阅读说明：本技术 用于快速缓解帕金森病的左旋多巴制剂 (Levodopa formulations for rapid relief of parkinson's disease ) 是由 M·弗瑞德 R·贝蒂凯 M·M·利普 于 2013-10-21 设计创作，主要内容包括：本申请的发明名称为用于快速缓解帕金森病的左旋多巴制剂。本发明提供为帕金森病患者的运动波动提供快速缓解的方法。本发明的方法包括通过吸入来肺部施用治疗有效浓度的左旋多巴,使得与吸入所述左旋多巴前所述患者血浆中的左旋多巴浓度相比,所述患者的血浆左旋多巴浓度在吸入后10分钟或更少时间内增加了至少约200ng/ml,并且其中所述患者的血浆浓度在吸入后至少15分钟的时间段内保持增加至少约200ng/ml。本发明的方法尤其适用于治疗由患者的左旋多巴血浆水平控制较差造成的运动波动。(The invention relates to a levodopa preparation for rapidly relieving Parkinson's disease. The present invention provides methods for providing rapid relief of motor fluctuations in parkinson's disease patients. The methods of the invention comprise pulmonary administration of a therapeutically effective concentration of levodopa by inhalation such that the patient's plasma levodopa concentration increases by at least about 200ng/ml within 10 minutes or less after inhalation compared to the levodopa concentration in the patient's plasma prior to inhalation of the levodopa, and wherein the patient's plasma concentration remains increased by at least about 200ng/ml for a period of at least 15 minutes after inhalation. The methods of the invention are particularly useful for treating motor fluctuations caused by poorly controlled plasma levels of levodopa in a patient.)

1. Use of at least one dose of levodopa in the manufacture of a medicament to be administered by inhalation to provide rapid relief of motor fluctuations in parkinson's disease patients, wherein:

the dose of levodopa comprises 90% by dry weight levodopa, 8% by dry weight Dipalmitoylphosphatidylcholine (DPPC) and 2% sodium chloride;

at least one dose of levodopa is administered to a parkinson's disease patient by inhalation;

wherein within about 10 minutes of levodopa administration by inhalation, the patient's plasma levodopa concentration is increased by at least about 200ng/ml compared to the patient's plasma levodopa concentration prior to administration; and is

Wherein said increase in plasma levodopa concentration of said patient of at least about 200ng/ml is maintained for a period of time of at least about 15 minutes after administration, wherein said dose comprises levodopa at a Fine Particle Dose (FPD) of about 40mg-50 mg.

2. The use of claim 1, wherein the dose contains a salt.

3. The use of claim 1, wherein the dose contains a phospholipid.

4. The use of claim 1, wherein said dose comprises about 50mg fpd of levodopa.

5. The use of claim 1, further comprising co-administering a dopa decarboxylase inhibitor to the patient.

6. The use of claim 1, wherein said increase in plasma levodopa concentration in said patient of at least about 200ng/ml is maintained for a period of time of at least about 20 minutes after administration.

7. The use of claim 1, wherein said increase in plasma levodopa concentration in said patient of at least about 200ng/ml is maintained for a period of time of at least about 30 minutes after administration.

8. The use of claim 1, wherein said increase in plasma levodopa concentration in said patient of at least about 200ng/ml is maintained for a period of time of at least about 60 minutes after administration.

9. The use of claim 1, wherein said dose of levodopa comprises about 40mg fpd of levodopa.

10. The use of claim 1, wherein the patient's plasma levodopa concentration does not increase by more than about 1000ng/ml within 10 minutes.

11. Use of at least one dose of levodopa in the manufacture of a medicament to be administered by inhalation to provide rapid relief of motor fluctuations in parkinson's disease patients, wherein:

the dose of levodopa comprises 90% by dry weight levodopa, 8% by dry weight Dipalmitoylphosphatidylcholine (DPPC) and 2% sodium chloride;

at least one dose of levodopa is administered to the patient by inhalation;

wherein the patient receives immediate relief of motor fluctuations within 10 minutes of the inhalation; and is

Wherein the patient maintains the relief for a period of at least 30 minutes,

wherein the dose comprises about a 40mg to 50mg Fine Particle Dose (FPD) of levodopa.

12. The use of claim 11, wherein an oral dose of levodopa is further administered to the patient.

13. The use of claim 11, wherein the relief of motor fluctuations is maintained for a period of at least 4 hours.

14. The use of claim 1, wherein the parkinson's disease patient is a grade 2, grade 3, or grade 4 parkinson's disease patient.

15. The use of claim 1, wherein said dose of levodopa is not affected by central nervous system food effects.

16. Use of one or more doses of levodopa in the manufacture of a medicament to be administered by inhalation to provide rapid relief of motor fluctuations in parkinson's disease patients, wherein:

the dose of levodopa comprises 90% by dry weight levodopa, 8% by dry weight Dipalmitoylphosphatidylcholine (DPPC) and 2% sodium chloride;

one or more doses of levodopa are administered by inhalation;

wherein T is^1/2/T^maxIs less than the ratio of (a) to (b) of 1/2,

wherein the dose comprises about a 40mg to 50mg Fine Particle Dose (FPD) of levodopa.

17. Use according to claim 16, wherein the ratio is less than 1/5.

18. The use of claim 5, wherein the dopa decarboxylase inhibitor is administered to the patient before, simultaneously with, or after levodopa administration by inhalation.

19. Use of at least one dose of levodopa in the manufacture of a medicament for providing rapid relief of motor fluctuations in parkinson's disease patients, wherein:

the dose of levodopa comprises 90% by dry weight levodopa, 8% by dry weight Dipalmitoylphosphatidylcholine (DPPC) and 2% sodium chloride;

at least one dose of said levodopa is administered to said patient such that said patient's plasma levodopa level is increased by about 200ng/ml,

wherein the dose comprises about a 40mg to 50mg Fine Particle Dose (FPD) of levodopa.

20. The use of claim 19, wherein the levodopa is administered by an oral route, a pulmonary route, or a parenteral route.

21. The use of claim 19, wherein the increase in plasma levodopa level is 200-, 300-, 450-, or about 400 ng/ml.

22. The use of claim 19, wherein said levodopa is administered by the pulmonary route and is administered to the pulmonary system at a dose of about 50mgFPD of levodopa.

23. The use of claim 19, wherein the patient has at least a 100% improvement in UPDRS score within 20 minutes of administration of the levodopa.

Background

The neuropathological features of parkinson's disease are degeneration of dopamine neurons in the basal nucleus and the neurological features are debilitating tremor, motor retardation and balance problems. It is estimated that more than one million people suffer from parkinson's disease. Almost all patients receive the dopamine precursor levodopa or "L-dopa" which normally binds to the dopa decarboxylase inhibitor carbidopa. L-dopa adequately controls the symptoms of parkinson's disease in its early stages. However, in the course of the disease, it tends to become less effective over a period of time (which may vary from months to years).

An example of a diminished effectiveness of L-dopa is the development of motor fluctuations in a subject undergoing treatment. By "motor fluctuations" is meant that the subject begins to show a variable response to dopamine replacement therapy such that in certain time periods the therapeutic agent exhibits good efficacy, while in other time periods the agent appears to have little effect. Motor fluctuations can be shown as 'decline-off' in efficacy, the efficacy of L-dopa treatment continues to be less than initially observed for a long time, and consequent 'on-off' symptoms of patients experiencing mobility fluctuations. Gradually, over a period of time, the efficacy of L-dopa (also known as "on-time") can decrease to the point where the effectiveness of dopaminergic therapy becomes severely limited.

