyophilization bottles and freeze dried.
B e i s P i el 3 In analoger Weise wie in Beispiel 1 beschrieben werden 60g Hydrochlorothiazid in 0,5 1 Wasser für Injektionszwecke und 300 ml einer 30%-igen Methylaminlösung aufgelöst und weiterverarbeitet. EXAMPLE 3 In a manner analogous to that described in Example 1 60g of hydrochlorothiazide in 0.5 1 of water for injections and 300 ml of a 30% methylamine solution dissolved and processed further.
Beispiel 4 l 60 g Hydrochlorothiazid und 200 g Kaliumcanrenoat werden in 0,5 1 Wasser (für Injektionszwecke) mit 180 ml 25%-iger Ammoniumhydroxid Lösung gelöst und auf 1 1 aufgefüllt. Example 4 becomes 60 g of hydrochlorothiazide and 200 g of potassium canrenoate in 0.5 l of water (for injections) with 180 ml of 25% ammonium hydroxide solution solved and filled to 1 1.
In analoger Weise wie in Beispiel 1 wird sterilfiltriert, unter aseptischen Bedingungen in Mengen zu je 1 ml in Lyophilisierflaschen abgefüllt und in bekannter Weise gefriergetrocknet. Die Wiederauflösung zu einer spritzfertigen Lösung erfolgt mit 5 ml Wasser oder mit 5 ml KOH-Glycin-Puffergemisch vom pH-Wert von 10,0; die spritzfertige Lösung hat einen pH-Wert von 9-11.In a manner analogous to Example 1, sterile filtration is carried out under aseptic conditions Conditions in quantities of 1 ml each filled into lyophilization bottles and in known Way freeze-dried. The redissolution to a ready-to-use solution takes place with 5 ml of water or with 5 ml KOH-glycine buffer mixture from pH of 10.0; the ready-to-use solution has a pH value of 9-11.
Beispiel 5 In analoger Weise wie in Beispiel 4 beschrieben werden 60 g Hydrochlorothiazid und 200 g Kaliumcanrenoat in 0,5 1 Wasser und 50 ml Diethylamin gelöst, auf l mit Wasser-aufgefüllt und gefriergetrocknet. Analoge Ergebnisse werden erhalten, wenn zum Lösen 300 ml einer 30%-igen Methylaminlösung verwendet werden. Example 5 Described in a manner analogous to that in Example 4 60 g hydrochlorothiazide and 200 g potassium canrenoate in 0.5 1 water and 50 ml diethylamine dissolved, made up to 1 liter with water and freeze-dried. Analogous results will be obtained when 300 ml of a 30% methylamine solution are used to dissolve.
Die Zubereitungen sämtlicher Beispiele wurden unmittelbar nach der Herstellung, sowie nach mehrmonatiger Lagerung bei Temperaturen von 80C, Raumtemperatur und 350C untersucht. Alle Analysenwerte für das Zersetzungsprodukt lagen deutlich unter 1,0%.The preparations of all examples were immediately after Production, as well as after several months of storage at temperatures of 80C, room temperature and 350C examined. All analysis values for the decomposition product were clear below 1.0%.
