(12) United States Patent
`Sonne
`
`US006193985B1
`US 6,193,985 B1
`*Feb. 27, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) TOCOPHEROL COMPOSITIONS FOR
`DELIVERY OF BIOLOGICALLY ACTIVE
`AGENTS
`
`(75) Inventor: Mette Rydahl Sonne, Brondby Strand
`(BK)
`(73) Assignee: A/S DumeX (DumeX Ltd), Copenhagen
`(BK)
`
`(*) Notice:
`
`This patent issued on a continued pros
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the tWenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. N0.: 08/856,054
`(22) Filed:
`May 14, 1997
`
`Related US. Application Data
`
`(63) Continuation of application No. 08/441,759, ?led on May
`16, 1995, now abandoned.
`Foreign Application Priority Data
`
`(30)
`
`May 16, 1994
`
`(GB) ................................................ .. 9409778
`
`(51) Int. Cl.7 ............................ .. A61K 9/00; A61K 9/107
`(52) US. Cl. ........................ .. 424/400; 424/439; 424/484;
`424/486; 514/772
`(58) Field of Search ................................... .. 424/439, 450,
`424/485, 486, 400, 484; 514/772
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3/1984 Peat.
`4,439,432
`4,628,052 * 12/1986 Peat .................................... .. 514/171
`4,847,072 * 7/1989 Bissett et al. ........................ .. 424/59
`4,863,720
`9/1989 Burghart et al. .
`4,950,664
`8/1990 Goldberg.
`4,960,814
`10/1990 Wu et al. .
`5,179,122 * 1/1993 Greene et al. ..................... .. 514/458
`5,364,631 * 11/1994 Janoff et al. .... ..
`..
`5,430,021 * 7/1995 Rudnic et al. ....................... .. 514/14
`
`FOREIGN PATENT DOCUMENTS
`
`70937/91
`3405240
`0 001 851 A1
`0387647
`0514967
`0539215
`0572190
`0636618
`WO 86/04233
`W0 89/03689
`W0 91/14463
`W0 91/16929
`W0 93/03720
`W0 93/18752
`W0 93/21905
`W0 94/20143
`W0 95/01785
`W0 95/11039
`W0 95/24892
`W0 95/30420
`
`8/1991 (AU).
`8/1985 (DE).
`5/1979 (EP).
`9/1990 (EP).
`11/1992 (EP).
`4/1993 (EP).
`12/1993 (EP).
`2/1995 (EP).
`7/1986 (W0).
`5/1989 (W0).
`10/1991 (W0).
`11/1991 (W0).
`3/1993 (W0).
`9/1993 (W0).
`11/1993 (W0).
`9/1994 (W0).
`1/1995 (W0).
`4/1995 (W0).
`9/1995 (W0).
`11/1995 (W0).
`
`OTHER PUBLICATIONS
`
`Sokol et al.; “Improvement of cyclosporin absorption in
`children after liver transplantation by means of Water
`—soluble vitamin E”; The Lancet; vol. 338: Jul. 27, 1991;
`pp.212—215.
`Lau et al.; “Absorption of diaZepam and loraZepam folloW
`ing intranasal administration”; International Journal of
`Pharmaceutics; 54 (1989) pp. 171—174.
`Ismailos et al.; “Enhancement of cyclosporin A solubility by
`d—alphatocopheryl—polyethylene—glycol—1000
`succinate
`(TPGS)”; European Journal of Pharmaceutical Sciences, 1
`pp. 269—271(May 1994).
`
`* cited by examiner
`
`Primary Examiner—Jeffrey C. Mullis
`(74) Attorney, Agent, or Firm—Watov & Kipnes, P.C.;
`Allen R. Kipnes
`
`(57)
`
`ABSTRACT
`
`The present invention provides the use of a tocopherol or a
`derivative thereof as a solvent and/or emulsi?er for substan
`tially insoluble and sparingly soluble biologically active
`agents, especially in the manufacture of pharmaceutical
`compositions. Such compositions are particularly suitable
`for transmucosal, and especially intranasal or rectal
`administration, or administration via the oral cavity.
`
`24213/88
`
`3/1989 (AU) .
