WO2016157064A1

WO2016157064A1 - Stable ricobendazole formulations

Info

Publication number: WO2016157064A1
Application number: PCT/IB2016/051744
Authority: WO
Inventors: Mehmet Fidan; Levent Kandemir; Recep Avci; Suna Ayse Akyil; Tuba Sandikci; Andreas Hartwig STECKEL
Original assignee: Deva Holding Anonim Sirketi
Priority date: 2015-03-30
Filing date: 2016-03-28
Publication date: 2016-10-06

Abstract

This invention relates to ricobendazole formulations used to control parasite species in animals and to treat the infections caused by such parasites and their methods of manufacture.

Description

DESCRIPTION

STABLE RICOBENDAZOLE FORMULATIONS

Technical Field

This present invention relates to the anthelmintically injectable formulations. Specifically, this present invention relates to use of injectable formulations of ricobendazole in the control and prevention of parasitic invasions and treatment of infection caused by parasites in warm-blooded animals.

Background art

Warm-blooded animals are exposed to invasions of parasites and face severe health problems.

The internally and externally reproducing parasites, i.e. intestinal worms and louses, are fed by the tissue, blood and liquid in the tissue of the animals. Internal parasites may cause a lack of appetite, poor digestion of nutrients, and a lack of nourishment, loss of blood and anemia. The animals invaded by internal parasites lose weight, consume less milk and have a poor immune system. The externally reproducing parasites cause crusting, loss of blood and anemia, and itching of skin, and carry diseases. If such parasites and the diseases they cause are not controlled and treated, they cause death of animals and global economic losses. The most common parasite is the worm group referred to as nematodes (roundworm/ringworm). Nematodes are found in the digestive system, intestinal system, heart, lungs, blood vessels and other tissues of the animals. Nematodes are the main reason of anemia, loss of weight and malnutrition in infected animals. They cause serious damage to the tissues of the involved organs.

Sheep, cattle, goat, horses and other domestic herbivores are especially exposed to the infections.

The most common nematodes transmitted to ruminant animals include Haemonchus and Ostertagia found in abomasum (fourth stomach section, omasum) Cooperia, Trichostrongylus and Nematodirus, which are usually found in the intestines, and Dictyocaulus strains found in the lungs. Therefore, in order to prevent an invasion of any of the parasites above, it is important to treat the animals to decrease and control growth of such parasites in animals.

Investigating the anthelmintic compositions has always been an area of interest in the veterinary pharmaceutical industry. The researchers aimed at the development of the anthelmintic compounds to treat and control the diseases caused by worm species that particularly affect cattle. The release of thiabendazole in 1961 introduced the first benzimidazole group anthelmintic product and this has been an important starting point to develop anthelmintic compounds with better characteristics in the veterinary drugs industry. Many anthelmintic agents were discovered with varying degrees of activity on some helminthes that cause infections.

The chemical name of albendazole is [5-(propylthyo)-l H- benzimidazole-2-yl)] carbamic acid methyl ester. And ricobendazole is the active metabolite of albendazole and it is absorbed by the gastrointestinal system and then reaches the liver, and then formed by commonly being metabolized by the flavin mono-oxygenase system. The chemical name of ricobendazole (albendazole sulfoxide) is methyl [5-(propan-l-sulphinyl)-lH-benzoimidazole-2-yl]-carbamate and it was first disclosed in patent No. US 3915986 (GlaxoSmithKline pic; 1974). Patent No. US 3915986 provides information about the preparation and use of albendazole sulfoxides.

Ricobendazole is an anthelmintic with a wide-spectrum activity used in veterinary drugs. It is considered that ricobendazole, a metabolite of albendazole, is the active part in use against systemic tissue infections. Ricobendazole reaches high plasma levels much faster than albendazole.

Ricobendazole binds to tubules of the sensitive helminths in skin and intestinal cells and inhibits polymerization of this substance in the form of microtubules. Loss of microtubules decreases intake of glucose and production of ATP and consumes glycogen reserves. Thus, the parasite, which loses its energy, is immobilized and removed from the environment. It was verified that ricobendazole is effective not only on all internal parasites but also the eggs of such parasites. Ricobendazole is very slightly soluble in water. This characteristic may make it difficult to prepare pharmaceutical formulations containing ricobendazole. Some approaches are seen in the patent literature to overcome this problem.

