Patent Application
20220296504
In patients with Parkinson's disease, OFF episodes occur when levodopa (L-DOPA) levels are sub-therapeutic, and can occur at first waking in the morning or sporadically throughout the day. Rapid reduction in OFF episodes would provide improved quality of life and activities of daily living by allowing for more ON time.
However, existing treatments for OFF episodes are inadequate. While there are emerging alternatives for OFF episodes, these new alternatives may be suboptimal for various subsets of Parkinson's disease patients. For example, the FDA recently approved levodopa for oral inhalation (INBRIJA) for treatment of Parkinson disease OFF episodes. However, given common age-related comorbidities, dose-to-dose consistency may be difficult to achieve. Moreover, reported side effects include cough and upper respiratory tract infection in patients who have restricted mobility. Sublingual apomorphine, also in development, has the ability to resolve OFF episodes but may suffer from tolerability issues due to a high incidence of induced nausea, and may be difficult for patients to manage.
There is, therefore, a need for new methods of treating OFF periods in patients with Parkinson's disease.
In a first aspect, methods are presented for treating OFF episodes in a patient with Parkinson's disease. The methods comprise administering to a subject with Parkinson's disease experiencing an OFF episode an effective dose of a dry pharmaceutical composition comprising L-DOPA, wherein the dose is administered by an intranasal delivery device that provides, following intranasal administration, (a) a mean peak plasma levodopa concentration (Cmax) of at least 200 ng/mL, with (b) a mean time to Cmax (Tmax) of levodopa of less than or equal to 60 minutes. In particular embodiments, the mean peak plasma levodopa concentration (Cmax) provided by the dose is at least 400 ng/mL.
In various embodiments, the dry pharmaceutical composition is a powder. In certain embodiments, the powder comprises L-DOPA in crystalline form. In certain embodiments, the powder comprises L-DOPA in non-crystalline, amorphous, form. In certain embodiments, the powder comprises L-DOPA in partially crystalline, partially amorphous form. In particular embodiments, the L-DOPA is an amorphous solid obtained by spray-drying.
In various embodiments, the dry pharmaceutical composition further comprises HPMC. In some embodiments, the dry pharmaceutical composition further comprises maltoside.
In typical embodiments, the method further comprises administering to the subject a peripherally-acting DOPA decarboxylase inhibitor (DDI). In specific embodiments, the (DDI) is administered orally.
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.
5.1. Definitions
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.
An “OFF” episode is defined as a period during which a patient with Parkinson Disease (PD) or a Parkinson syndrome who is receiving an anti-Parkinson treatment has a UPDRS III motor score >30.
“Maltoside” refers to N-Dodecyl-β-D-maltopyranoside (n-dodecyl β-D-maltoside).
A pharmaceutical composition is “dry” if it has a residual moisture content of no more than 10%.
Intranasal administration of levodopa is “adjunctive to” an oral treatment with a decarboxylase inhibitor when levodopa is administered intranasally in sufficient temporal proximity to a prior oral administration of decarboxylase inhibitor that the plasma Cmax of the intranasally administered levodopa is increased.
5.2. Other Interpretational Conventions
Particle sizes are sizes as reported by a Mastersizer 3000 laser diffraction particle size analyzer device (Malvern Panalytical).
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.
5.3. Summary of Experimental Observations
We have conducted four single dose PK studies in the cynomolgus monkey to examine the PK following intranasal administration of multiple powder formulations of levodopa (L-DOPA) delivered using a handheld, manually actuated, metered-dose intranasal administration device adapted for use with non-human primates, the nhpPOD Device. The formulations examined included an unmodified crystalline powder (median particle size 50 μm), a sifted formulation containing crystalline L-DOPA particles with size range of 20-40 μm, and spray dried formulations with L-DOPA alone or containing NaCl with and without HPMC, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or maltoside. We have found that spray-dried, amorphous, L-DOPA, formulated in a powder with HPMC and maltoside, when delivered intranasally to non-human primates with our intranasal delivery device, rapidly provides blood levels of levodopa above the level known to be correlated with improving OFF episodes in human patients.
Interim analysis of two of the cohorts enrolled in a phase IIa clinical trial in Parkinson disease patients demonstrated that a spray-dried formulation containing L-DOPA:NaCl:HPMC:Maltoside in the ratios 68:2:29:1 (wt %) delivered by a Precision Olfactory Delivery device was well tolerated. Interim pharmacokinetic data for cohort 1 (35 mg) and cohort 2 (70 mg) show that administration of a 70 mg dose reached blood concentrations in the range effective to treat OFF episodes with a mean time to Cmax (Tmax) of 30-60 minutes.
