MXPA01001059A - New injectable formulations containing ramoplanin - Google Patents

Abstract

The present invention relates to a new injectable formulation of ramoplanin or a compound of the ramoplanin family. More particularly, the injectable formulations of the invention are particularly suitable for intravenous (i.v.) administration. They contain the active principle(s) in a fat emulsion product for i.v. administration. The formulations of the invention are well tolerated and are effective in particular in severe Gram positive infections.

Description

NEW INJECTABLE FORMULATIONS CONTAINING RAMOPLANIN BACKGROUND OF THE INVENTION The present invention relates to a new injectable formulation of ramoplanin or a compound of the ramoplanin family. More particularly, the injectable formulations of the invention are particularly suitable for intravenous (i.v.) administration. The ramoplanin (INN) is a known member of the antibiotics of the cyclic peptides more precisely known as the glycolipodepsipeptides which have been described in the Patents of US Pat. Nos. 4,303,646 and 4,238,316. Originally, antibiotic A 16686 has been named. It is a complex substance whose separate factors Ai, A2 and A3 have been described in US 4, 427, 656.

Description of the Invention The factors of the bouquet A 'x, A' 2 and A '3, have been described in EP-B-318680, the aglycones of Ref: 124974 any of the above factors have been described in US 5,491,128 while the tetrahydrogenated derivatives of any of the above factors have been described in US 5,108,988. A method for selectively increasing the proportion of the unique principal components of A2 and A3 is described in EP 0259780. All of the aforementioned patents are incorporated herein for reference. The structure of ramoplanin and its factors and derivative has been described in various articles and publications, see R. Ciabatti et al., J. Antib. 1989, 254-267, J. K. Kettenring et al., J. Antiob. 1989, 268-275, R. Ciabatti and B. Cavalleri, Bioactive Metabolites from Microorganisms, Elsevier Science Publisher, 1989, 205-219 and M. Kurz and W. Guba, Biochemistry 1996, 35, 12570-12575. N. J. Skelton et al. in J. Am. Chem. Soc. 1991, 113, 7522-7530 describe another member of this family, which they call Ramoplanosa. These compounds can be represented by the following formula (Formula I): FORMULA I where R -CO-CH = CH-CH = CH-CH2-CH2-CH3, represents -CO-CH = CH-CH = CH-CH2-CH (CH3) 2, -CO-CH = CH-CH = CH -CH2-CH2-CH (CH3) 2, -CO-CH2-CH2-CH2-CH2-CH2-CH2_CH3, -CO-CH2-CH2-CH2-CH2-CH2-CH (CH3) 2, -CO-CH2- CH2-CH2-CH2-CH2-CH2-CH (CH3) 2 R 'represents alpha-D-mannopyranosyl or 2,0-alpha-D-mannoprani i 1 -alf aD-mannopyranosyl, or R' represents 2,3-di-di [alpha aD-mannopyranosyl] -D-mannopyranosyl wherein R represents - CO-CH = CH-CH-CH-CH2-CH (CH3) 2, a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof in any proportion. The configuration of the double bonds of the unsaturated portions mentioned above in the definition of R have been found to be 2 (E) or cis and 4 (Z) or trans in the literature indicated above. The following table specifies the meanings for R and R 'of the only factors or derivatives with reference to the previous formula: The aglycones correspond to the compounds indicated above where R 'represents hydrogen while the tetrahydrogenate derivatives correspond to the compounds reported above where the R portion is totally hydrogenated. It is said that pinoplanosa corresponds to * factor A2"where R 'represents 2, 3-O-di [alpha-D-mannopyranosyl] -D-mannopyranosyl.

