PT98612A - PROCESS FOR THE PREPARATION OF A SOLID COMPOSITION ORAL DOSAGE OF LOPERAMIDE COMPOUNDS - Google Patents

Description

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This invention relates to a process for the preparation of solid oral dosage compositions, preferably compressed unit dosage forms of a loperamide compound, which provides an effective and uniform dissolution profile when ingested by patients in need of their antidiarrheal effect. Loperamide hydrochloride (4-Xprcloxophenyl-4-hydroxy-N, N-dimethyl-alpha, alpha-diphenyl-1-pyridylbutyramide monohydrochloride) is the active ingredient of product R, antidiarrheal imodium AD (sold by McNeil Pharmaceutics), which is marketed in both liquid and solid dosage forms. Loperamide is indicated for the treatment and control of chronic and non-specific acute diarrhea associated with inflammatory bowel diseases. (Physicians Desk Reference, Forty Fourth Edition, page 1028, 1990). In addition, loperamide is a recommended drug for the treatment of mild cases of traveler's diarrhea, according to the Travelers article 'Diarrhea - Concensus Conference' (Jama, May 10, 1985, 235 (18), pages 2700-4). The process used in the production of a solid pharmaceutical dosage composition may be an important factor in obtaining the effective therapeutic level of the active ingredient (drug component). In particular, the method of processing may determine the efficiency of the release of the drug component from the solid dosage form into the dissolution medium. This release is also defined in terms of rate of dissolution and, in part, determines the efficacy of the active ingredient following ingestion by the patient to be treated. Process for the production of certain drug components are described in: (1) Pharmaceutical Dosage Forms: Tablets, Volume 1. " Chapter 2, Pages 61-107, 1980, which discloses a 2 35 1 5 10 15

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Method for the formulation of a pharmaceutical solid dosage composition by direct compression. This method comprises two steps. The first step consists in blending the active ingredient with an appropriate selection of pharmaceutically acceptable carrier materials, and is followed by the step of compressing the dried material into a solid dosage form. (2) Johansen et al., Journal of Pharmaceutical Sciences, 67 (1), 134-136 (1978), describing studies on the use of a solvent deposition technique with pheny- zutazone deposited on lactose, starch and silicon dioxide, and such as norethindrone and digoxin deposited on lactose. (3) Law et al., Drug Developmental Industrial Pharmacy, 16 (1) 137-147 (1990) which shows the effect on the rate of dissolution when griseofulvin is deposited on Primojel, Mobil Starch and Nymcel disintegrants using the solvent. (4) Gholmy et al., Drug Development and Industrial Pharmacy, 14 (11), 1587-1603 (1988), which discloses studies on the uniformity and rate of dissolution of digoxin tablets by simple mixing and solvent deposition. (5) Monkhouse et al., Journal of Pharmaceutical Sciences, 61 (9), 1430-1435 (1972). which describes a process for increasing the rates of dissolution of indomethacin, aspirin, sulfa-etidol, griseofulvin, reserpine, chloramphenicol, oxolinic acid, probucol and hydrochlorothiazide by equilibrating the drug in an organic solvent over an insoluble excipient with a large surface area ( an adsorbent).

It is an aim of the present invention to provide a process for the formulation of solid oral dosage compositions of loperamide compounds having a suitable dissolution profile. Yet another object is to provide processes for the preparation of a solid dosage composition of 3 35 1 5 10

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Compositions containing the loperamide compound having an improved dissolution profile to ensure a faster release of the loperamide compound from the solid oral dosage composition and / or to increase the possibility of obtaining consistently a therapeutically effective and safe level of loperamide compound in vivo. A further object is to provide solid dosage unit composition of compositions containing loperamide compound, having the loperamide compound uniformly dispersed therein, having an effective and rapid dissolution profile and / or consistently delivering an effective, uniform and safe therapeutic dose of compound of loperamide. It is another object to provide a process for the production of loperamide-containing compressed unit dosage compositions which contain the desired level of loperamide per unit dose and provide a safe and effective amount of loperamide to the patient under treatment in a short period of time. These and other objects of the present invention will become readily apparent from the detailed description which follows. All percentages and ratios used herein are by weight and all measurements taken at 25 ° C, unless otherwise specified. SUMMARY OF THE INVENTION The present invention involves a process for the production of a solid oral dosage composition of a loperamide compound, comprising the steps of: (a) dissolving a loperamide compound in an alcoholic solution comprising at least about 50% by volume of a lower alcohol selected from the group consisting of methanol, ethanol, propanol and mixtures thereof; (b) combination of pharmaceutically acceptable carrier materials with the alcohol solution containing the compound of 4-1

