Intranasal delivery of olanzapine by precision olfactory device

Methods are provided for acute treatment of agitation, including agitation in patients with schizophrenia or bipolar disorder, comprising administering to a subject with agitation an effective dose of a dry pharmaceutical composition comprising olanzapine, wherein the dose is administered by an intranasal delivery device that provides, following intranasal administration, (a) a mean peak plasma olanzapine concentration (Cmax) of at least 30 ng/mL, with (b) a mean time to Cmax (Tmax) of olanzapine of less than 0.5 hours. Dry pharmaceutical compositions and devices suitable for intranasal delivery of olanzapine are provided.

Of 130 million US emergency room visits per year, 1.7 million are estimated to involve agitated patients, including patients whose agitation is a manifestation of schizophrenia or bipolar disorder.

The current standard of care in treating acute and escalating agitation events in schizophrenia or bipolar I mania is to administer 5 mg, 7.5 mg or 10 mg of olanzapine, an atypical antipsychotic, by intramuscular injection (IM). While olanzapine IM is characterized by a rapid onset of action (mean maximum plasma concentration within 15 to 45 minutes), this route of administration is characterized by a number of injection-related acute side-effects, including injection site pain, over sedation, extrapyramidal symptoms, and akathisia (Atkins et al.,BMC Psychiatry14, 7 (2014); Battaglia et al.,Am. Emerg. Med.21:192-198 (2003); Kishi et al.,J. Psychiatr. Res.68:198-209 (2015)). Moreover, the invasive intramuscular injection process can lead to emotional trauma for the patient, whether cooperative or uncooperative, and can lead to physical assault on hospital staff attempting to administer the injection. Furthermore, IM injections are contraindicated in patients who are cooperative (Nordstrom et al.,West. J. Emerg. Med.13(1):3-10 (2012)).

Oral administration of olanzapine, either as a standard tablet or orally disintegrating tablet, is approved for acute treatment of manic or mixed episodes associated with bipolar 1 disorder and lacks many of the disadvantages of intramuscular injection in this patient population; however, there is significant lag before effective blood levels are achieved and agitation reduced.

Pulmonary delivery of the typical antipsychotic loxapine by oral inhalation was approved in 2017 for acute treatment of agitation associated with schizophrenia or bipolar 1 disorder in adults. However, the product label includes a black box warning that administration can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest (ADASUVE FDA product label, August 2017), and the product is available only under a risk evaluation and mitigation strategy (REMS).

An effective non-invasive treatment of acute agitation could shift treatment earlier in the agitation episode from the emergency room into the “community”, with significant benefits, including reduction of emergency department visits and health economic burden. There is, accordingly, a need for an acute treatment of agitation, including agitation related to schizophrenia and bipolar disease, with rapid onset of action and that does not require parenteral injection.

We have developed dry powder formulations of olanzapine suitable for intranasal delivery by a handheld, manually actuated, propellant-driven, metered-dose intranasal administration device. Following single dose PK studies in cynomolgus monkeys and in rodents, we conducted a phase I trial in healthy human subjects. In this phase I study, intranasal delivery of the olanzapine formulation resulted in similar or slightly higher plasma exposure (AUC) and maximum Cmaxas compared to the IM administered olanzapine at the same dose. Furthermore, the median Tmaxafter intranasal delivery of the formulation—ranging from 0.16-0.17 hrs across three tested doses was significantly shorter than the median Tmaxmeasured for both intramuscular and oral administration, demonstrating fast and effective absorption of olanzapine across nasal epithelium.

Pharmacodynamic effects were measured using three standardized behavioral tests. The behavioral tests showed that intranasal administration of olanzapine induces calming effects similar to or better than IM or oral administration of olanzapine. Consistent with the pharmacokinetic data, behavioral effects of olanzapine were observed significantly earlier in the subject groups treated with intranasal olanzapine (INP105) compared to the subject group treated with oral olanzapine (Zyprexa Zydis). These results show that intranasal delivery of olanzapine can be an effective method for acute treatment of agitation.

Accordingly, in a first aspect, methods are presented for acute treatment of agitation. The methods comprise intranasally administering an effective dose of a dry pharmaceutical composition comprising olanzapine to a subject exhibiting agitation.

In typical embodiments, the dry pharmaceutical composition is a powder. In some embodiments, the powder comprises the powder comprises olanzapine in a crystalline or amorphous form. In some embodiments, the olanzapine is an amorphous solid obtained by spray-drying. In some embodiments, the dry pharmaceutical composition comprises olanzapine in a partially crystalline and partially amorphous form.

In some embodiments, the median diameter of the olanzapine particle size distribution (D50) in the powder as measured by laser diffraction particle size analyzer, such as the Malvern Panalytical Mastersizer 3000, is between 1 μm and 100 μm, between 1 μm and 50 μm, or between 1 μm and 15 μm. In some embodiments, the median diameter of the olanzapine particle size distribution (D50) is between 7.5 μm and 15 μm.

In some embodiments, the dose is administered by an intranasal delivery device. In some embodiments, the intranasal delivery device is a handheld, manually actuated, metered-dose intranasal administration device. In some embodiments, the intranasal delivery device is a handheld, manually actuated, propellant-driven, metered-dose intranasal administration device.

In some embodiments, the dry pharmaceutical composition is, prior to device actuation, encapsulated within a capsule positioned within the device. In some embodiments, the dry pharmaceutical composition is, prior to device actuation, stored within a dose container that is removably coupled to the device.

In some embodiments, the intranasal delivery device is capable of delivering the dry pharmaceutical composition to the upper nasal cavity.

In some embodiments, the dry pharmaceutical composition comprises no more than 70 wt %, or no more than 60 wt % olanzapine. In some embodiments, the dry pharmaceutical composition comprises 10-60% wt % olanzapine, 20-60% wt % olanzapine, 25-55 wt % olanzapine, 30-50 wt % olanzapine, or 40-50 wt % olanzapine.

In some embodiments, the dry pharmaceutical composition comprises less than 3 wt %, less than 2 wt %, less than 1.5 wt %, less than 1 wt %, or less than 0.5 wt % water.

In some embodiments, the effective dose is a dose of olanzapine effective to reduce agitation within 60 minutes. In some embodiments, the effective dose of dry pharmaceutical composition comprises 1-30 mg of olanzapine; 2-20 mg of olanzapine; 5-15 mg of olanzapine; 5 mg of olanzapine, 10 mg of olanzapine; or 15 mg of olanzapine.

In some embodiments, the effective dose is administered as a single undivided dose. In some embodiments, the effective dose is administered as a plurality of equally divided sub-doses.

In some embodiments, the subject has schizophrenia. In some embodiments, the subject has bipolar disorder, optionally bipolar I disorder. In some embodiments, the subject has autism, dementia, PTSD, intoxication, or drug-induced psychotic state.

In some embodiments, the intranasal administration provides: (a) a mean peak plasma olanzapine concentration (Cmax) of at least 20 ng/mL, with (b) a mean time to Cmax(Tmax) of olanzapine of less than 1.5 hours.

In some embodiments, the intranasal administration provides: a mean time to Cmax(Tmax) of olanzapine of less than 1.0 hour; a mean time to Cmax(Tmax) of olanzapine of less than 0.75 hour; a mean time to Cmax(Tmax) of olanzapine of less than 0.50 hour or a mean time to Cmax(Tmax) of olanzapine of less than 0.25 hour.

In some embodiments, the intranasal administration provides: a mean peak plasma olanzapine concentration (Cmax) of at least 40 ng/mL; a mean peak plasma olanzapine concentration (Cmax) of at least 50 ng/mL; a mean peak plasma olanzapine concentration (Cmax) of at least 60 ng/mL; a mean peak plasma olanzapine concentration (Cmax) of at least 70 ng/mL; or a mean peak plasma olanzapine concentration (Cmax) of at least 80 ng/mL.

In another aspect, the present invention provides a dry pharmaceutical composition suitable for intranasal administration, comprising: olanzapine, and at least one excipient.

In some embodiments, the composition is a powder. In some embodiments, the composition comprises olanzapine in a crystalline or amorphous form. In some embodiments, the composition comprises olanzapine in amorphous form. In some embodiments, the amorphous olanzapine is obtained by spray-drying. In some embodiments, the composition comprises olanzapine in a partially crystalline and partially amorphous form.

