KR100544732B1 - The Composition of Oral Ivermectin Pastes for Estermination and Prevention of Canine Dirofilaria Immitis And a Method thereof - Google Patents

Abstract

The present invention relates to an oral ivermectin complex composition pasteurized to be easy to use and effective in preventing and eradicating canine dirofilaria immitis.

More specifically, in oral and external parasitic parasite preparations, dog heartworm comprising 0.01 to 1.00% by weight of the active ingredient ivermectin, 20.00 to 60.00% by weight polyunsaturated fatty acid, and 0.01 to 0.50% by weight fragrance Oral ivermectin paste composite composition for the prevention and eradication, and a preparation method thereof.

Ivermectin, polyunsaturated fatty acid, heartworm, paste, flavoring, fish oil, beef flavor

Description

The composition of Oral Ivermectin Pastes for Estermination and Prevention of Canine Dirofilaria Immitis And a Method

Figure 1 is a structural formula showing the chemical structure of ivermectin (ivermectin) used in the present invention.

The present invention relates to a composite composition of ivermectin for preventing canine heartworm. More specifically, the insecticidal effect of stage 4 and 5 larvae ( Larva 4,5) of dirofilaria immitis is widely used as a preventive agent for heartworm. The present invention relates to an oral ivermectin paste complex composition for preventing and eradicating canine heartworm that improves ease of use and dosing accuracy using polyunsaturated fatty acids and fragrances.

Ivermectin , as introduced in US Pat. No. 4,199,569, issued April 22, 1980 by chabala and fisher, is used for agricultural purposes for various parasites in crops and soils. It is a very effective antiparasitic agent useful for a wide range of in vitro and internal parasites in mammals.

In addition, as a semisynthetic derivative of ivermectin B produced by Actinomycetes called Streptomyces avermitilis, the independent component B _1a ( 22,23-dihydroavermectin B _1a , C ₄₈ H ₇₄ O ₁₄ ) was used. Gamma aminobutyric acid , an inhibitory neurotransmitter, which is an internal and external parasite control agent containing at least 80% and less than 20% of independent component B ₁₆ ( 22,23-dihydroavermectin B _1b , C ₄₇ H ₇₂ O ₁₄ ) Promotes the secretion of parasites by promoting the secretion of the so-called GABA) (Animal drug commentary, Jang-Rak Lee, 1994, Seoul National University Press, 192-3).

Therefore, ivermectin has excellent efficacy and safety. Injectables have been developed and sold for the treatment of nematodes (bovine and sheep internal parasites) and ticks (external parasites). Feed additives and injectables have been developed and marketed, respectively, for the control of insects and worms, as well as external parasites, mites, teeth and tridents. Tablets and chewable tablets have also been developed and marketed for the prevention of heartworm in dogs and cats.

Meanwhile, polyunsaturated fatty acid (PUFA) refers to a fatty acid composed of two or more double bonds. Unsaturated fatty acids having a double bond are chemically unstable compared to saturated fatty acids having no double bond, and are combined with oxygen in the air to oxidize to produce various oxides. Fatty acids with many double bonds are easier to oxidize, and these oxidations are promoted by light, metal ions, and temperature increase. Polyunsaturated fatty acids are mainly divided into omega 3 and omega 6 fatty acids found in vegetable foods and fish. Foods high in omega-3 fatty acids include fish oil, linseed oil, kerola oil, and walnut oil. Foods high in omega-6 fatty acids include soybean oil, corn oil, safflower oil, sunflower oil, cotton oil, peanut oil, and evening primrose oil. . However, these unsaturated fatty acids have the advantage of having an important function on the biological function, while the oxidation of the free radicals is very difficult to apply the technology is required.

Flavors have been developed and used in various kinds for the purpose of enhancing the palatability of food or drugs in animals and humans. For example, various flavors and seasonings can be added to enhance the taste of table medicine (see DE A 196 17 487, WO 95/31963 US 4 851 226). In addition, according to Korean Patent Publication No. 2003-0023874, fragrance is used for the preparation of in vivo insecticidal remedies for spontaneous oral ingestion by animals.

