Solid pharmaceutical compositions comprising ivermectin

Abstract

The present invention relates to a composition comprising ivermectin or pharmaceutically acceptable salt thereof prepared by wet granulation.

Description

[0001]SOLID^PHARMACEUTICAL^COMPOSITIONS^COMPRISING^IVERMECTIN^ ^ Field^of^invention^ The present invention relates to a composition comprising ivermectin or pharmaceutically acceptable salt thereof prepared by wet granulation. ^ 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 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 1    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. ^ Tablet form should have predictable and reproducible manner for releasing the active ingredients. 2      In view of the foregoing, there is a need to improve blend 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. The present invention provides a solution to these problems by providing novel compositions of ivermectin, antioxidant and stabilizer 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, at least one antioxidant, at least one stabilizer and at least one pharmaceutically acceptable salt 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 or mixtures thereof as a pharmaceutically acceptable excipient.   In other embodiment the pharmaceutical composition can be comprising at least one antioxidant wherein the at least one antioxidant can be selected from butylated hydroxyanisole (BHA), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, erythorbic acid or mixtures thereof. Preferably at least one antioxidant is butylated hydroxyanisole (BHA).   In other embodiment the pharmaceutical composition can be comprising at least one stabilizer wherein the at least one stabilizer can be selected from citric acid, aluminum monostearate, colloidal silicon dioxide, glyceryl monooleate, hydrophobic colloidal silica, myristyl alcohol or mixtures thereof. Preferably at least one stabilizer is citric acid.   In other aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Preparing a homogeneous solution with antioxidant and first solvent, b. Preparing a homogeneous solution with stabilizer and second solvent, c. Sieving and mixing Ivermectin and diluents, 3    d. Granulating in fluid bed dryer, e. Sieving and drying granules, f. Sieving lubricant and mixed with granules, and g. Compressing tablet and film coating.   In preferred aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Preparing a homogeneous solution with butylated hydroxyanisole and ethyl alcohol, b. Preparing a homogeneous solution with citric acid and water, c. Sieving and mixing Ivermectin, microcrystalline cellulose and pregelatinized starch, d. Granulating in fluid bed dryer, e. Sieving and drying granules, f. Sieving magnesium stearate and mixed with granules, and g. Compressing tablet compression 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, antioxidant, stabilizer, binder, disintegrants, lubricant, viscosity enhancer agent and solvent except active ingredient.   4    The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof, at least one antioxidant and at least one pharmaceutically acceptable excipient. The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof, at least one stabilizer and at least one pharmaceutically acceptable excipient. The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof, at least one antioxidant, at least one stabilizer and at least one pharmaceutically acceptable excipient. The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof, at least one antioxidant, at least one stabilizer and at least one pharmaceutically acceptable excipient wherein the composition is prepared by wet granulation.   The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof, butylated hydroxyanisole as an antioxidant, at least one stabilizer and at least one pharmaceutically acceptable excipient wherein the composition is prepared by wet granulation.   The present invention relates to a pharmaceutical composition comprising ivermectin or pharmaceutically acceptable salt thereof, butylated hydroxyanisole as an antioxidant, citric acid as a stabilizer and at least one pharmaceutically acceptable excipient wherein the composition is prepared by wet granulation.   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.   5    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.   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. 6      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, at least one antioxidant, at least one stabilizer and at least one pharmaceutically acceptable excipient wherein composition prepared by wet granulation improves blend uniformity, dissolution and produces tablets with the desired properties.   In other embodiment the inventors have found that the pharmaceutical composition comprises ivermectin, at least one antioxidant, at least one stabilizer and at least one pharmaceutically acceptable excipient wherein the composition prepared by wetgranulation improves tablet compressibility.  This can lead to more efficient tabletproduction, as less pressure may be required during the compression process, thereby reducing the energy consumption and cost of production. The new compositions can potentially address the current challenges in balancing the various properties of the tablet, such as its strength, disintegration time, and patient acceptability.   In one embodiment according to present invention, the pharmaceutical composition comprises ivermectin, butylated hydroxyanisole as an antioxidant, citric acid as a stabilizer and at least one pharmaceutically acceptable excipient wherein composition prepared by wet granulation improves blend uniformity, tablet compressibility, dissolution and produces tablets with the desired properties.   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. 7      Table^1:^Ivermectin film coated tablet composition ^ Ingredients^ Ratio^(%)^Ivermectin 2.0-7.0 Diluent 90.0-98.0 Antioxidant 0.001-0.03 Stabilizer 0.001-0.03 Lubricant 0.1-1.1 Total 100,00   In other aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Preparing a homogeneous solution with antioxidant and first solvent, b. Preparing a homogeneous solution with stabilizer and second solvent, c. Sieving and mixing Ivermectin and diluents, d. Granulating in fluid bed dryer, e. Sieving and drying granules, f. Sieving lubricant and mixed with granules, and g. Compressing tablet and film coating.   In preferred aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Preparing a homogeneous solution with butylated hydroxyanisole and ethyl alcohol, b. Preparing a homogeneous solution with citric acid and water, c. Sieving and mixing Ivermectin, microcrystalline cellulose and pregelatinized starch, d. Granulating in fluid bed dryer, e. Sieving and drying granules, f. Sieving magnesium stearate and mixed with granules, and g. Compressing tablet compression and film coating.   8    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. Examples^ Example^1^ The tablet composition according to the preferred embodiment of the present invention is given in Table 2 below. ^ Table^2:^Ivermectin film coated tablet composition Ingredients^^ Ratio^(%)^Ivermectin 3.5-6.5 Pregelatinized Starch 3.5-6.5 Microcrystalline Cellulose 87.0-91.5 Butylated Hydroxyanisole 0.001-0.03 Citric acid 0.001-0.03 Magnesium Stearate 0.1-1.1 Total 100,00 The composition in Table 2 were prepared by wet granulation. A homogeneous solution was prepared with butylated hydroxyanisole and ethyl alcohol. A homogeneous solution was prepared with citric acid and water. Then ivermectin, microcrystalline cellulose and pregelatinized starch were sieved and mixed. Granulation process was done in fluid bed dryer (FBD). The granules were sieved and dried. Then magnesium stearate was sieved and mixed with dried granules The tablets were compressed and film coated. ^ ^ Ivermectin^ Blend uniformity results of present invention compositions comprising ivermectin prepared by dry mix and wet granulation were compared.^ ^ 9    Table^3: Blend uniformity of Dry mix Dry Mix   % BHA  % ivermectin  % CA TOP Avg.  74,85  98,3  91,95 MID Avg  153,65  95,85  86,55 BOTTOM Avg  75,3  95,65  101,55 Table 3 shows that the trace amounts of BHA and Citric acid used in the composition prepared in the dry mixture were not homogeneously distributed in the composition and there were fluctuations in the amount distribution. Table^4: Blend uniformity of Wet granulation Wet granulation %BHA % ivermectin % CATOP Avg. 100,05 98,3 100,5 MID Avg 99.65 100.75 99,4 BOTTOM Avg 99,85 99,45 100.05 Table 4 shows that the trace amounts of BHA and Citric acid used in the composition prepared by wet granulation were homogeneously distributed in the composition and there were no fluctuations in the amount distribution. 10