In the following description and claims, the term 'ramoplanin' refers to the complex of ramoplanin where the factor A2 is the main component, with small amounts of factors A'2, i, A'i, A3, A '3 and other related substances that make up the rest of this active ingredient, "ramoplanin" is particularly preferred wherein the A2 factor represents at least 75% of the active ingredient. The term "a member of the pralineplanin family" refers to any of the compounds listed above that are presented in Formula I, and to any salt or mixture thereof in any proportion. Bouquetplanin family are unsuitable for iv administration due to drawbacks such as swelling and progressive necrotization at the injection site, and hemolysis as revealed by the discoloration of the urine. The formulations of the invention contain ramoplanin or a member of the ramoplanin family in a mixture with a fat emulsion product for intravenous administration. In general, for i.v. administration purposes. according to this invention, it is suitable to use liquid compositions wherein the ramoplanin or a member of the ramoplanin family is present in concentrations ranging from 1 to 20 mg / ml, preferably from 1.5 to 15 mg / ml, more preferably from approximately 3 to 5 mg / ml. In the current claims and descriptions the expressions 'fat emulsion product for intravenous injection' or 'fat emulsion product' identifies any of those fat emulsion products suitable for intravenous administration by means of a peripheral vein or by infusion of the vein central that are currently used mainly to ensure caloric intake when parenteral nutrition is required. Examples of these substances are for example described in US Pharmacopoeia, Martindale, The Extra Pharmacopoeia (31st edition, 1996, page 1377) or VIDAL 1996, page 814. The above expressions also include those emulsions which are used as colloidal carriers of drugs, examples of which are indicated in the book 'Submicron Emulsions in Drug Targeting and Delivery' edited by S. Benita, Horwood Academic Publishers, 1998, on pages 119-122. All the publications cited are incorporated herein for your reference. The aforementioned fat emulsion products are based mainly on an oil phase stabilized by emulsifier, such as phospholipids, poloxamers or other polyoxyethylene derivatives such as, for example, polysorbates or polyoxyethylene of castor oil.Typically, a fat emulsion product suitable for preparing a formulation of the invention comprises an oil phase (usually 2-40%, preferably, 5-25% w / v), and preferably consists of vegetable oils such as soybean oil, safflower oil, and cottonseed oil, emulsifiers (usually 0.2-5%, preferably, 0.5-2% weight / volume), preferably based on phospholipids from egg sources such as, egg lecithin or soy lecithin, and additives in the form of osmotic agents such as glycerol, sorbitol and xylitol. These fat emulsion products, as they are commercially available, are emulsions comprising the aforementioned oil phase, emulsifiers and additives dispersed in water for injection and the oil phase is generally present in the emulsion in a percentage (weight / volume) of the 5 to 25%. To prepare the formulation administrable by i.v. of this invention, the product of the fat emulsions can be used as such or diluted with saline or water for injection by adding to an osmotic agent (eg glucose) to lower the concentration of the oil phase to a lower value and, at the same time, maintain the desired osmolarity. In general, if the concentration of ramoplanin or a member of the ramoplanin family in the formulation is low, it is possible to decrease the percentage of the oil phase in this formulation i.v. For example, with the concentrations of ramoplanin of approximately 10 mg / ml, the percentage of the oil phase in the formulations i.v. of the invention can range between 4 and 40% (weight / volume) although those fat emulsions i.v. wherein the oil phase is between 4 and 25%, and more preferably, between 8 and 18%, with the range of 8-10% being currently the most preferred concentration. With the concentrations of ramoplanin of approximately 1 mg / ml, the percentage of the oil phase in the formulation i.v. it can be reduced to a range between 0.2 and 10% (weight / volume). Generally, the osmolarity of the formulation i.v. final is between 250 and 300 mOsm / L, while the value for pH must be compatible with the stability of ramoplanina (or a member of the ramoplanina family), and, therefore, usually, it should not be greater than 8. As is known in the art, the emulsion particle size needs to be controlled for an iv administration adequate, and that is achieved through conventional preparation and final formulation procedures. Examples of fat emulsion products that can be conveniently used according to the present invention are those listed on page 120 of the aforementioned book: 'Sub icron Emulsion in Drug Targeting and Delivery' wherein the oil phase consists of soybean oil , cottonseed oil, safflower oil or mixtures thereof.Soil oil, cottonseed oil and safflower oil contain long chain fatty acids comprising mainly linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid, essentially in the form of triglycerides.The soybean oil, cottonseed oil and safflower oil can be completely or in part replaced by any mixture of the above fatty acids in the form of triglycerides having a percentage (weight / weight) and a composition substantially similar to the previous oils or their mixtures. The above-mentioned getals or the triglycerides of long-chain fatty acids can be replaced by medium-chain triglycerides (Cß ~ C12). Typically, the fat emulsion product used for the preparation of the i.v. they contain an oil phase in the range from 2 to 40% (weight / volume), preferably, from 5 to 25%, more preferably from 7 to 20%, of emulsifier in a range ranging from 0.2 to 5% (weight / volume), preferably, from 0.6 to 2%, more preferably from 0.5 to 1.5%, and the additive is in an adequate amount to control osmolarity, preferably in a range from 1.5 to 5% (weight / volume), more preferably from 2 to 3%. In this oil phase consisting of soybean oil, cottonseed oil or safflower oil or mixtures thereof, or in mixtures of fatty acids which may replace all or part of the above oils, triglycerides of fatty acids are normally they are present in the following percentage ratio (weight / weight) indicated in square brackets: linoleic acid (40-70%), oleic acid (15-30%), 'palmitic acid (5-15%), linolenic acid (3) -12%), stearic acid (2-6%). As indicated above, for the preparation of the formulations i.v. of this invention, the aforementioned fat emulsion products are used as such or are diluted in an iso-osmotic solution of water for injection at a concentration of the oil phase in the final composition which is at least 0.2% (weight / volume ), normally, depending on the concentration of the ramoplanin or a family member of the ramoplanin that is present in the final composition. According to a preferred embodiment of this invention, those fat emulsion products that are currently available under the Intralipid®, Liposyn® and Lipofundin® brands can be used. For example, Intralipid® (Kabi Vitrum / Pharmacia) and Liposyn® II and Liposyn® III (Abbott), have a composition and physicochemical properties as indicated below: Table I. Composition and characteristics of various intravenous fat emulsions As indicated above, in the formulations according to this invention, ramoplanin or a member of the ramoplanin family as defined above are generally present in the compositions of the invention. -15 invention in an amount ranging from 1 to 20 < mg / ml, with a range of 1.5 to 15 mg / ml being currently the preferred one, and a range from about 3 to about 5 mg / ml being most preferred. Typically, the composition of the invention is a The composition in which the oil phase in the final fat emulsion is between 0.2 and 40% (weight / volume), with a range from 4-25% being the preferred, a range of 8-18% being even more preferred. a range of 8-10% being currently the most preferred. However, as mentioned above, the proportion of the oil phase can be adjusted to that of the antibiotic and to minor amounts of ramoplanin which may correspond to minor amounts of the oil phase in the composition. Experiments with representative examples of the compositions of the invention have shown a good tolerance at the injection site, in particular compared to the effects of the conventional i.v. of the same active principle. The results of a first series of tolerance studies in representative examples of the formulations of the invention in rats at a concentration of ramoplanin of 10 mg / ml (dose 20 mg / kg, administration volume 2 ml / kg), compared to an iv formulation of the same active principle, are summarized below. More particularly, the ramoplanin in a conventional aqueous vehicle (0.9% saline) or in the formulations of the invention wherein the proportion of the oil phase in the total formulation is between 2 and 8% (weight / volume) is administered in rats (3-5 animals / group) at a dose of 20 mg / kg (drug concentration of 10 mg / ml). The volume administered is 2 ml / kg, according to the weight of the animal on the day of administration, and the injection rate is 0.1 ml / seconds. Intravenous administration is in the vena cauda. Treatments are planned for 3 days at 24-hour intervals. The control rats receive either 0.9% saline or an equivalent volume of Intralipid® 10%. Behavior and physical appearance are frequently observed on the day of dosing. The appearance of the urine is also recorded within 3 hours after each daily treatment. The rats are sacrificed 24 hours after the last treatment. The results of these experiments are summarized in Table II.

