Title of Invention


Abstract The invention relates to the use of a polymer guanine derivative based on a diamine comprising oxyalkylene chains between two amino groups, whereby the guanine derivative is a product of polycondensation of a guanidine acid addition salt with a diamine comprising polyakylene chains between two amino groups, used in the production of an antimicrobially active medicament.
(39 of 1970)
COMPLETE SPECIFICATION (See section 10, rule 13)

GEOPHARMA PRODUKTIONSGMBH, of Richard neutral-gasses, A-1210 Wien, Austria;
The following specification particularly describes the invention and the manner in which it is to be performed.

The present invention relates to a pharmaceutical composition useful as an antimicrobial or microbicidal agent.
Especially in recent years the development of new antibiotics has been a race against the increasingly developing resistance of microorganisms. The treatment of nosocomial infections, often caused by resistant microorganisms, is one of the major problems encountered by hospitals all over the world. Infections in the field of dermatology such as infections after skin burns, wound infections, decubitus or acne often require lenghty treatments with antibiotics. At the same time, the development of resistances can frequently be observed in staphylococci and pseudomonas strains. Infections of the gastrointestinal tract by Helicobacter pylon also often represent a therapeutic problem. Moreover, especially conjunctivitides, infections of the ENT and genital regions caused by bacteria or viruses may mean therapeutic problems.
The present invention provides a pharmaceutical composition useful as an antimicrobial agent, said composition comprising a polymeric guanidine derivative based on a diamine containing oxyalkylene chains between two amino groups or pharmaceutically acceptable salts thereof in an amount of 0.01 to 5.0g per gram of total composition together with pharmaceutically acceptable excipients and adjuvants.
It is the object of the invention to provide a new drug composition having an increased effectiveness against a plurality of microorganisms.
According to the invention, said object is achieved by using a polymeric guanidine derivative based on a diamine containing oxyalkylene chains between two amino groups, with the guanidine derivative representing a product of polycondensation between a guanidine acid addition salt and a diamine containing polyalkylene chains between two amino groups, as well as the pharmaceutically acceptable salts thereof for the production of a drug composition with antimicrobial activity.

Furthermore, the invention relates to the use of polyoxyalkylene guanidine salts prepared by using triethylene glycol diamine (relative molecular mass: 148), polyoxypropylene diamine (relative molecular mass: 230) as well as polyoxyethylene diamine (relative molecular mass: 600).
Most preferably poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] having at least 3 guanidinium groups is contained as the drug substance, with the average molecular mass in particular ranging from 500 to 3.000 D.

The polymeric guanidine derivatives used in accordance with the invention are known from PCT/AT01/00134. By way of reference, the content of said literature is incorporated in the present specification.
The preparation of a preferred representative of the compounds used in accordance with the invention as well as the proof of the antimicrobial activity are described in the following. Exemplary for the class of compounds used in accordance with the invention, the antimicrobial activity of poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] with an average molecular mass of 1000 D is described hereafter (CAS No. 374572-91-5).
In order to prepare said compound, 4.43 moles of guanidiniura hydrochloride were dissolved in 4.03 moles of triethylene glycol diamine at 50°C. Subsequently, this was heated to 120°C and stirred for two hours at said temperature. Thereafter, said temperature was maintained for 2 hours, then a vacuum (0.1 bar) was applied and stirring under vacuum was continued for two more hours at 170°C. Subsequently, this was aerated to normal pressure, allowed to cool to 120°C and diluted with demineralized water to approx. 50%. It was neutralized to a pH of approx. 6 with phosphoric acid, allowed to cool and diluted to the desired concentration The molecular weight was determined to be 1000 D.
The drug substance poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] exhibits favourable pharmacodynamic properties, along with low toxicity and good tolerance from a pharmacological point of view, and can therefore be used as a medicine in antimicrobial therapy. The drug substance exhibits in particular an excellent antimicrobial activity which could be demonstrated by tests performed on a plurality of microorganisms such as multiresistant bacteria (which are resistant against common antibiotics), fungi (blastomyces, dermatophytes, mould fungi) and viruses such as Herpes simplex. Due to the quick microbicidal activity, a development of resistance is not to be expected, as shown also by tests performed on a comparatively large number of bacterial strains (30 bacterial species and 30 passages).
After an (intravenous or intraperitoneal) systemic administration of poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] in amounts of up to 15 mg/kg body weight, serum concentrations of up to 100 μg/ml are measured in the rat"s blood after two hours, whereby, at the same time, the tolerance is good. These concentrations are significantly above the required level to be expected in a therapeutic application. At the same time, good tolerance was observed even with such a high dosage, mortality or serious side-effects did

