JP2019108379A - Rapid relief of motor fluctuations in parkinson's disease - Google Patents

Abstract

To provide methods for treating OFF episodes in a Parkinson's disease patient.SOLUTION: The methods comprise administering levodopa to the pulmonary system of a patient, where after administration the patient's Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 score is improved by, for example, at least about 5 points compared to a placebo control and/or compared to the patient's UDPRS Part 3 score prior to the administration. About 30 mg to about 60 mg of fine particle dose of levodopa is administered to the patient's pulmonary system via inhalation.SELECTED DRAWING: Figure 1

Description

BACKGROUND ART Parkinson's disease (also referred to herein as "PD") is neuropathologically characterized as degeneration of dopamine neurons in the basal ganglia, and neurologically wasting tremor, bradykinesia and balance Characterized by difficulties. It is estimated that more than one million people suffer from Parkinson's disease. Most patients will often receive the dopamine precursor levodopa, or "L-Dopa", along with carbidopa, a dopa-decarboxylase inhibitor. In the early stages of Parkinson's disease, L-Dopa properly suppresses the symptoms of the disease. However, in the course of the disease, the effect tends to diminish after several months to several years.

  As one example where the effects of L-Dopa are diminished, motor symptom variability may develop in the subject being treated. “Motor symptom fluctuation” is a period during which the therapeutic agent exerts a sufficient effect and the symptoms of Parkinson's disease are appropriately suppressed (also referred to herein as “on time / episode” or “on”), The subject is on dopamine replacement therapy, as the drug appears to have little effect and there is also a period during which the symptoms of Parkinson's disease are aggravated (also referred to herein as “off time / episode” or “off”). It means that the reaction shown in. Starts to fluctuate. Motor symptom fluctuations can appear as "wearing off" and do not last as long as the effects of L-Dopa therapy were first observed, resulting in a patient experiencing motor disorder fluctuations "on-on" "Off" syndrome occurs. The effect of L-Dopa ("on-time") can be gradually reduced over time until the usefulness of dopaminergic therapeutics becomes significantly limited.

  The effects of L-Dopa in Parkinson's disease patients fluctuate, at least in part, the plasma half-life of L-Dopa tends to fall within a very short range of 1 to 3 hours, even when co-administered with carbidopa It is considered to be related to being there. In the early stages of the disease, this factor is alleviated by the dopamine storage capacity of targeted striatal neurons. L-Dopa is taken up and stored in neurons and released over time. However, as the disease progresses, degeneration of dopaminergic neurons reduces dopamine storage capacity.

  As a result, the positive effects of L-Dopa become increasingly correlated with fluctuations in plasma levels of L-Dopa. In addition, patients tend to experience problems including gastric emptying and intestinal malabsorption of L-Dopa. Voluntary gastric emptying of levodopa contributes to random fluctuations in motility. The patient's symptoms of Parkinson's disease become increasingly pronounced, and the range is from plasma recovery after L-Dopa administration, from recovery to classical Parkinson's disease symptoms seen when plasma levels decrease. It covers so-called dyskinesias, which are observed when the level is temporarily very high.

  There is still a need to provide rapid alleviation of motor symptoms and off episodes in Parkinson's patients, which are effective over a clinically relevant period, which results in sufficient response time to the patient. .

  The present invention is a method of treating off episodes of Parkinson's disease patients, comprising administering levodopa to the patient's pulmonary system, wherein after administration the patient's Unified Parkinson's Disease Rating Scale: UPDRS) Third part (also referred to herein as "UPDRS part III" or "UDPRS III") score is improved, for example by at least about 5 points relative to a placebo control, and / or after administration, the patient's unity Provided is a method wherein the Parkinson's Disease Rating Scale (UPDRS) third part score is improved, for example by at least about 5 points relative to the patient's UDPRS third part score prior to dosing. In a preferred embodiment, the patient's UDPRS third part score is improved, for example within about 60 minutes of administration of levodopa. The invention also provides methods of reducing the average daily off time and methods of delivering levodopa to a patient. The invention is particularly useful for reducing the average daily off time and off episode duration of Parkinson's disease patients.

FIG. 10 shows mean plasma levodopa concentration versus time data after 90/8/2 inhalation and after oral levodopa administration. FIG. 10 shows mean plasma levodopa concentration versus time after 90/8/2 inhalation as compared to oral administration. FIG. 6 shows plasma levodopa concentrations of individual subjects after 50 mg 90/8/2 inhalation or after oral administration of 100 mg levodopa (CD / LD 25/100 mg) under fed and fasted conditions. FIG. 10 shows levodopa AUC _0-∞ versus 90/8/2 microparticle dose. FIG. 10 shows levodopa C _max versus 90/8/2 microparticle dose. FIG. 1 shows pharmacokinetic modeling of mean plasma concentrations. The mark represents the measured mean concentration, and the straight line represents the concentration predicted by the model. FIG. 6 shows mean levodopa plasma concentrations with and without carbidopa (CD) pre-treatment. FIG. 7 is a diagram comparing plasma levodopa concentration and UPDRS score of a patient. Mean change in UPDRS third part score at the 6th visit, the primary endpoint, between patients who received a 50 mg 90/8/2 microparticle dose of study drug and those who received placebo It is the line graph which showed time (minute). Mean change in UPDRS third part score at the 4th visit, the primary endpoint, between patients who received a 35 mg 90/8/2 microparticle dose of study drug and patients who received placebo and patients receiving placebo It is the line graph which showed time (minute). It is a figure which shows that the deterioration of the on-time in which dyskinesia was recognized was not seen at all. FIG. 11A shows the time (hours) of dyskenisia with time difficulties (weeks) which is not difficult to cope between 90/8/2 and placebo. FIG. 11B shows the time (hours) for dyskinesia that is difficult to cope between 90/8/2 and placebo, along with the time period (weeks). It is a figure which shows that the deterioration of the on-time in which dyskinesia was recognized was not seen at all. FIG. 11A shows the time (hours) of dyskenisia with time difficulties (weeks) which is not difficult to cope between 90/8/2 and placebo. FIG. 11B shows the time (hours) for dyskinesia that is difficult to cope between 90/8/2 and placebo, along with the time period (weeks).

(Detailed Description of the Invention)
The defined half-life (T _1/2 ) is the time at which the concentration (C) of drug in body fluid or tissue reaches a concentration C / 2.

" ^CmaxPul " means the maximum plasma concentration (Cmax) observed in measurements after transpulmonary delivery. ^{"Cmax oral"} means the maximum plasma concentration observed in measurement after oral delivery.

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

"AUC ^Pul " means plasma concentration versus area under the curve (AUC) measured after pulmonary delivery. " ^AUCoral " means plasma concentration versus area under the curve (AUC) measured after oral delivery.

The term "coefficient of variation (CV)" expressed in% CV is the ratio of the standard deviation σ to the mean value μ: Cv = σ / μ
It is defined as

  As used herein, the terms "nominal dose" or "nominal powder dose" refer to the percentage of levodopa present in the total amount of particles contained in the container, and of levodopa available for administration to a patient. Represents the largest amount.

  "Particulate fraction" or "FPF" corresponds to the percentage of particles present in the container that have an aerodynamic diameter of less than 5.6 μm.

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

  As used herein, "shortening the average daily off time" of a patient refers to the average shortening time of the daily off time of the patient recorded in the patient diary or observed by the clinician.

  As used herein, the Unified Parkinson's Disease Rating Scale (UPDRS) is a well-established tool for measuring the signs and symptoms of Parkinson's disease. The UPDRS consists of four parts in total. Parts 1, 2 and 3 contain 44 questions. All items are graded from 0 (normal) to 4 (severe morbidity), unless otherwise stated, each item being defined by a short sentence. UPDRS includes both scoring by clinicians (motor function tests) and reporting of past mental functions and activities of daily living (ADL obtained by asking the patient questions). The first part measures mental state, behavior and mood including intellectual disability, thinking disorder, motivation / spontaneousness and depression. The second part measures daily life behavior (ADL) including conversation, fluency, swallowing, writing, cooking, clothing disorders, freezing while walking, tremor and paresthesias. The third part is a motor function test, and the scales include speech, facial expression, resting tremor, movement tremor, rigidity, finger taps, hand movements, hand rotation, supination, leg agility, It includes standing up from the chair, posture, walking motion, posture stability and body movement. The fourth part measures in particular the dyskinesia duration, motor impairment pain, duration and duration of off, treatment complications including sleep disorders.

  The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the specific embodiments of the invention are described for the purpose of illustration and not for the purpose of limiting the invention. The principle features of the invention can be used in various embodiments without departing from the scope of the invention. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include plural referents unless the context clearly dictates otherwise. Include.

  In the present invention, as used herein, the term "dose of levodopa" means a formulation comprising an amount of levodopa in a dosage form suitable for delivery to a patient by inhalation. In one embodiment, the 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. Reissue Patent No. RE 43711, both of which are incorporated by reference in their entirety. It is incorporated in the specification. The particles are preferably in the form of a dry powder and are characterized by properties such as the fine particle fraction (FPF), which will be described in more detail later, the geometrical dimensions and the aerodynamic dimensions.

  Gravimetric analysis using a cascade impactor is one of the methods of measuring the size distribution of suspended particles. The Andersen Cascade Impactor (ACI) is an eight-stage impactor that can separate an aerosol into nine different fractions based on aerodynamic size. The size cutoff value for each stage is determined by the flow rate at which the ACI operates. Preferably, ACI is calibrated at 60 L / min.

  In one embodiment, two-stage collapse ACI is used for particle optimization. The two-stage collapse ACI consists of stages 0, 2 and F of an eight-stage ACI, making it possible to collect two separate powder fractions. At each stage, the aerosol stream passes through the nozzles and strikes the surface. Particles of sufficient magnitude in inertia in the aerosol stream strike the plate. Small particles that are not large enough for the inertia to strike the plate remain in the aerosol stream and are carried to the next stage.

  ACI is calibrated so that the fraction of powder collected in the first stage is called the fine particle fraction FPF (5.6). This FPF corresponds to the% of particles whose aerodynamic diameter is less than 5.6 μm. The fraction of powder that passes through the first stage of the ACI and deposits on the collection filter is called FPF (3.4). This corresponds to the% of particles having an aerodynamic diameter of less than 3.4 μm.