Table II. The appearance of the urine, the general pathology at the injection site and the clinical observations of the rats treated with ramoplanin formulated with Intralipid® or in a conventional aqueous vehicle (0.9% saline) (a) In water for injection, q.s. 100% (b) Visual examination carried out within 2-3 hours after scheduled treatment (c) Exams that are carried out at the end of the 3 scheduled treatments (d) Corresponds to a dose of 20 mg / kg Treatments with ramoplanin at a concentration of 10 mg / ml in a conventional aqueous vehicle or in a formulation with 2% (weight / volume) of the oil phase causes a darkening or discoloration at the injection site (the tail). In contrast, treatment with the formulations of the invention wherein the oil phase is 4% (w / v) or greater is well tolerated. The tails do not show any sign of necrotic inflammation. After the immediate period after the dose of each treatment (3 h) with the formulations of the invention where the oil phase is 4% (w / v) or greater, the urine appears from a straw color to a dark yellow. In contrast, the rats are given a formulation with 2% (weight / volume) of oil phase or ramoplanin in a conventional aqueous vehicle develop a red or red to brown urine, within the same period after the dose. A second series of experiments are carried out to determine the tolerance of the formulation of the invention according to the same procedure described above but administering a dose corresponding to 10 mg / kg instead of 20 mg / kg to various groups of three rats during 3 days in 24 hour intervals. The concentration of ramoplanin in the formulation is 1 mg / ml instead of 10 mg / ml and the volume of the formulation administered to each rat is 10 ml / kg instead of 2 ml / kg. The fat emulsion product Intralipid® is added in several different proportions as represented in the following Table III where the same parameters as considered in Table II are indicated. The rats are sacrificed 24 hours after the last treatment.