`
`30 Claims, 2 Drawing Sheets
`
`AQUESTIVE EXHIBIT 1013 page 0001
`
`

`

`U.S. Patent
`
`Feb. 27, 2001
`
`Sheet 1 of2
`
`US 6,193,985 B1
`
`
`
`939v .028
`
`60
`
`120
`180
`TIME (min)
`
`240
`
`300
`
`+ DESMETHYL-DIAZEPAM
`-~l— DIAZEPAM
`
`FIG. 1
`
`AQUESTIVE EXHIBIT 1013 page 0002
`
`

`

`U.S. Patent
`
`Feb. 27, 2001
`
`Sheet 2 of2
`
`US 6,193,985 B1
`
`20v
`
`15~
`
`10
`
`
`
`CONC. (ng/ ml)
`
`0
`
`60
`
`120 180 240 300
`TIME (min)
`
`+ DIAZEPAM
`—l— DESMEIHYL-DIAZEPAM
`
`FIG. 2
`
`AQUESTIVE EXHIBIT 1013 page 0003
`
`

`

`US 6,193,985 B1
`
`1
`TOCOPHEROL COMPOSITIONS FOR
`DELIVERY OF BIOLOGICALLY ACTIVE
`AGENTS
`
`This is a continuation application of US. Ser. No.
`08/441,759 ?led on May 16, 1995 noW abandoned.
`The present invention is directed to neW pharmaceutical
`compositions for delivery of biologically active agents.
`More particularly, the invention concerns the use of a
`tocopherol or a derivative thereof to prepare compositions
`having loW irritability suitable for administration to mucosal
`membranes and Which may be used ef?ciently to administer
`drugs, Which are substantially insoluble or only sparingly
`soluble in Water.
`For systemic action, drugs are normally administered by
`mouth and are then absorbed in the gastrointestinal tract.
`HoWever, this mode of administration is not suitable in all
`circumstances, for example in the case of drugs Which are
`metabolised to any signi?cant degree by the liver or Which
`are poorly absorbed. In other cases, the oral route may be
`impractical, for example in patients suffering from nausea or
`Who are unconscious. Before surgery, oral administration is
`not advisable because of the risk of vomiting and in many
`cases, a more rapid effect may be required than can be
`achieved by the oral route.
`In these circumstances the parenteral route is frequently
`used, most notably intravenous or intramuscular injection.
`HoWever, Whilst this provides a convenient Way of achiev
`ing a strong and rapid systemic effect, it has a number of
`disadvantages including the requirement for sterile equip
`ment and trained personnel. It is also unpleasant to the
`patient.
`Moreover, in cases Where a systemic effect is not
`required, local administration may be preferable, for
`example to avoid side effects, to reduce the dosage, or
`simply to facilitate the administration.
`Such problems have lead in recent years to an increasing
`interest in developing formulations for the topical adminis
`tration of drugs, and in particular for topical administration
`involving absorption from mucous membranes.
`Topical administration has the advantage that drugs may
`be administered readily and simply to achieve a systemic or
`dermal, regional or localised effect, as required. HoWever,
`topical absorption of drugs through the skin can be sloW, and
`in many cases transmucosal routes of delivery are preferred.
`Since it may be performed by untrained personnel and
`permits therapeutic plasma levels of drugs rapidly to be
`achieved, intranasal administration has received particular
`attention in this regard.
`For topical delivery, biologically active drugs are nor
`mally administered in the form of aqueous solutions.
`HoWever, many biologically active compounds are substan
`tially insoluble or only sparingly soluble in Water and in such
`cases, organic solvents are required to dissolve these agents.
`The problem here is that mucosal tissues are generally very
`sensitive and such solvents are frequently too irritant to be
`of clinical use. Thus for example, Lau and Slattery [Int. J.
`Pharm. 1989, p. 171—74] attempted to administer the ben
`ZodiaZepines diaZepam and loraZepam by dissolving these
`compounds in a range of solvents including: triacetin,
`DMSO, PEG 400, Cremophor EL, Lipal-9-LA, isopropyla
`dipate and aZone dodecyle-aZa-cycloheptane-2-one. Whilst
`many of the solvents dissolved diaZepam and loraZepam in
`the desired concentrations, When administered to the nose
`they Were too irritant to be of use. Thus, Cremophor EL Was
`found to be the least irritative for mucosal tissue, but nasal
`absorption using this solvent is rather sloW and peak con
`centration is loW relative to that found after iv. administra
`tion.
