WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`International Bureau
`
`'
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) I11te1'n3fi0nal Patent Classificatmn 6 5
`(11) International Publication Number:
`WO 99/409001
`A61K 9/00, 9/02, 9/20, 9/70, A61M 31/00 A1
`
` (43) International Publication Date:
`
`19 August 1999 (19.08.99)
`
`(21) International Application Number:
`
`PCT/US99/03059
`
`(22) International Filing Date:
`
`11 February 1999 (1102.99)
`
`(30) Priority Data:
`09/022,436
`09/133,106
`09/177,997
`09/177,996
`
`12 February 1998 (1202.98)
`12 August 1998 (12.08.98)
`23 October 1998 (2310.98)
`23 October 1998 (23.l0.98)
`
`US
`US
`US
`US
`
`(81) Designated States: AL, AU, BA, BB, BG, BR, CA, CN, CU,
`CZ, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC,
`LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO,
`SG, SI, SK, SL, TR, Tl", UA, US, UZ, VN, YU, ARIPO
`patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian
`patent (AM, AZ,*BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(71) Applicant (for all designated States except US): TAYLOR
`PHARMACEUTICALS [US/US]; 2500 Milbrook Drive,
`Buffalo Grove, IL 60089-4694 (US).
`
`(72) Inventors; and
`(75) InventorslApplicants (for US only): ALAM, Abu [US/US];
`1471 Littlefield Court, Lake Forest, IL 60045 (US). CRUZ,
`Pablo, J. [US/US]; Apartment #3A, 1400 Wellington Way,
`Decatur, IL 62526 (US). GLAD, Keith [US/US]; 12 Country
`Towne Road, Springfield,
`IL 62707 (US). ROBERTS,
`Dennis [US/US]; 2631 Twin Oaks Court #122, Decatur, IL
`62526 (US).
`
`(74) Agents: GREEN, Robert, F. et al.; Leydig, Voit & Mayer,
`Ltd., Suite 4900, Two Prudential Plaza, 180 North Stetson,
`Chicago, IL 60601—6780 (US).
`
`(54) Title: DROPERIDOL COMPOSITIONS AND METHOD FOR USING SAME
`
`(57) Abstract
`
`Oral, sublingual, buccal, nasal and injectable dosage forms of droperidol are provided and a method for treating migraine using
`such formulations. The dosage forms include oral tablets, capsules, powders, effervescent formulations and syrups, sublingual tablets and
`solutions, buccal tablets, nasal solutions, suspensions, gels and injectable solutions.
`
`Lj
`Lannett Holdings, Inc. LAN 1028
`
`
`   
`


`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`
`
`

`
`W0 99/40900.
`
`PCT/US99/03059
`
`1
`
`DROPERIDOL COMPOSITIONS
`
`AND METHOD FOR USING SAME
`
`FIELD OF THE INVENTION
`
`5
`
`This invention relates to the field of migraine
`treatment.
`
`BACKGROUND OF THE INVENTION
`
`The prevalence of migraine is said to be
`
`10
`
`approximately 6% of the male population and l8% of the
`
`female population. Treatment for many patients having the
`
`occasional migraine usually involves simple analgesics,
`
`non—steroidal anti—inflammatory agents, or specific agents
`
`such as ergotamines or triptans. Approximately 10% of
`
`15 migraine sufferers have three or more attacks per month
`
`and warrant prophylactic treatment. Preventative agents
`
`such as beta—blockers,
`
`tricyclic antidepressants and
`
`divalproex sodium can reduce but not eliminate migraine
`
`attacks in some patients. Thus,
`
`there remains a need for
`
`20 migraine specific medications such as sumatriptan.
`
`In the
`
`remaining population of migraine sufferers, and in those
`
`with intolerable side-effects from available drugs,
`
`there
`
`is a lack of conventional pharmaceutical preparations that
`
`exhibit therapeutic effect, without severe side—effects.
`
`25
`
`Droperidol presently is marketed by Akorn,
`
`Inc.
`
`under the trademark Inapsine, as an injectable
`
`formulation used in anesthesia for preoperative surgery.
`
`It has never been approved for use in the treatment or
`
`management of migraine attacks.
`
`30
`
`The concentration of droperidol in the Inapsine is
`
`2.5 mg/ml. That is the only concentration of droperidol
`
`that has been approved for human injection.
`
`Further,
`
`droperidol is present as the lactate salt in Inapsine.
`
`No droperidol salt, other than the lactate, has been used
`
`35
`
`for human injection.
`
`

