IE912815A1 - Process for formulating a solid oral dosage form of¹loperamide compounds - Google Patents

Process for formulating a solid oral dosage form of¹loperamide compounds

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Publication number
IE912815A1
IE912815A1 IE281591A IE281591A IE912815A1 IE 912815 A1 IE912815 A1 IE 912815A1 IE 281591 A IE281591 A IE 281591A IE 281591 A IE281591 A IE 281591A IE 912815 A1 IE912815 A1 IE 912815A1
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IE
Ireland
Prior art keywords
loperamide
compound
solid oral
dosage form
alcoholic solution
Prior art date
Application number
IE281591A
Original Assignee
Procter & Gamble
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Procter & Gamble filed Critical Procter & Gamble
Publication of IE912815A1 publication Critical patent/IE912815A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12Antidiarrhoeals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

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

Description

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-l-p1peridinebutyramide monohydrochloride) 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 1n: (1) Pharmaceutical Dosage Forms: Tablets. Volume 1. Chapter 2, Pages 61-107, 1980, discloses a method for formulating a pharmaceutical solid dosage form by direct compression. This - 2 method consists of two steps. The first step is accomplished 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. (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., Drug Development and Industrial Pharmacy. 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 Development and Industrial Pharmacy. ]_4 (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, griseofulvin, reserpine, chloramphenicol, oxolinic 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 •Ε 912815 - 3 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 5% of loperamide; and (b) from about 95% to about 99.9% pharmaceutically acceptable 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 acceptable carrier materials with the loperamide compoundcontaining alcoholic solution; and (c) drying said combination of the loperamide compound and pharmaceutically acceptable carrier materials. 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 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 antidiarrheal 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 disclosures of all these patents being incorporated by reference herein in their entirety. 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, incorporated by reference in its entirety herein.
The loperamide compound, for purposes of the process of the present invention, 1s dissolved 1n 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 In the process of the present invention, the loperamide compound is dissolved in an alcoholic solution prior to combining - 5 the loperamide compound with the pharmaceutically acceptable 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 50% to about 100% by volume of the alcoholic solution, with the remaining portion of the solution preferably comprising water at a level from about 0% to about 50% 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 0% 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 Acceptable Carrier Materials In addition, the components of the manufacturing process and 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 with humans and/or other animals without undue adverse side effects (such as toxi25 city, irritation and allergic response), within a reasonable benefit/r1sk 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 1n a solid dose pharmaceutical composition. The class of possible pharmaceutically acceptable carrier materials includes dlslntegrants, 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 glycolate, and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, microcrystalline cellulose, ethylIE 912815 - 6 cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; acacia; talc; calcium sulfate; polyvinyl pyrrolidone; polyacrylamides; clays; ion-exchange resins; and certain algins.
Lubricants can also be used in the present invention to enhance the compression of the loperamide containing composition into a solid oral unit dose 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. In addition, coloring agents, anti-oxidants, and preservatives can also be present. Compositions for manufacturing solid oral unit dosage forms useful herein are described in the following references, incorporated herein in their entirety, Lieberman, et al., Pharmaceutical Dosage Forms; Tablets (1981), and Remington's Pharmaceutical Sciences. Seventh Edition. Chapter 90, pages 1603-1632, 1985.
The pharmaceutically acceptable carrier materials utilized in the present invention are collectively present in the final solid oral composition at a level from about 75% to about 99.9% by weight of the composition. Preferrably the pharmaceutically 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 99.5%. (d) Processing Method The present process for formulating a solid oral dosage form, preferably a unit dose form, of loperamide compounds first employs the above described alcoholic solution to dissolve the loperamide compound at levels as indicated. If a more economic method of manufacturing is desired, the loperamide compound30 containing 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 compound from the alcoholic solution.
The pharmaceutically acceptable carrier materials (preferably excepting the lubricant) are also prepared for the manufacturing - 7 process (preferably a granulation process). These pharmaceutically acceptable carrier materials are combined with the loperamide compound-containing alcoholic solution by utilizing an acceptable apparatus for combining these compounds (typically equipment for mixing or granulating 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 pharmaceutical 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 10 more detail hereinafter. A preferred mixer, because of its ease of production, is the Hobart mixer, e.g. model number N-50. The Hobart mixer resembles a common household freestanding mixer with rotating blades that provide a uniform mix of ingredients. Another preferred apparatus is the Patterson-Kelly twin-shell blender, because this blender allows precision blending of large quantities of powder. The preferred method herein involves granulation, performed by adding the loperamide compoundcontaining alcoholic solution to the mixing apparatus where the pharmaceutical carrier materials were initially prepared, and then by mixing until complete granulation is achieved.
Finally, after the combining of the loperamide compound and pharmaceutically acceptable carrier materials is complete, the loperamide compound-containing composition is dried, typically to a level of less than about 2% of alcoholic solution. Drying said loperamide compound-containing composition may be accomplished several ways. The loperamide composition 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-containing 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. (Remington's Pharmaceutical Sciences. Seventeenth .EHUop, pages 1610-1613, 1985, incorporated herein in its entirety.) The fluid bed dryer may also be employed to granulate the pharmaceutically acceptable carrier materials with the loperamide compound-containing alcoholic solution and drying the loperamide - 8 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 5 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 10 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 lubricant 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 sc) to about 20sc. The final unit dose form of the loperamide compound is preferably compressed to a hardness level of about 7sc on 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 1 Solid Unit Pose Form of Loperamide Hydrochloride A solid oral unit dosage form of loperamide hydrochloride, prepared by the method set forth in the present invention, contains the following components.
Components Weight % loperamide hydrochloride 0.80 polyvinylpyrrolidone 4.00 sodium starch glycol ate 4.00 microcrystalline cellulose! 90.95 magnesium stearate 0.25 ethanol2 (32.00) Microcrystalline cellulose is manufactured under the tradename Avicel· by FMC Corporation.
Ethanol (100% by volume) is used in the process and removed prior to tableting.
This composition is prepared by first dissolving the loperamide hydrochloride in ethanol to obtain a clear solution. Next, a mixture of polyvinylpyrrolidone, sodium starch glycol ate, 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 magnesium 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.
EXAMPLE 2 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.
Weight loperamide hydrochloride 0.80 polyv1ny1 pyrroli done 4.00 sodium starch glycol ate 4.00 microcrystalline cellulose 90.20 talc 1.00 ethanol! (32.00) ! Removed prior to tableting. - ίο Ingestion of two of these tablets after each unformed stool by humans in need of treatment for diarrhea provides rapid, safe, and effective relief.

