Flow resistance modulated aerosolized active agent delivery

Lýlbg

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition with active principle for the lung. More specifically, it is a method and device for administering a lung on a pharmaceutical composition with active ingredient to enhance overall bioavailability of the active ingredient by deep absorption into the lungs.

The accessibility is increased by adjusting the flow rate of the function of the device in a manner that is independent of the patient's guidance and flow rate monitoring.

Background of the Invention [0002] Effective administration is essential for any effective drug treatment. There are various ways of giving gifts and what's their own pros and cons. Medicinal lymph nodes with pills, capsules, elixirs, and the like are the most convenient method, but many drugs are broken down into the digestive tract before they are absorbed. HM subcutaneous injection is often an effective way to administer drugs in general, including the administration of proteins, but does not benefit from patients. Since injections of drugs, such as insulin once or more often, can often be a cause of bad obedience from the patient's hand, many other ways of donation have been developed, including administration of the skin, nasal, rectal, vaginal and in the lungs.

It is particularly interesting that the administration of the lung relies on the patient's inhalation of the active ingredient with the active principle that the active substance within the distribution can reach distant (pulmonary artery) regions of the lungs. This can be accomplished by using a device driven by a patient where it is the inlet flow forming the aerosol active impurity composition or by using dispersion or loom dusting equipment using pressure relief or propellant aerosols to aid aerosols and gefe the combination with the active effect.

It has been found that certain drugs are readily absorbed through the serotonin region directly into the bloodstream. Lung delivery is a special promise for the delivery of proteins and chain peptides, which is difficult to give with other administration routes. Thus, the administration of both donors and local donors in the treatment of pulmonary diseases is an effect.

Elliot and others in the East. Paediatr. J. (1987) 23: 293-297 gave a dose of six-fold human diarrhea with a respiratory tract of 6 diabetes with diabetes, suggesting that it was possible to have diabetes in these children, although the effectiveness of absorption was low (2025%) in compared to subcutaneous administration. Laube and others, U.S. Pat. No. 5,320,094, with regard to Elliot and many others, highlighted that although insulin has been administered to the lung, no patient responded adequately to insulin lung therapy to lower blood glucose to levels within the normal range. Laube and others suggest that the problem is a loss in the donor system and / or in the oral coccus due to the donor method, and that the intracellular lymph node should improve blood glucose levels. In order to achieve maximum pounds, the Laube and other pace of inspiratory flow rate at the atmospheric atmospheric rate at a flow rate of less than 30 liters / minute and at about 17 liters per minute. The donor system had a pharmacy to take the insulin, the outlet of each insulin was drawn, and upwardly limiting the flow rate to adjust the flow rate of the inhalation.

In U.S. Pat. No. ##. 60 / 078,212 of the same ownership was the above-mentioned speculation, and it was therefore noted that the administration of insulin at a rate of less than 17 liters per minute provided an increased level of insulin at shorter times than at a higher flow rate of inhalation.

U.S. Pat. 5,364,838 and 5,672,581 describe Rubsamen and others of the amount of insulin on the epidermis. The insulin is automatically discharged into the route of inspiratory flow in response to information obtained by determining the flow rate of the injection and the volume of the patient. The monitoring device transmits stable information to a microscope, and when a drunk man determines the optimal time interval in the respiratory tract is reached, a drill bit of a city opens a valve that allows for release of the insulin. The flow rate of inhalation ranges from about 0.1 to 2.0 lbs / sec, and the volume ranges from about 0.1 to 0.8 liposomes. WO 97/40819 discloses that slow flow of inhalation is the key to increased administration and precipitation medicines administered by the lungs.¹⁰. EPO 692990 B1 describes the deagglomerators for a dry-cleaner apparatus, and it is considered to be desirable to reduce the severity of the dosage jaws and / or the air inhaled air inhaled air at the airflow rate. Output The device responds to increased flow velocity with the rear edging of the channel space through which the air filled with powder passes, leading to a reduced throttle increase, but would be seen without variable bedspacing, providing a more effective discharge over the flow rate range.