`
`WO 99/40900_
`
`PCT/US99/03059
`
`2
`
`A limited, uncontrolled, non—blinded, use of
`
`droperidol lactate (2.5 mg/ml droperidol)
`
`to treat
`
`migraine attacks was attempted and the results published
`
`in Headache, April 1996, p.280.
`
`In that publication it
`
`5
`
`was reported that 20 patients received from 2.5 to 7.5 mg
`
`droperidol
`
`intravenously,
`
`in increments of 2.5 mg every
`
`30 minutes until the patient was headache free or until a
`
`total of three doses had been administered. All of the
`
`patients received prior treatment with migraine
`
`10
`
`therapies. Eighteen of the patients reported to be
`
`headache—free by the last dose. Although the article
`
`reports on apparently encouraging results in treating
`
`migraine attacks with droperidol, no definitive
`
`conclusions can be reached from the results reported in
`
`15
`
`that article as the number of patients treated was small,
`
`the study was not blinded, all patients received other
`
`agents to treat the migraine episode prior to receiving
`
`droperidol, and there was no placebo control. Also,
`
`there was no attempt to repeat the results with the
`
`20
`
`patients. Further, no attempt was made to prolong
`
`therapy beyond the initial treatment to a headache—free
`
`state and most patients had continuing symptoms to some
`
`degree within 24 hours after the last droperidol
`
`treatment.
`
`25
`
`The study used multiple treatments of droperidol,
`
`with many patients receiving more than 2.5 mg of
`
`droperidol to reduce the migraine symptoms.
`
`The problem
`
`with administering droperidol at such a concentration is
`
`that the patient receives a significant volume of fluid
`
`30
`
`in order to achieve a therapeutically effective amount of
`
`droperidol. This is of particular concern if the patient
`
`is receiving the droperidol through intramuscularly
`
`(I.M.)
`
`injection. Muscle pain and irritation and other
`
`problems may be associated with such large fluid
`
`35
`
`injections.
`
`

`
`W0 99/40900‘
`
`PCT/US99/03059
`
`3
`
`Additionally,
`
`the aforementioned study and article
`
`only used intravenous droperidol. Others also have used
`
`intramuscular droperidol in uncontrolled studies for
`
`treatment of migraine.
`
`The use of droperidol by
`
`injection raises several issues, not the least of which
`
`is inconvenience to the patient, caused by the need to
`
`have the droperidol administered by a health care
`
`professional.
`
`Accordingly, a need exists for a means to treat
`
`patients who suffer from, or are at risk of,
`
`a migraine
`
`episode,
`
`that does not require the use of injections of
`
`droperidol.
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, droperidol
`
`is supplied in a dosage form that provides better patient
`
`tolerance and improved ease of administration.
`
`The
`
`present injectable dosage forms provide a higher
`
`concentration of droperidol than has been available
`
`previously.
`
`In particular,
`
`the dosage forms contain from
`
`2.75 to 10.0 mg/ml of droperidol.
`
`The injectable dosage forms of the present invention
`
`may be used to treat migraine episodes,
`
`by administration
`
`intravenously
`
`(“I.V.”),
`
`intramuscularly (“I.M.”), or
`
`subcutaneously to a patient during a migraine attack,
`
`in
`
`an amount that is effective to treat symptoms of
`
`migraine.
`
`In another embodiment,
`
`the present invention relates
`
`to the use of oral dosage forms of droperidol.
`
`The oral
`
`dosage forms of the present invention comprise tablets,
`
`capsules, powders, syrups and effervescent compositions.
`
`In a further embodiment,
`
`the present invention
`
`relates to the use of sublingual and buccal dosage forms
`
`of droperidol.
`
`Such dosage forms comprise sublingual
`
`tablets and solution compositions that are administered
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`

`
`wo 99/4o9oo_
`
`PCT/US9 9103059
`
`4
`
`under the tongue and buccal tablets that are placed
`
`between the cheek and gum.
`
`In yet a further embodiment,
`
`the present invention
`
`relates to the use of nasal dosage forms of droperidol.
`
`Such dosage forms of the present invention comprise
`
`solution, suspension, and gel compositions for nasal
`
`delivery.
`
`10
`
`15
`
`The dosage forms of the present invention may be
`
`used to treat migraine episodes, by administration to a
`
`patient during a migraine attack,
`
`in an amount that is
`
`effective to treat symptoms of migraine.
`
`The dosage
`
`forms of droperidol may be used without pretreatment or
`
`in conjunction with other migraine therapies.
`
`The present invention also provides an injectable
`
`dosage form of droperidol that is more suitable for
`
`injection, as by having a tonicity adjusting agent
`
`present to render the formulation isotonic.
`
`Such a
`
`dosage form may have from 0.1 to 10 mg/ml of droperidol.
`
`Such a dosage form may also be pH adjusted to be of a
`
`20
`
`physiologic pH.
`
`The present invention also provides oral dosage
`
`forms of droperidol that comprise from 0.5 to 20 mg of
`
`droperidol per unit dosage.
`
`The present invention further provides sublingual
`
`and buccal dosage forms of droperidol that comprise from
`
`0.1 to 10 mg of droperidol per unit dosage.
`
`The present invention additionally provides nasal
`
`dosage forms of droperidol that comprise from 0.1 to 1.5
`
`mg of droperidol per unit dosage,
`
`in solution and gel
`
`forms and from 0.1 to 10 mg of droperidol in suspension
`
`form.
`
`The dosage forms of the present invention also may
`
`be used to treat patients that are suffering from tension
`
`headache, vertigo,
`
`hyperagitation, or hyperemesis
`
`gravidarum.
`
`The dosage forms also may be used as
`
`25
`
`30
`
`35
`
`
`
`

