Solid pharmaceutical compositions comprising ivermectin

Abstract

The present invention relates to a composition prepared by wet granulation comprising ivermectin or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipients thereof wherein ivermectin is in external phase of pharmaceutical composition.

Description

[0001]SOLID^PHARMACEUTICAL^COMPOSITIONS^COMPRISING^IVERMECTIN^ ^ Field^of^invention^ The present invention relates to a composition prepared by wet granulation comprising ivermectin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient wherein ivermectin is in external phase of pharmaceutical composition. ^ State^of^the^Art^ Ivermectin is described chemically as a mixture containing at least 90% 5-O demethyl- 22,23-dihydro avermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)- 22,23-dihydro-25-(1-methylethyl) avermectin A1b and its chemical structure is shown in the Scheme I. Ivermectin has molecular weight of 1736.2 g / mol. It is crystalline powder and insoluble in water, freely soluble in methylene chloride and soluble in ethanol. Ivermectin has been used as an antiparasitic agent to treat animal parasites, parasitic diseases except human use from the last quarter of 1900s. It is commercially available for animal use in the form of tablets, paste, or chewable for heartworm prevention and also topical solution for ear mite treatment, or in the solution form for other parasite problems in European countries. Ivermectin is commercially available under the tradename of Stromectol tablet for human use in the treatment of intestinal strongyloidiasis, parasites in the blood or tissue caused by Wuchereria bancrofti and human scabies. The medicine is available in the form of tablet and is used oral administration. Strongyloidiasis is a human parasitic disease caused by a nematode, or a roundworm, in the genus Strongyloides which is a type of helminth. There are over 40 species that can 1    infect birds, reptiles, amphibians, livestock and other primates. Strongyloides stercoralis is the primary species that can infect to human body. According to Siddiqui AA, Infection of Strongyloides stercoralis was firstly reported in the year 1876, in Vietnam. According to Schwartz RA, Strongyloidiasis was first described by Fulleborn in 1926. In general, strongyloidiasis causes no symptoms on patients. If present, symptoms may upper abdominal burning or pain, diarrhea, cough, rash, vomiting and weight loss. Strongyloidiasis stercoralis infection can be prevented through good personal hygiene. Wuchereria bancrofti is a common human parasite that is the major cause of lymphatic filariasis. This disease affects in tropical regions worldwide, especially in Central Africa, the Nile delta, South and Central America, and the tropical regions of Asia. In general, host of this parasite is mosquitoes. If left untreated, the infection can develop into a chronic disease called lymphatic filariasis. Scabies is a contagious skin infestation by a tiny burrowing mite called Sarcoptes scabiei. Scabies signs and symptoms can be intense itching, scales&blisters and irregular burrow tracks made up of tiny blisters or bumps on skin. Scabies is contagious and can spread quickly through close physical contact in a family, childcare group, school class, nursing home or prison. Scabies has been observed in humans since ancient times. In pharmaceutical industry, the oral administration route is prevalent and it has many advantages especially about patient compliance. One of the oral administration ways used commonly is tablet form. Tablet form has many advantages like cost-effective, lighter and compact, easiest and cheapest to package, can be masked by coating technique and greatest chemical and microbial stability over all oral dosage forms. General properties of tablet dosage forms; ^ Tablet should have elegant product without any cracks, discoloration or contamination. ^ Mechanical strength should be sufficient for production packaging, shipping and dispensing. ^ Physical properties should maintain the chemical and physical stability. 2    ^ Tablet form should have predictable and reproducible manner for releasing the active ingredients. In view of the foregoing, there is a need to decrease impurity, improve mixture uniformity and tablet compression in compositions comprising ivermectin, in the state of the art and to produce tablets with wet granulation of a specifically desired quality and dissolution profile and low impurity level. The present invention provides a solution to these problems by providing novel compositions of ivermectin wherein ivermectin is in external phase with wet granulation. These solutions will be described in detail. Brief^Description^of^the^invention^ The present invention provides a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients wherein ivermectin is in external phase wherein the composition is prepared by wet granulation. The composition dosage form can be a tablet or a capsule, preferably can be a tablet. The composition of present invention can be comprising diluents, lubricants, glidants, binders, disintegrants, antioxidants, stabilizers or mixtures thereof as a pharmaceutically acceptable excipient. In other aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition that ivermectin is used in external phase wherein the process comprising steps below: a. Preparing a homogeneous solution with an antioxidant and a stabilizer using solvents, b. Sieving and mixing diluents, c. Granulating in fluid bed dryer, d. Sieving and drying granules, e. Sieving and mixing Ivermectin and diluent, f. Sieving lubricant and mixed with granules in final mixture, and g. Compressing tablet and film coating. 3    In preferred aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition that ivermectin is used in external phase wherein the process comprising steps below: a. Preparing a homogeneous solution with citric acid and butylated hydroxyanisole using solvents, b. Sieving and mixing diluents, c. Granulating in fluid bed dryer, d. Sieving and drying granules, e. Sieving and mixing Ivermectin and diluent, f. Sieving magnesium stearate and mixed with granules in final mixture, and g. Compressing tablet and film coating. In other aspect of invention, a pharmaceutical composition for use in the treatment of internal nematode infections such as strongyloidiasis, demodicosis, onchocerciasis and COVID-19. Detailed^description^of^the^invention^ The aspects and disclosures according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to the ivermectin as defined hereinbefore and hereinafter. Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. Excipients that are used in tablet dosage form are diluent, binder, disintegrants, lubricant, viscosity enhancer agent and solvent except active ingredient. The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients wherein ivermectin is in external phase wherein the composition is prepared by wet granulation. 