US-A-5 027 806 discloses apparatus for rearranging drug tests. Further background information can be found in EP-A-0 808 635, US-A-4 592 348 and US-A-5 692 496.

We have now found out that in order to effectively deliver an active stimulant of the conduit in a convenient and consistent manner, it is desirable to maintain a low flow rate initially followed by a higher rate of flow for some hours.

Summary of the Invention The present invention provides a pharmaceutical composition comprising active patient patient lung. Existing outsourcing is defined in the independent claims.

Description of Images [0012]

Figure 1 is an overview of the embodiment of the present invention for the present invention in a dry powder composition.

Figure 2 is a graph showing the strength of the teat cup provided by device 1.

Figure 3 is a graph showing the resistance of the flow resistivity of the device to the 1st image that fell down.

Figure 4 shows the graph of the resistance of the flow rate corresponding to the resistance shown in Figure 3.

Fig. 5 shows green areas which are overlaid, cross-sectional and in accordance with the corresponding speed of attachment.

Figure 6 shows the patient's rate of incidence rate using device 1. Generates a variable flow resistance using maximum inhalation irritability.

Figure 7 shows the patient's inhalation volume chart using device 1. Generates a variable flow resistance using maximum inhalation experience.

Figure 8 shows a graph of the patient's comfortable rate of infiltration using equipment 1. forms a variable flow resistance.

Figure 9 shows the patient's inhalation volume chart using device 1. 20 forms with variable flow resistance at a comfortable inhalation rate.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method and apparatus for activating a pharmaceutical composition in which the flow resistance of the active ingredient pharmaceutical composition is changed by time. The invention is surprising in that it provides a more convenient and consistent level of functional activity.

Definitions As the "active ingredient" is described herein, it relates to a pharmaceutical composition, a combination of such polar spheres that provides some pharmacologically active activity, often binding. This includes phage, supplement, nutrient, drug vaccine, vitamin and other suppressive substances. The term also includes, as used herein, biochemical and pharmacologically active substances that lead to localized generalized effects in a patient. Active anti-inflammatory drugs, anti-inflammatory drugs and bronchodilators, and many inorganic and non-limiting compounds, including and without limitation, A-neurotransmitters, adrenergic fever, cholinergic agents, fibrosis, cardiovascular disorders, smooth flatulence, blood circulation, neurotransmitters, neuroefiector junctional sites, endocrine and hormonal systems, immune system, reproductive system, bone system, volunteers, nutrition and waste systems, the histamine system [and] midtaugakerfid. There are a choice of suitable excipients, for example, polysaccharides, dies, sleepers and tranquilizers, prescription drugs, tranquillizers, anticonvulsants, vasodilators, luminescence inhibitors, analgesics, antiinflammatory agents, myelosuppressants, antitussives, myelosuppressants, including counted adrenergic adrenergic drugs, adrenergic agents, and peptides that have the ability to induce life-threatening effects of anti-agonists, anti-fibrotic agents, anticholinergic agents, anti-narcotic drugs, neoplastic agents, antineoplastic agents, hypoglycemics, neurotransmitters and supplemental agents ,