`
`wo 99/4o900_
`
`PCT/US99/03059
`
`5
`
`antiemetics,
`
`to treat nausea and the like, such as that
`
`caused by chemotherapy.
`
`In each instance the dosage is
`
`administered in an amount sufficient to treat then
`
`patient’s symptoms.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`As indicated,
`
`the present
`
`invention provides
`
`injectable dosage forms of droperidol at concentrations
`
`from 0.1, 2.75, 5.5, 8.25 and 10.0 mg/ml droperidol that
`
`are particularly useful.
`
`The present invention also provides oral dosage
`
`forms of droperidol containing various amounts of
`
`droperidol, such as between about 0.5 and 20 mg
`
`droperidol per unit dosage, such as tablets and capsules,
`
`that are particularly useful.
`
`The present invention
`
`provides liquid solutions of droperidol, such as syrups,
`
`having a concentration of droperidol from about 0.5 mg to
`
`about 20 mg.
`
`Powders,
`
`in dry form, will contain from
`
`about 0.5 mg to about 20 mg droperidol and effervescent
`
`compositions which contain from about 0.5 mg to about 20
`
`mg, by weight.
`
`The present invention further provides sublingual
`
`and buccal dosage forms of droperidol containing various
`
`amounts of droperidol, such as between about 0.1 and 10
`
`mg droperidol per unit dosage, such as tablets and
`
`solutions,
`
`that are particularly useful. Typically the
`
`dosage will be 2 to 4 mg.
`
`The present invention still further provides nasal
`
`dosage forms of droperidol containing various amounts of
`
`droperidol, such as between about 0.5 and 1.5 mg
`
`droperidol per ml
`
`in the form of solutions and gels,
`
`that
`
`are particularly useful.
`
`Alternatively,
`
`the droperidol
`
`may be present as a suspension in an amount from about
`
`35
`
`0.1 to lO mg per ml.
`
`
`
`

`
`WO 99/40900_
`
`PCT/US99/03059
`
`6
`
`The droperidol may be present as the lactate, or
`
`other suitable organic salts of droperidol may be used,
`
`such as tartrate or acetate.
`
`The salt is usually formed
`
`in situ by the addition of a suitable organic acid,
`
`such
`
`as lactic acid, tartaric acid, acetic acid, or the like.
`
`The amount of acid that is added is usually sufficient to
`
`adjust the solution to a pH from about 3 to about 5.
`
`The injectable dosage forms of the present invention
`
`may be rendered isotonic,
`
`to increase patient tolerance.
`
`Accordingly,
`
`the solutions may be rendered isotonic by
`
`use of a suitable tonicity adjusting agent,
`
`such as
`
`glycerin. Accordingly, a sufficient amount of a tonicity
`
`adjusting agent may be present to render the solution
`
`isotonic, or nearly so.
`
`After the solution is formed, it should be
`
`sterilized, as by filtration, or any other suitable
`
`means. Alternatively,
`
`the solution may be terminally
`
`sterilized by autoclaving after filling into containers.
`
`The injectable dosage forms of the present invention
`
`include solutions contained in ampules, vials, prefilled
`
`syringes,
`
`and the like.
`
`Also, multi—dose vials may be
`
`used.
`
`In such an instance it is desirable to have a
`
`preservative present in the solution, such as a paraben,
`
`usually methyl and/or propyl paraben. Preservatives, of
`
`course, may be present in any of the dosage forms of the
`
`present invention.
`
`As indicated, patients that are suffering from a
`
`migraine episode,
`
`tension headache, vertigo,
`
`hyperemesis
`
`gravidarum, hyperagitation, or nausea may be treated.
`
`The patients are administered the droperidol, via I.V.,
`
`I.M., or subcutaneously.
`
`The droperidol is typically
`
`administered in dosages of 2.75 to l0.0 mg until the
`
`symptoms subside.
`
`The maximum dosage of droperidol
`
`administered to a patient at a single session usually
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
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`

