Flow resistance modulated aerosolized active agent delivery

The present invention relates to the administration to the lungs of an active agent composition. More specifically, it is a method of delivering an active agent formulation to the lungs and a device for improved systemic bioavailability of the active agent through absorption in the deep lungs. Bioavailability is improved by modulating the flow rate of the aerosol active agent in a manner independent of patient training and flow rate monitoring.

An important aspect of successful drug therapy is effective delivery to the patient. There are different methods of introduction, each with its own advantages and disadvantages. Oral administration of pills, capsules, elixirs, etc. is perhaps the most common method but many drugs are broken down in the gastrointestinal tract before they can be absorbed. Subcutaneous injections are often an effective method of systemic administration, including protein administration, but have poor patient acceptance. Since injections of a drug such as insulin once or more daily may result in poor patient compliance, many alternative routes of administration have been invented, including transdermal, nasal, rectal, vaginal, and pulmonary administration.

Of particular interest, administration of the drug to the lungs is based on the patient's inhalation of the active agent formulation such that the active drug in the dispersion can reach the distal (alveolar) lung area. This can be achieved by using a patient-controlled device in which an inhalable flow aerosolizing the active agent composition exists, or using a drug dispersion, or using an aerosol device using a pressurized gas or dispersing agent to convert the active agent composition into an aerosol and delivery.

Some drugs in the alveolar region have been found to be readily absorbed directly into the bloodstream. Lung delivery is particularly promising for the delivery of proteins and polypeptides that are difficult to administer by other means. Such pulmonary delivery is effective in both systemic and topical administration in the treatment of lung diseases.

Elliot et al, Aust Pediatr. J. (1987)) 23: 293-297 described the aerosol delivery of semisynthetic insulin to the airways of six diabetic children and found that these children could be controlled, although absorption was low (20-25%) compared to subcutaneous administration. ). Laube et al., U.S. Pat. 5320094, mentioning Elliot and several other studies, emphasized that although insulin was delivered to the lungs, none of the patients recovered from their lungs after insulin therapy to bring their blood glucose levels back to normal. Laube et al. Hypothesized that this problem was due to drug delivery in the system and / or the oral and pharyngeal route as a result of the administration, and that increasing lung deposition should improve blood glucose control. To achieve maximum delivery, Laube et al. Controlled the aerosol flow rate during inhalation inhalation at a flow rate of less than 30 liters / minute, preferably about 17 liters / minute. The intake system included a treatment chamber for receiving insulin, an outlet through which insulin was withdrawn, and a flow rate limiting port for controlling inhaled flow rate.

U.S. Patent Application 60/078212 investigates the above hypothesis and notes that delivery of insulin to the lungs at a rate of less than 17 liters per minute resulted in increased insulin levels in the blood faster than at higher inhalation flow rates.

Rubsamen et al., U.S. Pat. 5364838 and 5672581 describe aerosol delivery of a metered amount of insulin, the insulin is automatically released into the inhaled flow pathway based on information obtained from the determination of the inhaled flow rate and patient inspiratory volume. The recorder constantly sends information to the microprocessor, and when the microprocessor detects that the optimum point in the respiratory cycle has already been reached, the microprocessor triggers the opening of the valve to supply insulin. the inhalation flow rate is in the range of about 0.1 to 2.0 liters / second and the volume is in the range of about 0.1 to 0.8 liters.

WO 97/40819 discloses that low inhalation flow rates upon delivery to the lungs lead to higher drug delivery and deposition in the lungs. To obtain the desired flow rate (15-60 liters per minute), the resistance of the device is set to be 0.12 - 0.21 (cm H₂O)^1/2. EPO 692990 B1 describes deagglomerators for dry powder inhalers and notes that it is useful to reduce the airflow rate dependence on the dose administered and / or the inhaled aerosol portion of the powder. Deagglomerators respond to the increased flow rate by varying the geometry of the passageway through which the airborne powder passes, resulting in less pressure drop than would be observed in the absence of variable geometry, and provide more efficient deaggregation throughout the flow rate range.