In some embodiments, the median diameter of the olanzapine particle size distribution (D50) in the powder is between 1 μm and 100 μm, between 1 μm and 50 μm, or between 1 μm and 15 μm. In some embodiments, the median diameter of the olanzapine particle size distribution (D50) is between 7.5 μm and 15 μm.

In some embodiments, the dry pharmaceutical composition further comprises a permeation enhancer, wherein the permeation enhancer is selected from the group consisting of n-tridecyl-B-D-maltoside, n-dodecyl-β-D-maltoside, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and macrogol (15) hydroxystearate. In some embodiments, the permeation enhancer is 1,2-di stearoyl-sn-glycero-3-phosphocholine (DSPC).

In some embodiments, the dry pharmaceutical composition comprises less than 3 wt %, less than 2 wt %, less than 1.5 wt %, less than 1 wt %, or less than 0.5 wt % water.

In yet another aspect, the present invention provides a unit dose form containing a dry pharmaceutical composition provided herein.

In some embodiments, the unit dosage form contains 1-30 mg of olanzapine; 2-20 mg of olanzapine; 5-15 mg of olanzapine; 5 mg of olanzapine; 10 mg of olanzapine; or 15 mg of olanzapine.

In some embodiments, the unit dosage form is a capsule that encapsulates the dry pharmaceutical composition. In some embodiments, the unit dosage form is a dose container that stores the dry pharmaceutical composition, wherein the dose container is configured to removably couple to an intranasal delivery device.

Other features and advantages of the present disclosure will become apparent from the following detailed description, including the drawings. It should be understood, however, that the detailed description and the specific examples are provided for illustration only, because various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the detailed description.

5. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

A pharmaceutical composition is “dry” if it has a residual moisture content of no more than 5 wt %.

Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive.

Unless specifically stated or apparent from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural. That is, the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

In this disclosure, “comprises,” “comprising,” “containing,” “having,” “includes,” “including,” and linguistic variants thereof have the meaning ascribed to them in U.S. Patent law, permitting the presence of additional components beyond those explicitly recited.

Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean and is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the stated value.

5.3. Summary of Experimental Observations

We conducted two single dose PK studies in cynomolgus monkeys to examine the pharmacokinetics following administration of multiple powder olanzapine formulations delivered by the intranasal route using a non-human primate precision olfactory delivery (“nhpPOD” or “NHP-POD”) Device. The formulations examined included an unmodified crystalline powder, a formulation containing HPMC and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and a formulation containing HPMC and Pluronic F68. The placebo control, also delivered intranasally by the nhpPOD Device, was microcrystalline cellulose.

The PK results show that intranasal delivery using the nhpPOD Device of a formulation of olanzapine containing HPMC and DSPC results in similar plasma exposure (AUC) and Tmaxas intramuscular administration of olanzapine. In comparison to unformulated olanzapine (Cipla API), the formulated (HPMC/DSPC) powder results in a 1.7-fold higher AUC and a 2.8-fold shorter Tmax.

To further optimize the olanzapine (OLZ) formulations, approximately thirty different formulations were designed and manufactured for upper nasal delivery by a POD device. The formulations were tested, characterized and optimized for POD device compatibility. Stabilizers, permeation enhancers, particle size and manufacturing processes were also screened as part of the formulation development process.

In total, twenty of the formulations were evaluated in single dose PK studies in rat (data not shown) and non-human primates (NHPs). The results showed that administration of formulations F-OLZ #2, F-OLZ #5 and F OLZ #6 to NHPs via the NHP-POD device resulted in rapid uptake with short time to median Tmax(15, 15 and 23 min, respectively) and less than 7 min to exceed 40 ng/mL, which is approximately the plasma concentration achieved in stable non-agitated patients following 3×10 mg intramuscular injections (as reported in the Zyprexa NDA 21253). Delivery of formulations F-OLZ #1, F OLZ #3 and F-OLZ #4 to NHPs via the NHP-POD device resulted in slower plasma uptake compared to the other 3 formulations, but still resulted in Tmaxof 30-60 min, which is significantly faster than time to peak plasma concentration for oral olanzapine (OLZ) tablets or oral disintegrating tablets (Tmax˜5-8 hrs).

The pharmacodynamic effects of each nasal olanzapine formulation administered to NHPs were collected throughout each study. For lead formulations with shorter time to Tmax, visible calming, though not excessive sedation, was observed in the NHPs by the 7 min blood draw, and the effect continued through 24 hours. This reported calming effect was observed in all groups that received nasal olanzapine, though the time to onset was delayed and effect was less pronounced in groups with slower time to peak plasma concentration and with lower peak exposure.

Pharmacokinetics and pharmacodynamics effects of intranasal administration of formulation F-OLZ #2, an olanzapine formulation containing HPMC and DSPC (INP105), were further tested in healthy human subjects in a phase 1 clinical trial. In this study, intranasal delivery of the olanzapine formulation resulted in similar or slightly higher plasma exposure (AUC) and maximum Cmaxas compared to the IM administered olanzapine at the same dose. Furthermore, the median Tmaxafter intranasal delivery of the formulation was significantly shorter than the median Tmaxmeasured for the IM administered or orally administered olanzapine, demonstrating fast and effective absorption of olanzapine across nasal epithelium.

Pharmacodynamic effects were measured using three standardized behavioral tests—a Visual Analogue Scale (VAS); Agitation/Calmness Evaluation Scale (ACES); and Digit Symbol Substitution Test (DSST). The tests all showed that intranasal administration of olanzapine induces calming effects similar to or better than IM or oral administration of olanzapine. Furthermore, behavioral effects of olanzapine was observed significantly earlier in the subject groups treated with intranasal olanzapine (INP105) or IM olanzapine (Zyprexa IM), compared to the subject group treated with oral olanzapine (Zyprexa Zydis). This is consistent with the pharmacokinetic results where intranasal delivery of olanzapine was found to have significantly shorter median Tmaxas compared to IM or oral delivery. These results show that intranasal delivery of olanzapine can be an effective method for acute treatment of agitation.

5.4. Methods of Treating Agitation

Accordingly, in a first aspect methods are provided for acute treatment of agitation. The methods comprise intranasally administering an effective dose of a dry pharmaceutical composition comprising olanzapine to a subject exhibiting agitation.

5.4.1. Dry Powder Composition

In typical embodiments, the dry pharmaceutical composition is a powder.

In typical embodiments, the median diameter of the olanzapine particle size distribution (D50) in the powder, as measured by laser diffraction particle size analyzer, such as the Malvern Panalytical Mastersizer 3000, is 1 μm-500 μm. In some embodiments, the median diameter of the olanzapine particle size distribution (D50) in the powder is 1 μm-250 μm, 1 μm-100 μm, 1 μm-75 μm, 1 μm-50 μm, 1 μm-25 μm, 1 μm-20 μm, 1 μm-15 μm, or 2 μm-15 μm. In certain embodiments, the median diameter of the olanzapine particle size distribution (D50) in the composition is 2 μm-5 μm or 7.5 μm-15 μm.

In some embodiments, the powder comprises olanzapine in a crystalline form. In some embodiments, the powder comprises olanzapine in amorphous form. In some embodiments, the dry pharmaceutical composition comprises olanzapine in both crystalline and amorphous forms. In some embodiments, the dry pharmaceutical composition comprises olanzapine in a partially crystalline and partially amorphous form. In particular embodiments, the olanzapine is an amorphous solid obtained by spray-drying.

In some embodiments, the dry power composition further comprises a permeation enhancer selected from the group consisting of the permeation enhancer is selected from the group consisting of: n-tridecyl-β-D-maltoside, n-dodecyl-β-D-maltoside, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and macrogol (15) hydroxystearate. In some embodiments, the permeation enhancer is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

In some embodiments, the dry powder composition comprises both HPMC and DSPC.

In various embodiments, the dry powder composition further comprises a nonionic surfactant. In certain embodiments, the nonionic surfactant is an alkyl maltoside. In particular embodiments, the alkyl maltoside is n-dodecyl β-D-maltoside. In some embodiments, the nonionic surfactant is present in the dry powder composition at 0.1-10 wt/o, more typically 1-5 wt %. In particular embodiments, the nonionic surfactant is present at 1 wt %.