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- / loperamide; and (c) drying the combination of the loperamide compound and the pharmaceutically acceptable carrier materials. The present invention also relates to solid oral dosage combinations containing loperamide prepared by the present process. Such compositions comprise: (a) from 0.1% to about 5% loperamide; and (b) from about 95% to about 99.9% pharmacologically acceptable carrier, the compositions being prepared by the process according to the present invention. DETAILED DESCRIPTION OF THE INVENTION The process of the present invention utilizes two essential components: a loperamide compound and certain short chain alcohols, suitable for dissolution of the loperamide compound. In addition, the process of the present invention involves the production of a solid oral dosage composition of a loperamide compound through the steps of: (a) dissolving the loperamide compound in an alcoholic solution comprising the lower alcohol; (b) combining pharmaceutically acceptable carrier materials with the alcohol solution containing the loperamide compound; and (c) drying said combination of the loperamide compound and the pharmaceutically acceptable carrier materials. These and other agents optionally and preferably used in the process and compositions according to the present invention with the levels and amounts preferred therefor are described in more detail below. (a) Loperamide Compounds The term 1 'loperamide compounds', here 5 30 5 10

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Mod. 71-20,000 · χ. The term quot; 2,2-diaryl-4- (4,4-aryl-4-hydroxypiperidino) butyramides, their active metabolites, their pharmaceutically acceptable salts And mixtures thereof, having antidiarrheal and analgesic activities, which are disclosed and described in detail in U.S. Patent 3,714,159 issued Jan. 30, 1973 and U.S. Patent 3,884,916, issued in 2 (1) May 1975, both to Janssen et al., and in U.S. Patent 4,824,853, issued April 25, 1989 to Wals et al., the disclosures of all of these patents being incorporated herein in their entirety by reference. The preferred loperamide compound is loperamide per se and the loperamide hydrochloride salt, as described in The Merck Index, 11th ed. No. 5450, 1989, incorporated herein in its entirety by reference. For purposes of the process of the present invention , the loperamide compound is dissolved in a solution (as described below) at a level of from about 0.001% to about 5% by weight of the short chain alcohol present in the alcoholic solution. Preferably, the loperamide compound comprises about 2.5% by weight, of said alcohol in the alcoholic solution. The solid dosage compositions of the present invention also typically comprise a loperamide compound level of about 0.1% to about 25%, and preferably a level of about 0.1% to about 5% . More preferred is loperamide hydrochloride in unit dose solid form compositions (e.g., compressed tablets) at levels of about 0.5% to about 1%. (b) Alcoholic Solutions

In the process of the present invention, the loperamide compound is dissolved in an alcoholic solution prior to recombining the loperamide compound with the pharmaceutically useful carrier materials for the formulation of the compound; dosing ... solid. The alcohols are useful herein: for these 6 35 1 63689 Case: 4218

1 alcohol solutions are short chain alcohols selected from the group consisting of methanol, ethanol, propanol and mixtures thereof. Ethanol and propanol are preferred and are preferred. 5 10 15

Mod. 71-20,000 Âμ. The alcohol is present in the alcohol solution at a level of from about 50% to about 100% by volume of the alcoholic solution, the remaining portion of the solution preferably comprising water at a level of about 0% to about 50% by volume of the alcohol solution. Preferably, the alcohol is present in the alcoholic solution at a level of from about 95% to about 100% by volume of said solution, and the water is present at a level of from about 0% to about 5%, by volume solutions alcoholic beverages. The resulting solid oral compositions of the present invention contain very little, if any, of these short chain alcohols which are used in the processing of the compositions. (c) Pharmaceutically Acceptable Vehicle Materials In addition, the components of the production process and the compositions of the present invention include certain pharmaceutically acceptable carrier materials. The term " pharmaceutically acceptable carrier materials ", as used herein, means one or more solid or liquid ingredients suitable for use in humans and / or other anions without adverse side effects (such as toxicity, allergic response or irritation) within a reasonable benefit / risk ratio, and which ingredients ensure the integrity of the solid dosage form of a pharmaceutical composition, causing its binding, and enhancing ease of administration. A variety of pharmaceutically acceptable carrier materials may be used in a solid dosage pharmaceutical composition. The class of pharmaceutically acceptable carrier materials possible includes de-synthesizers, fillers or diluents, and binders. Some examples of substances that may serve 7 35 1 5 10