In the patent application No. EP0919231 (Biogenesis S A, 1997), the injectable benzimidazole formulations are disclosed and ricobendazole is dissolved in propylene glycol in the presence of HC1.

In the patent application No. WO2006022562 (Bomac Research Limited; 2004), it is suggested that a complex may be formed with cyclodextrine to overcome the problem related to insolubility of ricobendazole in water and the injectable formulations containing this complex are disclosed.

This present invention relates to the new, injectable liquid veterinary formulations containing ricobendazole and their methods of manufacture.

Specifically, the purpose of this present invention is to develop injectable stable liquid veterinary formulations containing ricobendazole, which will be used to control parasite species in the warm-blooded animals and to treat the infections caused by such parasites. Technical Problem

Ricobendazole is very slightly soluble, which is a common characteristic of anthelmintics. Ricobendazole is very slightly soluble in water but it can be dissolved in water under extreme conditions such as pH<2 or pH >11.

This characteristic restricts the areas of application of the molecule and this not only makes it impossible for the administer using easy-to-use dosage forms, such as the oral route or mixing with the drinking water, but also makes it difficult to prepare different dosage forms. And many problems occur during the preparation of injectable liquid formulations of ricobendazole. Solubility of benzimidazoles is also low similar to ricobendazole, thus they cannot be absorbed immediately and they may cause pain in the animals due to insufficient absorption and deposit of the formulation.

Water is not used in formulations of injectable ricobendazole, because ricobendazole is hydrolyzed in formulations containing water and the stability of the formulations containing water due to the degradation following hydrolysis and the animal cannot intake the required amounts of drug substance.

As ricobendazole is very slightly soluble in water and degrades, it was tried to dissolve it in another solvent other than water to develop formulations in injectable solution forms. In this context, in some studies in the state of the art, it was tried to dissolve ricobendazole in propylene glycol and HC1 was added in the solution to dissolve ricobendazole. However, water in HC1 may cause degradation of ricobendazole. In this context, it may be seen that the injectable products containing ricobendazole, which are supplied as ready-to-use solution in the market, do not have targeted stability.

Another important problem that should be overcome with regard to the injectable formulations containing ricobendazole is that the drug substance immediately oxidizes when it is exposed to oxygen. Therefore, some stability problems may be observed in the finished product, which are caused by the degradations due to oxidation. Oxidation of ricobendazole should be prevented in order to obtain stable products.

The inventors studied the injectable formulations containing ricobendazole in suspension form, which is still not used, and solution form and encountered various problems while developing formulations in both forms.

In injectable suspension formulations of ricobendazole, deposit and caking may be observed from manufacture to administration. Deposits of the solid particles in the suspension is normal but caking should be prevented, the deposits should be distributed by slight shaking, a homogeneous suspension should be obtained. After shaking, the solid particles in the suspension should not deposit immediately and the homogeneous suspension form should be maintained for a sufficient period of time to administer. It should be easy to draw the injectable suspension ricobendazole in the injector and inject it.

This easy drawing and injecting process depends on the viscosity of the suspension. In order to ensure such characteristics, the blockages caused by the particles in the suspension should also be prevented. The inventors noticed that ricobendazole is crystallized below 25 °C, even if it is dissolved in a solvent other that water during development studies of injectable ricobendazole veterinary formulation in solution form. If such crystallization is not prevented, it will be impossible to administer the product, so some studies were performed to overcome this problem. In the veterinary industry, stable and easy-to-use injectable formulations with higher ricobendazole activity without such problems are required.

Technical Solution The purpose of the inventors is to develop new injectable liquid ricobendazole veterinary formulations with improved physical characteristics, which are stable during the shelf-life compared to the existing products on the market.

The inventors studied injectable solution and suspension formulations containing ricobendazole, which overcome such problems.