5.4. Methods of Treating Parkinson's Disease OFF Periods
Accordingly, in a first aspect, methods are provided for treating OFF episodes in a patient with Parkinson's disease or a Parkinson syndrome, comprising administering to a patient with Parkinson's disease or a Parkinson syndrome experiencing an OFF episode an effective dose of a dry pharmaceutical composition comprising levodopa (L-DOPA), wherein the dose is administered by an intranasal delivery device that provides, following intranasal administration, (a) a mean peak plasma levodopa concentration (Cmax) of at least 200 ng/mL, with (b) a mean time to Cmax (Tmax) of levodopa of less than or equal to 60 minutes. In particular embodiments, the mean peak plasma levodopa concentration (Cmax) provided by the dose is at least 400 ng/mL.
5.4.1. Patients
In the methods described herein, intranasal administration of levodopa is used to treat OFF episodes that occur despite oral administration of an anti-Parkinson treatment.
In typical embodiments, the intranasal administration of levodopa is adjunctive to oral administration of a DOPA decarboxylase inhibitor (“DDI”). In typical embodiments, the intranasal administration of levodopa is adjunctive to oral treatment with a DDI and oral treatment with levodopa. In some embodiments, the intranasal administration of levodopa is adjunctive to oral treatment with an oral dosage form containing a fixed dose combination of a DDI and levodopa. In various embodiments, the oral DDI is benserazide or carbidopa. In some embodiments, the oral DDI is benserazide. In some embodiments, the oral DDI is carbidopa.
In some embodiments, the patient has Parkinson's disease (“PD”).
In some embodiments, the patient has a Parkinson syndrome. In various embodiments, the Parkinson syndrome is selected from post-encephalitic parkinsonism, symptomatic parkinsonism following carbon monoxide intoxication, or symptomatic parkinsonism following manganese intoxication.
5.4.2. Effective Dose
In the methods described herein, the effective dose is a dose of levodopa effective to reverse an OFF episode within 60 minutes.
In some embodiments, the effective dose of levodopa is 25-150 mg or 35 -140 mg. In certain embodiments, the effective dose of levodopa is 35 mg, 70 mg, 105 mg, or 140 mg.
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.
5.4.3. Dry Powder Composition
In various embodiments, the dry pharmaceutical composition is a powder.
In typical embodiments, the median diameter of the levodopa particle size distribution (D50) in the powder is 5 μm-500 μm. In some embodiments, the median diameter of the levodopa particle size distribution (D50) in the powder is 5 μm-250 μm, 5 μm-100 μm, 5 μm-75 μm, or 5 μm-50 μm. In certain embodiments, the median diameter of the levodopa particle size distribution (D50) in the composition is 10 μm-50 μm or 20 μm-40 μm.
Typically, the dry pharmaceutical composition comprises levodopa in a crystalline or amorphous form. In some embodiments, the dry pharmaceutical composition comprises levodopa in both crystalline and amorphous forms. In some embodiments, the dry pharmaceutical composition comprises levodopa in amorphous form. In particular embodiments, the amorphous levodopa is obtained by spray-drying.
In various embodiments, the dry pharmaceutical composition comprises no more than 80 wt % levodopa. In some embodiments, the composition comprises 50-80 wt % levodopa, 50-70 wt % levodopa, 65-70 wt % levodopa.
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 pharmaceutical composition at 0.1-10 wt %, more typically 1-5 wt %. In particular embodiments, the nonionic surfactant is present at 1 wt %.
In various embodiments, the dry pharmaceutical composition further comprises HPMC.
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 currently preferred embodiments, the dry pharmaceutical composition comprises 68 wt % levodopa, 2 wt % NaCl, 29 wt % HPMC, and 1 wt % n-dodecyl β-D-maltoside, and is a spray dried composition that comprises amorphous levodopa. In some embodiments, L-DOPA is spray dried in the presence of HPMC and/or maltoside. In other embodiments, HPMC and/or maltoside is added after spray drying of L-DOPA.
5.4.4. Device
In the methods described herein, the dose is administered by an intranasal delivery device that delivers a powder to the nasal cavity.
5.4.4.1. Nasal Drug Delivery Device
In various embodiments, the intranasal administration device is a nasal drug delivery device as described in U.S. Pat. No. 9,550,036, the disclosure of which is incorporated herein by reference in its entirety.
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 various embodiments, the intranasal administration device is a non-human primate precision olfactory delivery (“nhpPOD”) device described in
An additional embodiment of an nhpPOD device is shown in
With reference to
5.4.4.2. 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.