  The FPF (5.6) fraction has been shown to correlate with the proportion of powder deposited in the patient's lungs, whereas the FPF (3.4) produces a powder that reaches the deep lungs of the patient. It is shown that there is a correlation with the ratio.

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

  Another method of measuring the size distribution of suspended particles is multi-stage liquid impinger (MSLI). The Multi-Stage Liquid Impinger (MSLI) operates on the same principle as the Anderson Cascade Impactor (ACI), but the MSLI has five stages instead of eight. Furthermore, each stage of MSLI consists of a methanol wet glass frit instead of each stage consisting of solid plates. The wetting stage is used to prevent bounce and re-strike that can occur when using ACI. MSLI is used to obtain an index of powder flow rate dependency. This can be achieved by operating the MSLI at 30 L / min, 60 L / min and 90 L / min and measuring the proportion of powder collected by stage 1 and the collection filter. If the proportion on each stage is kept relatively constant throughout the different flow rates, the powder is considered to be close to flow rate independence.

The particles of the present invention have a tap density of less than about 0.4 g / cm ³ . As used herein, particles having a tap density of less than about 0.4 g / cm ³ are referred to as "aerodynamically light particles". For example, the particles have a tap density of less than about 0.3 g / cm ^3, less than about 0.2 g / cm ³ or about 0.1 g / cm ³ . Tap density should be measured using equipment known to those skilled in the art, such as Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, NC) or GEOPYCTM instrument (Micrometrics Instrument, Norcross, GA, 30093) Can. Tap density is one of the standard measures of envelope mass density. The tap density can be determined using the method of USP Bulk Density and Tapped Density (United States Pharmacopia convention, Rockville, MD, Tenth Edition Addendum, 4950-4951, 1999). Features that can contribute to low tap density include irregular surface texture and porous structure.

The envelope mass density of an isotropic particle is defined as the mass of the particle divided by the envelope volume of the smallest sphere that can contain the particle on the inside. In one embodiment of the invention, the particles have an envelope mass density of less than about 0.4 g / cm ³ .

  The particles of the invention have a preferred size, for example a geometric volume median diameter (VMGD) of at least about 1 micron (μm). In one embodiment, VMGD is any subrange comprised between about 1 μm to 30 μm or 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 the range of about 1 μm to 10 μm, about 3 μm to 7 μm, 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 envelope diameter (MMED) or geometric mass median diameter (MMGD) of at least 1 μm, for example around 5 μm or about 10 μm or more. For example, the particles range in subranges including MMGD greater than about 1 μm, including about 30 μm or 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 spray-dried particle diameter, eg, VMGD, can be measured using a laser diffraction instrument (eg, Helos from Sympatec (Princeton, NJ)). Other devices 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 particle composition and method of synthesis. The distribution of particle sizes in the sample can be selected to optimize deposition at the target site within the airway.

  Aerodynamically light particles are any part within which "aerodynamic mass median diameter" (MMAD), also referred to herein as "aerodynamic diameter" (MMAD), is contained within about 1 μm to about 5 μm or about 1 μm to about 5 μm. It is preferably in the range. For example, MMAD is about 1 μm to about 3 μm, or MMAD is about 3 μm to about 5 μm.

  Experimentally, it is possible to determine the aerodynamic diameter by using gravity settling, which uses the time taken by the population of particles to settle for a certain distance, using the aerodynamics of the particles. Directly estimate the target diameter. One of the methods to indirectly measure aerodynamic mass median diameter (MMAD) is multi-stage liquid impinger (MSLI).

から推定することが可能であり、式中、ｄ_ｇは幾何学的直径、例えばＭＭＧＤであり、ρは粉末密度である。 Aerodynamic diameter d _aer equation:

Where d _g is the geometric diameter, eg, MMGD, and ρ is the powder density.

Particles with a tap density of less than about 0.4 g / cm ³ , a median diameter of at least about 1 μm, such as at least about 5 μm, and an aerodynamic diameter of about 1 μm to about 5 μm, preferably about 1 μm to about 3 μm It is more likely to escape deposition in the oropharyngeal area by force and gravity and is targeted to the airways, particularly the deep lung. Use of large, porous particles as they can be aerosolized more efficiently than small, dense aerosol particles as currently used for inhalation therapy. Is advantageous.

  The large, aerodynamically light particles, which are preferably at least about 5 μm in median diameter, are also phagocytosed by alveolar macrophages due to the size exclusion of the particles from the cytoplasmic space, as compared to small, relatively dense particles. There is a high probability of successfully avoiding the action and clearance of phagocytes from the lungs. Phagocytosis of particles by alveolar macrophages increases rapidly and decreases as the particle size increases above about 3 μm (Kawaguchi, H. et al., Biomaterials, 7: 61-66 (1986); Krenis, L. J. and Strauss, B., Proc. Soc. Exp. Med., 107: 748-750 (1961); and Rudt, S. and Muller, R. H., J. Contr. Rel, 22: 263-272 (1992). ). For statistically isotropic particles, such as rough spheres on the surface, the envelope volume of the particles is approximately equal to the volume of cytoplasmic space required for complete phagocytosis of the particles in macrophages.

  Materials having surface roughness, diameter and tap density suitable for local delivery to selected airway areas such as deep lung or upper or middle airway may be processed. For example, upper airway delivery may use dense particles or large particles, or alternatively, a mixture of particles of various sizes in a sample may be prepared with the same or different therapeutic agents, and different doses of lung may be administered in a single dose. The area may be administered as a target. For delivery to the middle and upper airways, particles with an aerodynamic diameter range of about 3 to about 5 μm are preferred. For deep lung delivery, particles with an aerodynamic diameter range of about 1 to about 3 μm are preferred.

  In normal respiratory conditions, inertial collisions and gravitational sedimentation of aerosols are the main deposition mechanism in the airways and acinus of the lung (Edwards, D.A., J. Aerosol Sci., 26: 293-317 (1995) )). The importance of both deposition mechanisms increases in proportion to the mass of the aerosol, not the particle (or envelope) volume. The aerosol deposition site in the lungs is determined by the mass of the aerosol (at least for particles with an average aerodynamic diameter greater than about 1 μm), so all other physical parameters are the same and particle surface irregularities and particle irregularities Decreasing tap density by increasing porosity can increase the envelope volume of particles that can be delivered to the lungs.

によって表され、エンベロープ質量密度の単位はｇ／ｃｍ^３である（Ｇｏｎｄａ，Ｉ．，“Ｐｈｙｓｉｃｏ−ｃｈｅｍｉｃａｌ ｐｒｉｎｃｉｐｌｅｓ ｉｎ ａｅｒｏｓｏｌ ｄｅｌｉｖｅｒｙ，” ｉｎ Ｔｏｐｉｃｓ ｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ １９９１（Ｄ．Ｊ．Ａ．ＣｒｏｍｍｅｌｉｎおよびＫ．Ｋ．Ｍｉｄｈａ）編，ｐｐ．９５−１１７，Ｓｔｕｔｔｇａｒｔ：Ｍｅｄｐｈａｒｍ Ｓｃｉｅｎｔｉｆｉｃ Ｐｕｂｌｉｓｈｅｒｓ，１９９２））。 Particles with low tap density have a smaller aerodynamic diameter compared to the actual envelope sphere diameter. The relationship between the aerodynamic diameter d _aer and the envelope diameter d is a simplified equation:

And the unit of the envelope mass density is g / cm ³ (Gonda, I. “Physico-chemical principles in aerosol delivery,” in Topics in Pharmaceutical Sciences 1991 (D. J. A. Crommelin and K. K. (Midha) Ed., Pp. 95-117, Stuttgart: Medpharm Scientific Publishers, 1992)).

となり、式中、ｄは常に３μｍより大きい。例えば、エンベロープ質量密度μ＝０．１ｇ／ｃｍ^３を示す空気力学的に軽い粒子は、エンベロープ直径が９．５μｍの大きさの粒子で沈着が最大となる。粒子径が増大すると粒子間付着力が低下する（Ｖｉｓｓｅｒ，Ｊ．，Ｐｏｗｄｅｒ Ｔｅｃｈｎｏｌｏｇｙ，５８：１−１０）。したがって、粒子径が大きいと、食作用による喪失の減少に寄与することに加えて、エンベロープ質量密度の低い粒子の肺深部へのエアゾール化の効率が高くなる。 In the alveolar region of human lung, the maximum (about 60%) deposition of monodispersed aerosol particles occurs when the aerodynamic diameter is about d _aer = 3 μm (Heyder, J. et al., J. Aerosol Sci., 17: 811-825 (1986)). Aerodynamically light particles that contain monodisperse inhalable powders and maximum deep lung deposition have a small envelope mass density, so their actual diameter d is:

Where d is always greater than 3 μm. For example, aerodynamically light particles exhibiting an envelope mass density μ = 0.1 g / cm ³ have maximum deposition with particles having an envelope diameter of 9.5 μm. Interparticle adhesion decreases as particle size increases (Visser, J., Powder Technology, 58: 1-10). Thus, in addition to contributing to a reduction in phagocytotic loss, larger particle sizes increase the efficiency of aerosolizing particles with low envelope mass density to the deep lung.

  The aerodynamic diameter can be calculated to maximize deposition in the lungs. In the past, very fine particles that are less than about 5 microns, preferably about 1 to about 3 microns, and which undergo phagocytosis have been used to maximize deposition. If you select particles that are large in diameter but sufficiently light (and thus have the feature of being "aeortically light"), they will be delivered to the lung as well, but particles of large size will be phagocytosed. Absent. Delivery can be improved by using particles that are rough or uneven in surface as compared to particles that are smooth in surface.

In another embodiment of the present invention, the particles, the envelope mass density, also referred to as "mass density" is less than about 0.4 g / cm ³ herein. In some embodiments, the density of the particle is about ^{0.01g / cm 3, 0.02g / cm} 3, 0.03g / cm 3, 0.04g / cm 3, 0.05g / cm 3, 0. ^{06g / cm 3, 0.07g / cm} 3, 0.08g / cm 3, 0.09g / cm 3, 0.1g / cm less than ^{3, 0.02~0.05g /} cm ^{3, 0.02~0} It is .06 g / cm ³ . For the mass density and the relationship between mass density, mean diameter and aerodynamic diameter, see US Pat. No. 6,254,854, issued Jul. 3, 2001 to Edwards et al. (In its entirety by reference). (Incorporated herein).

