MXPA99002566A - Injectable formulations of avermectins and milbemycins - Google Patents

Abstract

The present application concerns injectable formulations of avermectins and milbemycins based on a solvent mixture which contains sesame seed oil, medium-chain triglycerides, glycol esters or fatty acid esters and another solvent of the series of monovalent or polyvalent aliphatic or aromatic alcohols and their derivatives (for example cyclic carbonates, acetates, acetals and ketals) or castor oil.

Description

INJECTABLE FORMULATIONS OF AVERMECTINES AND MILBEMICINS Field of the invention The invention rel to injectable formulations of Avermectins and Milbemycins based on mixtures of solvents, which contain sesame oil. Description of the prior art Injectable formulations of Ivermec-tine are known from EP-A 146 414. The formulations contain solvent mixtures consisting of propylene glycol and glycerol in the proportion of 60:40 V / V. It is known that polypropylene glycol can cause local incompatibilities at certain concentrations (see Review, B. Kruss, Acta Pharm, Technol. 35 (4) (1989) 187-196). Likewise, precipitation may occur in the tissue, around the point of application, of the w insoluble active product, constituted by Ivermectin. In this way, clear swellings and incompatibilities with the tissue at the injection points have been observed, when corresponding formulations are applied, which only partially remit after several weeks. Injectable formulations of certain Avermectins are known from EP-A 393 890. These are oleaginous formulations based on sesame oil and ethyl olein the proportion of 90:10 V / V. These formulations are compatible, but, nevertheless, they have the in- ref. It is convenient that the solubility of Avermectins / Milbemycins is often not sufficient to achieve an application of desired concentration of 1% M / V or gre. As a rule, solutions are obtained at 1% M / V supersatur under conditions of high temperature (T> 80 ° C), which, after the time, are re-disaggreg by crystallization at lower temperatures. Other injectable formulations of Avermectins are known from EP-A 45 655. The formulations described there contain relatively high proportions of emulsifiers and, in part, are poorly compatible. EP-A 413 538 injectable formulations of Avermectins containing Triacetin (glycerin tri-acet have been described. EP-A 535 734 describes injectable formulations of Avermectins based on Triacetin and hydrogen castor oil. Other formulations for the injection of Avermectins and Milbemycin have been described in EP-A 525 307. The preparation of the formulations is carried out by melting the glycerin tristearwith the active compound and mixed with a neutral oleaginous triglyceride and emulsified using, for example, methylcellulose and salts. The average particle size in the microemulsions, thus obtained, must be between 25 and 300 μm.