Table III. Appearance of urine, general pathology at the injection site and clinical observations of rats treated with ramoplanin formulated with Intralipid® or in a conventional aqueous vehicle (0.9% saline) (a) In water for injection, q.s. 100% (b) Visual examination carried out within 3 hours after scheduled treatment (c) Exams that are carried out at the end of the 3 scheduled treatments (d) Corresponds to a dose of 10 mg / kg The above data show that ramoplanin at a concentration of 1 mg / ml can be safely administered intravenously in experimental animals at a dose of 10 mg / kg when the drug is appropriately formulated according to this invention in the emulsion compositions containing Intralipid® in an amount such that in the oil phase it is at least 0.2% (weight / volume) of the total formulation. The effectiveness of the representative examples of the compositions of the invention in the experimental models in animals can be demonstrated in various experiments of acute septicemia in neutropenic or immunocompetent mice and in experiments of endocarditis and pneumococcal lobar pneumonia in rats. Experimental septicemia is induced by intraperitoneally inoculating (5-6 animals / dose / treatment group) a bacterial suspension of either a clinical isolate of a methicillin-resistant Staphylococcus strain (Staph. Aureus L613) or a streptococcus strain ( Strep pneumonia L 44) in immunocompetent mice or an enterococcal strain clinically isolated and resistant to glycopeptides (Ent. Fa eci um L569) in neutropenic mice. The immunocompetent mice are males and females of CDi mice (Charles River Labs., Calco, Italy) weighing from 18-22 g while the neutropenic mice are female NMRI mice of 6-8 weeks of age (Iffa Credo, France). Animals without treatment die within a period of 24-72 hours after infection. Treatment with antibiotics begins within 10 minutes after the injection. The ramoplanin in various concentrations is administered intravenously in a conventional aqueous vehicle or in the formulation of the invention in 8% (weight / volume) of oil-phase fat emulsion. Gentamicin, vancomycin, teicoplanin and rifampicin can be included as comparator drugs. 50% of the effective dose (ED50) and 95% of the confidence limits are calculated using the Spearman-Karber method by the percentage of animals that survive on day 10. The animals undergo treatment twice, first 10 minutes from the infection and then 24 hours later. When gentamicin or vancomycin are used as comparators, they are administered subcutaneously and the second injection is given 5 hours after infection. Rifampicin and teicoplanin are administered subcutaneously in a single dose 10 minutes after infection. The results of the experiments that are carried out as described above are indicated in the following table: Table IV. ED50 of ramoplanin in experimental septicemia in mice to ED50 of comparators are as follows: gentamicin 50.6 (37.3-68.7), rifampin 1.2 (0.9-1.5), vancomycin > 90% ED50 of the comparator (teicoplanin) is 5.4 (4.3-6.9). c ED50 of the comparator (teicoplanin) is 0.79 (0.65-0.96). d Confidence limit can not be calculated because the survival is either 0 or 100% in each treatment group.