In some embodiments, the nonionic surfactant is Pluronic PF68. In some embodiments, the nonionic surfactant is present in the dry powder composition at 20-40 wt %, more typically 25-35 wt %. In particular embodiments, the nonionic surfactant is present at 31 wt %.

In some embodiments, the dry powder composition further comprises an acid. In certain embodiments, the acid is citric acid. In some embodiments, the acid is present in the dry powder composition at 10-20 wt %, more typically 15-20 wt %. In particular embodiments, citric acid is present at 18 wt %.

In various embodiments, the dry powder composition further comprises a salt of a monovalent inorganic cation. Typically, the salt is NaCl. In some embodiments, the composition comprises 1-5 wt % NaCl, or 2-4 wt % NaCl.

In some embodiments, the dry powder composition comprises less than 3 wt %, less than 2.5 wt %, less than 2 wt %, less than 1.5 wt %, less than 1 wt %, less than 0.9 wt %, less than 0.8 wt %, less than 0.7 wt %, less than 0.6 wt %, or less than 0.5 wt % water.

In currently preferred embodiments, the dry powder composition comprises 50 wt % olanzapine, 42 wt % HPMC, and 8% DSPC. In some embodiments, the dry powder composition is a spray dried composition that comprises amorophous olanzapine. In some embodiments, olanzapine is spray dried in the presence of HPMC and/or DSPC. In other embodiments, HPMC and/or DSPC is added after spray drying of olanzapine.

In the methods described herein, the dose is administered by an intranasal delivery device that delivers a powder to the nasal cavity.

In some embodiments, the intranasal delivery device is a handheld, manually actuated, metered-dose intranasal administration device. In certain embodiments, the device is manually actuated, propellant-driven metered-dose intranasal administration device. In particular embodiments, the dry pharmaceutical composition is, prior to device actuation, encapsulated within a capsule present within the device. In some embodiments, the dry pharmaceutical composition is stored within a dose container that is removably coupled to the device prior to device actuation. For example, the dose container may be inserted into a portion of the device or may be coupled to the device such that the dose container is in fluid communication with the device.

In various embodiments, the intranasal delivery device includes a housing body, a propellant canister housed within the housing body, a compound chamber containing a drug compound or designed to receive a drug compound, a channel in fluid communication with the propellant canister and the compound chamber, and an outlet orifice at a distal end of the channel. In this configuration, propellant released from the canister travels through the channel, contacts the drug compound in the compound chamber, and propels the drug compound out the outlet orifice for delivery into an upper nasal cavity.

In typical embodiments, the intranasal delivery device is capable of delivering the dry pharmaceutical composition to the upper nasal cavity.

5.4.2.1. Nasal Drug Delivery Device

In various embodiments, the intranasal administration device is a non-human primate precision olfactory delivery (“nhpPOD”) device described inFIGS. 7A-E, also described in U.S. Pat. No. 9,550,036, incorporated by reference in its entirety herein. In one embodiment, the intranasal device is one of the embodiments of FIGS. 1, 2, and 9 of U.S. Pat. No. 9,550,036. In these embodiments, the drug compound is loaded directly into the compound chamber.

An example nhpPOD device is shown inFIG. 6.

With reference toFIG. 6, a metered dose inhaler (MDI) canister602dispensing 25 μl hydrofluoroalkane is attached to the plastic actuator604. The actuator is in gas communication with a polytetrafluoroethylene frit1704which has a 50 μm pore size. The frit606is in communication with the dose holding cylinder610which is placed inside the body612of the POD in order to create an aerosolized flow. On actuation, the HFA propellant802is converted to a gas by passing through the frit material606and then mixes with the dose610; the dose and propellant mixture then exits from the 23 gauge stainless steel tubing nozzle614which is covered with a fluorinated ethylene-propylene liner that is placed over the outside of the metal tip in order to protect the nasal epithelia from being damaged by the nozzle614during use. In one embodiment, the dose610is loaded directly into the body612without a holding cylinder.

5.4.2.2. Medical Unit Dose Container

In various embodiments, the intranasal administration device is a medical unit dose container as described in US 2016/0101245 A1, the disclosure of which is incorporated herein by reference in its entirety.

5.4.2.3. Intranasal Device with Inlet Interface

In various embodiments, the intranasal administration device is a medical unit dose container as described in U.S. application Ser. No. 16/198,312, filed Nov. 21, 2018, the disclosure of which is incorporated herein by reference in its entirety and repeated below for completeness.

As shown inFIGS. 5A and 5B, the intranasal device500is designed to deliver a consistent mass of compound into the nasal cavity. For example, but not limited to, the compound may be an intranasal formulation in a powder form. The device500targets a specific region of the nasal cavity utilizing a narrow, targeted delivery plume. Specifically, the device500provides the compound to the upper one third of the nasal cavity. In one embodiment, the device500is used to administer the compound into the upper nasal cavity of a human. The upper nasal cavity includes the olfactory region and the middle and upper turbinate regions. In another embodiment, the device500is used to administer the compound into the upper nasal cavity of a non-human primate. The device500is also designed to simplify clinician loading of the compound into the device500and use thereof. The device500may be re-used to administer several doses of the compound.

FIG. 5Billustrates a partial cross-sectional view of the device500for delivering a compound intranasally, with coupled tip, and separately, a perspective view of the tip when uncoupled. In the embodiment ofFIG. 5B, the device500includes an actuator body502, a propellant canister504, and a tip506. The tip506includes an outer wall508and an inner wall510, an exit channel512, an inlet interface514, one or more grooves528(shown inFIG. 5C), an outlet orifice516, and a nozzle518.FIG. 5Billustrates the compound container520coupled to the inlet interface514. The compound contained in the compound container520may be a liquid or a powder. In the embodiment ofFIG. 5B, the compound is a powder.

As shown inFIG. 5B, the device500includes a propellant canister504positioned within the actuator body502. The propellant canister504contains propellant. In one embodiment, the propellant may be pressurized. The propellant is a fluid, for example, a liquid or gas. In one aspect, the propellant is a liquid. In another aspect, the propellant is a gas. Propellants include pharmaceutically suitable propellants. Some examples of pharmaceutically suitable propellants include hydrofluoroalkane (HFA) including but not limited to HFA, HFA227, HFA134a, HFA-FP, HFA-BP and like HFAs. In one aspect, the propellant is liquid HFA. In another aspect, the propellant is gaseous HFA. Additional examples of suitable propellants include nitrogen or chloroflourocarbons (CFC). Additionally, propellants may be pressurized air (e.g. ambient air). The canister504may be a metered dose inhaler (MDI) device that includes a pressurized canister and metering valve522(including stem) to meter the propellant upon actuation. In one embodiment, a pump fitment (not shown) secures the metered valve522to the canister504and holds both components in place during device500use. One series of embodiments of the pump fitment consists of securing interfaces that retain the pump fitment within the actuator body502, provide vertical displacement, and prevent rotation during installation of the canister504.

The propellant canister504may have a capacity for distributing propellant for a certain number of doses. In one embodiment, the device500may be shipped without a canister504and the canister504may be loaded into the actuator body502by the user. In some embodiments, the propellant canister may be replaced with a new propellant canister, such that the device500may be reused. In one aspect, when the MDI device is actuated, a discrete amount of pressurized HFA fluid is released. The MDI may contain between about 30 to about 300 actuations, inclusive of endpoints, of HFA propellant. The amount of fluid propellant released upon actuation may be between about 20 microliters (μl) and about 200 μl inclusive of endpoints, of liquid propellant.

The actuator body502comprises a propellant channel524that is in fluid communication with the propellant canister504. The propellant channel524is in fluid communication with the inlet interface514, which is configured to couple to the compound container520such that propellant released from the propellant canister504can be introduced into the compound container520via the one or more grooves528on the inlet interface514. In the embodiment ofFIG. 5B, the propellant channel524includes a port526at a distal end for receiving the tip506. In this configuration, the tip506may be coupled and decoupled to the actuator body502by inserting the tip506into the port526. In other embodiments, the port526may be inserted into the tip506. In some embodiments, the port526and/or the tip506may include a sealing interface that creates an airtight seal between the propellant channel524and the tip506such that propellant released from the canister504does not escape out of the propellant channel524and is directed to the inlet interface514.