We have now found that in order to effectively deliver the active agent through the lungs in a convenient and repetitive manner, it is useful to maintain a low initial flow rate followed by a higher flow rate for a period of time.

Summary of the Invention

Accordingly, in one aspect, the invention relates to a device for delivering an aerosolized active agent composition to a human lung. The device consists of a flow resistance modulator which modifies the flow resistance of the active agent composition to produce an initial desired flow rate. The flow resistance modulator modifies the resistance in a manner independent of flow rate monitoring and patient training.

In another aspect, the present invention relates to a method of administering an active agent composition to a human lung. The method consists in initially providing a high resistance to the flow of the aerosol active agent composition, followed by a period of lower resistance.

Description of the drawing figures

FIG. 1 is a diagram of a device for delivering a dry powder active agent of the invention.

FIG. 2 is a view of FIG. Figure 1 is a graph of the aerosol concentration administered by the device shown in Fig.

FIG. 3 is a view of FIG. Time dependence of the resistance generated by the flow resistance modulator of the device of Fig. 1.

FIG. 4 is a flow rate graph corresponding to the resistance shown in FIG.

FIG. 5 is a graph of the flow modulator of the present invention and the corresponding flow rate.

FIG. 6 is a graph of patient inspiration rate using FIG. 1 device with variable flow resistance and maximum inhalation effort.

FIG. 7 is a graph of patient inspiratory volume using FIG. 1 device with variable flow resistance and maximum inhalation effort.

FIG. Fig. 8 is a graph of patient inspiratory rate using Figs. 1 device at variable flow resistance.

FIG. 9 is a graph of patient inspiratory volume using FIG. 1 device with variable flow resistance and comfortable inhalation speed.

Detailed Description of the Invention

The present invention provides a device for delivering an active agent composition to the lungs when the flow rate of the inhaled active agent composition changes over time. The invention is surprising in that it provides higher levels of active agent in the blood in a convenient and repeatable manner.

Definitions

As used herein, the term "active agent" includes an agent, a drug, a compound, a composition of a substance, or a mixture that provides a particular pharmacological, often beneficial, effect. The terms used herein also include any physiologically or pharmacologically active substance that produces a local or systemic effect on the patient. Active agents introduced may include antibiotics, antiviral agents, antiepileptics, analgesics, anti-inflammatory agents, and bronchodilators, and may include inorganic and organic compounds including, but not limited to, drugs acting on the peripheral nervous system, adrenergic receptors, cholinergic receptors, skeletal muscle and vascular system, smooth muscle, circulatory system, synoptic nodes, neuro-effector nodes, endocrine and hormonal systems, the immune system, the reproductive system, the bone system, the system of physiologically active substances, the digestive and excretion systems, the histamine system, the central nervous system. Suitable agents may be selected from, for example, polysaccharides, steroids, hypnotic and sedative agents, psychostimulants, tranquilizers, anticonvulsants, muscle relaxants, antiparkinsonian agents, analgesics, anti-inflammatory agents, anticonvulsant agents, antimicrobial agents, antimalarial agents, , sympathomimetics, polypeptides and proteins that can enhance physiological effects, diuretics, lipid regulating agents, anti-androgenic agents, anti-parasitic agents, neoplasmic, antineoplasmic, hypoglycemic agents, nutritional agents and supplements, growth supplements, fats, anti-enteritis agents, electrolytes, vaccines and diagnostic agents.