Canine heartworm is a parasitic disease caused by an infection of dirofilaria immitis belonging to the filamentous family. The parasite's dependent strain is a dog and is transmitted only by mosquitoes, which are intermediate hosts. Mature heartworms are found mainly in the right ventricle and pulmonary artery. Sometimes mature or immature heartworms are also found in other tissues such as the peritoneal cavity, bronchus, brain, and eyes, and in pregnant dogs, the microfilariae, which can pass through the placenta to the newborn, can't grow into an adult. It doesn't work. Heartworms are infected regardless of the age of the dog, but the most frequent age is 4 to 7 years of age, and can generally be transmitted from 6 months of age (The merk veterinary manual, 1998, Merk & Co., Inc., 93-94). About 10% of all domesticated dogs are infected, and 30% of Jindo-gun dogs are infected, so prophylaxis is very important.

For the dog heart onchocerciasis prevention ivermectin (ivermectin), di elchil cover margin (diethylcarbamazine; DEC), milbe azithromycin (milbemycin) and is dose orally (The merk veternary manual, 1998, Merk & Co., Inc., 94) Of these, ivermectin is the most used worldwide.

Ibermactin preparations, which are used to prevent dog heartworms, are available in tablets and chewable tables. That is, the method of preparing a stable aqueous solution of ivermectin is described in the Republic of Korea Patent Publication No. 86-1503, the method for preparing a composition of ivermectin for parenteral administration method, non-aqueous ivermectin parenteral The old formulation was also introduced in Korean Patent Publication No. 88-2366, and Korean Patent Publication No. 2000-25762 shows that vegetable oil is used as a solubilizing composition for ivermectins. There is also a prior art related to the ivermectin composition for skin application, the ibectin paste composite composition according to the present invention is an advanced technology as an oral heartworm prevention remedy.

For example, tablets (e.g., Heartguard; manufactured by Meralsa, USA; Heartgold; manufactured by ELT Science, Inc., Korea) may be mixed with ivermectin, an active ingredient, as a binder, disintegrant, lubricant, etc. It is a pharmaceutical formulation that is granulated and then compressed and coated with a coating agent.As a drug formulation is applied to a dog, which is a target animal, it is fixed to the subject, a pill under the tongue, and then forced to close the mouth and swallowed. Canine dogs are subject to severe stress and sometimes go wrong as bronchial pneumonia, causing problems. In addition, there is a hassle to observe whether the dog was dosed or spit after observing the dog for 2-3 minutes after administration.

In order to improve the problems of the tablets described above, in order to facilitate spontaneous oral ingestion of dogs, the active ingredient ivermectin is mixed with high-quality beef meat or chicken meat powder to prepare conventional binders, supplements and Chewable tables, which are tablets that can be chewed voluntarily by using preservatives (e.g., Heartguard plus chewable; Merial, Inc., Heartgold plus chewable; Eltscience, Inc., Korea), have also been developed and marketed. There are problems due to the unusual oral structure and physiological characteristics of the dog.

Dogs are very uncomfortable to administer orally due to their unusual oral and physiological characteristics. Therefore, this inconvenience is solved by enhancing the taste by adding to the dog's favorite food or the flavor or seasoning that the dog likes. Dogs have shorter labia oris compared to humans, so their oral muscle mobility is weak, making it difficult to chew and swallow the same medications (Livestock Anatomy, Yoon Seok-bong, 1982, Mun Un-dang, 270). In addition, dogs swallow only as much as they can swallow, so there is little mixing with saliva, so some pieces are lost when chewing or swallowing drugs such as tablets.

Barking is one of the instinctive and unusual behaviors of dogs. Barking acts first of all for barking behavior for instinctive self-protection when communicating with relatives, attracting attention of people or other familiar animals, relieving anxiety, and when intruders appear in or near their own zones. , Yeon-gwan Hall, 2004, Enicomm, 76). Therefore, the above-described bark behavioral factors during the administration of a drug such as chewables cause barking behavior prior to chewing and swallowing the drug, so the loss of the drug being administered is inevitable. Therefore, when administering a chewable tablet, as described above, the accuracy of the dosage due to some loss may be decreased, and in order to prevent this in advance, the dog to be administered should be stabilized and chewed and swallowed for several minutes.

Therefore, an object of the present invention is to solve the conventional problems, ivermectin paste composite composition of the new formulation to solve the disadvantages of the conventional tablets (tablets) and chewable tablets in the ivermectin preparation for dog heartworm prevention The purpose is to provide.

In the present invention, by using a licking action, one of the dog's physiological characteristics, by preparing an ivermectin paste complex composition comprising a polyunsaturated fatty acid and flavor in the active ingredient ivermectin by applying a recommended amount to the dog's nose, etc. It is possible to drastically improve the disadvantages of medication, inaccuracy of medication, and the like, such as no loss and immediately confirming intake.

