WO1995028919A1 - MEDICAMENT CONTAINING p-OXYBENZOIC ACID DERIVATIVE AND FIBRATE - Google Patents
MEDICAMENT CONTAINING p-OXYBENZOIC ACID DERIVATIVE AND FIBRATE Download PDFInfo
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- WO1995028919A1 WO1995028919A1 PCT/EP1995/001565 EP9501565W WO9528919A1 WO 1995028919 A1 WO1995028919 A1 WO 1995028919A1 EP 9501565 W EP9501565 W EP 9501565W WO 9528919 A1 WO9528919 A1 WO 9528919A1
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- the invention relates to preparations for the therapy of combined hyperlipidemia and in particular combination preparations containing a p-oxybenzoic acid derivative, such as lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol). and a fibrate.
- a p-oxybenzoic acid derivative such as lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol).
- Atherosclerosis and heart attacks are among the leading causes of death.
- the main risk factors here are high concentrations of serum cholesterol, high concentrations of LDL cholesterol (low density lipoprotein cholesterol), high concentrations of LP.a) (lipoprotein (a)), and low concentrations of HDL cholesterol (high density lipoprotein cholesterol) ), high concentrations of triglycerides in the serum, increased concentrations of fibrinogen in the serum as well as increased blood pressure and smoking.
- HMG-CoA reductase inhibitors such as lovastatin, pravastatin, simvastatin and other statins, reduce the concentrations of total cholesterol and LDL cholesterol in the serum, but they only reduce the concentration of triglycerides in the serum to a small extent (cf. H. Vanhanen and TA Wunschn, Euro. J. Clin. Pharmacol., Vol. 42 (1992), pp. 127-130).
- Substances from the class of fibrates primarily reduce the triglycerides and increase the HDL concentration, but have only a minor influence on the serum cholesterol (cf. P. Zimetbaum et al., J. Clin. Pharmacol. , Vol. 31 (1991), pp. 25-37).
- the concentration of LP (a) remains unaffected by both classes of substances.
- Certain p-oxybenzoic acid derivatives are known from EP-A-0 133 935 as lipid-lowering agents.
- An example of these compounds is Lifibrol, which primarily lowers LDL cholesterol, triglycerides and LP (a) (P. Schwandt, 62nd EAS Congress, Jerusalem, September 5-9, 1993).
- the present invention is intended to provide a means that, if possible
- Another object is to provide a method for producing a drug with the above-mentioned properties.
- a medicament is provided according to the invention which is a combination of a p-oxybenzoic acid derivative of the general formula
- X -CH (OH) -,.-C0-
- R 2 -OH, -NHCH 2 COOH, or a physiologically tolerable salt thereof and a fibrate and conventional carriers, auxiliaries and / or additives.
- R 1 preferably has the meaning -CH (CH 3 ) 2 , -C (CH 3 ) 3 , or -C (CH 3 ) 2 CH 2 OH or -C (CH 3 ) 2 -COOH.
- the p-oxybenzoic acid derivative is lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol).
- p-Oxybenzoic acid derivatives such as Lifibrol
- Lifibrol have a complex mechanism of action that has not been fully elucidated.
- the effect of such expresses itself Substances in an inhibition of cholesterol biosynthesis and an inhibition of cholesterol absorption.
- fibrates are understood to mean all substances belonging to the group of substances having a hypotriglyceridemic effect. Without being bound by theory, it is believed that fibrates increase the activity of lipoprotein lipase and therefore, above all, reduce triglycerides. A reduction in LDL cholesterol has also been observed in some fibrates.
- the fibrate is preferably selected from bezafibrate, clofibrate, ciprofibrate, gemfibrozil and fenofibrate.
- the combined therapy with substances from the series of fibrates (these are all substances belonging to the group of hypotriglyceridemic substances, such as bezafibrate, clofibrate, ciprofibrate, gemfibrozil, fenofibrate etc.) and substances from the class of p-oxybenzoic urederivate, such as Lifibrol, as well as Lifibrol metabolites, result in a completely new activity profile for the treatment of the multifactorial disease of arteriosclerosis.