Endocarditis experiments can be carried out in experimental animals (rats) with staphylococcus or enterococcus isolates. A polyethylene catheter is inserted through the aortic valve into the animal's left ventricle via the right carotid artery. Two days later, the animals are infected i.v. Treatment begins days after infection and continues for a total of 5 days. The surviving animals are sacrificed on day 7 after infection. The hearts of all animals that are homogenized are processed to determine the bacterial load, which is expected to be substantially reduced in the treatment group receiving the formulations of the invention, compared to the untreated controls. Pneumonia experiments can be carried out in immunocompetent and neutropenic rats with, for example, a clinically isolated strain resistant to penicillin from Strep. pneumoni ae. The anesthetized animals are infected by intrabronchial surgical implantation by means of intratracheal intubation, with a 40 μl inoculum containing approximately 106 to 10 7 logio CFU (colony forming units) of Strep. pneumoniae and they are allowed to recover. The therapy starts after 12 hours of infection and continues for a total of 3 days. The surviving animals are sacrificed on day 4 after infection. The lungs of all animals are homogenized and processed to determine the bacterial load, which is expected to be substantially reduced in the treatment group receiving the formulations of the invention, compared to the untreated control. The results indicated above show that the formulations of the invention are generally well tolerated, in particular at the site of injection, as demonstrated by the absence of necrotic inflammation and discoloration in the urine. The results indicate that the drug administered is effective to treat infections caused by multiresistant microorganisms. The formulations of the invention can therefore be effectively administered to a patient in need of this to control or cure infections sustained by microorganisms known to be susceptible to ramoplanin or to an antibiotic of the ramoplanin family. Of particular preference is the use of the formulations of the invention in the antibiotic treatment of serious Gram-positive infections such as bacteremia, neocarditis and pneumonia. In particular, the use of the formulations of the invention is especially suitable for the systemic treatment of severe infections caused by resistant or multiresistant Gram-positive microorganisms, such as negative staphylococci or coagulase-positive staphylococci resistant to penicillin or enterococci resistant to glycopeptide. In the present description, the term "patient" is intended to refer to warm-blooded animals such as rodents, felines, equines, bovines and primates, including humans, preferably with respect to the term "patient" according to the invention, in addition to of humans, there are the pets and animals of granjo.An example of the dose range of ramoplanin or a member of the family of ramoplanin that can be administered by the formulation of the invention, which is known to be effective for a therapy in humans, is preferably between 0.5 and 1 g / ml, while a preferred formulation contains between about 1 and 20 mg / ml preferably, between 1.5 and 15 mg / ml, more preferably, between about 3 to about 5 mg / ml of ramoplanin or a member of the ramoplanin family, particularly preferred is the use of the formulations of the invention in severe enterococcal infections, particularly those which are attributed to vancomycin resistant strains, for which there is no effective treatment currently available (see for example M. Edmon et al., Clinical Infectious Diseases, 1996; 23: 1234-1239). As well as infections where streptococci resistant to penicillin are present. In these treatments, the formulation of the invention is preferably used as a slow infusion in the central vein. The formulations of the invention are prepared according to conventional techniques, based on the present description. The pH of the present final preparation is less than 7 and preferably between 4 and 6.5, with a pH between 5.5 and 6.5 being currently the most preferred. If necessary, the pH of the final formulation is adjusted to the desired value by the procedures that are known.

