KR100355116B1 - premix compositions including avermectin derivatives for eradicating parasites and a process for their manufacture - Google Patents

Abstract

The present invention relates to a feed premix (hereinafter referred to as a 'premix') composition and a method for preparing the same, comprising an avermectin derivative having excellent thermal stability by maximizing stabilization of an active compound having excellent thermal stability in a feed premix. Specifically, the present invention relates to a composition and method for preparing a feed premix for endoparasite or ectoparasite eradication including corn cob, hydrogenated castor oil, and ivermectin, and having excellent thermal stability. By providing, without the degradation of the drug during manufacture, there is an effect to take the insect repellent in livestock by a simple method such as premix.

Description

Premix compositions including avermectin derivatives for eradicating parasites and a process for their manufacture}

The present invention relates to a feed premix (premix) comprising ivermectin, a macrocyclic lactone, which is very effective against a wide range of pests that are prevalent and afflicting plants and animals, and a method for preparing the same. will be.

In the development of the modern feed industry, a large number of antibiotics and the like are used as additives to prevent animal diseases and increase animal growth. US Pat. No. 3,455,696 describes the use of antibiotics by procaine penicillin, dihydropreptomycin or tetracycline.

Such additives are also passed through an extruder when the feed is processed into pellets into a final form, which requires a high temperature stability additive having a stable pharmaceutical activity at that temperature because the temperature is at least 100 ° C. There is a need to develop highly efficient animal feed with very high antiparasitic effects.

The present invention has been made in view of the above problems, and the object of the present invention is to provide a parasitic killing feed premix composition comprising avermectin derivative having excellent thermal stability, and a method of manufacturing the same.

Another object of the present invention is to provide a method for preparing the feed premix composition.

In order to achieve the above object, the present invention provides a composition of the parasite eradication feed premix comprising a corn cob (excipient), hydrogenated castor oil as an auxiliary, and an active compound.

In the present invention, premix and feed concentrates mean a mixture of the active compound and a suitable excipient, and a single feed, a mixture thereof or an inert excipient is included in the excipient.

In the present invention, the active compound is characterized in that the avermectin derivative, the basic avermectin derivative is a group of the formula 1 and 2 isolated from the fermentation broth of the microorganism Streptomyces avermitilis ( Streptomyces avermitilis ) Based on one or more compounds selected from the group consisting of: This can be selectively reduced to prepare the ivermectin compounds described above. Ivermectin is a novel substance and is a very effective antiparasitic agent useful for a wide range of in vitro and internal parasites in mammals, as well as for agricultural use for various parasites inhabiting crops and soil. Ivermectin is described in US Pat. No. 4,199,569, dated April 22, 1980, by Cabala and Fisher. Ivermectin is a mixture of 22, 23-dihydro C-076B1a and B1b in an approximately 80:20 ratio.

Ivermectin is isolated from the fermentation broth of microorganisms and is active against in vitro and parasites in livestock. Isolation and purification of this compound is described in US Pat. No. 4,310,519, published January 12, 1982.

All of the aforementioned avermectin derivative compounds differ only slightly in the bioactive range of the ivermectin compound, so that the processes and formulations of the present invention can be applied to all of them.

[Formula 1]

In [Formula 1], R is α-L-oleandrosyl-α-L-oleandroside having the structure of [Formula 2], hydrogen, lower alkanoyl (loweralkanoyl), α-L-oleandrosyl, 4′-lower alkanoyl or α-L-oleandrosyl or 4 ″ -lower alkanoyl-4 ′-(α-L-oleandrosyl) -α-L-oleandrosyl. Lower alkanoyl in the above means an alkanoyl group with 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, and pivaloyl. In addition, the lower alkanoyl group may be acetyl of disaccharides, monosaccharides, and aricon compounds.

The dotted line represents a single or double bond, R ₁ is a hydroxy group, and only when the dotted line represents a single bond, R ₂ is iso-propyl or secondary-butyl, R ₃ is methoxy or hydroxy to be. 22, 23-double bond can also be reduced.