5.4.4.3. Intranasal Device with Inlet Interface
In various embodiments, the intranasal administration device is a medical unit dose container as described in US 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 704 may have a capacity for distributing propellant for a certain number of doses. In one embodiment, the device 700 may be shipped without a canister 704 and the canister 704 may be loaded into the actuator body 702 by the user. In some embodiments, the propellant canister may be replaced with a new propellant canister, such that the device 700 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 (μ1) and about 200 μl inclusive of endpoints, of liquid propellant.
The actuator body 702 comprises a propellant channel 724 that is in fluid communication with the propellant canister 704. The propellant channel 724 is in fluid communication with the inlet interface 714, which is configured to couple to the compound container 720 such that propellant released from the propellant canister 704 can be introduced into the compound container 720 via the one or more grooves 728 on the inlet interface 714. In the embodiment of
The tip 706 may be coupled and decoupled to the actuator body 702, which enables a user to load and unload a compound container 720 to and from the inlet interface 714. The tip 706 includes the outer wall 708 and the inner wall 710, where the inner wall forms the exit channel 712 which extends between a proximal end and a distal end of the tip 706. The inlet interface 714 is positioned about a distal end of the outer wall 708, and the inlet interface 714 couples the compound container 720. 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 700, 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 706 via the inlet interface 714. 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 700 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 700 being prohibitively long. The time from propellant actuation to end of compound delivery is less than 1 second.
The grooves 728 in the proximal end of the tip 706 promote gas flow into the compound container 720. 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 720, which creates rapid agitation and entrainment of the powder. The semispherical shape of the compound container 720 promotes gas redirection to the exit channel 712 of the tip 706 as shown in
The actuator body 702 attached and seals to the propellant canister 704 and the tip 706, creating a pressurized flow path for the propellant gas. In certain aspects, the actuator body 702 is a reusable component. In certain aspects, the canister 704 is a reusable component.
In one example, the compound container 720 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 700 to fit same. Additionally, in another example, the compound container 720 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 700, the user or clinician will separate a prefilled formulation containing capsule, discard the cap, and install the capsule over the tip 706. An empty compound container 720 can also be filled by a clinician at time of use before installing the compound container 720 onto the tip 706. In certain examples, the capsule is a disposable component.
The tip 706 receives the compound container 720 during loading and is then coupled to the actuator body 702 prior to use. When the propellant canister 704 is actuated, expanding propellant gas is introduced into the compound container 720 via the grooves 728 around the inlet interface 714 of the tip 706. The resulting propellant gas jets agitate and entrain the powder formulation within the compound container 720, which then exits through the exit channel 712 and the outlet orifice 716 of the tip 706. In one example, the tip 706 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.
5.4.4.4.Intranasal Device with Plurality of Frits
5.5. Dry Pharmaceutical Composition
In another aspect, dry pharmaceutical compositions suitable for intranasal administration are provided. The compositions comprise levodopa, and at least one excipient.
In typical embodiments, the dry pharmaceutical composition is a powder.
In some embodiments, the median diameter of the levodopa particle size distribution (D50) in the powder is 5 μm-500 μm, 5 μm-250 μm, 5 μm-100 μm, or 5 μm-75 μm. In some embodiments, the median diameter of the levodopa particle size distribution (D50) in the powder is 5 μm 50 μm, 10 μm-50 μm, or 20 μm-40 μm.
In various embodiments, the composition comprises levodopa in a crystalline or amorphous form. In some embodiments, the composition comprises levodopa in amorphous form. In some embodiments, the composition comprises levodopa in a partially crystalline and partially amorphous form. In certain embodiments, the amorphous levodopa is obtained by spray-drying. In some embodiments, the composition comprises levodopa in a crystalline form and an amorphous form.
In various embodiments, the dry pharmaceutical composition comprises no more than 85 wt % levodopa, or no more than 80 wt % levodopa. In certain embodiments, the composition comprises 50-80 wt % levodopa, 50-70 wt % levodopa, or 65-70 wt % levodopa.
In typical embodiments, the dry pharmaceutical composition further comprises a nonionic surfactant. In some embodiments, the nonionic surfactant is an alkyl maltoside, and in currently preferred embodiments, the alkyl maltoside is n-dodecyl β-D-maltoside.
In some embodiments, the nonionic surfactant is present at 0.1-10 wt %, more preferably, 1-5 wt %. In particular embodiments, the nonionic surfactant is present at 1 wt %.
In various embodiments, the dry pharmaceutical composition further comprises hydroxypropyl methyl cellulose (HPMC).
In various embodiments, the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation. In typical embodiments, the salt is NaCl. In certain embodiments, the composition comprises 1-5 wt % NaCl or, more preferably, 2-4 wt % NaCl.
