Patent Application
20190240150
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 Psychiatry 14, 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 Cmax as compared to the IM administered olanzapine at the same dose. Furthermore, the median Tmax after intranasal delivery of the formulation—ranging from 0.16-0.17 hrs across three tested doses was significantly shorter than the median Tmax measured 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 further comprises a stabilizer, wherein the stabilizer is selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus), vinyl pyrrolidine-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolidine K30 (Kollidon K30), polyvinyl pyrollidone K90 (Kollidon K90), hydroxypropylcellulose (HPC), hydroxypropyl betacyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is hydroxypropylmethylcellulose (HPMC).
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-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 pharmaceutical composition further comprises an antioxidant, wherein the antioxidant is selected from the group consisting of: alpha tocopherol, ascorbic acid, ascorbyl palmitate, bronopol butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylene diainetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodiumthiosulfate, thymol, and vitamin E polyethylene glycol succinate.
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 dry pharmaceutical composition consists essentially of: 50 wt % olanzapine; 42 wt % HPMC; and 8 wt % DSPC.
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 comprises no more than 70 wt % olanzapine; 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; 30-40 wt % olanzapine; or 40-50 wt % olanzapine.
In some embodiments, the dry pharmaceutical composition further comprises a stabilizer, wherein the stabilizer is selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus), vinyl pyrrolinone-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolinone K30 (Kollidon K30), polyvinyl pyrrolidine K90 (Kollidon K90), hydroxypropylcellulose (HPC), hydroxypropyl betacyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is hydroxypropylmethylcellulose (HPMC).
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-3-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 further comprises an antioxidant, wherein the antioxidant is selected from the group consisting of alpha tocopherol, ascorbic acid, ascorbyl palmitate, bronopol butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylene diainetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
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 dry pharmaceutical composition consists essentially of: 50 wt % olanzapine; 42 wt % HPMC; and 8 wt % DSPC.
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.
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 %.
Ranges: throughout this disclosure, various aspects of the invention are presented in a range format. Ranges include the recited endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
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.
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 Tmax as 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 Tmax of 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 Cmax as compared to the IM administered olanzapine at the same dose. Furthermore, the median Tmax after intranasal delivery of the formulation was significantly shorter than the median Tmax measured 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 Tmax as compared to IM or oral delivery. 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 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.
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 various embodiments, the dry powder composition comprises no more than 70 wt % olanzapine. In some embodiments, the dry pharmaceutical composition comprises no more than 60 wt % olanzapine. In some embodiments, the composition comprises 10-70% wt % olanzapine, 20-70 wt % olanzapine, 10-60% wt % olanzapine, 20-60 wt % olanzapine, 25-55 wt % olanzapine, 30-50 wt % olanzapine, 30-40 wt % olanzapine or 40-50 wt % olanzapine.
In some embodiments, the dry powder composition further comprises a stabilizer selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus), vinyl pyrrolidine-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolidine K30 (Kollidon K30), polyvinyl pyrollidone K90 (Kollidon K90), hydroxypropylcellulose (HPC), hydroxypropyl betacyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is hydroxypropylmethylcellulose (HPMC).
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 antioxidant selected from the group consisting of alpha tocopherol, ascorbic acid, ascorbyl palmitate, bronopol butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylene diainetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodiumthiosulfate, thymol, and vitamin E polyethylene glycol succinate.
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.
In various embodiments, the intranasal administration device is a non-human primate precision olfactory delivery (“nhpPOD”) device described in
An example nhpPOD device is shown in
With reference to
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.