It is believed that the effect of L-dopa changes in parkinson's disease patients relates at least in part to the plasma half-life of L-dopa, which tends to be very short, in the range of 1 to 3 hours, even when co-administered with carbidopa. In the early stages of the disease, this factor is diminished by the dopamine storage capacity of the targeted striatal neurons. L-dopa is occupied and stored by neurons, and is released over time. However, as the disease progresses, dopaminergic neurons degenerate, resulting in a decrease in dopamine storage capacity.

Accordingly, the positive effect of L-dopa becomes more and more correlated with fluctuations in plasma levels of L-dopa. In addition, patients are prone to problems involving gastric emptying and poor intestinal uptake of L-dopa. Erratic gastric emptying of levodopa contributes to random fluctuations in mobility. When plasma levels drop to so-called dyskinesias, which temporarily rise too high after administration of L-dopa, patients show increasingly marked fluctuations in the symptoms of parkinson's disease, varying in the symptoms returning to classical parkinson's disease.

There remains a need to provide rapid relief of motor fluctuations in parkinson patients, where the effect occurs over a clinically meaningful period of time and where the effect allows the patient sufficient response time.

Summary of The Invention

The present invention provides a method that provides rapid relief of motor fluctuations in parkinson's patients, while also providing a prolonged duration of effect. The methods of the invention comprise pulmonary administration of a therapeutically effective concentration of levodopa by inhalation such that the concentration of levodopa in the patient's plasma increases by at least about 200ng/ml within 10 minutes or less after inhalation compared to the concentration of levodopa in the patient's plasma prior to inhalation of levodopa, and wherein the patient's plasma concentration remains increased by at least about 200ng/ml for a period of at least 15 minutes after inhalation. The methods of the invention are particularly useful for treating motor fluctuations caused by poorly controlled plasma levels of levodopa in a patient.

Brief Description of Drawings

FIG. 1: mean plasma levodopa concentration versus time data after 90/8/2 inhalation and oral levodopa administration.

FIG. 2: mean plasma levodopa concentration versus time data after inhalation 90/8/2 were compared to oral administration.

FIG. 3: plasma levodopa concentration in individual subjects following inhalation of 50mg 90/8/2 or oral administration of 100mg levodopa (CD/LD25/100mg) under fed and fasted conditions.

FIG. 4: AUC of levodopa_0-∞For 90/8/2 fine particle dose.

FIG. 5: levodopa C_maxFor 90/8/2 fine particle dose.

FIG. 6: pharmacokinetic modeling of mean plasma concentrations. The symbols represent the observed average concentration and the lines represent the concentrations predicted by the model.

FIG. 7: mean levodopa plasma concentrations with and without Carbidopa (CD) pretreatment.

FIG. 8: the patient's plasma levodopa concentration was compared to the UPDRS score.

FIG. 9: scheme 1.

Detailed Description

Definition of

Half life time (T)_1/2) Is the time at which the concentration (C) of the drug reaches a concentration C/2 in the body fluid or tissue.

“Cmax^Pul"means the observation measured after pulmonary deliveryTo maximum plasma concentration (Cmax). "Cmax^oralBy "is meant the maximum observed plasma concentration measured after oral delivery.

The area under the curve AUC corresponds to the integral of the plasma concentration over a given time interval. AUC is expressed in units of mass (mg, g) x liter-1 x hour and is a measure of bioavailability of a drug.

“AUC^PulBy "is meant the area under the plasma concentration versus time curve (AUC) measured after pulmonary delivery. "AUC^oralBy "is meant the area under the plasma concentration versus time curve (AUC) measured after oral delivery.

The term "coefficient of variation" (CV) expressed as% CV is defined as the ratio of the standard deviation σ to the mean μ:

C_v＝σ/μ

the phrase "nominal dose" or "nominal powder dose" as used herein means the percentage of levodopa present in the total mass of particles contained in the reservoir and represents the maximum amount of levodopa available for administration to a patient.

The fine particle fraction "or" FPF "corresponds to the percentage of particles having an aerodynamic diameter of less than 5.6 μm out of the mass of particles present in the reservoir.

The term "fine particle dose" as used herein is defined as the nominal dose multiplied by the FPF.

Abbreviation list

Features and other details of the invention are now more particularly described and pointed out in the claims. It should be understood that the particular embodiments of the present invention are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

According to the present invention, the term "dose of levodopa" as used herein means a formulation comprising an amount of levodopa in a dosage form suitable for delivery to a patient by inhalation. In one embodiment, a dose of levodopa according to the invention comprises particles containing levodopa. Particles and methods for delivering levodopa to the respiratory system are described, for example, in U.S. patent No. 6,514,482 and U.S. patent reissue No. RE43711, the contents of which are incorporated herein by reference in their entirety. The particles are preferably in dry powder form and are characterized by a Fine Particle Fraction (FPF), geometric and aerodynamic dimensions and by other characteristics as described below.

Gravimetric analysis using cascade impactors is a method of measuring the size distribution of airborne particles. The Anderson Cascade Impactor (ACI) is an eight stage impactor that can separate an aerosol into nine different fractions based on aerodynamic size. The size cutoff of each stage depends on the flow rate at which the ACI is operated. Preferably, the ACI is calibrated at 60L/min.

In one embodiment, two-stage collapse ACI is used for particle optimization. The two-stage collapsed ACI consists of stages 0, 2 and F of the eight-stage ACI and allows the collection of two separate powder fractions. At each stage, the aerosol stream passes through a nozzle and impinges on a surface. Particles in the aerosol with sufficient inertia will impact on the plate. Smaller particles that do not have sufficient inertia to impinge on the plate will remain in the aerosol stream and be carried to the next stage.

ACI is calibrated so that the fraction of powder collected on the first stage is referred to as the fine particle fraction FPF (5.6). This FPF corresponds to the percentage of particles having an aerodynamic diameter of less than 5.6 μm. The portion of the powder that passes through the first stage of the ACI and is deposited on the collection filter is referred to as the FPF (3.4). This corresponds to the percentage of particles having an aerodynamic diameter of less than 3.4 μm.

The FPF (5.6) portion has been shown to correlate with the portion of powder deposited in the patient's lungs, while the FPF (3.4) has been shown to correlate with the portion of powder reaching the depth of the patient's lungs.

At least 50% of the FPF of the particles of the invention is less than about 5.6 μm. For example, but not limited to, at least 60%, or 70%, or 80%, or 90% of the FPF of the particles is less than about 5.6 μm.

Another method for measuring the size distribution of airborne particles is the multi-stage liquid sampler (MSLI). The multi-stage liquid sampler (MSLI) operates on the same principle as the Anderson Cascade Impactor (ACI), but in MSLI there are five stages instead of eight. Furthermore, instead of each stage comprising a solid plate, each MSLI stage comprises a methanol-wetted frit. A wetted stage is used to prevent bounce and re-entrainment, which can occur in using ACI. MSLI was used to provide a flow rate dependent indication of the powder. This can be done by operating 30, 60 and 90L/min of MSLI and measuring grade 1 and collecting the fraction of powder collected on the filter. If the fraction on each stage remains relatively constant across different flow rates, the powder is considered to be close to flow independent.