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as pharmaceutically acceptable carrier materials are sugars, such as lactose, dextrose, mannitol, glucose and sucrose; starches, such as corn starch, sodium starch glycolate and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, microcrystalline cellulose, ethylcellulose, cellulose acetate; tragacanth powder; malt; gelatine; acacia; baby powder; calcium sulfate; polyvinylpyrrolidone; polyacrylamides; clays; ion exchange resins; and some alginas. Lubricants may also be used in the present invention to enhance compression of the loperamide-containing composition into a solid unit oral dosage form. Some examples of lubricants are stearic acid, magnesium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate or light mineral oil. Additionally, coloring agents, antioxidants and preservatives may also be present. Compositions for the production of solid oral dosage forms useful for this invention are described in the following references, incorporated herein in their entirety: Lieberman et al., Pharmaceutical Dosage Forms; Tablets (1981), and Remington Pharmaceutical Sciences, Seventh Edition, Chapter 90, pages 1603-1632, 1985. The pharmaceutically acceptable carrier materials used in the present invention are together present in the final solid oral composition at a level of about 75% to about of 99.9% by weight of the composition. Preferably, the pharmaceutically acceptable carrier materials are present at a level of about 95% to about 99.9%, but the most preferred level is about 99% to about 99.5%. (d) Method of Processing The present process for formulating an oral solid dosage composition, preferably in the form

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of unitary dosage of loperamide compounds first uses the above-described alcoholic solution to dissolve the loperamide compound at the indicated levels. If a more economical production process is desired, the alcohol solution containing the loperamide compound (once the fully dissolved loperamide compound) can be diluted so that the concentration of the lower alcohol is reduced, typically being less about 25%, in volueae of alcoholic solution. The dilution should not cause precipitation of the loperamide compound from the alcohol solution. Pharmaceutically acceptable carrier materials (except, preferably, the lubricants) are also prepared by the production process (preferably a granulation process). These pharmaceutically acceptable carrier materials are combined with the alcohol solution containing the loperamide compound by use of a device suitable for the combination of these compounds (typically an apparatus for mixing or granulating solid compositions). Examples of apparatuses useful for this invention are Planetary mixers such as the Hobart or Glen mixer which for this purpose have been the pharmaceutical industry for many years. Additional types of mixing equipment are the Patterson-Kelly twin frame mixer and the fluid bed granulator, which will be described in more detail below. A preferred mixer, due to its easy production, is the Hobart mixer, namely model number N-50. The Hobart mixer resembles an ordinary free-standing domestic mixer with rotating blades that provide a uniform blend of the ingredients. Another preferred apparatus is Patterson-Kelly dual frame mixer, because this mixer ensures premixing of large amounts of powder. The preferred method here involves granulation, performed by adding the alcohol solution containing the loperamide compound

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-8 to the mixing device where the pharmaceutical carrier materials were initially prepared, and then by mixing until complete granulation was obtained. Finally, after the combination of the loperamide compound and the pharmaceutically acceptable carrier materials is complete, the composition containing the loperamide compound is dried, typically to a level of less than about 2% alcoholic solution. Said drying of the loperamide compound-containing composition can be effected in several ways. The loperamide composition may be dried by placing said composition on trays and allowing them to air dry, oven dry or vacuum dry. It is also possible to dry the composition containing the loperamide compound in a fluidized bed drier. In the fluidized bed drier, the particles of the composition are stirred and forcibly dried by an ascending hot air stream. (Pharmaceutical Sciences, Seventeenth Edition, pages 1610-1613, 1985, incorporated herein in their entirety.) The fluidized bed dryer may also be used to granulate the pharmaceutically acceptable carrier materials with the alcohol solution containing the loperamide compound and to dry the composition in a single process. This process is accomplished by placing the pharmaceutical carriers in the fluidized bed dryer and simultaneously granulating them with a spray consisting of the alcohol solution containing the loperamide compound. Once the desired drying level is obtained, preferably that there is essentially no short chain alcohols in the solid composition in the solid composition, the loperamide composition is sifted to achieve a reduced and more uniform particle size. Preferably, said loperamide composition is sieved through a 40 mesh sieve. A desired pharmaceutically acceptable lubricant is then preferably introduced into the skin.

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composition of loperamide. The addition of a lubricant assists in the preparation of said loperamide composition for compression in a solid unit dosage form. The preferred lubricant is magnesium stearate. Once the lubricant is added to the dry pharmaceutical composition of the loperamide compound, the solid oral dosage composition is compressed, preferably using an acceptable tabletting process, to a unit dosage form of a hardness level, typically about 5sc (Strong-Cobb unit, referred to herein as 11sc ") to about 20sc. The final unit dosage form of the loperamide compound is preferably compressed to a hardness level of from 7æc to about 15æc, wherein loperamide is present in the composition at a level of from about 0.1mg to about 5mg and, preferably , at a level of about 2mg. The following examples further describe and demonstrate, the embodiments referred to within the scope of the present invention. The examples are given solely for the purpose of illustrating and not limiting the present invention, since various variations are possible without departing from its spirit and scope. EXAMPLE 1: Solid Unit Dose of Loperamide Hydrochloride