neuropathy, parathyroid hormone (PTH), tyrosin alfa 1, inhibitor Ilb / IIIa, alfe-1 antitypin, anti-respiratory syncytial virus antigens antigens, CFTR, DNA cleavage (deoxyribonuclease), protein enhancing geriatric / BPI, anti-CMV receptor, hepterfrumuboda-1, 13-cis retinoic acid, pentamidine isothiourea [pentamidine isethiouate], albatterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, triamolone acetamid, budesonid acetonide, ipratropium bromide, flunisol, sodium chromolyn, ergotamine tartrate and their analogues, antagonists and antagonists to the epidermis. In addition, active compounds may comprise a combination of nucleic acids present as residues as isolated nucleic acid molecules, viral pathways, related viral lines, nucleic acids that are linked or incorporated into a lipid or substance containing a lipid, DNA or RNA plasmid or other nucleic acid composition of the host suitable for introducing or transforming adrenal cells, particularly cells of the lung lung regions of the lung. The active compounds can be in a variety of forms, such as soluble and insoluble loose or unleaded molecules, components of molecular complexes or pharmacologically acceptable salts. Active agents can be molecules that occur in nature, or they can be produced using genetically modified technology, as one of the more amino acids has been used for harm. Furthermore, the active principle of the survival of the weak tissues of the protected viruses may conveniently be used as a therapeutic agent. DNA or RNA plasmid or other nucleic acid composition of the host suitable for introducing or transforming adrenal cells, particularly cells of the lung lung regions of the lung. The active compounds can be in a variety of forms, such as soluble and insoluble loose or unleaded molecules, components of molecular complexes or pharmacologically acceptable salts. Active agents can be molecules that occur in nature, or they can be produced using genetically modified technology, as one of the more amino acids has been used for harm. Furthermore, the active principle of the survival of the weak tissues of the protected viruses may conveniently be used as a therapeutic agent. DNA or RNA plasmid or other nucleic acid composition of the host suitable for introducing or transforming adrenal cells, particularly cells of the lung lung regions of the lung. The active compounds can be in a variety of forms, such as soluble and insoluble loose or unleaded molecules, components of molecular complexes or pharmacologically acceptable salts. Active agents can be molecules that occur in nature, or they can be produced using genetically modified technology, as one of the more amino acids has been used for harm. Furthermore, the active principle of the survival of the weak tissues of the protected viruses may conveniently be used as a therapeutic agent. such as soluble and insoluble loose or unleaded molecules, components of molecular complexes or pharmacologically meaningful salts. Active agents can be molecules that occur in nature, or they can be produced using genetically modified technology, as one of the more amino acids has been used for harm. Furthermore, the active principle of the survival of the weak tissues of the protected viruses may conveniently be used as a therapeutic agent. such as soluble and insoluble loose or unleaded molecules, components of molecular complexes or pharmacologically meaningful salts. Active agents can be molecules that occur in nature, or they can be produced using genetically modified technology, as one of the more amino acids has been used for harm. Furthermore, the active principle of the survival of the weak tissues of the protected viruses may conveniently be used as a therapeutic agent.

"Active ingredient formulations" are used as active agents as defined by suitable methods for the treatment of a lung. The active ingredient composition may be in the form of a dry powder, it may be a solution, suspension of a slurry prepared with a powder, which may coincide with a suitable low-volatile fuel and volatile. This reservation is based on more than one active effect, it is possible to put the active compound into active use, and the use of the term "substance" does not at all use the use of two or more such functional materials.

The rate at which the active ingredient aerosol composition is given is called "flow rate of inhalation".

The amount of active ingredient in the active ingredient spray composition will become the amount of active ingredient that is effective for treatment and is indispensable in order to achieve the desired results. In performance, it will vary widely and depend on the specific effects, severity of the condition, and the therapeutic effect sought. However, the device is generally useful in the case of active agents which need to be administered in the range of 0.001 mg / day to 100 mg / day, elevated to 0.01 mg / day to 50 mg / day.

The present invention is based at least on the unexpected results that when an active ingredient is administered to a patient at a low inhalation rate initially, the bioavailability of the active ingredient increases relative to that when the active principle is administered at a higher than the higher flow rate of inhalation.