The formulation i.v. of ramoplanin (or a member of the ramoplanin family) of this invention may be in the form of a ready-to-use dosage form containing both the antibiotic and the fat emulsion product or it may be in the form of a kit of reagents which comprises separate packages or separate containers containing ramoplanin (or a member of the ramoplanin family), and the fat emulsion product to constitute this formulation iv when it needs to be used. In particular, this set of reagents may consist of bottles or similar containers containing the dose of the sterile and lyophilized antibiotic, ampules containing water for injection in an amount sufficient to dissolve the antibiotic and bottles containing the sterile product of the fat emulsion in an appropriate amount to make the formulation iv desired. Examples of the specific formulations of the invention and methods for the formulation are indicated below.

Table V. Bouquetplanin formulations (10 mg / ml) in various dilutions of Intralipid® It is added slowly operatively to 10% of Intralipid® (Pharmacia), under moderate agitation, the glucose solution followed by the ramoplanin solution. The solution of ramoplanin in distilled water is prepared by dissolving 562 mg of ramoplanin (89% strength determined by HPLC titration) in distilled water (5 ml) and then giving the final volume (10 ml).

Table VI Bouleplanin formulations (1 mg / ml) in various dilutions of Intralipid® A solution of ramoplanin of 10 mg / ml of activity in NaCl 0.9% (w / vol) is prepared. This solution is sterilized by filtration with 0.22 μm pore size filters. 1 ml of the ramoplanin solution is added to an aliquot of Intralipid® diluted to the desired concentration by a slow addition of the appropriate volume of 0.9% NaCl. The mixture is stirred vigorously to obtain a homogeneous solution in the fat emulsion.

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (19)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A pharmaceutical formulation for intravenous administration characterized in that it comprises ramoplanin or a member of the ramoplanin family of the formula I where: R -CO-CH = CH-CH = CH-CH2-CH2-CH3, represents -CO-CH = CH-CH = CH-CH2-CH (CH3) 2, -CO-CH = CH-CH = CH-CH2-CH2-CH (CH3) 2, -CO-CH2-CH2-CH2-CH2-CH2-CH2.CH3, -CO-CH2-CH2-CH2-CH2-CH2-CH (CH3) 2l -CO- CH2-CH2-CH2-CH2-CH2-CH2-CH (CH3) 2

R 'represarta al D-mannopyranosyl or 2,0-alpha-D-mannopyranos i 1 -alf aD-mannopyranosyl, 0 R' represents 2,3-O-di [alpha-D-mannopyranosyl] -D-mannopyranosyl wherein R represents -C0- CH = CH-CH = CH-CH2-CH (CH3) 2, a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof in any proportion, in admixture with an amount of a fat emulsion product for intravenous administration wherein the concentration of the oil phase is at least 0.2% ( weight / volume), 2. A formulation in accordance with the claim 1, characterized in that the fat emulsion product comprises an oil phase, an emulsifier and an additive in the form of an osmotic agent.

3. A formulation in accordance with the claim 2, characterized in that the product of the fat emulsion comprises an oil phase of vegetable oils such as soybean oil, cottonseed oil, safflower oil or a mixture of these, an emulsifier based on phospholipids, preferably from a source of egg such as egg lecithin, soy lecithin or a mixture thereof, and an additive in the form of an osmotic agent such as sorbitol, glycerol, xylitol or mixtures thereof.