- substances from the series of fibrates (these are all substances belonging to the group of hypotriglyceridemic substances, such as bezafibrate, clofibrate, ciprofibrate, gemfibrozil, fenofibrate etc.) and substances from the class of p-oxybenzoic urederivate, such as Lifibrol, as well as Lifibrol metabolites, result in a completely new activity profile for the treatment of the multifactorial disease of arteriosclerosis.
- the exact dosage of the active ingredients depends on the age, body weight and condition of the patient. In particular, it depends on the desired degree of reduction in the concentration of LDL cholesterol in the serum. Accordingly, the dosage can be set individually for a patient by the doctor.
- the range of doses for the Lifibrol derived from the clinical studies is between 100 and 400 mg per day.
- the application range of the fibrates is the recommended base dose.
- the preparations according to the invention can be administered in any manner for therapeutic use as a medicament in the case of combined hyperlipidemia; however, they are preferably administered orally. Administration can be in one or more divided doses per day. Both active ingredients can be combined in one preparation or administered in separate preparations. A capsule or tablet is preferred as the galenic form. For this, the active ingredients' with conventional carriers, adjuvants and / or additives can be mixed. Common excipients such as lactose, sucrose, man are suitable as pharmaceutical carriers. ., Potato or corn starch, cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate, and polyethylene glycols.
- Preferred forms of administration are push-fit capsules made of hard gelatin and closed soft gelatin capsules.
- the pure active ingredient possibly with a small addition of lubricants, may be present in push-fit capsules.
- processing into granules is possible, potato or corn starch, microcrystalline cellulose, cellulose derivatives, gelatin or highly disperse silicas also being used as auxiliaries.
- the pure active ingredient When packaged in soft gelatin capsules, the pure active ingredient is dissolved or suspended in suitable liquids, e.g. in liquid polyethylene glycols or vegetable oils.
- R 1 H or a straight-chain or branched Cl-C4-alkyl group, in particular -CH (CH3) 2 and -C (CH3) 3, or -C (CH 3 ) 2CH 2 OH, or -C (CH 3 ) 2 - COOH.
- n 1, 2
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Abstract
Description
ARZNEIMITTEL ENTHALTEND P-OXYBENZOESAEUREDERIVAT UND FIBRATMEDICINAL PRODUCTS CONTAINING P-OXYBENZOESAE DERIVATIVE AND FIBRATE
Die Erfindung betrifft Präparate zur Therapie der kombinierten Hyperlipidämie und insbesondere Kombinationspräparate mit einem Gehalt an einem p- Oxybenzoesäurederivat, wie Lifibrol (4- (4' -tert.- Butylphenyl) -1- (4' -carboxyphenoxy) -2-butanol) . und einem Fibrat.The invention relates to preparations for the therapy of combined hyperlipidemia and in particular combination preparations containing a p-oxybenzoic acid derivative, such as lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol). and a fibrate.
Arteriosklerose und Herzinfarkte gehören zu den häufigsten Todesursachen. Die wesentlichen Risikofaktoren sind hierbei hohe Konzentrationen an Serumcholesterin, hohe Konzentrationen an LDL-Cholesterin (Low Density Lipoprotein- Cholesterin) , hohe Konzentrationen an LP.a) (Lipoprotein(a) ) , niedrige Konzentrationen an HDL-Cholesterin (High Density Lipoprotein-Cholesterin) , hohe Konzentrationen an Triglyceriden im Serum, erhöhte Konzentrationen an Fibrinogen im Serum sowie erhöhter Blutdruck und Rauchen.Atherosclerosis and heart attacks are among the leading causes of death. The main risk factors here are high concentrations of serum cholesterol, high concentrations of LDL cholesterol (low density lipoprotein cholesterol), high concentrations of LP.a) (lipoprotein (a)), and low concentrations of HDL cholesterol (high density lipoprotein cholesterol) ), high concentrations of triglycerides in the serum, increased concentrations of fibrinogen in the serum as well as increased blood pressure and smoking.