Compositions of active agents suitable for use in the present invention include dry powder, solutions, suspensions of aerosols and particles dispersed in dissolved solvents. A dry powder suitable for use in the present invention relates to a formidable active agent, a crystalline active agent, and a mixture of both non-formic and crystalline materials. The dry powder of the active agents has a diameter of particle size valid to enable the entry into the lumbar thrombosis of the lungs, i.e., a 10 μm mass median diameter (MMD) mass diameter less than 7.5 μm, and less than 5 pm, and usually in the range of 0.1 pm to 5 pm in diameter. The efficacy of the dose of DDE is> 30%, usually> 40%, heist> 50 and often> 60% and the size of the particle size is about 1.05.0 μm mass median aerodynamic diameter (MMAD), usually 1.5-4.5 MMAD and 1.5 to 1.0 μm MMAD. This active ingredient in dry form has a moisture content below about 10% by weight, usually below 5% by weight, and below 3% by weight in terms of weight. Such active ingredient powders are disclosed in WO 95/24183 and WO 96/32149, which is incorporated herein by reference. However, it is possible to provide larger amounts of DNA, such as those with MMDs between 10 and 30 pm, provided the MMAD particles are below 5.0 pm This active ingredient in dry form has a moisture content below about 10% by weight, usually below 5% by weight, and below 3% by weight in terms of weight. Such active ingredient powders are disclosed in WO 95/24183 and WO 96/32149, which is incorporated herein by reference. However, it is possible to provide larger amounts of DNA, such as those with MMDs between 10 and 30 pm, provided the MMAD particles are below 5.0 pm This active ingredient in dry form has a moisture content below about 10% by weight, usually below 5% by weight, and below 3% by weight in terms of weight. Such active ingredient powders are disclosed in WO 95/24183 and WO 96/32149, which is incorporated herein by reference. However, it is possible to provide larger amounts of DNA, such as those with MMDs between 10 and 30 pm, provided the MMAD particles are below 5.0 pm

Such data are described, for example, in PCT publications WO 97/44013 and WO 98/31346, and their analysis is incorporated herein by reference.

The active ingredient synthesis compositions are formulated with desiccant drying with adalatrid to formless dumps. Active substance from a large package, usually in a crystalline form, is dissolved in a physiologically acceptable hydrolysis solution, usually a citrate solution having a pH range of about 2 to 9. The active ingredient is dissolved at a concentration of 0.01% by weight to 1 % with respect to weight, usually from 0.1% to 0.2%. The solution can be wiped with a conventional dryer, which is useful from manufacturers such as Niro A / S (Danmdrku), Buchi (Switzerland), and similar, which leads to a powder that ct in adalatrid without fumes. It is also possible to create this free powder with freeze drying, air intake, or drying by evaporation of a suitable solution of active ingredient with additives forming the non-conformal structure. Formless compositions of the active agent thus produced may be crushed or grinded to produce particles within the scope of application. Active dry chemical agents may also be in a crystalline form. The crystalline dry powder is then prepared by crushing a jet milling crystalline active ingredient from a bulk package. The present active ingredient of the present invention is optionally combined with a load carrier for pharmaceuticals suitable for the delivery of a respiratory tract and in hing. Such loading agents can only play a dilution role when it is desirable to reduce the active substance's content in the powder, but may also accommodate the extraction of the powder into the dispersion apparatus to provide an effective and consistent coating of the active ingredient and to the optimal performance characteristics of the active ingredient such as the flux properties and density of the reproduction and filling of the powder. Such foods include but are not limited to (a) sugars, such as liqueurs such as fructose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, cellulose phosphate, and the like; cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose, maltdextrin, dextrin, and the like; (b) amino acids, such as glycine, arginine, aspartic acid, glutamic acid, system, perfume, and the like; (c) lifrsn soft made of liver acids and bdsum, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, riomethamine hydrochloride, and the like substance; (d) peptides and proteins such as aspartame, human blood lipid albumin, gelatin, and the like; and (e) alditol, such as mannitd, xylitol, and the like. Preferred group of carriers include lactose, trehalose, raffindene, maltdextrin, glycine, sodium citrate, human serum and human solvents. Active ingredient dry powder compositions can be provided by using the Inhal Therapeutic Systems dry powder applicator as disclosed in WO 96 / 09085 which is inserted herein by reference, but adapted to control flow resistance as noted below. The dry powder can also be administered by using a dosing device with a measure as silenced by Laube and others in U.S. Pat. 5,320,094, which is inserted here with the indication of a patient who has been driven by a patient like the one who is silent in U.S. Pat. 4,338,931, which is hereby inserted with reference.