Technical means of the present invention for achieving this purpose, in the oral or external parasitic parasitic preparations, 0.01 to 1.00% by weight of the active ingredient ivermectin, 20.00 to 60.00% by weight polyunsaturated fatty acid, 0.01 to 0.50% by weight fragrance It is characterized by containing.

In another technical solution, the oral and external parasitic preparations for oral use are 0.5 to 5.0% by weight of ethanol, 0.5 to 5.0% by weight of sodium carboxymethylcellulose, 0.1 to 2.0% by weight of xanthan gum, 0.001 to 0.4% by weight of methylparaben, It is characterized by containing 0.001-0.2% by weight of propylparaben, 0.001-0.1% by weight of polysorbate 80, 0.1-3.0% by weight of natural tocopherol, and 22.80-78.70% by weight of purified water.

Preferably, the polyunsaturated fatty acid is characterized in that one of fish oil or soybean oil.

More preferably, the flavor is characterized in that one of beef or chicken flavor.

In addition, according to the present invention, the first step of adding methyl paraben and propyl paraben after ivermectic is dissolved in ethanol; A second step of adding polysorbate 80 to the ivermectin mixture dissolved in ethanol in the first step, adding polyunsaturated fatty acid, warming and stirring; Adding a fragrance and natural tocopherol to the stirred ivermectin mixture solution in the second step and adding purified water to emulsify; Adding carboxymethylcellulose sodium and xanthan gum to purified water to boil for 5 minutes, and then cooling to 75 ° C; And a fifth step of adding purified water to a viscosity of 2000 to 10000 mm2 / s by mixing the ivermectin mixture of the third step and the mixture of the fourth step, and having a viscosity of 2000 to 10000 mm 2 / s.

The content of ivermectin used in the present invention is preferably 0.01-1.0% by weight. If the amount is less than 0.01% by weight, the dosage per dog is increased, which may cause inconvenience to small dogs. On the contrary, if the amount exceeds 1.0% by weight, the dosage per individual is too small to reduce the accuracy of the dosage. do.

The polyunsaturated fatty acid used in the present invention is preferably any one component selected from fish oil, soybean oil, corn oil, linseed oil, sunflower oil, cotton oil, peanut oil, and particularly preferably fish oil.

And the content of the polyunsaturated fatty acid is preferably 20-60% by weight, when less than 20% by weight is difficult to make the paste composition because the hardness is high, on the contrary, when more than 60% by weight causes a problem in stability is not preferable.

The fragrance used in the present invention is preferably any one component selected from beef flavor or chicken flavor and the content is preferably prepared by compounding 0.01% by weight to 0.5% by weight. Less than 0.01% by weight may cause a problem in palatability due to low palatability induction reaction, and when it exceeds 0.5% by weight it may not be desirable because palatability may be lowered due to a high irritant odor.

The present invention can be understood in more detail by the following examples and experimental examples, the following examples are only intended to illustrate the invention and are not intended to limit the scope of the invention.

Example

<Example 1>

① Dissolve 79mg of ivermectin standard in 500ml beaker, add 3ml of ethanol to dissolve it, and add 0.6mg of methylparaben and 0.3mg of propylparaben.

② Add 150g of fish oil to No. ① solution, warm it to 75 ℃ and add 50mg of Polysorbate 80 while stirring.

③ In solution ②, add 60mg of beef flavor and 3,000mg of natural tocopherol, and slowly add 100g of purified water to emulsify.

④ Separately, add 50 g of sodium carboxymethylcellulose and 2.5 g of xanthan gum to 500 ml of purified water and boil for 5 minutes and then cool to 75 ° C.

⑤ A solution of ivermectin composite paste for preventing heart worms was prepared such that the total amount was 300 g and the viscosity was 2,000-10,000 mm 2 / s while slowly adding solution ④ and purified water to solution ③.

<Example 2>

Except for using beef flavored cheese instead of beef flavor in Example 1 was prepared in the same manner as in Example 1.

<Example 3>

Except for the addition of beef flavoring was prepared in the same manner as in Example 1.

<Example 4>

A composition was prepared in the same manner as in Example 1, except that Uji was used instead of fish oil in Example 1.

<Example 5>

Except for the addition of beef flavoring was prepared in the same manner as in Example 4.

<Example 6>

Except for using the propylene glycol instead of fish oil in Example 1 was prepared in the same manner as in Example 1.

Comparative Example 1

Except for the addition of beef flavoring was prepared in the same manner as in Example 6.