  Particles having the above composition and aerodynamic properties may be made by several methods including, but not limited to, spray drying. Spray drying techniques are generally described, for example, K.I. It is described in "Spray Drying Handbook" by Masters (John Wiley & Sons, New York, 1984).

  The terms "effective amount" or "therapeutically effective amount" as used herein mean the amount necessary to obtain the desired effect or effect. The actual effective amount of drug may vary depending on the particular drug or combination thereof used, the particular composition to be formulated, the mode of administration, as well as the age, weight, condition of the patient and the severity of the episode being treated. In the case of a precursor of dopamine, an agonist or a combination thereof, it is an amount that alleviates a Parkinson's disease condition requiring treatment. Doses for particular patients are described herein and can be determined by one of ordinary skill in the art using conventional considerations (eg, by appropriate conventional pharmacological protocols).

  Administration of the particles to the respiratory system can be carried out by any means known in the art and the like. For example, the particles are delivered from an inhalation device such as a dry powder inhaler (DPI). Alternatively, metered dose inhalers (MDI), nebulizers or instillation techniques may be used.

In one embodiment, delivery of particles to the pulmonary system is described in US Pat. No. 6,858,199 entitled "High Efficient Delivery of a Large Therapeutic Mass Aerosol" and "Highly Efficient Delivery of a Large Therapeutic Mass Aerosol". According to the method described in US Pat. No. 7,556,798. Both of the above patents are incorporated herein by reference in their entirety. As disclosed herein, the particles are retained, contained, stored or enclosed in a container. The container, for example a capsule or blister, has a volume of at least about 0.37 cm ³ and is designed to be suitable for use in a dry powder inhaler. In addition, the volume of at least about 0.48 cm ^3, may be used a larger vessel with 0.67 cm ³ or 0.95 cm ^3. The term "container" as used herein is not particularly limited, but for example, for storing particles, powders or inhalable compositions, including capsules, blisters, film cover container wells, chambers, etc., in an inhalation device. Suitable means known to those skilled in the art are included. In one embodiment, the container is a capsule, for example, a capsule designated for a particular capsule size, such as 2, 1, 0, 00 or 000. Suitable capsules can be obtained, for example, from Shionogi (Rockville, Md.). In one embodiment, the capsule shell may comprise hydroxypropyl methylcellulose (HPMC). In a further embodiment, the capsule shell may comprise hydroxypropyl methylcellulose (HPMC) and titanium dioxide. Blisters can be obtained, for example, from Hueck Foils (Wall, NJ). Other containers suitable for use in the present invention and their volumes are known to those skilled in the art.

  In one embodiment, the invention provides the administration of L-Dopa to the pulmonary system in a small number of stages, preferably a single respiratory activation phase. In one embodiment, at least 50% of the mass of particles stored in the inhaler is delivered to the subject's respiratory system in a single breath activation phase. In one embodiment, at least 60%, preferably at least 70%, preferably at least 80% of the particles stored in the inhaler are delivered to the subject's respiratory system in a single respiratory actuation phase. In another embodiment, L-Dopa is delivered at least 1 to 80 milligrams by administering the particles contained in the container to the airways of the subject in a single breath. In addition, preferably at least 10 milligrams, 15 milligrams, 20 milligrams, 25 milligrams, 35 milligrams, 40 milligrams, 50 milligrams, 60 milligrams, 75 milligrams and 80 milligrams may preferably be delivered.

  Delivery of the particles to the pulmonary system in a single respiratory actuation phase is enhanced by using particles that disperse with relatively low energy, such as the energy normally supplied by the subject's inhalation. Such energy is referred to herein as "low." As used herein, "low energy administration" refers to administration where the energy applied to disperse and / or inhale the particles is within the range normally supplied by the subject upon inhalation.

  The invention also relates to methods of 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 such as dry powder particles suitable for pulmonary delivery comprising about 60-99% by weight (dry weight) of levodopa. Particularly preferred are particles comprising about 75% by weight or more of levodopa, more preferably particles comprising about 90% by weight or more of levodopa. The particles may consist exclusively of L-Dopa or may further comprise one or more additional components. Examples of such suitable additional ingredients include, but are not limited to, phospholipids, amino acids, sugars and salts. Examples of phospholipids include, but not limited to, phosphatidyl choline, dipalmitoyl phosphatidyl choline (DPPC), dipalmitoyl phosphatidyl ethanolamine (DPPE), distearoyl phosphatidyl choline (DSPC), dipalmitoyl phosphatidyl glycerol (DPPG) or any combination thereof Can be mentioned. The amount of phospholipid, eg DPPC, present in the particles of the invention is generally less than 10% by weight.

  Salts include small amounts of strong electrolyte salts 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. The amount of salt present in the particles is generally less than 10% by weight, for example less than 5% by weight.

  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 In the present specification, it is referred to as "90/8/2".

  In one embodiment, the present invention is a method of treating an off-period in a patient with Parkinson's disease, comprising administering levodopa to the patient's pulmonary system, wherein after administration the patient's Unified Parkinson's Disease Rating Scale (Unified Parkinson's'). Provides a method wherein the Disease Rating Scale (UPDRS) third part score is improved, for example by at least about 5 points relative to a placebo control. In one embodiment, the patient's UPDRS III score is improved, for example by at least about 8 points, preferably at least about 10 points, preferably at least about 12 points, relative to a placebo control. In one embodiment, the patient is administered about 30 to about 60 mg of fine particle dose (FPD) levodopa, preferably 90/8/2 FPD levodopa. In a preferred embodiment, 35 mg of FPD levodopa is administered to the patient's pulmonary system. In another preferred embodiment, a patient is administered 50 mg of FPD levodopa. In one embodiment, the patient does not experience an increase in dyskinesia relative to the level of dyskinesia prior to pulmonary administration of levodopa. In one embodiment, about 3 to about 4 off episodes per day are observed in the patient prior to levodopa administration. In one embodiment, the patient has about 4 to about 8 hours off episodes per day prior to levodopa administration. In one embodiment, the levodopa FPD is administered at the onset of the off symptom.

  In one embodiment, the present invention is a method of treating an off-period in a patient with Parkinson's disease, comprising administering levodopa to the patient's pulmonary system, wherein after administration the patient's Unified Parkinson's Disease Rating Scale (Unified Parkinson's'). Provided is a method wherein the Disease Rating Scale (UPDRS) third part score is improved, for example, by at least about 5 points relative to the patient's UPDRS III score prior to pulmonary administration. In one embodiment, the patient's UPDRS III score is improved, for example by at least about 8 points, preferably at least about 10 points, preferably at least about 12 points, relative to a placebo control. In one embodiment, the patient is administered about 30 to about 60 mg of fine particle dose (FPD) levodopa, preferably 90/8/2 FPD levodopa. In one embodiment, 35 mg of FPD levodopa is administered to the patient's pulmonary system. In another embodiment, a patient is administered 50 mg of FPD levodopa. In one embodiment, the patient does not experience an increase in dyskinesia relative to the level of dyskinesia prior to pulmonary administration of levodopa. In one embodiment, about 3 to about 4 off episodes per day are observed in the patient prior to levodopa administration. In one embodiment, the patient has about 4 to about 8 hours off episodes per day prior to levodopa administration. In one embodiment, the levodopa FPD is administered at the onset of the off symptom.

  In one embodiment, the invention is a method of reducing the average daily off-time of a Parkinson's patient, comprising administering levodopa at least once a day, preferably at least twice a day, to the patient's pulmonary system. And after administration, the average daily off time of the patient is reduced by at least about 1 hour, preferably at least about 2 hours, preferably at least about 3 hours, preferably at least about 4 hours, preferably at least about 5 hours or more , Provide a way. In one embodiment, the patient is administered about 30 to about 60 mg of fine particle dose (FPD) levodopa, preferably 90/8/2 FPD levodopa. In a preferred embodiment, 35 mg of FPD levodopa is administered to the patient's pulmonary system. In another preferred embodiment, a patient is administered 50 mg of FPD levodopa. In one embodiment, the patient does not experience an increase in dyskinesia relative to the level of dyskinesia prior to pulmonary administration of levodopa. In one embodiment, about 3 to about 4 off episodes per day are observed in the patient prior to levodopa administration. In one embodiment, the patient has about 4 to about 8 hours off episodes per day prior to levodopa administration. In one embodiment, the levodopa FPD is administered at the onset of the off symptom.

  In one embodiment, the present invention is a method of delivering levodopa to Parkinson's disease patients comprising administering levodopa to the patient's pulmonary system, wherein after administration the patient's Unified Parkinson's Disease Rating Scale (Unified Parkinson's's) Disease Rating Scale (UPDRS) A method is provided wherein the third part score is improved, for example, by at least about 5 points to about 12 points compared to the patient's UPDRS III score prior to pulmonary administration of levodopa. In one embodiment, the patient is administered about 30 to about 60 mg of fine particle dose (FPD) levodopa, preferably 90/8/2 FPD levodopa. In a preferred embodiment, 35 mg of FPD levodopa is administered to the patient's pulmonary system. In another preferred embodiment, a patient is administered 50 mg of FPD levodopa. In one embodiment, the patient does not experience an increase in dyskinesia relative to the level of dyskinesia prior to pulmonary administration of levodopa. In one embodiment, about 3 to about 4 off episodes per day are observed in the patient prior to levodopa administration. In one embodiment, the patient has about 4 to about 8 hours off episodes per day prior to levodopa administration. In one embodiment, the levodopa FPD is administered at the onset of the off symptom.

