DE1034327B - Process for the production of stable preparations such as powder, tablets, coated tablets and the like. Like., With a content of guaiaculene sulfonic acid salts - Google Patents
Process for the production of stable preparations such as powder, tablets, coated tablets and the like. Like., With a content of guaiaculene sulfonic acid saltsInfo
- Publication number
- DE1034327B DE1034327B DEC15400A DEC0015400A DE1034327B DE 1034327 B DE1034327 B DE 1034327B DE C15400 A DEC15400 A DE C15400A DE C0015400 A DEC0015400 A DE C0015400A DE 1034327 B DE1034327 B DE 1034327B
- Authority
- DE
- Germany
- Prior art keywords
- salts
- guaiaculene
- tablets
- sulfonic acid
- powder
- 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.)
- Pending
Links
Classifications
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung stabiler Präparate, wie Puder, Tabletten, Dragees u. dgl., mit einem Gehalt an guajazulensulfosauren Salzen Guajazulensulfosäure wird nach Treibs (Ann. d. Chem. Process for the production of stable preparations such as powder, tablets, Dragees and the like containing guaiaculene sulfonic acid salts is according to Treibs (Ann. d. Chem.
586, 202, 1954) durch Sulfonieren von Guajazulen (1, 4-Dimethyl-7-isopropylazulen) mittels eines Schwefeltrioxyd Dioxan-Adduktes hergestellt und als Natriumsalz in fester Form isoliert. Das reine, trockene Sulfonat soll nach Treibs beständig sein, während die alkoholfeuchte Substanz sich schnell unter Rückbildung von Guajazulen und weiteren Produkten zersetzt. 586, 202, 1954) by sulfonating guaiazulene (1,4-dimethyl-7-isopropylazulene) produced by means of a sulfur trioxide-dioxane adduct and as the sodium salt in solid form isolated. The pure, dry sulphonate should be resistant according to the Treibs, while the alcohol-moist substance quickly undergoes regression of guaiaculene and other products decomposed.
Das von Treibs erstmalig beschriebene, in Wasser lösliche guajazulensulfosaure Natrium wurde bisher nicht in pharmazeutischen Präparaten verwendet. Bei der Herstellung fester Zubereitungen, wie Puder, Tabletten, Dragées u. dgl., stellte es sich heraus, daß die Haltbarkeit von guajazulensulfosaurem Natrium nach Einarbeitung in solche Arzneiformen nicht den Anforderungen genügt, die an ein Handelspräparat, insbesondere bezüglich der Stabilität des Wirkstoffes, zu stellen sind. The water-soluble guajazulensulfosaure, first described by Treibs Sodium has not previously been used in pharmaceutical preparations. In the preparation of solid preparations such as powder, tablets, dragees and the like, it turned out that that the shelf life of sodium guajazulensulfosaurem after incorporation into such Dosage forms do not meet the requirements that a commercial preparation, in particular regarding the stability of the active ingredient.
Nach den deutschen Patentschriften 876 309, 941 639 werden natürliche und synthetische Azulene in wäßrigen Lösungen und wasserlösliche Zubereitungen dadurch stabilisiert, daß neben Lösungsvermittlern schwefelhaltige Verbindungen, wie Methionin, Methioninamid, Thioharnstoff, 2, 3-Dithiopropanol od. dgl., zugesetzt werden. According to German patents 876 309, 941 639, natural and synthetic azulenes in aqueous solutions and water-soluble preparations thereby stabilizes that in addition to solubilizers, sulfur-containing compounds such as methionine, Methionine amide, thiourea, 2,3-dithiopropanol or the like. Be added.
Es wurde nun gefunden, daß im Gegensatz zu den obengenannten natürlichen und synthetischen Azulenen guajazulensulfosaures Natrium durch alleinigen Zusatz eines antioxydativ wirkenden Stoffes nicht stabilisiert werden kann. Ein sehr augenfälliger Effekt tritt jedoch überraschenderweise bei der Herstellung von Puder, Tabletten, Dragées u. dgl. unter Verwendung von guajazulensulfosauren Salzen ein, wenn die guajazulensulfosauren Salze gemeinsam mit antioxydativ bzw. reduzierend wirkenden Verbindungen zusammen mit schwach basischen Alkali-und/oder Erdalkalisalzen als Stabilisatoren verarbeitet werden. Zur Aromatisierung können solchen Zubereitungen geeignete Aromastoffe zugesetzt werden. It has now been found that in contrast to the above natural and synthetic azulenes sodium guajazulensulfosaures by sole addition an antioxidant substance cannot be stabilized. A very obvious one However, the effect surprisingly occurs in the production of powder, tablets, Dragées and the like using guaiaculene sulfonic acid salts if the Guajazulensulfosauren salts together with antioxidative or reducing effects Compounds together with weakly basic alkali and / or alkaline earth salts as Stabilizers are processed. Such preparations can be used for flavoring suitable flavorings can be added.
