CA2088273C

CA2088273C - Processes for formulating a solid oral dosage form of loperamide compounds

Info

Publication number: CA2088273C
Application number: CA002088273A
Authority: CA
Inventors: Daniel Louis Barone; Francis Bernard Chapura; Shawn Alan Denny
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1990-08-09
Filing date: 1991-07-29
Publication date: 1996-05-14
Anticipated expiration: 2011-07-29
Also published as: JPH06500104A; AU661972B2; FI930536A0; IE912815A1; NZ239308A; WO1992002223A1; EP0542879A1; AU8440091A; CA2088273A1; PT98612A; FI930536L; FI930536A7

Abstract

Process for manufacturing a solid oral dosage form of a loperamide compound (preferably the hydrochloride salt of loper-amide) by dissolving a loperamide compound in a short chain alcohol (preferably ethanol) prior to combining with a pharmaceut-ically acceptable carrier(s). The present invention also relates to the solid oral dosage forms (preferably compressed unit dosage form) prepared by this process.

Description

W O 92/02223 2 0 8 ~ 2 7 ~ PC~r/US91/05291 PROCESS FOR FORMULATING A SOLID ORAL
DOSAGE FORM OF LOPERAMIDE COMPOUNDS

BACKGROUNQ OF THE INVENTION
This invention relates to a process for manufacturing a solid oral dosage forms, preferably compressed unit dose forms, of a loperamide compound, preferably loperamide hydrochloride, which provides a uniform and effective dissolution profile when ingested by patients in need of its antidiarrheal effect.
Loperamide hydrochloride (4-(p-chlorophenyl)-4-hydroxy-N, N-dimethyl-alpha, alpha-diphenyl-1-piperidinebutyramide mono-hydrochloride) is the active ingredient of the antidiarrheal product Imodium A-D (sold by McNeil Pharmaceutics), which is marketed in both a liquid and solid dose forms. Loperamide is indicated for the treatment and control of acute non-specific and chronic diarrhea associated with inflammatory bowel disease.
(PhYsicians Desk Reference. FortY Fourth Edition, page 1028, 1990). In addition, loperamide is a recommended drug for the treatment of mild cases of travelers' diarrhea, according to the article "Travelers' Diarrhea - Consensus Conference" (JAMA, May 10, 1985, 235(18), pages 2700-4) The process used in manufacturing a pharmaceutical solid dosage form can be an important factor in obtaining an effective therapeutic level of the active ingredient (drug component). In particular, the processing method can determine the efficiency of the release of the drug component from the solid dose form into the dissolution medium. This release is also stated in terms of its dissolution rate, and, in part, impacts the effectiveness of the active ingredient following ingestion by a patient being treated.
Manufacturing processes for certain drug components are described in:
(1) Pharmaceutical Dosaqe Forms: Tablets, Volume 1, Chapter 2, Pages 61-107, 1980, discloses a method for formulating a pharmaceutical solid dosage form by direct compression. This =

W O 92/02223 PC~r/US91/05291 2~8~2~3 - 2 -method consists of two steps. The first step is accompl1shed by mixing the active ingredient with an appropriate selection of pharmaceutically acceptable carrier materials, and is followed by the step of compressing the dry material into a solid dose form. s (2) Johansen et al., Journal of Pharmaceutical Sciences, 67 (1), 134-136 (1978), discloses research on the use of a solvent deposition technique with phenylbutazone deposited on lactose, starch, and silicon dioxide, as well as norethindrone and digoxin deposited on lactose.

(3) Law et al., ~rug DeveloDment and Industrial Pharmacv, 16 (1), 137-147 (1990), discloses the effect on the dissolution rate when griseofulvin is deposited on the disintegrants Primojel, Mobile Starch, and Nymcel using the solvent deposition system.

(4) Gholmy et al., Drug DeveloDment and Industrial Pharmacy, 14 (11), 1587-1603 (1988), discloses research on the uniformity and dissolution rate of digoxin tablets made by simple blending and solvent deposition.