In currently preferred embodiments, the dry pharmaceutical composition comprises 68 wt % levodopa, 2 wt % NaCl, 29 wt % HPMC, and 1 wt % n-dodecyl β-D-maltoside. In particularly preferred embodiments, the composition is a spray dried composition that comprises levodopa in amorphous form.
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 5.4 above.
In typical embodiments, the unit dosage form contains 25-150 mg of levodopa. In certain embodiments, the unit dosage form contains 35 -140 mg of levodopa. In particular embodiments, contains 35 mg of levodopa or 70 mg of levodopa.
In some embodiments, the unit dosage form is a capsule that encapsulates the dry pharmaceutical composition. In certain embodiments, the capsule is a hard capsule. In particular embodiments, the hard capsule is an HPMC hard capsule.
In some embodiments, the unit dosage form is a dose container that is configured to be removably coupled 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.
5.7.1. Example 1: Non-Human Primate PK Studies
A series of powder formulations of L-DOPA (levodopa) were developed and manufactured to assess the pharmacokinetics of intranasal administration of levodopa in non-human primates (“NHP”). The goal of the powder formulation development was to obtain a formulation that, following intranasal delivery using a non-human primate Precision Olfactory Delivery (“nhpPOD”) Device, would result in a rapid plasma concentration increase to >200 ng/mL, preferably >400 ng/mL, such that the formulation would be expected to positively impact “OFF” episodes in Parkinson's disease.
Four single dose PK studies in the cynomolgus monkey were performed to examine the PK following administration of multiple powder L-DOPA formulations delivered by the intranasal route using the nhpPOD Device. The formulations examined included an unmodified crystalline powder (median particle size of about 50 μm), a sifted formulation containing crystalline L-DOPA particles with a defined size range of 20-40 μm, and spray dried formulations with L-DOPA alone or containing NaCl with and without HPMC, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or maltoside. The placebo control, also delivered intranasally by the nhpPOD Device, was mannitol or microcrystalline cellulose (“MCC”). The formulations were delivered in the presence or in the absence of oral benserazide, a dopamine decarboxylase inhibitor.
Specifically, in the first single dose PK study (“2037-003”), a micronized crystalline levodopa powder (median particle size of about 50 μm) was administered without oral pretreatment of the animal with benserazide. In the second single dose PK study (“2037-004”), spray dried formulations of L-DOPA were administered in the presence of oral benserazide. In the third single dose PK study (“2037-006”), spray dried L-DOPA formulations including L-DOPA, NaCl, HPMC, maltoside, and/or DSPC, were administered in the presence of oral benserazide. In the fourth single dose PK study (“2037-007”), spray dried levodopa formulations from a second contract research organization that included maltoside at different concentrations (0.1, 0.5, 1%) were administered in the presence of oral benserazide. In each study, Cmax and Tmax were measured and compared to the value measured in other studies. Table 1 summarizes specific experimental conditions for each study.
aDDI refers to a peripherally-acting dopa decarboxylase inhibitor.
bn-Dodecyl β-D-maltoside (“DDN”) was used as maltoside.
notes:
5.7.1.1. Single Dose Intranasal Pharmacokinetic Study in the Cynomolgus Monkey (non-GLP, Research Study Number 2037-003)
A single dose PK study was performed in the cynomolgus monkey. Crystalline levodopa (L-DOPA) dry powder, manufactured by Teva, was administered intranasally using an nhpPOD Device (non-human primate Precision Olfactory Delivery Device). Two male and two female monkeys each were assigned to 5 groups according to the design outlined in Table 2. Control animals were dosed with mannitol (particle size <210 μm) dry powder, Groups 2-4 were dosed with unmodified crystalline L-DOPA (median diameter of the particle size distribution (D50) about 50 μm), and Group 5 was dosed with particle size sifted crystalline L-DOPA such that the particle size range was 20-40 μm. Blood samples (1.6 mL per time point with sodium metabisulfite stabilizer) were collected from fasted animals pre-dose, 3, 7, 15, 30, 45, 60, 90, 120, 180, 240 and 360 minutes after dosing in all groups. Plasma was isolated from whole blood and samples were frozen prior to analysis. PK non-compartmental analysis was performed on an individual animal basis using Phoenix WinNonlin (v6.3).
Study design is summarized in Table 2.