The particles of the present invention have less than about 0.4g/cm³The tap density of (1). Herein, has less than about 0.4g/cm³The particles of tap density of (a) are referred to as "aerodynamically light particles". For example, the particles have less than about 0.3g/cm³Or less than about 0.2g/cm³Has a tap density of less than about 0.1g/cm³The tap density of (1). Tap Density may be measured using an instrument known to those skilled in the art, such as a Dual platform microprocessor Controlled Tap Density Tester (Vankel, NC) or GEOPYC^TMMeasured with an Instrument (Micrometrics instruments corp., Norcross, GA 30093). Tap density is a standard measure of the mass density of the shell. Tap density can be determined by using the method in USP bulk and tap densities, the United states Pharmacopeia convention, Rockville, Md, tenth supplement, 4950-4951, 1999. Features contributing to low tap density include irregular surface texture andpore structure.

The shell mass density of an isotropic particle is defined as the mass of the particle divided by the minimum sphere shell volume within which the particle can be encapsulated. In one embodiment of the invention, the particles have less than about 0.4g/cm³The housing mass density of (a).

The particles of the present invention have a preferred size, for example a Volume Median Geometric Diameter (VMGD) of at least about 1 micrometer (μm). In one embodiment, the VMGD is about 1 μm to 30 μm, or any subrange encompassed by about 1 μm to 30 μm, such as, but not limited to, about 5 μm to about 30 μm, or about 10 μm to 30 μm. For example, the particles have a VMGD in a range of about 1 μm to 10 μm, or about 3 μm to 7 μm, or about 5 μm to 15 μm, or about 9 μm to about 30 μm. The particles have a median diameter, Mass Median Diameter (MMD), mass median shell diameter (MMED), or Mass Median Geometric Diameter (MMGD) of at least 1 μm, for example 5 μm or close to or greater than about 10 μm. For example, the particles have an MMGD of greater than about 1 μm and are in the range of about 30 μm, or any subrange encompassed by about 1 μm to 30 μm, such as, but not limited to, about 5 μm to 30 μm, or about 10 μm to about 30 μm.

The diameter of the spray dried particles, e.g. VMGD, can be measured using a laser diffractometer (e.g. Helos manufactured by Sympatec, Princeton, NJ). Other instruments for measuring particle size are well known in the art. The diameter of the particles in the sample will vary depending on factors such as the composition of the particles and the method of synthesis. The distribution of the size of the particles in the sample may be selected to allow optimal deposition to the target site within the respiratory tract.

The aerodynamic light particles preferably have a "mass median aerodynamic diameter" (MMAD), also referred to herein as an "aerodynamic diameter," of between about 1 μm and about 5 μm, or any subrange encompassed by about 1 μm to about 5 μm. For example, the MMAD is between about 1 μm and about 3 μm, or the MMAD is between about 3 μm and about 5 μm.

Experimentally, the aerodynamic diameter can be determined by gravity sedimentation, whereby the time for an aggregate of particles to settle a certain distance is used to directly infer the aerodynamic diameter of the particles. An indirect method for measuring Mass Median Aerodynamic Diameter (MMAD) is the multi-stage liquid sampler (MSLI).

Aerodynamic diameter d_aerIt can be estimated directly from the following equation:

d_aer＝d_g√ρ_tap

wherein d is_gIs the geometric diameter, e.g., MMGD, and ρ is the powder density.

Has a density of less than about 0.4g/cm³And aerodynamic diameters between about 1 μm and about 5 μm, preferably between about 1 μm and about 3 μm, are more capable of inertial escape and gravity deposition in the oropharyngeal region and target the airways, particularly the deep part of the lung. The use of larger, more porous particles is advantageous because they are more effectively aerosolized than smaller, denser aerosol particles (such as those currently used in inhalation therapy).

Larger aerodynamically light particles, preferably having a median diameter of at least about 5 μm, may also be more successful in avoiding phagocytic phagocytosis of alveolar macrophages and pulmonary clearance due to size exclusion of the particles by the phagocytic cytoplasmic cavity in comparison to smaller, relatively dense particles. As the particle diameter increases beyond about 3 μm, the phagocytosis of the particles by the macrophages of the vesicles is drastically reduced. Kawaguchi, H., et al Biomaterials, 7:61-66 (1986); krenis, L.J. and Strauss, B., Proc.Soc.exp.Med.,107: 748-; and Rudt, S. and Muller, R.H., J.Contr.Rel.,22: 263-plus 272 (1992). For a statistically isotropic shaped particle (such as a sphere with a rough surface), the particle envelope volume is approximately equal to the volume of the cytoplasmic cavity required for complete particle phagocytosis within macrophages.

The particles may be made of suitable materials and may be made to have a surface roughness, diameter and tap density for local delivery to selected regions in the respiratory tract, such as the deep parts of the lungs or the upper or middle parts of the airways. For example, higher density or larger particles may be used for upper airway delivery, or a mixture of different sized particles in a sample with the same or different therapeutic agents may be administered in one administration to target different regions of the lung. Particles having an aerodynamic diameter of about 3 μm to about 5 μm are preferred for delivery to the middle and upper portions of the airway. Particles having an aerodynamic diameter of about 1 μm to about 3 μm are preferred for delivery to the deep parts of the lung.

Inertial impaction and weight settling of aerosols are the major deposition mechanisms in the alveoli of the airways and lungs under normal respiratory conditions. Edwards, D.A., J.Aerosol Sci.26: 293-. The importance of both deposition mechanisms is proportional to the mass of the aerosol and not to the particle (or shell) volume. Since the site of aerosol deposition in the lung is determined by the mass of the aerosol (at least for particles with an average aerodynamic diameter greater than about 1 μm), the tap density is reduced by increasing the particle surface roughness and particle porosity to allow delivery of a larger volume of extra-particle shell into the lung, all other physical parameters being the same.

The low tap density particles have a small aerodynamic diameter compared to the actual shell sphere diameter. By simplifying the formula, the aerodynamic diameter d_aerIn relation to the shell sphere diameter d (Gonda, I., "Physico-chemical principles in aerosol delivery", in Topics in Pharmaceutical Sciences 1991(D.J.A.Crommelin and K.K.Midha eds.), pages 95-117, Stuttgart: medipharm scientific publishers, 1992)):

d_aer＝d√ρ

wherein the unit of the mass density of the shell is g/cm³。

The highest deposition (-60%) of monodisperse aerosol particles occurs at about d in the alveolar region in the human lung_aerIn the case of an aerodynamic diameter of 3 μm. Heyder, J.et al, J.Aerosol Sci.,17:811-825 (1986). Due to their smaller shell mass density, the actual diameter d of the aerodynamic light particles comprising monodisperse inhalation powders that will exhibit the highest lung deep deposition is:

d 3/√ ρ μm (where ρ_{_}<1g/cm³)；

Wherein dso is greater than 3 μm. For example, displayThe mass density of the shell is 0.1g/cm³Will exhibit the highest deposition of particles having a shell diameter of up to 9.5 μm. The increased particle size reduces interparticle adhesion. Visser, J., Powder Technology,58: 1-10. Thus, for particles of low shell mass density, in addition to contributing to lower phagocyte depletion, the large particle size increases the efficiency of nebulization to deep lung.