The structural formula may be represented by each compound of Table 1.

TABLE 1

R ₁ R ₂ R ₃ A1a Double bond Secondary-Butyl -OCH ₃ A1b Double bond Iso-propyl -OCH ₃ A2a -OH Secondary-Butyl -OCH ₃ A2b -OH Iso-propyl -OCH ₃ B1a Double bond Secondary-Butyl -OH B1b Double bond Iso-propyl -OH B2a -OH Secondary-Butyl -OH B2b -OH Iso-propyl -OH

In the above, a higher amount of a is found in the pair of 'a' and 'b' compounds, making up about 85 to 99% of the mixture of 'a' and 'b' compounds.

[Formula 2]

The active compounds, in particular the ivermectins mentioned in the present invention, can be added to the feed either by themselves or in the form of premixes or feed concentrates.

Ivermectin is a drug that paralyzes parasites by increasing GABA (gamma-aminobutyric acid), which interferes with neurotransmission between nerve cells and muscle cells.

In the case of animals, the intake may be contained in a suitable formulation via feed or beverage. Ivermectin can be administered in the form of conventional concentrations and formulations with the feed or feed formulation or beverage. Infections with Gram-negative or Gram-positive bacteria can be prevented, alleviated, and / or treated with this method and can also promote growth and feed utilization in this way.

The ivermectin is preferably 0.1 to 20% by weight of the total weight, more preferably 0.6 to 0.8% by weight of the total weight.

In addition, the excipient of the present invention may be used in addition to the above-mentioned corn, inorganic and organic materials which are physiologically acceptable inert replacement materials. Inorganic materials include, for example, conventional salts, carbonates such as calcium carbonate, bicarbonate, aluminum oxide, silica, alumina, precipitated or colloidal silicon dioxide and phosphate. Organic materials include, for example, sugars, cellulose, feed and feed, for example powdered milk, animal porridge, ground grain flour and broken grain flour and starch.

If the excipient is too much excipient, the fluidity of the premix is poor, and the particles can aggregate together. If the excipient is too low, it is dust and does not become a premix of particles having proper fluidity. In addition to the above hydrogenated castor oil, the adjuvant of the present invention is a preservative such as calcium propionate, an antioxidant such as butylhydroxytoluene, butylhydroxyanisole or tocopherol, a colorant or magnesium stearate, stearic acid. Glidants such as acids, talc, bentonite and degradation-promoting agents such as lubricants, starches or crosslinked polyvinyl pyrrolidones, binders such as starch, gelatin or linear polyvinyl pyrrolidone, may also be used with microcrystalline cellulose. Such as dry binders, bentonite, colloidal silica or aluminum monostearey Inorganic thickeners such as sodium, and the like can be used. Too much of the adjuvant may cause the particles of the premix to fall off due to too much adjuvant, and if the amount of the adjuvant is too low, it may cause dust and prevent premixing of particles having proper fluidity. It is more preferable that it is 6 to 10% by weight of the total weight.

The hydrogenated castor oil and the antioxidant in the adjuvant is preferably 0.1 to 10% by weight of the total weight, more preferably 0.1 to 1% by weight of the total weight.

The present invention also completely dissolves the avermectin compound in ethanol, and then sprays and sprays it in corn, the main excipient. After spraying a solution in which hydrogenated castor oil is dissolved in ethanol, it is spray-dried again, and an antioxidant solution is added thereto, followed by complete drying again.

The concentration of the premix in the feed is usually about 0.1 to 100 ppm, preferably 1 to 50 ppm, more preferably 2 to 10 ppm.

In general, pharmaceutical formulations suitable for animals are those in which, for example, improvement of flavor plays a role in absorption, or delayed release of the active compound after administration is sought. These are, for example, solid or suspending agents, such as powders, premixes, or thickening agents, granules, pellets, tablets, cyclic pills and capsules for oral or transdermal administration. They are optionally mixed with excipients with additional auxiliaries such as wetting agents, colorants, absorption enhancers, preservatives, antioxidants and light blockers to form the desired form. Excipients that may be mentioned are all physiologically acceptable inert replacements. In addition, inorganic and organic materials may also be used.