(5) Monkhouse et al., Journal of Pharmaceutical Sciences, 61 (9), 1430-1435 (1972), discloses an approach for increasing the dissolution rates of indomethacin, aspirin, sulfaethidole, griseo-fulvin, reserpine, chloramphenicol, oxol~nic acid, probucol, and hydrochlorothiazide by equilibration of the drug in an organic solvent on an insoluble excipient with an extensive surface (an adsorbent).
An object of the present invention is to provide a method for formulating solid oral dosage forms of loperamide compounds which will have a desirable dissolution profile. A further object is to provide processes for preparing a solid dosage form of loperamide compound-containing compositions having an improved dissolution profile to afford a faster release of loperamide compound from the solid oral dosage form, and/or to enhance the ability to consistently obtain a safe and therapeutically effective level of loperamide compound in vivo. An additional object is to provide a solid unit dosage form of loperamide compound-containing compositions, having loperamide compound dispersed uniformly therein, having a fast and effective dissolution profile, and/or consistently supplying a uniform, safe, and effective therapeutic WO 92/02223 2 ~ 8 ~ 2 7 3 PCI/US91/05291 dose of loperamide compound. A further object is to provide a process for manufacturing compressed loperamide-containing unit dosage forms which consistently contain the desired level of loperamide per unit dose and consistently deliver within a short period of time a safe and effective amount of loperamide to the patient being treated.
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 made at 25- C, unless otherwise specified.
SUMMARY OF THE INVENTION
The present invention involves a process for manufacturing a solid oral dosage form of loperamide compound comprising the steps of:
(a) dissolving a loperamide compound in an alcoholic solution comprising at least about 50% by volume of short chain alcohol selected from the group consisting of methanol, ethanol, propanol, and mixtures thereof;
(b) combining pharmaceutically acceptable carrier materials with the loperamide compound-containing alcoholic solution; and (c) drying the combination of the loperamide compound and pharmaceutically acceptable carrier materials.
The present invention also relates to loperamide-containing solid oral dosage compositions prepared by the present process.
Such compositions comprise:
(a) from about 0.1% to about 5X of loperamide; and (b) from about 95X to about 99.9% pharmaceutically accept-able carrier, and wherein further the compositions are prepared by a process according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention employs two essential components: a loperamide compound and certain short chain alcohols suitable for dissolving the loperamide compound.
Furthermore, the present invention process involves manufacturing a solid oral dosage form of loperamide compound by the steps of:
(a) dissolving the loperamide compound in an alcoholic solution comprising the short chain alcohol; (b) combining pharmaceutically -4- 20$8273 acceptable carriermaterials withthe loperamide compound-cont~inin~ alcoholic solution; and (c) drying said combination of the loperamide compound and pharmaceutically acceptable carrier m~t~ri~ . These and other agents optionally and preferably used in the process and compositions according to the present invention, as well as the levels and amounts preferred therefor, are described in greater detail hereinafter.
(a) Loperamide Compounds The term "loperamide compounds", as used herein, means compounds o which are members of the class of 2,2-diaryl-4-(4'-aryl-4' -hydroxy-piperidino) butyramides, active metabolites thereof, the pharmaceutically acceptable salts thereof, and mixtures thereof, having anti~ rrhe~l and analgesic activities, which are disclosed and described in detail in U.S. Patent 3,714,159, issued January 30, 1973 and U.S. Patent 3,884,916, issued May 20, 1975, both to Janssen et al., and U.S. Patent 4,824,853, issued April 25, 1989 to Wals et al.
The preferred loperamide compound is loperamide per se and the hydrochloride salt of loperamide, as described in The Merck Index, 11th Ed., No. 5450, 1989.
The loperamide compound, for purposes of the process of the present 2 o invention, is dissolved in an alcoholic solution (as described hereinafter) at a level 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. Also the solid dosage forms of the present invention typically comprise a level of loperamide compound from about 0.1% to about 25%, and preferably at a level from about 0.1% to about 5%. Most preferred is loperamide hydrochloride in solid unit dose form compositions (e.g., compressed tablets) at levels from about 0.5% to about 1%.
(b) Alcoholic Solutions 3 0 In the process of the present invention, the loperamide compound is dissolved in an alcoholic solution prior to combining ",~