The aerodynamic diameter may be calculated to provide the highest deposition in the lung. This is accomplished by using very small particles that are then phagocytosed, having diameters of less than about 5 microns, preferably between about 1 and about 3 microns. Particles selected from those having a larger diameter, but sufficiently light (thus characterized as "aerodynamically light"), produce the same delivery to the lung, but the larger size particles are not phagocytosed. By using particles having a rough or uneven surface relative to those having a smooth surface, improved delivery can be achieved.

In another embodiment of the invention, the particles have less than about 0.4g/cm³Is also referred to herein as "mass density". In some embodiments, the particle density is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, less than 0.1, 0.02 to 0.05, 0.02 to 0.06g/cm³. Mass density and the relationship between mass density, mean diameter and aerodynamic diameter are described in U.S. Pat. No. 6,254,854 to Edwards et al, 7.3.2001, which is incorporated herein by reference in its entirety.

Particles having the above-described composition and aerodynamic properties can be produced by several methods including, but not limited to, spray drying. Generally, Spray Drying techniques are described, for example, by K.Masters in "Spray Drying Handbook", John Wiley & Sons, New York, 1984.

The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount required to achieve a desired effect or efficacy. The actual effective amount of the drug may vary depending on the particular drug or combination thereof used, the particular formulation composition, the mode of administration, and the age, weight, condition, and severity of the episode being treated of the patient. In the case of dopamine precursors, agonists or combinations thereof, it is the amount that reduces the symptoms of parkinson's disease that need to be treated. Dosages for a particular patient are described herein and can be determined by one of ordinary skill in the art using routine considerations (e.g., with the aid of an appropriate conventional pharmacological protocol).

The particles may be administered to the respiratory system, such as by means known in the art. For example, particles are delivered from an inhalation device such as a Dry Powder Inhaler (DPI). Metered dose nebulizers (MDI), nebulizers, or drip techniques may also be used.

In one embodiment, Delivery of the particles to the pulmonary system is performed by the methods described in U.S. Pat. No. 6,858,199 entitled "High efficiency Delivery of a Large Therapeutic Mass Aerosol" and U.S. Pat. No. 7,556,798 entitled "High efficiency Delivery of a Large Therapeutic Mass Aerosol". The entire contents of these patents are incorporated herein by reference. As disclosed herein, the particles are held, contained, stored, or encapsulated in a reservoir. The receptacle, e.g. capsule or blister, has at least about 0.37cm³And may have a design suitable for use in a dry powder inhaler. Also useful are particles having a length of at least about 0.48cm³、0.67cm³Or 0.95cm³A larger reservoir of volume. As used herein, the term "reservoir" includes, but is not limited to, for example, capsules, blisters, container wells covered by a film, chambers, and other suitable means of storing particles, powder, or inhalable compositions in inhalation devices known to those skilled in the art. In one embodiment, the reservoir is a capsule, for example a capsule designated with a particular capsule size, such as 2, 1, 0,00, or 000. Suitable capsules are available, for example, from Shionogi (Rockville, MD). In one embodiment, the capsule shell may comprise Hydroxypropylmethylcellulose (HPMC). In another embodiment, the capsule shell may comprise Hydroxypropylmethylcellulose (HPMC) and titanium dioxide. Blisters are available, for example, from Hueck Foils (Wall, NJ). Other reservoirs and other volumes suitable for use with the present invention will be known to those skilled in the art.

In one embodiment, the present invention provides that L-dopa is administered to the pulmonary system in a few steps, and preferably in a single breath-initiated step. In one embodiment, at least 50% of the mass of particles stored in the inhaler reservoir is delivered to the respiratory system of the subject in a single breath actuation step. In one embodiment, at least 60%, preferably at least 70% and preferably at least 80% of the mass of the particles stored in the inhaler reservoir is delivered to the respiratory system of the subject in a single breath actuation step. In another embodiment, at least 1 to 80 milligrams of L-dopa is delivered to the respiratory tract of a subject by administering the particles encapsulated in a reservoir in a single breath. Preferably, at least 1015, 20, 25, 30, 35, 40, 50, 60, 75 and 80 milligrams may also preferably be delivered.

Delivery of particles to the pulmonary system during a single breath-initiated procedure is enhanced by using particles dispersed at a relatively low energy, such as at the energy typically provided by inhalation by the subject. Such energy is referred to herein as "low". As used herein, "low energy administration" refers to administration in which the energy applied to disperse and/or inhale the particles is generally within the range provided by the subject during inhalation.

The invention also relates to a method for efficiently delivering powder particles to the pulmonary system. For example, but not limited to, at least about 60%, preferably at least about 70% or preferably at least about 80% of the nominal powder dose is actually delivered.

In one embodiment, the composition for use in the present invention comprises particles suitable for pulmonary delivery, such as dry powder particles, comprising about 60-99 weight% (dry weight) levodopa. Particularly preferred are particles comprising about 75% or more by weight levodopa, and even more preferred about 90% or more by weight levodopa. The particles may consist entirely of L-dopa or may also include one or more additional components. Examples of such suitable additional components include, but are not limited to, phospholipids, amino acids, sugars, and salts. Specific examples of phospholipids include, but are not limited to, the phosphatidylcholines Dipalmitoylphosphatidylcholine (DPPC), Dipalmitoylphosphatidylethanolamine (DPPE), phosphatidylcholines Distearate (DSPC), Dipalmitoylphosphatidylglycerol (DPPG), or any combination thereof. The amount of phospholipids (e.g. DPPC) present in the particles of the invention is typically less than 10 wt%.

The salt includes a small amount of a strong electrolyte salt such as, but not limited to, sodium chloride (NaCl). Other salts that may be used include sodium citrate, sodium lactate, sodium phosphate, sodium fluoride, sodium sulfate, and calcium carbonate. Typically, the amount of salt present in the particles is less than 10 wt%, for example less than 5 wt%.

In a preferred embodiment, a formulation of levodopa suitable for pulmonary delivery to a patient by inhalation comprises 90% by weight levodopa, 8% by weight Dipalmitoylphosphatidylcholine (DPPC) and 2% by weight sodium chloride and is referred to herein as "90/8/2".

In one embodiment, the methods of the invention provide a method of rapidly alleviating motor fluctuations in parkinson's disease patients. The method of the invention is particularly useful for treating motor fluctuations caused by poor control of the patient's levodopa plasma levels.

In one embodiment, the method of the invention comprises pulmonary administration of a therapeutically effective concentration of levodopa by inhalation such that the concentration of levodopa in the patient's plasma increases by at least about 200ng/ml within 10 minutes or less after inhalation compared to the concentration of levodopa in the patient's plasma prior to inhalation of levodopa, and wherein the patient's plasma concentration remains increased by at least about 200ng/ml for a period of at least 15 minutes after inhalation.

In one embodiment, the patient's plasma levodopa concentration remains increased by at least about 200ng/ml for a period of at least about 20 minutes after administration. In one embodiment, the patient's plasma levodopa concentration maintains the at least about 200ng/ml increase for a period of at least about 30 minutes after administration. In one embodiment, the patient's plasma levodopa concentration maintains the increase of at least about 200ng/ml for a period of time of at least about 60 minutes after administration. In other embodiments, the increase is greater than 200ng/ml, 200 to 500ng/ml, 300 to 400ng/ml, or 250 to 450 ng/ml. In one embodiment, the patient's plasma levodopa concentration does not increase by more than about 1000ng/ml within 10 minutes.