  In one embodiment, after pulmonary administration of levodopa, the patient's UPDRS third part score is at least about 5 to about 15 points, preferably at least about 5 to about 12 points, preferably at least about 5 relative to the placebo control. An improvement of about 10 points, preferably at least about 5 to about 8 points. In one embodiment, after pulmonary administration of levodopa, the patient's UDPRS third part score is at least about 2 to about 15 points, preferably at least about 2 to about 12 points, preferably at least about 2 compared to the placebo control To about 10 points, preferably at least about 2 to about 8 points, preferably at least about 2 to about 5 points, preferably at least about 3 to about 15 points, preferably at least about 3 to about 12 points, preferably at least about 3 To about 10 points, preferably at least about 3 to about 8 points, preferably at least about 3 to about 5 points, preferably at least about 4 to about 15 points, preferably at least about 4 to about 12 points, preferably at least about 4 ~ Improve about 10 points, preferably at least about 4 to about 8 points

  In one embodiment, within about 60 minutes after pulmonary administration of levodopa, preferably within about 30 minutes after administration, preferably within about 20 minutes after administration, preferably within about 10 minutes after administration, the patient's UDPRS third part Scores are improved relative to placebo controls. In one embodiment, the patient's UDPRS third part score relative to a placebo control within about 60 minutes, preferably within about 30 minutes, preferably within about 20 minutes, preferably within about 10 minutes after administration of levodopa An improvement of at least about 2 points, preferably at least about 5 points, preferably at least about 8 points, preferably at least about 10 points, preferably at least about 12 points, preferably at least about 15 points. In one embodiment, the patient does not experience an increase in dyskinesia relative to the level of dyskinesia prior to pulmonary administration of levodopa. In one embodiment, about 3 to about 4 off episodes per day are observed in the patient prior to levodopa administration. In one embodiment, the patient has about 4 to about 8 hours off episodes per day prior to levodopa administration.

  In one embodiment, the patient's UDPRS third part score after administration is at least 2 points, preferably at least about 3 points, preferably at least about 2 points relative to the patient's UPDRS third part score before transpulmonary administration of levodopa 4 points, preferably at least about 5 points, preferably at least about 6 points, preferably at least about 7 points, preferably at least about 8 points, preferably at least about 9 points, preferably at least about 10 points, preferably at least about 11 The points are improved, preferably at least about 12 points, preferably at least about 13 points, preferably at least about 14 points, preferably at least about 15 points.

  In one embodiment, within about 60 minutes, preferably within about 30 minutes, preferably within about 20 minutes, preferably within about 10 minutes after levodopa administration, the patient's UDPRS third part score is before pulmonary administration of said levodopa Improved over their UPDRS III scores. In one embodiment, within about 60 minutes, preferably within about 30 minutes, preferably within about 20 minutes, preferably within about 10 minutes of levodopa administration, the patient's UDPRS third part score is prior to levodopa pulmonary administration An improvement of at least about 2 points, preferably at least about 5 points, preferably at least about 8 points, preferably at least about 10 points, preferably at least about 12 points, preferably at least about 15 points relative to the patient's UPDRS III score Ru. In one embodiment, the patient does not experience an increase in dyskinesia relative to the level of dyskinesia prior to pulmonary administration of levodopa. In one embodiment, about 3 to about 4 off episodes per day are observed in the patient prior to levodopa administration. In one embodiment, the patient has about 4 to about 8 hours off episodes per day prior to levodopa administration. In one embodiment, the levodopa FPD is administered at the onset of the off symptom.

  In one embodiment, the contents of the at least one capsule containing levodopa of said FPD are administered to the patient by inhalation. In one embodiment, the contents of at least two capsules comprising the FPD levodopa, preferably 90/8/2 FPD levodopa, are administered to the patient by inhalation. In one embodiment, a particulate dose of levodopa is delivered to the pulmonary system from at least one capsule by an inhalation device. In one embodiment, the inhalation device is a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

  In one embodiment, the methods of the invention provide for the rapid relief of motor symptom variability in Parkinson's disease patients. The methods of the present invention are particularly useful in treating motor symptom fluctuations that result from inadequate control of levodopa plasma levels in patients.

  In one embodiment, the method of the invention increases the patient's plasma levodopa concentration by at least about 200 ng / ml relative to the patient's plasma levodopa concentration prior to levodopa inhalation within about 10 minutes after inhalation, and after inhalation Transpulmonary administration of levodopa by inhalation at a therapeutically effective concentration, wherein the patient's plasma concentration is maintained at least about 200 ng / ml increased for at least about 15 minutes.

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

  In one embodiment, the method of the invention comprises administering about 20 mg to about 75 mg of levodopa to the patient by inhalation, providing the patient with immediate relief of exercise symptom variability within 10 minutes of the inhalation, For a minute, the patient is provided with a rapid alleviation of the movement symptom fluctuation of a Parkinson's disease patient in which the relaxation is maintained.

  In any of the methods of the present invention, the area under the curve (AUC) of levodopa in the patient's plasma about 10 minutes after administration of one dose of levodopa by inhalation is compared to the patient's levodopa concentration prior to levodopa administration by inhalation. It increases by at least about 1000 ng min / ml for every 4 mg of levodopa administered. In one embodiment, the AUC of said levodopa in plasma about 10 minutes after administration of one dose of levodopa by inhalation is for each 4 mg of levodopa administered relative to the patient's plasma levodopa concentration prior to levodopa administration by inhalation Increase by at least about 1000-1500 ng min / ml.

  In any of the methods of the present invention, levodopa is delivered within about 10 minutes of administration of one dose of levodopa by inhalation, as compared to levodopa plasma concentration of the patient prior to levodopa administration by inhalation of the patient. The patient's plasma levodopa concentration increases by at least about 175 ng / ml every 10 mg and the patient's plasma concentration is at least about 15 minutes, preferably about 20 minutes, preferably about 25 minutes, preferably about 30 minutes, preferably about 45 minutes after administration Or preferably maintain the increase of at least about 175 ng / ml for about 60 minutes.

In one embodiment, the invention provides a method for providing rapid relief of motor symptom variability in Parkinson's disease patients, comprising administering about 20 mg to about 75 mg levodopa to the patient by inhalation, wherein orally administered levodopa dose is greater than the quotient is 1 to ^Cmax Pul ^{/ AUC Pul} when the same relative to the dose administered by pulmonary delivery in ^{Cmax oral / AUC} oral, provides methods.

In one embodiment, the invention provides a method for providing rapid relief of motor symptom variability in Parkinson's disease patients comprising administering one or more doses of levodopa by inhalation, wherein T ^1/2 / T ^max The method is provided, wherein the ratio of is less than 1/2, preferably less than 1/5.

  In one embodiment, the dose used in any of the methods of the invention comprises about 10 mg to about 75 mg of levodopa delivered to a patient. In one embodiment, the dose comprises about 12 mg to about 35 mg of levodopa. In one embodiment, the dose of levodopa comprises at least about 10 mg levodopa, preferably at least about 25 mg levodopa, preferably at least about 35 mg levodopa, preferably at least about 50 mg levodopa, preferably at least about 75 mg 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 60 mg. In another embodiment, the amount of levodopa delivered to the pulmonary system after inhalation of one or more capsules is about 35-55 mg, about 30-50 mg, about 40-50 mg, about 45-55 mg.

  In one embodiment, the dose of levodopa used in any one of the methods of the invention comprises about 30 mg to about 60 mg of levodopa of FPD. In one embodiment, the dose used in any of the methods of the invention is levodopa of about 35 mg FPD. In one embodiment, the dose used in any one of the methods of the invention is about 50 mg of levodopa of FPD.

  In some embodiments, after inhalation of powder of levodopa 1 capsule, rapid motor symptom relief or increase in plasma levodopa occurs. In another embodiment, after inhalation of 2 capsules, 3 capsules, 4 capsules or 5 capsules, rapid exercise relief or an increase in plasma levodopa occurs.

  In one embodiment, the dose used in any of the methods of the invention comprises a salt. In one embodiment, the dose comprises phospholipids.

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

  In one embodiment, any of the methods of the invention may further comprise performing oral administration of levodopa to said patient.

  In one embodiment, any of the methods of the invention maintain the alleviation of exercise symptom variability for at least 2 hours, preferably at least 3 hours, preferably at least 4 hours, preferably at least 5 hours, more preferably at least 6 hours or more. To do.

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

  In any of the methods of the invention, administration of levodopa is not affected by the dietary effects of the central nervous system.

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

  Administration of two or more dopamine precursors, including but not limited to L-Dopa, carbidopa, apomorphine and benserazide, dopa decarboxylase inhibitors or combinations thereof simultaneously or sequentially with administration of levodopa by inhalation according to the present invention It can be implemented. In one embodiment, administration of two or more dopamine precursors or dopadecarboxylase inhibitors may be administered by intramuscular, subcutaneous, oral and other routes of administration. In one embodiment, these other agents are also co-administered from the pulmonary system. These compounds or compositions may be administered prior to, after or simultaneously with pulmonary administration of levodopa by inhalation, and administration of levodopa by inhalation according to the methods described herein. When used with, it is considered as "co-administered".

となり、式中、「ｗ／ｏ ＣＤ」はカルビドパを投与しないことを意味し、「ｗ／ＣＤ」はカルビドパを投与することを意味し、「ＩＮＮ」は患者にレボドパを送達する経肺経路を表し、ｏｒａｌは患者にレボドパを送達する経口経路を表す。 In one embodiment, the patient may not require co-administration of a dopa decarboxylase inhibitor or may reduce the dose or frequency of a dopa decarboxylase inhibitor. In another embodiment, the patient may not require co-administration of carbidopa or may have lower carbidopa dose or frequency as compared to a patient receiving oral administration of L-Dopa. In further embodiments, the patient may not require co-administration of benserazide or may be able to reduce the dose or frequency of benserazide relative to patients receiving oral administration of L-Dopa. In one embodiment, the relationship between reliance on carbidopa and levodopa administered by the pulmonary route and levodopa administered by the oral route is:

Where “w / o CD” means not to administer carbidopa, “w / CD” means to administer carbidopa, “INN” means transpulmonary route to deliver levodopa to patient , Oral represents oral route to deliver levodopa to the patient.

  In one embodiment, it is necessary to determine the exact dose of levodopa in order to "turn on" the patient. For example, in one embodiment, the dose of levodopa should increase the patient's plasma levodopa concentration by about 200 ng / ml to 500 ng / ml. It is interesting that this slight increase in levodopa concentration applies to a wide variety of patient dosing schedules. Patients who may need to have levodopa plasma levels of 1500-2000 ng / ml to be turned "on" can be turned on with levodopa 200-500 ng / ml in plasma, whereas "on" Patients who may need to have levodopa plasma levels of 500-1000 ng / ml to achieve can be turned on by levodopa 200-500 ng / ml in plasma. More specifically, the patient can be turned on by increasing the patient's plasma concentration by 200-400 ng / ml, 250-450 ng / ml, 300-400 ng / ml or about 375-425 ng / ml.