Als physiologisch verträgliche, antioxydativ wirkende Verbindungen können insbesondere an sich bekannte phenolische Antioxydantien, wie Gallussäureester, anorganische Reduktionsmittel und/oder Salze und Verbindungen der Ascorbinsäure, verwendet werden. Hierbei ist es zweckmäßig, daß die Menge der verwendeten antioxydativ wirkenden Verbindungen die jeweils verwendete Menge der guajazulensulfosauren Salze nicht überschreitet. Weiterhin ist es zweckmäßig, die schwach basischen Alkali-und/oder Erdalkalisalze in Mengen zu verwenden, die wenigstens dem Anteil der verwendeten guajazulensulfosauren Salze entsprechen. Vorzugsweise werden diese Alkali-und/oder Erdalkalisalze jedoch in mehrfachen Anteilen, bezogen auf die guajazulensulfosauren Salze, mitverarbeitet. As physiologically compatible, antioxidant compounds can in particular phenolic antioxidants known per se, such as gallic acid esters, inorganic reducing agents and / or salts and compounds of ascorbic acid, be used. It is useful here that the amount of antioxidant used active compounds, the amount of guaiaculene sulfonic acid salts used in each case does not exceed. It is also useful to use the weakly basic alkali and / or Alkaline earth salts to be used in amounts that are at least equal to the proportion of that used correspond to guajazulensulfosauren salts. These are preferably alkali and / or Alkaline earth salts, however, in multiple proportions, based on the guajazulensulfosauren Salts, processed as well.
Der stabilisierende Effekt verschiedener Substanzen geht aus Tabelle I hervor. Die darin enthaltenen Angaben wurden durch Auswertung zahlreicher Einzelversuche gewonnen. The stabilizing effect of various substances is shown in the table I emerged. The information contained therein was obtained through the evaluation of numerous individual experiments won.
Es wurden jeweils Tabletten zu 350 mg hergestellt, welche neben 2 mg guajazulensulfosaurem Natrium und üblichen Tablettengrundmassen die in der Tabelle angegebenen Zusätze enthielten. Die Tabletten wurden sodann bei Zimmertemperatur und bei 45° C in verschlossenen Glasgefäßen gelagert (bei der Stabilitätskontrolle pharmazeutischer Präparate entspricht eine 45°C-Lagerung erfahrungsgemäß etwa der fünffachen Lagerungszeit bei Zimmertemperatur). Die analytische Kontrolle des Gehaltes an unverändertem guajazulensulfosaurem Natrium erstreckte sich über einen Zeitraum von 4 bis 8 Monaten In Tabelle I wird angegeben a) die prozentuale Abnahme von guajazulensulfosaurem Natrium in Tabletten, welche bei Zimmertemperatur oder 45° C gelagert wurden, b) eine merkliche Bildung von Guajazulen als Zersetzungsprodukt von guajazulensulfosaurem Natrium bei 45° C-Lagerung. In each case, tablets of 350 mg were produced, which in addition to 2 mg sodium guajazulensulfosaurem and usual tablet base masses in the table specified additives contained. The tablets were then placed at room temperature and stored at 45 ° C in closed glass vessels (for stability control For pharmaceutical preparations, experience has shown that storage at 45 ° C corresponds approximately to this five times the storage time at room temperature). The analytical control of the content of unchanged sodium guaiaculene sulfate extended over a period of time from 4 to 8 months In Table I is given a) the percentage decrease in guaiaculene sulfosate Sodium in tablets that have been stored at room temperature or 45 ° C, b) a noticeable formation of guaiaculene as a decomposition product of guaiaculene sulfonic acid Sodium at 45 ° C storage.
Tabelle I
In Versuchsreihe 5 wurden Ansätze mit und ohne Guajazulenbildung beobachtet. In test series 5, approaches with and without guaiaculene formation were used observed.
Während durch die Antioxydantien allein praktisch keine Verbesserung der Haltbarkeit von guajazulensulfosaurem Natrium zu erzielen ist, läßt ein Zusatz von Natriumbicarbonat bereits einen deutlichen Effekt erkennen. While there was practically no improvement from the antioxidants alone the shelf life of sodium guaiaculene sulfate is to be achieved, leaves an additive already see a clear effect of sodium bicarbonate.
In Kombination mit Natriumbicarbonat bzw. Natriumbicarbonat und Magnesiumtrisilikat wird von den drei genannten Antioxydantien, welche jeweils verschiedenen Verbindungsklassen angehören, die Haltbarkeit des guajazulensulfosauren Natriums deutlich heraufgesetzt. In combination with sodium bicarbonate or sodium bicarbonate and magnesium trisilicate is made up of the three named antioxidants, which are each different classes of compounds belong, the shelf life of sodium guaiacolsulfonate is significantly increased.
Die Kombination aus Gallussäurepropylester und Natriumbicarbonat besitzt die stärkste stabilisierende Wirkung.The combination of propyl gallate and sodium bicarbonate possesses the strongest stabilizing effect.
