Injectable formulations containing ramoplanin

Details Injectable formulations containing ramoplanin Injectable formulations containing ramoplanin

2001-01-30

2004-04-13

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S013800, C530S317000, C530S326000, C424S450000

Reexamination Certificate

active

06720305

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.
Ramoplanin (INN) is a known member of the cyclic peptide antibiotics more precisely known as glycolipodepsipeptides which has been described in U.S. Pat. No. 4,303,646 and U.S. Pat. No. 4,328,316. Originally it has been named antibiotic A 16686. It is a complex substance whose separate factors A
1
, A
2
and A
3
have been described in U.S. Pat. No. 4,427,656.
Ramoplanin factors A′
1
, A′
2
and A′
3
have been described in EP-B-318680, the aglycones of any of the above factors have been described in U.S. Pat. No. 5,491,128 while the tetrahydrogenated derivatives of any of the above factors have been described in U.S. Pat. No. 5,108,988. A method for selectively increasing the ratio of single major components A
2
A
3
is described in EP 0259780. All the above mentioned patents are incorporated herein by reference.
The structure of ramoplanin and its factors and derivatives have been described in several articles and publications, see R. Ciabatti et al., J. Antib. 1989, 254-267, J. K. Kettenring et al., J. Antob 1989, 268-275, R. Ciabatti and B. Cavalleri, Bioactive Metabolites from Microorganisms, Elsevier Science Publishers, 1989, 205-219 and M. Kurz and W. Guba, Biochemistry 1996, 35, 12570-124575.
R′ represents alpha-D-mannopyranosyl or s-o-alpha-D-mannopyranosyl-alpha-D-mannopyranosyl.
N. J. Skelton et al. in J. Am. Chem. Soc. 1991, 113, 7522-7530 describe another member of this family, which they call Ramoplanose.
These compounds can be represented by the following formula (Formula I):
wherein:
R represents —CO—CH═CH—CH═CH—CH
2
—CH
2
—CH
3
,
—CO—CH═CH—CH═CH—CH
2
—CH (CH
3
)
2
,
—CO—CH═CH—CH═CH—CH
2
—CH
2
—CH (CH
3
)
2
,
—CO—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH
3
,
—CO—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH (CH
3
)
2
or
—CO—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH (CH
3
)
2
R′ represents alpha-D-mannopyranosyl or 2-O-alpha-D-mannopyranosyl-alpha-D-mannopyranosil,
or
R′ represents 2,3-O-di[alpha-D-mannopyranosyl]-D-mannopyranosyl when R represents —CO—CH═CH—CH═CH—CH
2
—CH(CH
3
)
2
,
a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof in any proportion.
The configuration of the double bonds of the unsaturated moieties reported above in the definition of R have been found to be 2 (E) or cis and 4 (Z) or trans in the literature reported above.
The following table specifies the meanings for R and R′ of the single factors or derivatives with reference to the above formula:
Factor
R
R′
A
1
—CO—CH═CH—CH═CH—CH
2
—
2-O-alpha-D-manno-
CH
2
—CH
3
pyranosyl-alpha-D-
mannopyranosyl
A
2
—CO—CH═CH—CH═CH—
2-O-alpha-D-manno-
CH
2
—CH(CH
3
)
2
pyranosyl-alpha-D-
mannopyranosyl
A
3
—CO—CH═CH—CH═CH—CH
2
—
2-O-alpha-D-manno-
CH
2
—CH(CH
3
)
2
pyranosyl-alpha-D-
mannopyranosyl
A′
1
—CO—CH═CH—CH═CH—
Alpha-D-
CH
2
—CH
2
—CH
3
mannopyranosyl
A′
2
—CO—CH═CH—CH═CH—
Alpha-D-
CH
2
—CH(CH
3
)
2
mannopyranosyl
A′
3
—CO—CH═CH—CH═CH—CH
2
—
Alpha-D-
CH
2
—CH(CH
3
)
2
mannopyranosyl
The aglycones correspond to the compounds reported above wherein R′ represents hydrogen while the tetrahydrogenate derivatives correspond to the compounds reported above wherein the mojety R is fully hydrogenated.
Ramoplanose is reported to correspond to “factor A
2
” wherein R′ represents 2,3-O-di[alpha-D-mannopyranosyl]-D-mannopyranosyl.
In the following description and claims, the term “ramoplanin” refer to a ramoplanin complex wherein factor A
2
is the major component, with a small amounts of factors A′
2
, A
1
, A′
1
, A
3
, A′
3
and other related substances accounting for the remainder of this active ingredient.
Particularly preferred is “ramoplanin” wherein factor A