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`W0 99/40900
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`PCT/US99/03059
`
`7
`
`will be 7.5 mg, although it may on occasion be as high as
`
`10 mg.
`
`As indicated, patients that are suffering from a
`
`migraine episode,
`
`tension headache, vertigo, hyperemesis
`
`gravidarum, hyperactivity, or nausea may be treated.
`
`The
`
`patients may be orally administered the droperidol,
`
`typically in dosages of 2 mg to 20 mg, until the symptoms
`
`subside.
`
`The maximum dosage of droperidol orally
`
`administered to a patient at a single session usually
`
`will be 10 mg, although it may on occasion be as high as
`
`20 mg.
`
`The patients may be administered the droperidol via
`
`the sublingual or buccal route,
`
`typically in dosages of 1
`
`mg to 10 mg, until the symptoms subside.
`
`The maximum
`
`dosage of droperidol administered to a patient at a
`
`single session usually will be 10 mg.
`
`The patients also may be nasally administered the
`
`droperidol,
`
`typically in dosages of 1 mg to 3 mg, until
`
`1O
`
`15
`
`the symptoms subside.
`
`Fifty (50)
`
`percent of the dose is
`
`20
`
`administered into each nostril.
`
`The maximum dosage of
`
`droperidol administered to a patient at a single session
`
`usually will be 10 mg.
`
`The patients receiving droperidol to treat migraine
`
`may be treated with droperidol as a single therapy.
`
`By
`
`this it is meant that other agents used to treat an
`
`active episode of migraine need not be used prior to or
`
`in conjunction with the droperidol treatment. Many
`
`patients receive various medications for prophylaxis
`
`against active migraine episodes, but such prophylactic
`
`therapy is not considered to be pretreatment of an active
`
`migraine episode, prior to droperidol treatment.
`
`Such
`
`therapy is nonspecific in that the goal is to prevent or
`
`reduce the number of occurrences of active migraine
`
`headache, but not
`
`the treatment of a specific migraine
`
`episode.
`
`The present dosage forms will be useful as a
`
`25
`
`30
`
`35
`
`
`
`

`
`WO 99/40900
`
`PCT/US99/03059
`
`8
`
`first—line treatment of active migraine headache without
`
`the prior use of traditional migraine therapy, or as a
`
`rescue medication when other treatment has failed;
`
`Presently, an active migraine episode may be treated
`
`with any of a number of therapies,
`
`including the
`
`following:
`
`Simple analgesics,
`
`such as aspirin or
`
`acetaminophen,
`
`combination analgesics as with caffeine,
`
`vasoconstrictors, narcotics,
`
`and the like.
`
`As indicated,
`
`the use of droperidol
`
`in accordance
`
`with the present invention does not require the prior
`
`administration of such other agents for treating
`
`migraine.
`
`The migraine patients to whom droperidol should be
`
`administered are those that are experiencing a migraine
`
`episode or are at risk of such an episode.
`
`Such patients
`
`may be generally described as those meeting the
`
`diagnostic criteria for “migraine with aura” or “migraine
`
`without aura” as detailed in:
`
`“Classification Committee
`
`of the International Headache Society. Classification
`
`and Diagnostic Criteria For Headache Disorders, Cranial
`
`Neuroalgia and Facial Pain”, Cephalgia,
`
`l988, Vol. 8,
`
`Supp. 77 at pp. 19-21; or meeting the diagnostic criteria
`
`for “status migrainosus”, as detailed therein at pp. 26-
`27.
`
`For some patients it may be beneficial to administer
`
`an additional dose of droperidol after the headache has
`
`subsided to reduce the probability that the headache will
`
`return in a short period of time.
`
`Such an additional
`
`dose of droperidol may be used to avoid the use of a
`
`sedative or other analgesics within the next
`
`few hours
`
`after the headache symptoms have subsided. Presently it
`
`is typical for patients, after they have been rendered
`
`headache—free,
`
`to resort to such remedies as sedation or
`
`use of analgesics shortly after the headache symptoms
`
`have subsided to reduce the recurrence of the migraine
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`

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`WO 99/40900_
`
`PCT/US99/03059
`
`9
`
`symptoms after the patient has become headache—free.
`
`The
`
`present
`
`invention may avoid the need for such remedies.
`
`The droperidol of use in accordance with the present
`
`invention may be administered by I.V.,
`
`I.M. or
`
`5
`
`subcutaneously.
`
`If administered intravenously,
`
`the rate
`
`of infusion is not critical and will usually be
`
`administered by I.V. push in a pre—established line.
`
`Usually the droperidol will be administered
`
`intramuscularly or subcutaneously as a bolus.
`
`10
`
`Sublingual and buccal delivery allows droperidol to
`
`dissolve in the immediate vicinity where the product is
`
`placed and then the drug enters directly into the blood
`
`stream to exert its pharmacological effect rapidly,
`
`thereby, by—passing the gastric juices, acid environment
`
`15
`
`and enzymes present in the gastrointestinal tract and at
`
`the same time by—passing the liver which is the target
`
`organ for metabolism of the drug when administered
`
`orally.
`
`The highly vascular mucosal lining between the
`
`cheek and gum where buccal tablets are placed or under
`
`20
`
`the tongue where sublingual tablets or solutions are
`
`placed are ideal and convenient locations for the
`
`droperidol to be absorbed. Moreover,
`
`the smaller total
`
`dose of droperidol ranging from 0.5 to l0 mg for
`
`therapeutic effect also lends itself for effective dosage
`
`25
`
`design by the sheer physical size.
`
`Nasal delivery allows droperidol to be absorbed
`
`directly into the systemic circulation from the nasal
`
`mucosa thus, enabling the drug to exert its
`
`pharmacological effect immediately. Nasal delivery,
`
`30
`
`unlike the oral route, escapes degradation which can be
`
`caused by gastrointestinal environment and liver first-
`
`past metabolism.
`
`The bioavailability by nasal delivery
`
`therefore, closely approximate the intramuscular
`
`would,
`route.
`
`35
`
`