It was tried to overcome the common problem in preparation of both forms, i.e. degradation of ricobendazole due to oxidation. The inventors used antioxidant to prevent oxidation and subsequent degradation of ricobendazole. It was seen that the appropriate amount of antioxidant used by the inventors improved the stability of the formulations produced in solution and suspension form.

The inventors not only used antioxidants to prevent oxidation of ricobendazole but also prepared solution and suspension formulations in a nitrogen medium to minimize the contact between ricobendazole and oxygen. The inventors provided some common solutions for the common problems of the solution and suspension forms of ricobendazole above and also conducted some studies to overcome the problems specific to each form.

The inventors did not use water in solution and suspension forms as ricobendazole is degraded in the presence of water. An oily-phase carrier was preferred in the injectable formulations in solution and suspension forms according to this invention.

While use of oily-phase eliminated the degradation problem due to the hydrolysis of ricobendazole in the formulation in suspension form, the inventors needed different approaches to ensure stability of the solution form.

In order to ensure stability of the solution the use of HCl in the formulation was eliminated contrary to the information in the state of the art. Therefore, they prevented degradation caused by water inflow caused by HCl using HCl salt of ricobendazole in lieu of the ricobendazole in the injectable solution formulation.

During development of the injectable formulations in solution form according to this invention, the inventors conducted studies about the problem of crystallization of the product under 25 °C when only one oily-phase carrier is used. It is surprising that the inventors found that they could prevent crystallization of the product using two oily-phase carriers rather than only one oily- phase carrier in a study they conducted to overcome this problem. In addition, they also found that oily-phase carriers should be anhydrous as ricobendazole is very sensitive to water. Even the small amounts of water in the excipients used in the formulation may cause degradation of ricobendazole.

In conclusion, the inventors succeeded in the preparation of injectable ricobendazole solution formulations with superior characteristics than the existing products.

The inventors also endeavor to overcome the problems of the suspension formulations containing injectable ricobendazole according to this invention. The inventors used an appropriate amount of viscosity-increasing agent in the suspension formulations to ensure that the injectable suspension has the optimum viscosity values. While developing the suspension formulations according to this invention, anticoagulant agents were used in addition to the viscosity agent. Use of the anticoagulant agent not only helps in achieving optimum viscosity values for the suspension but also improves physical stability. Ensuring physical stability prevents deposit of the solid particles for a definite period of time or prevents caking, even if they deposit. Thus, the injectable ricobendazole suspension formulations, which maintain their homogeneous natures, can be obtained. The viscosity-increasing agent and the anticoagulant agent used in appropriate amounts allow easy drawing of the suspension into the injector and its easy injection.

The injectable formulation containing ricobendazole allows a larger surface area of the drug substance in the suspension, thus allows easier absorbance.

The inventors developed a form, which has not been marketed yet, with the suspension formulation according to this invention and eliminated the dissolution and degradation problems of ricobendazole and thus satisfied an important requirement in the veterinary drugs industry.

Thanks to the injectable ricobendazole formulations prepared in solution and suspension form according to this invention, it is aimed at the obtaining of new formulations, which overcome all of the problems related to such forms and improved physical and chemical characteristics. And it has been possible to develop ready-to-use, injectable solution and suspension formulations, which remain stable throughout their shelf-lives.

Using the formulations according to this invention, the injectable formulations, which are easy to administer and do not cause the disadvantages seen with administration via oral route, have been developed. This invention prevents loss of the drug substance caused by fodder eaten by the animal, factors such as ruminal flora and allows production of cost-effective veterinary formulations.

Thanks to the injectable solution and suspension forms according to this invention, ricobendazole is absorbed faster via the plasma and reaches the high concentration required faster. Thus, it reaches the maximum therapeutic level in the areas where the parasites are involved, and directly fights against the parasites.

This invention will ensure that warm-blooded animals benefit from the anthelmintic formulation containing ricobendazole at the highest level and prevent diseases and death of animals due to parasite species. Thus, the economic losses caused by dying animals will be decreased.

The injectable formulations containing ricobendazole, which is effective as an anthelmintic, are used in the control of parasites and treatment of the infectious diseases caused by such parasites. Ricobendazole formulations according to this invention shows high activity against the helminthic infections seen in the lungs, digestive system, and intestines of the animals, especially those important in economic terms.