`
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`Triglycerides such as vegetable oils are generally non
`irritant, but usually these oils are too poor as solvents to be
`of any use.
`Attempts have been made to develop various other
`vehicles for transmucosal delivery of drugs, such as
`benZodiaZepines, having limited Water solubility. Thus, for
`example WO 86/04233 of Riker discloses a pharmaceutical
`composition Wherein the drug (eg. diaZepam) is dissolved in
`a mixture of propellant and co-solvent eg. glycerolphos
`phatide. The composition requires a pressuriZed system and
`at least one halogenated hydrocarbon aerosol propellant.
`In US. Pat. No. 4,863,720 of Burghardt, a sublingual
`sprayable pharmaceutical preparation is disclosed, in Which
`the active drug can be a benZodiaZepine, optionally com
`prising polyethylene glycol (PEG) and requiring ethanol, di
`and/or triglyceride of fatty acids and a pharmaceutically
`acceptable propellant gas.
`US. Pat. No. 4,950,664 of Rugby-Darby describes the
`nasal administration of benZodiaZepines in a pharmaceuti
`cally acceptable nasal carrier. The carrier may be a saline
`solution, an alcohol, a glycol, a glycol ether or mixtures
`thereof.
`In PCT WO 91/16929 of Novo Nordisk, glycofurols or
`ethylene glycols are suggested as carriers for a variety of
`drugs, including benZodiaZepines, Which may be used on
`mucous membranes.
`Another solution proposed to this problem, has been the
`use of micelles or liposomes, but these are frequently
`dif?cult to produce on a technical scale.
`A further constraint concerning nasal administration is
`that a small administration volume is required; it is not
`generally possible to administer more than about 0.1 ml per
`dose per nostril. Therefore, a great need exists for solvents,
`in Which, on the one hand the solubility of the active drug
`is high, and Which, on the other hand, are non-irritating to
`the mucosa.
`The aim of the present invention is to provide a solution
`to the above mentioned problems.
`Tocopherols and their derivatives such as esters for
`example, are Widely used in vitamin supplementation and as
`antioxidants in the food industry and in many pharmaceu
`tical compositions. HoWever, although in a feW cases, a
`potential use in formulating pharmaceutical compositions
`has been reported, tocopherols and derivatives thereof have
`not generally previously been proposed as drug carriers.
`Thus for example, European Patent Application No.
`539,215 of Stafford-Miller suggests a possible use of Vita
`min E and its derivatives as penetration enhancers in topical
`compositions.
`WO 89/03689 of The Liposome Co., describes a lipo
`some system based on acid derivatives of ot-tocopherol in a
`loW pH aqueous medium for delivery of drugs Which
`tolerate, or require, acid conditions.
`The present invention is based on the surprising obser
`vation that tocopherols and derivatives thereof are excellent
`solvents for drugs Which are substantially insoluble or
`sparingly soluble in Water, Whilst at the same time having a
`very loW irritative potential for mucosal tissues.
`As Will be described in more detail beloW, it has also
`been found that certain tocopherol derivatives are efficient,
`non-irritant emulsi?ers for such drugs, When dissolved in a
`tocopherol-based solvent.
`In one aspect, the present invention thus provides the use
`of a tocopherol or a derivative thereof as a solvent and/or
`emulsi?er for substantially insoluble and sparingly soluble
`biologically active agents, especially in the manufacture of
`pharmaceutical compositions.
`
`AQUESTIVE EXHIBIT 1013 page 0004
`
`

`

`US 6,193,985 B1
`
`10
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`3
`A further aspect of the invention provides a composition
`for delivery of a substantially insoluble or sparingly soluble
`biologically active agent, comprising said agent dissolved in
`a tocopherol or a derivative thereof.
`Tocopherols are a range of natural and synthetic
`compounds, also knoWn by the generic term Vitamin E.
`ot-Tocopherol (chemical name: 2,5,7,8-tetramethyl-2-(4‘,8‘,
`12‘-trimethyldecyl)-6-chromanole) is the most active and
`Widely distributed in nature, and has been the most Widely
`studied. Other members of the class include beta, gamma,
`and delta tocopherols but these are not used in pure form in
`therapeutics, although they are present in foodstuffs. Toco
`pherols occur in a number of isomeric forms, the D and DL
`forms being most Widely available.
