CA2037663C - Use of complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in the obtaining of anti-ulcer drugs, new complexes and chelates resp., of antibiotics with bivalent and/trivalent metals and processes for the obtaining thereof - Google Patents

Use of complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in the obtaining of anti-ulcer drugs, new complexes and chelates resp., of antibiotics with bivalent and/trivalent metals and processes for the obtaining thereof

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Publication number
CA2037663C
CA2037663C CA002037663A CA2037663A CA2037663C CA 2037663 C CA2037663 C CA 2037663C CA 002037663 A CA002037663 A CA 002037663A CA 2037663 A CA2037663 A CA 2037663A CA 2037663 C CA2037663 C CA 2037663C
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CA
Canada
Prior art keywords
azithromycin
chelates
complexes
bivalent
antibiotics
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.)
Expired - Fee Related
Application number
CA002037663A
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French (fr)
Other versions
CA2037663A1 (en
Inventor
Slobodan Djokic
Zlatko Vajtner
Hrvoje Krnjevic
Nevenka Lopotar
Lidija Kolacny-Babic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pliva Farmaceutika dd
Original Assignee
Pliva Farmaceutska Kemijska Prehrambena I Kozmeticka Industrija dd
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Publication of CA2037663A1 publication Critical patent/CA2037663A1/en
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Publication of CA2037663C publication Critical patent/CA2037663C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to the use of complexes and chelates resp., of antibiotics, especially azithromycin, with bivalent and/or trivalent metals in the obtaining of antiulcer drugs, to new complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals and to processes for the obtaining thereof.

Description

2 ~

Use of complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in the obtaining of antiulcer drugs, new complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals and processes for the obtaining thereof The present invention relates to the use of complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in the obtaining of antiulcer drugs, to new com-plexes and chelates resp., of antibiotics with bivalent and/or trivalent metals and to processes for the obtaining thereof.

It has been known that some organic compounds form metal complexes and chelates,thereby changing their physical-chemical properties (solubility, stability, melting point etc.) and the pharmacokinetics as well as the pharmacodynamics in biologically active compounds.

There was described (BE patent 892,3S7) the formation of Co+2 complexes of macro-lide antibiotics, especially of erythromycin, the starting substance for obtaining N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A (non-proprietary name azithro-mycin; proprietary name Sumamed~ (PLIVA, Zagreb, Yugoslavia), whereas J. Pharm.
Pharmac. 18, (1966) 727 asserts that with other divalent metal ions (Cu+2, Ca+2, Mg+2, Ni+2 and Zn+2) no comlexes are formed. On the contrary, we have found that azithromycin forms complexes with bivalent metals yielding products of a high antibiotic activity (HU patent 198,507).

It has been known that illter o/i~7 Al-Mg gel is applied as antacid in the treatment of duodenal or gastric ulcer giving relief to the gastric mucosa and keeping the pH of the gastric juice between 4.5 and 5.5. For the same purpose also some antibiotics have been used in order to eradicate the microorganisms HeIicob~lcterpyloli and C~ pylob~cter jeju~li which are allégedly one of the factors causing the development and the relapse of duodenal or gastric ulcers. Since it has been pres-lmed that Helicob~cterrJyloli inhabits .. . .

~3~63 the mucous region of the gastric membrane - whereby the often unsuccessful eradica-tion and the resulting reccurences have been explained - there have been applied ever increasing doses and durations of treatment with various antibiptics. Even azitromycin is no exception.

It has been found, and this represents one object of the present invention, that com-plexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in the form of gels may be used in the obtaining of antiulcer drugs, which has not been as yet described according to the Applicants' Prior Art search.
.
Complexes and chelates resp., of antibiotics with bivalent and/or triva]ent nnetals are novel and they represent a further object of the present invention.

A further object of the present invention are processes for the obtaining of complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in high yields as well as of pharmaceutical preparations indicated for the treatment of u]cer diseases.

Particularly there should be cited azithromycin.

As complex- and chelate-forming metals there are used metals of the II and III group, which form physiologically tolerated compounds.

Particularly there should be cited Mg+2, Al+3, Fe+3, Rh+3, La+3, and Bi+3.