The total doses achieved as well as the dose per cm2 of calculated nasal surface area in each group are displayed in Table 3.
anasal surface area (NSA) was calculated using the equation, NSA= 15.1 + 5.1 (Body Weightkg) (Harris, J Aerosol Med. 2003 Summer; 16(2): 99-105) (“Harris 2003”), and the group average body weight
bn = 5; male from Group 4 added to Group 3 for dose and PK analysis, as it only received one dose per nostril due to a visible nose bleed after the second spray.
cn = 3, one male was removed from Group 4 and added to Group 3 for dose and PK analysis, as it only received half the intended dose.
In a few animals, struggling during dose administration led to partial delivery of the intended dose. These animals included one female in Group 2, and one male and one female in Group 3. One male in Group 4 was not administered the 2′ dose (sprays 3 and 4) in either nostril due to red discharge from the nose/muzzle. As this animal only received 1 dose to both nostrils, he was subsequently allocated to Group 3 for dose and PK analysis.
The calculated mean PK parameters are tabulated in Table 4, and the average plasma concentration-time curves are shown in
Following intranasal administration of unmodified crystalline L-DOPA, dose-dependent PK was observed. The earliest time point drug was measured was 3 minutes, and the median Tmax was delayed at approximately 60-90 minutes or greater. The results shown for Group 5, where a smaller particle size L-DOPA was administered (20-40 μm), suggests that a smaller particle size may increase the rate and extent of nasal uptake and subsequent systemic exposure, as a slightly higher AUC and Cmax was demonstrated compared to the unmodified bulk crystalline levodopa (D50=50 μm) 10 mg group.
The maximum Cmax achieved following the 40 mg dosing was 150 ng/mL. Multiple factors may contribute to this lower than expected Cmax and longer than expected Tmax, including, e.g., chemical and physical properties of the levodopa powder, such as crystalline polymorphic state and particle size, as well as the lack of a DOPA decarboxylase inhibitor (DDC inhibitor; DDI) pre-treatment. Lastly, some monkeys in this study may have swallowed part of the dose delivered to the nasal cavity, as suggested by the second peak in the plasma concentration-time curves, which may partially be a consequence of the impact force of the propellant used in the nhpPOD Device.
5.7.1.2. Single Dose Intranasal Pharmacokinetic Study in the Cynomolgus Monkey (Non-GLP, Study 2037-004)
A single dose PK study was performed in the cynomolgus monkey, where L-DOPA dry powder (sifted or spray dried formulation) was administered intranasally using an optimized nhpPOD Device to reduce the impact of the propellant compared with the drug delivery device used in Study 2037-003.
Two male and two female monkeys each were assigned to four L-DOPA-dosed groups and one male and female were assigned to the control group according to the design outlined in Table 5. Each animal was pretreated with the DOPA decarboxylase inhibitor, benserazide, orally (size 3 capsule), receiving a 5 mg oral dose at 24, 16, 8 and 0.75 hours prior to being dosed intranasally with control material or L-DOPA. Control animals were dosed with MCC powder, Group 2 was dosed with particle size sifted crystalline L-DOPA (particle size range 20-40 μm), and Groups 3 to 5 were dosed with various excipient/spray dried formulations of L-DOPA. Blood samples (1.6 mL with sodium metabisulfite stabilizer) were collected from fasted animals pre-dose, 3, 7, 15, 30, 45, 60, 90, 120, 240, 360 and 600 minutes after dosing. Plasma was harvested from whole blood and samples were frozen prior to analysis by AIT Bioscience, Indiana, USA. Non-compartmental PK analysis was performed on an individual animal basis using Phoenix WinNonlin (v6.3).
aparticle size sifted, 20-40 μm, manufactured by Teva
bL-DOPA:NaCl, ratio of 98:2, manufactured by Bend Research, Oregon, USA
cL-DOPA:HPMC:NaCl, ratio of 70:28:2, manufactured by Bend Research, Oregon, USA
dspray dried L-DOPA manufactured by Bend Research, Oregon, USA
The achieved total doses and dose per cm2 of calculated nasal surface area are detailed in Table 6 and the average plasma concentration-time curves are shown in
aNasal surface area (NSA) was calculated using the equation, NSA = 15.1 + 5.1(BWkg) (Harris 2003), and the group average body weight.
Animals tolerated dosing intranasally with placebo and L-DOPA. Two L-DOPA males jerked their heads after actuation of the intranasal dose, but a complete dose was delivered. A puff of powder left the nostril of one male in Group 3 directly after administration.