`As used herein, the term “tocopherol” includes all such
`natural and synthetic tocopherol or Vitamin E compounds.
`The melting point of natural ot-tocopherol is betWeen 2.5
`and 35° C. ot-Tocopherol is a viscous oil at room
`temperature, is soluble in most organic solvents, but
`insoluble in Water.
`Although tocopherols are available naturally in food
`stuffs and may be extracted from plants, ot-tocopherol is noW
`mainly produced synthetically.
`Any of the forms or isomers of tocopherols and their
`derivatives, eg. esters may be used according to the present
`invention. Thus for eXample, ot-tocopherol can be used as
`such or in the form of its esters such as ot-tocopherol acetate,
`linoleate, nicotinate or hemi succinate-ester, many of Which
`are available commercially.
`A special article of commerce is called TenoX GT-2 and
`consists of 70% tocopherol of natural origin, Which has been
`concentrated from vegetable oil. This oil has a mild odour
`and a gentle taste.
`The compositions of the present invention are particu
`larly suited for application to mucous membranes in animals
`or humans, to deliver systemically substantially insoluble or
`sparingly soluble biologically active agents in a manner
`Which ensures that a clinical effect is reached at least as
`rapidly as by conventional oral administration, With for
`instance tablets.
`Thus, the compositions of the invention may be used for
`controlled release delivery of bioactive agents to achieve a
`bene?cial or therapeutic effect over a prolonged period of
`time.
`The compositions of the invention may also be applied to
`achieve a local effect, Where desired, on the mucous mem
`branes or the underlying tissue.
`HoWever, Whilst the bene?cial effects of the invention
`are particularly apparent in transmucosal delivery, the utility
`of the invention is not limited and compositions according to
`the invention may also be administered topically to all body
`surfaces, including the skin and all other epithelial or serosal
`surfaces, as Well as parenterally or enterally, eg. as implants
`or by intravenous, intramuscular or subcutaneous injection,
`by infusion, or orally.
`Transmucosal delivery is preferred hoWever, and com
`positions according to the invention may be administered to
`mucosal membranes for eXample in the nose, vagina,
`rectum, ears, eyes, oral cavity, lungs, genito-urinary tracts,
`and gastro-intestinal tract. Nasal, rectal and oral cavity
`administrations are particularly preferred.
`The compositions of the invention may be used directly
`as solutions of the bioactive agent in the tocopherol solvent.
`HoWever such solutions are viscous, and the viscosity may
`be too high for certain applications, for eXample to achieve
`a sprayable formulation for nasal application.
`Viscosity can be reduced by addition of co-solvents such
`as ethanol, but this is less desired, since solutions of this kind
`tend to be irritating to certain mucosal tissues.
`
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`Alternatively, the tocopherol solutions may be
`emulsi?ed, to obtain formulations of loWer viscosity. This
`may be achieved in knoWn manner, by miXing the
`tocopherol-based “oil phase” containing the dissolved bio
`active agent With an appropriate aqueous phase, eg. Water,
`saline or buffer solutions.
`Methods and appropriate aqueous media for obtaining
`emulsions are Well knoWn in the art and described in the
`literature. Emulsions according to the invention may be
`oil-in-Water (O/W) or Water-in-oil (W/O) emulsions. Gen
`erally speaking, O/W emulsions may be achieved When the
`oil phase contains up to about 70% lipids. W/O emulsions
`are formed When the oil phase exceeds ca. 70%.
`For nasal administration, due to the small administration
`volume required, it has generally been found that a high
`concentration of the oil (or lipid) phase is required. Emul
`sions With high lipid content are technically dif?cult to
`achieve and may be unstable. It may therefore be necessary
`to employ an emulsi?er in order to form a stable emulsion.
`AWide range of emulsi?ers are Well knoWn, both in the food
`and pharmaceutical arts, and are Widely described in the
`literature. HoWever, stability and viscosity may still be a
`problem, Where very high contents of the oil phase are
`required. Moreover, some of the more Widely available
`commercial emulsi?ers, eg. phospholipids, polysorbates or
`various sorbitan esters of fatty acids may be irritating to the
`more sensitive mucosal tissues, such as those of the nose.
