IE20000248A1 - An adduct containing Clarithromycin and Ranitidine - Google Patents
An adduct containing Clarithromycin and RanitidineInfo
- Publication number
- IE20000248A1 IE20000248A1 IE20000248A IE20000248A IE20000248A1 IE 20000248 A1 IE20000248 A1 IE 20000248A1 IE 20000248 A IE20000248 A IE 20000248A IE 20000248 A IE20000248 A IE 20000248A IE 20000248 A1 IE20000248 A1 IE 20000248A1
- Authority
- IE
- Ireland
- Prior art keywords
- ranitidine
- adduct
- clarithromycin
- hydrate
- base
- Prior art date
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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/552—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An adduct contains Clarithromycin and Ranitidine either in the form of a base or a base hydrate in which the molar ratio of Clarithromycin to ranitidine in the adduct is at least 2:1. The adduct has high stability and is particularly useful in a single dose formulation for the treatment of gastrointestinal disorders.
Description
It inhibits the gastric acid secretion and is widely used in the treatment of gastrointestinal disorders. For the eradication of Helicobacter pylori infections, which are closely related to peptic ulcer diseases, bismuth compounds such as Ranitidine bismuth citrate are commonly administered.
A combination therapy comprising Ranitidine and antibacterial agents is also generally accepted. The activity of Ranitidine, especially against Helicobacter organisms, can be significantly increased by co-administration of antibiotics. A variety of antibiotics are suitable for this purpose, e.g. tetracyclines, penicillins, carbapenems, cephalosporins, aminoglycosides or macrolide antibiotics. Clarithromycin appears to show in combination with Ranitidine higher eradication rates regarding Helicobacter infections than any other antibiotic (Arzneim.-Forsch. 45(2), 184-186 [1995]).
Europeanpatent application EP 533 281 describes the use of Ranitidine bismuth citrate in combination with various types of antibiotics for the treatment or prevention of gastrointestinal disorders. The individual components may be coadministered in separate or single compositions.
While such combination products are useful, it is generally difficult to provide such combination products in acceptable formulations. One of the problems with
IE000248
RUSS 18/C. IE
-2combined therapies is one of patient compliance, especially when different quantities or numbers of the individual elements are to be administered.
This invention is directed towards providing a novel presentation for such combination products which will overcome at least some of these problems.
Statements of Invention
The invention provides novel pharmaceutically active and stable adducts containing Clarithromycin and Ranitidine or a hydrate thereof wherein the molar ratio of Clarithromycin to Ranitidine in the adduct is at least 2:1.
The preferred H2-receptor antagonist is Ranitidine which is preferably introduced as the base hydrate.
The ratios may be integers or non-integers.
The invention also provides a process for the preparation of an adduct of the invention in which Clarithromycin and Ranitidine are reacted in an organic or aqueous solvent. Preferably the reaction temperature is from 20°C to 25°C. Ideally, the solvent is petroleum ether.
The invention further provides the use of the adducts of the invention for the treatment of gastrointestinal disorders.
In addition, the invention provides a pharmaceutical formulation including an adduct of the invention.
IE000248
RUSS 18/C, IE
Detailed description of the invention
It has surprisingly been found that Ranitidme can be bound to Clarithromycin by formation of adducts. This feature is of significance for the preparation of novel combination products, especially for the treatment of gastrointestinal disorders. The Ranitidine can be administered simultaneously with the Clarithromycin in one unit. The ratio of Ranitidine to Clarithromycin can be readily varied, as required. The formed adducts may be readily used for final product formulations, e.g. for the manufacture of tablets or capsules. No pre-mixing of the individual components is required.
It has been observed that the Ranitidine is especially suitable to form adducts with Clarithromycin. Ranitidine may be used conveniently as the base without converting it into a pharmaceutically acceptable and stable salt prior to the formation of the adduct.
Ranitidine may be reacted with Clarithromycin to produce novel adducts which are of high stability. The adducts are antibiotically active and suitable for the treatment of gastrointestinal disorders.
Adducts prepared from Ranitidine base hydrate and Clarithromycin were found to be of particular interest. Ranitidine base hydrate is described in detail in our WO-A-99/65890 the entire contents of which are incorporated herein by reference. Such adducts can be obtained via a very simple process in high quality and quantitative yield under very mild reaction conditions.
The novel adducts may be conveniently formulated, e.g. preferably into orally administerable medicaments such as tablets or capsules. Those skilled in the art can decide which excipients, carriers, solvents, fillers, lubricants, techniques and quantities are employed in the formulation process.
IE000248
RUSS18/C/IE
-4The invention will be more clearly understood from the following example.
Preparation of a Clarithromycin-Ranitidine-[2:1] adduct
2.50 kg (3.33 mol) of Clarithromycin and 640 g (1.67 mol) of Ranitidine base 5 hydrate are suspended in approximately 7-8 1 of a suitable solvent such as petroleum ether. The mixture is agitated preferably at room temperature for several hours. The product is filtered off, washed with some solvent and dried under vacuum, optionally at elevated temperature. A quantitative yield is typically obtained.
Analytical data:
Mp.: 210.4-211.9°C.
FT-IR (KBr): V [cm1] = 3488, 2978, 2940, 1733, 1691, 1458, 1379, 1171, 1107, 1051, 1011 (Figure 1).
Powder X-ray peaks of medium and high intensity:
Clarithromycin-Ranitidine [2:1]: 20 = 8.81, 9.75, 11.04, 11.68, 13.98, 15.35, 16.69, 17.06, 17.45, 18.27, 19.27, 20.04, 20.67, 22.36 (Figure 2).
Clarithromycin: 20 = 5.09, 6.80, 9.42, 10.38, 10.65, 12.11, 12.37, 13.99, 14.32,
.48, 16.47, 19.11, 21.41, 23.11, 23.93 (Figure 3).
Ranitidine: 20 = 8.91, 16.19, 17.21, 17.74, 19.94, 22.30, 25.66, 26.09, 28.04 (Figure 4).
=~
IE000248
RUSS 18/C/IE
-5Antibiotic Activity
Micrococcus luteus from stock was streaked on a nutrient agar plate to confirm colony morpbiology, colour and purity. After 24 hours incubation at 37°C an isolated colony is picked and inoculated into 10 ml of nutrient broth. This is incubated overnight at 37°C and is subsequently used as the inoculum.
mg of each of the test compounds is weighed and dissolved in 10 ml of analar methanol in sterile 20 ml universal containers. This is then diluted with ringers buffer solution to give a concentration of 1 mg/ml.
Quantitation of activity is determined using an MIC (Mean Inhibitory Concentration) liquid tube assay. For each test substance the following concentrations are set up: 10 pg/ml, 5 pg/ml, 1 ug/ml, 0.5 pg/ml, 0.1 pg/ml, 0.05 pg/ml and 0.01 pg/ml. Each contained nutrient broth and 0.1 ml of overnight culture of Micrococcus luteus.
The tubes were incubated at 37°C and observed for growth after 24 hours and 48 hours. Growth is assessed by dense turbidity, optical density at 660 nm using a spectrophotometer or clarity. The MIC is the last concentration where growth inhibited.
The following table gives the MIC values for the compounds examined:
Compound _MIC [ug/mll
Clarithromycin <0.01
Clarithromycin-Ranitidine [2:1] < 0.01
Ranitidine Base Hydrate no significant antibiotic activity
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (13)
1. An adduct containing Clarithromycin and Ranitidine or a hydrate thereof wherein the molar ratio of Clarithromycin to Ranitidine in the adduct is at least 2:1.
2. An adduct as claimed in claim 1 wherein the Ranitidine is present in the form of Ranitidine base.
3. An adduct as claimed in claim 1 wherein the Ranitidine is present in the form of Ranitidine base hydrate.
4. An adduct substantially as hereinbefore described with reference to the examples.
5. A process for the preparation of an adduct as claimed in any preceding claim wherein Clarithromycin and Ranitidine or a hydrate thereof are reacted in an organic or aqueous solvent.
6. A process as claimed in claim 5 wherein the reaction temperature is from 20°C to 25°C.
7. A process as claimed in any of claims 5 to 6 wherein the organic solvent is petroleum ether.
8. A process for the preparation of an adduct substantially as hereinbefore described with reference to the examples.
9. An adduct containing Clarithromycin and Ranitidine or a hydrate thereof whenever prepared by a process as claimed in any of claims 5 to 8. IE000248 RUSS18/C/IE -710. Use of an adduct containing Clarithromycin and Ranitidine or a hydrate thereof for the treatment of gastrointestinal disorders.
10. 11. Use as claimed in claim 10 wherein the adduct is as claimed in any of 5 claims 1 to 4 or 9.
11. 12. A pharmaceutical formulation including an adduct containing Clarithromycin and Ranitidine or a hydrate thereof wherein the molar ratio of Clarithromycin to Ranitidine in the adduct is at least 2:1.
12.
13. A formulation as claimed in claim 12 wherein the adduct is as claimed in any of claims 1 to 4 or 9.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE2000/0248A IE83226B1 (en) | 2000-04-04 | An adduct containing clarithromycin and ranitidine |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IEIRELAND29/04/199919990357 | |||
IE990357 | 1999-04-29 | ||
IE990993 | 1999-11-29 | ||
IE2000/0248A IE83226B1 (en) | 2000-04-04 | An adduct containing clarithromycin and ranitidine |
Publications (2)
Publication Number | Publication Date |
---|---|
IE20000248A1 true IE20000248A1 (en) | 2000-11-29 |
IE83226B1 IE83226B1 (en) | 2004-01-14 |
Family
ID=
Also Published As
Publication number | Publication date |
---|---|
WO2000066174A2 (en) | 2000-11-09 |
WO2000066174A3 (en) | 2001-03-15 |
AU3668000A (en) | 2000-11-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1071331C (en) | Anti-helicobacter acyl derivatives of azolones | |
HUT73176A (en) | Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents | |
US5395615A (en) | Free amine benzophenanthridine alkaloid compositions | |
SK79599A3 (en) | 8-cyano-1-cyclopropyl-6-fluoro-7-(2-oxa-5,8- -diazabicyclo[4.3.0]non-8-yl)-1,4-dihydro-4-oxo-3-quinolone carboxylic acid, the use thereof and medicaments comprising the same | |
UA105775C2 (en) | Rifamycin derivatives | |
FR2493852A1 (en) | NOVEL ANTIBIOTICS, THEIR PREPARATION AND THEIR USE | |
US6077830A (en) | Bismuth salts of antibiotics of the moenomycin group, processes for their preparation, their use and pharmaceuticals comprising such salts | |
US6242424B1 (en) | Moenomycin and its derivatives for the production of pharmaceuticals, and pharmaceuticals containing moenomycin or its derivatives | |
CN103030684B (en) | Novel bleomycin analogue as well as preparation method and application thereof | |
CN107641119B (en) | Monocycle beta-lactam-siderophore conjugates and its preparation method and application | |
EP0787494B1 (en) | Use of rifamycin derivatives for the manufacture of a medicament for the treatment of diseases caused by infections of helicobacter pylori | |
IE20000248A1 (en) | An adduct containing Clarithromycin and Ranitidine | |
HU205932B (en) | Process for producing triacetate derivative of bu-3420t antibioticum and pharmaceutical compositions containing them | |
IE83226B1 (en) | An adduct containing clarithromycin and ranitidine | |
US9862680B2 (en) | Peripherally substituted monocyclic beta-lactams | |
US6599885B2 (en) | Derivatives of erythromycin, clarithromycin, roxithromycin or azithromycin with antibiotic and mucolytic activity | |
EP0203559A1 (en) | Penicillin derivative containing naphthyridine | |
EP0369503B1 (en) | Method for the control of pneumocystis carinii | |
AU626576B2 (en) | Crystalline (5r,6s)-2-carbamoyloxymethyl-6-{(1r)- hydroxyethyl}-2-penem-carboxylic acid and its pharmaceutical formulation | |
CN115160276B (en) | Pyrylium salt compound and preparation method and application thereof | |
GB2088864A (en) | Doxycycline monosodium tetrametaphosphate complexes and their preparation | |
BE886301A (en) | NOVEL ANTIBIOTICS, THEIR PREPARATION AND THEIR USE | |
JPS62174099A (en) | Novel glycopeptide antibiotic substance pa-42867-a and pa-42867-b and production thereof | |
EP0861660A1 (en) | Curative medicine for disease caused by infection of Helicobacter | |
MXPA98001875A (en) | Salts of bismuto of antibiotics of the lamoenomycin group, procedure for its preparation, its use and medicines containing such sa |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Patent lapsed |