Experimental Example 1

Stability Comparison Test

1. Experimental method

1 g of Examples 1, 2, 3, 4, 5, 6 and Comparative Example 1 were injected into a sterile plastic syringe and then stored at 40 (± 1) ° C and 75 (±) ° C RH conditions at 2-month intervals. , Viscosity and content of ivermectin were checked.

Table 1 Composition of ivermectin paste used in stability test

Kinds Ivermectin Paste Composition Example 1 Ivermectin + fish oil + beef flavor Example 2 Ivermectin + fish oil + cheese flavor Example 3 Ivermectin + fish oil Example 4 Ivermectin + Uji + Beef Flavor Example 5 Ivermectin + Uji Example 6 Ivermectin + propylene glycol + beef flavor Comparative Example 1 Ivermectin + propylene glycol

2. Experimental Results

As a result, the change of appearance did not show color change until after 6 months in Examples 1,2 and 3, but in Example 3 and 4, turbidity was observed to be dark brown after 6 months, and in Example 6 and Comparative Example 1 After 4 months, turbidity was observed to be dark brown. This means that Examples 1, 2, and 3 are superior in stability to Examples 4, 5, 6, and Comparative Example 1. Viscosity change was uniform in the range of 300 mm 2 / s without significant change in Examples 1, 2 and 3, but Examples 4 and 5 increased the viscosity as time passed, on the contrary, Example 6 and Comparative Example 1 At, the viscosity gradually decreased over time. The ivermectin content showed almost stable titer retention in Examples 1, 2, 3, 4, 5, 6 and Comparative Example 1, but decreased slightly with time in Examples 4 and 5. The experimental results are shown in [Table 2] below.

[Table 2] Table showing the appearance, hardness and ivermectin content changes over time.

division Kinds Elapsed time Start of test After 2 months After 4 months After 6 months Constellation Example 1 partridge No change No change No change Example 2 partridge No change No change No change Example 3 partridge No change No change No change Example 4 partridge No change No change Dark brown Example 5 partridge No change No change Dark brown Example 6 partridge No change Dark brown Dark brown Comparative Example 1 partridge No change Dark brown Dark brown Longitude (1) Example 1 4950 5030 5010 5005 Example 2 5070 6030 6210 5960 Example 3 4890 4900 5130 5190 Example 4 5630 6230 8400 11210 Example 5 6210 6730 9230 10450 Example 6 4520 3980 2120 1890 Comparative Example 1 4940 3980 1670 1540 Ivermectin Content (2) Example 1 101.4 99.8 100.3 97.5 Example 2 99.8 98.1 97.3 98.1 Example 3 98.7 100.4 98.9 96.8 Example 4 99.4 98.4 95.2 93.1 Example 5 102.3 99.6 98.1 95.3 Example 6 101.2 100.3 102.6 99.7 Comparative Example 1 97.4 98.1 97.9 06.5

(1) Unit: mm2 / s

(2)% of reference content 263.3mcg / g

Experimental Example 2

Palatability test

1. Experimental method

Example 1, 2, 3, 4, 5, 6 and Comparative Example 1 1g per horse's nose was applied to the dog's nose and tongue was selected from 70 dogs of 8-10 months old Yorkshire terrier dogs. The degree of palatation was observed to confirm palatability.

2. Experimental Results

As a result, in Example 1, 8 out of 10 total test heads showed palatability index 4 and the remaining 2 heads showed palatability index 3, and Example 2 showed palatability among 10 heads. Three indexes of four, two palatability indexes, two palatability indexes, four palatability indexes, and two palatability indexes were two, and the palatability was significantly lower than that of the first embodiment. The palatability was remarkably low, with two indexes of two, five palatability indexes and one palatability index. Although Example 4 was generally excellent in palatability, it was lower than Example 1, and Example 5 showed almost similar palatability as Example 3. Example 6 showed similar palatability to Example 2, and in Comparative Example 1, palatability index 2 was 1, palatability index 1 was 2, palatability index 0 was 7, and the palatability was the lowest. . The experimental results are shown in [Table 3] below.

TABLE 3 Table showing palatability index of dogs according to the examples.

