Patent Publication Number: US-2021187216-A1

Title: Nasal Administration

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of application Ser. No. 15/481,975, filed Apr. 7, 2017, which is a continuation of application Ser. No. 12/594,365, filed Apr. 30, 2010, now U.S. Pat. No. 9,649,456, which is a national stage of International Application No. PCT/GB2008/001226, filed Apr. 7, 2008, which claims priority to Great Britain Application No. 0706744.0, filed Apr. 5, 2007. The disclosures of all applications cited in this paragraph are incorporated herein in their entirety by reference. 
    
    
     The present invention relates to the nasal administration of powdered substances, in particular drugs, and in particular substances which require a rapid onset of action, such as in the treatment of pain, including headaches, for example, cluster headaches and migraine, and neuropathic pain. 
     Referring to  FIG. 1( a ) , the nasal airway  1  comprises the two nasal cavities separated by the nasal septum, which airway  1  includes numerous ostia, such as the paranasal sinus ostia  3  and the tubal ostia  5 , and olfactory cells, and is lined by the nasal mucosa. The nasal airway  1  can communicate with the nasopharynx  7 , the oral cavity  9  and the lower airway  11 , with the nasal airway  1  being in selective communication with the anterior region of the nasopharynx  7  and the oral cavity  9  by opening and closing of the oropharyngeal velum  13 . The velum  13 , which is often referred to as the soft palate, is illustrated in solid line in the closed position, as achieved by providing a certain positive pressure in the oral cavity  9 , such as achieved on exhalation through the oral cavity  9 , and in dashed line in the open position. 
     The present inventors have surprisingly identified that a rapid systemic uptake can be achieved, as compared to the conventional delivery of an equivalent liquid substance, by the delivery of a powdered substance to the posterior region of the nasal airway, and in particular the upper posterior two thirds. 
     The posterior region of the nasal airway is that region which is posterior of the nasal valve NV, as illustrated in  FIG. 1( b ) . The nasal valve comprises the anterior bony cavum which contains inferior turbinate erectile tissue and septal erectile tissue, which are supported respectively by compliant ala tissue and the rigid cartilaginous septum (Cole, P (The Respiratory Role of the Upper Airways, a selective clinical and pathophysiological review. 1993, Mosby-Year Book Inc. ISBN1.55664-390-X)). These elements combine to form a dynamic valve, which extends over several millimetres, that adjusts nasal airflow, and is stabilized by cartilage and bone, modulated by voluntary muscle and regulated by erectile tissue. The lumen of the nasal valve is the section of narrowest cross-sectional area between the posterior and anterior regions of the nasal airway, and is much longer and narrower dorsally than ventrally, and this lumen defines a triangular entrance which extends to the piriform region of the bony cavum. The nasal valve is lined in its anterior part with transitional epithelium, with a gradual transition posterior to respiratory epithelium. The nasal valve and anterior vestibule define roughly the anterior one-third of the nose. 
     The posterior region of the nasal airway is that region which is lined with respiratory epithelium, which is ciliated, and olfactory epithelium, which comprises nerves which extend downwards through the cribiform plate CP from the olfactory bulb, whereas the anterior region of the nasal airway is that region which is lined with squamous epithelium, which is not ciliated, and transitional epithelium. The olfactory epithelium extends on both the lateral and medial sides of the nasal airway, and typically extends downwards about 1.5 to 2.5 cm. 
     The upper posterior region is the region above the inferior meatus IM, as illustrated in  FIG. 1( b ) , and encompasses the middle turbinate, the sinus ostia in infundibulum (ostia to maxillary, frontal and ethmoidal sinuses), the olfactory region, and the upper branches of the trigeminal nerve, and is that region which includes veins which drain to the venous sinuses that surround the brain. 
     As illustrated in  FIG. 1( b ) , the posterior region of the nasal airway is the nasal region posterior of an imaginary vertical plane VERT 1  which is located at a position corresponding to one-quarter of the distance between the anterior nasal spine AnS, which is a pointed projection at the anterior extremity of the intermaxillary suture, and the posterior nasal spine PnS, which is the sharp posterior extremity of the nasal crest of the hard palate and represents the transition between the nose and the nasopharynx, which corresponds to a distance posterior of the anterior nasal spine AnS of between about 13 mm and about 14 mm (Rosenberger, H (Growth and Development of the Naso-Respiratory Area in Childhood, PhD Thesis, Laboratory of Anatomy, School of Medicine, Western Reserve University, Presented to the Annual Meeting of the American Laryngological, Rhinological and Otological Society, Charleston, S.C., USA, 1934) defines the distance between the anterior nasal spine AnS and the posterior nasal spine PnS as being 56 mm in eighteen year old boys and 53.3 mm in eighteen year old girls). As again illustrated in  FIG. 1( b ) , the posterior nasal region is bounded posteriorly by an imaginary vertical plane VERT 2  which extends through the posterior nasal spine PnS. 
     As further illustrated in  FIG. 1( b ) , the upper region of the nasal airway is an upper segment of the nasal airway which is bounded by the cribiform plate CP and a horizontal plane HORIZ which is located at a position corresponding to one-third of the distance between the nasal floor NF of the nasal airway and the cribiform plate CP, which corresponds to a height of typically between about 13 and about 19 mm above the nasal floor NF (Zacharek, M A et al (Sagittal and Coronal Dimensions of the Ethmoid Roof: A Radioanatomic Study, Am J Rhino 2005, Vol 19, pages 348 to 352) define the distance from the nasal floor NF to the cribiform plate CP as 46+/−4 mm). 
     The upper posterior region is thus that upper posterior region which is bounded by the above-defined vertical and horizontal planes VERT 1 , HORIZ. 
     The prior art includes a number of comparative studies which compare the pharmacokinetics of substances which are delivered intranasally as liquids and powders. Examples of such studies include the following. 
     Marttin et al (Nasal absorption of dihydroergotamine from liquid and powder formulations in rabbits, J. Pharm. Sci., 86(7), pages 802 to 807, 1997) compared powder and liquid formulations of dihydroergotamine which contained cyclodextrins, and reported the time maximum plasma concentration T max  to be broadly comparable for a range of powder and liquid formulations. 
     Matsuyama et al (Improved nasal absorption of salmon calcitonin by powdery formulation with N-acetyl-L-cysteine as a mucolytic agent, J. Cont. Rel., 115, pages 183 to 188, 2006) compared the intranasal administration of powders and liquids with and without N acetyl cysteine in rats. The powder formulations used in these studies contained ethylcellulose and sodium glycocholate as absorption enhancers, and, despite the use of these absorption enhancers, in the formulations lacking N acetyl cysteine, there was no apparent difference in the time maximum plasma concentration T max  between the powder and liquid formulations. 
     Schipper et al (Nasal insulin delivery with dimethyl beta cyclodextrin as an absorption enhancer in rabbits: powder more effective than liquid formulations, Pharm. Res., 10, pages 682 to 686, 1993) compared the intranasal administration of powders and liquids containing dimethyl beta cyclodextrin as an absorption enhancer, and determined the peak plasma concentration C max  for the powder formulation to be greater than that for the liquid formulation. 