DETAILED DESCRIPTION OF THE INVENTION: The object of the present invention are injectable formulations of Avermectins and Milbemycins based on a mixture of solvents, containing sesame oil, medium chain triglycerides or glycol esters or fatty acid esters and another solvent. The formulations contain, preferably 1. active product 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 mono- or polyvalent, aliphatic or aromatic alcohols and their derivatives (for example cyclic carbon, acet, acetals / ketals) or castor oil; . if necessary, other auxiliary products. The formulations according to the invention have excellent solubility for the active products. The high viscosity of the sesame oil can be adjusted to a desired low amount by the addition of medium chain triglycerides or octano/ propylene glycol decanoor, especially, ethyl ole In addition, the solubility of the active product can be improved, the viscosity reduced further and the bioavailability of the active product improved by the addition of smaller volumes of hydrophilic solvents such as benzyl alcohol, propylene glycol or polypropylene carbonate under the maintenance of a single phase system. Castor oil has, as a single triglyceride, a high dissolution potential for the active products considered. The active compounds used in the formulations according to the invention are known. The Avermectins were isolated from the microorganism Streptomyces avermitilis as a microbial metabolite (US Pat. No. 4 310 519) and can be presented mainly in the form of mixtures, consisting of the components Ala, Alb, A2a, A2b, Bla, Blb. , B2a and B2b (I. Putter et al., Experentia 37 (1981) page 963, Birkháuser Verlag (Switzerland)). Also interesting are synthetic derivatives, especially 22, 23-Dihydroavermectin B ^ (Ivermectin) (US Pat. Pat. No. 4,199,569). Milbemycin B-41 was isolated by fermentation from Streptomyces hygroscopi-cus (see "Milbemycin.- Discovery and Development" I. Junya et al., Annu. Rep. Sankyo Res. Lab. 45 (1993), pages 1-98; JP-Pat 8 378 549; GB 1 390 336). The use of Avermectins, for example of 22, 23-Dihydroavermectin B ^ (Ivermectin), and of Milbemycins as endoparasiticides is known and is the subject of a large number of patent applications as well as compilations (for example biological effects in : "Ivermectin and Abamectin" .C. Campbell, Ed., Springer Verlag, New York, NY, 1989; "Avermectins and Milbemycins Part II" HG Davis et al., Chem. Soc. Rev. 20 (1991), pages 271- 339, chemical modifications in: G. Lukacs et al. (Eds.), Springer Verlag, New York, (1990), chapter 3; Cydectin® [Moxidectin and derivatives]: GT Cárter et al., J. Chem. Soc. Chem Commun (1987), pages 402-404); EP 423 445-A1) "Doramectin - a potent novel endectozide" A.C. Goudie et al. Vet. Parasitol. 49 (1993), pages 5-15). Special mention should be made of Avermectins and their derivatives of the general formula (I) in which the residues R1 to R4 have the meaning indicated in table 1 below and X means a single or double bond between the position C22-Y c23"(" C22R1"X-C23R2 ~ ^ • In the case of a double bond , the substituents (R1, R) are in the C22- and C23- position. 22, 23-Dihydroavermectin Bl means Ivermectin; sec-Bu = secondary butyl; iso-Pr = isopropyl; Chx = cyclohexyl; -Me = methyl. The Avermectins and the 22, 23-Dihydroavermectins B- (Ivermectins) of the general formula (I) are generally used in the form of mixtures. In this case, the product Abamectin, which contains Avermectin B-1, and its hydrogenation products, 22, 23-Dihydroavermectin B- ^ (Ivermectin), is of special interest. The compounds designated by "b" of the macrocyclic lactones, which have an iso-propyl moiety in the C2 ^ position, do not necessarily have to be separated from the compounds "a", which have a sec-butyl group in the C25 position. In general, the mixture of both substances is isolated, constituted by > 80% of the sec-butyl derivative (Bla) and < 20% of the iso-propyl derivative (Blb), and can be used according to the invention. In addition, the substituents at the C13- and C23 position can be arranged on the stereoisomers both at the a and the ß position on the ring system, ie they can be above or below the plane of the molecule . In any case all the stereoisomers according to the invention are encompassed. Milbemycins can be cited especially. The Milbemycins have the same macropolic ring structure as the Avermectins or the 22, 23-Dihydroavermec-tines Bj ^ (Ivermectins), but, however, do not carry substituents of any type (ie non-existent fragment of the Oleandrosa disaccharide). ) in position 13 (R5 = hydrogen-no). By way of example, Milbemycins of the class of macrocyclic lactones can be mentioned as compounds with the general formula (II) wherein the residues R1 to R5 have the meaning indicated in table 2 below: iso-Pr = isopropyl. The active products must be indicated in a very special way. 'Avermectin (Abamectin) 22, 23-Dihydroavermectin ^ a / ^ > .b (Ivermectin) Doramectin Moxidectin. The active compounds are present in the formulations according to the invention in concentrations of 0.2 to 5%, preferably 0.5 to 2%, particularly preferably 1% M / V. The sesame oil used in the formulations according to the invention (66 to 90% V / V) is known. The viscosity reducers used in the formulations according to the invention, especially ethyl oleate, are known.

Other good solvents which can be used as an injectable component for the active compounds are, in particular, benzyl alcohol, propylene glycol, glycerin-mal, propylene carbonate, triacetin, Myvacete® (brand registered by Eastman), propylene glycol diacetate, polyethylene glycol 400, tetraglycol. as well as castor oil. Particularly preferred are benzyl alcohol (1 to 5% V / V) and castor oil (10 to 20% V / V). The solubility of Ivermectin rises, in benzyl alcohol, to > 40% by weight, in castor oil ~ 4% by weight. Other additions for the formulations according to the invention are stabilizers such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or gallate in propyl in a total amount of up to 1000 ppm. Particularly suitable combinations and concentrations of the stabilizers are, for example, 100 ppm of BHA or 100 ppm of BHA plus 150 ppm of propyl gallate or 200 ppm of BHA plus 100 ppm of propyl gallate. The viscosity of the formulations according to the invention are between 20 to 60 mPas. s (20 ° C), preferably between 25 to 55 mPas. s (20 ° C), particularly preferably between 30 and 51 mPa.s (20 ° C). The following examples explain the invention.