4. A formulation in accordance with the claim 3, characterized in that the oil phase is in a range from 0.2 to 40% (weight / volume), preferably, from 4 to 25%, more preferably, from 8 to 18%, and, more preferably, from 8 to 10%. % of the final formulation.

5. A formulation according to any of claims 1 to 4, characterized in that the fat emulsion product used for the preparations or formulations contains from 2 to 40%, (weight / volume), preferably, from 5 to 25%, more preferably from 7 to 20% of the oil phase, from 0.2 to 5%, (weight / volume), preferably, from 0.6 to 2%, more preferably, from 0.5 to 1.5% of emulsifier and an additive in a suitable amount to control the osmolarity, preferably in a range from 1.5 to 5% (weight / volume), preferably from 2 to

6. A formulation according to any of claims 1 to 5, characterized in that the oil phase contains long chain fatty acids in the form of triglycerides in the following proportions by weight: Linoleic acid 40-70% Oleic acid 15-30% Palmitic acid 5-15% Linolenic acid 3-12% Stearic acid 2-6%

7. A formulation according to any of claims 1 to 6, characterized in that the product of the fat emulsion used for the preparation of this formulation comprises a composition selected from those indicated in the following tables: and water for the injection q.s. to 100%

8. A formulation according to claim 6 or 7, characterized in that the soybean oil and / or the cottonseed oil and / or the safflower oil are totally or partially replaced by a mixture and long chain fatty acids in the form of triglycerides to form a composition wherein these fatty acids are present in respective proportions as indicated in these claims and, optionally part of the above oils or the long chain fatty acids are replaced by medium chain (C6-C12) triglycerides.

9. A formulation according to any of claims 1 to 8, characterized in that the concentration of the oil phase is between 4 and 25% (weight / volume), preferably between 8 and 18%, more preferably between 8 and 10% of the final formulation.

10. A formulation according to claim 9, characterized in that the concentration of the oil phase is between 8 and 10% (weight / volume) of the final formulation.

11. A formulation according to any one of claims 1 to 10, characterized in that the ramoplanin is present at a concentration between 1 and 20 mg / ml, preferably from 1.5 to 15 mg / ml, more preferably, from about 3 to about 5 mg / ml.

A formulation according to any of claims 1 to 11, characterized in that the pH of the final formulation is less than 8, preferably, less than 7.

13. A formulation according to any of claims 1 to 10, characterized in that the pH of the final formulation is between 4 and 6.5.

14. A formulation according to any of claims 1 to 13, characterized in that it is for the treatment of infections caused by agents that are susceptible to ramoplanin or an antibiotic of the ramoplanin family.

15. A formulation according to any of claims 1 to 13, characterized in that it is for the treatment of a serious infection caused by Gram-positive such as bacteremia, endocarditis or pneumonia.

16. A formulation according to any one of claims 1 to 13, characterized in that it is for the treatment of severe infections caused by drug-resistant or multiresistant Gram-positive microorganisms such as coagulase-positive and negative staphylococci, penicillin-resistant streptococci or resistant enterococci. to the glycopeptides.

17. A formulation according to any of claims 1 to 16, characterized in that the factor A2 of ramoplanin is present in an amount of at least 75%.

18. A pharmaceutical composition characterized in that it consists of a ready-to-use dose form or of a set of reagents comprising separate packages or separate containers containing ramoplanin or a member of the ramoplanin family and the fat emulsion product for constitution of a formulation according to any one of claims 1 to 17.

19. A kit of reagents according to claim 18, characterized in that it consists of bottles or similar containers containing the dose of lyophilized sterile antibiotic, ampules containing water for injection in an amount sufficient to dissolve the antibiotic and bottles containing the sterile product of fat emulsion in an appropriate amount to constitute the iv formulation desired.