Injectable formulations of avermectins and milbemycins

Details Injectable formulations of avermectins and milbemycins Injectable formulations of avermectins and milbemycins

1999-03-10

2003-09-09

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S030000, C514S341000, C514S772000, C514S943000, C424S422000

Reexamination Certificate

active

06617314

ABSTRACT:

The invention relates to new injection formulations of avermectins and milbemycins based on solvent mixtures which contain sesame oil.
Injection formulations of ivermectin are disclosed in EP-A 146 414. The formulations contain a solvent mixture of propylene glycol and glycerol formal in the ratio 60:40 v/v. It is known of propylene glycol that in certain concentrations it can cause local intolerabilities (see review: B. Kruss, Acta Pharm. Technol. 35(4) (1989) 187-196). The precipitation of the water-insoluble active compound ivermectin can also occur in the tissue around the administration site. Thus when using corresponding formulations marked swellings and tissue incompatibilities were observed at the injection sites, some of which only receded after several weeks.
Injection formulations of specific avermectins are disclosed in EP-A 393 890. They are oil formulations based on sesame oil and ethyl oleate in the ratio 90:10 v/v. These formulations are tolerable, but have the disadvantage that the solubility for avermectin/milbemycins is often inadequate to achieve a concentration of 1% m/v or higher which is desirable for use. As a rule, under elevated temperature conditions (T≧80° C.) supersaturated 1% n/v solutions are obtained, which permanently crystallize out again at lower temperatures.
Further injection formulations of avermectins are disclosed in EP-A 45 655. The formulations described there contain comparatively high amounts of emulsifiers and in some cases are not very tolerable.
Injection formulations of avermectins which contain triacetin (glycerol triacetate) are described in EP-A 413 538. In EP-A 535 734, injection formulations of avermectins based on triacetin and hydrogenated castor oil are described.
Further formulations for the injection of milbemycins and avermectins are described in EP-A 525 307. The formulations are prepared by fusing glycerol tristearates with the active compound and mixing with an oily neutral triglyceride and emulsifying using, for example, methylcellulose and salts. The average particle size in the microemulsion thus obtained should be between 25 and 300 &mgr;m.
The present invention relates to injection formulations of avermectins and milbemycins based on a solvent mixture comprising sesame oil, medium-chain triglycerides or glycol esters or fatty acid esters and a further solvent.
The formulations preferably contain:
1. active compound 0.2 to 5% m/v;
2. sesame oil 60 to 90% v/v;
3. medium-chain triglycerides or glycol esters or fatty acid esters 10 to 30% by volume;
4. 1 to 20% by volume of benzyl alcohol or propylene glycol or other suitable aliphatic or aromatic mono- or polyhydric alcohols and their derivatives (e.g. cyclic carbonates, acetates, acetals/ketals) or castor oil;
5. if appropriate, further auxiliaries.
The formulations according to the invention have an outstanding solubility for the active compounds.
The high viscosity of sesame oil can be adjusted to a desired low value by addition of medium-chain triglycerides or propylene glycol octanoate/decanoate or particularly ethyl oleate. Additionally, the solubility of the active compound can be improved, the viscosity further reduced and the bioavailability of the active compound improved by addition of relatively small volumes of hydrophilic solvents such as benzyl alcohol, propylene glycol or propylene carbonate with retention of a single-phase system. Castor oil is the only triglyceride which has a high solvent potential for the active compounds in question.
The active compounds employed in the formulations according to the invention are known.
Avermectins were isolated from the microorganism
Streptomyces avermitilis
as microbial metabolites (U.S. Pat. No. 4,310,519) and can occur essentially as a mixture consisting of the eight components A
1a
, A
1b
, A
2a
, A
2b
, B
1a