The tip506may be coupled and decoupled to the actuator body502, which enables a user to load and unload a compound container520to and from the inlet interface514. The tip506includes the outer wall508and the inner wall510, where the inner wall forms the exit channel512which extends between a proximal end and a distal end of the tip506. The inlet interface514is positioned about a distal end of the outer wall508, and the inlet interface514couples the compound container520. In the embodiment ofFIG. 5B, the inlet interface514is a collar that may be inserted into the compound container520. In other embodiments, the inlet interface514may be a ring, band, port, or strap that interfaces with the compound container520. The inlet interface514includes one or more grooves528(shown inFIG. 5C) for directing propellant released from the canister504into the compound container520coupled to the inlet interface514. The released propellant then contacts the compound within the compound container520, agitating and entraining the compound and propelling the compound through the exit channel512and out the outlet orifice516located at a distal end of the exit channel512. In the embodiment ofFIG. 5B, the tip506includes a nozzle at the distal end of the exit channel512for directing the released propellant and the compound out of the outlet orifice in a narrow plume.

FIG. 5Cis a perspective view of the tip506and a compound container, in accordance with one or more embodiments. In the embodiment ofFIG. 5C, the compound container520is a capsule. The capsule may be comprised of two portions fitted together. When separated, a portion of the capsule (e.g., a half-capsule, as shown inFIGS. 5E-5G) may be coupled to the tip506. In use, the compound container520may contain a compound within the capsule. In one example, the compound is a powder. As shown inFIG. 5E, the half-capsule comprises an exit opening532of the compound container520. The exit opening532may be coupled to the inlet interface514, as shown inFIGS. 5F-5G. In the embodiments ofFIGS. 5F-5G, the inlet interface514is inserted into the exit opening532, and the compound container520may be secured to the inlet interface514via an interference fit. In an alternate embodiment, the exit opening532may be inserted into the inlet interface514. As shown inFIGS. 5G-5H, the tip506has the outer wall508and the inner wall510, where the exit channel512is formed by a bore or lumen through the inner wall510. The exit opening532is fitted about the inlet interface514such that the compound container520and the exit channel512are in fluid communication.

As shown inFIGS. 5F, 5G, and 5J, the inlet interface514is, for example, a ring, band, port, collar, or strap interfacing with the compound container520. As shown inFIGS. 5C, 5E, 5F, 5K, 5L, 5M, 5N, 5O, and 5P, one or more grooves528are positioned on the inlet interface514and create a flow path for the propellant released from the propellant canister504to travel into the compound container520. An example of the grooves528includes but is not limited to channels, slots, radial ports, or passageways. The grooves528provide a pathway via the inlet interface514by which the propellant flows into the compound container520. In one example, there are a plurality of grooves528. The grooves528may be equally spaced about the inlet interface514. The grooves528may be of equal size to each other or may be of differing sizes. The grooves528run along a length of the inlet interface514such that, when the compound container520is coupled to the inlet interface514, a first portion of each groove528is exposed within the propellant channel524and a second portion of each groove528is positioned within the compound container520. As shown inFIG. 5C, the inlet interface514includes a ledge530that is designed to abut the compound container520when coupled to the inlet interface514and the grooves528extend past the ledge530such that the grooves528are not fully covered by the compound container520.

In use, as shown by the direction of the arrows inFIG. 5D, the propellant released from the canister504flows through the propellant channel524and into the compound container520via the grooves528. The exit channel512is aligned with the exit opening532of the compound container520. The propellant flows in the grooves528of the inlet interface514, into the compound container520to agitate the powder, and the powder and the propellant exit the compound container520via the exit opening532congruent with the exit channel512. The propellant and powder mixture are carried through the exit channel512through the nozzle518and exit the device500at the outlet orifice516. In one example, the tip506may have one or a plurality of outlet orifices. The plume exiting the outlet orifice516has a narrow spray plume.

In one example of use of the device500, at time of use, a user separates a pre-filled capsule into its two halves. In one example, the capsule is prefilled with a powder compound. The half-capsule is coupled to the tip506via the inlet interface514. As shown inFIGS. 5Pand5Q, the tip506is then coupled to the actuator body502. A propelling gas, for example from either a refrigerant or compressed gas source, is directed through the propellant channel524and towards the filled powder capsule. The grooves528around the inlet interface514of the tip506introduce high velocity jets of propellant gas which agitate the dry powder into a suspension within the propellant gas (data not shown but confirmed with high speed close up video). Grooves528that introduce gas tangentially to the semispherical-shaped bottom of the compound container520creates jets which enhance stirring and entrainment of powder. Once the powder has been suspended, it is evacuated through the exit opening532, into the exit channel512, and out the outlet orifice516of the device500.

Generally, when accelerating a powder formulation through a restricting orifice, any constricting junction will cause the powder to clog. Since the powder administered by this device500is suspended within the propellant gas prior to evacuation, it can be further throttled and directed without device clogging. As a result, a much larger mass of powder can be delivered through a much smaller outlet orifice without the device500being prohibitively long. The time from propellant actuation to end of compound delivery is less than 1 second.

The grooves528in the proximal end of the tip506promote gas flow into the compound container520. In one example, the HFA gas is directed (e.g. orthogonally or near-orthogonally) at the surface of the powder dose residing in the compound container520, which creates rapid agitation and entrainment of the powder. The semispherical shape of the compound container520promotes gas redirection to the exit channel512of the tip506as shown inFIG. 5D. The arrows ofFIGS. 5B and 5Dshow the direction of propellant flow after the device500has been actuated.

The actuator body502attached and seals to the propellant canister504and the tip506, creating a pressurized flow path for the propellant gas. In certain aspects, the actuator body502is a reusable component. In certain aspects, the canister504is a reusable component.

In one example, the compound container520is a standard Size 3 drug capsule, although one of skill in the art would know how to use other sized drug capsules and modify the device500to fit same. Additionally, in another example, the compound container520may not be a capsule, but another container capable of containing a compound, such as but not limited to an ampoule. In one example, the ampoule may be made of plastic, and in one example it may be a blow fill sealed ampoule. To load the device500, the user or clinician will separate a prefilled formulation containing capsule, discard the cap, and install the capsule over the tip506. An empty compound container520can also be filled by a clinician at time of use before installing the compound container520onto the tip506. In certain examples, the capsule is a disposable component.

The tip506receives the compound container520during loading and is then coupled to the actuator body502prior to use. When the propellant canister504is actuated, expanding propellant gas is introduced into the compound container520via the grooves528around the inlet interface514of the tip506. The resulting propellant gas jets agitate and entrain the powder formulation within the compound container520, which then exits through the exit channel512and the outlet orifice516of the tip506. In one example, the tip506is a disposable component.FIG. 5Killustrates example measurements of the tip506with units in inches. In the embodiment ofFIG. 5N, the inlet interface514may include a radius along a bottom edge222to aid placement of the compound container520onto the tip506. The radius of curvature may range between approximately 0.005 inches to 0.025 inches, inclusive.

FIGS. 5T and 5Uillustrate perspective views of a second embodiment of a tip534. Similar to the tip506, the tip534may be coupled and decoupled to the actuator body502, which enables a user to load and unload a compound container536to and from the tip534for delivery to an upper nasal cavity of a user using the device500. As shown inFIGS. 5T and 5U, a compound container536is a capsule. The compound container536may, in one example, contain a powder. In the embodiments ofFIGS. 5T and 5U, the tip534includes an inlet interface538for coupling the compound container536, where the inlet interface538has a puncture member540. The puncture member540is designed to puncture the compound container536to create an opening in the compound container536. The puncture member540may comprise a sharp point, a sharp angle, a blade-like edge, or other suitable geometries for puncturing the compound container536. In one embodiment, the inlet interface538includes more than one puncture member540, where each puncture member540is designed to puncture the compound container536. The puncture members540may be positioned about the inlet interface538in a pattern, symmetrically, or at random. In one example, in use, a user may remove the tip534from the actuator body502, load the compound container536into the port526of the propellant channel524, and then insert the tip534back into the port526. As the tip534is coupled to the actuator body502, the puncture member540punctures the capsule. In this configuration, the punctured capsule fits around the puncture member540, as shown inFIG. 5U. In alternate embodiments, the puncture member542may comprise a plurality of puncture points544that each puncture the compound container536. The plurality of puncture points544may be spaced about the puncture member542.