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 in
As shown in
The propellant canister 504 may have a capacity for distributing propellant for a certain number of doses. In one embodiment, the device 500 may be shipped without a canister 504 and the canister 504 may be loaded into the actuator body 502 by the user. In some embodiments, the propellant canister may be replaced with a new propellant canister, such that the device 500 may 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 body 502 comprises a propellant channel 524 that is in fluid communication with the propellant canister 504. The propellant channel 524 is in fluid communication with the inlet interface 514, which is configured to couple to the compound container 520 such that propellant released from the propellant canister 504 can be introduced into the compound container 520 via the one or more grooves 528 on the inlet interface 514. In the embodiment of
The tip 506 may be coupled and decoupled to the actuator body 502, which enables a user to load and unload a compound container 520 to and from the inlet interface 514. The tip 506 includes the outer wall 508 and the inner wall 510, where the inner wall forms the exit channel 512 which extends between a proximal end and a distal end of the tip 506. The inlet interface 514 is positioned about a distal end of the outer wall 508, and the inlet interface 514 couples the compound container 520. In the embodiment of
As shown in
In use, as shown by the direction of the arrows in
In one example of use of the device 500, 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 tip 506 via the inlet interface 514. As shown in
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 device 500 is 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 device 500 being prohibitively long. The time from propellant actuation to end of compound delivery is less than 1 second.
The grooves 528 in the proximal end of the tip 506 promote gas flow into the compound container 520. 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 container 520, which creates rapid agitation and entrainment of the powder. The semispherical shape of the compound container 520 promotes gas redirection to the exit channel 512 of the tip 506 as shown in
The actuator body 502 attached and seals to the propellant canister 504 and the tip 506, creating a pressurized flow path for the propellant gas. In certain aspects, the actuator body 502 is a reusable component. In certain aspects, the canister 504 is a reusable component.
In one example, the compound container 520 is 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 device 500 to fit same. Additionally, in another example, the compound container 520 may 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 device 500, the user or clinician will separate a prefilled formulation containing capsule, discard the cap, and install the capsule over the tip 506. An empty compound container 520 can also be filled by a clinician at time of use before installing the compound container 520 onto the tip 506. In certain examples, the capsule is a disposable component.
The tip 506 receives the compound container 520 during loading and is then coupled to the actuator body 502 prior to use. When the propellant canister 504 is actuated, expanding propellant gas is introduced into the compound container 520 via the grooves 528 around the inlet interface 514 of the tip 506. The resulting propellant gas jets agitate and entrain the powder formulation within the compound container 520, which then exits through the exit channel 512 and the outlet orifice 516 of the tip 506. In one example, the tip 506 is a disposable component.
As shown in
As shown in
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.
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 of dry pharmaceutical composition comprises 1-30 mg, 2-20 mg, 5-15 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, mg, 19.15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 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 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.
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 various embodiments, the dry pharmaceutical composition comprises no more than 70 wt % olanzapine. In some embodiments, the composition comprises no more than 60 wt % olanzapine. In some embodiments, the composition comprises 10-70% wt % olanzapine, 20-70 wt % olanzapine, 10-60% wt % olanzapine, 20-60 wt % olanzapine, 25-55 wt % olanzapine, 30-50 wt % olanzapine, 30-40 wt % olanzapine or 40-50 wt % olanzapine.
In some embodiments, the pharmaceutical composition further comprises a stabilizer selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus), vinyl pyrrolinone-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolinone K30 (Kollidon K30), polyvinyl pyrrolidine K90 (Kollidon K90), hydroxypropylcellulose (HPC), hydroxypropyl betacyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is hydroxypropylmethylcellulose (HPMC).
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 pharmaceutical composition further comprises an antioxidant selected from the group consisting of alpha tocopherol, ascorbic acid, ascorbyl palmitate, bronopol butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylene diainetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
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.
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.
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”).
The study design of the non-human primate PK study is outlined below:
AMCC (Hetween) 102 Microcrystalline Cellulose
BIntranasal (IN) administration using the powder nhpPOD Device.
CBlood samples collected at pre-dose (0), 0.05, 0.117, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 10, 18, 24, 36 hours post dose.
D2 mg of olanzapine API was dosed with 2 mg excipient mixture for a total powder dose of 4 mg to the right naris.
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.
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.
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.