, B
1b
, B
2a
and B
2b
(I. Putter et al., Experentia 37 (1981) p. 963, Birkhäuser Verlag (Switzerland)). In addition the synthetic derivatives, in particular 22,23-dihydroavermectin B
1
(ivermectin), are also of interest (U.S. Pat. No. 4,199,569). Milbemycin B-41 D was isolated from
Streptomyces hygroscopicus
by fermentation (cf. “Milbemycin: Discovery and Development”, I. Junya et al., Annu. Rep. Sankyo Res. Lab. 45 (1993), pp. 1-98; JP Pat. 8 378 549; GB 1 390 336).
The use of the avermectins, e.g. 22.23-dihydroavermectins B
1
(ivermectin) and milbemycins as endoparasiticides is known and is the subject of numerous patent applications and review articles (e.g. biological actions in: “Ivermectin and Abamectin”, W. C. Campbell, Ed., Springer Verlag, New York, N.Y., 1989; “Avermectins and Milbemycins Part II” H. G. Davies et al., Chem. Soc. Rev. 20 (1991) pp. 271-339; chemical modifications in: G. Lukacs et al. (Eds.), Springer Verlag, New York, (1990), Chapter 3; Cydectin® [moxidectin and derivatives]: G. T. Carter et al., J. Chem. Soc. Chem. Commun. (1987), pp. 402-404); EP 423 445-A1) “Doramectin—a potent novel endectocide” A. C. Goudie et al., Vet. Parasitol. 49 (1993), pp. 5-15).
Avermectins and their derivatives which may be particularly emphasized are those of the general formula (I)
in which
the radicals R
1
to R
4
have the meaning indicated in Table 1 which follows and X can represent a single or double bond between the C
22
- and C
23
-positions (—C
22
R
1
—X—C
23
R
2
—)
If there is a double bond, there are no substituents (R
1
, R
2
)in the C
22
- and C
23
-positions.
TABLE 1
Macrocyclic lactone
—C
22
R
1
—X—C
23
R
2
—
R
3
R
4
Avermectin A
1a
—CH═CH—
-sec-Bu
—Me
Avermectin A
1b
—CH═CH—
-iso-Pr
—Me
Avermectin A
2a
—CH
2
—CHOH—
-sec-Bu
—Me
Avermectin A
2b
—CH
2
—CHOH—
-iso-Bu
—Me
Avermectin B
1a
—CH═CH—
-sec-Bu
—H
Avermectin B
1b
—CH═CH—
-iso-Pr
—H
Avermectin B
2a
—CH
2
—CHOH—
-sec-Bu
—H
Avermectin B
2b
—CH
2
—CHOH—
-iso-Pr
—H
22.23-dihydroavermectin B
1a
—CH
2
—CH
2
—
-sec-Bu
—H
22.23-dihydroavermectin B
1b
—CH
2
—CH
2
—
-iso-Pr
—H
Doramectin
—CH═CH—
—Chx
—H
22.23-Dihydroavermectin B
1
is ivermectin; sec-Bu = secondary butyl; iso-Pr = isopropyl; Chx = cyclohexyl; —Me = methyl
As a rule, the avermectins and 22,23-dihydroavermectins B
1
(ivermectin) of the general formula (I) are employed as mixtures. Of particular interest in this connection is the product abamectin, which contains the avermectins B
1
, and their hydrogenation products, the 22,23-dihydroavermectins B
1
(ivermectin).
The compounds of the macrocyclic lactones marked with “b” which in the C
25
-position have an iso-propyl radical, do not necessarily have to be separated from the “a” compounds, which have a sec-butyl group in the C
25
-position. Generally the mixture of both substances, consisting of >80% sec-butyl derivative (B
1a
) and <20% iso-propyl derivative (B
1b
), is isolated, and can be used according to the invention. Additionally, in the stereoisomers the substituents in the C
13
- and C
23
-positions can be arranged on the ring system both in the &agr;- and &bgr;-positions, i.e. relocated above or below the plane of the molecule. In each case, all stereoisomers are taken into account according to the invention.
The milbemycins may be mentioned particularly. The milbemycins have the same macrolide ring structure as the avermectins or 22,23-dihydroavermectins B
1
(ivermectin), but carry no substituents (i.e. missing oleandrose disaccharide fragment) in position 13 (R
5
=hydrogen).
As examples of milbemycins from the class of macrocyclic lactones, the compounds having the general formula (II) may be mentioned
in which
the radicals R
1
to R
4
have the meaning indicated in Table 2 which follows:
TABLE 2
Macrocyclic
lactone
R
1
R
2
R
3
R
4
R
5
Milbemycin
—H
—H
-iso-Pr
—H
—H
B41 D

Nemadectin
—H
—OH
—H
—H

Moxidectin
—H
═N—O—Me
—H
—H
iso-Pr = isopropyl
The active compounds which may be very particularly emphasized are
avermectin B
1a
/B
1b
(abamectin),
22,23-dihydroavermectin B
1a
/B
1b
(ivermectin),
doramectin,
moxidectin.
The active compounds are present in the formulations according to the invention in concent

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