Idealerweise sollten bei Patienten mit einer kombinierten Hyperlipidämie möglichst viele dieser Risikofaktoren im Rahmen einer medikamentösen Therapie Arteriosklerose- gefährdeter Patienten günstig beeinflusst werden (vgl. z.B. S.M. Grundy, Am. J. Cardiol., Bd. 70 (1992), S. 271-321). Es gibt bisher jedoch keine Möglichkeit zu einer umfassenden Therapie der genannten Risikofaktoren bei Arteriosklerose-gefährdeten Patienten.Ideally, in patients with combined hyperlipidemia, as many of these risk factors as possible should be favorably influenced as part of drug therapy for patients at risk of atherosclerosis (see, for example, SM Grundy, Am. J. Cardiol., Vol. 70 (1992), pp. 271-321 ). So far, however, there is no possibility of comprehensive treatment of the risk factors mentioned in atherosclerosis-endangered patients.
HMG-CoA-Reduktase-Hemmer, wie Lovastatin, Pravastatin, Simvastatin und weitere Statine, reduzieren zwar die Konzentrationen an Gesamtcholesterin und LDL-Cholesterin im Serum, sie verringern aber nur in geringem Masse die Konzentration an Triglyceriden im Serum (vgl. H. Vanhanen und T.A. Miettinen, Euro. J. Clin. Pharmacol., Bd. 42 (1992), S. 127-130) .HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, simvastatin and other statins, reduce the concentrations of total cholesterol and LDL cholesterol in the serum, but they only reduce the concentration of triglycerides in the serum to a small extent (cf. H. Vanhanen and TA Miettinen, Euro. J. Clin. Pharmacol., Vol. 42 (1992), pp. 127-130).
Substanzen aus der Klasse der Fibrate, wie Bezafibrat, Clofibrat und Gemfibrozil, reduzieren primär die Triglyceride und erhöhen die HDL-Konzentration, haben aber nur einen geringen Einfluss auf das Serumcholesterin (vgl. P. Zimetbaum et al., J. Clin. Pharmacol., Bd. 31 (1991), S. 25-37).Substances from the class of fibrates, such as bezafibrate, clofibrate and gemfibrozil, primarily reduce the triglycerides and increase the HDL concentration, but have only a minor influence on the serum cholesterol (cf. P. Zimetbaum et al., J. Clin. Pharmacol. , Vol. 31 (1991), pp. 25-37).
Die Konzentration an LP(a) bleibt von beiden Substanzklassen unbeeinflusst.The concentration of LP (a) remains unaffected by both classes of substances.
Als Lipidsenker sind aus EP-A-0 133 935 bestimmte p- Oxybenzoesäurederivate bekannt. Ein Beispiel für diese Verbindungen ist Lifibrol, das primär das LDL-Cholesterin, die Triglyceride und das LP(a) senkt (P. Schwandt, 62nd EAS Congress, Jerusalem, 5.-9. September 1993).Certain p-oxybenzoic acid derivatives are known from EP-A-0 133 935 as lipid-lowering agents. An example of these compounds is Lifibrol, which primarily lowers LDL cholesterol, triglycerides and LP (a) (P. Schwandt, 62nd EAS Congress, Jerusalem, September 5-9, 1993).
Die Kombination von Fibraten mit HMG-CoA-Reduktase- Hemmern kann wegen der dabei auftretenden schweren Nebenwirkungen nicht zur Therapie der kombinierten Hyperlipidämie eingesetzt werden (vgl. D.R. Illingworth und S. Bacon, Circulation, Bd. 79 (1989), S. 590-596)).The combination of fibrates with HMG-CoA reductase inhibitors cannot be used for the therapy of combined hyperlipidemia because of the serious side effects that occur (cf. DR Illingworth and S. Bacon, Circulation, Vol. 79 (1989), p. 590- 596)).
Nach den vorstehenden Ausführungen besteht ein dringender Bedarf an einem hochgradig wirksamen und dennoch gut verträglichen Mittel zur Therapie der kombinierten Hyperlipidämie. Eine Aufgabe der Erfindung besteht daher darin, ein neues Arzneimittel zur Therapie der kombinierten Hyperlipidämie bereitzustellen.According to the foregoing, there is an urgent need for a highly effective yet well tolerated agent for the therapy of combined hyperlipidemia. It is therefore an object of the invention to provide a new medicament for the therapy of combined hyperlipidemia.