Kinds Palatability index (1) Head total 4 3 2 One 0 Example 1 8 heads 2 heads - - - 10 heads Example 2 3 heads 2 heads 4 heads 1 head - 10 heads Example 3 - 2 heads 2 heads 5 heads 1 head 10 heads Example 4 6 heads 2 heads 2 heads - - 10 heads Example 5 - 1 head 3 heads 4 heads 2 heads 10 heads Example 6 4 heads 3 heads 2 heads 1 head - 10 heads Comparative Example 1 - - 1 head 2 heads 7 heads 10 heads

(1) Palatability index: 4: Completely licked with tongue over 1-2 times

                3: completely licked with tongue 3-4 times

                       2: completely licked with tongue over 5 times

                       1: part is missing and not completely licked

                       0: avoiding licking

Experimental Example 3

Palatability comparison test with chewable

1. Experimental method

20 10-year-old Yorkshire terriers were selected to apply to 10 dogs Example 1 0.5 g per head of the composition on the nose, and as a control, Ibermectin tablets Heart Gold Plus sable available ELT Science Co., Ltd. The product, National Veterinary Research and Quarantine Service License No. 115-34), was placed on the bottom of the hand wearing clean white gloves and tested for palatability.

2. Test result

As a result of palatability test with existing chewable tablets, Experimental Example 1 shows that 8 heads were completely ingested within 1 minute of 10 heads and 2 heads were completely ingested within 2 minutes. In the control group, 5 heads were completely ingested within 1 minute of the total 10 heads, and 2 heads were completely ingested within 2 minutes. 70% of the heads showed satisfactory palatability, but some were lost and completely ingested. Soybeans that had not been ingested at all within one or five minutes did not show any palatability compared to Example 1. The experimental results are shown in [Table 4] below.

TABLE 4 Table showing palatability index according to Example 1 and the control.

division Experimental Example 1 Control The total number of fish eaten within 1 minute 8 heads 5 heads Number of animals consumed completely within 2 minutes 2 heads 2 heads Total number of meals consumed within 3 minutes - 1 head Number of animals that have lost part and have not been consumed completely - 1 head Number of animals not eaten at all within 5 minutes - 1 head Total number 10 heads 10 heads

As can be seen from the above, in the present invention by using the licking action of one of the dog's physiological characteristics to prepare an ivermectin paste composite composition comprising a polyunsaturated fatty acid and flavor in the active ingredient ivermectin By applying the recommended amount to the nose, there is no loss, and it is possible to drastically improve the discomfort of medication, and the inaccuracy of medication, such as checking whether it is ingested immediately.

In addition, the oral ivermectin paste composite composition for preventing and eradicating canine heartworm prepared by the present invention can be conveniently and precisely dosed, thereby significantly reducing the disadvantages of conventional tablets or chewable tablets. You can solve it.

Claims (7)

In oral and external parasitic preparations, Oral ivermectin paste complex composition for the prevention and eradication of dog heartworm, characterized by containing 0.01 to 1.00% by weight of the active ingredient ivermectin, 20.00 to 60.00% by weight polyunsaturated fatty acid, and 0.01 to 0.50% by weight fragrance . According to claim 1, wherein the oral or external parasitic agent is 0.5 to 5.0% by weight of ethanol, 0.5 to 5.0% by weight of sodium carboxymethylcellulose, xanthan gum 0.1 to 2.0% by weight, methyl paraben 0.001 to 0.4% by weight, propyl paraben Oral ivermectin for the prevention and eradication of dog heartworm, characterized by containing 0.001-0.2% by weight, polysorbate 80 0.001-0.1%, natural tocopherol 0.1-3.0%, and purified water 22.80-78.70% by weight Paste composite composition. According to claim 1, wherein the polyunsaturated fatty acid oral ivermectin paste composite composition for preventing and eradicating dog heartworm, characterized in that one of the fish oil or soybean oil. The oral ivermectin paste complex composition for preventing and eradicating canine heartworm according to claim 1, wherein the flavor is either beef or chicken flavor. Adding ivermectic to ethanol to dissolve and adding methylparaben and propylparaben; A second step of adding polysorbate 80 to the ivermectin mixture dissolved in ethanol in the first step, adding polyunsaturated fatty acid, warming and stirring; Adding a fragrance and natural tocopherol to the stirred ivermectin mixture solution in the second step and adding purified water to emulsify; Adding carboxymethylcellulose sodium and xanthan gum to purified water to boil for 5 minutes, and then cooling to 75 ° C; The fifth step of adding the purified water to the viscosity of 2000 ~ 10000mm2 / s by mixing the ivermectin mixture of the third step and the mixture of the fourth step, the dog heartworm prevention and eradication comprising a Method for preparing oral ivermectin paste composite composition for. 6. The method of claim 5, wherein the polyunsaturated fatty acid is one of fish oil or soybean oil. The method of claim 5, wherein the flavor is one of beef or chicken flavor, oral ivermectin paste composite composition for the prevention and eradication of dog heartworm.

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