KR20010013139A - Anthelmintic compositions - Google Patents

Abstract

The present invention relates to anthelmintic compositions containing niclosamide or a salt thereof as active ingredient, and methods to form such compositions.

Description

Insecticidal compositions

The present invention relates to an insect repellent composition. More particularly, the present invention relates to an insect repellent composition containing niclosamide as an active ingredient.

Niclosamide (2 ', 5-dichloro-4'-nitrosalicylanilide) is a known insect repellent marketed under the Lintex trade name by Pty Limited. Known niclosamide compositions are in the form of suspensions in which niclosamide is suspended in a liquid medium. These suspending agents are usually administered at a dosage rate of 1 ml per 4 kg of body weight as 20% preparations (niclosamide g / carrier 100 ml) in animals, in particular sheep, to control parasites of tapeworms and / or conical bugs.

Nurtaeva KS, Bekhill AF, and Vorobeva ZG, 1973 Med Parazitol (Mosk) 42:86, described various types of Niclosa. Studies on the antiparasitic efficacy of mead salts have been reported. Sodium salt showed good activity. The compound tested was provided as a suspension in water or as a mixture with 5% starch.

Surprisingly, when niclosamide is administered according to the invention in a composition according to the invention, it has been found that niclosamide can be used to effectively exterminate the parasites of tapeworms and / or conical bugs by using seemingly reduced dose rates. lost.

According to the invention there is provided an antiparasitic composition in solution form containing a pharmacologically acceptable organic solvent and a pharmacologically acceptable salt of niclosamide dissolved in the organic solvent.

The organic solvent may comprise a polar organic solvent, and the organic solvent is preferably propylene glycol; glycerin; Polyethylene glycol; Glycofurol; Isopropanol; 2-pyrrolidine; A solvent selected from the group consisting of derivatives of 2-pyrrolidine and mixtures of these solvents. In one embodiment of the invention, the solvent may comprise a mixture of propylene glycol and glycerin, preferably in a 1: 1 (volume: volume) ratio. In another embodiment of the present invention, the solvent may comprise propylene glycol.

In one embodiment of the invention, the niclosamide salt may comprise a nonmetal salt. In one preferred embodiment of the invention, the salt may comprise the meglumine salt of niclosamide. Other nonmetal salts of niclosamide are known, such as piperazine salts and ethanolamine salts.

In another embodiment of the invention, the niclosamide salt may comprise a metal salt. Metal salts may include tin salts. However, preferably the salt comprises a metal salt selected from the group consisting of alkali metal salts and alkaline earth metal salts. In a preferred embodiment of the invention, the metal salt comprises the sodium salt of niclosamide.

The niclosamide salt dissolved in the organic solvent is preferably formed in situ. This can be achieved by dissolving a suitable base to form the niclosamide salt in the solvent and adding the niclosamide salt to the solvent. Preferably, the base is first dissolved in a solvent, followed by the addition of niclosamide. Stirring and / or heating may be used to promote the dissolution of the compound in the solvent. The solution can also be filtered.

In one preferred embodiment of the invention, sodium hydroxide is dissolved in a solvent and then niclosamide is added to this solution. In this way, a stable solution is formed.

Insect repellent compositions may also contain additional active ingredients. These components may be to broaden the therapeutic spectrum of the formulation.

Thus, for example, the composition may contain a base or hydrohalogen salt of levamisol as an auxiliary active ingredient such that the resulting formulation is effective for tapeworms and cone-shaped worm parasites (due to the presence of niclosamide) and for roundworms where levamisol is known to be effective. For example as a hydrochloride or as a phosphate salt.

Antioxidants may also be included in the solution, which is preferably added at the time the base is added to the solvent. Antioxidants may include sodium metabisulfite.

Other auxiliaries may also be added, such as suitable preservatives and flavoring agents.

The composition of the present invention can be used as an insect repellent for livestock or humans. It may be administered orally [as a liquid in liquids or capsules or in the form of tablets or granules prepared using the solutions mentioned above].

According to another aspect of the present invention

Providing a pharmacologically acceptable organic solvent;

-Dissolving niclosamide in a solvent by forming a pharmacologically acceptable soluble salt of niclosamide in the solvent

Provided is a method of forming an antiparasitic composition in solution form.

Niclosamide can be dissolved in a solvent by providing a pharmacologically acceptable salt of niclosamide and dissolving the salt in an organic solvent.

In another preferred embodiment, the dissolved salts of niclosamide are formed in situ. Preferably, the dissolved salts of niclosamide are formed in situ as described above.

The method is preferably carried out under anhydrous conditions.

The present invention is described in more detail by the following examples, which however do not limit the scope described above to the illustrated embodiments.

Example 1

Niclosamide solution as sodium salt based on propylene glycol

0.5 g of ground [ie powdered] NaOH and 0.1 g of ground sodium metabisulfite were dissolved in 100 mL of propylene glycol with stirring.

Proper heating of propylene glycol may be necessary to facilitate dissolution of the material. To this solution 4 g of powdered anhydrous niclosamide was slowly added until dissolved while stirring to form a 4% (nicklosamide g / propylene glycol 100 ml) solution of niclosamide. . The resulting solution was filtered and injected into a sealed bottle. Care must be taken to prevent water from entering the solution as it degrades the final product, as evidenced by browning clear solutions.

Initial trials were performed on lambs with 4% solution to test for tapeworm and conical fluke infections. Initial results indicate that lesser amounts of niclosamide according to the present solution are as effective as higher amounts of niclosamide provided in conventional niclosamide suspensions.