     Resta et al (A comparison of sodium cromoglycate nasal solution and powder in the treatment of allergic rhinitis, Br. J. Clin. Pract., 46, pages 94 to 98, 1992) compared the intranasal administration of powder and solution formulations of sodium cromoglycate in humans, and determined the powder formulation to be somewhat more effective. 
     Pontiroli et al (Nasal administration of glucagons and human calcitonin to healthy subjects: a comparison of powders and spray solutions and of different enhancing agents, Eur. J. Clin. Pharmacol., 37, pages 427 to 430, 1989) compared the intranasal administration of liquid and powder formulations of calcitonin in humans and determined that the absorption was comparable in these formulations. 
     Ishikawa et al (Insoluble Powder Formulation as an Effective Nasal Drug Delivery System, Int. J. Pharm., 224, pages 105 to 114, 2001) reported that that permeability of powder and liquid formulations of elcatonin across excised rabbit mucosa was comparable. In vivo, the powder formulation gave greater bio-availability, which was attributed to the use of insoluble calcium carbonate in delaying residence time. 
     The prior art also teaches that the use of powdered substances can lead to reduced bio-availability, which would be understood as a clear prejudice to the use of powdered substances. 
     Callens et al (Influence of multiple nasal administrations of bio-adhesive powders on the insulin BA, Int. J. Pharm., 250, pages 415 to 422, 1993) studied the intranasal administration of insulin powders and attributes the longer residence times of powder formulations as being disadvantageous, particularly after multiple administrations, in leading to reduced bio-availability. 
     The prior art also studies the effect of deposition in anterior and posterior regions of the nasal airway. 
     Pringels et al (Influence of deposition and spray pattern of nasal powders on insulin bioavailability, Int. J. Pharm., 310(1-2), pages 1 to 7, 2006) compared the bioavailability of insulin powders, in a starch formulation, which was delivered to rabbits and reported that deposition posterior to the nasal valve resulted in lower bio-availability than anterior deposition. 
     This teaching is to the delivery of powdered substances to the anterior region of the nasal cavity, in order to provide for improved bio-availability, and is contrary to the present invention. 
     In terms of general considerations regarding nasal drug delivery, Behl et al (Effects of physiochemical properties and other factors on systemic nasal drug delivery, Advanced Drug Delivery Reviews, 29, pages 89 to 116, 1998) provides a comprehensive review of systemic nasal drug delivery. 
     Also, McMartin, C et al (Analysis of Structural Requirements for the Absorption of Drugs and Macromolecules from the Nasal Cavity, J. Pharm. Sci., 76(7), 1987, pages 535 to 540) provides a general review of the nasal administration of drugs, in particular those drugs which cannot be given orally because of linkages which are polar or susceptible to degradation in the GI tract. This review concludes that drugs of up to a molecular weight of 1000 should be administrable without the use of adjuvants, and that this property could be used for the administration of polar drugs, for example, peptides. 
     In one aspect the present invention provides a delivery device for delivering a powdered substance to the posterior region of a nasal cavity of a subject, the delivery device comprising: a nosepiece for insertion into a nasal cavity of a subject through which a powdered substance is delivered to the posterior region of the nasal cavity of the subject; and a substance supply unit which is operable to deliver a powdered substance through the nosepiece. 
     In one embodiment the substance supply unit comprises a container-receiving unit which comprises a container chamber for receiving a substance-containing container which contains a powdered substance to be delivered to the nasal cavity of the subject, and the container chamber includes an outlet which is in fluid communication with the nosepiece such as to provide for delivery of the powdered substance from the container chamber to the nosepiece. 
     In one embodiment the container comprises a capsule. 
     In one embodiment the capsule is formed from a cellulose derivative, and preferably hydroxypropyl methylcellulose (HPMC). 
     In another embodiment the capsule is formed from a gelatine derivative. 
     In one embodiment the capsule is coated with a hydrophobic material, and preferably parylene. 
     In one embodiment the nosepiece is configured, when inserted into the nasal cavity, to extend into the nasal valve and provide for expansion thereof. 
     In one embodiment the nosepiece is configured such as to obstruct the nasal valve. 
     In one embodiment the nosepiece is configured such as to close the nasal valve, and thereby substantially prevent deposition of substance anteriorly of the same. 
     In one embodiment the delivery device further comprises: a mouthpiece through which the subject in use exhales to cause closure of the oropharyngeal velum of the subject. 
     In one embodiment the delivery device further comprises: a flow channel fluidly connecting the nosepiece and the mouthpiece, whereby exhaled air from an exhalation breath is delivered through the nosepiece. 
     In one embodiment the container chamber includes an inlet which is fluidly connected to the mouthpiece, such that exhaled air from an exhalation breath acts to entrain powdered substance as contained by the container and deliver the same through the nosepiece. 
     In one embodiment the container-containing member includes a flow passage in which the container is disposed, such as to be rotatable therewithin when an air flow is delivered therethrough. 
     In another embodiment the delivery device further comprises: a flow channel fluidly connected to the nosepiece through which a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, is in use delivered to the nosepiece; and a gas supply unit for supplying a gas flow to the flow channel. 
     Preferably, the delivery device is configured such that at least 55% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     More preferably, the delivery device is configured such that at least 60% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Yet more preferably, the delivery device is configured such that at least 65% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Still more preferably, the delivery device is configured such that at least 70% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Still yet more preferably, the delivery device is configured such that at least 80% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Preferably, the delivery device is configured such that at least 35% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     More preferably, the delivery device is configured such that at least 40% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     Yet more preferably, the delivery device is configured such that at least 45% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     Still more preferably, the delivery device is configured such that at least 50% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     Yet still more preferably, the delivery device is configured such that at least 55% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     In one embodiment the powdered substance contains substantially entirely active substance and no introduced excipients, and in particular adjuvants. 
     In one embodiment the powdered substance has a pH of between about 4.5 and about 5.3, and preferably about 4.8. 
     In one embodiment the powdered substance has a particle size distribution of 10% less than about 20 μm, 50% less than about 50 μm and 90% less than about 150 μm, and preferably 10% less than about 10 μm, 50% less than about 30 μm and 90% less than about 90 μm. 
     In one embodiment the powdered substance has an untapped bulk density of between about 0.3 g/ml and about 0.5 g/ml, and preferably about 0.4 g/ml. 
     In one embodiment the powdered substance has a tapped bulk density of between about 0.5 g/ml and about 0.75 g/ml, and preferably about 0.63 g/ml. 