Examples of useful agents of the present invention include, but are not limited to, insulin, calcitonin, erythropoietin (EPO), factor VIII, factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), alpha-1 proteinase inhibitor, elcatonin, granulocyte colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon-gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somastatin, somastatin analogues including octreotide, vasopressin analog, follicle stimulating hormone (FSH), insulin-like growth factor, insulin, 1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (MCSF), nerve growth factor, parathyroid hormone (PTH), thymosin alfa-1, lib / llla inhibitor, antitrypsin alfa-1, respiratory syncytial virus antibody, fibrotic-cystic degeneration transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal and permeability enhancing protein (BPI), , interleukin-1 receptor, 13-cis retinolic acid, pentamidine isethionate, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, ipratropium bromide, flunisolide, fluticasone, cromoline sodium, ergotamine tartrate and analogs, agonists and antagonists of the foregoing. The active agent may further comprise nucleic acids in the form of pure nucleic acids in viral vectors fused to viral particles, nucleic acids bound to or incorporated in lipid or lipid-containing materials, plasmid DNA or RNA or other types of nucleic acid constructs, suitable cells. , specifically, transfection or transformation of lung alveolar cells. The active agent may be in various forms, such as soluble and insoluble charged or non-charged molecules, components of molecular complexes or pharmaceutically acceptable salts. The active agents may be naturally occurring molecules or may be obtained recombinantly with one or more amino acids added or deleted. In addition, the active agent may contain live suppressed or dead viruses suitable for use as a vaccine.

"Aerosol active agent composition" means an active agent as described above in a composition suitable for administration to the lungs. The aerosol active agent formulation may be in the form of a dry powder, may be in the form of a solution, a suspension or a solid suspension, which may be aerosolized, or

Ί be mixed with a highly volatile, low boiling dispersant. It is understood that more than one active agent may be included in the aerosol active agent formulation, and the use of the term "agent" does not mean that the use of two or more such agents is eliminated.

The term "inspiratory flow rate" refers to the flow rate at which the active agent composition is administered.

The amount of active agent in the aerosolized active agent composition will be that required to deliver a therapeutically effective amount of the active agent to achieve the desired result. In practice, it varies within wide limits, depending on the particular agent, the severity of the condition, and the desired therapeutic effect. However, the device will generally be suitable for active agents to be administered in a dosage of 0.001 mg / day to 100 mg / day, preferably 0.01 mg / day to 50 mg / day.

The present invention is based, at least in part, on the unexpected finding that when the active agent is administered to a patient at an initially low inspiratory flow rate, the bioavailability of the active agent is increased compared to the active agent being administered at a constant but higher inhalation flow rate.

The active agent dosage forms suitable for use in the present invention include dry powders, suspensions or solid suspensions for aerosolization, and particles suspended or dissolved in a dispersing agent. Dry powders suitable for use in the present invention include amorphous active agents, crystalline active agents, and mixtures of both amorphous and crystalline active agents. The dry powder of the active agents has a particle size selected to allow penetration into the lung alveoli, that is to say, preferred is 10 μηη mass median diameter (MMD), preferably less than 7.5 μιτι, and preferably less than 5 μιτι, generally, the diameter range is 0.1 pm to 5 pm. the delivered dose efficiency (DDE) for this powder is> 30%, usually> 40%, preferably> 50% and often> 60%, and the particle size distribution of the aerosol is approximately 1.0-5.0 μιτι mass average aerodynamic diameter ( MMAD), usually 1.5-4.5 μιτι MMAD and preferably 1.5-4.0 μιτι MMAD. These dry powder active agents have a moisture content of less than about 10% by weight, typically less than about 5% by weight, and preferably less than about 3% by weight. Such active agent powders are described in WO 95/24183 and WO 96/32149, which are incorporated herein by reference. However, it may be possible to introduce larger particles with an MMD of 10-30 μιτι if the particle MMAD is less than 5.0 μηπ. Such particles are described, for example, in PCT Publication Nos. WO 97/44013 and WO 98/31346, which are incorporated herein by reference.

The dry powder formulation of the active agent is preferably formulated by spray drying under conditions providing a substantially amorphous powder. The weight of the active agent, usually in crystalline form, is dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH in the range of about 2 to 9. The dissolved active agent is present in a concentration of 0.01% to 1% by weight, typically 0.1% to 0.2%. The solutions can then be spray-dried in a conventional machine commercially available from suppliers such as Niro A / S (Denmark), Buchi (Switzerland) and the like to obtain a substantially amorphous powder. This amorphous powder may also be obtained by lyophilization, vacuum drying, or by evaporation of a suitable solution of the active agent under conditions to obtain an amorphous structure. The amorphous form of the active agent thus obtained can be triturated or ground to give particles of the desired size. The active agents in the form of a dry powder may also be in crystalline form. The crystalline dry powder may be obtained by crushing or grinding the crystalline active agent in a jet mill.