Insbesondere soll mit der vorliegenden Erfindung ein Mittel bereitgestellt werden, das nach MöglichkeitIn particular, the present invention is intended to provide a means that, if possible
• die Konzentration an Triglyceriden im Serum reduziert;• reduces the concentration of triglycerides in the serum;
• die Gesamtkonzentration an Cholesterin im Serum verringert;• decreased the total concentration of cholesterol in the serum;
• die Konzentration an HDL im Serum erhöht;• increases the concentration of HDL in the serum;
• die Konzentration an LDL im Serum verringert;• decreases the concentration of LDL in the serum;
• die LP(a) -Konzentration im Serum verringert; und• decreases the LP (a) concentration in the serum; and
• die Konzentration an Fibrinogen im Serum verringert.• Reduces the concentration of fibrinogen in the serum.
Dabei soll angesichts der Tatsache, dass eine kombini. ce Hyperlipidämie in der Regel eine Langzeittherapie erfordert, besondere Aufmerksamkeit auf eine gute Verträglichkeit des Mittels gerichtet werden. Ferner soll berücksichtigt werden, dass für eine erfolgreiche Langzeittherapie die Compliance des Patienten unerlässlich ist und das Mittel daher einfach und ohne erhebliche Belastung des Patienten verabreichbar sein muss.Given the fact that a kombini. ce hyperlipidemia usually requires long-term therapy, special attention should be paid to good tolerability of the agent. Furthermore, it should be taken into account that patient compliance is essential for successful long-term therapy and that the agent must therefore be easy to administer and without significant strain on the patient.
Eine weitere Aufgabe besteht in der Bereitstellung eines Verfahrens zur Herstellung eines Arzneimittels mit den vorstehend genannten Eigenschaften.Another object is to provide a method for producing a drug with the above-mentioned properties.
Es wurde nun festgestellt, dass die vorstehend genannten Aufgaben gelöst werden, indem ein Kombinationspräparat mit einem Gehalt an einem oder mehreren p-Oxybenzoesäurederivaten der nachstehend angegebenen Formel und einem oder mehreren Fibraten sowie ein Verfahren zur Herstellung des Präparats bereitgestellt werden. Das Wesen der Erfindung besteht also darin, dass die Verabreichung von mindestens zwei Substanzen mit hypolipidämischer Wirkung ermöglicht wird, wobei mindestens eine der Substanzen unter p-Oxybenzoesäurederivaten und mindestens eine weitere unter Fibraten ausgewählt ist.It has now been found that the above objects are achieved by providing a combination preparation containing one or more p-oxybenzoic acid derivatives of the formula given below and one or more fibrates, and a method for producing the preparation. The essence of the invention is therefore that the administration of at least two substances with a hypolipidemic effect is made possible, at least one of the substances being selected from p-oxybenzoic acid derivatives and at least one further being selected from fibrates.
Insbesondere wird erfindungsge äss ein Arzneimittel bereitgestellt, das eine Kombination aus einem p- Oxybenzoesäurederivat der allgemeinen FormelIn particular, a medicament is provided according to the invention which is a combination of a p-oxybenzoic acid derivative of the general formula
worinwherein
R1 = H oder eine geradkettige oder verzweigte Cl- C4-Alkylgruppe, insbesondere -CH(CH3)2 oder -C(CH3)3, oder -C(CH3)2CH2OH, oder -C(CH3)2-COOH, n = 1, 2R 1 = H or a straight-chain or branched Cl-C4-alkyl group, in particular -CH (CH3) 2 or -C (CH3) 3, or -C (CH 3 ) 2 CH 2 OH, or -C (CH 3 ) 2 -COOH, n = 1, 2
X = -CH(OH) -, .-C0- R2 = -OH, -NHCH2COOH bedeuten, oder einem physiologisch verträglichen Salz davon und einem Fibrat sowie übliche Trägerstoffe, Hilfsmittel und/oder Zusatzstoffe enthält.X = -CH (OH) -,.-C0- R 2 = -OH, -NHCH 2 COOH, or a physiologically tolerable salt thereof and a fibrate and conventional carriers, auxiliaries and / or additives.