The calculated mean PK parameters for all animals are shown in Table 7, and the mean plasma concentration-time curves are shown in
These Cmax levels were significantly higher, approximately 10-fold, compared to Cmax levels measured in the absence of the orally administered DOPA decarboxylase inhibitor, benserazide (compare Table 4). The median Tmax observed with these formulations was 45-60 minutes, an improvement over the Tmax observed in the absence of orally administered DOPA decarboxylase inhibitor. The spray dried L-DOPA:HPMC:NaCl formulation resulted in a slightly lower Cmax (785 ng/mL) and longer Tmax than the other formulations. HPMC is a commonly used excipient that increases residence time on the nasal epithelium, although these results suggest that HPMC may slow the rate of uptake of L-DOPA across the epithelium.
In summary, the maximum mean plasma level achieved was 1,030 ng/mL following delivery of 20 mg crystalline particle size sifted L-DOPA (Teva), although two of the spray dried formulations, L-DOPA:NaCl and L-DOPA (Bend) achieved similar Cmax levels (>900 ng/mL). Improved (faster) Tmax values (45-60 min) were observed in this study for all L-DOPA formulations tested compared to L-DOPA administered in the absence of the oral DOPA decarboxylase inhibitor, benserazide (>90 min; study 2037-003).
Exposure levels (AUC) increased 3-to 4-fold when L-DOPA was administered by an optimized nhpPOD Device with oral benserazide pretreatments (5 mg×4 doses over 24 hours), and overall the large AUC and long half-life for all groups suggest reasonable absorption of L-DOPA across the nasal epithelium regardless of formulation tested in this study.
The control group male had no measurable L-DOPA LOQ of 10 ng/mL) in plasma samples collected at any time point. The control group female, however, did have low levels of L-DOPA in plasma samples collected from 3 to 120 minutes (12.7-20.3 ng/mL). This was considered likely to be due to low endogenous levels of L-DOPA.
5.7.1.3. Single Dose Intranasal Pharmacokinetic Study in the Cynomolgus Monkey (non-GLP, study 2037-006)
A third single dose PK study was performed in the cynomolgus monkey, where L-DOPA dry powder (spray dried formulations) were administered intranasally using an nhpPOD Device. Two male and two female monkeys each were assigned to five groups, of which only four are described here. Each group was administered a different spray dried formulation of L-DOPA, according to the design outlined in Table 8. Each animal was pretreated with oral benserazide (size 3 capsule) such that each animal in Groups 1-4 received a 5 mg dose at 24, 16, 8 and 0.75 hours prior to being dosed intranasally with L-DOPA. The Groups 2 and 3 test product had a slight difference in the manufacturing process (different L-DOPA starting material particle size), but otherwise the formulations tested were the same.
Blood samples (1.6 mL stabilized with sodium metabisulfite) were collected from fasted animals pre-dose, 3, 7, 15, 30, 45, 60, 90, 120, 240, 360 and 600 minutes after dosing from animals in all groups. Plasma was isolated from whole blood and samples were frozen prior to analysis by AIT Bioscience, Indiana, USA. Non-compartmental PK analysis was performed on an individual animal basis using Phoenix WinNonlin (v6.3).
Results are displayed in Table 9 and
5.7.1.4. Single Dose Intranasal Pharmacokinetic Study in the Cynomolgus Monkey (Non-GLP, Research Study Number 2037-007)
A fourth single dose PK study was performed in the cynomolgus monkey. L-DOPA dry powder (spray dried) formulations were administered intranasally using an nhpPOD Device. Ten male and ten female monkeys were assigned to five groups. Each group was administered a different spray dried formulation of L-DOPA, according to the design outlined in Table 10. Each animal was pretreated with oral benserazide (size 3 capsule) such that each animal in Groups 1-5 received a 5 mg oral dose at 24, 16, 8 and 0.75 hr prior to being dosed intranasally with L-DOPA.
Blood samples (1.6 mL stabilized with sodium metabisulfite) were collected from fasted animals pre-dose, 3, 7, 15, 30, 45, 60, 90, 120, 240, 360 and 600 minutes after dosing from animals in all groups. Plasma was isolated from whole blood and samples were frozen prior to analysis by AIT Bioscience, Indiana, USA. Non-compartmental PK analysis was performed on an individual animal basis.
Results are displayed in Table 11 and
5.7.1.5. Materials and Methods
Materials and methods for the studies described above are described here.
5.7.1.5.1. Summary
5.7.1.5.2. nhpPOD devices
The nhpPOD device described in section 5.3.4.4 and
5.7.1.5.3. Methods
Bioanalysis of NHP Plasma Samples for Levodopa
A non-GLP bioanalytical method was developed for analysis of levodopa in NHP plasma at AIT Bioscience (Indianapolis, Ind., USA). This method was based on a validated method for the quantitation of levodopa in rat plasma, previously developed and validated at AIT Bioscience for Impel.