The process for obtaining complexes and chelates resp., of azithromycin is performed by means of reacting the antibiotic in the form of free bases or salts, especially hydrochlorides, with salts of bivalent and/or trivalent metals such as Mg+2, Al+3, Fe+3, Rh+3, La+3, and Bi+3, especially chlorides, in a ratio of 2:1, at room temperature, in aclueous solutioll or in a mixt~lre of water/alcohol, at a pH of 8.0 - 11.0, or with metal hydroxides and/or carbonates, subsalicylates or their gels, which are used as antacids sucll as aluminium hydroxide-magnesium carbonate, sucralfate and bismuth subsalicy-late, in a ratio of 1:1 to 1:4. The process is most suitably performed with the antibio~ic base in alcollol such as methanol or ethanol. The product is isolated in a conventional manner, e.g. by evaporation of the solvent (alcohol) from the reaction mixture under reduced pressure and the isolation of the product by means of filtration.

~7~

The product is formulated by known methods into pharmaceuticals such as granules or chewing tablets or aclueous suspensions.

It has been found that $he azithromycin chelates with aluminium and magnesium in a ratio of 1:1 to 1:4, in the form of gels as well as with other gels, which are applied as ant-acids, are retained within 24 hours in the mucous region of the rat stomach in a 1.5- to 6()-fold concentrations (Tables 1 and 2), which exceed the Minimal Inhibitory and Bac-tericidal Concentrations for Helicobacter pylori and Campylobncter jejcllli; accordingly, said preparations are more indicated for the treatment of gastric diseases such as gastric or duodenal ulcers than the parent azithromyein. Furtheron, it has been clemonstrated by toxieological investigations that the pharmaceutical formulations do not change the toxicity of the active ingredient.

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~37~3 The invention is illustrated by the following Examples:

Exampie 1 In 50 mL (0~02 mole) of a solution of azithromycin in 95% ethanol there were dissolved 0.067 g AIC13 (0.0l M solution with respect to Al+3) and upon adjusting the pH value to 8.6 with 0.1 N NaOl~ it was kept stirring for 1 hour at room temperature in a nitrogen stream.
Upon addition of 30 mL water the reaction mixture was evaporated under reduced pressure to about half its volume, whereupon it was kept stirring for two hours and the pH was kept constant (pH state) at 8.9 with 0.1 N NaOH. The white precipitate was aspirated, washed with 3 x 10 mL of water and dried, yielding 0.6~ g of the product (89.0%), m.p. 125-128 ~C.

Analysis: Al (atomic absorption spectrometry method):
Calc.: 1.77%
Found: 1.73%

Activity: 852 E/mg Sarcina lutea ATCC 9341 Example 2 In accordance with the process described in Example 1 with the sole exception that AlCl3 was replaced by the addition ot 0.136 g FeCl3 x 6 H2O and the pH was kept at 9.0, there was obtailled 0.72 g of a light grey product (92.5%); m.p. 130-133 ~C.
Analysis: Fe (atomic absorption spectrometry method):
Calc.: 3.59%
Found: 3.71%
.

Activity: 840 E/mg Sarcina i~lten ATCC 9341 ~3~

Example 3 0.750 g of azithromycin were charged into a 100 mL flask and dissolved in 50 mL of water under the addition of 1 N HCI (pH approx. 6.0). ~ubsequently, there were added 0.136 g FeCI3 x 6 H2O and it was kept stirring upon gradually adjusting the pH value to 8.9 with 0.1 N NaOH. The reaction mixture was kept stirring for 2 hours at a constant pH value, whereupon the light grey product was aspirated, washed with 3 x 10 mL of water, and dried.
There was obtained 0.70 g of the product (89.9%). The analysis of the product was identical as in Example 2.

Example 4 In accordance with the process described in Example 1 with the sole exception that AICl3 was replaced by the addition of 0.132 g RhC13 x 3 H2O there was obtained 0.67 g of a light grey product (83.6%); m.p. 120-123 ~C.