`
`WO 99/40900_
`
`TABLETS
`
`PCT/US99/03059
`
`10
`
`In order to form tablets,
`
`there are used carriers
`
`such as vehicles
`
`(e.g.
`
`lactose, white sugar,
`
`sodium
`
`chloride,
`
`glucose,
`
`urea,
`
`starches,
`
`calcium carbonate,
`
`kaolin, crystalline cellulose, silicic acid, etc.),
`
`binders (e.g. water, ethanol, propanol, simple syrup,
`
`glucose solution,
`
`starch solution,
`
`gelatin solution,
`
`carboxymethyl cellulose,
`
`shellac,
`
`methyl cellulose,
`
`potassium phosphate,
`
`polyvinylpyrrolidone,
`
`etc.),
`
`disintegrators (e.g. dry starch,
`
`sodium alginate, agar
`
`powder,
`
`sodium hydrogen carbonate, calcium carbonate,
`
`polyoxyethylene sorbitan fatty acid esters,
`
`sodium
`
`laurylsulfate, stearic monoglyceride, starches,
`
`lactose,
`
`etc.),
`
`disintegration inhibitors
`
`(e.g.
`
`white sugar,
`
`stearin, cacao butter,
`
`hydrogenated oils,
`
`etc.),
`
`absorption promoters (e.g. quaternary ammonium base,
`
`sodium laurylsulfate, etc.),
`
`wetting agents (e.g.
`
`glycerin, starches, etc.),
`
`adsorbents (e.g.
`
`starches,
`
`lactose, kaolin, bentonite,
`
`colloidal silicates,
`
`etc.),
`
`lubricants (e.g. purified talc,
`
`stearates, boric acid
`
`powder, polyethylene glycol, etc.),
`
`and the like.
`
`Moreover,
`
`the tablets may be in the form of a
`
`conventional non—coated tablet, or a sugar—coated tablet,
`
`gelatin—coated tablet, enteric coated tablet,
`
`film coated
`
`tablet, or double or multiple layer tablet.
`
`CAPSULES
`
`The capsules may also contain the following
`
`ingredients: a binder such as microcrystalline cellulose,
`
`gum tragacanth or gelatin; an excipient such as starch or
`
`lactose, a disintegrating agent such as alginic acid,
`
`Primogelm, cornstarch and the like; a lubricant such as
`
`magnesium stearate or Sterotex“; a glidant such as
`
`colloidal silicon dioxide; and a sweetening agent such as
`
`sucrose or saccharin may be added or a flavoring agent
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`

`
`wo 99140900
`
`PCT/US99/03059
`
`11
`
`such as peppermint, methyl salicylate, or orange
`
`flavoring.
`
`POWDERS
`
`To form a useful powder,
`
`the droperidol may be
`
`admixed with at least one inert customary excipient
`
`(or
`
`carrier) such as sodium citrate of dicalcium phosphate or
`
`(a) fillers or extenders, as for example, starches,
`
`lactose, sucrose, glucose, mannitol and silicic acid,
`
`(b)
`
`binders, as for example, carboxymethylcellulose,
`
`alignates, gelatin, polyvinylpyrrolidone, sucrose and
`
`acadia,
`
`(c) humectants, as for example, glycerol,
`
`(d)
`
`disintegrating agents, as for example, agar—agar, calcium
`
`carbonate, potato or tapioca starch, alginic acid,
`
`certain complex silicates and sodium carbonate,
`
`(e)
`
`solution retarders, as for example paraffin,
`
`(f)
`
`absorption accelerators, as for example, quaternary
`
`ammonium compounds,
`
`(g) wetting agents, as for example,
`
`cetyl alcohol and glycerol monostearate,
`
`(h) adsorbents,
`
`as for example, kaolin and bentonite, and (i)
`
`lubricants,
`
`as for example,
`
`talc, calcium stearate, magnesium
`
`stearate, so_id polyethylene glycols,
`
`sodium lauryl
`
`sulfate or mixtures thereof.
`
`10
`
`15
`
`20
`
`25
`
`EFFERVESCENT POWDER
`
`Effervescent powder may be formulated by the aid of
`
`agents such as sodium bicarbonate, citric acid anhydrous,
`
`calcium phosphate monobasic, calcium phosphate dibasic,
`
`polyvinylpyrrolidone, polyethylene glycol powder, silica
`
`30
`
`gel, L—Leucine,
`
`sodium benzoate, simethicone, mineral
`
`oil,
`
`isopropyl alcohol, water, flavoring agents, sugar,
`
`sorbitol, aspartame, saccharin and coloring agents.
`
`
`
`