FIGS. 5V and 5Willustrate perspective views of a puncture member542that may be used with the tip534, in accordance with one or more embodiments. As shown inFIG. 5V, the puncture member542may be a collar, ring, band, port or strap that couples with the punctured compound container536. The puncture member542includes one or more puncture grooves546that, similar to grooves528, form a flow path between the propellant channel524and the compound container536. The propellant from the propellant canister504enters via the one or more puncture grooves546of puncture member542and flows along the puncture grooves546and into the punctured compound container536. As shown inFIGS. 5V and 5W, the puncture member542includes a plurality of puncture openings548. In the embodiments ofFIGS. 5V, 5W, 5X, the puncture openings548are in fluid communication with the exit channel512. The propellant from the propellant canister504flows into the puncture grooves546, mixes with the powder in the punctured compound container536, and flows into the puncture openings544to the exit channel512. The arrows ofFIG. 5Xillustrate the flow path of the propellant. The exit channel512provides a route for the propellant and the powder to the nozzle518and the outlet orifice516. The mixture of propellant and powder exit the device500via the outlet orifice516. The plume exiting the device500is a narrow spray plume. In this embodiment, the puncture member542may be integrally molded as a single piece or may consist of two or more pieces. In one example, the puncture member542may be a separately molded piece acting in association with the inlet interface538(where the capsule attaches). In some embodiments, an inlet interface may include more than one puncture member542.

As shown inFIGS. 5V and 5W, as an alternate to the capsule being manually separated prior to placement on the tip534, the tip534may include an integrated puncture member542and puncture grooves546. In order to create a repeatable puncture of the compound container536, a puncture member542comes to a single point, puncture point544. In one example, the puncture point544includes puncture openings546that are radially spaced about the puncture point544. The puncture openings546are in fluid communication with the exit channel512for the powder to be evacuated from the compound container536.

As shown inFIG. 5X, by allowing the propellant flow path to be created with an inline puncture motion, loading the compound container536onto the tip534is simplified for the user, as the compound container536does not require manual manipulation and separation. In one example, the puncture member542is formed integrally with the tip534. In one example, the filled compound container536may be filled and installed into either the actuator body502or the tip534during manufacturing of the device500. At time of use, a user may apply a linear motion to drive the puncture member542into the pre-filled compound container536, creating a complete gas flow path for dosing prior to propellant actuation.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

Powder Capsule

In one embodiment, a device was constructed and tested. Testing was conducted for residual powder in the compound container after actuation. The device has equivalent performance of powder delivery, as determined by residuals after actuation, when 2 or more but less than 6 grooves on the inlet interface are used. In this example, the grooves are in combination with 63 mg of HFA propellant and a 0.040″ outlet orifice of the nozzle. Four grooves (every 90 degrees) were found to provide uniform gas delivery.

Dose Mass

Dose mass reproducibility testing was conducted. The standard deviation on dose delivery shows the device is capable of delivering consistent dose masses. The mean residual of dose left in the device was <5%, showing very little dose is lost in the device.

5.4.2.4. Intranasal Device with Plurality of Frits

FIG. 7Aillustrates another example of a non-human primate precision olfactory delivery device700, andFIG. 7Billustrates a side view and a cross-sectional view of an actuator body710of the intranasal device700ofFIG. 7A. The device700may deliver a compound that is a liquid, a powder, or some combination thereof. The device700includes a propellant canister705, the actuator body710, an extension tube715, and a tip720. Similar to the device1, the propellant canister705is in fluid communication with the actuator body710such that propellant released from the propellant canister705travels through the actuator body710, through the extension tube715, through the tip720, and out an exit opening725of the tip720. A compound may be loaded into the tip720such that as the propellant travels through the tip720, the propellant contacts the compound and propels the compound to the exit opening725, where the propellant and compound exit as a plume.

FIG. 7Cillustrates a side view of the extension tube715of the intranasal device700ofFIG. 7A. The extension tube715is a tube comprising an internal channel that creates fluid communication between the actuator body710and the tip720. In the embodiments ofFIGS. 7A to 7D, a first end730of the extension tube715couples to the actuator body710and a second end735of the extension tube715couples to the tip720each via a respective connecting interface740a,740b(collectively referred to as “740”). The connecting interface740comprises a luer lock having a male or a female end on each side of the luer lock. In the embodiment ofFIGS. 7A to 7D, each connecting interface740comprises a luer lock having two male ends. Accordingly, the male ends of the connecting interface740ainsert into the actuator body710and the first end730, respectively, and the male ends of the connecting interface740binsert into the tip720and the second end735, respectively. As illustrated inFIG. 7C, the second end735may include a plurality of frits745positioned within an internal channel of the luer lock. A frit745may be configured to convert a liquid propellant into a gas as the propellant passes through the frit745. Alternatively, the extension tube715inFIG. 7Bcan be configured to convert liquid propellant into a gas. The frit745may be composed of porous material. The number of frits745may vary in different embodiments. As the number of frits increases, the strength of the plume may be reduced, for example, in terms of its impact force, velocity, plume width, other similar metrics, or some combination thereof. Similarly, the length of the extension tube715may be adjusted such that the propellant has a longer or shorter distance to travel through. Calibrating the strength of the plume may enable the device700to accurately deliver the compound to the nasal cavity.FIG. 7Dillustrates a zoomed-in view of the connecting interface740bat the second end735of the extension tube715ofFIG. 7C—a first example embodiment750includes a single frit745, and a second example embodiment755includes three frits745stacked in succession. The number of frits745may be selected based on the type of compound. For example, a single frit745may be used for a powder compound, while three frits745may be used for a liquid compound, or vice versa.

FIG. 7Eillustrates a side view and a cross-sectional view of the tip720of the intranasal device ofFIG. 7A. The tip720is designed to be inserted into a nasal opening. The tip720comprises an internal channel760and the exit opening725for delivering the compound to the nasal cavity. In the embodiment ofFIG. 7E, the tip720comprises a frit745seated within the internal channel760. The frit745may be configured to convert a liquid propellant into a gas as the propellant passes through the frit745. The frit745may be composed of porous material. In the embodiment ofFIG. 7E, tip720further comprises a nozzle765at a distal end of the tip720near the exit opening725. The nozzle765may enhance deposition of the compound within the nasal cavity, such as to the upper olfactory region of a user. In some embodiments, the nozzle765may include a single orifice, and, in alternate embodiments, the nozzle765may include a plurality of orifices (e.g., between 2 to 11 orifices). In some embodiments, the tip720may not include a nozzle. Different embodiments of tips may be used based on different types of compounds to be delivered to the nasal cavity of the user. For example, a tip for delivering a powder compound may not include a nozzle, while a tip for delivering a liquid compound may include a nozzle, or vice versa. In addition, the number of orifices in the nozzle may similarly vary based on the type of compound. A compound may be loaded into the tip720such that the compound is contained within the internal channel760. In the embodiment ofFIG. 7E, the compound is loaded into the tip720through an opening770at a proximal end of the tip720before the frit745is seated within the internal channel760. The frit745is then inserted to contain the compound inside the tip720. In an alternate embodiment, for example an embodiment in which the tip720does not include a nozzle765, the compound may be loaded into the tip through the exit opening725. In the configuration ofFIG. 7E, the propellant travels from the propellant canister705, through the actuator body710and extension tube715, through the tip720and contacts the frit745, and then contacts the compound within the internal channel760, propelling the compound through the exit opening725, where the propellant and compound exit as a plume that is delivered within the nasal cavity of the user.

5.4.3. Effective Dose

In the methods described herein, the effective dose is a dose of dry powder composition that comprises olanzapine in an amount effective to reduce agitation. In some embodiments, the effective dose is a dose that comprises olanzapine in an amount effective to reduce agitation within 60 minutes, within 50 minutes, within 40 minutes, within 30 minutes, within 20 minutes, or within 10 minutes.

In some embodiments, the effective dose is administered as a single undivided dose. In some embodiments, the effective dose is administered as a plurality of equally divided sub-doses.

In the methods described herein, intranasal administration of olanzapine is used to acutely treat agitated patients. In some embodiments, the patient is an agitated emergency department patient.