The active agent dry powder of the present invention may optionally be combined with pharmaceutical carriers or excipients suitable for administration to the respiratory tract and the lungs. Such carriers may serve as the simplest mass enhancers to reduce the concentration of active agent delivered to the patient in the powder, but may also serve to increase the powder dispersion in the powder dispersion device for more efficient and reproducible administration of the active agent and to improve the manipulation characteristics of the active agent. as fluidity and consistency to facilitate powder production and filling. Such excipients include, but are not limited to, (a) carbohydrates such as monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose and the like; disaccharides such as lactose, trehalose, cellobiose and the like; and polysaccharides such as raffinose, maltodextrins, dextrans and the like; (b) amino acids such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine and the like; (c) organic salts derived from organic acids and bases such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride and the like; (d) peptides and proteins such as aspartame, human serum albumin, gelatin, etc .; and (e) alditols such as mannitol, xylitol and the like. Preferred carriers include lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, human serum albumin and mannitol.

The dry powder formulation of the active agent may be administered using the Inhale Therapeutic Systems dry powder inhaler as described in WO 96/09085, which is incorporated herein by reference but adapted to control flow rate as described below. The dry powder may also be administered using a metered dose inhaler as described in Laube et al. No. 5320094, which is incorporated herein by reference or as a patient controlled device, I believe as described in U.S. Pat. No. 4338931, which is cited herein.

Aerosolized solutions can be obtained by converting commercially available solutions of the active agent compositions. These solutions may be administered by means of a jet nebulizer, such as Randrop, manufactured by Puritan Bennett, the use of which is described in Laube et al. Other methods of administering solutions, suspensions are described in Rubsamen et al. U.S. Pat. 5672581. A device using a vibrating piezoelectric block is described in Ivri et al. U.S. Pat. 5586550, which is cited herein.

Dispersant systems may include an active agent dissolved in a dispersing agent or particles suspended in a dispersing agent. Both forms of this type of drug are described in Rubsamen et al. No. 5672581, which is cited herein.

In order to achieve better bioavailability of the active agent, the devices described above must be modified to limit the initial rate of inhalation flow of the active agent composition. We have found that if a low inspiratory flow rate is detected at baseline, the limitations can be removed and a higher flow rate allowed. If no higher flow rate is set, the patient will feel frustrated and stop breathing.

The present invention provides an initial rate of less than 15 liters per minute, preferably less than 10 liters per minute, often 5-10 liters per minute, for a period of less than 10 seconds, preferably less than 5 seconds, and often 3 to 5 seconds. After this initial period of restricted flow rate, flow rate restrictions are removed and the flow rate becomes the patient's normal inspiratory flow rate. This flow rate is 1-30 liters per minute. To accomplish this, a flow resistance modulator is introduced into the device, (the breath sensor is triggered by a pressure sensor on the device. To obtain the flow rate described above, the resistance modulator is set to high resistance, 0.4-2 (cm H2O).^1/2/ SLM (where SLM is liters per minute at standard temperature and pressure), typically 0.4-1.5 (cm H2O)^1/2/ SLM and often 0.5-1.0 (cm H2O)^1/2/ SLM. When the initial period of restricted flow ends, as determined by the pressure sensor, the flow resistance modulator is set so as to cause little or no resistance. The resistance will be 0-0.3 (cm H2O)^1/2/ SLM, usually 0-0.25 (cm H2O)^1/2/ SLM and often 0-0.2 {cm H₂O)^1/2/ SLM. Accordingly, the normal, comfortable flow rate of the patient's inspiratory flow is determined. An example of a flow rate modulation system is shown in Figs. 1. In this system, the flow rate modulator is a valve (100) disposed within the inlet air tube (102) of the device (104). The flow meter (106) and the computer (108) are used solely for research purposes to evaluate patient behavior in response to flow restrictions. The pressure sensor (110) measures the start of the inspiration and triggers the valve opening. Although the flow rate modulator in this case is a microprocessor-controlled valve, a simple mechanical valve system can also be used. In addition, a flow or pressure sensor could be used to detect the onset of respiration.