Claims

CLAIMS^ 1. A pharmaceutical composition prepared by wet granulation comprising ivermectin or a pharmaceutically acceptable salt thereof, at least one antioxidant, and at least one stabilizer.

2. The pharmaceutical composition according to claim 1, wherein the composition dosage form is tablet or capsule.

3. The pharmaceutical composition according to claim 2 wherein the composition dosage form is tablet.

4. The pharmaceutical composition according to claim 1, characterized in further comprising at least one pharmaceutically acceptable excipient selected from, diluents, lubricants, glidants, binders, disintegrants or mixtures thereof.

5. The pharmaceutical composition according to claim 1, wherein said antioxidant is selected from the group comprising of butylated hydroxyanisole (BHA), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, erythorbic acid or mixtures thereof.

6. The pharmaceutical composition according to claim 5, wherein antioxidant is butylated hydroxyanisole (BHA).

7. The pharmaceutical composition according to claim 1, wherein said stabilizer is selected from citric acid, aluminum monostearate, colloidal silicon dioxide, glyceryl monooleate, hydrophobic colloidal silica, myristyl alcohol or mixtures thereof.

8. A pharmaceutical composition according to any one of the proceeding claims for use in the treatment of internal nematode infections, preferably strongyloidiasis, demodicosis, onchocerciasis or COVID-19.

9. A wet granulation process for manufacturing a pharmaceutical composition according to claim 1, comprising steps of: a. Preparing a homogeneous solution with antioxidant and first solvent,b. Preparing a homogeneous solution with stabilizer and second solvent, c. Sieving and mixing Ivermectin and diluent d. Granulating in fluid bed dryer e. Sieving and drying granules f. Sieving Lubricant and mixed with dried granules g. Compressing tablet and film coating.

10. The wet granulation process for manufacturing a pharmaceutical composition according to claim 9, comprising steps of: a. Preparing a homogeneous solution of butylated hydroxyanisole and ethyl alcohol, b. Preparing a homogenous solution of citric acid and water, c. Sieving and mixing Ivermectin, microcrystalline cellulose and pregelatinized starch d. Granulating in fluid bed dryer e. Sieving and drying granules f. Sieving Magnesium stearate and mixed with dried granules g. Compressing tablet and film coating.

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