Vorzugsweise hat in der vorstehenden allgemeinen Formel R1 die Bedeutung -CH(CH3)2, -C(CH3)3, oder -C(CH3)2CH2OH oder -C(CH3)2-COOH.In the above general formula R 1 preferably has the meaning -CH (CH 3 ) 2 , -C (CH 3 ) 3 , or -C (CH 3 ) 2 CH 2 OH or -C (CH 3 ) 2 -COOH.
Insbesondere handelt es sich bei dem p- Oxybenzoesäurederivat um Lifibrol (4- (4' -tert.-Butylphenyl) - 1- (4' -carboxyphenoxy) -2-butanol) .In particular, the p-oxybenzoic acid derivative is lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol).
p-Oxybenzoesäurederivate, wie Lifibrol, weisen einen komplexen Wirkungsmechanismus auf, der nicht vollständig geklärt ist. Insbesondere äussert sich die Wirkung derartiger Substanzen in einer Hemmung der Choleεterinbiosynthese sowie einer Hemmung der Cholesterinresorption.p-Oxybenzoic acid derivatives, such as Lifibrol, have a complex mechanism of action that has not been fully elucidated. In particular, the effect of such expresses itself Substances in an inhibition of cholesterol biosynthesis and an inhibition of cholesterol absorption.
Unter Fibraten werden erfindungsgemäss alle zur Gruppe der hypotriglyzeridämisch wirkenden Substanzen gehörenden Stoffe verstanden. Ohne an eine Theorie gebunden zu sein, nimmt man an, dass Fibrate die Aktivität von Lipoprotein- Lipase erhöhen und daher vor allem zur Verringerung der Triglyceride führen. Bei einigen Fibraten wurde auch eine Reduktion an LDL-Cholesterin beobachtet.According to the invention, fibrates are understood to mean all substances belonging to the group of substances having a hypotriglyceridemic effect. Without being bound by theory, it is believed that fibrates increase the activity of lipoprotein lipase and therefore, above all, reduce triglycerides. A reduction in LDL cholesterol has also been observed in some fibrates.
Erfindungsgemäss wird das Fibrat vorzugsweise unter Bezafibrat, Clofibrat, Ciprofibrat, Gemfibrozil und Fenofibrat ausgewählt.According to the invention, the fibrate is preferably selected from bezafibrate, clofibrate, ciprofibrate, gemfibrozil and fenofibrate.
In einer klinischen Untersuchung an Patienten mit einer kombinierten Hyperlipidämie wurde eine kombinierte Verabreichung von Lifibrol u- i einem Fibrat auf die hyperlipidämische Wirkung hin untersucht.In a clinical study in patients with combined hyperlipidemia, a combined administration of Lifibrol and a fibrate was examined for the hyperlipidemic effect.
Dabei hat sich gezeigt, dass die kombinierte Therapie mit Lifibrol und Fibraten zu einer Verbesserung der meisten der genannten Risikofaktoren führt. Die Verbesserung der Risikofaktoren ist stärker ausgeprägt, als es bei einer reinen Addition der Wirkungen beider Substanzen hätte erwartet werden können. Es wurde eine starke Senkung der Konzentrationen an Gesamtcholesterin, LDL-Cholesterin, Fibrinogen und LP(a) gesehen und gleichzeitig eine Erhöhung der Konzentration an HDL-Cholesterin festgestellt.It has been shown that the combined therapy with Lifibrol and fibrates leads to an improvement in most of the risk factors mentioned. The improvement in risk factors is more pronounced than would have been expected if the effects of both substances were added together. A sharp decrease in the concentrations of total cholesterol, LDL cholesterol, fibrinogen and LP (a) was seen and at the same time an increase in the concentration of HDL cholesterol was found.
Diese überraschenderweise festgestellte synergistische Wirkung hat insofern eine besondere Bedeutung, als sie eine niedrige Dosierung der Einzelkomponenten zulässt. Dies wiederum führt bei einer Langzeittherapie zu erheblich geringeren Nebenwirkungen. Da nur geringe Mengen an Wirkstoffen verabreicht werden müssen, wird ferner die Compliance des Patienten erhöht.This surprisingly found synergistic effect is of particular importance insofar as it permits a low dosage of the individual components. In turn, this leads to considerably fewer side effects in long-term therapy. Because only small amounts of Active substances must be administered, the patient's compliance is also increased.