`
`W0 99/40900
`
`PCT/US99/03059
`
`SYRUPS AND SOLUTIONS
`
`l2
`
`Droperidol syrups and solutions may be made by
`
`adding ingredients such as water, sugar,
`
`fructose,
`
`sorbitol, aspartame, saccharin, polyethylene glycol,
`
`5
`
`propylene glycol, alcohol, bentonite,
`
`tragacanth,
`
`alginates, gelatin, carboxymethylcellulose,
`
`methylparaben, propylparaben,
`
`sodium benzoate, flavoring
`
`agents and coloring agents.
`
`10
`
`SUBLINGUAL TABLETS
`
`In order to form tablets,
`
`there are used carriers
`
`such as vehicles
`
`(e.g.
`
`lactose, white sugar, mannitol,
`
`glucose, starches, calcium carbonate, crystalline
`
`cellulose,
`
`silicic acid, etc.), binders (e.g. water,
`
`ethanol, myranol, glucose solution,
`
`starch solution,
`
`gelatin solution, polyvinylpyrrolidone, etc.),
`
`disintegrators (e.g. dry starch,
`
`sodium, alginate,
`
`sodium
`
`hydrogen carbonate, calcium carbonate, polyoxyethylene
`
`sorbitan fatty acid esters,
`
`sodium laurylsulfate, stearic
`
`monoglyceride, starches,
`
`lactose, etc.), absorption
`
`promoters (e.g. quaternary ammonium base,
`
`sodium
`
`laurylsulfate, etc.), wetting agents (e.g. glycerin,
`
`starches, etc.),
`
`lubricants
`
`(e.g.
`
`stearates, polyethylene
`
`glycol, etc.),
`
`and the like.
`
`Moreover,
`
`the tablets may
`
`be in the form of a conventional tablet, or a molded
`
`tablet.
`
`BUCCAL TABLETS
`
`In order to formulate into tablets, various carriers
`
`and excipients are used to offer the acceptable
`
`characterists such as:
`
`lactose, sugar, mannitol, acacia,
`
`providone, cyclodextrins, hydroxypropylmethylcellulose,
`
`ethylcellulose, methylcellulose,
`
`sodium
`
`carboxymethylcellulose, microcrystalline cellulose,
`
`Carbapol 934,
`
`stearic acid, magnesium stearate,
`
`locust
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`

`
`W0 99/40900
`
`PCT/US99/03 059
`
`13
`
`bean gum, xanthan gum, water, alcohol,
`
`isopropanol and
`
`artificial flavoring and sweetening agents.
`
`SOLUTIONS
`
`In order to formulate into solutions, various
`
`carriers, excipients, pH adjusters are employed such as:
`
`water, sugar,
`
`lactic acid, acetic acid,
`
`fructose,
`
`glucose, saccharin, polyethylene glycol, propylene
`
`glycol, alcohol, bentonite,
`
`tragacanth, gelatin,
`
`alginates, aspartame, sorbitol, methylparaben,
`
`propylparaben,
`
`sodium benzoate, artifical flavoring and
`
`coloring agents.
`
`NASAL SOLUTIONS, SUSPENSIONS AND GELS
`
`In order to formulate droperidol solutions, various
`
`carriers, excipients, pH adjusters are employed such as:
`
`water,
`
`lactic acid, acetic acid, citric acid,
`
`tartaric
`
`acid, polyethylene glycol, glycerin, guar gum,
`
`sodium
`
`chloride,
`
`tragacanth, methylcellulose,
`
`hydroxypropylmethylcellulose,
`
`sodium alginate,
`
`sodium
`
`carboxymethylcellulose, carbomer, methylparaben,
`
`propylparaben and sodium benzoate.
`
`Examples of the preparation and compositions of
`
`10
`
`15
`
`20
`
`typical formulations containing droperidol are described
`
`25
`
`here.
`
`However,
`
`it is to be understood that these
`
`examples are given by way of illustration only and are
`
`not to be construed as limiting the invention either in
`
`spirit or in scope as many modifications both in
`
`materials and in methods will be apparent to those
`
`3O
`
`skilled in the art.
`
`The present invention will be described in terms of
`
`the following non—limiting examples.
`
`35
`
`
`
`