  Increasing a patient's plasma concentration by 200-500 ng / ml can be performed by various methods. Levodopa can be administered orally, transpulmonary, or intimately to the patient. When administered by the pulmonary route, levodopa at a dose of 25 to 50 mg may be delivered to the patient's pulmonary system. In one embodiment, the dose delivered to the patient's pulmonary system may be 25-35 mg, 27-32 mg, 28-32 mg, 29-31 mg or about 30 mg. Delivering a dose to the patient's pulmonary system can be performed in a variety of ways. In one embodiment, the capsule comprises 35-40 mg levodopa powder, said capsule providing 40-60% of the powder in the capsule to the patient's pulmonary system, said powder comprising 75-98% levodopa.

  The following examples are intended to illustrate the invention but should not be construed as limiting the scope of the invention.

Example 1
Overview 90/8/2 dry to evaluate safety, tolerability and levodopa pharmacokinetics (PK) after administration of 90/8/2 transpulmonary levodopa powder in healthy adult subjects in comparison with oral levodopa A powder levodopa formulation was prepared. The transpulmonary levodopa powders described in these examples all consist of powders of 90% levodopa, 8% dipalmitoylphosphatidylcholine and 2% sodium chloride by dry weight, and are herein 90/8. Call it / 2. This data is compared with levodopa PK after single inhaled 90/8/2 administration and levodopa (LD) orally administered under fasted or fed conditions, as well as when pretreated with carbidopa (CD) And a comparison of PK when not carried out. This includes the following two parts for healthy adult male and female subjects: Part A-part of dose escalation compared to oral levodopa; and part B-90/8/2 ± part of carbidopa pre-treatment It was a test consisting of

  Part A was an open-label, three-period crossover single dose escalation study. Each subject receives a single oral dose of CD / LD (25/100 mg) in a fed or fasted state in one session and inhaled 90/8 two different doses in two different treatment sessions / 2 (10 mg and 30 mg or 20 mg and 50 mg levodopa microparticle dose (FPD)) were administered in single, incremental doses. Two groups of nine subjects each were enrolled.

  Part B was an open-label, randomized two-period balanced crossover study. Evaluation of safety, tolerability and levodopa PK after administering a single inhaled 90/8/2 dose (40 mg levodopa FPD) with and without prior treatment with CD in 8 subjects Carried out.

  Blood samples are collected over 24 hours and validated using Simbec Research Limited (UK) with a lower limit of determination of 9.84 ng / mL using a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay. Plasma levodopa concentration was measured. Pharmacokinetic analysis was performed using a non-compartmental method followed by a PK model using a two-compartment model with lag time. In 90/8/2 administered by inhalation at a dose of 10 to 50 mg levodopa FPD, after administration of microparticles at a dose of 20 to 50 mg to healthy adults, a rapid increase in plasma levodopa concentration in proportion to the dose is observed And reached levels deemed to be therapeutically relevant within 5-10 minutes.

The levodopa plasma concentration after 90/8/2 inhalation increased faster than the concentration after oral administration in fasted conditions, and much faster than the concentration in fed conditions. Drug expressed as a portion of the area under the plasma concentration versus time curve AUC (AUC _{0-10 m 2} ) which is a fraction of the area under the curve and the highest plasma concentration (C _{max, 10 m 2} ) observed in the first 10 minutes after dosing From the first 10 minutes of exposure, it was found that after 90/8/2 inhalation systemic exposure was observed in a much shorter time than after oral administration.

  The variability in plasma concentration between subjects was much smaller with inhalation than with oral administration and was expected with pulmonary administration. This analysis also found that fasting absorbed faster than fed when orally administered, but was still much slower than inhalation. In pharmacokinetic modeling, the lag time after oral administration in the fasted or fed state is about 9 to 10 minutes, while the lag time after 90/8/2 inhalation is less than 0.5 minutes all right. In addition, the absorption half-life was shorter after inhalation than oral administration.

After 90/8/2 inhalation, systemic levodopa exposure was proportional to the 90/8/2 dose administered. Dose-normalized _Cmax and AUC were very similar throughout the 90/8/2 dose administered. Dose-normalized (based on estimated microparticle dose) inhalation doses are 1.3 to 1.6 times oral doses based on AUC and 1.6 to 2.9 times based on C _max Met. As described in the literature, after oral administration, significant C _max reduction and T _max prolongation were observed in fed subjects, but AUC was found to differ between fed and fasted subjects. It was not.

Absorbed in a short time from the plasma concentration in part B of the study, inhaling 90/8/2 of a 40 mg microparticle dose with or without carbidopa pre-treatment in a crossover design, with or without carbidopa pre-treatment It has been found that the concentration has reached levels that could be therapeutic levels. Plasma levodopa clearance was approximately 4 times faster without CD pre-treatment. Similarly, C _max and AUC were lower and T _max and T _1/2 were somewhat shorter with no pre-CD treatment. The main findings of this study are:
• Plasma levodopa concentration increased rapidly by inhalation 90/8/2;
Systemic exposure to levodopa for the first 10 minutes after dosing based on C _max and AUC was much higher with 90/8/2 inhaled administration than with oral drug administration;
In healthy adults, levodopa plasma concentrations that appeared to be therapeutically relevant were obtained within 5 to 10 minutes after inhalation of a fine particle dose of 20 to 50 mg;
• Variation in plasma levodopa concentration between subjects was much smaller after inhalation than oral administration and was expected for pulmonary administration;
Systemic levodopa exposure was proportional to levodopa microparticle dose administered;
Pharmacokinetic modeling has shown that inhalation 90/8/2 has a much shorter lag time and faster absorption rate than oral administration;
・ Dose-normalized dose (based on estimated microparticle dose) inhalation dose based on AUC is 1.3 to 1.6 times that on oral administration, and C _max is 1.6 to 2.9 Was twice;
• Without carbidopa pretreatment, plasma levodopa clearance was approximately quadrupled and levodopa exposure decreased.

Introduction In this example, we use 90/8/2 as an episodic treatment for exercise symptom variability ("off episode") in Parkinson's disease patients who show intermittent inadequate responses to standard oral medications. Was tested. 90/8/2 can be used as an adjunct to a Parkinson's disease dosing regimen that includes the patient's existing dopa decarboxylase inhibitors (ie, carbidopa or benserazide). This trial is the first trial of 90/8/2 in humans, and the safety, tolerability and levodopa pharmacokinetics (PK) after 90/8/2 administration in healthy adult subjects. It is designed to be evaluated in comparison to oral levodopa.

  The safety and tolerability results were tested in clinical trials. This PK data analysis compares the PK of levodopa after single inhalation administration of 90/8/2 and levodopa (LD; L-Dopa) orally administered in fasted or fed conditions, as well as by carbidopa (CD) A comparison of levodopa PK with and without treatment is described. Oral levodopa was administered as a conventionally formulated carbidopa / levodopa combination formulation.

Study Design and Objectives This study is a two part study involving healthy adult male and female subjects:
Part A: Part of dose escalation as compared to oral levodopa.
Part B: 90/8/2 ± part of Carbidopa pre-treatment.

  The primary pharmacokinetic objective of study part A was to examine the pharmacokinetics of levodopa after a 90/8/2 dose of a single inhaled dose in healthy adults. The second objective was to examine the dose proportionality of levodopa after single inhaled dose administration and to compare the PK of oral levodopa administered in fasted or fed conditions with 90/8/2. The purpose of Part B was to compare the tolerance and pharmacokinetics of 90/8/2 with and without pre-carbidopa treatment.

Part A was an open-label, three-period crossover single dose escalation study. All subjects were treated with oral carbidopa one day before and on the day of treatment with the study drug. Each subject receives a single oral dose of CD / LD (25/100 mg) in a fed or fasted state in one session and 90/8/8 of two different inhaled doses in two different sessions. 2 was administered in a single incremental dose. Two groups of nine subjects each were enrolled. A summary of the study design in Part A is shown in Table 1 below:

Part B was an open-label, two-period equilibrium crossover test. After preliminary review of the safety and PK data obtained in Part A, a regimen defined as follows for an equal number of subjects:
Regimen A: Perform CD pre-treatment 90/8/2
Regimen B: 90/8/2 without CD pre-treatment
Eight subjects were pretreated with and without CD pre-treatment, in a randomized and balanced manner, such as in two administration sequences, A → B or B → A. Evaluation of safety, tolerability and levodopa PK after administration of single inhalation 90/8/2 dose (40 mg of Levodopa FPD) was performed.

  Carbidopa treatments in Part A and Part B of the study were standardized according to the schedule in Table 2.

  In part A, before dosing and at 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 120 minutes, 4 hours, 8 hours, 16 hours and 24 hours after CD / LD oral administration Blood samples were collected. For the Part A and Part 90 90/8/2 Inhalation Session, additional samples were taken after 1, 2 and 5 minutes in addition to this same time sample. Plasma levodopa concentration was measured by Simbec Research Limited using validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) with a lower limit of quantification of 9.84 ng / mL (2, 3).

Method of pharmacokinetic analysis
Non-compartmental analysis Data analysis was performed on plasma concentration and time of each subject and each treatment. Non-compartmental analysis was performed with WINNONLIN® Professional version 5.3. The area under the curve (AUC 0 _{-t 2} ) from time 0 to the last measurable time point was estimated using the linear trapezoidal method. The elimination rate constant (λ) is estimated using linear regression over the last three time points and used to determine the terminal half-life (T _1/2 ) and the 0-infinity AUC (AUC ₀ Estimated _∞ ):
T _1/2 = In (2) / λ
AUC _{0 to ==} AUC _{0 to t} + C _t / λ
Where C _t is the last measurable concentration predicted by the regression line. The quotient of serum clearance divided by bioavailability (CL / F) and the apparent distribution volume of the terminal phase divided by bioavailability (Vz / F) into the following equation:
CL / F = dose / AUC _{0 to ∞}
Vz / F = dose / (λ × AUC _{0 to ∞} )
The maximum concentration (C _max ) and the time it was observed (T _max ) were determined directly from the data.