W O 92/02223 2 ~ 8 8 2 7 3 PC~r/US91/05291 the 1Operamide compound with the pharmaceutically acteptable - carrier materials useful for formulating the desired solid dose form. The alcohols useful herein for these alcoholic solutions are short chain alcohols selected from the group consisting of methanol, ethanol, propranol, and mixtures thereof. Preferred are ethanol and propanol, with ethanol being the most preferred.
The alcohol is present in the alcoholic solution at a level of from about 50K, to about 100% by volume of the alcoholic solution, with the remaining portion of the solution preferably comprising water at a level from about OY. to about 50X, by volume of the alcoholic solution. Preferrably, alcohol is present in the alcoholic solution at a level from about 95% to about 100% by volume of said solution, and water is present at a level from about OX to about 5% by volume of alcoholic solutions. The final solid oral compositions of the present invention contain very little, and preferably none, of these short chain alcohols which are used in the processing of the compositions.
(c) PharmaceuticallY AcceDtable Carrier Materials In addition, the components of the manufacturing process and compositions of the present invention include certain pharmaceu-tically acceptable carrier materials. The term ~pharmaceutically acceptable carrier materialsn, as used herein, means one or more solid or liquid ingredients, suitable for use with humans and/or other animals without undue adverse side effects (such as toxi-city, irritation and allergic response), within a reasonable benefit/risk ratio, and which ingredients provide the integrity of a solid dosage form of a pharmaceutical composition, causing it to bind, and increasing the ease of administration.
A variety of pharmaceutically acceptable carrier materials may be used in a solid dose pharmaceutical composition. The class of possible pharmaceutically acceptable carrier materials includes disintegrants, fillers or diluents, and binders. Some examples of substances whch can serve as pharmaceutically acceptable carrier materials are sugars such as lactose, dextrose, mannitol, glucose, and sucrose; starches such as corn starch, sodium starch glyco-late, and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, microcrystalline cellulosel, ethyl-20882~3 cellulose, cellulose acetate; powdered tr~g~c~nth; malt; gelatin; acacia; talc, calcium sulfate; polyvinylpyrrolidone; polyacrylamides; clays; ion-exchange resins; and certain algins.
Lubricants can also be used in the present invention to enhance the compression of the loperamide cont~ining cornposition into a solid oral unit dose form. Some examples of lubricants are stearic acid, m~gn~sium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyethylene glycol 400-0,polyethylene glycol 6000, sodium lauryl sulfate, or light mineral oil. In 0 addition, coloring agents, anti-oxidants, and ~ese.~ es can also be present.
Compositions for m~nllf~cturing solid oral unit dosage forms useful herein are described in the following references, Lieberman, et al., Ph~rm~(~eutical Dosa~eForms; Tablets (1981), and Remin~ton's Ph~rm~ceutical Sciences, Seventh Edition. Chapter 90, pages 1603-1632, 1985.
The pharmaceutically acceptable carrier m~t~ s ntili7~1 in the present invention are collectively present in the fmal solid oral composition at a levelfrom about 75% to about 99.9% by weight of the composition. Preferably the ph~rm~eutically acceptable carrier materials are present at a level from about 95% to about 99.9%, and most preferred level is from about 99% to about 2 o 99.5%.
(d) Processin~ Method The present process for formulating a solid oral dosage form, preferably a unit dose form, of lop~ de compounds first employs the above described alcoholic solution to dissolve the loperamide compound at levels as indicated.
If a more economic method of manllf~ lring is desired, the loperamide compound-co~ g alcoholic solution (once the loperamide compound is completely dissolved) may be diluted such that the short chain alcohol concentration is reduced, typically being at least about 25% by volume of the alcoholic solution. Dilution should not cause precipitation of the loperamide 3 o compound from the alcoholic solution.
The ph~rm~ceutically acceptable carrier materials (preferably excepting the lubricant) are also prepared for the m~nllf~cturing process (preferably a ~1 .~