Preparation of Plasma Samples for Analysis of Levodopa
Sodium metabisulfite (4% by volume of a 100 mg/mL solution in sterile water) was added as stabilizer (e.g. 10.4 μL of the 100 mg/mL sodium metabisulfite solution was added to 250 μL of blood) within a few minutes after each blood collection followed by thorough, gentle mixing by inversion prior to being placed on wet ice. The tubes were kept protected from light (i.e. in a closed cooler and/or covered with aluminum foil) and generally centrifuged within 15 minutes of collection. Samples were centrifuged under refrigeration (set to +4° C. and 1500 g RCF) for targeted 10 minutes. Plasma was recovered, transferred using a micropipette into separate tubes and placed on dry ice, pending storage in a freezer set to maintain −70° C. until shipment.
Preparation of Calibration Standards and Quality Control Samples
Stock solutions of levodopa were prepared to 2.00 mg/mL in 0.1N perchloric acid and stored in amber glass at 2-8° C.
K2EDTA fortified NHP plasma was prepared by mixing 100 mg/mL aqueous sodium metabisulfite with NHP plasma in a 4:96 ratio.
Calibration Standard (CS) spiking solutions (100,000 ng/mL to 200 ng/mL) were prepared by dilution of a stock solution with 100 mg/mL sodium metabisulfite solution. CS were then prepared by diluting these spiking solutions with K2EDTA fortified NHP plasma in a 5:95 ratio to achieve nominal concentrations of 5,000 to 10.0 ng/mL, in 8 levels.
QC spiking solutions were similarly prepared by dilution of a separate stock solution with 100 mg/mL sodium metabisulfite solution. QC were then prepared by diluting these spiking solutions with K2EDTA fortified NHP plasma in a 5:95 ratio to achieve nominal concentrations of 3,750, 300, 30, and 10.0 ng/mL.
CS and QC pools were prepared and sub-divided into single-use aliquots stored in polypropylene vials at −80° C. Aliquots of the CS and QC pools were thawed for one-time use on wet ice.
A sample volume of 50.0 μL was aliquoted into a 1.2 mL 96-well plate and mixed with 25.0 μL internal standard solution (2000 ng/mL L-DOPA-2,5,6-D3 in 2N perchloric acid). Then, 125 μL of water was added to each well. The plates were covered and the mixtures were vigorously shaken, vortexed to mix, and centrifuged. Using a Tomtec Quadra96 liquid handler, a 100 μL aliquot of the supernatant was transferred to a clean 96-well plate for LC-MS/MS injection.
Samples were analyzed on a Waters Acquity liquid chromatograph interfaced with a Thermo Scientific TSQ Vantage triple quadrupole mass spectrometer with ESI ionization. Each extracted sample was injected (10.0 μL) onto an Acquity HSS C18 column (2.1×50.0 mm; 1.8 μm) equilibrated at 30° C. Mobile Phase A was 100-0.1 water-formic acid. Mobile Phase B was 100-0.1 acetonitrile-formic acid.
The LC gradient is tabulated in Table 13 below.
The retention time, mass transition and precursor charge state for each compound are as follows:
Peak area ratios from the calibration standard responses were regressed using a (1/concentration2) linear fit for levodopa. The regression model was chosen based upon the behavior of the analyte across the concentration range used during method development.
Pharmacokinetic Parameter Calculations and Data Analysis
Plasma concentration-time data for levodopa was used to determine pharmacokinetic (PK) parameters. Non-compartmental analysis (NCA) was performed on the individual subject plasma concentration data using the software Phoenix WinNonlin (v6.3).
The following pharmacokinetic parameters were determined: Cmax, Tmax, Tlast, AUClast, and t1/2 where possible. Various additional pharmacokinetic parameters were automatically generated by Phoenix WinNonlin software but were not presented in this report. The following configuration was used for the analysis:
Model type selection (Plasma 200-202) was based on the biological matrix (plasma) and the dose type was based on the route of administration (extravascular). Observed parameters were used for the analysis. The acceptance criteria for Kel determination were regression of at least three time points in the apparent terminal elimination phase, excluding Cmax, otherwise t1/2 was not determined or reported. Nominal blood sampling times and nominal dose levels were used. Concentrations reported as below the lower limit of quantification were treated as zero (0).
5.7.2. Example 2: Phase IIa, Randomized, Double Blind, Placebo Controlled, Single Ascending Dose, Safety and Pharmacokinetic/Pharmacodynamic Study of INP103 (POD L-DOPA) Administered in the Presence of Benserazide to Levodopa Responsive Parkinson's Disease Patients
5.7.2.1. Study Design
A powder formulation of L-DOPA (levodopa) was tested in a randomized, double-blind, placebo controlled, single ascending dose study to demonstrate safety, tolerability and PK/pharmacodynamics of L-DOPA delivered by the 1231 Precision Olfactory Delivery (“POD®”) device to human subjects. The 1231 POD device is a handheld, manually actuated, propellant-driven, metered-dose administration device intended to deliver a powder drug formulation to the nasal cavity.