The partial AUC (AUC _0-10m ) for the first 10 minutes after drug administration was calculated by the trapezoidal method. The highest plasma concentration ( _{Cmax, 10 m2} ) observed in the first 10 minutes was determined as the highest plasma concentration observed from the time of administration up to the sampling time up to 10 minutes later. The ratio of inhalation to oral exposure was calculated by dividing the _Cmax or AUC after dose-normalized 90/8/2 inhalation by the dose-normalized parameter after oral administration. The exposure ratio based on AUC is the relative bioavailability of inhaled drug to oral drug.

The time taken to reach half of the maximum observed plasma concentration, an additional parameter, by linear interpolation between the two time points divided by two the plasma concentration flanking the plasma concentration calculated from C _max (T _{Cmax 50} ) Calculated (Microsoft Excel).

Pharmacokinetic Modeling Pharmacokinetic modeling was performed using WINNONLTN® Professional Version 5.3. A number of different models were evaluated, including one-compartment models and two-compartment models, with or without lag time. The models evaluated were all used as primary inputs. Akaike's Information Criterion, residual sum of squares, relative values of estimated parameters and their respective standard error estimates, correlation between measured and predicted concentrations, and general trends of differences between predicted and measured concentrations Models were evaluated based on a number of diagnostic criteria.

The model that best described most of the plasma concentration versus time curves was a two-compartment model with lag time (WINNONLIN® model 12). Because subjects who received inhalation 90/8/2 had extremely short estimated lag times, in most cases less than one minute, most of the data sets were well described even in models without lag times. However, lag time models were used for all subjects and all treatments to compare with the data set obtained by oral administration. Most of the data sets were better described for the two-compartment model than for the one-compartment model. In some cases, it was not possible to fit the 1-compartment model. When the one-compartment model was superior, the difference between the two models based on statistical criteria was extremely small. For this reason, the results of a model using a two-compartment model are described here. Two-compartment model In the model of Scheme 1, the distribution volume divided by the fraction of absorbed dose (V / F), lag time (T _lag ), rate constant related to absorption and disappearance (k 01 and k 01 respectively) Estimates of the rate constant (k12 and k21) between k10) and the compartments are obtained. From k12, k21 and k10, rate constants, α and β, related to the distribution phase and the elimination phase of the curve were calculated. Other secondary parameters calculated from the first-order parameters include AUC, _Cmax , _Tmax , CL / F, as well as the half-life related to the absorption phase, distribution phase and elimination phase of the curve (T _{1/2 k 01} , Τ _{1⁄2 α} , Τ _{1/2 β} ) are included. The model is an equation:
C _t = Ae ^−αt + Be ^−βt + Ce ^−k01t
C _t is the concentration of levodopa in plasma at time t after administration, A, B and C are the y-axis intercepts of the distribution phase, extinction phase and absorption phase of the curve, from dose, volume and rate constants Calculated

いずれの解析にも均一重み付けを用い、アッセイによる定量化レベルを下回る値（ＢＬＱ、９．８４ｎｇ／ｍＬ未満）として報告された血漿中濃度は、欠測値として処理した。解析から除外したデータポイントはなかった。 Scheme 1

Uniform weighting was used for both analyses, and plasma concentrations reported as values below the assay quantification level (BLQ, less than 9.84 ng / mL) were treated as missing values. There were no data points excluded from the analysis.

Results and Discussion 90/8/2 dosed by inhalation at doses of 10 to 50 mg levodopa FPD, a rapid dose of plasma levodopa concentration proportional to dose after 20 to 50 mg fine particle dose levodopa administered to healthy adults An increase was seen, reaching levels considered to be therapeutically relevant (400-500 ng / mL) within 5-10 minutes.

  FIG. 1 shows mean plasma levodopa concentrations after 90/8/2 inhalation and after 100 mg oral administration under fed and fasted conditions. Individual value and concentration versus time plots are given by inhalation administration of 10 mg, 20 mg, 30 mg and 50 mg levodopa with and without carbidopa pre-treatment and 100 mg levodopa under fed and fasted conditions, respectively. Calculated for oral administration.

  The plasma levodopa concentration after 90/8/2 inhalation increased faster than the concentration after oral administration in fasted conditions, and much faster than the concentration in fed conditions. Therapeutically relevant plasma concentrations were reached approximately 5 minutes after 90/8/2 inhalation. Within 5 minutes of inhaling 90/8/2 of 20-50 mg of FPD, plasma levels will be 400-500 ng / mL or higher, to the extent observed to be considered therapeutically relevant. There is (4). Plasma concentrations reached after administration of 90/8/2 of 40 mg and 50 mg of FPD were in the same range as observed after oral CD / LD (25/100 mg) administration (FIG. 3).

FIG. 2 shows the mean plasma concentration for the first 10 minutes compared to the concentration after oral administration. Table 3 shows both the AUC (AUC _{0-10 m 2} ) and the highest plasma concentration (C _{max, 10 m 2} ) observed during the first 10 minutes of exposure for the first 10 minutes after drug administration. It is represented by. In some subjects, C _{max, 10 m} was observed in less than 10 minutes.

Oral administration results in faster absorption in the fasted state than in the fed state, but is still much slower than after inhalation. As described in the literature (5), after oral administration, a considerable decrease in C _{max and} an increase in T _max were observed in fed subjects, but the AUC (Table 5) shows that fed subjects and fasted subjects There was no difference between them.

  The inter-subject variability in plasma concentrations after treatment was much less after 90/8/2 inhalation than after oral administration. As shown in FIG. 3, after inhalation (filled marks), most of the subjects who received 50 mg of 90/8/2 had plasma concentrations exceeding 400 ng / mL at 10 minutes after administration, and some subjects Exceeded 400 ng / mL in 5 minutes, and all exceeded 400 ng / mL by 20 minutes. After oral administration (white marks), the response was much slower, with no subject reaching 400 ng / mL within 10 minutes of administration. From the individual plasma concentration and variability data of the other dose groups, levodopa FPD doses of 20 mg or more show that some subjects have plasma concentrations exceeding 400 ng / mL within 5 to 10 minutes after administration. It can be seen that the variability was much smaller than after oral administration. The magnitude of the variation in% CV of plasma concentration within the treatment group at a given sampling time is shown in Table 4 and within the first 30 minutes of administration, 90/8/2 treatments It can be seen that the variation of the subjects was less than half of the fasted oral group and about one fifth of the whole oral subjects (the combination of fed and fasted subjects).

A summary of pharmacokinetic parameters estimated by non-compartmental analysis is shown in Table 5. Parameter estimation of individual subjects from non-compartmental PK analysis of 10 mg, 20 mg, 30 mg and 50 mg inhalation doses with and without CD pre-treatment and 100 mg oral doses under fasting and fed conditions I asked for the value. The results show that levodopa exposure was proportional to the 90/8/2 dose administered. Dose-normalized _Cmax and AUC are very similar across the 90/8/2 dose. Furthermore, dose proportionality is shown in Table 4 and Table 5. There is no difference in T _1/2 at any dose.

From the dose normalized AUC _0-2 ratio, the bioavailability of inhaled 90/8/2 to oral levodopa for individual subjects was calculated. Because each subject in Study Part A received one oral dose and two inhaled doses, two bioavailability estimates were obtained for each subject and one for each inhaled dose. Calculations of relative exposure were also performed at dose-normalized C _max values. Separate calculations were performed for oral doses administered under fed and fasted conditions. The mean and standard deviation of the calculated relative bioavailability values are shown in Table 6. Individual values as relative levodopa exposure after inhalation of 90/8/2 (10 to 50 mg levodopa microparticle dose) compared to oral administration of carbidopa / levodopa, 25/100 mg calculated from dose-normalized _Cmax Calculated. It appears that there is no significant difference between fed and fasted subjects or between dose groups. Dose-normalized doses (based on estimated microparticle doses) after inhalation were approximately 1.3 to 1.6 times that of oral administration based on AUC and approximately 1.6 times that of oral administration based on C _max. It was -2.9 times.

Plasma concentration versus time profiles were best described by a two-compartment model with lag time at primary input. The individual data sets were modeled using the WINNONLIN® model 12 and a plot of measured versus predicted concentrations versus time was made. In some cases, estimates of the terminal half-life (T _{1 / 2β} ) were extremely large, as concentrations were nearly the same or varied at several points in the terminal phase of the curve and the slope was flat. . In many such cases, the large value of T _{1/2 β} resulted in an extremely large estimate of AUC. Variations in the parameter estimates from the model also resulted in some outliers in some parameter estimates. Such values were either excluded from data analysis or treated statistically as outliers. Instead, summarize data by median rather than mean. Thus, the data presented is unusually high or low but does not significantly affect the group's summary statistics.

From the results of pharmacokinetic modeling shown in Table 7, it can be seen that there was a lag time of about 9 minutes after oral administration. By comparison, the lag time associated with inhalation 90/8/2 was a negligible value of less than 0.5 minutes. Furthermore, the absorption rate of inhalation 90/8/2 was faster (T _{1/2 k 01} shorter) than that after oral administration in the fasted state, which was about 10 times that in the fed state. Because the lag time is much shorter and the rate of absorption is much faster after 90/8/2 inhalation, the amount of systemic exposure observed within the first 5 to 10 minutes of dosing is higher than for oral dosing. I will explain. In addition, from the time to reach 50% of the calculated parameter C _max (T _Cmax 50), _90/8/2 inhalation resulted in levodopa systemic exposure in a shorter time than oral administration. I understand. Absorption was much faster than loss, except for oral administration in the fed state.

  The combined effect of lag time and absorption rate on plasma concentration during the first few minutes of dosing is shown in FIG. 6, which represents pharmacokinetic modeling of mean plasma concentration data. This plot shows the concentrations predicted by the pharmacokinetic model of 90/8/2 inhalation and oral levodopa administration over the first 60 minutes from administration. Marks represent mean concentrations observed and lines represent concentrations predicted by pharmacokinetic models. The well-correlated predicted and measured values indicate that the model fully explains the data. This figure also shows that 90/8/2 inhalation results in a rapid increase in plasma levodopa concentration, achieving a plasma concentration that appears to be clinically relevant within 5 to 10 minutes after administration. It is possible and describes another observation of the test that the dose is dose proportional.