Note: V / V = Volume / Volume corresponds to the percentage in volume, M / V = Mass / Volume 1% M / V means, for example, 10 mg of active product in 1 ml of solution. Example 1 Sesame oil q.s. 100% V / V Ethyl Oleate 10% V / V Benzyl Alcohol 2% V / V Ivermectin 1% M / V Butyl Hydroxyanisole (BHA) 100 ppm (0.01% M / V) Density: 0.922 g / ml Viscosity: 44 mPa. s at 20 ° C 85 mPa.s at 5 ° C 24 mPa.s at 39 ° C Example 2 Sesame oil q.s. 100% V / V Ethyl oleate 20% V / V Castor oil 10% V / V Ivermectin 1% M / V Butylhydroxyanisole (BHA) 100 ppm (^ 0.01% M / V) Density: 0.927 g / ml Viscosity : 38 mPa.s at 20 ° C 83 mPa.s at 5 ° C General preparation routine for examples 1 and 2 as sterile solutions for injection; Sesame oil and ethyl oleate, provided with 100 ppm BHA, are placed in a stainless steel container and homogenized with stirring. Ivermectin, dissolved or solubilized in benzyl alcohol or in castor oil, is introduced by further stirring. The mixture is heated to 40 to 60 ° C, to ensure rapid and complete dissolution of the active product (all under nitrogen gasified). It is then filtered, sterilely, at the same temperature through a 0.22 μm filter (a 0.45 μm or 1 μm filter is pre-connected by re-gla-general), The aseptic packaging is then checked in brown glass jars. The formulations thus prepared are excellently compatible when used in cattle. They are also stable to storage for at least 6 weeks at temperatures of 60 ° C. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (6)

R E I V I N D I C A C I O N S Having described the invention as above it is claimed as property contained in the following: 1.- Injectable formulations of Avermectins and VñJtßmcuBB based on a mixture of disriLβaites, cha chaba-fas parxμe have sesame oil, medium chain triglycerides or glycol esters or fatty acid esters and another solvent from the group consisting of mono- or polyvalent aliphatic or aromatic alcohols and their derivatives (for example cyclic carbonates, acetates, acetals, ketals) or castor oil. 2. Formulations according to claim 1, characterized in that they have the following composition:

1. active product 0.2 to 5% M / V;

2. Sesame oil 60 to 90% V / V;

3. 10 to 30% by volume of medium chain triglycerides or glycol esters or fatty acid esters;

4. 1 to 20% co-solvents from the group consisting of mono- or polyvalent aliphatic or aromatic alcohols and their derivatives or castor oil;

5. if necessary, other auxiliary products. 3 . ~ have the following composition: 0.2 to 5% M / V of an Avepnectin or Milbemycin in a solvent mixture consisting of 60 to 90% V / V of sesame oil, as well as 10 to 30% V / V of ethyl oleate or Miglyol® 812 or Miglyol® 840 and 1 to 5% V / V of benzyl alcohol or 120 to 20% V / V of castor oil as well as, if necessary, up to 1000 ppm of stabilizers. because they have the following composition: 1% M / V of Ivermectin, 65 to 90 V / V of sesame oil, 10 to 20% V / V of ethyl oleate and 1 to 3% V / V of benzyl alcohol or 10% V / V of castor oil as well as, if necessary, up to 500 ppm of stabilizers. 5. Process for obtaining the formulations according to claim 1, characterized in that the active product is dissolved or solubilized in castor oil or in benzyl alcohol and the remaining solvent is added or because the active product is dissolved in a mixture constituted by the three solvents.

6. Use of castor oil or benzyl alcohol as solubility enhancers in a formulation according to claim 1.