The formulations produced according to this invention are particularly preferably effective in the treatment and control of gastroenteritis caused by the gastrointestinal thread worms in sheep and cattle, parasitic bronchitis caused by lung nematodes, strip infestations and chronic butterfly infestation.

The formulation according to this invention shows a wide-spectrum activity against the parasites seen in the sheep and cattle. The formulation according to this invention is effective in mature and immature parasite forms. The injectable formulations containing ricobendazole according to this invention are particularly effective on Trichostronglylus, Haemonchus, Ostertagia, Cooperia, Capillaria, Chabertia, Nematodirus, Bunostomum, Strongyloides, Oesophagostomum, Trichuris, Dictyocaulus, Fasciola, Moniezia, and Cysticercus bovis parasites.

Benzimidazole is metabolized in the rumen when administered to the ruminants via the enteral route. Then, it is absorbed via gastrointestinal mucus and the anthelmintic is carried to the plasma, where it shows penetration. However, this process may be negatively affected by physiological, functional and metabolic factors. One of the physiological factors that should be considered is that, especially in young animals, the esophagus is blocked and so the drug substance goes directly into the rumen, where most of the drugs become inactive. Another physiological factor is that, when the animal eats a very fibrous feed, this feed blocks the rumen. In such case, benzimidazole cannot reach the required plasma concentration level and show the required anthelmintic impact.

The changes in gastrointestinal microphores is another disadvantage of oral administration of this drug substance.

In the oral administration method, which is mostly preferred in case of animals, the drug substance is mixed with drinking water. However, this method is not suitable for administration of ricobendazole. As ricobendazole is very slightly soluble in water, it deposits in water and blocks drinking water systems and the amount of drug substance in the drinking water decreases due to these deposits.

Administration of ricobendazole via injection is a more preferred method as is the case in many other drug substances. As the drug substance is injected directly to the area of interest or into the blood circulation, it is typically more effective. When compared to other routes, such as the digestive system, the loss of drug substance in the injection path is minimal. Therefore, the required quantity of the drug substance is decreased, which means less cost. In addition, thanks to the injectable dosage forms, the impact of the feed on the bioavailability of the drug is eliminated. Due to these many advantages, administration of ricobendazole via injection is preferred.

The formulations according to this invention are in an injectable liquid form for veterinary drugs.

The injectable veterinary formulations according to this invention contain ricobendazole between 5%-30% (weight/total liquid volume) or an equivalent amount of its salt.

The injectable veterinary formulations according to this invention contain ricobendazole preferably between 10%- 15% (% weight/total liquid volume) or an equivalent amount of its salt.

The injectable liquid veterinary formulation according to this invention may be a solution or suspension. The injectable solution formulation according to this invention is prepared by dissolving ricobendazole in at least one oily-phase carrier. At least one antioxidant is added into the solution prepared and all steps of the manufacturing process are performed in a nitrogen medium. The injectable solution according to this invention preferably contains ricobendazole as salt. The salt form used in the formulations according to this invention is preferably hydrochloride salt.

The injectable solution according to this invention contains at least one pharmaceutically acceptable excipient in addition to ricobendazole.

The pharmaceutically acceptable excipient in the injectable solution according to this invention is selected from a group including but not limited to the oily-phase carrier, antioxidant, pH agent, and their combinations. The pharmaceutically acceptable oily-phase carrier in the injectable solution according to this invention may be selected from a group including but not limited to ethanol, isopropanol, polyethylene glycol, diethylene glycol, glycerin, propylene glycol, and combination thereof.

The injectable solution according to this invention preferably contains a mixture of at least two oily-phase carriers. In a more preferred embodiment, the injectable solution contains a mixture of ethanol and propylene glycol as the oily-phase carrier.

The pharmaceutically acceptable antioxidant in the injectable solution according to this invention may be selected from a group including but not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), hypophosphorous acid, monothioglycerol, potassium metabisulphite, propoyl gallate, sodium bisulphite, sodium formaldehyde sulfoxylate, sodium metabisulphite, sodium sulphite, sodium thiosulfate, sulphure dioxide, tocopherols, and combination thereof.