Mobile Phase A was 97.5:2.5 water:ammonium acetate (200 mM, pH 4.0).
Mobile Phase B was 97.5:2.5 acetonitrile:ammonium acetate (200 mM, pH 4.0).
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 cm2 of 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 in
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 Tmax as 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.
Approximately thirty different olanzapine (OLN) formulations were designed and manufactured for upper nasal delivery by a POD device.
Stabilizers, permeation enhancers, antioxidants, particle size and manufacturing processes were also screened as part of the formulation development process. Specifically, stabilizers tested in the experiment include hydroxypropylmethylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus), vinyl pyrrolidine-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolidine K30 (Kollidon K30), polyvinyl pyrollidone K90 (Kollidon K90), hydroxypropylcellulose (HPC), hydroxypropyl betacyclodextrin (HPBCD), mannitol, and lactose monohydrate. Permeation enhancers tested in the experiment include 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. Antioxidants tested in the experiment include alpha tocopherol, ascorbic acid, ascorbyl palmitate, bronopol butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylene diainetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodiumthiosulfate, thymol, and vitamin E polyethylene glycol succinate.
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 (
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.
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:
AIntranasal (IN) administration of the formulations was administered using the powder nhpPOD Device shown in FIG. 2, to awake NHPs.
BBlood samples were collected at pre-dose (0), 0.05, 0.117, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 10, 18, 24 hours post dose into K2EDTA tubes with OLZ stabilizer.
C2 mg of olanzapine API was dosed through one spray to a single naris.
D The six lead compounds (F-OLZ #1-6) were tested in multiple PK studies using the identical study design provided in Table 7.
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.
ANot available.
1Not determined.
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 in
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 Tmax of 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.
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.
Ps. Aeruginosa -
Staph. Aureus -
Ps. Aeruginosa -
Staph. Aureus -
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.
Period 1:
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.
Period 2:
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:
APost-Amendment Note: In cohort 1, 2 subjects already received Zyprexa 10 mg IM in the first dosing period based on the original (v1.0) version of the protocol. Subjects originally assigned to this Period 1 dosing arm continue with dosing as already allocated for Period 2.
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.
Pharmacodynamics:
The following tests were performed, in sequence, at the specified PD assessment time points:
1. Subjective sedation by Visual Analogue Scale (VAS)
2. Agitation/Calmness Evaluation Scale (ACES)
3. Attention by Digit Symbol Substitution Test (DSST).
Pharmacokinetics:
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.
Pharmacokinetic Assessments:
Plasma concentration-time data for olanzapine were used to determine pharmacokinetic (PK) parameters. The following pharmacokinetic parameters were determined: Cmax, Tmax, Tlast, AUClast, and t1/2 where possible. Results are displayed in Table 12 and
AExcluding Subject 103-011 (Period 2) and 103-054 (Petiod 1) results. Data is under investigation.
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 Cmax as compared to the IM administered olanzapine (Zyprexa) at the same dose. The earliest time point drug was measured was 5 minutes, and the median Tmax was approximately 0.16-0.17 hr after intranasal delivery of a formulation of olanzapine, significantly shorter than the median Tmax measured 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 Cmax and a significantly shorter Tmax were demonstrated compared to the IM administered olanzapine (Zyprexa IM) or orally administered olanzapine (Zydis ODT).
Pharmacodynamic Assessments:
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 in
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 in
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 in
Maximum changes in DSST from baseline are presented in
PK/PD Plots:
Olanzapine concentration-time profiles and DSST or ACES-time profiles for each subject group are superimposed and presented in
Conclusions:
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 Tmax of 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.
The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety.
While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.
This application claims priority to U.S. Provisional Application Nos. 62/776,414, filed Dec. 6, 2018; 62/774,088, filed Nov. 30, 2018; and 62/614,324, filed Jan. 5, 2018, each of which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62614324 | Jan 2018 | US | |
| 62774088 | Nov 2018 | US | |
| 62776414 | Dec 2018 | US |