     In another aspect the present invention provides a method of delivering a powdered substance to the posterior region of a nasal cavity of a subject, the method comprising the steps of: fitting a nosepiece to a nasal cavity of a subject; and delivering a powdered substance through the nosepiece to the posterior region of the nasal cavity of the subject. 
     In one embodiment the powdered substance is delivered from a container chamber which houses a container which contains a powdered substance to be delivered to the nasal cavity of the subject, and the container chamber includes an outlet which is in fluid communication with the nosepiece such as to provide for delivery of the powdered substance from the container chamber to the nosepiece. 
     In one embodiment the container comprises a capsule. 
     In one embodiment the capsule is formed from a cellulose derivative, and preferably hydroxypropyl methylcellulose (HPMC). 
     In another embodiment the capsule is formed from a gelatine derivative. 
     In one embodiment the capsule is coated with a hydrophobic material, and preferably parylene. 
     In one embodiment the nosepiece is configured, when inserted into the nasal cavity, to extend into the nasal valve and provide for expansion thereof. 
     In one embodiment the nosepiece is configured such as to obstruct the nasal valve. 
     In one embodiment the nosepiece is configured such as to close the nasal valve, and thereby substantially prevent deposition of substance anteriorly of the same. 
     In one embodiment the method further comprises the step of: closing the oropharyngeal velum of the subject. 
     In one embodiment the method further comprises the step of: the subject exhaling through a mouthpiece to cause closure of the oropharyngeal velum of the subject. 
     In one embodiment the mouthpiece is fluidly connected to the nosepiece, whereby exhaled air from an exhalation breath is delivered through the nosepiece. 
     In one embodiment the container chamber includes an inlet which is fluidly connected to the mouthpiece, such that exhaled air from an exhalation breath acts to entrain powdered substance as contained by the container and deliver the same through the nosepiece. 
     In one embodiment the container chamber includes a flow passage in which the container is disposed, such as to be rotatable therewithin when an air flow is delivered therethrough. 
     In another embodiment the method further comprises the step of: delivering a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, to the nosepiece. 
     Preferably, at least 55% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     More preferably, at least 60% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Yet more preferably, at least 65% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Still more preferably, at least 70% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Yet still more preferably, at least 80% of the dose as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve. 
     Preferably, at least 35% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     More preferably, at least 40% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     Yet more preferably, at least 45% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     Still more preferably, at least 50% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     Yet still more preferably, at least 55% of the dose as initially deposited in the nasal cavity is deposited in the upper posterior two thirds thereof. 
     In one embodiment the powdered substance contains substantially entirely active substance and no introduced excipients, and in particular adjuvants. 
     In one embodiment the powdered substance has a pH of between about 4.5 and about 5.3, and preferably about 4.8. 
     In one embodiment the powdered substance has a particle size distribution of 10% less than about 20 μm, 50% less than about 50 μm and 90% less than about 150 μm, and preferably 10% less than about 10 μm, 50% less than about 30 μm and 90% less than about 90 μm. 
     In one embodiment the powdered substance has an untapped bulk density of between about 0.3 g/ml and about 0.5 g/ml, and preferably about 0.4 g/ml. 
     In one embodiment the powdered substance has a tapped bulk density of between about 0.5 g/ml and about 0.75 g/ml, and preferably about 0.63 g/ml. 
     In one embodiment the time maximum plasma concentration T max  is less than about 25 minutes. 
     In one embodiment the time maximum plasma concentration T max  is less than about 20 minutes. 
     In one embodiment the peak plasma concentration C max  for the active substance is at least 10 ngml −1  for a 10 mg dose of the active substance. 
     In one embodiment the peak plasma concentration C max  for the active substance is at least 15 ngml −1  for a 20 mg dose of the active substance. 
     Preferably, the ratio of the nasal absorption fraction to total bio-availability (BA) is greater than about 1. 
     More preferably, the ratio of the nasal absorption fraction to total bio-availability (BA) is greater than about 1.5. 
     Yet more preferably, the ratio of the nasal absorption fraction to total bio-availability (BA) is greater than about 2.0. 
     In one embodiment the powdered substance comprises a triptan. 
     In one embodiment the powdered substance comprises sumatriptan. 
     In another embodiment the powdered substance comprises one or more of risatriptan, naratriptan, eletriptan, frovatriptan and zolmitriptan. 
     In another embodiment the powdered substance comprises an analgesic. 
     In one embodiment the powdered substance comprises an opiod. 
     In another embodiment the powdered substance comprises an ergotamine, such as one or more of dihydroergotamine mesylate, ergonovine maleate and ergotamine tartarate with caffeine. 
     In a further embodiment the powdered substance comprises one or more of fentanyl, oxycondone, hydromorphone, morphine, codeine, ketobemidone and cocaine. 
     In a further embodiment the powdered substance comprises a benzodiazepine, such as midazolam. 
     In a yet further embodiment the powdered substance comprises a non-steroidal anti-inflammatory drug (NSAID), such as one or more of aspirin, ibuprofen, naproxen, indomethacin, diclofenac and ketoprofen. 
     In a still further embodiment the powdered substance comprises a peptide or protein. 
     In one embodiment the peptide or protein has a molecular weight greater than about 1000. 
     In one embodiment the powdered substance comprises one or more of insulin, including its analogues and derivatives, desmopressin and calcitonin. 
     In a yet still further embodiment the powdered substance comprises one or more of a vaccine, an immunomodulator and an immunostimulator. 
     In one embodiment the method is for the treatment of pain. 
     In one embodiment the method is for the treatment of headaches. 
     In one embodiment the method is for the treatment of cluster headaches. 
     In another embodiment the method is for the treatment of migraine. 
     In another embodiment the method is for the treatment of neuropathic pain. 
     In another embodiment the method is for inducing sedation. 
     In a further embodiment the method is for the treatment of a partial or full epilepsy seizure. 
     In a yet further embodiment the method is for the treatment of a panic disorder. 
     In a still further embodiment the method is for the treatment of insomnia. 
     In a still yet further embodiment the method is for the treatment of jet-lag. 
     In yet another embodiment the method is for regulating blood glucose levels. 
     In still another embodiment the method is for influencing satiety or the sense of satiety. 
     In yet still another embodiment the method is for delivering a memory-enhancing agent prior to a learning episode. 
     The present applicant has developed a novel nasal delivery system, as disclosed in WO-A-2000/051672, the content of which is herein incorporated by reference, which provides for the delivery of drugs and vaccines in a bi-directional air flow through the two nasal passages when connected in series by closure of the oropharyngeal velum. 
    