They may also contain additional auxiliaries such as, for example, substances such as silica, bentonite, which regulate the flow and mixing capacity. In addition, antioxidants such as BHT or preservatives such as calcium propionate may be added. In addition, liquids such as paraffin oil, vegetable oil and propylene glycol can be added to the premix and mixed for powder bonding.

The active compounds may be present in their own form or in mixed formulations such as other active compound inorganic acid salts, trace elements, vitamins, proteins, colorants, fats or flavors.

The premix containing the active compound is preferably administered with a feed.

Vegetable single feeds such as hay, beets, grains, grain by-products, animal single feeds such as meat, fat, milk products, products, and also vitamins, proteins, amino acids such as DL-methionine, calcium carbonate and conventional Salts such as salts are included in the feed.

The present invention seeks to facilitate the use of avermectin compounds by using the premix formulations described below.

Ivermectin premix uses corn cob as a main excipient, hydrogenated castor oil as an adjuvant to help disperse coating of ivermectin to excipients, and antioxidants, lubricants, etc. Can be.

In addition, the composition of the present invention may include excipients such as perfumes, preservatives, antioxidants, stabilizers, pigments.

An unexpected feature of the present invention lies in the thermal stability of the avermectin compound.

The premix formulations mentioned provide sufficient doses of avermectin compounds to eradicate almost all internal parasites of the host animal.

There is a need for premix formulations with high activity against both internal and external parasites.

The formulations of the present invention obtain good thermal stability as shown in the examples below.

The following examples are provided to allow a more complete understanding of the ivermectin premix formulation.

These examples should not be considered as limiting the invention.

Example 1.Preparation of 0.6 wt% Premix

The following ingredients were used to prepare ivermectin premixes (premixes) containing 0.6% by weight of active ingredient.

Ivermectin 0.6% by weight

8% by weight hydrogenated castor oil

0.5 wt% antioxidant (BHT)

Corn cob 90.9 wt%

Ivermectin was dissolved in ethanol and sprayed onto the mixing mixture with corn. After spraying and drying, a solution of hydrogenated castor oil dissolved in ethanol was sprayed and dried. Again, an antioxidant (BHT) was dissolved in ethanol, spray sprayed, dried, and then cooled.

Example 2. Preparation of 0.8 wt% Premix

As in Example 1, but 0.8 wt% ivermectin, 90.7 wt% corn cob.

Experimental Example: Thermal Stability Test of Premix

270 g of lithium chloride (Lithum chloride) was dissolved in DW 200ml to maintain about 10% water content. Since this solution dissolves lithium chloride by adding more than saturation (Lithum chloride 1g / 1.3ml DW), an undissolved solid precipitated below. This solution was placed in a desiccator and tested under the following conditions.

Condition 1 (UPC Condition): 130 degrees-8 minutes

Condition 2 (Expander Condition): 95 degrees-15 seconds

Condition 3 (Pellet Condition): 80 degrees-10 seconds

30 minutes before the desiccator was put in the oven in which the above temperature conditions were set, and then 1 g of the ivermectin premix of the present invention was placed for the above condition time. The powder, which was treated for each hour, was extracted by adding 20 ml of methanol and shaking with a wrist action shaker for 40 minutes. After extraction, it was passed through a 4um filter to prepare a sample for HPLC analysis.

Table 2 is a comparison of the thermal stability between the two experiments by the above process using a premix of other companies as a control.