2
represents at least, 75% of the active ingredient.
“A member of the ramoplanin family” refers to any of the compounds reported above that are represented by Formula I, any salt or any mixture thereof in any proportion.
Ramoplanin as well as any members of the ramoplanin family are unsuitable for i.v. administration because of drawbacks such as swelling and progressive necrotization at the site of injection, and haemolysis as revealed by urine discoloration.
The formulations of the invention contain ramoplanin or a member of the ramoplanin family in admixture with a fat emulsion product for intravenous administration.
In general, for i.v. administration purposes according to this invention, it is suitable to utilize liquid compositions wherein ramoplanin or a member of ramoplanin family is present in concentration from 1 to 20 mg/ml, preferably, from 1.5 to 15 mg/ml, most preferably, from about 3 to about 5 mg/ml.
In the current description and claims the expressions “fat emulsion product for intravenous injection” or “fat emulsion product” identify any of those fat emulsion products suitable for intravenous administration via a peripheral vein or by a central venous infusion that are currently used mainly to assure calories intake when parenteral nutrition is required. Examples of these substances are for instance reported in US Pharmacopeia, Martindale, The Extra Pharmacopeia (31
st
edition, 1996, page 1377) or VIDAL 1996, page 814. The above expressions include also those emulsions used as colloidal drug carriers, examples of which are reported in the book “Submicron Emulsions in Drug Targeting and Delivery” edited by S. Benita, Horwood Academic Publishers, 1998, at pages 119-122. All above cited publications are incorpored hereby by reference.
The above said fat emulsion products are largely based on an oil phase stabilized by emulsifiers, like phospholipids, poloxamers or other polyoxyethylene derivatives such as, for instance, polysorbates or polyoxyethylene 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% weight/vol), preferably consisting of vegetable oils such as soybean oil, safflower oil and cottonseed oil, emulsifiers (usually 0.2-5%, preferably, 0.5-2% weight/vol), preferably based on phospholipids of egg source such as egg lecithin or soybean lecithin, and additives as osmotic agents such as glycerol, sorbitol and xylitol.
These fat emulsion products, as commercially available, are emulsions comprising the above mentioned oil phase, emulsifiers and additives dispersed in water for injection and the oil phase is generally present in the emulsion in a percentage (weight/vol) of 5 to 25%. For preparing the i.v. administrable formulation of this invention, the fat emulsion product may be used as such or diluted with saline or water for injection added with an osmotic agent (eg. glucose) to decrease the oil phase concentration to a lower value and, at the same time, maintaining the desired osmolarity.
In general, if the concentration of ramoplanin or a member of ramoplanin family in the formulation is low, it is possible to lower the percentage of the oil phase in said i.v. formulation.
For instance, with ramoplanin concentrations of about 10 mg/ml, the percentage of the oil phase in the i.v. formulations of the invention may range between 4 to 40% (weight/vol) although are preferred those i.v. fat emulsions wherein the oil phase is between 4 and 25%, and, more preferably, between 8 and 18%, with the range 8-10% being currently the most preferred concentration.
With ramoplanin concentrations of about 1 mg/m the percentage of the oil phase in the i.v. formulation can be lowered to a range between 0.2 and 10% (weight/vol).
Generally, the osmolarity of the final i.v. formulation is between 250 and 300 mOsm/L, while the value of the pH must be compatible with the stability of ramoplanin (or a member of the ramoplanin family), and, therefore, usually, it should not be

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