Analysis: Rh (polarographic method; 1 M pyridine - 1 M KCI, E"2 = -0 40 V; SCE (Saturated Calomel Electrode) Calc.: 6.42%
Found: 6.15~o Activity: 834 E/mg Sarci~a l~eo ATCC 9341 Example S

In accordance with the process described in Example 1 with the sole exception that AICI3 was replaced by the addition of 0.186 g of LaCI3 x 7 H2O and the pH was kept at 9.2, there was obtained 0.66 ~ of a white product (80.5%); m.p. 118-122 ~C.
AllalySis La (atomic absorptioll spectrometry method):
Calc.: 8.47%
Found: 8.10%

Activity: 830 E/mg Snrci ~a lu~ea ATCC 9341 Example 6 203~53 In accordance with the process described in Example 1 with the sole exception that AICl3 was replaced by the addition of 0.158 g of BiCI3, there v~as obtained 0.70 g of a product ~ (82.0%).

Analysis: Bi (atomic absorption spectrometry method):
Calc.: 12.25%
Found: 12.00%

Activity: 812 E/mg Sarcina lutea ATCC 9341 Example 7 ln accordance with the process described in Example 3 with the sole exception that FeCl3 was replaced by the addition of 0.102 g MgCI2 x 6 H2O and the pH was kept at 8.6, there was obtained 0.55 g (75.0%) of a white product.

Analysis: Mg (atomic absorption spectrometry method):
Calc.: 1.2~%
Found: 1.54%

Activity: 850 E/mg Sarci)la ll~ea ATCC 9341 Example 8 5.0 g of azithromycin were charged into a 100 mL flask and dissolved in 50 mL of methanol.
Upon the addition of 5.0 g of aluminium hydroxide-magnesium carbonate gel it was kept stirring t'or 2 hours in a nitrogen stream. The suspension was then evaporated to dryness Ull-der reduced pressure and the obtained product (9.5 g) was air-dried.

Activity: 430 E/mg Snrci~la lutea ATCC 9341 2~r~3 Example 9 In accordance with the process described in E~xample 8 with the sole exception that S.0 g of aluminium hydroxide-magnesium carbonate gel were replaced by 10.0 g thereof and that there were used 100 mL of 95% ethanol instead of methanol, there were obtained 14.3 g of the product.

Activity: 295 E/mg Snrcina l~ten ATCC 9341 Example 10 .
In accordance with the process described in Example 8 with the sole exception that 5.0 g of aluminium hydroxide-magnesium carbonate gel ~vere replaced by 20.0 g thereof, Lhere were obtained 23.5 g o~ the product.

Activity: 160 E/mg Snrci~ln l~ltea ATCC 9341 Example 11 In accordance with the process described in Example 8 with the sole exception that aluminium hydroxide-magnesium carbonate gel was replaced by 5.0 g of sucralfate, there w ere obtained 9.5 g of the product.

~ctivity: 435 E/mg Snrci~ln lu~en ATCC 9341 Example 12 In accordance witll the process described in Example 8 with the sole exception that aluminium hydroxide-magnesium carbonate gel was replaced by 5.0 g of bismuth sub-salicylate, there were obtained 9.3 g of the product.

Activity: 420 E/mg Snrcinn /~en ATCC 9341

Claims (20)

