CA1124178A - Nabilone granulation - Google Patents

Nabilone granulation

Info

Publication number
CA1124178A
CA1124178A CA343,252A CA343252A CA1124178A CA 1124178 A CA1124178 A CA 1124178A CA 343252 A CA343252 A CA 343252A CA 1124178 A CA1124178 A CA 1124178A
Authority
CA
Canada
Prior art keywords
nabilone
ethanol
granulation
solution
pvp
Prior art date
Legal status (The legal status 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 status listed.)
Expired
Application number
CA343,252A
Other languages
French (fr)
Inventor
James W. Conine
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Application granted granted Critical
Publication of CA1124178A publication Critical patent/CA1124178A/en
Expired legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Abstract

Abstract A solution of nabilone and PVP in anhydrous ethanol is used to granulate ethanol-insoluble pharma-ceutically-acceptable excipients such as starch.

Description

X-5076 -1~

Title NABILONE GRANULATION
Nabilone[trans-dl-1-hydroxy-3-(1',1'-dimethylheptyl)-6,6 dimethyl-6a,7,8,9,10,10a-hexahydrodibenzo[b,d]pyran-9-one] is encompassed within a group of useful intermediates prepared by Farenholtz, et al., J. AmO Chem. Soc., 88, 2079 (1966), 89, 5934 (19571 for the preparation of ~9-THC (tetrahydrocannabinol) and its alkylated congeners having alkyl groups of from 1 to 10 carbon atoms at C-3. (~9-THC is trans-dl-l-hydroxy 3 n-pentyl-6,6,9~-trimethyl~-6a,7,8, lOa- tetrahydrodibenzo-[b,d]pyran). Archer, U.S. Patents No. 3,928,598, 3,953,603, 3,9446,673, and 3,98~,188 disclosed tha~ nabilone, in addition to beiny a "useful in-termediary", had activity as an ant.i-depressant, anti-anxiety, analgesic and/or sedative drug, and Archer and Lemberger further extencled its useful actions tv that of anti-emetic and for the treatment of g1aucoma, U.S. Patents ~o. 4,087,545 and 4,087,547.
Nabilone is not well absorbed from the ir.testine upon oral administration. Thakker, et al., J.
Pharm. Pharmac., 29, 783 ~1977~ describe some useful formulations for nabilone including a dispersion in polyvinylpyrrolidinone. Thakker, et al~ mix nabilone with PVP in a ratio of 1:2-20 in a solvent such as ethanol and then remove the solvent by evaporation in vacuo. The product thus obtained is a ylassy solid which must first be broken up and then reduced to a fine powder in order to disperse it uniformlY in other pharmaceutical excipients prior to filling into telescoping gelatin capsules.
This invention is a process to provide a granulation formulation for nabilone which avoids the inconvenience and difficulties of the aforesaid Thakk~r et al solid dispersion.
Specifically the invention provides a solution of nabilone and polyvinylpyrrolidone in ethanol as a granulating solution. This solution is then used to granulate pharmaceutical excipients and carriers such - as starch, lactose, cellulose and the like. After drying and grinding, the powdered granular material is : suitable for blending with other materials to make a formulation suitable for filling into telescoping gelatin capsules as provided. In other words, the nabilone-PVP dispersion of Thakker et al. (loc. cit.) is formed in situ as a granulation for excipients which are insoluble in ethanol. The ratio of nabilone to PVP
contains, in the novel granulation as in the Thakker et - 20 al. dispersions, one par~ of nabilone to 2 to 20 parts of PVP.
A granulation thus prepared is shown to have excellent s~ability as regards nabilone, and dissolution data has shown that the granulation is equivalent to the Thakkex et al. dispersion prepared as a glas~ in the rotary evaporator and then powdered.
Equivalent bioavailability has been demonstrated in doss fox the granulation of th~s invention as compared with the Thakker et al. dispersion.
Other nabilone dispersions prepared by Thakker, et al., including one in polyethylene glycol, ~-5076 -3-can be prepared similarly in situ on the particularexcipient using our novel process as described for the nabilone-PVP dispersion abo~e; solution in ethanol followed by yranulation of an ethanol~insoluble excipi-ent.
This invention is further illustrated by the following specifi.c example.
Example 1 Five gram~ of nabilone were dissolved in 125 ml. of anhydrous ethanol .45 g. of polyvinylpyr-rolidone (PVP) were dissolved therein. The resulting viscous solution was added to 450 g. of starch flowable powder in a Hohart mixer. A small amount of additional anhydrous ethanol was used to rinse the nabilone-PVP
solution into the mixer. After thorough mixing, the granulation was wet screened through a no. 4 screen (a no. 6 screen can also be used). The screened granula-tion was air dried and then ground to the desired size in a ball mill.
A nabilone-PVP-starch granula~ion so prepared can be further blended with other excipients to give a final mixture having the desirad nabilone concentration ~or loading into empty telescoping gelatin capsules.
Other ethanol insoluble excipients such as lactose, mannitol and dextrose can be used in place of flowable ~tarch in preparing the above granula-tion.
. .