In one embodiment, the method of the invention provides rapid relief of motor fluctuations in a parkinson's patient, the method comprising administering to the patient by inhalation about 20mg to about 75mg levodopa, wherein the patient achieves direct relief of motor fluctuations within 10 minutes of said inhalation, and wherein the patient maintains said relief for a period of at least 30 minutes.

According to any of the methods of the invention, the area under the curve (AUC) of levodopa in the plasma of a patient increases by at least about 1000ng-min/ml per 4mg of levodopa administered at about 10 minutes after administration of a dose of levodopa by inhalation compared to the patient's plasma levodopa concentration prior to administration of levodopa by inhalation. In one embodiment, the AUC of said levodopa in plasma increases by at least about 1000ng-min/ml per 4mg of levodopa administered at about 10 minutes after administration of a dose of levodopa by inhalation compared to the patient's plasma levodopa concentration prior to administration of levodopa by inhalation.

According to any of the methods of the invention, the patient's plasma levodopa concentration increases by at least about 175ng/ml per 10mg of levodopa delivered within about 10 minutes of administration of a dose of levodopa by inhalation compared to the patient's plasma levodopa concentration prior to administration of levodopa by inhalation, wherein said patient's plasma levodopa concentration maintains said increase of at least about 175ng/ml for a period of at least about 15 minutes, preferably about 20 minutes, preferably about 25 minutes, preferably about 30 minutes, preferably about 45 minutes or preferably about 60 minutes after administration.

In one embodiment, the present invention provides a method of providing rapid relief of motor fluctuations in parkinson's disease patients, the method comprising administering to the patient by inhalation about 20mg to about 75mg of levodopa, wherein Cmax is^Pul/AUC^PulDivided by Cmax^Oral/AUC^OralGreater than 1, wherein the dose of orally administered levodopa is related to pulmonary deliveryThe dose delivered was relatively the same.

In one embodiment, the present invention provides a method of providing rapid relief of motor fluctuations in parkinson's disease patients, said method comprising administering one or more doses of levodopa by inhalation, wherein T is^1/2/T^maxIs less than 1/2 and preferably less than 1/5.

In one embodiment, the dose for use in any of the methods of the invention comprises from about 10mg to about 75mg of levodopa delivered to the patient. In one embodiment, the dose comprises about 12mg to about 35mg of levodopa. In one embodiment, the dose of levodopa comprises at least about 10mg of levodopa, preferably at least about 25mg of levodopa, preferably at least about 35mg of levodopa, preferably at least about 50mg of levodopa and preferably at least about 75mg of levodopa.

In one embodiment, the amount of levodopa delivered to the pulmonary system after inhalation of one or more capsules is about 25 to about 60mg of levodopa. In another embodiment, the amount of levodopa delivered to the pulmonary system after inhalation of one or more capsules is about 35 to 55mg, about 30 to 50mg, about 40 to 50mg, about 45 to 55 mg.

In some embodiments, rapid motor relief or plasma increase of levodopa occurs upon inhalation of the powder in one capsule of levodopa. In other embodiments, rapid motor relief or plasma increase of levodopa occurs upon inhalation of the powder in two, three, four or five capsules.

In one embodiment, the dosage for use in any of the methods of the invention contains a salt. In one embodiment, the dose contains a phospholipid.

In one embodiment, any of the methods of the invention further comprises co-administering a dopa decarboxylase inhibitor to the patient. In one embodiment, the dopa decarboxylase inhibitor is administered to the patient before, simultaneously with, or after administration of levodopa by inhalation.

In one embodiment, any of the methods of the invention further comprises administering an oral dose of levodopa to the patient.

In one embodiment, any of the methods of the invention comprises maintaining the relaxation of the motor fluctuations for at least 2 hours, preferably at least 3 hours, preferably at least 4 hours, preferably at least 5 hours and more preferably at least 6 hours or more.

In one embodiment, the parkinson's disease patient treated according to any of the methods of the invention is a grade 2, grade 3 or grade 4 parkinson's disease patient.

According to any of the methods of the invention, the dose of levodopa is not affected by central nervous system food effects.

In a preferred embodiment, the dose of levodopa for use in any one of the methods of the invention comprises 90% by weight levodopa, 8% by weight Dipalmitoylphosphatidylcholine (DPPC) and 2% by weight sodium chloride.

Administration of more than one dopamine precursor, dopa decarboxylase inhibitor, or combinations thereof (including but not limited to L-dopa, carbidopa, apomorphine, and benserazide) may be provided, with levodopa being administered by inhalation either simultaneously or chronologically in accordance with the present invention. In one embodiment, the administration of more than one dopamine precursor or dopa decarboxylase inhibitor can be administered by intramuscular, subcutaneous, oral, and other routes of administration. In one embodiment, these other agents may also be co-administered via the pulmonary system. These compounds or compositions may be administered before, after, or simultaneously with the administration of levodopa by inhalation, and when used in conjunction with the administration of levodopa by inhalation according to the methods described herein, are considered to be "co-administration".

In one embodiment, the patient does not require co-administration of a dopa decarboxylase inhibitor, or allows for lower or less frequent doses of a dopa decarboxylase inhibitor. In another embodiment, the patient does not require co-administration of carbidopa, or allows for a lower or less frequent dose of carbidopa as compared to a patient receiving L-dopa orally. In another embodiment, the patient does not require co-administration of benserazide or allows for lower or less frequent doses of benserazide than patients receiving L-dopa orally. In one embodiment, the relationship between the dependence on carbidopa between levodopa administered by the pulmonary route and levodopa administered by the oral route is:

wherein "w/o CD" means without carbidopa, "w/CD" means with carbidopa, "INN" means pulmonary route, and oral means oral route of levodopa delivery to a patient.

In one embodiment, a precise dose of levodopa is required to turn on the patient. For example, in one embodiment, the dose of levodopa must increase the patient's plasma levodopa concentration by between about 200ng/ml and 500 ng/ml. Interestingly, this small increase in levodopa concentration is applicable to a wide range of patient dosing schedules. Patients who need to have a plasma level of levodopa of 1500-. More specifically, the patient can be started by increasing the plasma concentration of the patient by 200-400ng/ml, 250-450ng/ml, 300-400ng/ml or about 375-425 ng/ml.

Increasing the plasma concentration of a patient by 200ng/ml can be accomplished in a variety of ways. The patient may be administered levodopa orally, by pulmonary route or parenterally. If administered by the pulmonary route, a patient may be provided with levodopa at a dose of 25-50mg to the patient's pulmonary system. In one embodiment, the dose provided to the pulmonary system of the patient may be 25-35mg, 27-32mg, 28-32mg, 29-31mg, or about 30 mg. Providing doses to a patient's pulmonary system can be accomplished in a variety of ways. In one embodiment, the capsule contains 35-40mg of levodopa powder, the capsule provides 40-60% of the powder in the capsule to the pulmonary system of the patient and the powder comprises 75-98% levodopa.

The following examples are intended to illustrate the invention and are not to be construed as limiting its scope.