    
     
       The present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which: 
         FIG. 1( a )  schematically illustrates the anatomy of the upper respiratory tract of a human subject; 
         FIG. 1( b )  illustrates the segmentation of a nasal cavity in accordance with a preferred embodiment of the present invention; 
         FIG. 2  illustrates a nasal delivery device in accordance with one embodiment of the present invention; 
         FIG. 3  illustrates the nasal delivery device of  FIG. 2 , where operative in delivering substance to the nasal cavity of the subject; 
         FIG. 4  illustrates the time course for the measured blood plasma concentrations of sumatriptan for the 10 mg intranasal administration of the present invention as employed in Example #1 as compared to historic data for 10 mg Imitrex (RTM) intranasal administration; and 
         FIG. 5  illustrates median maps for theta and alpha relative energies for the 10 mg and 20 mg nasal administrations of the present invention and the 6 mg comparator sub-cut administration as employed in Example #1. 
     
    
    
       FIGS. 2 and 3  illustrate a nasal delivery device in accordance with one embodiment of the present invention. 
     The delivery device comprises a housing  15 , a capsule-receiving unit  16  for receiving a capsule C, a nosepiece unit  17  for fitting to a nasal cavity of a subject, a mouthpiece unit  19  through which the subject exhales, and a capsule-piercing mechanism  20 , which is operable to pierce a capsule C as contained by the capsule-receiving unit  16  and thereby prime the delivery device for operation. 
     The housing  15  includes a first, nosepiece aperture  21 , in this embodiment at the upper end of the housing  15 , which receives the nosepiece unit  17 , and a second, lateral aperture  22 , in this embodiment in an end wall of the housing  15 , through which extends an actuator button  81  of the capsule-piercing mechanism  20 , as will be described in more detail hereinbelow. 
     The capsule-receiving unit  16  comprises a capsule-receiving member  23 , in this embodiment an elongate, upstanding chamber which is disposed opposite the nosepiece aperture  21  in the housing  15 , for receiving a capsule C, in this embodiment as contained within a capsule-containing member  49  of the nosepiece unit  17 , as will be described in more detail hereinbelow. 
     In this embodiment the capsule-receiving member  23  includes an inlet  24  and an outlet  25  for providing for an air flow therethrough, with the outlet  25 , as defined by an upper, downstream end of the capsule-receiving member  23 , being adapted to receive the capsule-containing member  49  of the nosepiece unit  17 , such that the capsule-containing member  49  is a sealing fit within the capsule-receiving member  23 . 
     The nosepiece unit  17  comprises a main body member  45  which is configured to fit in the nosepiece aperture  21  of the housing  15 , a nosepiece  47  which extends outwardly of the main body member  45  for fitting to the nostril of the subject, and a capsule-containing member  49  which extends inwardly of the main body member  45  and contains a capsule C, the contents of which are to be delivered to the nasal cavity of the subject. In this embodiment the capsule C is a hydroxypropyl methylcellulose (HPMC) capsule which contains a particulate substance, such as a powdered substance, and typically a pharmaceutical substance. In other embodiments the capsule C could be formed substantially of another cellulose derivative, such as hydroxypropylcellulose, methylcellulose, ethylcellulose and carboxymethylcellulose. In an alternative embodiment the capsule C can be formed from a gelatine derivative. In one embodiment the capsule C can be coated with a hydrophobic material, such as parylene. 
     In this embodiment the nosepiece  47  has a substantially frusto-conical outer section  53  for guiding the nosepiece unit  17  into a nasal passage of the subject and providing a fluid-tight seal with the nares of the nostril, and includes an inner channel  55 , here of substantially cylindrical section, through which substance is delivered to a posterior region of the nasal passage of the subject, in this embodiment an upper posterior region as bounded by a vertical plane which is located posterior of the anterior nasal spine AnS at a position corresponding to one-quarter of the distance between the anterior and posterior nasal spines AnS, PnS and a horizontal plane which is located above the nasal floor at a height one-third of the distance between the nasal floor and the cribiform plate. As discussed hereinabove, the present inventors have recognized that an increased delivery of powdered substance to the upper posterior region of the nasal passage surprisingly provides for a very rapid onset of action as compared to the conventional nasal administration of a liquid substance. 
     In this embodiment the nosepiece  47  is configured to deliver a significant fraction of substance to the upper posterior region of the nasal passage, here an initial deposition of greater than 30% of the delivered dose. 
     In this embodiment the nosepiece  47 , in providing a fluid-tight seal with the nostril of the subject, provides for bi-directional delivery through the nasal airway of the subject, as disclosed in the applicant&#39;s earlier WO-A-2000/051672. In another embodiment, however, the nosepiece  47  need not provide a sealing fit, thus encompassing delivery to the nasal cavity, but not necessarily bi-directional delivery. 
     In this embodiment the nosepiece  47  includes a trap element  57 , typically a perforated or mesh element, for preventing any foreign matter, such as a part of the capsule C, which is above a predetermined size from passing through the nosepiece  47  and into the nasal cavity of the subject. 
     The capsule-containing member  49  includes an elongate flow passage  63 , in this embodiment cylindrical in shape, in which the capsule C is oriented axially therealong such as to be rotatable therewithin when an air flow is delivered therethrough, and an inlet aperture  65  in fluid communication with one, the downstream, end of the flow passage  63 , which inlet aperture  65  provides a flow restriction to an air flow as delivered therethrough and acts as a seat for one, the lower, end of the capsule C prior to the delivery of an air flow through the flow passage  63 . 
     The capsule-containing member  49  further includes a plurality of, in this embodiment first and second piercing apertures  71 ,  73  in a lateral wall thereof for enabling the capsule C to be pierced at locations spaced along the axial length thereof. In this embodiment the first, lower aperture  71  is located such that the capsule C is pierced at a location above the height of the dose of substance as contained thereby when the lower end of the capsule C is seated in the inlet aperture  65  of the flow passage  63 . In this way, the dose of substance as contained by the capsule C is not released into the flow passage  63  until an air flow is delivered through the flow passage  63 . 
     In this embodiment the nosepiece unit  17  is provided as a replaceable unit which is replaced following each operation of the delivery device. In this embodiment the nosepiece unit  17  can be packaged in air-tight packaging, for example, an aluminum foil package. 
     The mouthpiece unit  19  comprises a mouthpiece  77 , in this embodiment as gripped in the lips of the subject, through which the subject exhales to deliver an entraining air flow through the capsule-receiving unit  16 , and an air chamber  78 , in this embodiment an elongate tubular section, which fluidly connects the mouthpiece  77  and the capsule-receiving unit  16 . 
     In this embodiment the air chamber  78  has a greater volume than the capsule-receiving member  23  of the capsule-receiving unit  16 , and preferably has a volume at least twice that of the capsule-receiving member  23 . 
     In this embodiment the air chamber  78  incorporates a temperature regulator  79 , here formed as a condenser for cooling the exhaled air flow, at least at the upstream end thereof. With this configuration, the exhaled air flow is cooled during exhalation. 