Claims (9)

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 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 loperamide 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 loperamide compound, according to either of Claims 1 or 2, wherein said alcoholic solution contains ethanol as the short chain alcohol.
4. A process for formulating a solid oral dosage form of loperamide compound, according to any of Claims 1-3, wherein said alcoholic solution comprises from 50% to 100% of ethanol and from 50% to 0% of water.
5. A process for formulating a solid oral dosage form of loperamide compound, according to any of Claims 1-4, wherein said loperamide compound is dissolved in said alcoholic solution at a level from 0.001% to 5% by weight of said short chain alcohol present in the alcoholic solution. - 12
6. A process for formulating a solid oral dosage form of loperamide compound, according to any of Claims 1-5, wherein said combination of loperamide compound and pharmaceutically acceptable carrier materials is dried to less than 2% of alcoholic solution, and wherein further the dried composition of loperamide compound and pharmaceutically acceptable carrier materials is screened through a 40 mesh screen.
7. A process for formulating a solid oral dosage form of loperamide compound, according to any of Claims 1-6, wherein after the screening step a pharmaceutically acceptable lubricant is added.
8. A process for formulating a solid oral dosage form of loperamide compound, according to any of Claims 1-7, wherein said composition is compressed into a unit dose form comprising from O.lmg to 5mg of loperamide hydrochloride and the composition is compressed to a level of hardness from 5sc to 20sc.
9. 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 50% to 100% ethanol and from 50% to 0% water, and wherein further 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 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 5sc to 20sc. 11. 11. 12. 12. 13 . 13 . A solid oral dosage form of loperamide compound prepared according to the process of any of Claims 1-9 comprising: (a) from 0.1% to 5% loperamide hydrochloride; and (b) from 95% to 99.9% pharmaceutically acceptable carrier materials; and wherein further said composition comprises less than 2% of ethanol. A process according to claim 1, substantially as hereinbefore described and exemplified. A solid oral dosage form of loperamide compound whenever formulated by a process claimed in a preceding claim. A solid oral dosage form of loperamide compound according to claim 10, substantially as hereinbefore described and exemplified.
IE281591A 1990-08-09 1991-08-08 Process for formulating a solid oral dosage form of¹loperamide compounds IE912815A1 (en)

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EP (1) EP0542879A1 (en)
JP (1) JPH06500104A (en)
AU (1) AU661972B2 (en)
CA (1) CA2088273C (en)
FI (1) FI930536A0 (en)
IE (1) IE912815A1 (en)
NZ (1) NZ239308A (en)
PT (1) PT98612A (en)
WO (1) WO1992002223A1 (en)

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WO2005117834A1 (en) * 2004-05-27 2005-12-15 Janssen Pharmaceutica N.V. Solid dispersions of a basic drug compound and a polymer containing acidic groups
US10508373B2 (en) 2016-05-13 2019-12-17 Nike, Inc. Embroidered article

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1332236C (en) * 1985-10-11 1994-10-04 Lourens Wals –,-–-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, n-oxides
DE3906779A1 (en) * 1989-03-03 1990-09-06 Hoechst Ag Compositions against animal parasites (parasites of animals)
GB8908361D0 (en) * 1989-04-13 1989-06-01 Beecham Group Plc Composition
NZ233403A (en) * 1989-04-28 1992-09-25 Mcneil Ppc Inc Simulated capsule-like medicament

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FI930536A (en) 1993-02-08
EP0542879A1 (en) 1993-05-26
NZ239308A (en) 1994-04-27
CA2088273A1 (en) 1992-02-10
PT98612A (en) 1992-06-30
FI930536A0 (en) 1993-02-08
AU661972B2 (en) 1995-08-17
JPH06500104A (en) 1994-01-06
WO1992002223A1 (en) 1992-02-20
AU8440091A (en) 1992-03-02
CA2088273C (en) 1996-05-14

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