Exposure solutions can be created by air-cooled solutions of active-active-compound compositions. These solutions are administered by a dose meter, ie aerosol dispensers for a controlled dose dose, such as "Raindrop", manufactured by Puritan Dennett, and the use of which is quiet by Laube and ddrum. Other behaviors for the solutions, suspensions of these abusive solutions are silenced by Rubsamen and ddrum ί U.S. Pat. 5,672,581. A bucket using a vibrating piezoelectric member is silenced by Ivri and odrum in U.S. Pat. 5,586,550, which is hereby inserted with reference.

A drive system may comprise active agents solubilised if the particles are dispersed in the propellant. The boats of these types of combinations are silenced by Rubsamen and ddrum 1 U.S. Pat. 5,672,581, which is hereby inserted with reference.

In order to increase the presence of the active substance, it is important to change the bunad that is silenced to limit the migration rate of the active ingredient combinations. We have discovered that when low inhalation flow rates have been reached, lowering pressure and allowing higher flow rates can be relieved. If the higher rate of infection is not reached, the patient becomes resistant to breath and stops breathing.

According to the invention there will be a flow rate of less than about 15

Iftrum per minute, boils less than 10 liters per minute and more between about 5 and 10 hours per minute, reaches less than 10 seconds, less than 5 seconds and often between 3 and 5 seconds. After this start-up period with limited flow rates, this flow rate limitation will be reduced and the flow rate will become the editable flow of the patient's respiratory tract. This flow rate is between about 15 and 80 liters per minute, usually between about 15 and 60 liters per minute and often between about 15 and 30 liters per minute. In order to do this, there is a set of flow resistors installed in the equipment. The pressure sensor of the device will determine the volume of the inhalation. The resistance of the bottle resistors will be set to a higher resistance, between about 0.4 and 2 (cm HzO)^{l / z}/ SLM (where SLM is in lefts per minute at standard temperature and pressure), usually between about 0.4 and 1.5 (cm H2O)^1Q/ SLM and often between about 0.5 and 1.0 (cm H2O)^IAE/ SLM to achieve the flow rate determined by the unit. Requires the initial flow of limited flow, as determined by the pressure sensor and the predetermined period, will adjust the flow resistance so that it will allow little or no resistance to flow. The resistance will be between 0 and 0.3 (cm

H2O)^1Z2/ SLM, usually between 0 and 0.25 (cm H2O)^1/2/ SLM and often between 0 and 0.2 (cm H2O)^{1 / z}/ SLM. The comfortable and comfortable flow rate of the patient's intake will be so close. The behavior of the flow rate control system is shown in Figure 1. In this system σ, the flow control valve is closed (100) as a city seat on the input section (102) of the device (104) to control the flow rate of the intake air. Flowmeters (106) and levels (108) are only useful for evaluating patient patronage in response to flow limitation in a study case. Pressure sensor (110) measures the start of the injection and causes the opening of the valve (100). Even if the flow rate is shown in this case, driven by the end of the engine, a single mechanical closing system can also be used. Further, you can use a different flow sensor for each pressure sensor to sense the onset of injection.

The further embodiment of the present invention is further characterized by the fact that the impact of the particles is difficult and the boiler is proportional to the flow velocity and the wind turbine diameter is calculated in accordance with the following jdfnu:

I = kd²Q

I = the number of particles that collide and K k = the proportion of d = MMAD particles

Q = Flow Rate According to the above, it is possible to give larger particles by using the low starting amount of the present invention without increasing the number of particles and the combustion particles provided that most of the active ingredient is administered over a period of time low flow rate. At the beginning when the flow rate is low and the airborne concentration is high, ie the number of particles in the ventricle is at its peak, the particles will be given deeper lungs rather than collapse and the boiling effect of the active agent will increase.