In another aspect of the present invention, the effect of the particles on the throat is found to be proportional to the flow velocity and the square of the aerodynamic diameter according to the following equation:

l = vol²Q where I = number of particles acting on the throat; k = proportionality factor, d = particle MMAD,

Q = flow rate.

According to the above equation, it is possible to introduce larger particles using a lower initial flow rate of the present invention without increasing the number of particles, provided that the major portion of the active agent is introduced during the low flow rate period. Initially, when the flow rate is low and the aerosol concentration is high, that is, the number of particles in the aerosol is maximal, the particles will be delivered to the deep lungs better than the throat, and the bioavailability of the active agent will increase.

The aerosol concentration excited in Figs. 1 as shown in FIG. In the case of a 0.5 liter aerosol, the graph shows that the concentration of the first 0.1-0.2 liter is highest and then decreases. Therefore, it is important to administer the initial aerosol portion at a low flow rate to avoid throat effects and increase bioavailability. The flow rate modulator for this purpose is shown in Figs. 3. During the initial 3 s the resistance is high (0.65 (cm H₂O)¹'²/ SLM), then the valve opens and the resistance becomes the normal resistance of the device (in this case 0.15 (cm H2O)^1/2/ SLM). As can be seen from Figs. At 4 flow rates, the inspiratory flow rate is approximately 10 SLM during the initial period and then changes to 25-30 SLM. The flow profile of the flow rate modulator of the present invention and the associated flow rate profile are shown in Fig. 5. Resistance varies from high to low over the initial 5 s (0.9 to 0.20 (cm H2O)^1/2/ SLM). As can be seen from Figs. At 5 flow rates, the inspiratory flow rate is less than 20 SLM for an initial 3 s initial period and then changes to approximately 30 SLM. In both of these cases, since the aerosol concentration in the first 0.1 to 0.2 liters is the highest, most of the active agent is delivered during the initial 3 s. This increases the delivery of the active agent to the deep lung and its bioavailability.

The present invention is illustrated by the following examples. They do not limit the scope of the invention. Variations and equivalents of examples will be readily apparent to those skilled in the art from the description, drawings, and claims of the present invention.

Examples Example

To determine the relationship between flow resistance and flow rate, 10 volunteers, 5 males, and 5 females were asked to breathe at 3 different resistances and to construct breathing at both maximum and comfortable speeds. The results are shown in Figs. 6-9. FIG. 6 and 7 show flow rates at maximum and comfortable inspiratory rates for men and women. FIG. 8th and 9 represent the volume of aerosol inhaled at maximum and comfortable inhalation rates and resistance as described above.

The resistance to a comfortable flow rate of 10 liters per minute is approximately 0.3 (cm H)₂O)^1/2/ SLM). In addition, the volume of aerosol inhaled at higher flow resistance decreases as inhalation becomes more difficult and less comfortable as the resistance increases. In fact, if the resistance after the initial aerosol delivery period decreases, the inhaled volume will not be significantly reduced compared to the volume delivered at a constant low flow resistance delivery rate.

example

Materials and Methods

Materials

Crystalline human zinc insulin, 26.3 U / mg, from Eli Lilly and Company, Indianapolis, IN, and purity by reverse phase HPLC> 99%.

Mannitol according to U.S. Pharmacopoeia was obtained from Roosuette Corporation (Gurnee, IL).

Glycine was obtained from Sigma Chemical Company (StLouis, Missouri).

Sodium citrate dihydrate according to U.S. Pharmacopoeia was obtained from JTBaker (Philipsburg, NJ).