Example 1

SUMMARY

90/8/2 Dry powder levodopa formulations were provided to evaluate the safety, tolerability and levodopa Pharmacokinetics (PK) of oral levodopa in adult healthy volunteers after 90/8/2 pulmonary levodopa powder administration. The pulmonary levodopa powder described in these examples consists of 90% levodopa particles, 8% dipalmitoylphosphatidylcholine, and 2% sodium chloride (all on a dry weight basis) and is referred to herein as "90/8/2". This data provides PK descriptions of levodopa after a single inhalation 90/8/2 dose, comparison to orally administered Levodopa (LD) under fasting and fed conditions, and PK comparisons with and without Carbidopa (CD) pretreatment. This is a two-part study in healthy adult male and female subjects, as follows: part a-dose escalation profile compared to oral levodopa; and part B-90/8/2 plus or minus the carbidopa pretreatment link.

Part a is an open label, 3 cycle crossover, single dose escalation study. Each subject received a single oral dose of CD/LD (25/100mg) in the fed or fasted state for one course of treatment and 90/8/2(10 and 30mg or 20 and 50mg levodopa Fine Particle Dose (FPD)) in two different treatment courses in a single dose escalation.

Part B is an open label, randomized, two-cycle, cycle balanced crossover study. Eight subjects were evaluated for safety, tolerability and levodopa PK after administration of a single 90/8/2 inhaled dose (40mg levodopa FPD) with and without CD pretreatment.

Blood samples were collected after 24 hours and plasma levodopa concentrations were determined by Simbec Research corporation (UK) using a validated liquid chromatography-tandem mass spectrometer (LC-MS) assay with a lower limit of quantitation of 9.84 ng/ml. A non-compartmental analysis method was used followed by pharmacokinetic analysis by PK modeling using a two-compartment model with lag time. 90/8/2 administered at a dose of 10 to 50mg levodopa FPD by inhalation rapidly produced a dose-proportional increase in plasma levodopa concentration reaching potentially therapeutically relevant levels within 5 to 10 minutes after a 20 to 50mg fine particle dose in healthy adults.

After inhalation 90/8/2, levodopa plasma concentrations increased faster than those administered orally in fasting conditions, and much faster than those in fed conditions thereafter. Exposure within the first ten minutes following dose administration, expressed as the area under the plasma concentration versus time curve, i.e., AUC (AUC) from 0 to 10 minutes_0-10m) And the maximum plasma concentration (C) observed within the first 10 minutes after administration_max,10m) It was shown that after 90/8/2 inhalation, there was earlier systemic exposure compared to oral administration.

Subject to subject variability in plasma concentrations is greatly reduced by inhalation compared to oral administration, and is expected to occur in pulmonary administration. The analysis also showed that oral administration in the fasted state resulted in faster absorption compared to the fed state, but still much lower than later inhalation. Pharmacokinetic modeling indicates a lag time of about 9 to 10 minutes after oral administration in the fed or fasted state, compared to a lag time of 90/8/2 of less than 0.5 minutes after inhalation. Furthermore, the half-life of absorption after inhalation is shorter than for oral administration.

Following 90/8/2 inhalation, systemic levodopa exposure was proportional to the 90/8/2 dose administered. Dose normalization C_maxAnd AUC were very similar over the 90/8/2 dose administered. Dose normalized (based on estimated fine particle dose) exposure after inhalation is greater than 1.3 to 1.6 times AUC based and greater than C based_max1.6 to 2.9 times. As described in the literature, C was observed in fed subjects after oral administration_maxConsiderable reduction and T_maxThe AUC was considerably prolonged, however, between fed and fasted subjects, similar.

Plasma concentrations in study part B were shown to reach potential therapeutic watersThe rapid absorption of the flat plasma concentration, in part B, was an inhalation of a 40mg 90/8/2 fine particle dose with or without pretreatment with carbidopa in a crossover design. In the absence of CD pretreatment, plasma levodopa clearance is approximately four-fold faster. Accordingly, in the absence of CD pretreatment, C_maxAnd AUC is lower, and T_maxAnd T_1/2Slightly shorter. The main findings of this study were:

inhalation 90/8/2 resulted in a rapid increase in plasma levodopa concentration;

c-based within the first 10 minutes after inhalation with 90/8/2, compared to oral drug administration_maxAnd AUC is much greater with systemic exposure to levodopa;

healthy adults reach potentially therapeutically relevant levodopa plasma concentrations within 5 to 10 minutes after inhalation of a 20 to 50mg fine particle dose;

subject to subject variability in plasma levodopa concentration following inhalation is significantly less compared to oral administration, and is expected to occur in pulmonary administration;

systemic levodopa exposure is proportional to the administered levodopa fine particle dose;

pharmacokinetic modeling indicates that inhalation 90/8/2 has a much shorter lag time and a much faster absorption rate than oral administration;

dose normalized (based on estimated fine particle dose) exposure after inhalation, greater than 1.3 to 1.6 times AUC based and greater than C based, compared to oral administration_max1.6 to 2.9 times;

in the absence of carbidopa pretreatment, plasma levodopa clearance is approximately four-fold greater and levodopa exposure is reduced.

Introduction to the design reside in

In this example, 90/8/2 was tested as a phasic treatment of motor fluctuations (off-phase episodes) in patients with parkinson's disease who experienced inadequate response to their standard oral drug regimens. 90/8/2 can be used as an adjunct to patients 'existing Parkinson's disease regimens that include levodopa decarboxylase inhibitors (i.e., carbidopa or benserazide). This study was the first study for humans at 90/8/2 and was designed to evaluate safety, tolerability, and levodopa Pharmacokinetics (PK) after 90/8/2 administration compared to oral levodopa in adult healthy volunteers.

Safety and tolerability results were tested in clinical trials. This PK data provides PK specifications for levodopa after a single inhalation 90/8/2 dose, compared to levodopa (LD; L-dopa) administered orally under fasting and fed conditions, and compared to the PK of levodopa with and without Carbidopa (CD) pretreatment. Oral levodopa is administered, as conventionally specified, in combination with a carbidopa/levodopa formulation.

Study design and purpose

This is a two-part study in healthy adult male and female subjects, as follows:

part A: the dose escalation segment of oral levodopa was compared.

Part B: 90/8/2 + -carbidopa pretreatment link

The primary pharmacokinetic objective of part a of this study was to investigate the pharmacokinetics of levodopa following administration of a single inhaled dose of 90/8/2 in healthy adults. A second objective was to explore the dose proportionality of levodopa following administration of a single inhaled dose and compare the PK of 90/8/2 with oral levodopa administered in the fasted or fed state. The purpose of part B was to compare the tolerability and pharmacokinetics of 90/8/2 with and without carbidopa pretreatment.

Part a is an open label, 3 cycle crossover, single dose escalation study. All subjects were treated with oral carbidopa for one day prior to and on the day of study drug treatment. Each subject received a single oral dose of CD/LD (25/100mg) in the fed or fasted state for one course of treatment and two different inhaled doses of 90/8/2 in a single dose escalation over two different courses of treatment. Two groups of nine subjects were enrolled. The study design of part a is summarized in table 1 below:

table 1: part a study design.

90/8/2 shows the estimated fine particle dose (FPD; i.e. 'Lung delivery' dose); CD/LD (25mg/100mg) was administered orally.