The injectable solution according to this invention preferably contains butylated hydroxyanisole (BHA) as a pharmaceutically acceptable antioxidant. The pharmaceutically acceptable pH agent in the injectable solution according to this invention may be selected from citric acid, fumaric acid, tartaric acid, and combination thereof.

In another embodiment, the injectable liquid veterinary formulation is a suspension.

The injectable suspension formulation according to this invention is prepared by dissolving at least one antioxidant and at least one viscosity-increasing agent in at least one oily-phase carrier, adding at least one anticoagulant agent in this mixture and suspending the ricobendazole in the final mixture. Ricobendazole is added into the oily-phase carrier mixture in a nitrogen medium.

The injectable suspension according to this invention contains ricobendazole in free form or as a salt. The salt form used in the formulations according to this invention is preferably hydrochloride salt.

The injectable suspension according to this invention contains at least one pharmaceutically acceptable excipient in addition to ricobendazole.

The pharmaceutically acceptable excipient in the injectable suspension according to this invention is selected from a group including but not limited to the oily-phase carrier, viscosity- increasing agent, antioxidant, anticoagulant agent, wetting agent, surfactant, and r combination thereof.

The injectable suspension formulation according to this invention contains ricobendazole or a pharmaceutically acceptable salt thereofas well as at least one oily-phase carrier, at least one viscosity-increasing agent, at least one antioxidant, and at least one anticoagulant agent. The pharmaceutically acceptable oily-phase carrier in the injectable suspension according to this invention may be selected from a group comprisingbut not limited to peanut oil, soybean oil, sesame oil, coconut oil, almond oil, rapeseed oil, cotton oil, castor oil, hydrogenated castor oil, corn oil, olive oil, mineral oil, safflower oil, sunflower oil, vegetable oil, phenol, dimethyl sulfoxide, ethyl acetate, methyl isobutyl, ketone, and combination thereof.

The injectable suspension according to this invention preferably contains coconut oil as pharmaceutically acceptable oily-phase carrier. The pharmaceutically acceptable viscosity-increasing agent in the injectable suspension according to this invention may be selected from a group comprising but not limited to xanthan gum, hydroxypropyl methyl cellulose, carbomer (Carbomer 910, Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 941, Carbomer 1342, Carbomer Copolymer, Carbomer Homopolymer NF, Carbomer Interpolymer), carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, carrageenan, microcrystalline cellulose, dextrin, maltodextrin, glycerol polyethylene glycol, ricinoleate (Kolliphor El), gelatin, guar gum, gellan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminium cilicate, polyvinylpyrrolidone, starch, and combination thereof.

The injectable suspension according to this invention preferably contains glycerol polyethylene glycol ricinoleate (Kolliphor El) as a pharmaceutically acceptable viscosity-increasing agent.

The pharmaceutically acceptable antioxidant in the injectable suspension according to this invention may be selected from a group comprisingbut not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), hypophosphorous acid, monotioglycerol, potassium metabisulphite, propoyl gallate, sodium bisulphite, sodium formaldehyde sulfoxylate, sodium metabisulphite, sodium sulphite, sodium thiosulfate, sulphure dioxide, tocopherols, and combination thereof.

The injectable suspension according to this invention preferably contains butylated hydroxyanisole (BHA) as a pharmaceutically acceptable antioxidant.

The pharmaceutically acceptable anticoagulant agent in the injectable suspension according to this invention may be selected from silicon dioxide and colloidal silicone dioxide.

The pharmaceutically acceptable wetting agent in the injectable suspension according to this invention may be selected from polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate and fatty acid monoglyceride or diglyerides, and combination thereof. The pharmaceutically acceptable surfactant in the injectable suspension according to this invention may be selected from fatty sulfate esters, fatty sulfonates, cetyl trimethylammonium bromide, and combination thereof.

The injectable liquid ricobendazole veterinary formulations according to this invention is preferably administered via subcutaneous injection.

Each of the anthelmintic compounds is well-known by the practitioners in this field. The preferred quantity of ricobendazole is determined based on the parasite species and weight of animal to be treated. The dose administered varies between 3.75 mg/kg animal weight and 7.5 mg/kg animalweight.