Part B Plasma concentrations obtained in part B of the crossover design study inhaling 90/8/2 of 40 mg of Levodopa FPD with or without carbidopa pre-treatment are shown in FIG. Peak plasma concentrations and exposures were higher with carbidopa pretreatment. Plasma levodopa clearance was about 4 times faster without CD pre-treatment. Similarly, C _max and AUC were lower and T _max and T _1/2 were somewhat shorter with no pre-CD treatment (Table 8).

Conclusion The main findings of this study were: (i) rapid increase of plasma levodopa concentration by inhalation 90/8/2; (ii) first 10 minutes after dosing based on C _max and AUC Systemic exposure to levodopa was much higher with 90/8/2 inhalation administration than with oral drug administration; (iii) after 90/8/2 administration of levodopa microparticle dose of 20-50 mg in healthy adults Plasma levodopa concentrations that appeared to be therapeutically relevant within 5 to 10 minutes were obtained; (iv) variability in plasma levodopa concentrations between subjects was much smaller after inhalation than oral administration (V) systemic levodopa exposure was proportional to levodopa microparticle dose administered; (vi) from pharmacokinetic modeling, inhalation 90/8/2 has a much shorter lag time than oral administration and absorption rate Vii) Dose-normalized dose-based inhalation (based on estimated particulate dose) dose based on AUC is 1.3 to 1.6 times that of oral administration, based on C _max Was 1.6 to 2.9 times oral administration; and viii) without carbidopa pre-treatment, the plasma levodopa clearance was about 4 times and the levodopa exposure decreased.

Example 2
A phase 2 study examining two doses of transpulmonary levodopa (test drug 25 mg and 50 mg) included a multicenter randomized double blind placebo controlled single dose crossover of three groups (placebo, 25 mg and 50 mg) Design trials included the "open label" oral Sinemet group. A continuous assessment of L-Dopa plasma levels, motor response and safety was performed at each visit to 24 PD patients (24) treated in this study. Patients in the OFF state were administered the study drug and continuous assessment was initiated prior to dosing and continued up to 180 minutes post dose. Motor function was measured using tapping test, Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 (UPDRS III) and "meaningful" on and off subjective ratings. Safety parameters monitored included lung function, laboratory data, EGC and vital signs (blood pressure, heart rate and blood pressure at rest). This study was designed to measure the time, size and persistence of the effects of transpulmonary levodopa on motor function and to evaluate the safety and tolerability of transpulmonary levodopa in Parkinson's patients.

  The inventors have found that in comparison between pharmacokinetic and pharmacodynamic parameters, a surprising steep curve is seen between the off-state and on-state patients. FIG. 8 compares the patient's plasma levodopa concentration with the UPDRS score. UPDRS is a standard test that tests the response to drug treatment and disease progression in Parkinson's disease patients. As can be seen from FIG. 8, the difference in levodopa plasma concentration between on and off patients is very small. A levodopa plasma concentration of only 200-400 ng / ml produces a difference between off and on. What really stands out is that of the four patients shown here, all show significant differences in the baseline plasma concentrations of levodopa. The difference in this baseline plasma levodopa level is related to the fact that the effective dose or effective concentration of levodopa effective for the patient varies with each patient. Although the effective dose or concentration may vary within the patient population, the increment of plasma concentration required to go from off to on is extremely small.

Example 3
Phase 2 (b) Randomized, Double-Blind, Placebo-Controlled Trial Design and Methods of a Phase 2b Trial Using 90/8/2 This trial is for Parkinson's disease (PD) with motor symptom variability (off episodes) A randomized, double-blind, placebo-controlled, multicenter trial of inhaled (inhaled levodopa [LD] powder) or placebo treating up to 3 off-episodes per day for subjects. Subjects were randomized at a 1: 1 ratio to receive either inhalation 90/8/2 (also referred to herein as "the study drug") or a placebo. Randomization was stratified by the subject's Hänner and Yar stages (<2.5 and> 2.5) to balance disease severity in each group.

  90/8/2 LD FPD consists of homogeneous particles composed of 90% LD, 8% dipalmitoylphosphatidylcholine (DPPC) and 2% sodium chloride (NaCl). 90/8/2 was delivered using an inhalation device for powder inhalation as described in US Pat. No. 8,496,002, which is incorporated herein by reference. 90/8/2 is a size 00 hypromellose designed to deliver to the lungs an FPD of about 17 mg dose of inhalable LD, each with a nominal fill weight of 32 mg (LD per capsule 27.6 mg) Provided in (hydroxypropyl methylcellulose [HPMC]) capsules.

  The two selected 90/8/2 dose levels (about 34 mg of FPD and 50 mg of FPD) were taken from the safety and pharmacokinetic (PK) data obtained in the study of healthy adult subjects and in this specification. The safety of Example 1, the PK obtained in the test of Example 1 performed on healthy adult subjects, and the safety, PK and drugs obtained in the test performed on PD patients described in Example 2 It is based on kinetic data. To maintain blindness, all patients receive the same appearance of the study drug kit, with the same number of capsules for each dose (2 capsules for weeks 1 and 2 and 3 capsules for weeks 3 and 4) Instructed to inhale the Patients were allowed to drink some water as needed during capsule inhalation and inhalation.

  The placebo inhalation powder was provided in a size 00 HPMC capsule, each with a nominal fill weight of 10 mg. The placebo inhaled powder is NF, which is inhalation grade lactose monohydrate. The particle size of the lactose was chosen so that deposition of the inhaled powder on the head was comparable and mimicking the sensation of inhalation.

  Two 90/8/2 doses of Dose Level 1 (DL1) at approximately 35 mg LD microparticle dose (FPD) per episode treatment and Dose Level 2 (DL2) at approximately 50 mg LD FPD during the study period I examined the level. The first dose of blinded inhalation study drug DL1 was administered at the clinic at the 3rd visit (ie, 2 doses of either 90/8/2 or placebo were inhaled); each 90/8/2 capsule About 17.5 mg of LD FPD is delivered. The first dose of DL2 blinded study drug was given at the 5th visit (ie, 3 doses of either 90/8/2 or placebo was inhaled).

  The study consisted of 3 periods of screening, treatment and follow-up, with a total of 7 visits (2 screening visits, 4 treatment visits and 1 follow-up visit). Each subject had a treatment period of about 4 weeks and a test period of about 8 to 10 weeks. Each patient will self-administer up to three doses of inhaled study drug per day for four weeks. From screening to the final study visit, there were no changes in the subject's usual PD medication or dosing schedule.

Subject eligibility Male and female subjects aged 30 to 80 years have been diagnosed with idiopathic PD after age 30; meet stages 1 and 2 of the UK Brain Bank criteria; corrected version Hene and Yaar on Are classified into stages 1 to 3; self-reporting and PD diary confirmation of motor symptom fluctuation over an average day off time of at least 2 hours per day during awakening during daytime (except morning off time); acceptable Subjects who showed LD response were eligible to participate in this study. Subjects must have received a stable therapeutic dose / regimen including oral LD for at least 2 weeks prior to the first screening visit; at daytime awakening for regimens containing LD / Dopamine decarboxylase inhibitors (DDI) A dosing schedule of at least 4 doses should be included. Subjects need to have other PD medications stable for at least 4 weeks prior to the first screening visit. Subjects should have at least a 25% difference between UPDRS third part scores recorded off and on at screening. The subject should understand daily dosing (with or without the assistance of a caregiver) during the study and should not change it. The subject must be a person whose cognitive function is confirmed to be normal by having a score of 25 or more by the Mini Mental State Examination (MMSE). The subject should be a person with a screening FEV1 predicted by on-state spirometry of> 60%, an FEV1 / FVC ratio of 75% or more at screening, and no history of lung disease.

Evaluation criteria and evaluation items The purpose and variables of the test are described in Table 9.

  Efficacy was assessed by both in-clinic and at-home (outpatient) assessments outlined by the following criteria:

In-clinic criteria : UPDRS third part exercise score; time from the administration of the study drug in the clinic until the off episode disappears to ON state (evaluated by the examiner); frequency of dyskinesia after administration of the study drug Duration and severity

At-home criteria : Time from subject administration of study drug to time when off episode disappears to on state (from inhaled medication records), on-time without daily dyskinesia, dyskinesia (sometimes difficult to cope with) PD diary information on on-time and off-time for which it is accepted or not.

  The following exploratory assessments were performed: PGI-C, PDQ-39, efficacy criteria described above (to assess potential differences between two dose levels in the 90/8/2 treatment group).

  Physical examination, adverse event (AE) report, vital signs at standard and standing time (blood pressure and heart rate), respiratory rate, laboratory test values (hematology, biochemistry), electrocardiogram (ECG) and lung function evaluation Safety was assessed from spirometry for. In addition, assessments were performed to assess suicidality, lethargy and impulse control behavior at baseline and at follow-up visits.

Baseline characteristics Patients 86 patients were enrolled in the study. The patient awake on / off state (off time, on time with no dyskinesia, no on dyskinesia, on time with no dyskinesia, on dyskinesia with difficulty) The screening PD diary, which records the time) and the sleep time, is filled in completely. In addition, the following information about each off episode seen during awakening during the day for 7 days prior to the second visit: start time of off episode, start time of next on time, and how to use the patient's standard LD medication Have an On / Off Episode Screening and Dosing Record.

  These patients reported that about one-third to one-half awake time was off, despite patients taking their currently used levodopa treatment regimen about every three hours (Table 10) And 11)).

  Thus, as shown in Tables 12 and 13, it is clear that managing off-period for PD patients is an important unmet need. Table 12 shows the mean value of the administration regimen of each patient before administration of study drug or placebo.

  Table 13 shows the daily mean off-time and mean on-time that the patient reported in the diary prior to study drug or placebo administration.

  The UPDRS third part score at baseline was measured prior to the screening phase of the Phase 2b study and either group receiving the study drug or placebo. The data is shown in Table 14.

  The total number of days recorded for trials exposed to either study drug or placebo was approximately 6.5 patient years (2,369 patient days). The total number of off-periods treated was equal to the total dose administered, which was approximately 4,484, with 2314 doses for placebo and 2369 doses for study drug. The total number of placebo or study drug capsules used throughout the study was 11,115. One patient was a patient who received a dose reduction for difficult dyskinesia, but received a placebo. One patient who received the study medication was dosed down because of nausea. Based on the patient's own records, the average daily use of study drug was 2.1 times / day, excluding the “off” time of the early morning.