In some embodiments, the patient has schizophrenia, bipolar disorder, dementia, or autism. In some embodiments, the patient has bipolar I disorder. In some embodiments, the patient has acute agitation unrelated to schizophrenia, bipolar disorder or autism. In certain embodiments, the patient has refractory panic disorder, post traumatic stress disorder, agitation associated with dementia, agitation related to a drug-induced psychotic state, intoxication, or agitation/aggression coupled with intellectual disability.

In various embodiments of the methods described herein, the intranasal administration provides (a) a mean peak plasma olanzapine concentration (Cmax) of at least 20 ng/mL, with (b) a mean time to Cmax(Tmax) of olanzapine of less than 1.5 hours.

In some embodiments, the intranasal administration provides a mean peak plasma olanzapine concentration (Cmax) of at least 25 ng/mL, at least 30 ng/mL, at least 40 ng/mL, at least 50 ng/mL, at least 60 ng/mL, at least 70 ng/mL, or at least 80 ng/mL.

In some embodiments, the intranasal administration provides a mean time to Cmax(Tmax) of olanzapine of less than 1.0 hour, less than 0.75 hour, less than 0.50 hour, or less than 0.25 hour.

In currently preferred embodiments, the intranasal administration provides a mean peak plasma olanzapine concentration of at least 40 ng/mL with a mean time to Cmax(Tmax) of less than 30 minutes, or more preferably, less than 20 minutes.

5.5. Dry Pharmaceutical Composition

In another aspect, dry pharmaceutical compositions suitable for intranasal administration are provided. The compositions comprise olanzapine and at least one excipient.

In typical embodiments, the dry pharmaceutical composition is a powder.

In some embodiments, the composition comprises olanzapine in a crystalline form. In some embodiments, the composition comprises olanzapine in an amorphous form. In some embodiments, the composition comprises olanzapine in a partially crystalline and partially amorphous form. In particular embodiments, the olanzapine is an amorphous solid obtained by spray-drying. In some embodiments, the composition comprises olanzapine in a crystalline form and an amorphous form.

In typical embodiments, the median diameter of the olanzapine particle size distribution (D50) in the powder, as measured by laser diffraction particle size analyzer, such as the Malvern Panalytical Mastersizer 3000, is 1 μm-500 μm. In some embodiments, the median diameter of the olanzapine particle size distribution (D50) in the powder is 1 μm-250 μm, 1 μm-100 μm, 1 μm-75 μm, 1 μm-50 m, 1 μm-25 μm, 1 μm-20 μm, 1 μm-15 μm, or 2 μm-15 μm. In certain embodiments, the median diameter of the olanzapine particle size distribution (D50) in the composition is 2 μm-5 μm or 7.5 μm-15 μm.

In some embodiments, the dry pharmaceutical composition further comprises a permeation enhancer selected from the group consisting of n-tridecyl-B-D-maltoside, n-dodecyl-β-D-maltoside, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and macrogol (15) hydroxystearate. In some embodiments, the permeation enhancer is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

In some embodiments, the dry pharmaceutical composition comprises both HPMC and DSPC.

In various embodiments, the dry pharmaceutical composition further comprises a nonionic surfactant. In certain embodiments, the nonionic surfactant is an alkyl maltoside. In particular embodiments, the alkyl maltoside is n-dodecyl β-D-maltoside. In some embodiments, the nonionic surfactant is present in the dry powder composition at 0.1-10 wt %, more typically 1-5 wt %. In particular embodiments, the nonionic surfactant is present at 1 wt %. In some embodiments, the nonionic surfactant is Pluronic PF68. In some embodiments, the nonionic surfactant is present in the dry powder composition at 20-40 wt %, more typically 25-35 wt %. In particular embodiments, the nonionic surfactant is present at 31 wt %.

In some embodiments, the dry pharmaceutical composition further comprises an acid. In certain embodiments, the acid is citric acid. In some embodiments, the acid is present in the dry powder composition at 10-20 wt %, more typically 15-20 wt %. In particular embodiments, citric acid is present at 18 wt %.

In various embodiments, the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation. Typically, the salt is NaCl. In some embodiments, the composition comprises 1-5 wt % NaCl, or 2-4 wt % NaCl.

In some embodiments, the dry pharmaceutical composition further comprises less than 3 wt %, less than 2.5 wt %, less than 2 wt %, less than 1.5 wt %, less than 1 wt %, less than 0.9 wt %, less than 0.8 wt %, less than 0.7 wt %, less than 0.6 wt %, or less than 0.5 wt % water.

In currently preferred embodiments, the dry pharmaceutical composition comprises 50 wt % olanzapine, 42 wt % HPMC, and 8% DSPC. In some embodiments, the dry pharmaceutical composition is a spray dried composition that comprises amorophous olanzapine. In some embodiments, olanzapine is spray dried in the presence of HPMC and/or DSPC. In other embodiments, HPMC and/or DSPC is added after spray drying of olanzapine.

5.6. Unit Dosage Form

In another aspect, unit dosage forms are provided. The unit dosage form contains a dry pharmaceutical composition as described in Section 5.5 above.

In typical embodiments, the unit dosage form contains 1-30 mg of olanzapine. In some embodiments, the unit dosage form contains 2-20 mg of olanzapine. In some embodiments, the unit dosage form contains 5-15 mg of olanzapine. In some embodiments, the unit dosage form contains 5 mg of olanzapine. In some embodiments, the unit dosage form contains 10 mg of olanzapine. In some embodiments, the unit dosage form contains 15 mg of olanzapine.

In some embodiments, the unit dosage form is a capsule that encapsulates the dry pharmaceutical composition. In some embodiments, the capsule is a hard capsule. In some embodiments, the hard capsule is an HPMC hard capsule.

In some embodiments, the unit dosage form is a dose container that stores the dry pharmaceutical composition, wherein the dose container is configured to removably couple to an intranasal delivery device. In particular embodiments, the dose container is a tip that is configured to be removably coupled to an intranasal delivery device.

5.7. Experimental Examples

The invention is further described through reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting.

A single dose pharmacokinetics (PK) study in the cynomolgus monkey was performed to examine the PK following administration of multiple powder olanzapine formulations delivered by the intranasal route using a non-human primate precision olfactory delivery (“nhpPOD”) Device. The formulations examined included an unmodified crystalline powder of olanzapine (“API”), a formulation containing hydroxypropylmethylcellulose (“HPMC”) and 1,2-distearoyl-sn-glycero-3-phosphocholine (“DSPC”), and a formulation containing HPMC and Pluronic F68. The placebo control, also delivered intranasally by the nhpPOD Device, was microcrystalline cellulose (“MCC”).

5.7.1.1. Study Design

The study design of the non-human primate PK study is outlined below:

The IM dose in non-human primates (“NHP”) was calculated in mg/kg using a 10 mg human equivalent dose (FDA allometric scaling guidance). The monkey intranasal doses were selected based on comparison to a 10-15 mg olanzapine dose to humans using nasal surface area calculations.

Sample Collection

Blood samples were collected, centrifuged to isolate plasma, and were frozen until analysis by LC/MS/MS to measure olanzapine and n-desmethyl olanzapine levels.

Sample Preparation and LC/MS/MS Analysis

Control matrix used included 0.25 Percent Ascorbic Acid fortified plasma. Additionally, BAM0501 procedures assume that all unknown samples are fortified prior to receipt and assay. AIT Bioscience Bioanalytical Method BAM0501.01 was used for the quantitation of olanzapine and N-desmethyl olanzapine in K2EDTA monkey plasma. This method was developed to cover the range of 0.0500-50.0 ng/mL of olanzapine and N-desmethyl olanzapine using olanzapine-D8 and N-desmethyl olanzapine-D8 as the respective internal standards. Two sets of calibration standards were included in each analytical run, one set placed at the beginning and one at the end.

Samples were maintained cold until the point of aliquoting. A sample volume of 100 μL was aliquoted directly to a Waters, Ostro 96-well solid support plate. Then, 300 μL of internal standard solution (1 ng/mL for each ISTD) prepared in 100:1, acetonitrile:formic acid was added to the plate. The wells were mixed well to induce protein precipitation. Then, samples were passed through the bed with the eluate collected into a clean 96-well plate. Samples were then evaporated to dryness under nitrogen at 25° C. and reconstituted in 100 μL of 87.5:10:2.5, water:acetonitrile:ammonium acetate (200 mM, pH 4.0).