Another embodiment of this invention relates to the injectable, liquid veterinary formulations containing ricobendazole or a pharmaceutically acceptable salt thereof as the drug substance, which has an anthelmintic effect, and its methods of manufacture.

The injectable solution formulations according to this invention is manufactured using the state of the art methods.

The injectable suspension formulations according to this invention is manufactured using the state of the art methods.

The injectable solution and suspension formulations according to this invention are manufactured in a nitrogen medium. The inventors conducted assay analysis of some commercially available products containing ricobendazole between 10% and 15% and studied the quantities of ricobendazole in such shelf samples. Two of the reference products analyzed in the assays are the injectable solutions containing ricobendazole at 10%, while the other two contained ricobendazole at 15%. The assay results of such reference products are given in Table 1. Table 1

As seen in Table 1, the commercially available solution products, which should contain ricobendazole at 10% and 15%, do not contain sufficient amounts of ricobendazole.

The inventors prepared the formulations in solution and suspension forms dispensed according to this invention and studied their stabilities. In such stability studies, first, the assays of the injectable solution prepared using ricobendazole HC1 in an amount, which is equivalent to ricobendazole at 15%, were conducted for three months at 25 °C under relative humidity of 60+5% and at 30 °C under relative humidity of 65+5%.

The stability results of the solution studied for three months at 25 °C under relative humidity of 60+5% are given in Table 2.

Table 2

The stability results of injectable solutions prepared using ricobendazole HC1 in an amount, which is equivalent to ricobendazole at 15%, and studied for three months at 30 °C under relative humidity of 65+5% are given in Table 3. Table 3

As seen in Table 2 and Table 3, the stability of the solution formulations prepared using ricobendazole HCl salt according to this invention was achieved.

The inventors also studied the stability of the injectable formulation prepared in suspension form. For this purpose, the formulations were prepared using both free ricobendazole and ricobendazole HCl.

Month 1 stability results of the suspension formulation prepared using ricobendazole HCl in an amount, which is equivalent to ricobendazole at 15%, at 25 °C under relative humidity of 60+5%, at 30°C under relative humidity of 65+5% and at 40°C under relative humidity of 75+5% are given in Table 4.

Table 4

Month 1 stability results of the suspension formulation prepared using free ricobendazole at 15% at 25°C under relative humidity of 60+5%, at 30°C under relative humidity of 65+5% and at 40°C under relative humidity of 75+5% are given in Table 5. Table 5

As seen in Table 4 and Table 5, the stability of the suspension formulations prepared using ricobendazole in free form or its salt according to this invention was achieved.

It is seen that very good stability values are achieved, if all of the stability results of the solution and suspension formulations prepared according to this invention are reviewed.

It is clear that the injectable solution and suspension formulations containing ricobendazole according to this invention makes a significant contribution to the veterinary drug industry.

Examples of the pharmaceutical formulations according to this invention are given below. Such examples are given to explain the invention and the invention is not limited to these examples.

Example 1:

Composition of the injectable solution containing ricobendazole at 15%

Table 6

The injectable solution formulation was prepared according to the composition above using the following steps.

1. One half of propylene glycol is taken into the container and nitrogen is passed for 1 hour. 2. Ethanol (anhydrous) and butylated hydroxyanisole (BHA) is added into the container.

3. The mixture obtained is mixed for 30 minutes under nitrogen.

4. Ricobendazole HC1 is added into the container and mixed until it dissolves under nitrogen.

5. 4. The mixture in step 4 is brought to the volume with the remaining half of the propylene glycol and mixed for 10 minutes under nitrogen.

Example 2:

Composition of the injectable suspension containing ricobendazole at 15%

Table 7

The injectable suspension formulation was prepared according to the composition above using the following steps. 1. BHA and Kolliphor El is added and dissolved in 250 ml of coconut oil.

2. Aerosil 200 is added into the mixture obtained in step 1 and it is homogenized. 3. Ricobendazole is slowly added into the mixture obtained in step 2 and then homogenized. This process is performed under nitrogen gas.

