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`
`US 20050153956A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2005/0153956 A1
`Merkus
`(43) Pub. Date:
`Jul. 14, 2005
`
`(54) PHARMACEUTICAL COMPOSITIONS
`COMPRISING MIDAZOLAM IN A HIGH
`CONCENTRATION
`
`(76) Inventor: Franciscus Wilhelmus Henricus
`Maria Merkus, Kasterlee (BE)
`
`Correspondence Address;
`Leopold Presser, Scully,
`Scott, Murphy & Presser
`P]aZa_Ste_300
`400 Garden City
`Garden City, NY 11530 (Us)
`
`(21) Appl, No;
`
`11/034,474
`
`(22) Filed:
`
`Jan. 13, 2005
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 14, 2004 (GB) ................................ .. GB 0 400 804
`
`Publication Classi?cation
`
`(51) Int. Cl.7 .............................................. .. A61K 31/5513
`(52) US. Cl. ............................................................ .. 514/221
`
`ABSTRACT
`(57)
`Compositions of midaZolam, a benZodiaZapine, in concen
`trations of 35-100 mg/ml are disclosed for the treatment of
`anxiety, epilepsy and epileptic seizures, invasive surgical
`procedures and diagnostic procedures and sedation. These
`compositions are particularly characterized by a solubiliZer
`such an propylene glycol. Preferably, the compositions are
`aqueous solutions for intranasal administration.
`
`AQUESTIVE EXHIBIT 1021 page 0000
`
`

`

`US 2005/0153956 A1
`
`Jul. 14, 2005
`
`PHARMACEUTICAL COMPOSITIONS
`COMPRISING MIDAZOLAM IN A HIGH
`CONCENTRATION
`
`FIELD OF THE INVENTION
`
`[0001] The present invention relates to the administration
`of benZodiaZepines such as midaZolam. In particular, the
`invention provides improved midaZolam compositions for
`intranasal administration comprising high concentrations of
`midaZolam.
`
`DISCUSSION OF THE PRIOR ART
`
`[0002] MidaZolam is a potent benZodiaZepine derivative
`With sedative, anXiolytic, hypnotic, amnesic, anticonvulsant
`and muscle relaXant pharmacological properties. Because of
`the basicity of this molecule, it is possible to prepare salts
`(e.g., With hydrochloric, maleic and lactic acid) Which are
`soluble in Water. From these salts, stable aqueous solutions
`With a pH of 3.5 can be made for intravenous and intramus
`cular injections of midaZolam (Smith et al., 1981; Gerecke,
`1983; Persson et al., 1988). FolloWing administration by
`injection, midaZolam is characteriZed by a fast onset of
`action as Well as short duration of action, due to its rapid
`metabolic inactivation by liver enZymes. MidaZolam is
`about tWice as potent as the classical benZodiaZepine diaZ
`epam (Randell and Kytta, 1998).
`[0003] For drug administration in general, the oral route is
`probably the most popular route. HoWever, this mode of
`administration is not suitable for midaZolam, as orally
`delivered midaZolam is extensively degraded by ?rst-pass
`elimination and has also been found to be a substrate for the
`intestinal drug ef?ux transporter (Allonen et al., 1981;
`Crevoisier et al., 1983; Tolle-Sander et al., 2003). The oral
`absorption of midaZolam is therefore relatively loW and
`variable, With absolute bioavailabilities ranging from just 15
`to 27% in children (Payne et al., 1989) and from 31 to 72%
`in healthy adults (Allonen et al., 1981; HeiZmann et al.,
`1983). Other disadvantages associated With the oral admin
`istration of midaZolam are the sloW onset of action and the
`observed loW peak plasma concentrations. These disadvan
`tages are also observed When midaZolam is administered
`rectally (Saint-Maurice et al., 1986; Malinovsky et al., 1993,
`1995).
`[0004] Rapid onset of the therapeutic action of midaZolam
`can be achieved by intravenous and intramuscular injection
`(Taylor et al., 1986; Burstein et al., 1997; Uygur-Bayramicli
`et al., 2002). HoWever, this mode of administration has a
`number of obvious disadvantages Which make it unattrac
`tive. For example, injections are painful and not Well
`accepted by the patients, particularly not by young children.
`[0005] In light of the foregoing, intranasal delivery of
`midaZolam is a very attractive alternative mode of admin
`istration.
`[0006] Intranasal drug administration is painless, results in
`rapid drug absorption and avoids hepatic ?rst-pass elimina
`tion. An additional advantage is the ease of administration,
`leading to better patient compliance. The mucosa of the
`nasal cavity is constructed from a highly vasculariZed tissue
`covered by a pseudostrati?ed columnar epithelium With
`numerous microvilli. It has a much higher permeability than
`other mucosal surfaces, including the sublingual area, vari
`
`ous regions of the gastrointestinal tract, and the buccal
`mucosa. In addition, nasal midaZolam administration results
`in pharmacokinetic and pharmacodynamic pro?les, Which
`are very similar to those observed after intravenous injec
`tions (Walbergh et al., 1991; Bjorkman et al., 1997; Burstein
`et al., 1997).
`[0007] A number of studies have been reported Which
`demonstrate the bene?cial effects of intranasally adminis
`tered midaZolam in patients, both in children and adults.
`When administered in this Way, midaZolam appears to have
`a rapid onset of action (about 10 minutes) and a relatively
`short duration of action (30 to 60 minutes).
`[0008] Nasal midaZolam at dosages of 0.2 mg/kg has been
`shoWn to have sedative and anXiolytic effects in children
`undergoing various diagnostic and minor surgical proce
`dures, and none of the children had clinical signs of respi
`ratory depression, bradycardia or other side effects (Wilton
`et al., 1988; Karl et al., 1992; Davis et al., 1995). Compa
`rable clinical results have also been published for nasal
`midaZolam in dosages of 0.3 and 0.4 mg/kg (TherouX et al.,
`1993; Malinovsky et al., 1995; Kogan et al., 2002). No
`additional bene?t is found for the midaZolam dose of 0.3
`mg/kg compared to the loWer dose of 0.2 mg/kg (Wilton et
`al., 1988; Davis et al., 1995).
`[0009] Nasal midaZolam (0.2 mg/kg) also suppresses
`acute seiZures and improves the EEG background in epilep
`tic children (O’Regan et al., 1996; Lahat et al., 1998, 2000).
`As stated by O’Regan et al., (1996): “The EEG technicians
`Welcomed the intranasal administration of benZodiaZepines.
`Their time Was no longer Wasted in Waiting for medical staff
`to achieve satisfactory intravenous access for the drugs.
`Often there is a dif?culty in siting a butter?y needle or
`cannula, causing the child to cry, become very restless, or to
`pull the leads off”. Moreover, Lahat et al. (2002) concluded
`that intranasal midaZolam could be provided not only in
`medical centres but, With appropriate instruction, by the
`parents of children With febrile seiZures at home.
`[0010] In adult patients undergoing gastrointestinal endo
`scopy, intranasal administration of midaZolam (0.1 mg/kg) is
`used for the induction of sedation and the nasal route has
`been shoWn to cause feWer side effects than intravenous
`injection (Uygur-Bayramicli et al., 2002). Nasal midaZolam
`is also effective in the short-time management of seiZures in
`adolescent and adult patients With severe epilepsy (Scheep
`ers et al., 2000). In this clinical study the midaZolam dosage
`used Was 5 and 10 mg in patients Weighing less than 50 kg
`and more than 50 kg, respectively. Case reports have also
`shoWn the sedative effect of midaZolam (0.25 mg/kg) in an
`adult patient With a seiZure disorder (Cheng, 1993) and the
`seiZure-terminating activity of nasal midaZolam (dose of 4
`mg) in an adult epileptic Woman (Kendall et al., 1997).
`[0011] While the above discussed studies have demon
`strated the ef?cacy of nasally administered midaZolam, it
`should be noted that in all clinical studies mentioned above
`the commercially available injection solutions, containing
`midaZolam at concentrations of 5 mg/ml (Dormicum®,
`Hoffmann-La Roche, SWitZerland), Were used. The use of
`solutions With this concentration of midaZolam requires very
`large volumes of liquid to be applied intranasally, ranging
`from 1 ml in children to even 4-5 ml in adults.
`[0012] When such large volumes of liquid are adminis
`tered intranasally, a large portion of the volume actually
`
`AQUESTIVE EXHIBIT 1021 page 0001
`
`

`

`US 2005/0153956 A1
`
`Jul. 14, 2005
`
`drops out of the nose and/or Will be swallowed, resulting, at
`best, in part of the dose being administered orally rather than
`nasally. This oral midaZolam absorption is clearly shoWn by
`Burstein et al. (1997). As discussed above, the orally admin
`istered midaZolam Will have a signi?cantly reduced thera
`peutic effect compared to the intranasally administered
`midaZolam.
`
`[0013] The nasal administration of such large volumes of
`solution also accounts for a number of unpleasant side
`effects sometimes experienced by patients, including lacri
`mation, burning sensations, irritation in the nose and throat,
`and general discomfort (Lugo et al., 1993; Burstein et al.,
`1997; Kogan 2002). In addition, treatment failure can occur
`due to the inadequate technique of delivering unphysiologi
`cally large volumes of the midaZolam solution (Scheepers et
`al., 2000).
`[0014] A further problem is clearly the loss of a large
`proportion of the composition and of the midaZolam, Which
`leads to inconsistent and unpredictable amounts of mida
`Zolam being absorbed.
`
`[0015] It is therefore clear that the use of commercially
`available midaZolam injection solutions for intranasal mida
`Zolam administration is inefficient and unpleasant for the
`patients, due to the necessary large volumes applied. This
`can lead to reduced nasal bioavailability and ineffective
`plasma peak concentrations of midaZolam and therefore to
`an insufficient therapeutic efficacy.
`
`[0016] For efficient and comfortable nasal drug delivery,
`volumes of about 200 pl (100 pl into each nostril) are
`normally the maximum that should be administered to a
`patient. This implies that there is an urgent need for the
`availability of nasal formulations With highly increased
`midaZolam concentrations in comparison With the mida
`Zolam injection solutions.
`
`[0017] A feW nasal midaZolam formulations have been
`developed Which seek to reduce the total volume of liquid to
`be delivered intranasally to the patients. These formulations
`are described in detail in Table 1 beloW.
`
`TABLE 1
`
`Nasal Midazolam Formulations
`
`Reference
`
`Composition
`
`Lui et al. (1991)
`
`Midazolam HCl 11.1 mg/ml
`Methocel 1.5% (W/v)
`Water
`Loftsson et al. (2001) Midazolam base 17 mg/ml
`SBEBCD 14% (W/v)
`HPMC 0.10% (W/v)
`Benzalkonium chloride 0.02% (W/v)
`EDTA 0.1% (W/v)
`Phosphoric acid 0.43% (v/v)
`Water
`Midazolam HCl 30.9 mg/ml
`Benzyl alcohol 1% (v/v) = 10.46 mg/ml
`Propylene glycol 25%
`(v/v) = 259 mg/ml
`Water
`
`Knoester et al.
`(2002a)
`
`pH
`
`about 4
`
`4.3
`
`4
`
`HPMC, hydroxypropyl methylcellulose 4000
`SBE?CD, sulfobutylether-[5-cyclodextrin sodium salt (Captisol ®)
`
`[0018] The midaZolam formulation used in Lui et al.
`(1991) is an acidic solution of midaZolam hydrochloride
`
`(11.1 mg/ml) and 1.5% methocel as a viscosity-enhancing
`agent. It is prepared by freeZe-drying the commercially
`available midaZolam injection solution. The dried product is
`dissolved in Water and mixed With the appropriate volume of
`a 7.5% methocel aqueous solution.
`
`[0019] The formulation has been tested for nasal mida
`Zolam absorption in dogs, and not in human subjects.
`HoWever, nasal administration of a total volume of 200 pl of
`this formulation Will not achieve therapeutically effective
`midaZolam plasma levels in humans, because the midaZolam
`concentration in this formulation is far too loW.
`
`[0020] The nasal formulation used by Loftsson et al.
`(2001) comprises midaZolam hydrochloride (17 mg/ml)
`With 14% sulfobutylether-[3-cyclodextrin sodium salt
`(SBEBCD; Captisol®) as solubiliZer in an acidic solution at
`pH 4.3. The presence of 0.1% hydroxypropyl methylcellu
`lose (HPMC) has an additional solubiliZing effect. This
`formulation also contains 0.02% benZalkonium chloride and
`0.1% EDTA as preservatives.
`
`[0021] Acute intranasal administration of this midaZolam
`formulation in healthy volunteers (100-160 pl into each
`nostril) is associated With mild to moderate transient irrita
`tion of the nasal mucosa (Gudmundsdottir et al., 2001).
`
`[0022] A further disadvantage associated With this formu
`lation is that the preservative mixture of 0.02% benZalko
`nium chloride/0.1% EDTA inhibits the ciliary movement in
`vitro and is classi?ed as ciliostatic (Merkus et al., 2001).
`Also the use of the high Captisol® concentration (14%)
`required to solubliZe midaZolam Will also lead to a strong
`ciliostatic effect.
`
`[0023] It is knoWn that ciliary beating is the major factor
`in normal functioning of the nasal mucociliary clearance,
`Which is a very important defence mechanism of the respi
`ratory tract (Marttin et al., 1998). Nasal administration of the
`midaZolam formulation of Loftsson et al. (2001) can there
`fore be expected to disturb the mucociliary clearance of the
`patients. More importantly, the midaZolam concentration of
`this nasal formulation is too loW to provide adequate thera
`peutic efficacy of the drug.
`
`[0024] The intranasal midaZolam formulation used by
`Knoester et al. (2002a, 2002) and Tenk et al. (2003) consists
`of midaZolam hydrochloride (30.9 mg/ml) in a mixture of
`25% (v/v) propylene glycol and Water (pH 4). It also
`contains 1% (v/v) benZyl alcohol as a preservative. A dose
`of 5 mg midaZolam base is delivered by tWo sprays of 90 pl
`and, for a dose of 10 mg midaZolam base, 4 sprays of 90 pl
`are needed (providing a total dose of 360 pl).
`
`[0025] The use of this formulation for intranasal mida
`Zolam administration in healthy volunteers and in epilepsy
`patients, providing a dose of 5 mg or 10 mg (90-180 pl in
`each nostril), causes nasal irritation, lacrimation and irrita
`tion of the throat in almost all subjects, as Well as a bitter
`taste (Knoester et al., 2002; Tenk et al., 2003). In in vitro
`experiments With ciliated tissue, this midaZolam formulation
`has been shoWn to be ciliostatic, probably due, in particular,
`to the presence of 25% propylene glycol and 1% benZyl
`alcohol (Merkus et al., 2001). It is evident from these studies
`that the volume of the formulation used to administer a dose
`of 5 and 10 mg via the nose is very large (tWo and four nasal
`sprays), and this is probably the cause of many of these
`
`AQUESTIVE EXHIBIT 1021 page 0002
`
`

`

`US 2005/0153956 A1
`
`Jul. 14, 2005
`
`adverse side effects. These adverse effects could prohibit the
`use of this formulation in clinical practice.
`
`SUMMARY OF THE INVENTION
`
`[0026] In light of the foregoing, it is clear that there is the
`need for a midaZolam formulation Which is speci?cally
`formulated for intranasal administration, in order to over
`come all of the various disadvantages associated With the
`knoWn formulations Which are administered intranasally. It
`is therefore an aim of the present invention to provide a
`formulation With a high enough midaZolam concentration to
`alloW adequate doses of midaZolam to be ef?ciently and
`comfortably administered via the intranasal route in a small
`volume. The formulation should also cause as little irritation
`as possible and have as high a bioavailability as possible.
`Finally, the formulation should have a similar or reduced
`ciliostatic effect in in vitro experiments, compared to the
`knoWn nasal formulations.
`
`[0027] These and other objects of the invention are
`achieved by providing a pharmaceutical composition Which
`comprises a solution of high concentration midaZolam and a
`solubiliZer. The composition is preferably provided in the
`form of an aqueous solution and preferably administered
`intranasally. Such composition can be administered to
`patients in the treatment of anxiety, epilepsy and epileptic
`seiZures, invasive surgical procedures and diagnostic proce
`dures and sedation.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0028] According to a ?rst aspect of the present invention,
`a pharmaceutical composition is provided, Wherein the com
`position is a solution comprising midaZolam in a concen
`tration of at least 35 mg/ml (based on the free base form of
`midaZolam), and a solubiliZer. The composition may contain
`midaZolam either in the form of its free base or a pharma
`ceutically acceptable salt thereof.
`[0029] The compositions according to the present inven
`tion are preferably suitable for intranasal administration.
`
`[0030] In one embodiment of the invention, the concen
`tration of midaZolam is at least 40 mg/ml, or at least 50
`mg/ml. The midaZolam concentration may also be less than
`100 mg/ml, less than 75 mg/ml or less than 60 mg/ml. In a
`preferred embodiment, the midaZolam concentration is
`35-75 mg/ml.
`[0031] In a particularly preferred embodiment of the
`present invention, the composition is an aqueous solution.
`The aqueous solutions of the present invention containing
`high midaZolam concentrations are facilitated by the inclu
`sion in the solution of a solubiliZer. Particularly effective
`solubiliZers include propylene glycol, glycerol, polyethylene
`glycol, povidone and ethanol, or combinations thereof. The
`inclusion of solubiliZers not only enables the formation of an
`aqueous midaZolam solution, but also alloWs that solution to
`have a high midaZolam concentration. The preferred solu
`biliZers for inclusion in the compositions of the present
`invention are discussed in greater detail beloW.
`
`[0032] The prior art does not disclose nasal midaZolam
`formulations having such high midaZolam concentrations.
`The reason for this is that it Was previously considered that
`the limited solubility of midaZolam meant that concentra
`
`tions of up to around 30 mg/ml Was the maximum possible
`(see Table 1). HoWever, this is not true, especially When
`using propylene glycol alone as the solubiliZer or propylene
`glycol in combination With glycerol and optionally one or
`more of polyethylene glycol, povidone, and ethanol; and
`Water. It Was also considered in the prior art that the
`formulations for nasal administration should have a pH of no
`less than about 4, as the intranasal administration of a
`formulation With a loWer pH Was thought to be too uncom
`fortable, due to irritation. These prejudices have led the
`skilled person to administer large volumes intranasally,
`leading to the above discussed problems.
`
`[0033] Contrary to the common opinion of the skilled
`person, the nasal administration of formulations having a pH
`loWer than 4 is not unacceptable to patients. More impor
`tantly, the loWer pH alloWs greater amounts of midaZolam to
`be dissolved, alloWing composition With higher concentra
`tions of midaZolam to be prepared Which, in turn, enables
`smaller volumes of formulation to be administered.
`
`[0034] The high midaZolam concentration has a number of
`surprising advantages. Firstly, as discussed above, it means
`that smaller volumes of the solution can be administered in
`order to achieve a desired therapeutic effect. This reduces
`the Waste due to varying amounts of the composition being
`sWalloWed or dropping out of the nose, so that more of the
`administered midaZolam is properly absorbed and has the
`desired therapeutic effect. This also reduces the unpleasant
`taste and irritation Which accompanies sWalloWing of the
`nasal composition. It also increases the dose consistency and
`predictability. This, in turn, enables one to achieve a speci?c
`therapeutic effect, as the plasma levels achieved folloWing
`intranasal administration Will be predictable and control
`lable. As discussed beloW, different midaZolam plasma lev
`els result in different therapeutic effects on the patient. The
`midaZolam compositions for intranasal administration dis
`closed in the prior art do not result in consistent or predict
`able plasma levels and so do not permit accurate dosing to
`achieve a speci?c therapeutic effect.
`
`[0035] The high midaZolam concentration also means that
`some therapeutic effects Which Were previously dif?cult or
`impossible to achieve using knoWn midaZolam composi
`tions can noW be reliably achieved. If one can administer
`just 50-100 pl per nostril instead of 2, 4 or even 10 times that
`volume per nostril, this Will clearly be bene?cial, especially
`if the patient is nervous or is a crying child or the like.
`Therefore, in one embodiment of the invention, the compo
`sition provides a therapeutically effective dose of midaZolam
`in a total volume of up to about 200 pl. Preferably, the
`composition provides a therapeutically effective dose of
`midaZolam in a volume of up to about 100 pl, it being
`possible to administer this dose to each nostril.
`
`[0036] Another bene?t associated With administering a
`smaller volume of the composition intranasally is that it
`results in a smaller area of deposition Within the nose. This
`localised administration Within the nose means that any
`transient irritation Will also be localised and limited to a
`small area Within the nose and throat. This, once again,
`reduces the discomfort experienced by the patient.
`[0037] Additionally, the high midaZolam concentration
`has also been demonstrated to enhance diffusion of the
`active agent through the nasal epithelium, resulting in faster
`absorption compared to that observed With solutions having
`
`AQUESTIVE EXHIBIT 1021 page 0003
`
`

`

`US 2005/0153956 A1
`
`Jul. 14, 2005
`
`lower midaZolam concentrations. This not only means a
`faster onset of the therapeutic effect, but also a reduction in
`the time for Which the active agent is in contact With the
`nasal epithelium. Again, this Will reduce the patient’s dis
`comfort, as the midaZolam itself is an irritant. Also, less of
`the midaZolam formulation Will reach the throat and so there
`is less chance for irritation by the formulation ingredients
`and for experiencing the bitter taste of midaZolam.
`
`[0038] In one embodiment of the invention, the mida
`Zolam included in the composition is a salt of midaZolam,
`such as midaZolam hydrochloride, midaZolam maleate or
`midaZolam lactate. Preferably, the composition comprises
`midaZolam hydrochloride.
`
`[0039] In a preferred embodiment of the invention, the
`solubiliZer comprises propylene glycol. Propylene glycol is
`a good solubiliZer for midaZolam including salts thereof, eg
`HCl, especially When the midaZolam is to be formulated as
`an aqueous solution. In addition to the propylene glycol, the
`solubiliZer may further comprise one or more of the folloW
`ing: glycerol, polyethylene glycol, povidone, and ethanol.
`Water is included in the formulation of the preferred solu
`tions.
`
`[0040] In an alternative embodiment of the invention, the
`solubiliZer comprises glycerol, another good solubiliZer for
`midaZolam When an aqueous solution is to be formed. In
`addition to the glycerol, the solubiliZer may further comprise
`one or more of the folloWing: propylene glycol, polyethyl
`ene glycol, povidone, and ethanol. Water is included in the
`formulation of the preferred solutions.
`
`[0041] In a particularly preferred embodiment of the
`invention, the composition is a solution of midaZolam com
`prising 90-10%, 80-20%. 70-30%, 60-40% or 40-50% (v/v)
`solubiliZer, preferably propylene glycol. The composition
`preferably also comprises 10-90%, 20-80%, 30-70%,
`40-60% or 50-60% (v/v) Water. Furthermore, the composi
`tion preferably comprises 40-75 mg/ml midaZolam. A com
`position comprising 40-50% (v/v) propylene glycol and
`50-60% (v/v) Water is considered as being particularly
`advantageous.
`[0042] In one embodiment of the invention, the composi
`tion comprises a combination of propylene glycol and
`glycerol. Glycerol has a sWeet taste and, in addition to acting
`as an eXcellent solubiliZer, it also serves to mask the taste of
`the midaZolam, should some of the solution go doWn the
`back of the throat of the patient.
`[0043] Propylene glycol and glycerol have further advan
`tages. Compositions comprising solubiliZers containing pro
`pylene glycol (>15% v/v) and/or glycerol (>20% v/v) do not
`need to include a preservative, because it is knoWn from the
`literature that these concentrations of glycerol and of pro
`pylene glycol act as antimicrobial preservatives (Handbook
`of Pharmaceutical EXcipients, Third Edition, The Pharma
`ceutical Press, London 2000).
`[0044] Propylene glycol, glycerol, polyethylene glycol
`and povidone are also attractive solubiliZers for use in a
`nasal solution because they do not have a strong adverse
`effect on ciliary movement. In in vitro experiments, accord
`ing to a previously published method (Merkus et al, 2001),
`the effect of four different solubiliZers [25% propylene
`glycol, 15% glycerol, 25% polyethylene glycol 400 and 5%
`povidone], dissolved in a Locke-Ringer solution, on the
`
`ciliary beat frequency (CBF) of ciliated tissue taken from
`chicken embryo tracheal tissue Was measured.
`[0045] All four compounds shoWed a decrease in CBF
`after 15 minutes. HoWever, after rinsing With Locke-Ringer
`solution, the effects on CBF appeared to be completely
`reversed Within 20 minutes.
`[0046] The solubiliZers used in the compositions of the
`present invention should cause as little irritation as possible
`When administered in vivo, and preferably no irritation at all.
`While transient and mild irritation can be tolerated by
`patients, this should be kept to a minimum in order to avoid
`unnecessary discomfort.
`[0047] The preferred solubiliZers used in the present
`invention and discussed above Will not cause unnecessary
`irritation upon intranasal administration.
`[0048] Despite the reduction in the amount of sWalloWed
`composition achieved by using the compositions of the
`present invention, it is nevertheless possible that a very
`small part of the midaZolam dose Will reach the throat,
`Which may lead to a bitter taste. Therefore, in another
`embodiment of the invention, one or more sWeeteners are
`included in the composition, to mask the bitter taste of
`midaZolam. According to this embodiment, the formulation
`may comprise midaZolam in a concentration of at least 35
`mg/ml, a solubiliZer and a sWeetener.
`[0049] Suitable sWeeteners for inclusion in the composi
`tions of the present invention include saccharin and saccha
`rin alkali salts (Which may be included in an amount of about
`0.1-5% W/v), aspartame (Which may be included in an
`amount of about 0.1-5% W/v), acesulfame K and cyclamate.
`[0050] Further additional components Which may be
`included in the compositions of the present invention
`include ?avouring agents, preservatives, buffers, stabilising
`agents and pH adjusting agents, knoWn from the pharma
`ceutical literature (Martindale 33rd edition, The Pharmaceu
`tical Press, London 2002). In a preferred embodiment, the
`composition is free from any buffers.
`[0051] Suitable ?avouring agents include vanilla (vanil
`lin), mint, raspberry, orange, lemon, grapefruit, caramel,
`cherry ?avours and combinations of these.
`[0052] Suitable stabiliZing agents include cyclodeXtrins
`such as beta-cyclodeXtrin (Which may be included in an
`amount of about 1%) and derivatives of beta-cyclodeXtrin
`(Which may be included in an amount of about 1-4%).
`[0053] In an alternative embodiment, the compositions
`according to the present invention are free from any preser
`vatives and/or stabilising agents. In another embodiment, the
`composition is free from benZyl alcohol
`[0054] In a yet another embodiment of the invention, the
`compositions further comprise a viscosity enhancing agent.
`Viscosity enhancing agents are Well knoWn to the person
`skilled in the art from the pharmaceutical literature and Will
`include agents such as cellulose derivatives. Enhancing the
`viscosity of the solution can enhance the delivery of the
`midaZolam. Viscosity enhancing agents such as cellulose
`derivatives may also serve to increase the stability of the
`solutions.
`[0055] The enhanced absorption of midaZolam using the
`compositions according to the present invention means that
`the compositions of the invention may be free from any
`absorption enhancers.
`
`AQUESTIVE EXHIBIT 1021 page 0004
`
`

`

`US 2005/0153956 A1
`
`Jul. 14, 2005
`
`[0056] The pH of the composition is preferably Within the
`range of 2.5 to 7. In one embodiment, the pH of the
`composition is less than 4, and is preferably greater than 2.5.
`More preferably, the pH of the composition is betWeen 3 and
`4. Particularly preferably, the pH is about 3; and most
`preferably 3.2 Despite there being a general prejudice
`against compositions for nasal administration having such a
`loW pH value, it has been found that there are no adverse
`effects or disadvantages associated With a composition hav
`ing a pH in this range. Indeed, the midaZolam is more
`soluble at loWer pHs, making it easier to formulate solutions
`With high midaZolam concentrations.
`[0057] A pharmaceutically acceptable acid may be added
`to the solution in order to adjust the pH.
`
`[0058] The free midaZolam base is rather lipophilic With a
`partition coefficient betWeen octanol and phosphate buffer
`(pH 7.5) of about 475. Therefore, the aqueous solubility of
`the midaZolam base at neutral pH is too loW to prepare
`suitable midaZolam formulations and for this purpose mida
`Zolam salts (e.g., With hydrochloride) have to be used.