`
`
`
`wo 99/4o9oo_
`
`EXAMPLE 1 Tablet Formulation
`
`14
`
`PCT/US99/03059
`
`INGREDIENT
`
`Droperidol
`
`(mg)
`
`Lactose (mg)
`
`Corn Starch (mg)
`
`Magnesium Stearate (mg)
`
`0.5
`
`MG/TABLET
`0.5
`
`20
`
`MG/TABLET
`2O
`
`50
`
`10
`
`__0L
`
`50
`
`10
`
`1
`
`Tablet Weight:
`
`61.0 mg
`
`81 mg
`
`Tablet Process:
`
`The ingredients of 1,000 tablets
`
`for 0.5 mg formulation and 81 g for 20 mg formulation)
`
`(61 9
`are
`
`blended in a suitable mixer and then are compressed into
`tablets using standard concave punches. Tablets are
`
`packaged into bottles or individual blister strips.
`
`The tablets can be further coated using either
`
`aqueous film coating in a suitable coating pan and dried.
`
`10
`
`The coated tablets are packaged into bottles or
`
`individual blister strips.
`
`The tablets can be further coated using conventional
`
`sugar coating procedure in a suitable coating pan and
`
`dried.
`
`The tablets are packaged into bottles or
`
`15
`
`individual blister strips.
`
`EXAMPLE 2 Capsule Formulation
`
`INGREDIENT
`
`Droperidol
`
`(mg)
`
`Lactose (mg)
`
`Polyvinylpyrrolidone (mg)
`
`Corn Starch (mg)
`
`Magnesium Stearate (mg)
`
`MG/c9P;_1fsULE
`
`0.5
`
`Q
`MG/ CAPSULE
`20
`
`50
`
`5
`
`25
`
`1
`
`50
`
`5
`
`25
`
`2
`
`Capsule Weight
`
`81.5 mg
`
`102.0 mg
`
`Capsule Process:
`
`The ingredients are blended for
`
`20
`
`1,000 capsules
`
`(81.5 g for 0.5 mg formulation and 102 g
`
`for 20 mg formulation)
`
`in a suitable mixer,
`
`then filled
`
`
`
`

`
`W0 99/40900‘
`
`PCT/US99/03059
`
`15
`
`into hard shell capsules using conventional procedure.
`
`The capsules are cleaned and packaged into bottles or
`
`individual blister strips.
`
`5
`
`EXAMPLE 3 Power Formulation
`
`INGRED I ENT
`
`Droperidol
`
`(mg)
`
`Sucrose (mg)
`
`Carboxymethylcellulose (mg)
`
`Peppermint Spray Dried Flavor
`
`( mg )
`
`0.5
`
`20
`
`MG/BLISTER
`PACK
`
`MG/BLISTER
`PACK
`
`0.5
`
`50
`
`10
`
`2
`
`20
`
`50
`
`10
`
`3
`
`Powder Weight:
`
`62.5 mg
`
`83 mg
`
`Powder Process:
`
`The ingredients of 1,000 powder
`
`units (62.5 g for 0.5 mg formulation and 83 g for 20 mg
`
`formulation) are blended in a suitable mixer and filled
`
`10
`
`into individual blister packs.
`
`EXAMPLE 4 Effervescent Tablet and Powder
`
`INGREDIENT
`
`Droperidol
`
`(mg)
`
`Sodium Bicarbonate (mg)
`
`Citric Acid Anhydrous
`
`(mg)
`
`Saccharin (mg)
`
`Silica Gel
`
`(mg)
`
`MG%IT
`
`0.5
`
`50
`
`30
`
`l
`
`5
`
`MG/26-(:1IT
`
`20
`
`80
`
`50
`
`l
`
`7
`
`UNIT WEIGHT
`
`86.5 mg
`
`158 mg
`
`Tablet Process:
`
`The ingredients are blended for
`
`15
`
`1,000 tablets (86.5 g for 0.5 mg formulation and 158 g
`
`for 20 mg formulation)
`
`in a suitable mixer and compressed
`
`into tablets under controlled environmental condition
`
`with relative humidity <30%.
`
`The tablets are packaged in
`
`

`
`W0 99/4090!)
`
`PCT/US99/03059
`
`1 6
`
`glass bottles or individually in an aluminum foil pouch
`
`to protect from moisture during storage.
`
`Powder Process:
`
`The ingredients are blended for
`
`1,000 powder units (86.5 g for 0.5 mg formulation and 158
`
`g for 20 mg formulation)
`
`in a suitable mixer in an
`
`environmental condition of relative humidity <309.
`
`The
`
`individual powder units are packaged in an aluminum foil
`
`pouch to protect form moisture during storage.
`
`10
`
`EXAMPLE 5 Syrup and Solution Formulation
`
`INGREDIENT
`Droperidol
`
`(mg)
`
`Lactic Acid gs to pH (mg)
`
`Sucrose (mg)
`
`Citrus Flavor
`
`(mg)
`
`Methylparaben (mg)
`
`Propylparaben (mg)
`
`Water, qs.ad (ml)
`
`9.-_§
`MG/ML
`0.5
`
`3.5
`
`50 mg
`
`0.1
`
`l
`
`0.2
`
`1
`
`£9
`MG/5 ML
`20
`
`3.5
`
`250
`
`0.5
`
`5
`
`1
`
`5
`
`TOTAL WEIGHT
`
`1 ml
`
`(lg)
`
`5 ml
`
`(5g
`
`Syrup and Solution Process:
`
`In a suitable Vessel,
`
`droperidol is dissolved with lactic acid with pH adjusted
`
`to about 3.5 in sufficient quantity of water.
`
`The
`
`remaining ingredients are then added and dissolved.
`
`Sufficient water is then added for 1,000 units (1,000 ml
`
`for 0.5 mg formulation and 5,000 ml for 20 mg
`
`formulation).
`
`The solution is filtered and filled into
`
`bottles.
`
`15
`
`20
`
`25
`
`
`
`