Results The primary endpoint of the Phase 2b trial is to assess the difference between the study drug and placebo in the mean change (10 to 60 minutes after dosing) from the UPDRS third part score average before the 6th visit It was to do (DL2). The same difference between the fourth visit and the fifth visit (first DL2 administration) using DL1 was used as a secondary endpoint. In accordance with the UPDRS, the clinically significant difference (CID) in UPDRS motor scores is 2.5 points minimum, 5.2 points medium, and 10.8 points large CID (Shulman et al, Arch Neurol , Vol. 67 (Jan 2010)).

  90/8/2 met the primary endpoint of a statistically significant reduction (over 10 to 60 minutes after dosing) from placebo of UPDRS 3rd part motor score average value at the 6th visit, dose 50 mg . Clinically meaningful reduction of UPDRS III was obtained at 60 minutes in 87% of patients. In addition, 90/8/2 is the fourth visit, the fifth visit, and the sixth visit all the time points evaluated for both study doses (35 mg and 50 mg) (ie 10, 20, 30, 30 minutes and After 60 minutes) showed a clinically relevant statistically significant decrease. The clinically relevant improvement of UPDRS III was evident even after only 10 minutes of dosing. After treatment at the sixth visit, 90/8/2 (dose 50 mg), a clinically significant response was maintained for at least 60 minutes after dosing. The difference between 90/8/2 and placebo was statistically significant at each time point after dosing.

  Table 15 shows a comparison of the pre-administration UPDRS scores of the test drug group and the placebo group in the prescreening and the fourth visit (V4), the fifth visit (V5) and the sixth visit (V6). Dose level 1 (DL1) was delivered at the 4th visit and dose level 2 (DL2) was delivered at the 5th and 6th visit.

  As shown in FIGS. 9 and 10, there were statistical differences in the test drugs administered at 50 mg FPD (FIG. 9) and 35 mg (FIG. 10) at any time point.

  Table 16 shows the average value of the maximum change in the third part of UPDRS for the fourth to sixth visits.

  Table 17 shows the average value of the maximum percentage change (%) of the third part of UPDRS for the fourth to sixth visits.

Summary As the data described herein, in phase 2b trials, statistical significance of UPDRS third part score average from pre-administration at 10 to 60 minutes after administration of the sixth visit compared to placebo Major endpoints were obtained that showed significant mean change. The data also shows that the shape of the UPDRS time curve shows a rapid and sustained response, with a 35 mg (DL1) dose amplitude similar to the 50 mg dose (DL2), but with a slight effect duration It turned out that there is a short possibility. Besides, the maximum change and the maximum change percentage of the UDPRS third part score are statistically significant at every visit and dose, and a large gap is seen in V4 (DL1) before the placebo response is attenuated It was done.

  The data also showed stable, clinically significant and statistically significant improvement of the daily off-time, as shown in FIG. 11, without the increase in on-time where dyskinesia was observed. FIG. 11 shows data comparing difficult dyskinesias and non-healing dyskinesias (as reported by patients themselves in their PD diary) reported by the test patients in the study drug group with the placebo group. The studies of Examples 1 and 2 and this example also show that the drug is safe and well tolerated at all dose levels tested in all Phase 1, Phase 2a and Phase 2b studies. Is shown.

  The patent and scientific literature referred to herein demonstrates the knowledge that is available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. Published foreign patents and foreign patent applications cited herein are hereby incorporated by reference. Other published references, materials, manuscripts and scientific literature cited herein as being incorporated herein by reference.

  Although the present invention is specifically illustrated and described with reference to its preferred embodiments, it will be understood by those skilled in the art without departing from the scope of the present invention as encompassed by the appended claims. It will be understood that various modifications may be made in the form and details thereof. In addition, it should be understood that the embodiments described herein are not mutually exclusive and that all or some of the features of the various embodiments may be combined in accordance with the present invention.

Claims (47)

  A method of treating an off episode of a Parkinson's disease (PD) patient, comprising administering levodopa to the patient's pulmonary system, wherein after administration the Unified Parkinson's Disease Rating Scale of said patient (Unified Parkinson's Disease Rating Scale: UPDRS) The method wherein the third part score is improved by at least 5 points compared to the placebo control.   The method according to claim 1, wherein the patient's UDPRS third part score is improved by at least 5-10 points relative to a placebo control.   The method according to claim 1, wherein about 30 mg to about 60 mg of fine particle dose (FPD) levodopa is administered to the pulmonary system of the patient.   The method according to claim 1, wherein the patient is administered 35 mg or 50 mg of FPD levodopa.   The method according to claim 1, wherein the patient does not have an increase in dyskinesia compared to the level of dyskinesia before transpulmonary administration of levodopa.   The method according to claim 1, wherein the patient has about 3 to about 4 off episodes per day.   The method of claim 1, wherein the patient has about 4 to about 8 hours of off episodes per day.   The method according to claim 1, wherein within 60 minutes after administration of levodopa of said FPD, said patient's UDPRS third part score is improved by at least 5 to 10 points compared to a placebo control.   The method according to claim 1, wherein the contents of at least one capsule containing levodopa of said FPD are administered to said patient by inhalation.   10. The method of claim 9, wherein the contents of at least two capsules comprising levodopa of FPD are administered to the patient by inhalation.   10. The method of claim 9, wherein the particulate dose of levodopa is delivered from the at least one capsule to the pulmonary system by an inhalation device.   The method according to claim 11, wherein the inhalation device is a dry powder inhaler (DPI) or a metered dose inhaler (MDI).   The method according to claim 1, wherein the administration is performed at the onset of an off symptom.   A method of treating an off-period in a patient with Parkinson's disease, comprising administering levodopa to the patient's pulmonary system, wherein said patient's UDPRS third score scores said UPDRS of said patient before administering levodopa in said FPD. A method wherein at least about 5 to about 12 points are improved as compared to the score.   15. The method of claim 14, wherein about 30 mg to about 60 mg of fine particle dose (FPD) levodopa is administered to the pulmonary system of the patient.   15. The method of claim 14, wherein the patient is administered 35 mg or 50 mg of FPD levodopa.   15. The method of claim 14, wherein the patient does not have an increase in dyskinesia compared to the level of dyskinesia prior to pulmonary administration of the levodopa.   15. The method of claim 14, wherein the patient has about 3 to about 4 off episodes per day.   15. The method of claim 14, wherein the patient has about 4 to about 8 hours of off episodes per day.   15. The method of claim 14, wherein the patient's UDPRS third part score is improved by at least 8 points within 60 minutes of administration of levodopa of the FPD.   15. The method of claim 14, wherein the contents of the at least one capsule containing levodopa of FPD are administered to the patient by inhalation.   22. The method of claim 21, wherein the contents of at least two capsules comprising levodopa of FPD are administered to the patient by inhalation.   22. The method of claim 21, wherein the microparticle dose is delivered from the at least one capsule to the pulmonary system by an inhalation device.   24. The method of claim 23, wherein the inhalation device is a dry powder inhaler (DPI) or a metered dose inhaler (MDI).   15. The method of claim 14, wherein the administration is performed at the onset of an off symptom.   15. The method of claim 14, wherein the patient's UDPRS third part score is improved by at least 8 points relative to the patient's UPDRS score prior to administering levodopa of the FPD.   A method of reducing the average daily off time of a patient with Parkinson's disease, comprising administering levodopa at least twice a day to the patient's pulmonary system, said average daily off time of said patient being reduced by at least one hour Method.   28. The method of claim 27, wherein the average daily off time of the patient is reduced by at least 3 hours.   28. The method of claim 27, wherein about 30 mg to about 60 mg of fine particle dose (FPD) levodopa is administered to the pulmonary system of the patient.   28. The method of claim 27, wherein the patient is administered 35 mg or 50 mg of FPD levodopa.   28. The method of claim 27, wherein the patient does not experience an increase in dyskinesia compared to the level of dyskinesia prior to pulmonary administration of levodopa.   28. The method of claim 27, wherein the patient has about 3 to about 4 off episodes per day.   28. The method of claim 27, wherein the patient has about 4 to about 8 hours of off episodes per day.   A method of delivering levodopa to a patient with Parkinson's disease comprising administering levodopa to the patient's lung system, said patient's Unified Parkinson's Disease Rating Scale (UPDRS) third part score , A method that improves at least 8 points relative to the patient's UPDRS score prior to administration.   35. The method of claim 34, wherein the patient's UDPRS third part score is improved by at least 8 points within 60 minutes of administration of levodopa in the FPD.   A method of delivering levodopa to Parkinson's disease patients, comprising administering levodopa to the patient's pulmonary system, and after administration, said patient's Unified Parkinson's Disease Rating Scale (UPDRS) third The method wherein the part score is improved by at least 5 points compared to the placebo control.   37. The method of claim 36, wherein within 60 minutes after administration of levodopa of said FPD, said patient's UDPRS third part score is improved by at least 5-10 points relative to a placebo control.   37. The method of claim 36, wherein about 30 mg to about 60 mg of FPD levodopa is administered to the pulmonary system of the patient.   37. The method of claim 36, wherein the patient is administered 35 mg or 50 mg of FPD levodopa.   37. The method of claim 36, wherein the patient does not have an increase in dyskinesia compared to the level of dyskinesia prior to pulmonary administration of the levodopa.   37. The method of claim 36, wherein the contents of the at least one capsule containing levodopa of FPD are administered to the patient by inhalation.   42. The method of claim 41, wherein the contents of at least two capsules comprising levodopa of FPD are administered to the patient by inhalation.   42. The method of claim 41, wherein the particulate dose of levodopa is delivered from the at least one capsule to the pulmonary system by an inhalation device.   44. The method of claim 43, wherein the inhalation device is a dry powder inhaler (DPI) or a metered dose inhaler (MDI).   37. The method of claim 36, wherein said administration is performed at the onset of an off symptom.   35. The method of claim 34, wherein about 30 mg to about 60 mg of FPD levodopa are administered to the pulmonary system of the patient.   35. The method of claim 34, wherein the patient is administered 35 mg or 50 mg of FPD levodopa.

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