Samples were analyzed on a Dionex UltiMate 3000 liquid chromatograph interfaced with a Thermo Scientific TSQ Quantiva triple quadrupole mass spectrometer with ESI ionization. Each extracted sample was injected (10 μL) onto a Waters BEH C18 column (2.1×50 mm; 1.7 μm) equilibrated at 40° C.

The LC gradient is shown below:

The retention time, mass transition and precursor charge state for each compound are as follows:

Raw data from the mass spectrometer was acquired and processed in Thermo Scientific LCquan. Peak area ratios from the calibration standard responses were regressed using a (1/concentration2) linear fit for olanzapine and N-desmethyl olanzapine. The regression model was chosen based upon the behavior of the analyte(s) across the concentration range used during development.

The total doses of olanzapine achieved as well as the dose per cm2of nasal surface area in each group are displayed in the table below:

The calculated mean PK parameters for olanzapine are tabulated below in Table 5, and the average plasma concentration-time curves are provided inFIG. 1. For this document, only the olanzapine PK is reported (not the n-desmethyl olanzapine).

The PK results show that intranasal delivery using the nhpPOD Device of a formulation of olanzapine containing HPMC and DSPC results in similar plasma exposure (AUC) and Tmaxas the IM administered olanzapine. In comparison to unformulated olanzapine (Cipla API), the formulated (HPMC/DSPC) powder results in a 1.7-fold higher AUC and a 2.8-fold shorter Tmax.

5.7.2. Example 2: Rodent and Non-Human Primate PK Studies

5.7.2.1. Manufacturing and Analytical Testing

Approximately thirty different olanzapine (OLN) formulations were designed and manufactured for upper nasal delivery by a POD device.

The formulations were tested, characterized and optimized for POD device compatibility. The formulations were analyzed by an Impel-developed high pressure liquid chromatography/diode array detector method optimized for Impel's OLZ formulations. Their solid states were further characterized by X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Moisture content was measured by Karl Fischer titration or loss on drying. Particle size distribution was measured by laser diffraction (Malvern Panalytical). POD device compatibility for species-specific (rat-POD and NHP-POD (FIG. 2)), clinical, and to-be-marketed devices was also tested using a gravimetric method that determines compatibility through residual and variability in delivery (coefficient of variation).

In total, twenty of the formulations were evaluated in single dose PK studies in rat (data not shown) and non-human primates (see below). The twenty formulations include six lead formulations (F-OLZ #1-6), the compositions of which are provided in Table 6 below.

5.7.2.2. Study Design

The formulations were evaluated at a single dose in rats (data not shown) and in NHP. The study design of the NHP PK study for six lead formulations (F-OLZ #1-6) is outlined below:

Blood samples were collected and centrifuged to isolate plasma. The plasma was analyzed by chromatography-mass spectrometry-mass spectrometry (LC/MS/MS) method optimized to measure olanzapine.

Raw data from the mass spectrometer was acquired and processed by non-compartmental analysis using Phoenix WinNonlin (v6.3 and v 8.0). Tolerability and pharmacodynamic impacts of each nasal OLZ formulation were also observed and recorded throughout the study.

Short-term (1 week) stability of the formulations was assessed under accelerated conditions (40° C./75% relative humidity). Chemical stability, physical stability (data not shown), and device compatibility tests were used to select formulations for in vivo studies and to identify potential degradants. Short-term formulation stability results for the six lead formulations are shown in Table 8.

The short-term stability results demonstrate that the six lead formulations have good purity over the brief accelerated period. Powder flow characteristics of the formulations impacted device compatibility as shown by differences in variability.

One of the six lead formulations, F-OLZ #2, was tested on stability for 5 months and had >99% assay and <1% total impurities over the long-term storage period. Furthermore, device uniformity (compatibility of the device delivering the formulation) results for F-OLZ #2 over the 5-month period were excellent, demonstrating that even with minor changes to powder characteristics (e.g., moisture content), the formulation continues to perform well with POD technology (Table 9). These results demonstrate that good shelf-life for POD-OLZ is feasible, especially considering that the stability study was conducted without the opportunity to optimize packaging during this early stage.

PK study results of the six lead formulations (F-OLZ #1-6) in NHPs are provided inFIGS. 3 and 4. Specifically,FIGS. 3 and 4provide plasma concentration time curves from blood samples collected following administration of one of the six different olanzapine (OLZ) formulations. Various PK parameters following the olanzapine administration by the NHP-POD device are also summarized in Table 10.

The results showed that administration of formulations F-OLZ #2, F-OLZ #5 and F-OLZ #6 to NHPs via the NHP-POD device resulted in rapid uptake with short time to median Tmax(15, 15 and 23 min, respectively) and less than 7 min to exceed 40 ng/mL, which is approximately the plasma concentration achieved in stable non-agitated patients following 3×10 mg intramuscular injections (Zyprexa NDA 21253). Delivery of formulations F-OLZ #1, F-OLZ #3 and F-OLZ #4 to NHPs via the NHP-POD device resulted in slower plasma uptake compared to the other 3 formulations, but still resulted in Tmaxof 30-60 min, which is significantly faster than time to peak plasma concentration previously reported for oral olanzapine (OLZ) tablets or disintegrating tablets (Tmax˜5-8 hrs).

All six formulations delivered by the NHP-POD device were well tolerated following single dose administration to NHPs. No visible irritation was observed following administration or 24 hours after delivery. Additionally, though not shown in this Example, 14-day sub-chronic toxicity in rat was studied with nasal olanzapine delivery. No macroscopic or microscopic findings were reported suggesting that acute and repeat exposure nasal olanzapine will be well tolerated in human patients.

The pharmacodynamic effects of each nasal olanzapine formulation administered to NHPs were collected throughout each study. For lead formulations with shorter time to Tmax, visible calming, though not excessive sedation, was observed in the NHPs by the 7 min blood draw, and the effect continued through 24 hours. This reported calming effect was observed in all groups that received nasal olanzapine, though the time to onset was delayed and effect was less pronounced in groups with slower time to peak plasma concentration and with lower peak exposure.

This series of pre-clinical studies demonstrated that tested lead olanzapine formulations have chemical stability, excellent purity, and device compatibility over at least 5 months, suggesting a reasonable shelf-life will be feasible for a powder POD-OLZ product. Moreover, nasal delivery of olanzapine by the POD device resulted in rapid uptake across the nasal epithelium in NHP, with lead formulations resulting ˜15 min time to maximum plasma concentration, comparable to the intramuscular injection of olanzapine. Olanzapine nasal formulations delivered by NHP-POD device were well tolerated and exhibited rapid calming effects, both positive attributes of a potential treatment for acute agitation.

The results have led to the identification of a lead formulation.

5.7.3. Example 3: A Phase 1 Clinical Trial of INP105 (Olanzapine Delivered Intranasally by 1231 POD® Device) in Healthy Human Volunteers

5.7.3.1. Study Formulation

Based on the results described in Example 2 above, the F-OLZ #2 formulation was chosen for the first human clinical trial. The dry powder formulation contains olanzapine, HPMC and DSPC in the weight ratios of OLZ:HPMC:DSPC (50:42:8 w/w). Further characteristics of the cGMP batch are provided in Table B below. Stability data for the encapsulated cGMP drug product is provided in Table C below.

5.7.3.2. Study Design

The powder formulation of olanzapine was tested in a randomized, double-blind, placebo-controlled and active-controlled, ascending-dose, 2-way, 2-period, incomplete block, crossover, Phase 1 trial to compare the safety, tolerability, PK and PD of three single doses of INP105 (olanzapine delivered by 1231 POD® Device) with the safety, tolerability, PK and PD of one dose of intramuscular olanzapine (Zyprexa IM, 5 mg) and one dose of olanzapine administered orally using an orally disintegrating tablet (ODT) (Zyprexa Zydis, 10 mg). Randomization for Periods 1 and 2 was performed for each subject on Day 1. The 1231 POD® device is a handheld, manually actuated, propellant-driven, metered-dose administration device designed to deliver a powder drug formulation of olanzapine to the nasal cavity.