`IoniZation of a drug Will increase its aqueous solubility. In
`acidic solutions, midaZolam as Well as other 1,4-benZodiaZ
`epines are knoWn to undergo reversible and pH-dependent
`ring-opening through the formation of aldehyde or ketone
`and a primary amine (Gerecke, 1983; Olivier et al, 2001;
`Loftsson et al., 2001). In the commercially available intra
`venous solutions of midaZolam (5 mg/ml) With a pH of 3.3
`to 3.5 the drug consists of 80-85% in the ring-closed form
`and 15-20% in the ring-open form (Gerecke, 1983).
`[0059] In this solution the ring-open form is considered as
`a prodrug of midaZolam, because the ring is completely
`closed When the pH is increased to 7.4.
`
`[0060] Intranasal administration of midaZolam is charac
`teriZed by rapid midaZolam absorption, reaching maXimum
`plasma concentrations in 5-15 minutes. The drug is subse
`quently eliminated from the blood circulation With half-lives
`ranging betWeen 1 and 2.4 hours in children and healthy
`adults, Which are not substantially different from that after
`intravenous injection of midaZolam (Rey et al., 1991; Bjork
`man et al., 1997; Burstein et al., 1997; Loftsson et al., 2001;
`Knoester et al., 2002; Tenk 2003).
`[0061] Using the available midaZolam injection solutions
`for intranasal midaZolam delivery in children, healthy vol
`unteers and adult surgical patients, mean absolute bioavail
`abilities of 50, 55 and 83% respectively, have been reported
`(Rey et al., 1991; Burstein et al., 1991; Bjorkman et al.,
`1997).
`[0062] Examples of compositions according to the present
`invention are set out beloW.
`
`EXAMPLE 1
`[0063] MidaZolam HCl 35-75 mg/ml (i.e., 35-75 mg/ml
`midaZolam free base)
`[0064] Propylene glycol q.s. (in an amount sufficient to
`solubiliZe midaZolam)
`[0065] Water
`[0066] Optionally, one or more of the folloWing additional
`components may be added: polyethylene glycol, glycerol,
`povidone, ethanol, sWeetener, ?avouring substance, preser
`vative, pH adjusting agent and stabiliZing agents.
`[0067] This composition is preferably formulated as a
`nasal spray or nasal drops or liquid for children and adults
`With a volume of 50-100 pl, for intranasal administration.
`
`[0068] The composition has a pH of betWeen 2.5 and 7,
`preferably betWeen 3 and 4.
`
`EXAMPLE 2
`[0069] MidaZolam HCl 35-75 mg/ml (i.e., 35-75 mg/ml
`midaZolam free base)
`[0070] Propylene glycol 5-50% (v/v)
`[0071] Glycerol 5-50% (v/v)
`[0072] Polyethylene glycol 5-50% (v/v)
`[0073] Povidone 1-20% (W/v)
`[0074] Water
`[0075] The composition is formulated as a nasal spray or
`nasal drops or liquid With a volume for children and adults
`of 50-100 pl.
`[0076] The pH of the solution should be betWeen 2.5 and
`7, preferably betWeen 3 and 4.
`
`EXAMPLE 3
`
`[0077] MidaZolam HCl 35, 40, 45 or 50 mg/ml, respec
`tively, (i.e. 35, 40, 45 or 50 mg/ml midaZolam free
`base)
`[0078] Propylene glycol 15-30% (v/v)
`[0079] Glycerol 15%-30% (v/v)
`[0080] Saccharin sodium 10-50 mg/ml
`[0081] Water
`[0082] The volume for intranasal administration is 50-100
`pl.
`[0083] The pH of the solution should be betWeen 2.5 and
`7, preferably betWeen 3 and 4.
`
`EXAMPLE 4
`
`[0084] MidaZolam HCl 35, 40, 45 or 50 mg/ml, respec
`tively, (i.e., 35, 40, 45 or 50 mg/ml midaZolam free
`base)
`[0085] Propylene glycol 20-50% (v/v)
`[0086] Povidone 1-10% (W/v)
`[0087] Water
`[0088] The volume for nasal administration is 50-100 pl.
`[0089] The