Claims (2)

X-5076-Canada -4-The embodiments of the invention for which an exclusive property or privilege is claimed are defined as follows:
1. A process which formulates nabilone for oral administration to mammals which comprises dissolv-ing nabilone and polyvinylpyrrolidone or polyethylene glycol in anhydrous ethanol and using the thus-formed viscous solution to granulate a pharmaceutically-accepta-ble ethanol-insoluble excipient by thoroughly mixing the solution with the excipient, and then drying the thus-formed granulation.
2. A process of claim 1 which comprises dis-solving polyvinylpyrrolidone and nabilone in ethanol to form the granulating solution.
CA343,252A 1979-03-09 1980-01-08 Nabilone granulation Expired CA1124178A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19,810 1979-03-09
US06/019,810 US4195078A (en) 1979-03-09 1979-03-09 Nabilone granulation

Publications (1)

Publication Number Publication Date
CA1124178A true CA1124178A (en) 1982-05-25

Family

ID=21795156

Family Applications (1)

Application Number Title Priority Date Filing Date
CA343,252A Expired CA1124178A (en) 1979-03-09 1980-01-08 Nabilone granulation

Country Status (16)

Country Link
US (1) US4195078A (en)
EP (1) EP0015635A1 (en)
JP (1) JPS55133309A (en)
AU (1) AU531805B2 (en)
BE (1) BE881049A (en)
CA (1) CA1124178A (en)
CH (1) CH643840A5 (en)
DK (1) DK8080A (en)
FR (1) FR2450606A1 (en)
GB (1) GB2045080B (en)
IE (1) IE49243B1 (en)
IL (1) IL59098A (en)
IT (1) IT1193886B (en)
LU (1) LU82072A1 (en)
NZ (1) NZ192557A (en)
ZA (1) ZA80104B (en)

Families Citing this family (15)

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Publication number Priority date Publication date Assignee Title
US4327080A (en) * 1981-07-13 1982-04-27 E. R. Squibb & Sons, Inc. Novel Bendroflumethiazide formulations and method
JPS59155309A (en) * 1983-02-22 1984-09-04 Teijin Ltd Active type vitamin d3 composition and its preparation
NZ211545A (en) * 1984-04-11 1987-09-30 Ici Australia Ltd Composition having particulate trace element suspended in matrix of solid polyethylene glycol
US4747881A (en) * 1985-02-05 1988-05-31 Warner-Lambert Company Ingestible aggregate and delivery system prepared therefrom
US4818539A (en) * 1985-02-05 1989-04-04 Warner-Lambert Company Ingestible aggregate and delivery system prepared therefrom
US4843098A (en) * 1985-02-05 1989-06-27 Warner-Lambert Company Ingestible aggregate and delivery system prepared therefrom
US4790991A (en) * 1985-02-05 1988-12-13 Warner-Lambert Company Ingestible aggregate and delivery system prepared therefrom
US4851392A (en) * 1985-02-05 1989-07-25 Warner-Lambert Company Ingestible aggregate and delivery system prepared therefrom
US4844908A (en) * 1986-11-27 1989-07-04 Duphar International Research B.V. Method of preparing tablets with clovoxamine fumarate and tablets thus prepared
EP0547796A1 (en) * 1991-12-17 1993-06-23 Konica Corporation Solid chemicals for processing silver halide photographic light-sensitive material
US6566560B2 (en) 1999-03-22 2003-05-20 Immugen Pharmaceuticals, Inc. Resorcinolic compounds
WO2002026224A2 (en) * 2000-09-28 2002-04-04 Immugen Pharmaceuticals, Inc. Methods and compounds for inhibiting eicosanoid metabolism and platelet aggregation
AU2002213429A1 (en) * 2000-09-28 2002-04-08 Immugen Pharmaceuticals, Inc. Antiviral methods and compounds
WO2003080043A1 (en) * 2002-03-18 2003-10-02 Immugen Pharmaceuticals, Inc. Topical formulations of resorcinols and cannibinoids and methods of use
CA2845443A1 (en) * 2014-03-04 2015-09-04 Pharmascience Inc. Orally disintegrating tablet of nabilone and method of manufacturing