Die kombinierte Therapie mit Substanzen aus der Reihe der Fibrate (das sind alle zur Gruppe der hypotriglyzeridämisch wirkenden Substanzen gehörenden Stoffe, wie beispielsweise Bezafibrat, Clofibrat, Ciprofibrat, Gemfibrozil, Fenofibrat usw.) und der Substanzen aus der Klasse der p- Oxybenzoes urederivate, wie Lifibrol, sowie auch Lifibrol- Metabolite ergeben demnach ein völlig neues Wirkprofil für die Behandlung der multifaktoriellen Erkrankung der Arteriosklerose.The combined therapy with substances from the series of fibrates (these are all substances belonging to the group of hypotriglyceridemic substances, such as bezafibrate, clofibrate, ciprofibrate, gemfibrozil, fenofibrate etc.) and substances from the class of p-oxybenzoic urederivate, such as Lifibrol, as well as Lifibrol metabolites, result in a completely new activity profile for the treatment of the multifactorial disease of arteriosclerosis.
Erfindungsgemäss hängt die genaue Dosierung der Wirkstoffe vom Alter, Körpergewicht und Zustand des Patienten ab. Insbesondere hängt sie vom gewünschten Ausmass der Verringerung der Konzentration an LDL-Cholesterin im Serum ab. Dementsprechend kann die Dosierung individuell für einen Patienten vom Arzt eingestellt werden.According to the invention, the exact dosage of the active ingredients depends on the age, body weight and condition of the patient. In particular, it depends on the desired degree of reduction in the concentration of LDL cholesterol in the serum. Accordingly, the dosage can be set individually for a patient by the doctor.
Im allgemeinen liegt jedoch der sich aufgrund der klinischen Untersuchungen ableitende Bereich der Dosierungen für das Lifibrol zwischen 100 und 400 mg pro Tag. Der Applikationsbereich der Fibrate liegt bei der jeweils empfohlenen Basisdosis.In general, however, the range of doses for the Lifibrol derived from the clinical studies is between 100 and 400 mg per day. The application range of the fibrates is the recommended base dose.
Für die therapeutische Anwendung als Arzneimittel bei kombinierter Hyperlipidämie können die erfindungsgemässen Präparate auf beliebige Weise verabreicht werden; vorzugsweise werden sie jedoch oral verabreicht. Die Verabreichung kann in einer oder mehreren geteilten Dosen pro Tag erfolgen. Beide Wirkstoffe können in einem Präparat vereinigt oder in getrennten Präparaten verabreicht werden. Als galenische Form wird eine Kapsel oder Tablette bevorzugt. Dazu können die Wirkstoffe'mit üblichen Trägerstoffen, Hilfsmitteln und/oder Zusatzstoffen gemischt werden. Als pharmazeutische Trägerstoffe eignen sich gängige Hilfsstoffe, wie Lactose, Saccharose, Mann. ., Kartoffel- oder Maisstärke, Cellulosederivate oder Gelatine, gegebenenfalls unter Zusatz von Gleitmitteln, wie z.B. Magnesium- oder Calciumstearat, sowie Polyethylenglykole.The preparations according to the invention can be administered in any manner for therapeutic use as a medicament in the case of combined hyperlipidemia; however, they are preferably administered orally. Administration can be in one or more divided doses per day. Both active ingredients can be combined in one preparation or administered in separate preparations. A capsule or tablet is preferred as the galenic form. For this, the active ingredients' with conventional carriers, adjuvants and / or additives can be mixed. Common excipients such as lactose, sucrose, man are suitable as pharmaceutical carriers. ., Potato or corn starch, cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate, and polyethylene glycols.