     In this embodiment the temperature regulator  79  comprises a labyrinthine structure. In another embodiment the temperature regulator  79  could be provided by a filter element, which could also act as a microbiological filter. 
     In one embodiment the temperature regulator  79  could include means for drying the condensate as collected therein when the delivery device is not in use. 
     In one embodiment the air chamber  78  is removable, such as to allow for cleaning or replacement. 
     This arrangement has been found to provide for reliable operation of the delivery device, in delivering substance from the capsule C. The present inventors have established that the provision of moist exhaled air directly to the capsule C can sometimes prevent the required rotation of the capsule C, and thereby prevent proper release of the substance as contained thereby. By providing a volume of cooler air, and arranging for that volume of cooler air to be delivered initially in a burst, the required rotation of the capsule C is seen repeatedly. 
     The capsule-piercing mechanism  20  comprises an actuator button  81  which extends through the lateral aperture  22  in the housing  15  such as to allow for operation by the subject, a plurality of, in this embodiment first and second piercing elements  83 ,  85  which are supported by the actuator button  81  and extend forwardly thereof, such that, on depression of the actuator button  81  from a retracted position to an extended position, the piercing elements  83 ,  85  are driven through respective ones of the piercing apertures  71 ,  73  in the lateral wall of the capsule-containing member  49  to pierce the capsule C. 
     In this embodiment the capsule-piercing mechanism  20  includes a resilient element  87  which acts to bias the actuator button  81  outwardly towards the retracted position, such that, following depression of the actuator button  81  to pierce the capsule C, the actuator button  81  is returned to the retracted position. In this embodiment the resilient element  87  is formed as an integral part of the actuator button  81 , but in other embodiments could be provided by a separate element, such as a compression spring. 
     Operation of the delivery device will now be described hereinbelow. 
     Firstly, taking the delivery device in hand, and with a nosepiece unit  17  inserted in the housing  15 , the subject depresses the actuator button  81  of the capsule-piercing mechanism  20  such as to pierce the capsule C as contained in the capsule-containing member  49 . 
     By depressing the actuator button  81 , the capsule C is pierced by the piercing elements  83 ,  85  at two locations spaced along the axial length thereof. In this embodiment the first, lower piercing element  83  acts to pierce the capsule C at a location just above the height of the substance as contained by the capsule C, the capsule C only being part filled, and the second, upper piercing element  85  acts to pierce the upper, distal end of the capsule C. 
     The actuator button  81  is then released, which causes the actuator button  81  to be returned to the retracted position under the bias of the biasing element  87 . In this way, the delivery device is primed and ready for use. 
     The subject then inserts the nosepiece  47  into one of his/her nasal passages until the nosepiece  47  abuts the nares of the nostril such as to establish a fluid-tight seal therewith, at which point the distal end of the nosepiece  47  extends about 2 cm into the nasal passage of the subject, and grips the mouthpiece  77  in his or her lips. 
     The subject then begins to exhale through the mouthpiece  47 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the nasal airway of the subject, with the air flow passing into the one nasal passage, around the posterior margin of the nasal septum and out of the other nasal passage, thereby achieving a bi-directional air flow through the nasal airway of the subject. 
     When the subject exhales with sufficient force, the capsule C is lifted from the seat as defined by the inlet aperture  65  of the capsule-containing member  49  and the capsule C is rotated, which rotation acts to release the substance from within the capsule C which is entrained by the exhaled air flow and delivered to the posterior region of the nasal cavity of the subject. With continued exhalation, the capsule C continues to rotate. 
     This operation of the delivery device can be repeated with a new capsule C. In this embodiment the entire nosepiece unit  17  is replaced, but in other embodiments either the capsule-containing member  49  or just the capsule C could be replaced. 
     The present invention will now be described hereinbelow with reference to the following non-limiting Examples. 
     EXAMPLE #1 
     The purpose of this study was to study the pharmacokinetics of sumatriptan where intranasally delivered using the above-described bi-directional nasal administration system. 
     In this study, twelve healthy subjects were studied. 
     In separate sessions, the subjects received 10 mg and 20 mg of sumatriptan base by the bi-directional administration system of the above-described embodiment, from which a powdered sumatriptan formulation was nasally administered, with 20 mg of the sumatriptan base being delivered in two successive 10 mg doses through the respective nostrils of the subjects, and 6 mg of sumatriptan base (IMIGRAN (RTM) Injection pre-filled syringe as available from GlaxoSmithKline) by sub-cut administration. 
     In this study, the sumatriptan administrations were administered 15 minutes prior to the administration of glyceryltrinitrate (GTN), which allowed the effect on quantitative wake EEG to be studied in subjects suffering from migraine, where GTN is expected to induce migraine in 75% of subjects who have a history of migraine. 
     The powdered sumatriptan formulation was contained in an HPMC capsule and comprised a 10 mg dose of micronized sumatriptan succinate powder and contained no excipients, such as adjuvants. 
     The sumatriptan succinate powder has a pH (1% w/v in water) of 4.77. In a preferred embodiment the sumatriptan succinate powder has a pH of between about 4.5 and about 5.3, and preferably about 4.8. 
     The sumatriptan succinate powder has a particle size distribution of 10% less than 8.08 μm, 50% less than 29.77 μm and 90% less than 88.54 μm. In a preferred embodiment the sumatriptan succinate powder has a particle size distribution of 10% less than about 20 μm, 50% less than about 50 μm and 90% less than about 150 μm, and preferably 10% less than about 10 μm, 50% less than about 30 μm and 90% less than about 90 μm. 
     The sumatriptan succinate powder has an untapped bulk density of 0.415 g/ml and a tapped bulk density of 0.632 g/ml. In a preferred embodiment the sumatriptan succinate powder has an untapped bulk density of between about 0.3 g/ml and about 0.5 g/ml, and preferably about 0.4 g/ml. In a preferred embodiment the sumatriptan succinate powder has a tapped bulk density of between about 0.5 g/ml and about 0.75 g/ml, and preferably about 0.63 g/ml. 
     Venous blood samples, each having a volume of 5 ml, were drawn just prior to administration and at 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 120, 240, 360, 480 and 720 minutes after administration, and the blood plasma concentration of sumatriptan was determined. 
     From these measured blood plasma concentrations, average values for the time maximum plasma concentration T max , the peak plasma concentration C max , the area under the curve (AUC) at times 20, 30, 60 and 120 minutes and ∞, which assumes a zero plasma concentration at 12 hours, and the bio-availability BA were determined for evaluable subjects, as set out in Table I hereinbelow. For comparison, the corresponding pharmacokinetic parameters for the intranasal administration of liquid sumatriptan succinate sprays (10 mg and 20 mg sumatriptan base) (Imitrex (RTM) as available from GlaxoSmithKline). The historical data source for the Imitrex (RTM) nasal spray is the NDA (#20-626), Study #2a, as submitted by Glaxo Wellcome Inc. to the FDA, USA. 
     