Part B is an open label, two cycle, cycle balance crossover study. After preliminary review of safety and PK data in part a, eight subjects were evaluated for safety, tolerability, and levodopa PK in a randomized, balanced manner after administration of a single 90/8/2 inhaled dose (40mg levodopa FPD) with and without CD pretreatment, such that an equal number of subjects received either of two dosing sequences a- > B or B- > a, as defined below:

scheme A: 90/8/2 use of CD pretreatment

Scheme B: 90/8/2 pretreatment without CD

Carbidopa treatment was standardized for part a and part B of the study according to the schedule in table 2.

In part a, blood samples were collected before dosing and 10 min, 20 min, 30 min, 45 min, 60 min, 75 min, 90 min, 120 min, 4 hours, 8 hours, 16 hours, and 24 hours after oral administration of CD/LD. During the 90/8/2 inhalation therapy session in part A and part B, samples were collected at the same time, plus samples at 1, 2, and 5 minutes. Plasma levodopa concentrations were determined by Simbec Research using a validated liquid chromatography-tandem mass spectrometer (LC-MS) assay with a lower limit of quantitation of 9.84ng/ml (2, 3).

Table 2: carbidopa treatment schedule.

When oral and inhalation dosing sessions are scheduled to occur within two consecutive days, the CD dosing regimen administered for the first dosing session suitably encompasses the CD pre-treatment required for the second dosing session. Subjects in parts a and B (+ CD) received 3 doses of CD the day before receiving study medication.

Not applicable to subjects who entered the fed state at random.

Note: at T0, 25mg carbidopa was also administered as part of the oral CD/LD administration

Pharmacokinetic analysis method

Non-compartmental analysis

Data analysis was performed on plasma concentrations and time for each subject and each treatment. Use of

Professional version 5.3 performs non-compartmental analysis. Estimation of area under the curve from time zero to the last measurable time point (AUC) using linear trapezoidal method_0-t). Estimating an elimination rate constant (λ) using linear regression over the last three or more time points, the elimination rate constant (λ) being used to estimate the terminal half-life (T) from the following equation_1/2) And AUC (AUC) from zero to infinity_0-∞)：

T_1/2＝ln(2)/λ

AUC_0-∞＝AUC_0-t+C_t/λ

Wherein C is_tThe last measurable concentration predicted for the regression line. Serum clearance divided by bioavailability (CL/F) and apparent volume of distribution in the terminal phase divided by bioavailability (Vz/F) were estimated from the following formula:

CL/F ═ dose/AUC_0-∞

Vz/F dose/(λ AUC)_0-∞)

Determination of maximum concentration (C) directly from the data_max) And the observed time (T)_max)。

The partial AUC (AUC) over the first 10 minutes after drug administration was calculated by the trapezoidal method_0-10m). Maximum plasma concentration (C) observed in the first 10 minutes_max,10m) Determined from administration up to and including 10 minutes of samplingThe highest plasma concentration in between. By standardizing 90/8/2 post-inhalation dose C_maxOr AUC divided by the dose normalization parameter after oral administration to calculate the ratio of inhalation to oral exposure for each subject. The AUC-based exposure ratio is the relative bioavailability of the inhaled to oral drug.

By accommodating the slave C_maxLinear interpolation between two time points of plasma concentration divided by 2 calculated plasma concentration another parameter, i.e. the time to reach half the observed maximum plasma concentration (T.sub.T._Cmax50)。

Pharmacokinetic modeling

Use ofProfessional edition 5.3 performs pharmacokinetic modeling. Many different models were evaluated, including one-compartment and two-compartment models with and without lag time. All evaluated models have a first instruction (firstorder) input. The model is evaluated based on a plurality of diagnostic criteria, including the Aikaike information criterion, the sum of squares of the residuals, the relative values of the estimated parameters and their corresponding standard error estimates, the correlation of the observed and predicted concentrations, and the overall trend of the change between the predicted and observed concentrations.

The model that best describes most of the plasma concentration versus time curve is a two-compartment model with lag time: (

Model 12). The data set from subjects receiving inhalation 90/8/2 is mostly well described by models that do not have lag times, since the estimated lag times from these subjects are very short, in most cases less than a minute. However, for comparison of data sets from oral administration, the lag time model was used for all subjects and treatments. The two-compartment model describes most data sets better than the one-compartment model. In some cases, a compartmental model is not suitable. In the case where one of the compartmental models is better, the criteria are based on statistical diagnosisThe difference between the two models is very small. Thus, the results of modeling using a two-compartment model are presented herein. Modeling of the two-compartment model in protocol 1, resulting in a fraction of the distribution volume divided by the absorbed dose (V/F), the lag time (T)_lag) Rate constants associated with absorption and elimination, k01 and k10, respectively, and estimates of rate constants k12 and k21 in the atrioventricular chamber rate constants α and β associated with the distribution and elimination of the curves are calculated from k12, k21 and k10 other secondary parameters calculated from the primary parameters include AUC, C_max、T_maxCL/F and half-life (T) associated with the absorption, distribution, elimination phases of the curve_1/2k01、T_1/2α、T_1/2β). The model can be represented by the following formula:

C_t＝Ae^-αt+Be^-βt+Ce^-k01t

C_tfor plasma levodopa concentration at time t after administration, A, B, C is the y-axis intercept of the distribution, elimination and absorption phases of the curve, and is calculated from dose, volume and rate constants.

A uniform weight was used in all analyses and plasma concentrations reported as being below the quantified level tested (BLQ, <9.84ng/ml) were treated as missing values. No data points were excluded from the analysis.

Results and discussion

90/8/2 administered at a dose of 10 to 50mg levodopa FPD by inhalation rapidly produced a dose-proportional increase in plasma levodopa concentration reaching potentially treatment-related levels (400 to 500ng/ml) within 5 to 10 minutes after a fine particle dose of 20 to 50mg levodopa in healthy adults.

Figure 1 shows the mean levodopa plasma levodopa concentration after 90/8/2 inhalation and after a 100mg oral dose under fed and fasted conditions. Individual values and concentration versus time curves were extrapolated for each inhaled dose of 10mg, 20mg, 30mg and 50mg levodopa, as well as for oral 100mg levodopa with and without carbidopa pretreatment under fed and fasting conditions, respectively.

Plasma levodopa concentrations after inhalation 90/8/2 increased faster than those after oral administration under fasting conditions, and much faster than those under fed conditions. About five minutes after inhalation 90/8/2, potentially therapeutically relevant plasma concentrations were reached. Within five minutes of inhalation 90/8/2(20 to 50mg FPD), plasma concentrations of 400 to 500ng/ml or higher have been observed with a range of potential therapeutic relevance (4). Plasma concentrations achieved after 90/8/2(40 and 50mg FPD) were in the same range as those observed after oral CD/LD (25/100mg) administration (FIG. 3).

Figure 2 shows the mean plasma concentrations over the first ten minutes compared to the mean plasma concentrations after oral administration. The exposure within the first ten minutes after drug administration is expressed in table 3 as AUC (AUC) from 0 to 10 minutes_0-10m) And the maximum plasma concentration (C) observed in the first ten minutes_max,10m) And both. In some individuals, C is observed in less than 10 minutes_max,10m。

Oral administration in the fasted state results in faster absorption compared to the fed state, but still much lower than after inhalation. C was observed in the fed subjects after oral administration as described in document (5)_maxConsiderable reduction and T_maxThe considerable prolongation, however, the AUC (table 5) was similar between fed and fasted subjects.