A solid oral dosage composition of loperamide hydrochloride, prepared by the process disclosed in this invention, contains the following components:

Components Weight (%) Loperamide hydrochloride 0.80 polyvinylpyrrolidone 4.00 Sodium starch glycollate 4.00 Microcrystalline cellulose1 90.95 11 35

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Microcrystalline cellulose is produced under the trade designation Avicel ™ by FMC Corporation. (100% by volume) is used in the process and removed prior to tablet formation. This composition is prepared first by dissolving the loperamide hydrochloride in ethanol to give a clear solution. Thereafter, a mixture of polyvinylpyrrolidone, sodium starch glycollate and Avicel® is granulated with the alcohol solution of loperamide hydrochloride. This composition is then dried in a fluidized bed drier and screened through a 40 mesh screen. Finally, the magnesium stearate is added and the composition is compressed to a hardness level of 11 sec. Intake of two pellets, after each bowel movement, by a human in need of treatment for diarrhea provides rapid, safe and effective relief. A solid oral dosage composition of loperamide hydrochloride, prepared by the process previously described in Example 1, contains the following components: Component Weight (%) â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ loperamide 0.80 polyvinylpyrrolidone 4.00 sodium starch glycolate 4.00 microcrystalline cellulose 90.20 35 talc 1.00 12

Claims (1)

Mod. 71-20,000 · χ. - 636.89 Case: 4218 1 ethanol (32.00) 5 ^ Removed prior to tablet formation. Intake of two of these pellets, after each bowel movement, by a human in need of treatment for diarrhea provides rapid, safe and effective relief. Claims ls. A process for the preparation of a solid oral dosage composition of loperamide compound comprising: (a) dissolving a loperamide compound in an alcoholic solution, wherein said alcoholic solution comprises at least 50% by volume, of a lower alcohol selected from the group consisting of methanol, ethanol, propanol and mixtures thereof; (b) the combination of pharmaceutically acceptable carrier materials with the alcohol solution contains loperamide compounds; and (c) drying said combination of loperamide compounds and pharmaceutically acceptable carrier materials. 2 - . 5. A process according to claim 1, wherein the loperamide compound is selected from the group consisting of loperamide, its pharmaceutically acceptable salts and mixtures thereof. A process according to claim 1, and 2, wherein said alcoholic solution contains ethanol as the lower alcohol. 4§. A process according to any one of claims 1-3, characterized in that said alcoholic solution comprises from 50% to 100% ethanol: from 50% to 5% by weight. - 90/06 20 30 63689 Case: 4218 of water. 5S. 3. A process according to any one of claims 1-4, wherein said lopera-mide compound is dissolved in said alcoholic solution to a level of 0.001% by weight of said short alcohol present in the alcoholic solution. 68. A process according to any of claims 1-5, wherein said combination of loperamide compound and pharmaceutically acceptable carrier materials is dried to less than 2% alcoholic solution and further by the dry combination of loperamide compost and of pharmaceutically acceptable carrier materials is sieved through a 40 mesh screen. 7S. A process according to any of claims 1-6, characterized in that a pharmaceutically acceptable lubricant is added after the sieving step. 8S. A composition as claimed in any one of claims 1-7, wherein said composition is compressed in a unit dosage form comprising 0.1 mg to 5 mg of loperamide hydrochloride and the composition is compressed to a hardness level of 5 sec to 20 sec . 9S. A process for the preparation of an oral solid dosage composition of loperamide hydrochloride, comprising: (a) dissolving loperamide hydrochloride in an alcoholic solution comprising from 50% to 100% ethanol and from 50% to 0% water and in that the loperamide hydrochloride is dissolved in said alcoholic solution at a level of from 0.001% to 5%, by weight of the ethanol present in the alcoholic solution; (b) granulating pharmaceutically acceptable materials with the alcohol solution containing loperamide hydrochloride; 14 35 1 δ 10 15 Mod. 71-20,000 · χ. 20 (C) drying granulates containing loperamide hydrochloride to essentially remove all ethanol; and (d) compressing the dried granules in a unit dosage form to a hardness level of 5sc to 20sc. 10-. A process for the preparation of a solid oral dosage composition of loperamide compound according to claims 1-9, characterized in that it is mixed; (a) from 0.1% to 5% of loperamide hydrochloride; and (b) from 95% to 99.9% of pharmaceutically acceptable carrier materials; and wherein said composition further comprises less than 2% ethanol. Ask your Excellency. deign to defer as he requires. Lisbon, -8 AG0.1S9 of the Property Industriei Cartório-Arc * p? Conceição, 3, i. · -]] # ® 15 35