1. The use of complexes and chelates of azithromycin with bivalent, trivalent or both metals in the obtaining of antiulcer drugs wherein the metals are selected from Mg+2, Al+3, Fe+3, Rh+3, La+3, and Bi+3.
2. The use as claimed in claim 1, of chelates of azithromycin with antacids selected from the group of salts of Al, Mg, and Bi in the form of gels.
3. The use as claimed in claim 1, of chelates of azithromycin with aluminium hydroxide-magnesium carbonate in the form of gels.
4. The use as claimed in claim 1, of chelates of azithromycin with sucralfate in the form of gels.
5. The use as claimed in claim 1, of chelates of azithromycin with bismuth-subsalicylate in the form of gels.
6. Complexes and chelates of azithromycin with bivalent, trivalent or both metals wherein the metals are selected from Mg+2, Al+3, Fe+3, Rh+3, La+3, and Bi+3.
7. Complexes and chelates of azithromycin with antacids selected from the group of salts of Al, Mg, and Bi in the form of gels.
8. A chelate of azithromycin with aluminium hydroxide-magnesium carbonate in the form of gels.
9. A chelate of azithromycin with sucralfate in the form of gels.
10. A chelate of azithromycin with bismuth-subsalicylate in the form of gels.
11. A complex of azithromycin with Mg+2.
12. A complex of azithromycin with Al+3.
13. A complex of azithromycin with Fe+3.
14. A complex of azithromycin with Rh+3.
15. A complex of azithromycin with La+3.
16. A complex of azithromycin with Bi+3.
17. Complexes and chelates of azithromycin with Mg+2, Al+3, Fe+3, Rh+3, La+3, and Bi+3 in the ratio of 1:1 to 1:4.
18. Complexes and chelates of azithromycin with Mg+2, Al+3, Fe+3, Rh+3, La+3, and Bi+3 in the ratio of 2:1.
19. A process for preparing a chelate of azithromycin with a complex metal salt wherein said salt is selected from the group consisting of aluminium hydroxide-magnesium carbonate, bismuth-subsalicylate and bismuth sucralfate, which comprises reacting said azithromycin with said salt in an alcohol, in a weight ratio of 1:1 to 1:4, and evaporating said alcohol to obtain a dry residue to thereby isolate said chelate.
20. The process of claim 19, wherein said alcohol is methanol or ethanol.
CA002037663A 1990-03-07 1991-03-06 Use of complexes and chelates resp., of antibiotics with bivalent and/or trivalent metals in the obtaining of anti-ulcer drugs, new complexes and chelates resp., of antibiotics with bivalent and/trivalent metals and processes for the obtaining thereof Expired - Fee Related CA2037663C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
YU45590A YU45590A (en) 1990-03-07 1990-03-07 NEW COMPLEXES OR CHELATES OF ANTIBIOTICS WITH TWO-VALENT AND / OR TROVALENT METALS AND PROCEDURES FOR THEIR OBTAINING
YUP-455/90 1990-03-07

Publications (2)

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CA2037663A1 CA2037663A1 (en) 1991-09-08
CA2037663C true CA2037663C (en) 1999-01-19

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US (1) US5498699A (en)
EP (1) EP0445743B1 (en)
JP (1) JP2731636B2 (en)
CN (2) CN1041166C (en)
AT (1) ATE143266T1 (en)
BG (1) BG61230B1 (en)
CA (1) CA2037663C (en)
CZ (1) CZ280181B6 (en)
DE (1) DE69122282T2 (en)
DK (1) DK0445743T3 (en)
ES (1) ES2094763T3 (en)
GR (1) GR3021947T3 (en)
HR (1) HRP940256B1 (en)
HU (2) HU209455B (en)
PL (1) PL166279B1 (en)
RO (1) RO107660B1 (en)
RU (2) RU2039060C1 (en)
SI (1) SI9010455B (en)
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HRP940256B1 (en) 1998-10-31
CA2037663A1 (en) 1991-09-08
DK0445743T3 (en) 1997-02-17
DE69122282D1 (en) 1996-10-31
SI9010455A (en) 1997-08-31
ES2094763T3 (en) 1997-02-01
CS9100587A2 (en) 1991-10-15
RU2039060C1 (en) 1995-07-09
CN1041166C (en) 1998-12-16
SK279278B6 (en) 1998-09-09
HU910740D0 (en) 1991-09-30
ATE143266T1 (en) 1996-10-15
RO107660B1 (en) 1993-12-30
HRP940256A2 (en) 1997-06-30
BG61230B1 (en) 1997-03-31
CN1051560C (en) 2000-04-19
HUT56849A (en) 1991-10-28
US5498699A (en) 1996-03-12
EP0445743B1 (en) 1996-09-25
SI9010455B (en) 2000-04-30
EP0445743A2 (en) 1991-09-11
CZ280181B6 (en) 1995-11-15
CN1054534A (en) 1991-09-18
PL166279B1 (en) 1995-04-28
HU211475A9 (en) 1995-11-28
DE69122282T2 (en) 1997-04-24
EP0445743A3 (en) 1992-10-07
YU45590A (en) 1992-07-20
GR3021947T3 (en) 1997-03-31
JPH06184186A (en) 1994-07-05
HU209455B (en) 1994-06-28
RU2039061C1 (en) 1995-07-09
CN1168891A (en) 1997-12-31
JP2731636B2 (en) 1998-03-25

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