not occur. Therefore, poly-[2-(2-ethoxyethoxyethyl) guanidinium hydrochloride] can be used as an antimicrobial agent.
The drug substance can be administered as a medicine in a suitable drug form alone or together with inorganic or organic pharmacologically indifferent adjuvants. The substance can, for example, be used as a component of an ointment or a solution, wherein the concentration in the ointment may amount to approx. 0.01 to 5g drug substance per g of ointment or, in the solution, up to a concentration of 15 mg/kg body weight. Due to the above-mentioned favourable pharmacological properties, the application as an ointment or as a solution can be regarded as favourable in a plurality of indications. In particular infections of the skin, mucous membranes, eyes or of the gastrointestinal tract are considered for this purpose. In these areas, the drug substance according to the invention can thus make an important contribution to the avoidance of resistances against antibiotics.
Antimicrobial activity
In order to assay the antimicrobial activity, 334 microorganisms, clinically relevant isolates
and ATCC strains as reference germs were tested for their minimum inhibition
concentrations (MIC). Furthermore, the time- and concentration-dependent destruction of
germs (killing curves) and, moreover, the potential for the development of resistances was
1. Microorganisms:
In total, 323 bacteria of various species, 10 blastomyces as well as one dermatophyte were used. The tested microorganisms were isolated from the respiratory tract, the urogenital tract, from blood and other biological materials of patients in accordance with standard laboratory methods and were characterized precisely.
2. Test substance:
The above-described poly-[C2-(2-ethoxy)-ethoxyethyl)-guanidium-chloride] (molecular mass: 1000 D) was used as a stock solution in a 25% aqueous solution. This solution was diluted with sterile water to the respective ready-for-use concentration. The test substances are stored at room temperature.
3. Determination of minimum inhibition concentration (MIC):
The activities of the test substance were examined by the microdilution method in Mueller-Hinton broth according to NCCLS guidelines. The microbial inoculum amounted to at least

The clinical effectiveness of the drug substance in 12 selected patients is summarized in Table 6. Type of treatment, duration of treatment, principal clinical signs and clinical success can be seen as well.
In short, a convincing clinical effectiveness could be observed in all 12 cases after a treatment period of 2 to 28 days. A clear improvement of principal signs occurred, whereas locai tolerance was excellent. In none of the cases, side-effects such as reddening, irritations or nausea occurred.
Table 6

We claim:
1. A pharmaceutical composition useful as an antimicrobial agent, said composition comprising poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] in an amount of 0.01 to 5.0g per gram of total composition together with pharmaceuncally acceptable excipients and adjuvants.
2. A composition as claimed in claim 1, wherein the poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] has three guanidinium groups.
3. A composition as claimed in claims 1 and 2, wherein the molecular mass of poly-[2-(2-ethoxyethoxyethyl)guanidinium hydrochloride] ranges from 500D to 3000D.
Dated this 19th day of September, 2005




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Patent Number 221040
Indian Patent Application Number 1020/MUMNP/2005
PG Journal Number 35/2008
Publication Date 29-Aug-2008
Grant Date 12-Jun-2008
Date of Filing 19-Sep-2005
Applicant Address Strohgasse 14C, A-1030 Wien (AT)
# Inventor's Name Inventor's Address
1 GEORGOPOULOS, Apostolos Kaasgrabengasse 123 B, A-1190 Wien,
PCT International Classification Number A61K 31/155
PCT International Application Number PCT/AT2004/000097
PCT International Filing date 2004-03-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 A453/203 2003-03-20 Austria