Bevorzugte Verabreichungsformen sind Steckkapseln aus Hartgelatine sowie geschlossene Weichgelatinekapseln. In Steckkapseln kann gegebenenfalls der reine Wirkstoff, eventuell mit einem geringen Zusatz an Gleitmitteln, enthalten sein. Bei entsprechenden physikalischen Eigenschaften der Wirkstoffe ist eine Verarbeitung zu Granulaten möglich, wobei als Hilfsstoffe Kartoffel- oder Maisstärke, mikrokristalline Cellulose, Cellulosederivate, Gelatine oder auch hochdisperse Kieselsäuren mitverwendet werden.Preferred forms of administration are push-fit capsules made of hard gelatin and closed soft gelatin capsules. The pure active ingredient, possibly with a small addition of lubricants, may be present in push-fit capsules. With appropriate physical properties of the active ingredients, processing into granules is possible, potato or corn starch, microcrystalline cellulose, cellulose derivatives, gelatin or highly disperse silicas also being used as auxiliaries.
Bei Konfektionierung in Weichgelatinekapseln wird der reine Wirkstoff in geeigneten Flüssigkeiten gelöst oder suspendiert, z.B. in flüssigen Polyethylenglykolen oder Pflanzenölen.When packaged in soft gelatin capsules, the pure active ingredient is dissolved or suspended in suitable liquids, e.g. in liquid polyethylene glycols or vegetable oils.
Dementsprechend wird erfindungsgemäss ein Verfahren zur Herstellung eines Arzneimittels bereitgestellt, wobei ein p- Oxybenzoesäurederivat der allgemeinen FormelAccordingly, a method for producing a pharmaceutical is provided according to the invention, wherein a p-oxybenzoic acid derivative of the general formula
RJ θ V-(CH2)n—X-CH2—O (C )—∞ — R'R J θ V- (CH 2 ) n —X-CH 2 —O (C) —∞ - R '
worinwherein
R1 = H oder eine geradkettige oder verzweigte Cl- C4- lkylgruppe, insbesondere -CH(CH3)2 und -C(CH3)3, oder -C(CH3)2CH2OH, oder -C(CH3)2-COOH. n = 1, 2R 1 = H or a straight-chain or branched Cl-C4-alkyl group, in particular -CH (CH3) 2 and -C (CH3) 3, or -C (CH 3 ) 2CH 2 OH, or -C (CH 3 ) 2 - COOH. n = 1, 2
X = -CH(OH) -, -CO- R2 = -OH, -NHCH2COOH bedeuten, oder ein physiologisch verträgliches Salz davon und ein Fibrat in an sich bekannter Weise mit üblichen Trägerstoffen, Hilfsmitteln und/oder Zusatzstoffen gemischt und in die gewählte Zubereitungsform, wie eine Tablette oder Kapsel, gebracht werden. X = -CH (OH) -, -CO- R 2 = -OH, -NHCH 2 COOH, or a physiologically tolerable salt thereof and a fibrate in a manner known per se mixed with conventional carriers, auxiliaries and / or additives and in the selected form of preparation, such as a tablet or capsule.
Claims
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU35562/95A AU3556295A (en) | 1994-04-26 | 1995-04-25 | Medicament containing p-oxybenzoic acid derivative and fibrate |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4414538A DE4414538A1 (en) | 1994-04-26 | 1994-04-26 | Preparations for the therapy of combined hyperlipidemia containing a p-oxybenzoic acid derivative and a fibrate |
| DEP4414538.1 | 1994-04-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995028919A1 true WO1995028919A1 (en) | 1995-11-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1995/001565 Ceased WO1995028919A1 (en) | 1994-04-26 | 1995-04-25 | MEDICAMENT CONTAINING p-OXYBENZOIC ACID DERIVATIVE AND FIBRATE |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU3556295A (en) |
| DE (1) | DE4414538A1 (en) |
| EE (1) | EE9400266A (en) |
| WO (1) | WO1995028919A1 (en) |
| ZA (1) | ZA953416B (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6982251B2 (en) | 2000-12-20 | 2006-01-03 | Schering Corporation | Substituted 2-azetidinones useful as hypocholesterolemic agents |
| US7030106B2 (en) | 2001-01-26 | 2006-04-18 | Schering Corporation | Sterol absorption inhibitor compositions |
| US7053080B2 (en) | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| US7056906B2 (en) | 2001-09-21 | 2006-06-06 | Schering Corporation | Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women |
| US7071181B2 (en) | 2001-01-26 | 2006-07-04 | Schering Corporation | Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors |
| US7132415B2 (en) | 2001-09-21 | 2006-11-07 | Schering Corporation | Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors |
| US7192944B2 (en) | 2003-03-07 | 2007-03-20 | Schering Corp. | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7208486B2 (en) | 2003-03-07 | 2007-04-24 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7235543B2 (en) | 2003-03-07 | 2007-06-26 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7417039B2 (en) | 2001-01-26 | 2008-08-26 | Schering Corporation | Use of substituted azetidinone compounds for the treatment of sitosterolemia |
| US7459442B2 (en) | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7560449B2 (en) | 2002-11-06 | 2009-07-14 | Schering Corporation | Methods and therapeutic combinations for the treatment of demyelination |
| RU2362547C2 (en) * | 2003-02-28 | 2009-07-27 | Сарл Галени Инновасьон | Way of reception of pharmaceutical composition in form of tablets containing fibrate and tablets made in this way |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0133935A2 (en) * | 1983-07-20 | 1985-03-13 | Klinge Pharma GmbH | p-oxybenzoic acid derivatives, methods for preparing them, and their use for the preparation of medicaments with hypolipemic activity |
-
1994
- 1994-04-26 DE DE4414538A patent/DE4414538A1/en not_active Withdrawn
- 1994-11-11 EE EE9400266A patent/EE9400266A/en unknown
-
1995
- 1995-04-25 WO PCT/EP1995/001565 patent/WO1995028919A1/en not_active Ceased
- 1995-04-25 AU AU35562/95A patent/AU3556295A/en not_active Abandoned
- 1995-04-26 ZA ZA953416A patent/ZA953416B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0133935A2 (en) * | 1983-07-20 | 1985-03-13 | Klinge Pharma GmbH | p-oxybenzoic acid derivatives, methods for preparing them, and their use for the preparation of medicaments with hypolipemic activity |
Non-Patent Citations (2)
| Title |
|---|
| DINH, D.M. ET AL: "Lifibrol increases hepatic cholesterol 7Ó-hydroxylase activity in Sprague-Dawley rats", DRUG DEVELOPMENT RESEARCH, vol. 33, pages 439 - 447 * |
| ILLINGWORTH, D.R. ET AL: "The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia", METABOLISM, vol. 39, no. 4, pages 403 - 409 * |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6982251B2 (en) | 2000-12-20 | 2006-01-03 | Schering Corporation | Substituted 2-azetidinones useful as hypocholesterolemic agents |
| US7417039B2 (en) | 2001-01-26 | 2008-08-26 | Schering Corporation | Use of substituted azetidinone compounds for the treatment of sitosterolemia |
| US7030106B2 (en) | 2001-01-26 | 2006-04-18 | Schering Corporation | Sterol absorption inhibitor compositions |
| US7071181B2 (en) | 2001-01-26 | 2006-07-04 | Schering Corporation | Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors |
| US7612058B2 (en) | 2001-01-26 | 2009-11-03 | Schering Corporation | Methods for inhibiting sterol absorption |
| US7056906B2 (en) | 2001-09-21 | 2006-06-06 | Schering Corporation | Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women |
| US7132415B2 (en) | 2001-09-21 | 2006-11-07 | Schering Corporation | Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors |
| US7053080B2 (en) | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| US7560449B2 (en) | 2002-11-06 | 2009-07-14 | Schering Corporation | Methods and therapeutic combinations for the treatment of demyelination |
| RU2362547C2 (en) * | 2003-02-28 | 2009-07-27 | Сарл Галени Инновасьон | Way of reception of pharmaceutical composition in form of tablets containing fibrate and tablets made in this way |
| US7368563B2 (en) | 2003-03-07 | 2008-05-06 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7378518B2 (en) | 2003-03-07 | 2008-05-27 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7235543B2 (en) | 2003-03-07 | 2007-06-26 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7459442B2 (en) | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7368562B2 (en) | 2003-03-07 | 2008-05-06 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7208486B2 (en) | 2003-03-07 | 2007-04-24 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7192944B2 (en) | 2003-03-07 | 2007-03-20 | Schering Corp. | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4414538A1 (en) | 1995-11-02 |
| EE9400266A (en) | 1996-02-15 |
| AU3556295A (en) | 1995-11-16 |
| ZA953416B (en) | 1996-01-11 |
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