4    The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof wherein ivermectin is in external phase wherein the composition is prepared by wet granulation decreases impurity, improves mixture uniformity, tablet compressibility, dissolution and produces tablets with the desired properties. The present invention relates to a process for pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fillers, disintegrants, binders, surfactants, solvents and other materials known to one of ordinary skill in the art and the mixtures thereof. In other embodiment according to present invention, the amount of ivermectin can be between 2.0-7.0 % based on the total weight of the composition. Preferably ivermectin in an amount of between 4.0- 6.0 %, more preferably ivermectin amount can be 4.5%, 4.6%, 4.7%, 4.8, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4% or 5.5% by weight based on the total amount of composition of the present invention. Most preferably the amount of ivermectin can be 5.0% by weight based on the total amount of composition of the present invention. Diluents or fillers or bulking agents can also be used in the process. Because most dosages require only very small quantities of Active Pharmaceutical Ingredients (APIs), diluents often comprise a significant proportion of the dosage form. Suitable diluents according to the present invention are selected from the group including, but are not limited to, lactose, microcrystalline cellulose, pregelatinized starch starches, calcium phosphates, sucrose, maltodextrin, mannitol, sorbitol, and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred diluents are pregelatinized starch, microcrystalline cellulose or mixture thereof. The fillers or diluents can be comprised in an amount in a range of about between 90.0- 98.0% based on the total weight of the composition. Preferably the amount of filler can be between 93.5-96.0% by weight of total composition of present invention. 5    Suitable solvents according to the present invention comprise, but are not limited to, hexane, water, ethyl alcohol, methyl alcohol and mixtures thereof. In other embodiment composition may comprise one or more solvent. Preferably composition may comprise first and / or second solvent. First solvent can be ethyl alcohol. Second solvent can be water. Suitable antioxidant according to the present invention include, but are not limited to, butylated hydroxyanisole (BHA), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, erythorbic acid and mixtures thereof. The preferred antioxidant can be butylated hydroxyanisole (BHA). In other embodiment the amount of antioxidant can be between 0.001-0.03% by weight of total composition of present invention. Suitable stabilizer according to the present invention include, but are not limited to, citric acid, aluminum monostearate, colloidal silicon dioxide, glyceryl monooleate, hydrophobic colloidal silica, myristyl alcohol and mixtures thereof. The preferred stabilizer is citric acid. In other embodiment the amount of stabilizer can be between 0.001-0.03% by weight of total composition of present invention. Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate. The inventors surprisingly have found that the pharmaceutical composition comprises ivermectin wherein ivermectin is in external phase wherein composition prepared by wet granulation, decreases impurity, improves blend uniformity, tablet compressibility, dissolution and produces tablets with the desired properties. 6    Compositions in which ivermectin is used in the external phase have advantages in terms of impurity, blend uniformity, tablet compressibility and dissolution results compared to the compositions used in the internal phase. The lubricants can be comprised in an amount in a range of about 0.1-1.1% based on the total weight of the composition. In one embodiment according to present invention, the pharmaceutical composition is prepared by wet granulation comprises ivermectin and at least one pharmaceutically acceptable excipients, wherein ivermectin is in external phase of pharmaceutical composition improves mixture uniformity, tablet compressibility, dissolution and produces tablets with the desired properties. Some examples of the active ingredient Ivermectin being in the internal and external phases of the formulation are given below. Example 1: Pharmaceutical composition comprising ivermectin in the internal phase. Table^1:^Ivermectin film coated tablet composition (Internal phase) ^ Ingredients^ Ratio^(%)^Internal^Phase^ ^Ivermectin 2.0-7.0 Diluent(s) 90.0-98.0 Stabilizer 0.001-0.03 Antioxidant 0.001-0.03 External^Phase Diluent^ 2.0-5.0Lubricant 0.1-1.1 Total 100,00 In other aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition that ivermectin is used in internal phase wherein the process comprising steps below: 7    a. Preparing a homogeneous solution with an antioxidant using solvent, b. At least one diluent and ivermectin is added and mixed, c. Sieving, d. Granulating in fluid bed dryer, e. Sieving and drying granules, f. Sieving and mixing diluent, g. Sieving lubricant and mixed with granules in final mixture, and h. Compressing tablet and film coating. Example 2: Pharmaceutical composition comprising ivermectin in the external phase. Table^1:^Ivermectin film coated tablet composition (External phase) ^ Ingredients^ Ratio^(%)^Internal^Phase^ ^Diluent(s) 90.0-98.0 Stabilizer 0.001-0.03 Antioxidant 0.001-0.03 External^Phase Ivermectin 2.0-7.0 Diluent 2.0-5.0 Lubricant 0.1-1.1 Total 100,00 In other aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition that ivermectin is used in external phase wherein the process comprising steps below: a. Preparing a homogeneous solution with an antioxidant and a stabilizer using solvents, b. Sieving and mixing diluents, c. Granulating in fluid bed dryer, d. Sieving and drying granules, e. Sieving and mixing Ivermectin and diluent, f. Sieving lubricant and mixed with granules in final mixture, and g. Compressing tablet and film coating. 8    In preferred aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition that ivermectin is used in external phase wherein the process comprising steps below: a. Preparing a homogeneous solution with citric acid and butylated hydroxyanisole using solvents, b. Sieving and mixing diluents, c. Granulating in fluid bed dryer, d. Sieving and drying granules, e. Sieving and mixing Ivermectin and diluent, f. Sieving magnesium stearate and mixed with granules in final mixture, and g. Compressing tablet and film coating. In other aspect of invention, a pharmaceutical composition for use in the treatment of internal nematode infections such as strongyloidiasis, demodicosis, onchocerciasis and COVID-19. ^ Ivermectin^ Impurity^result^ The total impurity of ivermectin in the external phase was 2.4 at 40 C Month 1, while the total impurity of ivermectin in the internal phase was 3.4 at 40 C Month 1. Impurity increase is observed and in the results of 40 C 3 month, it was observed that it increased from 3% when ivermectin was in the external phase to 4.6% when ivermectin was in the internal phase. As a result, when ivermectin is in the external phase of pharmaceutical composition, impurities were decreased. 9