granulation process). These ph~rrn~reutically acceptable carrier materials are combined with the lopeldll~ide compound-cont~inin~ alcoholic solution by lltili7in~ an acceptable ~L)pa~d~ s for combining these compounds (typically equipment for mixing or gr~n~ tin~ solid compositions). Some examples of apparatuses useful herein are the Planetary mixers, such as the Hobart mixer or the Glen mixer which have served this purpose in the rh~rrn~ceutical industry for many years. Additional types of mixing equipment are the Patterson-Kelly twin-shell blender, and the Fluid-bed granulator, which will be described in more detail hereinafter. A p.~efell~d mixer, because of its ease ofproduction, is the Hobart mixer, e.g. model number N-50. The Hobart mixer resembles a common household freest~n~ling mixer with rotating blades that provide a ull~rollll mix of ingredients. Another ~l~re-l~,d ~aldlus is the Patterson-Kelly twin-shell blender, because this blender allows precision blending of large q~l~ntities of powder. The pl~r~ ,d method herein involves granulation, performed by adding the loperamide compound-cont~ining alcoholic solution to the mixing a~L)aLdl~ls where the pharmaceutical carrier m~trri~l.c were initially prepared, and then by mixing until complete gr~mll~tion is achieved.
2 o Finally, after the combining of the lopeldll~ide compound and ph~rrn~ceutically acceptable carrier materials is complete, the loperamide compound-cont~ining composition is dried, typically to a level of less than about 2% of alcoholic solution. Drying said loperamide compound-cont~inin~
composition may be accomplished several ways. The loperamide composition 2 5 may be dried by placing said composition on trays and allowing them to air-dry, oven dry, or drying under a vacuum. It is also possible to dry the loperamide compound-co~ illg composition in a fluid bed dryer. In the fluid bed dryer, the particles of the composition are tumbled and dried by the force of an upward stream of heated air. (Remin~ton's Ph~rm~reutical Sciences.
Seventeenth Edition, pages 1610-1613, 1985.) The fluid bed dryer may also be employed to granulate the ph~rrn~reutically acceptable carrier m~trri~l~ with the lop~ ide compound-co~ alcoholic solution and drying the loperamide ~. .

W O 92/02223 PC~r/US91/05291 ~r~ 2 ~ 8 ~ 2 ~ 3 - 8 -f composition in a singular process. This method is accomplished by placing the pharmaceutical carriers in the fluid bed dryer and simultaneously granulating them with a spray consisting of the loperamide compound-containing alcoholic solution. Once the desired dryness level is obtained, preferably such that there is essentially no short chain alcohol remaining in the solid composition, the loperamide composition is screened to achieve a reduced and more uniform particle size. Preferably said loperamide composition is screened through a 40-mesh screen.
A desired pharmaceutically acceptable lubricant is preferably then introduced into the loperamide composition. The addition of a lubricant assists in preparing the said loperamide composition for compression into a solid unit dosage form. The preferred lubri-cant is magnesium stearate. Once the lubricant is added to the dried pharmaceutical composition of loperamide compound, the oral solid dose form is preferably compressed, using an acceptable tableting process, into a unit dose form to a hardness level typically from about 5sc (Strong-Cobb unit, herein referred to as "scn) to about 20sc. The final unit dose form of the loperamide compound is preferably compressed to a hardness level of about 7sc to about 15sc, and wherein the loperamide is present in the composition at a level of about O.lmg to about 5mg, and preferably at a level of about 2mg.
The following examples further describe and demonstrate the referred embodiments within the scope of the present invention.
The examples are given solely for the purpose of illustration, and are not to be construed as limitations of the present invention since many variations thereof are possible withut departing from its spirit and scope.
EXAMPLE l Solid Unit Dose Form of Loperamide ~Ydrochloride A solid oral unit dosage form of loperamide hydrochloride, prepared by the method set forth in the present invention, contains the following components.

WO 92/02223 2 ~ 8 8 2 7 3PCr/l~S91/0~291 ~ g ComDonents Wei9ht %
loperamide hydrochloride 0.80 polyvinylpyrrolidone 4.00 sodium starch glycolate 4.00 microcrystalline cellulose1 90.95 magnesium stearate 0.25 ethanol2 (32.00) 1 Microcrystalline cellulose is manufactured under the tradename Avicel by FMC Corporation.
2 Ethanol (lOOX by volume) is used in the process and removed prior to tableting.
This composition is prepared by first dissolving the loper-amide hydrochloride in ethanol to obtain a clear solution. Next, a mixture of polyvinylpyrrolidone, sodium starch glycolate~ and Avicel~ is granulated with the alcoholic solution of loperamide hydrochloride. This composition is then dried` in a fluid bed dryer and screened through a 40-mesh screen. Finally, the mag-nesium stearate is added and the composition compressed to a hardness level of llSC.
Ingestion of two of the tablets, after each unformed stool, by a human in need of treatment for diarrhea provides rapid, safe, and effective relief.

Solid Unit Dose Form of Loperamide HYdrochloride A solid oral unit dosage form of loperamide hydrochloride, prepared by the method set forth in Example 1 hereinbefore, contains the following components.
Com w nents Weiqht %
loperamide hydrochloride 0.80 polyvinylpyrrolidone 4.00 sodium starch glycolate 4.00 microcrystalline cellulose 90.20 talc 1.00 ethanol1 (32.00) 1 Removed prior to tableting.