`
`WO 99/40900_
`
`PCT/US99/03059
`
`17
`
`Example 6 — Sublingual Tablet Formulation
`
`Ingredient
`
`0.1 mg/
`Tablet
`
`10 mg/
`Tablet
`
`(mg)
`Droperidol
`Mannitol
`(mg)
`Microcrystalline cellose (mg)
`Magnesium Stearate (mg)
`
`0.1
`5
`20
`0.1
`
`10
`10
`20
`0.1
`
`Total Weight/Tablet:
`
`25.2 mg
`
`40.1 mg
`
`Tablet Process:
`
`The ingredients of 1,000 tablets (25.6 g
`
`for 0.1 mg formulation and 40.1 g for 10 mg formulation)
`
`are blended in a suitable mixer and then compressed into
`
`tablets. Tablets are packaged into bottles or individual
`
`blister strips.
`
`10
`
`EXAMPLE 7 - Sublingual Tablet Formulation
`
`INGREDIENT
`
`o .1 mg/ Tablet
`
`10 mg/Tablet
`
`(mg)
`Droperidol
`Sucrose (mg)
`Magnesium Stearate (mg)
`
`0.124 *
`30.0
`0.106
`
`12.4 **
`30.0
`0.2
`
`Total Weight/Tablet:
`
`30.23 mg
`
`42.6 mg
`
`0.1 mg. Droperidol = 0.124 mg Droperidol Lactate
`*
`** 10 mg Droperidol
`= 12.4 mg Droperidol Lactate
`
`Tablet Process:
`
`The ingredients of 1,000 tablets
`
`(30.23 g
`
`for 0.1 mg formulation and 42.6 g for 10 mg formulation)
`
`are blended in a suitable mixer and then compressed into
`
`tablets. Tablets are packaged into bottles or individual
`
`blister strips.
`
`15
`
`20
`
`
`
`

`
`W0 99/40900
`
`PCT/US99/03059
`
`EXAMPLE 8 - Buccal Tablet Formulation
`
`18
`
`INGREDIENT
`
`0 . 1 mg/
`Tablet
`
`10 mg/
`Tablet
`
`(mg)
`Droperidol
`Spray Dried Lactose (mg)
`Hydroxypropylmethylcellulose (mg)
`Sucrose (mg)
`Taragacanth (mg)
`Magnesium stearate (mg)
`
`0.1
`10
`20
`l0
`5
`0.3
`
`10
`20
`30
`10
`10
`0.5
`
`Total Weight/Tablet
`
`45.4 mg
`
`80.5 mg
`
`Tablet Process:
`
`The ingredients of 1,000 tablets (45.4 g
`
`of the 0.1 mg formulation and 80.5 g of the 10 mg
`
`5
`
`formulation) are blended in a suitable mixer and
`
`compressed into tablet by using flat faced punches and
`
`die.
`
`The tablets are filled into bottles or individual
`
`blister strips.
`
`10
`
`EXAMPLE 9 - Sublingual Solution Formulation
`
`INGREDIENT
`
`0.1 mg/0.1 ml
`
`10 mg/0.5 ml
`
`(mg)
`Droperidol
`to pH
`Lactic acid qs.
`Citrus flavor (mg)
`Sucrose (mg)
`Sodium benzoate (mg)
`Water qs. ad.
`(ml)
`
`Total Weight:
`
`0.1
`3.5
`0.1
`l0
`0.1
`0.1
`
`10
`3.5
`0.2
`15
`0.2
`0.5
`
`0.1 ml
`
`(0 1 9)
`
`0.5 ml
`
`(0 5 9)
`
`Solution process:
`
`In a suitable vessel, droperidol
`
`is dissolved with lactic acid with pH adjusted to about
`
`3.5 in sufficient quantity of water.
`
`The remaining
`
`15
`
`ingredients are then added and dissolved. Sufficient
`
`water is then added for l,0OO units (100 ml for 0.5 mg
`
`formulation and 500 ml for 10 mg formulation).
`
`The
`
`solution is filtered and put into bottles equipped with a
`
`dropper to allow the solution to be placed accurately
`
`20
`
`und