       
         
           
               
               
               
               
               
               
             
               
                   
                 TABLE I 
               
               
                   
                   
               
               
                   
                 10 mg 
                 20 mg 
                 6 mg 
                 10 mg 
                 20 mg 
               
               
                   
                 Invention 
                 Invention 
                 Sub-Cut 
                 Imitrex 
                 Imitrex 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 T max /min 
                 20 
                 20 
                 10 
                 90 
                 90 
               
               
                 C max /ng ml −1   
                 10.5 
                 15.9 
                 87.4 
                 7.2 
                 12.8 
               
               
                 C 20 /ng ml −1   
                 10.5 
                 15.9 
                 66.4 
                 4.2 
                 7.1 
               
               
                 AUC 120 /ng min 
                 800 
                 1350 
                 4473 
                 690 
                 1182 
               
               
                 ml −1   
               
               
                 AUC ∞ /ng min ml −1   
                 2137 
                 3105 
                 7467 
                 1734 
                 3375 
               
               
                 AUC 60 /ng min ml −1   
                 474 
                 764 
                 3278 
                 278 
                 477 
               
               
                 AUC 30 /ng min ml −1   
                 236 
                 372 
                 1999 
                 97 
                 172 
               
               
                 AUC 20 /ng min ml −1   
                 136 
                 215 
                 1372 
                 48 
                 93 
               
               
                 BA/% 
                 17.2 
                 12.5 
                 100 
                 13.9 
                 13.6 
               
               
                   
               
            
           
         
       
     
     As can be seen, the nasal administration of the present invention shows a significantly greater peak plasma concentration C max  as compared with the existing Imitrex (RTM) nasal administration system having the same nominal amount of succinate base, and the concentration at twenty minutes C 20  is more than twice the concentration achieved by the existing Imitrex (RTM) nasal administration system. 
     In fact, the nasal administration system of the present invention has been established, by gamma-scintigraphic studies (in vivo and in vitro), to emit approximately 70% of the dose as contained in the capsule C, and even with an overage of 5% which is present in the capsule C, the actual amount of succinate base which is delivered by the nasal administration system of the present invention is about 8 mg for a 10 mg nominal and 16 mg for a 20 mg nominal. Thus, even more markedly improved results are predicted as compared with the existing Imitrex (RTM) nasal administration system on a dose-for-dose basis. 
     In addition, the nasal administration of the present invention shows a markedly shorter time maximum plasma concentration T max  as compared to the existing Imitrex (RTM) nasal administration system having the same nominal amount of succinate base. In the present invention, the time maximum plasma concentration T max  is about 20 minutes, which is about 70 minutes faster than that achieved with the conventional Imitrex (RTM) nasal administration system, and is approaching that of sub-cut delivery. 
     This markedly increased time maximum plasma concentration T max  lends the present invention to indications where a rapid onset of action is required. In the present Example, this event is migraine, but the present invention can be utilized to treat pain in general, including other headaches, such as cluster headaches, and neuropathic pain, to induce sedation, to ameliorate or abort another CNS event, to abort a partial or full epilepsy seizure, to treat a panic disorder, to treat insomnia, to treat jet-lag, to regulate blood glucose levels, to influence satiety or the sense of satiety, or to deliver a memory-enhancing agent prior to a learning episode. 
     Further, in the nasal administration of the present invention, the area under the curve to 30 minutes (AUC 30 ) is greater than twice that achieved with the conventional Imitrex (RTM) nasal administration system and approaching 2.5 times greater for the 10 mg nominal dose. 
     Still further, in the nasal administration of the present invention, the area under the curve to 20 minutes (AUC 20 ) is greater than twice that achieved with the conventional Imitrex (RTM) nasal administration system and approaching three times greater for the 10 mg nominal dose. 
     In addition, with the nasal administration of the present invention, the time course for the measured blood plasma concentration following administration shows a bifurcated trace, which has two peaks and is indicative of a hybrid absorption mechanism, with the early absorption being nasal absorption and the later, delayed absorption being oral or GI absorption. Studies have shown that oral absorption is very limited within a period of 20 minutes following administration, and thus it can be assumed that the absorption in the period to 20 minutes following administration relates essentially only to nasal absorption. 
     On this basis, the bi-directional administration of the present invention provides a significantly greater ratio of nasal absorption fraction to total bioavailability (BA), which clearly demonstrates the improved pharmacokinetics of the present invention. The present invention achieves a ratio of about 2.21, which compares with a ratio of about 0.71 for the conventional Imitrex (RTM) nasal administration system, where the nasal absorption fraction of the total BA is about 10% (Fuseau, E et al, Clinical Pharmacokinetics of Intranasal Sumatriptan, Drug Deposition, 41(11), 2002, pages 801 to 811) and the total BA after nasal administration is about 14%. From data available for other triptans delivered both as a nasal spray and orally (Goadsby, P, Zolmitriptan Intranasal: A Review of the Pharmacokinetics and Clinical Efficacy, Headache, 2006, 46, pages 138 to 149), zolmitriptan has a ratio of about 0.75, where the fraction of nasal absorption is about 30% and the total BA is about 40%. In this study, the fraction absorbed nasally was calculated by preventing absorption via the GI tract through the use of charcoal. 
     The markedly-improved pharmacokinetics of the nasal administration of the present invention is clearly shown in  FIG. 3 , which shows the time course for the averaged measured blood plasma concentration following administration of the sumatriptan succinate powder (10 mg sumatriptan base) by the bi-directional nasal administration of the present invention as compared to the corresponding historic averaged measured blood plasma concentration following intranasal administration of the 10 mg sumatriptan base Imitrex (RTM) nasal spray administration system. 
     The efficacy of the present invention is particularly surprising as the formulation of the present invention includes no absorption enhancer or muco-adhesive. 
     In the EEG analysis, the EEG profiles for the subjects when treated with the 10 mg and 20 mg intranasal administration of the present invention were broadly similar to the 6 mg sub-cut administration. 
     Previously, Thomaides, T et al, EEG and topographic frequency analysis in migraine attack before and after sumatriptan infusion, Headache, 36, pages 111 to 114, 1996, have determined that the main effects on the EEG associated with GTN-induced headaches are significant increases in relative values for the delta and theta frequency bands, with decreases in the alpha and beta frequency bands not reaching significance. 
     The treatment effects on the EEG relative energy parameter for each recording time are summarized in Table II hereinbelow for each frequency band (FB). A significant (p&lt;0.05 for sufficiently large number of scalp electrodes) IMP drug to comparator increase is indicated by a closed arrow, and a significant IMP drug to comparator decrease is indicated by an open arrow. An arrow between brackets indicates a statistical trend (4-5 electrodes display p&lt;0.05). 
     