Claims

CLAIMS^ 1. A pharmaceutical tablet composition prepared by wet granulation comprising ivermectin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient characterized in that ivermectin is in external phase of tablet.

2. The pharmaceutical tablet composition according to claim 1, wherein the excipient is selected from, diluents, lubricants, glidants, binders, disintegrants, antioxidants, stabilizers or mixtures thereof.

3. A pharmaceutical tablet composition according to preceding claims for use in the treatment of internal nematode infections preferably, strongyloidiasis, demodicosis, onchocerciasis or COVID-19.

4. A wet granulation process for manufacturing a pharmaceutical tablet composition according to claim 1, comprising steps of: a. Preparing a homogeneous solution of at least one antioxidant and a stabilizer b. Sieving and mixing diluents, c. Granulating in fluid bed dryer, d. Sieving and drying granules, e. Sieving and mixing Ivermectin with diluent, f. Sieving lubricant and mixed with granules in final mixture, and g. Compressing tablet and film coating.

5. The wet granulation process for manufacturing a pharmaceutical tablet composition according to claim 4, comprising steps of: a. Preparing a homogeneous solution with citric acid and butylated hydroxyanisole b. Sieving and mixing diluents, c. Granulating in fluid bed dryer, d. Sieving and drying granules, e. Sieving and mixing Ivermectin with diluent, f. Sieving magnesium stearate and mixed with granules in final mixture, and g. Compressing tablet and film coating.

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