Example 2

Evaluation of Efficacy of Oral Niclosamide Formulations on Perennial Natural Infection of Moniezia expansa in Lambs

A 20% (niclosamide g / carrier 100 ml) suspension [standard] of the 4% niclosamide solution [test product] according to the present invention prepared as described in Example 1 for the Moniegia expansa was tested. Water was compared with the available niclosamide formulations prepared at various dose rates. Standards were administered at a prescribed dose rate of 50 mg / kg.

Testing was conducted on Applicant's farm "Londebult" in the Bobsfontein region of South Africa.

Intake investigations and staining and identification of the Moniegia expanel were performed in the laboratory. A Dorper lamb about 2 months old was used during the test. During the test period the lambs were kept in cages and fed with lucerne through the water.

Tapeworm remedies were tested in lambs that were found to be naturally infected by preliminary testing. Moniegia Expan is easily diagnosed in living animals. Diagnosis was made using egg form and excreted single insulators, although digested and difficult to identify accordingly. The test was performed with a staggered series of critical control trials.

The animals were divided into groups, some animals were treated with the test product (various dose rates) for three consecutive days in each group, some animals were treated with a standard (a prescribed dose rate of 50 mg / kg), and some Animals were left as comparative untreated controls [control].

Animals included in each stagger were equipped with fecal collection bags for one day before treatment and three days after treatment. It was observed for the presence of single insulator in the collected waste.

Animals included in each stagger were slaughtered four days after treatment according to the following method:

1. The animals were euthanized, peeled, and the abdominal cavity opened. The gastrointestinal tract was removed and the small intestine and cecum / colon were recovered. Animal numbers are labeled here.

2. The cabinet was placed in a bucket. Water was added to both ends of the intestine so that both ends of the intestine were filled about 1 to 2 meters.

3. Water flowed through the intestine at both ends until a loop formed at the bottom end of the bucket.

4. One end of the intestine was extended and water was gently pushed through the trachea between the fingers.

5. A pair of viscera scissors was then used to make an incision along its entire length, flushed with water to thoroughly wash the wall. The intestines were sealed in glass bottles and formalin was added for preservation. This process was done for later investigation.

6. The intake was collected and passed through an Endecotts sieve and stored in glass bottles for direct sunlight in a laboratory plastic pan.

The result is:

Number of animals Aid Dose rate Animals infected with parasites at necropsy 7 Trial product 6 mg / kg 2 7 Trial product 8 mg / kg 2 7 Trial product 10 mg / kg 0 5 Trial product 20 mg / kg 0 3 Trial product 40 mg / kg 0 9 Standard 50 mg / kg 0 5 Control - 5

The results indicate that the test product is as effective as the standard even at a low dose rate of 10 mg compound / kg compared to the dose rate of 50 mg standard / kg.

It will be understood that many modifications of detail are possible without departing from the scope and spirit of the invention.

Claims (24)

An antiparasitic composition in the form of a solution containing a pharmacologically acceptable organic solvent and a pharmacologically acceptable salt of niclosamide dissolved in the organic solvent. The composition of claim 1 wherein the organic solvent comprises a polar organic solvent. The process of claim 2, wherein the organic solvent is propylene glycol; glycerin; Polyethylene glycol; Glycofurol; Isopropanol; 2-pyrrolidine; A composition selected from the group consisting of derivatives of 2-pyrrolidine and mixtures of these solvents. 4. The composition of claim 3, wherein the solvent comprises a mixture of propylene glycol and glycerin. 4. The composition of claim 3 wherein the solvent comprises propylene glycol. The composition of claim 1 wherein the salt of niclosamide comprises a nonmetal salt. 7. The composition of claim 6, wherein the salt comprises a meglumine salt of niclosamide. The composition according to any one of claims 1 to 5, wherein the salt of niclosamide comprises a metal salt. The composition of claim 8 wherein the salt comprises a metal salt selected from the group consisting of alkali metal salts and alkaline earth metal salts. 10. The composition of claim 9 wherein the metal salt comprises a sodium salt of niclosamide. The composition of claim 1, wherein the salt of niclosamide dissolved in the organic solvent is formed in situ. 12. The composition of claim 11, wherein the dissolving salt is formed by dissolving a base suitable for forming the niclosamide salt in a solvent and adding niclosamide to the solvent. 13. The composition of claim 12, wherein the base is first dissolved in a solvent and then niclosamide is added. The composition of claim 10 wherein the dissolved sodium salt is formed in situ by dissolving sodium hydroxide in a solvent, followed by the addition of niclosamide to form a stable solution. The composition of claim 1, further comprising at least one additional active ingredient. The composition of claim 15 comprising levamisol as base or hydrohalogen salt. 17. The composition of any one of claims 1 to 16, wherein the composition comprises an antioxidant in solution. 18. The composition of claim 17, wherein the antioxidant comprises sodium metabisulfite. The composition of any one of claims 1 to 18 in an orally administrable form. Providing a pharmacologically acceptable organic solvent; Pharmacologically acceptable soluble salts of niclosamide in the solvent to dissolve the niclosamide in the solvent A method of forming an insect repellent composition in the form of a solution. The method of claim 20, wherein the niclosamide is dissolved in the solvent by providing a pharmacologically acceptable salt of niclosamide and dissolving the salt in an organic solvent. The process according to claim 20, wherein a dissolved salt of niclosamide is formed in situ by dissolving a base suitable for forming a salt of niclosamide in a solvent and adding niclosamide to the solvent. Insecticidal compositions in the form of solutions substantially described herein with reference to the Examples. A method of forming an insecticidal composition in solution form substantially as described herein with reference to the Examples.