In Period 1, subjects were assigned to 1 of 3 cohorts (n=12 per cohort). Within each cohort, subjects were randomized 6:6 to one of two reference therapy treatment groups receiving a single dose of Zyprexa IM or Zyprexa Zydis, as outlined in Table 11. Dose administration occurred at Visit 2 on Day 1 (relative to each cohort). Each cohort was scheduled to allow time for Period 2 safety assessments to occur prior to dose escalation in the next cohort period 2 dosing. Subjects remained confined to the study site for 72 hours after dosing. Subjects returned to the study site on Days 5 and 6 (Visits 3 and 4) for follow-up assessments.

In Period 2, subjects returned to the study site after a washout period of at least 14 days. Subjects from each Period 1 cohort received a single dose of INP105 (5, 10 or 15 mg) or placebo in a 9:3 ratio, as outlined in Table 11. Dose administration occurred on Day 15. (Dosing was permitted to occur later than the calendar Day 15 as required for scheduling (up to 2 days) but not before Day 15.) Ascending-dose levels of INP105 (5, 10 or 15 mg) were administered to ascending cohort numbers as follows:

Dose escalation between cohorts in Period 2 was performed in sequence. After 48 hours of inpatient confinement for the last available subject in each cohort, all available safety data from the preceding dose level of INP105 were reviewed before initiating dosing in the next higher dose cohort. Cohort 3, Period 2 was divided up into a “sentinel” group of 4 subjects with double blind dosing spaced at least 30 minutes apart. If no safety concerns were reported, the remaining 8 subjects were all dosed the next day.

Safety and Tolerability:

Safety was determined by evaluating physical examination findings, nasal examination findings, ECGs, vital signs, clinical laboratory parameters, concomitant medication usage and adverse events (AEs). If deemed necessary, additional safety measurements were performed at the discretion of the Investigator, SME or LMM.

The following tests were performed, in sequence, at the specified PD assessment time points:

1. Subjective sedation by Visual Analogue Scale (VAS)Subjects were asked to assess their own level of sedation during the study with the descriptive anchor terms Alert/Drowsy, Foggy/Clear-headed and Energetic/Lethargic.

3. Attention by Digit Symbol Substitution Test (DSST).Requires response speed, sustained attention, visual spatial skills and set shifting. Subjects record the symbols that correspond to a series of digits as outlined on the test paper. Completion of the task is timed. Data are summarized by treatment. The relationship between PD variables and PK is analyzed on an exploratory basis.

Olanzapine (OLZ) concentration-time profiles for each administration method are presented graphically. Plasma OLZ PK parameters: mean time to maximum plasma drug concentration (Tmax), maximum observed drug plasma concentration (Cmax), area under the curve (AUC) from time zero to the time of the last measurable concentration (AUC0-last), terminal elimination rate constant (kel), AUC from time zero to infinity (AUC0-inf), elimination half-life (t1/2), total apparent body clearance (CL/F) and apparent volume of distribution at the terminal phase (Vz/F) (where data are sufficient for parameter determination) were calculated.

Plasma concentration-time data for olanzapine were used to determine pharmacokinetic (PK) parameters. The following pharmacokinetic parameters were determined: Cmax, Tmax, Tlast, AUClast, and t1/2where possible. Results are displayed in Table 12 andFIGS. 8A-C.

Intranasal administration of olanzapine (INP105) using the 1231 POD device provides dose-dependent Cmax. All doses provide mean Cmax>30 ng/ml with mean Tmax<0.2 hour.

The PK results show that intranasal delivery using the nhpPOD Device of a formulation of olanzapine containing HPMC and DSPC results in similar or slightly higher plasma exposure (AUC) and maximum Cmaxas compared to the IM administered olanzapine (Zyprexa) at the same dose. The earliest time point drug was measured was 5 minutes, and the median Tmaxwas approximately 0.16-0.17 hr after intranasal delivery of a formulation of olanzapine, significantly shorter than the median Tmaxmeasured for the IM administered olanzapine (0.33-0.36 hr) or orally administered olanzapine (2 hr). The results suggest that intranasal administration of a formulation of olanzapine containing HPMC and DSPC increases the rate and extent of uptake and subsequent systemic exposure, as a slightly higher AUC and Cmaxand a significantly shorter Tmaxwere demonstrated compared to the IM administered olanzapine (Zyprexa IM) or orally administered olanzapine (Zydis ODT).

Measurement of a Visual Analogue Scale (VAS) score was conducted for each subject by asking the subject to assess his or her own level of sedation during the study with the descriptive anchor terms: Alert/Drowsy, Foggy/Clear-headed and Energetic/Lethargic. Average VAS scores with respect to the three categories for each subject group treated with the INP105, IM olanzapine (Zyprexa IM), oral olanzapine (Zydis ODT) or placebo are displayed inFIG. 9. The results show that administration of olanzapine provided dose-dependent behavioral effects in all subject groups treated with olanzapine regardless of the routes of administration.

Pharmacodynamic effects were further assessed by Agitation/Calmness Evaluation Scale (ACES). ACES is a single-item scale developed to assess the level of agitation-calmness where 1=marked agitation; 2=moderate agitation; 3=mild agitation; 4=normal; 5=mild calmness; 6=moderate calmness; 7=marked calmness; 8=deep sleep; and 9=unable to be aroused. Maximum ACES changes compared to the baseline are presented inFIG. 10and ACES-time profiles for each administration method are presented inFIGS. 11A-B. The ACES data confirmed dose-dependent sedation effects in all subject groups treated with olanzapine regardless of the routes of administration. Intranasal olanzapine (INP105) induced similar sedation effects to IM olanzapine (Zyprexa IM) at the same dose. Furthermore, the ACES-time profiles presented inFIGS. 11A-Bshow that sedation effects of olanzapine appear significantly earlier in the subject groups treated with intranasal olanzapine (INP105) or IM olanzapine (Zyprexa IM), compared to the subject group treated with oral olanzapine (Zyprexa Zydis). These results are consistent with the PK study results, where median Tmaxfor the intranasally administered olanzapine (0.16-0.17 hr) or the IM administered olanzapine (0.33-0.36 hr) was found to be significantly shorter than for orally administered olanzapine (2 hrs).

Additionally, attention by Digit Symbol Substitution Test (DSST) was conducted to assess response speed, sustained attention, visual spatial skills and set shifting in response to olanzapine administration. Each subject was instructed to record the symbols that correspond to a series of digits as outlined on the test paper. Completion of the task was timed and data are summarized and provided inFIGS. 12 and 13A-B. The maximum DSST changes compared to the baseline presented inFIG. 12show that administration of olanzapine decreases response speed in a dose dependent manner regardless of the route of administration.

Maximum changes in DSST from baseline are presented inFIG. 12, and DSST-time profiles are presented inFIGS. 13A-B. The DSST-time profiles presented inFIGS. 13A-Bshow that behavioral effects of olanzapine start significantly earlier in the subject groups treated with intranasal olanzapine (INP105) or IM olanzapine (Zyprexa IM), compared to the subject group treated with oral olanzapine (Zyprexa Zydis). These results are consistent with the PK study results as well as PD study results based on ACES profiles, described above.

Olanzapine concentration-time profiles and DSST or ACES-time profiles for each subject group are superimposed and presented inFIGS. 14A-Fand15A-F (DSST) andFIGS. 16A-Fand17A-F (ACES). The graphs show that intranasal administration (INP105) or IM administration of olanzapine (Zyprexa IM) induced rapid increase of olanzapine concentration and rapid behavioral changes as measured by DSST or ACES. On the other hand oral administration of olanzapine (Zyprexa Zydis) induced significantly slower responses, both in the olanzapine concentrations and in the DSST or ACES responses.

The data show that olanzapine delivered by intranasal administration has dose-dependent pharmacokinetics and provides a mean peak plasma olanzapine concentration (Cmax) of at least 30 ng/mL, with a mean time to Cmax(Tmax) of less than 15 minutes, approaching a Tmaxof 10 minutes. Furthermore, olanzapine administered by the POD device provide a large AUC, a short mean time to Cmax(Tmax) and rapid behavioral effects, similar to or better than IM olanzapine (Zyprexa) at the same dose, suggesting effective absorption of olanzapine across the nasal epithelium. This shows that intranasal delivery of olanzapine can be an effective method for acute treatment of agitation.

6. INCORPORATION BY REFERENCE

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety.