WO2000066174A2 - Compounds - Google Patents
Compounds Download PDFInfo
- Publication number
- WO2000066174A2 WO2000066174A2 PCT/IE2000/000041 IE0000041W WO0066174A2 WO 2000066174 A2 WO2000066174 A2 WO 2000066174A2 IE 0000041 W IE0000041 W IE 0000041W WO 0066174 A2 WO0066174 A2 WO 0066174A2
- Authority
- WO
- WIPO (PCT)
- 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
Definitions
- Ranitidine is a H 2 -receptor antagonist of formula (I):
- 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.
- 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
- European patent 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 co- administered in separate or single compositions.
- One of the problems with combined 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.
- 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 H 2 -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.
- the reaction temperature is from 20°C to 25°C.
- the solvent is petroleum ether.
- the invention further provides the use of the adducts of the invention for the treatment of gastrointestinal disorders.
- the invention provides a pharmaceutical formulation including an adduct of the invention. Detailed description of the invention
- 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.
- 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 gastiointestinal 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.
- novel adducts may be conveniently formulated, e.g. preferably into orally administerable medicaments such as tablets or capsules.
- 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.
- the invention will be more clearly understood from the following example.
- Powder X-ray peaks of medium and high intensity Powder X-ray peaks of medium and high intensity:
- Clarithromycin-Ranitidine [2:1]: 2 ⁇ 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).
- 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.
- Quantitation of activity is determined using an MIC (Mean Inhibitory Concentration) liquid tube assay.
- concentrations are set up: 10 ⁇ g/ml, 5 ⁇ g/ml, 1 ⁇ g/ml, 0.5 ⁇ g/ml, 0J ⁇ g/ml, 0.05 ⁇ g/ml and 0.01 ⁇ g/ml.
- concentrations are set up: 10 ⁇ g/ml, 5 ⁇ g/ml, 1 ⁇ g/ml, 0.5 ⁇ g/ml, 0J ⁇ g/ml, 0.05 ⁇ g/ml and 0.01 ⁇ g/ml.
- 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.
- Clarithromycin-Ranitidine [2:1] ⁇ 0.01 Ranitidine Base Hydrate no significant antibiotic activity
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- 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
"COMPOUNDS"
Introduction
Ranitidine is a H2-receptor antagonist of formula (I):
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]).
European patent 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 co- administered 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
combined 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.
Detailed description of the invention
It has surprisingly been found that Ranitidine 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 gastiointestinal 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.
The invention will be more clearly understood from the following example.
Preparation of a Clarithromvcrn-Ranitidine-[2:l] adduct
2.50 kg (3.33 mol) of Clarithromycin and 640 g (1.67 mol) of Ranitidine base 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 [cm 1] = 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]: 2Θ = 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: 2Θ = 5.09, 6.80, 9.42, 10.38, 10.65, 12.11, 12.37, 13.99, 14.32, 15.48, 16.47, 19.11, 21.41, 23.11, 23.93 (Figure 3).
Ranitidine: 2Θ = 8.91, 16.19, 17.21, 17.74, 19.94, 22.30, 25.66, 26.09, 28.04 (Figure 4).
Antibiotic 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.
10 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 μg/ml, 5 μg/ml, 1 μg/ml, 0.5 μg/ml, 0J μg/ml, 0.05 μg/ml and 0.01 μg/ml. Each contained nutrient broth and 0J 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 [μg/mll
Clarithromycin ≤ o.oi
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
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.
10. Use of an adduct containing Clarithromycin and Ranitidine or a hydrate thereof for the treatment of gastrointestinal disorders.
11. Use as claimed in claim 10 wherein the adduct is as claimed in any of claims 1 to 4 or 9.
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.
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 |
|---|---|---|---|
| AU36680/00A AU3668000A (en) | 1999-04-29 | 2000-04-04 | Compounds |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE990357 | 1999-04-29 | ||
| IE990357 | 1999-04-29 | ||
| IE990993 | 1999-11-29 | ||
| IE990993 | 1999-11-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000066174A2 true WO2000066174A2 (en) | 2000-11-09 |
| WO2000066174A3 WO2000066174A3 (en) | 2001-03-15 |
Family
ID=26320246
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IE2000/000041 WO2000066174A2 (en) | 1999-04-29 | 2000-04-04 | Compounds |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU3668000A (en) |
| WO (1) | WO2000066174A2 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0533281A1 (en) * | 1991-09-20 | 1993-03-24 | Glaxo Group Limited | The use of ranitidine bismuth citrate and one or more heliocobacte pylon-inhibiting antibiotics with manufacture of a medicament for treating gastrointestinal disorders |
| WO1998056357A1 (en) * | 1995-12-19 | 1998-12-17 | Abbott Laboratories | A controlled release formulation for poorly soluble basic drugs |
| WO1999065890A1 (en) * | 1998-06-17 | 1999-12-23 | Russinsky Limited | Ranitidine adduct |
-
2000
- 2000-04-04 AU AU36680/00A patent/AU3668000A/en not_active Abandoned
- 2000-04-04 WO PCT/IE2000/000041 patent/WO2000066174A2/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0533281A1 (en) * | 1991-09-20 | 1993-03-24 | Glaxo Group Limited | The use of ranitidine bismuth citrate and one or more heliocobacte pylon-inhibiting antibiotics with manufacture of a medicament for treating gastrointestinal disorders |
| WO1998056357A1 (en) * | 1995-12-19 | 1998-12-17 | Abbott Laboratories | A controlled release formulation for poorly soluble basic drugs |
| WO1999065890A1 (en) * | 1998-06-17 | 1999-12-23 | Russinsky Limited | Ranitidine adduct |
Non-Patent Citations (1)
| Title |
|---|
| FROTZ H ET AL: "Ä Ranitidine and clarithromycin for eradication of Helicobacter pylori in patients with duodenal ulcerÜ. Ranitidin und Clarithromycin zur Eradikation von Helicobacter pylori bei Patienten mit Ulcus duodeni." ARZNEIMITTEL-FORSCHUNG, (1995 FEB) 45 (2) 184-6. , XP002155014 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000066174A3 (en) | 2001-03-15 |
| IE20000248A1 (en) | 2000-11-29 |
| AU3668000A (en) | 2000-11-17 |
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