Intranasal administration was performed with single ascending doses of one (35 mg), two (70 mg) or four (140 mg) administrations (puffs) of L-DOPA into the naris. L-DOPA was administered 60 minutes after oral benserazide hydrochloride 25 mg. An inert, visually similar product without L-DOPA (microcrystalline cellulose) was administered as a placebo.
L-DOPA responsive Parkinson's disease patients were enrolled in the study. The subjects were males or females between 40 and 80 years of age, diagnosed with idiopathic Parkinson's disease, and prone to and able to recognize OFF episodes when their usual medication has worn off. For enrollment, they must have been shown to be responsive to L-DOPA medication showing more than 30% improvement in MDS-UPDRS Part III Motor Examination score.
All of the subjects received oral benserazide hydrochloride (benserazide) 25 mg on arrival at the research site (and 60±5 minutes prior to L-DOPA or placebo dosing) and the time recorded. The subjects were divided into three cohorts and each cohort was treated as follows. Cohort 1: Each subject in this cohort received one dose of 35 mg of L-DOPA or placebo delivered by one actuation of the POD device. Cohort 2: Each subject in this cohort received two 35 mg doses of L-DOPA or placebo delivered by two actuations of the POD device, for a total of 70 mg of L-DOPA or placebo. Cohort 3: Each subject in this cohort received four 35 mg doses of L-DOPA or placebo delivered by four actuations of the POD device, for a total of 140 mg of L-DOPA or placebo.
Safety and tolerability, pharmacokinetics and pharmacodynamics of intranasally delivered L-DOPA were assessed in the subjects as described below.
Safety and Tolerability Assessments: Specific assessments to evaluate treatment safety included the following: overall dyskinesia assessment, nasal inspection (as part of physical examinations), the frequency and type of AEs, concomitant medications (including any short acting anti-OFF medication, permissible only at/after 120 minutes post dosing on dosing days alongside the subject's delayed usual anti-PD morning dose), clinical laboratory testing, 12-lead ECGs and vital signs (to include supine and standing blood pressure, all other vital signs supine only). All treated subjects were observed for 240 minutes post dose and underwent follow-up evaluations (by appropriately trained/qualified staff) at Day 7.
Pharmacokinetic Assessments: PK blood samples were collected (recommended to be from an indwelling cannula positioned so that it does not interfere with arm movements) within 15 minutes prior to dosing and at 30, 60, 90 and 120 minutes after dosing (with L-DOPA).
Pharmacodynamics Assessments: Measurement of a full MDS-UPDRS score was conducted at the start of all visits. Changes from baseline in MDS-UPDRS Part III scores were estimated using a Mixed Model for Repeated Measures (MMRM) with treatment group (L-DOPA 35 mg, 70 mg, or 140 mg, or placebo), time point (15, 30, 45, 60, 90 or 120 minutes) and the interaction between treatment group and time point as fixed factors.
Dyskinesia assessment, nasal inspection, laboratory evaluations, vital signs assessments (including supine and standing blood pressure, all other vital signs supine only) and ECG parameters showed no significant difference between the subjects treated with L-DOPA and placebo. The results demonstrate that L-DOPA delivered by the POD is safe and tolerable.
L-DOPA concentrations in the PK blood samples were summarized with descriptive statistics (arithmetic and geometric mean, SD, median, minimum, and maximum) by treatment group and time point. In addition, PK parameters (AUC0-2h, Cmax, Tmax) were summarized with descriptive statistics by treatment group.
5.7.2.2. Study Formulation
The study drug was a spray-dried formulation containing L-DOPA:NaCl:HPMC: Maltoside in the weight ratios of 68:2:29:1 (INP103).
5.7.2.3. Study Results
An interim analysis of data from cohorts 1 and 2, with partial data read-out, demonstrated that INP103 was well tolerated. Interim pharmacokinetic data for cohort 1 (35 mg) and cohort 2 (70 mg) are shown in
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 is a continuation of U.S. application No. 16/240,642, which claims priority to U.S. provisional Application Nos. 62/700,591, filed Jul. 19, 2018, and 62/614,310, filed Jan. 5, 2018, each of which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62614310 | Jan 2018 | US | |
| 62700591 | Jul 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16240642 | Jan 2019 | US |
| Child | 17498381 | US |