Die nach der vorliegenden Erfindung hergestellten Produkte finden die gleiche arzneiliche Verwendung wie Azulenpräparate. Find the products made according to the present invention same medicinal use as azulene supplements.
Beispiel 20 g guajazulensulfosaures Natrium werden in einer Lösung von 7, 0g Gallussäurepropylester in 500 ccm Methanol gelöst. Etwa ein Drittel dieser Lösung wird mit iiblichen Tablettengrundstoffen zu einem Granulat verarbeitet, die restlichen zwei Drittel werden den gebräuch lichen Tablettenspreng-und-gleitmitteln hinzugefügt. Example 20 g of sodium guaiaculene sulfate are in a solution of 7.0 g of propyl gallate dissolved in 500 cc of methanol. About a third of this The solution is processed into granules with the usual tablet raw materials the remaining two thirds are the common tablet disintegrants and lubricants added.
Granulat und Pulversubstanzen werden getrocknet. Nach gründlichem Durchmischen mit 200, 0 g Natriumbicarbonat wird die auf ein Gesamtgewicht von 3, 5 kg gebrachte Masse zu 10 000 Tabletten mit je 350mg Gewicht gepreßt.Granules and powder substances are dried. After thorough Mixing with 200.0 g of sodium bicarbonate is added to a total weight of 3, 5 kg of mass pressed into 10,000 tablets, each weighing 350 mg.
Falls eine Aromatisierung erwünscht ist, wird das Aromatikum entweder der alkoholischen Wirkstofflösung zugesetzt oder mit einem Teil der Pulvermischung angerieben und in der Gesamtmasse gleichmäßig verteilt. If flavoring is desired, the aromatic will be either added to the alcoholic active ingredient solution or with part of the powder mixture rubbed and distributed evenly in the total mixture.
Claims (5)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEC15400A DE1034327B (en) | 1957-08-30 | 1957-08-30 | Process for the production of stable preparations such as powder, tablets, coated tablets and the like. Like., With a content of guaiaculene sulfonic acid salts |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEC15400A DE1034327B (en) | 1957-08-30 | 1957-08-30 | Process for the production of stable preparations such as powder, tablets, coated tablets and the like. Like., With a content of guaiaculene sulfonic acid salts |
Publications (1)
Publication Number | Publication Date |
---|---|
DE1034327B true DE1034327B (en) | 1958-07-17 |
Family
ID=7015831
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DEC15400A Pending DE1034327B (en) | 1957-08-30 | 1957-08-30 | Process for the production of stable preparations such as powder, tablets, coated tablets and the like. Like., With a content of guaiaculene sulfonic acid salts |
Country Status (1)
Country | Link |
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DE (1) | DE1034327B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0088382A1 (en) * | 1982-03-09 | 1983-09-14 | Nippon Shinyaku Company, Limited | Stabilization of azulene derivatives |
EP0088958A1 (en) * | 1982-03-09 | 1983-09-21 | Nippon Shinyaku Company, Limited | Stabilization of azulene derivatives |
US5433959A (en) * | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US6749864B2 (en) | 1986-02-13 | 2004-06-15 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
CN102114010A (en) * | 2010-03-24 | 2011-07-06 | 四川国康药业有限公司 | Medicinal composition for treating gastrointestinal disorders as well as preparation method and application thereof |
-
1957
- 1957-08-30 DE DEC15400A patent/DE1034327B/en active Pending
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0088382A1 (en) * | 1982-03-09 | 1983-09-14 | Nippon Shinyaku Company, Limited | Stabilization of azulene derivatives |
EP0088958A1 (en) * | 1982-03-09 | 1983-09-21 | Nippon Shinyaku Company, Limited | Stabilization of azulene derivatives |
US4533552A (en) * | 1982-03-09 | 1985-08-06 | Nippon Shinyaku Co., Ltd. | Stabilization of azulene derivatives |
US5433959A (en) * | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US5639478A (en) * | 1986-02-13 | 1997-06-17 | Takeda Chemical Industries, Ltd. | Method to stabilize a pharmaceutical composition and its production |
US5879708A (en) * | 1986-02-13 | 1999-03-09 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US6017560A (en) * | 1986-02-13 | 2000-01-25 | Takeda Chemical Industries, Ltd. | Process for producing stabilized pharmaceutical composition |
US6123962A (en) * | 1986-02-13 | 2000-09-26 | Takeda Chemical Industries, Inc. | Process for producing stabilized pharmaceutical composition |
US6296875B1 (en) | 1986-02-13 | 2001-10-02 | Takeda Chemical Industries, Ltd. | Method for producing a granule |
US6380234B1 (en) | 1986-02-13 | 2002-04-30 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition and its production |
US6521256B2 (en) | 1986-02-13 | 2003-02-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US6749864B2 (en) | 1986-02-13 | 2004-06-15 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
CN102114010A (en) * | 2010-03-24 | 2011-07-06 | 四川国康药业有限公司 | Medicinal composition for treating gastrointestinal disorders as well as preparation method and application thereof |
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