`The inventors have surprisingly found hoWever that
`tocopherol derivatives, particularly certain esters, may
`themselves form efficient, non-irritating emulsi?ers to
`enable stable emulsions to be formed, even Where high lipid
`levels are involved eg. about 50—70%. Particular mention
`may be made in this regard of Vitamin E TPGS Which is a
`Water soluble derivative of Vitamin E and consists of
`ot-tocopherol, Which is esteri?ed With succinic acid, the
`other acidic group of the latter being esteri?ed With poly
`ethylene glycol 1000. Vitamin E TPGS is an almost odour
`less Waxy amphiphilic substance With a molecular Weight
`about 1513. The melting point is about 36° C. and its
`solubility in Water is about 20%.
`Stable emulsions may readily be achieved according to
`the invention using a range of tocopherols or derivative
`compounds as solvents, With Vitamin E TPGS as emulsi?er,
`and any suitable aqueous medium.
`A further aspect of the invention thus provides a com
`position suitable for delivery of substantially insoluble or
`sparingly soluble biologically active agents, comprising a
`tocopherol or a derivative thereof, and Vitamin E TPGS as
`emulsi?er.
`The tocopherol derivative emulsi?er of the invention
`may be used alone or in conjunction With other knoWn
`emulsi?ers eg. phospholipids, polysorbates, sorbitan esters
`of fatty acids, cetearyl glucoside or poloXamers.
`It has furthermore surprisingly been shoWn that various
`other solvents may be used in the emulsion system described
`above, Without compromising the stability of the emulsion.
`When the emulsion according to the present invention is
`of the oil-in-Water type, it is desirable that the droplet siZe
`is as small as possible. It has been shoWn that by using
`systems according to the invention, for eXample,
`ot-tocopherol, Water, Vitamin E TPGS and bioactive agent,
`it is possible to form stable emulsions With an initial droplet
`siZe in the range 0.01—100 pm, preferably 0.01—50 pm, most
`preferably 0.1—20 pm.
`The compositions Which may be prepared according to
`the present invention, may contain any biologically active
`agent Which is insoluble or sparingly soluble in Water, ie.
`
`AQUESTIVE EXHIBIT 1013 page 0005
`
`

`

`US 6,193,985 B1
`
`5
`With a solubility in Water (W/v) Which is 3% or less. For
`example such agents may include any bioactive agent Which
`has less than 1% (W/v) solubility in Water. Representative
`active agents from a range of different therapeutic groups are
`listed beloW, by Way of exempli?cation.
`Hormones and hormone-like substances of the steroid
`group:
`Corticosteroids such as cortisone, hydrocortisone,
`prednolone, prednisolone, triamcinolone acetonide,
`dexamethasone, ?unisolide, budesonide, toxicorole
`pivalate, betametasone, beclomethasone dipropionate,
`?uticasone etc;
`Sex-hormones such as: estradiol, progesterone, testosterone
`etc;
`Antibiotics: Tetracyclines such as tetracycline, doxycycline,
`oxytetracycline, chloramphenicol etc; Macrolides such as
`erythromycin and derivatives, etc;
`Antivirals: such as acyclovir, idoxuridine, tromantadine etc;
`Antimycotics: MiconaZole, ketoconaZole, ?uconaZole,
`itraconaZole, econaZole, terconaZole, griseofulvin, and
`polyenes such as amphotericin B or nystatine etc;
`Anti-amoebics: MetronidaZole, metronidaZole benZoate and
`tinidaZole etc;
`Anti-in?ammatory drugs: NSAID’s such as indomethacin,
`ibuprofen, piroxicam, diclofenac etc;
`Anti-allergics: Disodium cromoglycate etc;
`Immunosuppressive agents: cyclosporins etc;
`Coronary drugs: including vasodilators such as
`nitroglycerin, isosorbide dinitrate, Calcium-antagonists
`such as verapamile, nifedipine and diltiaZem, Cardiac
`glycosides such as digoxine.
`Analgesics: eg. morphine, buprenorphine, etc;
`Local anaesthetics: eg. lidocaine, etc;
`Anxiolytics, sedatives & hypnotics: diaZepam, nitraZepam,
`?uraZepam, estaZolam, ?unitraZepam, triaZolam,
`alpraZolam, midaZolam, temaZepam, lormetaZepam,
`brotiZolam, clobaZam, clonaZepam, loraZepam,
`oxaZepam, buspirone, etc;
`Migraine relieving agents: sumatriptan, ergotamines and
`derivatives etc;
`Drugs against motion sickness: eg. cinnariZine, anti
`histamines, etc;
`Anti-emetics: eg. ondansetron, tropisetron, granisetrone,
`metoclopramide, etc.
`Others: such as disul?ram, vitamin K, etc.
`The emulsions according to the present invention are
`especially suitable for nasal application because of their loW
`index of irritability and are therefore particularly Well suited
`to the delivery of biologically active drugs in?uencing the
`central nervous system (CNS).
`Other biologically active agents Which may be used
`include peptides, hormones, etc. The active substance may
`be present in an amount of from about 0.0001% to 50% of
`the total composition, preferably 0.001% to 40% (W/W).
`Generally speaking compositions of the invention may
`contain from 1 to 99.99% (W/W), preferably 20 to 99.99%,
`most preferably 40 to 99.99% (W/W) of the tocopherol or
`tocopherol derivative solvent. The emulsion used in com
`positions of the invention may contain 1 to 95% (W/W) of the
`tocopherol or derivative thereof, preferably 20 to 95%
`(W/W), most preferably 35 to 80% (W/W).
`As mentioned above, the emulsions of the present inven
`tion can be prepared by conventional means, by heating the
`oil and aqueous phases separately, and then mixing the tWo
`phases. The active ingredient can be dissolved in the lipid
`fraction of the tocopherol solvent and other solvents may be
`added if desired. The emulsi?er, eg. Vitamin E TPGS, and
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`optionally other emulsi?ers, can be added to either the oil
`and/or the Water phase. The Water phase is then vigorously
`mixed With the oil phase. Mixing, eg. stirring may be
`continued as required eg. for up to 2 hours. Depending on
`the viscosity of the emulsion, a magnetic stirrer, a loW shear
`mixer or the like can be used. If necessary, the emulsion can
`be processed by a loW shear mixer and a high pressure
`homogeniZer to achieve the desired droplet siZe. The for
`mulations may be inspected microscopically to measure the
`droplet siZe and to be sure that no precipitation has taken
`place. The type of emulsion formed may be determined
`readily by a colour test using an oil- and/or Water-soluble
`dye. To con?rm the result, it may be examined Whether the
`emulsion is easy to Wash off With Water or not. An O/W
`emulsion is coloured With the Water-soluble dye and is very
`easy to Wash off With Water. A W/O emulsion is coloured
`With the oil-soluble dye and is very dif?cult to Wash off With
`Water.
`In a further aspect, the present invention thus provides a
`method of preparing a composition for delivery of a sub
`stantially insoluble or sparingly soluble biologically active
`agent, said method comprising dissolving said agent in an
`amount of a tocopherol or a derivative thereof, suf?cient to
`dissolve said agent.
`In a preferred aspect, the method of the invention further
`comprises forming an emulsion of said tocopherol/
`biologically active agent solution, by mixing With an aque
`ous phase, optionally in the presence of an emulsi?er,
`preferably vitamin E TPGS.
`The compositions of the invention may take any of the
`conventional pharmaceutical forms knoWn in the art, and
`may be formulated in conventional manner, optionally With
`one or more pharmaceutically acceptable carriers or excipi
`ents. Thus for example the compositions may take the form
`of ointments, creams, solutions, salves, emulsions, lotions,
`liniments, aerosols, sprays, drops, pessaries, suppositories,
`tablets, capsules or loZenges.
`In a still further aspect, the present invention provides the
`use of a tocopherol or a derivative thereof for the preparation
`of a composition for delivery of a substantially insoluble or
`sparingly soluble biologically active agent to a human or
`non-human animal subject.
`Alternatively vieWed, the invention can be seen to provide
`a method of treatment of a human or non-human animal
`subject by delivery of a substantially insoluble or sparingly
`soluble biologically active agent, said method comprising
`administering to said subject a composition of the invention
`as hereinbefore de?ned.
`The formulations according to the invention may be
`optimiZed With respect to bioadhesion, sprayability and
`viscosity, as desired. Thus for example, the folloWing
`co-solvents may be added:
`Vegetable oils such as sesame- or olive- or fractionated
`coconut oil, alcohols such as ethanol, propylene glycol,
`glycerol, polyethylene glycol or benZyl alcohol; or triacetin.
`To optimiZe the stability of the emulsions, it may be
`appropriate to add surfactants such as Vitamin E TPGS
`poloxamers (eg. Pluronic®), cetearyl glucoside, polysor
`bates or sorbitan esters of fatty acids, or any of the other
`surfactants Well knoWn in the art, or other stabilisers such as
`xanthan gum, or propylene glycol alginate.
`It is also possible to enhance the bioadhesive properties of
`the formulations according to the present invention by
`addition of bioadhesive polymers such as:
`polyacrylic polymers such as carbomer and carbomer
`derivatives, eg. Polycarbophil or Carbopol etc;
`cellulose derivatives such as hydroxymethyl-cellulose,
`hydroxyethylcellulose, hydroxypropyl-cellulose or
`sodium carboxymethylcellulose etc;
`
`AQUESTIVE EXHIBIT 1013 page 0006
`
`

`

`US 6,193,985 B1
`
`7
`natural polymers like gelatin, sodium alginate, pectin etc;
`more generally, any physiologically acceptable polymer
`shoWing bioadhesive characteristics may be used.
`To ensure that the formulations have a reasonable shelf
`life it may be desirable to include preservatives such as
`benZalkonium chloride, sodium edetate, sorbic acid, potas
`sium sorbate, phenoxyethanol, phenetanol, parabens or oth
`ers knoWn in the art. Addition of odour- or taste-masking
`compounds can also be desirable.
`The invention Will noW be described in more detail in the
`folloWing non-limiting Examples, With reference to the
`draWings in Which:
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph shoWing mean serum concentrations
`(ng/ml) against time (minutes) after intranasal administra
`tion of 2.5 mg diaZepam (Formulation C) -A- Desmethyl
`diaZepam -I- DiaZepam;
`FIG. 2 is a graph shoWing mean serum concentrations
`(ng/ml) against time (minutes) after oral administration of
`2.0 mg diaZepam (Formulation D) -I- DesmethyldiaZepam
`-§- DiaZepam;
`
`10
`
`15
`
`20
`
`EXAMPLES
`As already mentioned, administration of drugs With very
`loW Water solubility to the nose is difficult, because of the
`limited volume Which is acceptable for the nose (about 100
`pl). The ?rst example has a very high concentration of
`diaZepam, and it is possible to administrate diaZepam to the
`nose and to achieve a rapid clinical effect.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Example 1
`A diaZepam nosedrop preparation is made as follows:
`(100 g)
`5 g of diaZepam is mixed With 44 g of Tenox GT2, and 22
`g of triacetin, and 5 g of Vitamin E TPGS. The oil phase is
`heated sloWly to a homogeneous phase is achieved. To the
`Water phase, 1.45 g of Pluronic F-68 (poloxamer 188) and
`0.01 g of benZalkonium chloride are added, the Water phase
`is heated sloWly to a homogeneous phase is achieved. The
`Water phase is vigorously mixed into the oil phase by using
`a magnetic stirrer. Thereafter, the emulsion is cooled to room
`temperature still on the magnetic stirrer. The emulsion Was
`a pale yelloW o/W emulsion, Where the mean droplet siZe
`Was about 1—2 pm.
`This formulation (1) Was tested in 8 rabbits in a random
`iZed cross-over study compared With a commercially avail
`able diaZepam formulation, Stesolido 5mg/ml for injection,
`(2)
`Formulation 1 Was given intranasally (in) With a Eppen
`dorf Multipette® 4780. Each rabbit Was held in a supine
`position during and one minute after in. dosing in one
`nostril. The rabbits receive a volume that equals 2 mg
`diaZepam, 40% of formulation 1. After each administration
`the actual dose received is estimated by visual inspection of
`the pipette tip and the rabbit nostrils. Only applications
`volumes estimated to 80% are accepted.
`Formulation 2 Was given as an ear-vein infusion during M
`minute. The rabbits received 0.4 ml Stesolid® 5 mg/ml
`(equals 2 mg diaZepam). The rabbits Were placed in a supine
`position for half a minute to attain the same experimental
`conditions as for in. dosing.