[Table 2] Result of comparative thermal stability test

The present invention Contrast Product Control group Room temperature 113.67 110.58 Pellet condition 80 ℃ -10 seconds 113.28 108.98 Expander Condition 95 ℃ -15 seconds 112.36 103.37 UPC condition 130 ℃ -8 minutes 111.17 100.70

The degradation rate of ivermectin of the premix of the present invention was smaller than that of the drug of the comparative example as a control product. As can be seen from the results, the feed premix composition of the present invention is almost unaffected at high temperature conditions, whereas the control product can be seen to be destabilized by heat at high temperature conditions. It was found that the thermal stability was superior to that of the control product.

The present invention provides a feed premix formulation having excellent thermal stability, so that there is no degradation of the drug during manufacture, and the insect repellent is taken to livestock by a convenient method such as premix.

Claims (14)

(correction) a) avermectin derivatives which are active compounds ; b) corn cob, an excipient; And c) A parasitic killing feed premix composition comprising: a hydrogenated castor oil as an adjuvant. (delete) According to claim 1, wherein the avermectin derivative is a parasitic eradication feed premix composition, characterized in that at least one compound selected from the group consisting of 1 and 2. [Formula 1] [Formula 2] In [Formula 1], R is α-L-oleandrosyl-α-L-oleandroside having the structure of [Formula 2], hydrogen, lower alkanoyl (loweralkanoyl), α-L-oleandrosyl, 4′-lower alkanoyl -α-L-oleandrosyl or 4 ″ -lower alkanoyl-4 ′-(α-L-oleandrosyl) -α-L-oleandrosyl, wherein lower alkanoyl is acetyl, propionyl, butyryl, fivaro By 2 to 6 carbon atoms, such as work, refers to the alkanoyl group, in addition to the lower alkanoyl group may be acetyl of disaccharides, monosaccharides and aricon compounds. In addition, said dotted line represents a single or double bond, R <1> is a hydroxyl group, it exists only when a dotted line represents a single bond, R <2> is iso-propyl or secondary-butyl, and R <3> is methoxy or hydroxy. 22, 23-double bond can also be reduced. (correction) 4. The feed premix composition for parasite eradication according to claim 3, wherein the abuckmectin derivative is ivermectin. According to claim 4, wherein the ivermectin is parasitic eradication feed premix composition, characterized in that 0.1 to 20% by weight of the total weight. According to claim 1, wherein the premix composition is a parasitic eradication feed premix composition, characterized in that it further comprises an excipient made of an inorganic or organic material that is an inert replacement material. The parasite according to claim 1 or 6, wherein the inorganic material is at least one compound selected from the group consisting of calcium carbonate, bicarbonate, aluminum oxide, silica, alumina, precipitated or colloidal silicon dioxide and phosphate. Eradication feed premix composition. The method according to claim 1 or 6, wherein the organic material is at least one material selected from the group consisting of sugar, cellulose, feed food, powdered milk, animal porridge, ground grain flour, broken grain flour and starch. A parasitic eradication feed premix composition. The method of claim 1, further comprising at least one adjuvant selected from the group consisting of preservatives, antioxidants, colorants, glidants, glidants, degradation-promoting agents, binders, and inorganic thickeners. Premix Composition. According to claim 1, wherein the hydrogenated castor oil is parasitic eradication feed premix composition, characterized in that 1 to 20% by weight of the total weight. 10. The method according to claim 9, wherein the antioxidant is at least one compound selected from the group consisting of butylhydroxytoluene, butylhydroxyanisole and tocopherol parasite eradication feed premix composition. The method of claim 11, wherein the butyl hydroxytoluene is parasitic eradication feed premix composition, characterized in that 0.1 to 10% by weight of the total weight. (correction) According to claim 1, wherein the avermectin derivative is 0.6-0.8% by weight, 6-10% by weight of hydrogenated castor oil as an adjuvant, and the parasitic eradication feed comprising the remainder as an excipient corn cob (corn cob) Premix Composition. (correction) Dissolving an avermectin derivative which is an active compound in alcohol; Mixing the solution in corn and then drying; And Mixing and drying the hydrogenated castor oil dissolved in alcohol in the dried corn cob: Method of producing a feed premix composition for eradicating parasites with increased heat stability .