WO 92/02223 PCI`/US91/05291 2~ 3 - lo- ~

Ingestion of two of these tablets after each unformed stool by humans in need of treatment for diarrhea provides rapid, safe, and effective relief.

WHAT IS CLAIMED IS:

Claims

1. A process for formulating a solid oral dosage form of loperamide compound, said process comprising the steps of:
(a) dissolving a loperamide compound in an alcoholic solution, wherein said alcoholic solution comprises at least about 50% by volume of short chain alcohol selected from the group consisting of methanol, ethanol, propanol, and mixtures thereof;
(b) combining pharmaceutically acceptable carrier materials with the loperamide compound-containing alcoholic solution; and (c) drying said combination of loperamide compound and pharmaceutically acceptable carrier materials.

2. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 1, wherein the loperamide compound is selected from the group consisting of loperamide, the pharmaceutically acceptable salts thereof, and mixtures thereof.

3. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 1, wherein said short chain alcohol is selected from the group consisting of ethanol, propanol, and mixtures thereof.

4. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 1, wherein said alcoholic solution contains ethanol as the short chain alcohol.

5. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 4, wherein said alcoholic solution comprises from about 50% to about 100% of ethanol and from about 50% to about 0% of water.

6. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 5, wherein said alcoholic solution comprises from about 95% to about 100% of ethanol, and from about 5% to about 0% of water.

7. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 2, wherein said loperamide compound is dissolved in said alcoholic solution at a level from about 0.001% to about 5% by weight of said short chain alcohol present in the alcoholic solution.

8. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 7, wherein said loperamide compound is dissolved in said alcoholic solution at a level of about 2.5% by weight of said short chain alcohol present in the alcoholic solution.

9. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 7, wherein said combin-ation of loperamide compound and pharmaceutically acceptable carrier materials is dried to less than about 2% of alcoholic solution.

10. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 9, further comprising the step of screening said dried composition of loperamide compound and pharmaceutically acceptable carrier materials through a 40 mesh screen.

11. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 10, wherein after the screening step a pharmaceutically acceptable lubricant is added.

12. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 11, wherein said lubricant is magnesium stearate.

13. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 12, wherein said compo-sition is compressed into a unit dose form comprising from about 0.1mg to about 5mg of loperamide hydrochloride and the composition is compressed to a level of hardness from about 5sc to about 20sc.

14. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 13, wherein loperamide hydrochloride is present in the unit dose form at a level of about 2mg.

15. A process for formulating a solid oral dosage form of loper-amide compound, according to Claim 1, wherein said dried composition of loperamide compound and pharmaceutically acceptable materials composition is compressed into a unit dose form to a level of hardness from about 5sc to about 20sc.

16. A process for formulating a solid oral unit dose form of loperamide hydrochloride, said process comprising the steps of:
(a) dissolving loperamide hydrochloride in an alcoholic solution comprising from about 50% to about 100% ethanol and from about 50% to about 0% water, and wherein further the loperamide hydrochloride is dissolved in said alcoholic solution at a level of from about 0.001%
to about 5% by weight of the ethanol present in the alcoholic solution;
(b) granulating pharmaceutically acceptable carrier materials with the loperamide hydrochloride-containing alcoholic solution;
(c) drying the loperamide hydrochloride-containing granulates to remove essentially all of the ethanol; and (d) compressing the dried granules into a unit dose form to a level of hardness of from about 5sc to about 20sc.

17. A solid oral dosage form of loperamide compound prepared according to the process of Claim 1.

18. A solid oral dosage form of loperamide hydrochloride prepared according to the process of Claim 2.

19. A solid oral dosage form of loperamide compound prepared according to the process of Claim 6 comprising:
(a) from about 0.1% to about 5% loperamide hydrochloride;
and (b) from about 95% to 99.9% pharmaceutically acceptable carrier materials; and wherein further said composition comprises less than about 2%
of ethanol.

20. A solid oral dosage form of loperamide compound prepared according to the process of Claim 9.

21. A solid oral dosage form of loperamide compound in unit dose form prepared according to the process of Claim 13.

22. A solid oral dosage form of loperamide compound in unit dose form prepared according to the process of Claim 15.

23. A solid oral unit dosage form of loperamide hydrochloride prepared according to the process of Claim 16 comprising:
(a) from about 0.5% to about 1% loperamide hydrochloride;
and (b) from about 99% to about 99.5% pharmaceutically-acceptable carrier materials.