       
         
           
               
             
               
                 TABLE II 
               
             
            
               
                   
               
               
                 Sumatriptan Intranasal 
               
            
           
           
               
               
               
            
               
                   
                 10 mg 
                 20 mg 
               
               
                 FB 
                 Invention 
                 Invention 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 time (min) 
                 Δ 
                 ϑ 
                 α 
                 β 
                 Δ 
                 ϑ 
                 α 
                 β 
               
               
                   
               
               
                 First 10 
                 (↑) 
                   
                 (    ) 
                   
                 ↑ 
                   
                 
                   
                 
                   
               
               
                 20 
                   
                 ↑ 
                 
                   
                 
                   
                   
                 (↑) 
                 
                   
                 
               
               
                 30 
                   
                 ↑ 
               
               
                 40 
                   
                   
                   
                   
                   
                   
                 
                   
                 
               
               
                 50 
               
               
                 60 
               
               
                 70 
                   
                   
                   
                 
                   
                 
               
               
                 80 
               
               
                 90 
               
               
                 2 h 
                   
                   
                   
                   
                   
                   
                 
                   
                 
               
               
                 4 h 
               
               
                 6 h 
               
               
                 8 h 
                   
                   
                   
                   
                   
                   
                 
                   
                 
               
               
                   
               
            
           
         
       
     
     As regards the theta relative energy, increases in theta relative energy were observed, as compared with the 6 mg sub-cut comparator administration. The largest differences with active comparator, which occurred over almost the entire right half and left posterior scalp from 20 to 40 minutes, were observed for the 10 mg administration, and these differences were less pronounced for the 20 mg administration. 
     As regards the delta relative energy, increases in the delta relative energy were more transient in the first 10 minutes for the 10 mg and 20 mg administrations, but more pronounced for the 20 mg administration. 
     As regards the alpha relative energy, both the 10 mg and 20 mg administrations decreased the alpha relative energy for a duration of 20 minutes over large portions of the anterior scalp, and additionally over the period from 30 to 40 minutes for the 20 mg administration. 
     Only few unsystematic modifications were observed in the absolute frequency band energies. For the additional parameters, it is worthwhile to note that the ASI, a measure of cortical arousal, was decreased for both the 10 mg and 20 mg administrations over large portions of the anterior scalp and displayed between 10 and 40 minutes, in addition spreading over posterior scalp regions for the 20 mg administration. 
       FIG. 4  illustrates median maps for theta and alpha relative energies for the 10 mg and 20 mg nasal administrations of the present invention and the 6 mg comparator sub-cut administration. 
     As illustrated, in the present study, the most salient effects of the 6 mg sub-cut administration were in sustained reductions from 0 to 40 minutes in theta activity (row 3), mostly in relative spectral contributions, and this was accompanied for a period of about half an hour by increased relative beta contributions. In addition, there were some signs of decreased delta activity (absolute and relative) but little effects in alpha activity emerged, but noting the trends for occipital increases (row 6). Overall, the best EEG-markers reflecting the restoring potential of sumatriptan are the relative energy values. 
     In the present study, pre-treatment with the 6 mg sub-cut administration completely prevented the excess in theta induced by sublingual GTN and resulted in depressed theta for 40 minutes. This is in agreement with studies by others. Indeed, in subjects in which an excess by more than 15% of theta (delta only a few percent) had been induced by the GTN challenge, this effect was reversed within 30 minutes after treatment with sumatriptan pharmacotherapy. And, when given via the intranasal route of administration, the 10 mg and 20 mg nasal administrations of sumatriptan powder induced, coarsely speaking, a similar EEG profile as the sub-cut comparator. 
     The fact that the nasal administrations of the present invention provide a similar EEG profile as the sub-cut comparator is particularly surprising given the very large differences in the C max  values for the nasal administrations of the present invention (10.5 and 15.9) as compared to the sub-cut comparator (87.4). The reason for this surprising result is not known, but the present inventors speculate that there could be a number of reasons. Firstly, it is known that the rate of abruption is apparently more important than the extent of absorption (Fox, W, Onset of Effect of 5-HT1B/1D Agonists: A Model with Pharmacokinetic Validation, Headache, 44, 2004, pages 142 to 147), and the rate of absorption of the sumatriptan powder of the present invention is similar to the sub-cut comparator and much faster than that of the conventional Imitrex (RTM) nasal administration system. Another possible reason is a direct nose-to-brain absorption mechanism, which has been shown in animal studies. A further possible reason is absorption through “counter current” transport via the sinus cavernous and the carotid artery, and, whilst sumatriptan passes the BBB poorly, sumatriptan is able to pass the BBB to some extent. A still further possible reason is direct or indirect action via the trigeminal and olfactory nerves, which is involved in the pathogenesis of migraine. 
     EXAMPLE #2 
     This study provides for characterization of the deposition as achieved by the nasal administration system of the present invention as used in the above-described study. 
     In this study, eight healthy subjects were studied. 
     In separate sessions, the subjects each received a test powder formulation, comprising radio-labelled lactose, using the nasal administration system of the present invention. 
     The lactose powder, as supplied by Friesland Foods Domo (Zwolle, The Netherlands), had a nominal mean particle size of 15 μm, with 10% having a particle size of less than 3 μm, 50% having a particle size less than 15 μm and 90% having a particle size less than 38 μm. 
     The lactose powder was “hot” radio-labelled with technetium 99Tc, using the labelling procedure disclosed in Karhu, M et al, International Journal of Pharmaceutics, 196, 2000, pages 95 to 103 ( 2 . 1 —Labelling of lactose particles). In this procedure, the lactose powder was dispensed in a lead box with a HEPA-filtered air stream and using an aseptic technique. 
     The deposition of the test powder in the nasal cavity was imaged using a scintillation camera system, here a VERTEX camera as supplied by ADAC Laboratories (USA) which was equipped with a low energy parallel hole high resolution VXGP collimator. 
     The powder was administered with the subjects sitting in the upright position, and, following administration, the subjects sat back such that the floor of the nasal cavity was projected at between 30 and 45 degrees with respect to the y-axis of the camera detector. This re-positioning took approximately 1 minute from the dose administration and imaging was initiated immediately thereafter. A total of 16 images, each containing 128×128 pixels, were acquired at two minute intervals. The subjects were instructed not to sniff during the imaging procedure. 
     As a consequence of the variation in administered activity, the acquired images were normalized so that the first image in each series, which represents the initial deposition, had a total image intensity equal to 100,000 within a region drawn around the nose as appearing in the cumulative images. As the floor of the nose and the curvature of the pharynx were clearly visible in the cumulative images as derived from each of the series, each series of images could conveniently be aligned. 
     Nasal dimensions were measured by acoustic rhinometry using Rhin2000 anatomic nose adaptors as supplied by RhinoMetrics (Lynge, Denmark), to verify normal nasal dimensions and to assist in nasal segmentation. Acoustic rhinometry identified the location of the minimal cross-sectional area corresponding to the head of the inferior turbinate, the head of the middle turbinate and the transition to the epipharynx. 
     In order to allow for characterization of the deposition, the nose region was segmented into six rectangular nasal regions, as illustrated in  FIG. 1( b ) , namely, a lower anterior region (LA), a mid anterior region (MA), an upper anterior region (UA), a lower posterior region (LP), a mid posterior region (MP) and an upper posterior region (UP), and one pharyngeal region. 
     The vertical segmentation VERT 1  which defines the anterior and posterior segments is at a point just posterior to the anterior limitation of the inferior turbinate, and the vertical segmentation VERT 2 , which defines the posterior nasal segment and the nasopharynx is at the posterior margin of the inferior turbinate. In this embodiment, for the purposes of the detection analysis, the anterior bound of the anterior segment was set at 15 pixels anterior to the vertical segmentation VERT 1  and the posterior bound of the nasopharynx region was set at 15 pixels posterior to the vertical segmentation VERT 2 . 
     The horizontal segmentation HORIZ 1 , HORIZ 2  which define the lower, mid and upper vertical segments are at heights of one-thirds and two-thirds of the distance between the lower and upper boundaries of the nasal cavity as defined by the nasal floor and the cribiform plate. In this embodiment the nasal floor was determined to be about 4 mm (c2 pixels) above a radio-labelled marker at the palette in the oral cavity, and the height of the nasal cavity was determined from the location of the olfactory bulb, which was determined to be between 38 and 45 mm (c18-21 pixels) depending upon the subject. 
     Table III below shows the mean values for the initial deposition in the six nasal segments and the nasopharynx, as represented by the first in the series of images for each of the subjects. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE III 
               