4. The mixture obtained in step 3 is brought to 1000 ml with coconut oil and then mixed. This process is performed under nitrogen gas.

Claims

1. An anthelmintic veterinary formulation containing ricobendazole, characterized in that the formulation is in injectable liquid form.

2. A pharmaceutical formulation according to Claim 1, wherein ricobendazole is in the form of a pharmaceutically acceptable salt thereof.

3. A pharmaceutical formulation according to Claim 1, wherein ricobendazole or pharmaceutically acceptable salt thereof in the formulation is between 5%-30% .

4. A pharmaceutical formulation according to Claim 1, wherein the ricobendazole or pharmaceutically acceptable salt thereof in the formulation is preferably at 10% .

5. A pharmaceutical formulation according to Claim 1, wherein the ratio of ricobendazole or pharmaceutically acceptable salt thereof in the formulation is preferably at 15%

6. A pharmaceutical formulation according to Claim 1, wherein the formulation is in the form of injectable solution.

7. A pharmaceutical formulation according to Claim 6, wherein the pharmaceutically acceptable excipient is selected from the oily-phase carrier, antioxidant, pH agent, and combination thereof.

8. A pharmaceutical formulation according to Claim 6, wherein the formulationcomprising preferably at least one oily-phase carrier and at least one antioxidant.

9. A pharmaceutical formulation according to Claim 6, wherein the pharmaceutically acceptable oily-phase carrier is selected from ethanol, isopropanol, polyethylene glycol, diethylene glycol, glycerin, propylene glycol, and combination thereof.

10. A pharmaceutical formulation according to Claim 6, wherein the pharmaceutically acceptable oily-phase carrier comprisingpreferably propylene glycol and ethanol combination.

11. A pharmaceutical formulation according to Claim 6, wherein the pharmaceutically acceptable antioxidant is selected from ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), hypophosphorous acid, monotioglycerol, potassium metabisulphite, propoyl gallate, sodium bisulphite, sodium formaldehyde sulfoxylate, sodium metabisulphite, sodium sulfite, sodium thiosulfate, sulphure dioxide, tocopherols, and combination thereof.

12. A pharmaceutical formulation according to Claim 6, wherein the pharmaceutically acceptable antioxidant comprising preferably butylated hydroxyanisole.

13. A pharmaceutical formulation according to Claim 6, wherein the pharmaceutically acceptable pH agent is selected from citric acid, fumaric acid, tartaric acid, and combination thereof.

14. A pharmaceutical formulation according to Claim 1, wherein the formulation is in the form of injectable suspension.

15. A pharmaceutical formulation according to Claim 14, wherein the pharmaceutically acceptable excipient is selected from the oily-phase carrier, viscosity-increasing agent, antioxidant, anticoagulant agent, wetting agent, surfactant, and combination thereof.

16. A pharmaceutical formulation according to Claim 14, whereinthe formulation copmprising preferably at least one oily-phase carrier, at least one viscosity-increasing agent, at least one antioxidant and at least one anticoagulant agent.

17. A pharmaceutical formulation according to Claim 14, wherein the pharmaceutically acceptable oily-phase carrier comprising preferably Coconut oil.

18. A pharmaceutical formulation according to Claim 14, wherein the formulation comprising glycerol polyethylene glycol ricinoleate (Kolliphor El) as pharmaceutically acceptable viscosity- increasing agent.

19. A pharmaceutical formulation according to Claim 14, wherein the pharmaceutically acceptable antioxidant comprising preferably butylated hydroxyanisole.

20. A pharmaceutical formulation according to Claim 14, wherein the pharmaceutically acceptable anticoagulant agent is selected from silicon dioxide and colloidal silicon dioxide.

21. A pharmaceutical formulation according to Claim 14, wherein the pharmaceutically acceptable wetting agent is selected from polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate and oil acid monoglyceride or diglyerides, and combination thereof.

22. A pharmaceutical formulation according to Claim 14, wherein the pharmaceutically acceptable surfactant is selected from fatty sulfate esters, fatty sulfonates, cetyl trimethylammonium bromide, and combination thereof.