Verglei chsversuch Hydrochlorothiazid wurde mit Natriumhydroxid-und Kaliumhydroxidlösungen gelöst, wobei sowohl bei einem überschuß von Lauge wie einem Unterschuß und abfiltrieren des ungelösten Hydrochlorothiazid nach dem Sterilfiltrieren, Abfüllen und Gefriertrocknen Produkte entstanden, die bereits; innerhalb von 24 Stunden bei Raumtemperatur den Grenzwert von 1,0% 4-Amino-6-chlorbenzol-1,3-disulfonamid überschritten. Comparative experiment Hydrochlorothiazide was made with sodium hydroxide and Potassium hydroxide solutions dissolved, both with an excess of alkali as one Deficiency and filtering off the undissolved hydrochlorothiazide after sterile filtering, Bottling and freeze-drying products emerged that already existed; within 24 Hours at room temperature exceeded the limit of 1.0% 4-amino-6-chlorobenzene-1,3-disulfonamide exceeded.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823241765 DE3241765A1 (en) | 1982-11-11 | 1982-11-11 | Stable compositions for injection, containing hydrochlorothiazide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823241765 DE3241765A1 (en) | 1982-11-11 | 1982-11-11 | Stable compositions for injection, containing hydrochlorothiazide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3241765A1 true DE3241765A1 (en) | 1984-05-17 |
Family
ID=6177906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19823241765 Withdrawn DE3241765A1 (en) | 1982-11-11 | 1982-11-11 | Stable compositions for injection, containing hydrochlorothiazide |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3241765A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0253226A1 (en) * | 1986-07-12 | 1988-01-20 | Roche Diagnostics GmbH | Aqueous alcaline injectable solution of torasemid ready for use and process for preparation thereof |
| EP0691814A1 (en) * | 1993-04-02 | 1996-01-17 | The Regents Of The University Of California | Method and composition for treatment of osteoporosis |
| US5932252A (en) * | 1988-10-21 | 1999-08-03 | The Regents Of The University Of California | Method and composition for treatment of osteoporosis |
| WO2006064281A1 (en) * | 2004-12-17 | 2006-06-22 | Jin Jun Zhang | A treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| CN100372534C (en) * | 2006-04-20 | 2008-03-05 | 南京海辰药业有限公司 | Torasemide freeze-drying preparation and prepn. method |
| US7985405B2 (en) | 2002-09-17 | 2011-07-26 | Jin Jun Zhang | Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
-
1982
- 1982-11-11 DE DE19823241765 patent/DE3241765A1/en not_active Withdrawn
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0253226A1 (en) * | 1986-07-12 | 1988-01-20 | Roche Diagnostics GmbH | Aqueous alcaline injectable solution of torasemid ready for use and process for preparation thereof |
| US4861786A (en) * | 1986-07-12 | 1989-08-29 | Boehringer Mannheim Gmbh | Composition for a stable vein compatible injectable solution of torasemide process for the preparation and method of use |
| US5932252A (en) * | 1988-10-21 | 1999-08-03 | The Regents Of The University Of California | Method and composition for treatment of osteoporosis |
| EP0691814A1 (en) * | 1993-04-02 | 1996-01-17 | The Regents Of The University Of California | Method and composition for treatment of osteoporosis |
| EP0691814A4 (en) * | 1993-04-02 | 1998-09-23 | Univ California | Method and composition for treatment of osteoporosis |
| US7875270B2 (en) | 2002-09-17 | 2011-01-25 | Abbott Medical Optics Inc. | Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| US7985405B2 (en) | 2002-09-17 | 2011-07-26 | Jin Jun Zhang | Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| US8114432B2 (en) | 2002-09-17 | 2012-02-14 | Jin Jun Zhang | Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| JP2008524194A (en) * | 2004-12-17 | 2008-07-10 | ジン ジュン ザン， | Treatment solution and method for preventing posterior capsule opacity by selectively inducing detachment and / or death of lens epithelial cells |
| AU2005315335B2 (en) * | 2004-12-17 | 2009-06-04 | Jin Jun Zhang | A treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| WO2006064281A1 (en) * | 2004-12-17 | 2006-06-22 | Jin Jun Zhang | A treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| CN101146516B (en) * | 2004-12-17 | 2011-04-13 | 张进军 | Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| JP4906737B2 (en) * | 2004-12-17 | 2012-03-28 | ジン ジュン ザン， | Treatment solution and method for preventing posterior capsule opacity by selectively inducing detachment and / or death of lens epithelial cells |
| EP2269576A3 (en) * | 2004-12-17 | 2012-04-04 | Jin Jun Zhang | A Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells |
| CN100372534C (en) * | 2006-04-20 | 2008-03-05 | 南京海辰药业有限公司 | Torasemide freeze-drying preparation and prepn. method |
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