Family Cites Families (22)

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FR886435A (en) * 1941-09-29 1943-10-14 Advanced knitting needle
US3136692A (en) * 1961-06-30 1964-06-09 Strong Cobb Arner Inc Effervescent composition containing polyvinylpyrrolidone
DE1467792A1 (en) * 1965-05-21 1968-12-12 Brunnengraeber & Co Gmbh Dr Ch Disintegrants for pharmaceutical pellets
CA885974A (en) * 1968-04-02 1971-11-16 R. Telfer William Ferrous fumarate capsule and preparation
IL32673A (en) * 1968-08-05 1973-11-28 Ciba Geigy Ag A granular material containing oily or liquid therapeutically usable furanosides and a process for its manufacture
US3632778A (en) * 1970-06-10 1972-01-04 Hoffmann La Roche Tablets containing l-dopa
NL7112288A (en) * 1970-09-16 1972-03-20
JPS5418330B2 (en) * 1973-03-16 1979-07-06
US3851032A (en) * 1973-04-23 1974-11-26 Sterling Drug Inc Process of preparing a solid fine crystalline paracetamol polymer complex composition
US3864492A (en) * 1973-08-01 1975-02-04 Abbott Lab Method of treating depression using 1,4{40 -dihydroxy-3-n-pentyl-6,6,9-trimethyl-6a,7,10,10a-tetra-hydrodibenzo{8 b,d{9 pyran
US3944673A (en) * 1973-11-05 1976-03-16 Eli Lilly And Company Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs
IE39678B1 (en) * 1973-11-05 1978-12-06 Lilly Co Eli A polymorphic form of a dibenzopyranone
US3920809A (en) * 1973-11-05 1975-11-18 Lilly Co Eli Dibenzo(b,d)pyranone dispersions
US3953603A (en) * 1973-11-05 1976-04-27 Eli Lilly And Company Hexahydro-dibenzo[b,d,]pyran-9-ones as psychotropic, particularly anti-depressant drugs
US4024275A (en) * 1973-11-05 1977-05-17 Eli Lilly And Company Method of reducing elevated blood pressure with dihydroxy-hexahydrodibenzo(b,d)pyrans
US3987188A (en) * 1973-11-05 1976-10-19 Eli Lilly And Company Hexahydro-dibenzo[b,d]pyran-9-ones as sedative drugs
AT329556B (en) * 1974-10-24 1976-05-25 Lilly Co Eli PROCESS FOR PRODUCING A NEW STABLE POLYMORPHIC CRYSTALLINE FORM OF 1-HYDROXY-3- (1 ', 1'-DIMETHYLHEPTYL) -6,6-DIMETHYL-6,6A, 7,8,10,10A-HEXAHYDRO-9H-DIBENZO ( B, D) PYRAN-9-ON
US4143129A (en) * 1975-10-11 1979-03-06 Lilly Industries Limited Cephalexin tablets
US4087545A (en) * 1976-02-17 1978-05-02 Eli Lilly And Company Hexahydro-dibenzo[b,d]pyran-9-ones as antiemetic drugs
US4087546A (en) * 1976-02-17 1978-05-02 Eli Lilly And Company Hexahydro-dibenzo[b,d]pyran-9-ones as antiasthmatic drugs
US4087547A (en) * 1976-02-17 1978-05-02 Eli Lilly And Company Hexahydro-dibenzo[b,d]pyran-9-ones in treatment of glaucoma
US4088777A (en) * 1976-02-17 1978-05-09 Eli Lilly And Company Hexahydro-dibenzo[b,d]pyran-9-ones as anticonvulsant drugs

Also Published As

Publication number Publication date
DK8080A (en) 1980-09-10
JPS55133309A (en) 1980-10-17
CH643840A5 (en) 1984-06-29
GB2045080A (en) 1980-10-29
IL59098A0 (en) 1980-05-30
NZ192557A (en) 1981-05-01
EP0015635A1 (en) 1980-09-17
JPH0142923B2 (en) 1989-09-18
AU5455480A (en) 1980-09-11
FR2450606B1 (en) 1983-04-15
IT8019114A0 (en) 1980-01-09
AU531805B2 (en) 1983-09-08
IT1193886B (en) 1988-08-31
BE881049A (en) 1980-07-09
LU82072A1 (en) 1980-04-23
FR2450606A1 (en) 1980-10-03
ZA80104B (en) 1981-08-26
IL59098A (en) 1983-09-30
IE49243B1 (en) 1985-09-04
IE800042L (en) 1980-09-09
US4195078A (en) 1980-03-25
GB2045080B (en) 1983-05-25

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