Table 3: 90/8/2 levodopa exposure following administration of inhaled or oral levodopa.

Post-treatment plasma concentrations varied much less between subjects following inhalation 90/8/2 than following oral administration. As seen in figure 3, following inhalation (filled symbols), the plasma concentrations of most subjects receiving 50mg 90/8/2 were above 400ng/ml 10 minutes post-dose, some were above 400ng/ml at 5 minutes, and all were above 400ng/ml by 20 minutes. After oral administration (open symbols), the response was much slower, with no subject reaching 400ng/ml within 10 minutes of administration. Individual plasma concentration and variability data for the other dose groups indicate that over 5 to 10 minutes of dosing, in some subjects, over the levodopa FPD dose and plasma concentration of 20mg, over 400ng/ml is reached, and the response is much less variable than after oral administration. The degree of variability, expressed as% CV in plasma concentrations in the treated group at a given sampling time, is shown in table 4, indicating that the variability of 90/8/2-treated subjects was less than half that seen in the fasted oral group and about five times less than all oral subjects (combined fed and fasted) within the first 30 minutes of dosing.

Table 4: variability of plasma levodopa concentration (% CV).

Refers to the estimated levodopa fine particle dose

Oral levodopa dose 100mg

A summary of the pharmacokinetic parameters estimated by the non-compartmental analysis is shown in table 5. Individual parameter estimates were determined from non-compartmental PK analyses of inhaled doses of each 10mg, 20mg, 30mg and 50mg and oral doses of 100mg with and without CD pretreatment under fed and fasted conditions. The results indicate that levodopa exposure is proportional to the 90/8/2 dose administered. Dose normalization C_maxAnd AUC were very similar at all 90/8/2 doses. Dose proportionality is further illustrated in fig. 4 and 5. For all doses, T_1/2Are similar.

Table 5: levodopa pharmacokinetic parameters (mean ± SD) estimated by non-compartmental analysis.

Dosage: levodopa dose

Means estimated fine particle dose

Median value

AUC normalized from dose_0-∞The bioavailability relative to oral levodopa inhalation 90/8/2 was calculated for individual subjects. Since each subject in part a of the study received one oral and two inhaled doses, two bioavailability estimates were determined for each subject, once per inhaled dose. Also dose-normalized C_maxValues were calculated for relative exposure. Oral doses administered under fed and fasted conditions were calculated separately. The mean and standard deviation of the relative bioavailability calculations are shown in table 6. A single value was calculated as the relative levodopa exposure after inhalation 90/8/2(10-50mg levodopa fine particle dose) compared to the carbidopa/levodopa 25/100mg oral administration calculated from dose normalized Cmax. There appears to be no major difference between fed and fasted subjects or dose groups. Dose normalized (based on estimated fine particle dose) exposure after inhalation, greater than about 1.3 to 1.6 times AUC based, and greater than C based, compared to oral administration_max1.6 to 2.9 times.

Table 6: exposure rates for inhalation 90/8/2 (mean. + -. SD) relative to oral levodopa

The best description of the plasma concentration versus time curve is through a two-compartment model with a first command input and a lag time. Use of

The model 12 models a single data set and makes observed and predicted concentration versus time plots. In some cases, the terminal half-life (T) is due to several points with similar or fluctuating concentrations in the terminal phase of the curve_1/2β) Is very large, resulting in a gentle slope. In many of these cases, a large T_1/2βVery large estimates were made for AUC. Other variations in model parameter estimates cause fewer outliers in some parameter estimates. These valuesAre not excluded from data analysis or statistically processed as outliers. Instead, the data is summarized by the median value rather than the mean value. Thus, very high or very low values remain in the given data, but do not impose too great an impact on the group summary statistics.

The pharmacokinetic modeling results shown in table 7 indicate that there is a lag time of about nine minutes after oral administration. By comparison, the lag time associated with inhalation 90/8/2 is negligible, less than 0.5 minutes. In addition, the absorption rate of inhaled 90/8/2 is faster (shorter T) than after oral administration in the fasted state_1/2k01) And is about ten times faster than absorption in the fed state. After inhalation 90/8/2, the much shorter lag time and the much faster absorption rate indicate that greater systemic exposure was observed within the first 5 to 10 minutes after dosing compared to oral administration. The calculated parameter reaches C_max50% of the time (T)_Cmax50) Inhalation 90/8/2 was also shown to produce systemic exposure to levodopa more early than oral administration. Apart from oral administration in the fed state, absorption is much faster than elimination.

The combined effect of lag time and absorption rate of plasma concentration over the first few minutes after administration is shown in fig. 6, which fig. 6 shows a pharmacokinetic modeling of mean plasma concentration data. This graph shows the concentrations of 90/8/2 inhaled within the first 60 minutes after dosing and levodopa administered orally as predicted by pharmacokinetic models. Symbols represent the observed mean concentrations and lines represent the concentrations predicted by the pharmacokinetic model. A good correlation of the predicted values with the observed values indicates that the model describes the data well. The figure also shows other observations from studies in which inhalation 90/8/2 resulted in a rapid increase in plasma levodopa concentration, with potentially clinically relevant plasma concentrations that could be reached within 5 to 10 minutes of administration, and exposure was dose-proportional.

Table 7: pharmacokinetic parameters (median) estimated by pharmacokinetic modeling

Means estimated fine particle dose

Part B

Plasma concentrations for study part B in which 90/8/2(40mg levodopa FPD) was inhaled with or without carbidopa pretreatment in a crossover design are shown in figure 7. Peak plasma concentrations and exposure were higher with carbidopa pretreatment. In the absence of CD pretreatment, plasma levodopa clearance is approximately four-fold faster. Accordingly, in the absence of CD pretreatment, C_maxAnd AUC is lower, and T_maxAnd T_1/2Slightly shorter (table 8).

Table 8: levodopa pharmacokinetic parameters (mean + -SD) estimated by non-atrioventricular analysis after inhalation of 40mg 90/8/2 with and without carbidopa pretreatment

Median value

Conclusion

The main findings of this study were: (i) inhalation 90/8/2 resulted in a rapid increase in plasma levodopa concentration; (ii) in contrast to oral drug administration, the first 10 minutes after administration with 90/8/2 inhalation, based on C_maxAnd AUC is much greater for systemic exposure of levodopa; (iii) potentially therapeutically relevant plasma levodopa concentrations are reached within 5 to 10 minutes after 90/8/2 doses at 20 to 50mg levodopa fine particle doses in healthy adults; (iv) the subject to subject variability in plasma levodopa concentration is greatly reduced after inhalation compared to oral administration; (v) systemic levodopa exposure is proportional to the administered levodopa fine particle dose; (vi) pharmacokinetic modeling indicates that inhalation 90/8/2 has a much shorter lag time and a much faster absorption rate than oral administration; vii) dose normalized (based on estimated fine particle dose) exposure after inhalation, greater than 1.3 to 1.6 times AUC based, and greater than C based, compared to oral administration_max1.6 to 2.9 times; and viii) high plasma levodopa clearance in the absence of carbidopa pretreatmentAbout four times greater and the levodopa exposure decreased.