Obtaining the powder

The insulin powder was prepared by dissolving the insulin mass in a sodium citrate buffer containing mannitol and glycine to a total solids concentration of 7.5 mg / ml and a pH of 6.7 ± 0.3. The spray dryer is set to have an inlet temperature between 110 and 120 ° C, a fluid delivery rate of 5 ml / min, and an outlet temperature between 70 and 80 ° C. The solutions are then filtered through a 0.22 μίτι filter and dried by spraying on a Buchi Spray Drier to form a fine amorphous powder. The resulting powder is stored in carefully sealed containers in a dry environment (relative humidity <10%).

Powder analysis

The particle size distribution of the powder was measured by liquid deposition centrifugation on a Horiba CAPA-700 particle size analyzer followed by measurement of the powder dispersion on a Sedisperse A-11 (Micrometrics, Norcross, GA) instrument. The moisture content of the powder was measured according to the Kari Fisher methodology using a Mitsubishi CA-06 moisture meter. The particle size distribution in the aerosol was measured using a cascade separator (Graseby Andersen,

Smyrna, GA). The introduced dose efficiency (DDE) was evaluated using Inhale Therapeutic Systems aerosol devices similar to those described in WO 96/09085. DDE is defined as the percentage of the nominal dose contained in the cartridge container, which is shifted in the mouthpiece of an aerosol device and collected on a glass filter (Gelman, 47 mm diameter), evacuated under vacuum (30 l / min) for 2.5 s. DDE is calculated by dividing the weight of the powder collected on the filter by the weight of the powder contained in the cartridge.

Insulin integrity before and after powder treatment was measured by comparison with standard human insulin by dissolving weighed portions of the powder in distilled water and comparing these solutions with the stock solution injected into the spray dryer. Whether the insulin molecule underwent modifications or degradation during processing was determined by evaluating the retention time and peak area of ​​rpHPLC. UV spectra data at 278 nm and insoluble aggregates at 400 nm were used to determine insulin concentration. In addition, the pH of the stock solution and the reconstituted solution were measured. The amorphous nature of the insulin powder was confirmed by a polarized light microscope.

Research! N vlvo

To determine the influence of changes in inhalation rate on the bioavailability of inhaled insulin, subjects were injected with 2 mg of insulin using FIG. 1. Each procedure consists of two inhalations of 1 mg each. Inhalers used by Inhale Therapeutic Systems (San Carlos, CA) described in U.S. Pat. No. 5,740,794, which is cited herein. The procedures are as follows:

A. Inhalation of insulin with a particle size of 3.6 μM MMAD (high DDI) using a standard breathing maneuver and inhaler (without elevation).

B. Inhaled administration of insulin with a particle size of 3.6 μM MMAD (high DDI) at an inhalation rate limited to about 10 liters per minute in the system shown in FIG. 1 (elevation).

C. Inhalation of insulin with a particle size of 2.6 μM MMAD (low DDI) at an inhalation rate limited to about 10 liters per minute in the system shown in FIG. 1 (rise).

The insulin powder formulation has a mean particle diameter of less than 5 microns, and the inhaler disperses the powder and generates drug-like aerosol beads in a volume of approximately 240 ml. The volume of the holding chamber is a small fraction (> 2 liters) of deep inhalation. The chamber is designed so that during inhalation, ambient air is pushed into the chamber, thereby pushing the aerosol out of the chamber and deep into the lungs.

24 patients receive a volume of blood sufficient to give 1 ml of plasma and collect in heparinized tubes for 30 and 15 min. before insulin administration and at 0 time immediately prior to insulin administration and also 5.10, 20, 30.45, 60, 90, 120, 180, 240, 300 and 360 minutes after the start of the inhalation. The bioavailability of a sample of insulin taken at 360 minutes is shown in Table 1, expressed in pU.min / ml (microliter units of insulin per milliliter of plasma). These numbers indicate that low initial flow rate and subsequent higher flow rate provide greater bioavailability of insulin than with consistently higher flow rates (average 11% increase in Case B compared to Case A. The combination of low initial flow rate with small particle size further increased bioavailability (average increase of 242% in case C compared to case B).

table

AUC360 (area under the curve) iU.min / ml)

<td>Subject No.</td><td></td><td>A no rise high DDI</td><td>B elevation high DDI</td><td>C elevation low DDI</td>