`The rabbits Were then tested With respect to pharmaco
`dynamic response in the folloWing Way:
`Hind legs to one side and the rabbit must stay in this
`position even after a ?rm tip With a ?nger on the hip.
`
`8
`The test is immediately repeated With both legs placed
`on the other side.
`The rabbits Were tested approximately once per minute
`until positive pharmacodynamic response, and thereafter
`tested every 2 minutes. Total test period is 20 minutes. The
`same person has dosed and tested all the rabbits in the
`present study.
`The time to pharmacodynamic response is 4.4 minutes
`(mean, n=8) using formulation 1 and 1.6 minutes (mean,
`n=8) using formulation 2.
`Example 2
`A diaZepam nosedrop preparation is made as folloWs:
`(100 g)
`5 g of diaZepam is mixed With 45.4 g of Tenox GT2, and
`22.7 g of triacetin, and 15 g of Vitamin E TPGS. The oil
`phase is heated sloWly to a homogeneous phase is achieved.
`To the Water phase, 1.45 g of Pluronic F-68 (poloxamer 188)
`and 0.01 g of benZalkonium chloride are added, the Water
`phase is heated sloWly to a homogeneous phase is achieved.
`The Water phase is vigorously mixed to the oil phase by
`using a magnetic stirrer. Thereafter, the emulsion is cooled
`to room temperature still on the magnetic stirrer. The emul
`sion is a clear orange W/o emulsion.
`A less concentrated formulation of diaZepam is required
`for the rectal administration, but still it can be very difficult
`to ?nd an acceptable vehicle With loW irritation.
`Example 3
`A diaZepam enema preparation is made as folloWs: (100
`g)
`1 g of diaZepam is mixed With 40 g of (-tocopherol, and
`15 g of Vitamin E TPGS. The oil phase is heated sloWly to
`a homogeneous phase is achieved. 5 g of ethanol is added to
`the oil phase immediately before mixing With the Water
`phase. To the Water phase, 2.5 g of Pluronic F-68 (poloxamer
`188), and 0.01 g of benZalkonium chloride, and 0.05 g of
`disodium edetate are added, the Water phase is heated sloWly
`to a homogeneous phase is achieved. The Water phase is
`vigorously mixed to the oil phase by using a magnetic stirrer.
`Thereafter, the emulsion is cooled to room temperature still
`on the magnetic stirrer. The emulsion is a White o/W emul
`sion.
`CinnariZine is used for motion sickness. Like diaZepam,
`the drug has a very loW Water solubility. It Will be a great
`advantage if the patient can administer the drug easily and
`have a rapid effect.
`
`Example 4
`A cinnariZine nosedrop formulation is made as folloWs:
`(100 g)
`5 g of cinnariZine is mixed With 64 g of ot-tocopherol, and
`8 g of Vitamin E TPGS. The oil phase is heated sloWly to a
`homogeneous phase is achieved. To the Water phase, 1.5 g
`of Pluronic F-68 (poloxamer 188), and 0.01 g of benZalko
`nium chloride, and 0.05 g of disodium edetate are added, the
`Water phase is heated sloWly to a homogeneous phase is
`achieved. The Water phase is vigorously mixed to the oil
`phase by using a magnetic stirrer. Thereafter, the emulsion
`is cooled to room temperature still on the magnetic stirrer.
`The emulsion is a White o/W emulsion.
`MiconaZole is used for the local treatment of infections
`caused by fungi. The next tWo formulations shoW formula
`tions for use in the oral cavity and the vagina.
`Example 5
`A miconaZole preparation for the oral cavity is made as
`folloWs: (100 g)
`
`60
`
`65
`
`AQUESTIVE EXHIBIT 1013 page 0007
`
`

`

`US 6,193,985 B1
`
`9
`20 g of miconaZole is mixed With 58.8 g of ot-tocopherol,
`and 13 g of Vitamin E TPGS. The oil phase is heated slowly
`to a homogeneous phase is achieved. 5 g of ethanol is added
`to the oil phase immediately before mixing With the Water
`phase. To the Water phase, 1.5 g of Pluronic F-68 (poloxamer
`188), and 0.01 g of benZalkonium chloride, and 0.05 g of
`disod