               
                   
                   
               
               
                   
                 Image 
                 Percentage (%) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Upper Anterior (UA) 
                 1.7 
               
               
                   
                 Mid Anterior (MA) 
                 10.7 
               
               
                   
                 Lower Anterior (LA) 
                 5.9 
               
               
                   
                 Upper Posterior (UP) 
                 17.4 
               
               
                   
                 Mid Posterior (MP) 
                 41.4 
               
               
                   
                 Lower Posterior (LP) 
                 20.9 
               
               
                   
                 Nasopharynx (NP) 
                 2.0 
               
               
                   
                   
               
            
           
         
       
     
     As can be seen, the bi-directional administration system provides for initial deposition of greater than 80% beyond the nasal valve of the total dose as deposited in the nasal cavity, and greater than 57% of the total dose as deposited in the nasal cavity is deposited in the upper posterior two thirds of the nasal cavity. This deposition pattern contrasts markedly with existing nasal delivery devices, where between 50 and 80% of the delivered dose is deposited anterior of the nasal valve. 
     The present inventors attribute this deposition pattern as an important contributing factor to the surprisingly enhanced efficacy as achieved in the study of Example #1. As mentioned hereinabove, the present inventors postulate that deposition in the upper posterior region, and in particular the upper posterior two thirds, which has a single-cell mucosal layer, allows for a direct nose-to-brain absorption mechanism, absorption through “counter current” transport via the sinus cavernous and the carotid artery, and direct or indirect action via the olfactory and trigeminal nerves, which is involved in the pathogenesis of migraine. 
     Finally, it will be understood that the present invention has been described in its preferred embodiments and can be modified in many different ways without departing from the scope of the invention as defined by the appended claims. 
     The present invention has been exemplified in relation to sumatriptan, but it will be understood that the present invention has application to many other substances, including other triptans, such as risatriptan, naratriptan, eletriptan, frovatriptan and zolmitriptan, and other analgesics, such as ergotamines, including dihydroergotamine mesylate, ergonovine maleate and ergotamine tartarate with caffeine, fentanyl, oxycondone, hydromorphone, morphine, codeine, ketobbemidone, cocaine and opiods in general. 
     The present invention also has application to benzodiazepines, such as midazolam. 
     The present invention further has application in relation to non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin, ibuprofen, naproxen, indomethacin, diclofenac and ketoprofen. 
     The present invention still further has application in relation to proteins and peptides, in particular having a molecular weight greater than 1000 g/mol, which typically have a very low oral bio-availability, often less than 1%. 
     Particular examples include insulin, including its analogues and derivatives, desmopressin and calcitonin. 
     The present invention yet still further has application in relation to powder vaccines, immunomodulators and immunostimulators. 
     In summary, the present invention has application in relation to the following broad definitions of molecules.
     (I) Small molecules (&lt;1000) with relatively fast nasal absorption and high nasal BA, such as fentanyl, midazolam and oxycodone. The present invention suggests far more rapid CNS effects than compared to the prior art nasal administration systems, which could be because of differences between arterial and venous concentrations, where arterial absorption is between about 25% and 50% greater than venous absorption, possible “counter current” transport to the sinus cavernous and the carotid artery, which must pass the BBB, which has been shown to be about 25% greater in animal studies, and possible direct N 2 B transport along the olfactory and trigeminal nerves (Einer-Jensen, N et al, Pharmacol. Toxicol., 87(6), 2000, pages 276 to 278, Einer-Jensen, N et al, Exp. Brain Res., 130(2), 2000, pages 216 to 220, and Dale, O et al, Intranasal Midazolam: a comparison of two delivery devices in human volunteers, J. Pharmacy and Pharmacology, 58, 2006, pages 1311 to 1318). N 2 B transport and clinical effects via the trigeminal nerves are not, however, necessarily reflected in the traditional PK profile.   (II) Small and medium sized molecules with relatively poor BA, such as sumatriptan and zolmitriptan. For the sumatriptan powder of the present invention, sumatriptan passes the BBB relatively poorly, but animal studies suggest that sumatriptan can be transported directly to the brain by direct N 2 B mechanisms (Gladstone, J P, Newer formulations of triptans: Advances in migraine treatment, Drugs, 63, 2003, pages 2285 to 2305). The present invention provides for increased absorption, which is particularly relevant where rapid absorption and a fast onset of action are desirable. The present invention suggests more rapid CNS effects, which could be because of possible direct N 2 B uptake, possible “counter current” transport to the sinus cavernous and the carotid artery, where the molecule is able to pass the BBB, and possible direct N 2 B transport along the olfactory and trigeminal nerves.   (III) Larger molecules (&gt;1000), including peptides and proteins, which have low nasal BA, typically between about 3 and 15%, and very poor oral BA, typically less than 1%, because of degradation in the GI tract. The present invention, in providing a powder formulation, is particularly suited to the delivery of peptides and proteins, where the powder can provide for improved nasal absorption, but also can have improved stability. For these substances, it is postulated that there may be a dedicated transport mechanism along the olfactory and trigeminal nerves directly to the cerebral structures, which is not via the CSF. As such, measurements from the CSF may not show the presence of active substance, but a substantial effect may be present in the brain and exert clinical effects, as exemplified in a recent study (Thorne, R G et al, Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration, Neuroscience, 127(2), 2004, pages 481 to 496).