<td> 50180001</td><td></td><td> 728</td><td> 2300</td><td> 4403</td>

<td> 50180002</td><td></td><td> 1187</td><td> 1394</td><td> 2704</td>

<td> 50180003</td><td></td><td> 944</td><td> 1191</td><td> 3490</td>

<td> 50180004</td><td></td><td> 1973</td><td> 737</td><td> 2600</td>

<td> 50180005</td><td></td><td> 3362</td><td> 4243</td><td> 7294</td>

<td> 50180006</td><td></td><td> 2217</td><td> 2948</td><td> 5452</td>

<td> 50180007</td><td></td><td> 1507</td><td> 1017</td><td> 2554</td>

<td> 50180008</td><td></td><td> 795</td><td> 996</td><td> 1900</td>

<td> 50180009</td><td></td><td> 2447</td><td> 2250</td><td> 3593</td>

<td> 50180010</td><td></td><td> 5644</td><td> 5613</td><td> 12474</td>

<td> 50180011</td><td></td><td> 1714</td><td> 441</td><td> 2206</td>

<td> 50180012</td><td></td><td> 523</td><td> 393</td><td> 2602</td>

<td> 50180013</td><td></td><td> 1036</td><td> 1129</td><td> 1794</td>

<td> 50180014</td><td></td><td> 2823</td><td> 2834</td><td> 4468</td>

<td> 50180015</td><td></td><td> 1835</td><td> 2038</td><td> 2488</td>

<td> 50180016</td><td></td><td> 1623</td><td> 1102</td><td> 2636</td>

<td> 50180018</td><td></td><td> 2317</td><td> 1965</td><td> 5561</td>

<td> 50180019</td><td></td><td> 690</td><td> 1175</td><td> 2373</td>

<td> 50180020</td><td></td><td> 1399</td><td> 1113</td><td> 3045</td>

<td> 50180021</td><td></td><td> 681</td><td> 834</td><td> 2157</td>

<td> 50180022</td><td></td><td> 1093</td><td> 2137</td><td> 3564</td>

<td> 50180023</td><td></td><td> 1931</td><td> 2157</td><td> 5098</td>

<td> 50180024</td><td></td><td> 255</td><td> 134</td><td> 183</td>

<td> 50180028</td><td></td><td> 731</td><td> 822</td><td> 1627</td>

<td>Avg.</td><td></td><td> 1644</td><td> 1707</td><td> 3594</td>

<td>STD</td><td></td><td> 1158</td><td> 1263</td><td> 2440</td>

<td>RSD</td><td></td><td> 70</td><td> 74</td><td> 68</td>

Ratio of AUC360 (area under the curve)

<td>B / A Take off influence</td><td>C / B DDI | rear</td>

<td> 3.16</td><td> 1.91</td>

<td> 1.17</td><td> 1.94</td>

<td> 1.26</td><td> 2.93</td>

<td> 0.37</td><td> 3.53</td>

<td> 1.26</td><td> 1.72</td>

<td> 1.33</td><td> 1.85</td>

<td> 0.67</td><td> 2.51</td>

<td> 1.25</td><td> 1.91</td>

<td> 0.92</td><td> 1.60</td>

<td> 0.99</td><td> 2.22</td>

<td> 0.26</td><td> 5.00</td>

<td> 0.75</td><td> 6.62</td>

<td> 1.09</td><td> 1.59</td>

<td> 1.00</td><td> 1.58</td>

<td> 1.11</td><td> 1.22</td>

<td> 0.68</td><td> 2.39</td>

<td> 0.85</td><td> 2.83</td>

<td> 1.70</td><td> 2.02</td>

<td> 0.80</td><td> 2.74</td>

<td> 1.22</td><td> 2.59</td>

<td> 1.96</td><td> 1.67</td>

<td> 1.12</td><td> 2.36</td>

<td> 0.53</td><td> 1.37</td>

<td> 1.12</td><td> 1.98</td>

<td> 1.11</td><td> 2.42</td>

<td> 0.58</td><td> 1.20</td>

<td> 52</td><td> 50</td>