The concentration of aerosol emitted from device 1 is shown in Figure 2. For 0.5-point of lukewarm, the graphid indicates the strength of the first 0.1 to 0.2 liters is the highest and then the strength decreases. Therefore, it is important to provide low-flowing parts of the air vents to prevent collision and cough collision and increase accessibility. Resistant image of the flsdishradans in order to implement this is shown ή 3. The resistance is high (0.65 (cm H₂O)^1Q / SLM) in the first 3 seconds of the time, the valve is side elevation and the resistance changes in the apparent resistance of the device (in this case 0.15 (cm H2O)^LFL/ SLM). As can be seen from the 4th row of image 4, the flash resolution of the initial timing is about SLM 10 and changes the page up to about 25-30 SLM. Resistance image for the further invention of the invention and its flow rate pattern is shown in Figure 5. The resistance change is from high to low (0.9 to 0.20 (cm H₂O)^{l / 2}/ SLM) in the 5 start seconds of the season. As shown in Figure 5, the flsh rate of input is the first 3 seconds of the time less than 20 SLM, which changes to approximately 30 SLM. In both these cases, the bulk of the active ingredient is given in the first 3 seconds of the period, with the concentration of the airspace in the first 0.1 to 0.2 liters the greatest. This increases the amount of digestion and therefore the bioavailability of the active ingredient.

[0031] The following examples illustrate the present invention. They are not intended to limit the scope of the invention. Changes from them and the same will be revealed to those who are familiar with the light in the light of the present existence, the images and the powers.

examples

Daanil In order to determine the relationship between flow resistance and flow rate, 10 volunteers, 5 men (M) and 5 females (F) were asked to pull the breath against 3 different resistors and instructed to breathe both at the maximum speed and at a comfortable speed. The results are shown in Figures 6-9. Pictures 6 and 7 are flow rates for maximum and comfortable inhalation rates for men and women. Figures 8 and 9 show the volume of aerosol inhaler at high and convenient inhalation velocity and resistance as described above.

The resistance to maintaining a comfortable flow rate of 10 liters per minute is approximately 0.3 (cm H 2 O 2 / SLM). Furthermore, the inhalation volume decreases with higher flow resistance due to inhalation becoming increasingly difficult and more uncomfortable if the resistance increases, if the resistance is reduced after the initial time of the aerosol dispenser, the inhalation volume will not significantly decrease from the volume given at the rate of delivery of a constant low flow resistance.

Example 2

EfiiiogAðferðir

Elemental Crystalline Synthetic Sulfur, 26.3 U / mg is obtained from Eli Lilly and Company,

Indianapolis, IN and was confirmed to be> 99% pure as measured by reverse phase HPLC. USP mannitol is obtained from Roquette Corporation (Gurnee, IL). Glycine was purchased from Sigma

Chemical Company (St. Louis, Missouri). Sodium citrate dihydrate, USP, is obtained from JT

Baker (Phillipsburg, NJ).

Powdered powder. Insulin powder is prepared by dissolving the crystalline insulin from a large package of sodium citrate juice solution containing mannitol and glycerin to give a final concentration of 7.5 mg / ml and a pH of 6.7 ± 0.3. Dry drying is effected at an inlet temperature between 110 ° C and 120 ° C and a flow rate of 5 ml / min leading to an outlet temperature between 70 ° C and 80 ° C. The solutions are side-by-side through 0.22 pm and dried in Buchi Spray Dryer to form a fine white amorphous powder. Duration of storage time is well in well dry conditions (<10% RH).

Detection of powder The particle size distribution of the powder is measured by vapor deposition in the Horiba CAPA-700 Particle Size Analyzer in centrifugal distributions of the powder Sedisperse A-11 (Micrometries, Norcross, GA). The moisture content of the powder is measured with Karl Fischer technology using the Mitsubishi CA-06 Moisture Meter. The aging of the skin is msld using a cascade impactor (Graseby Andersen, Smyrna, GA). DDE efficacy is evaluated using Inhale Therapeutic Systems aerosol equipment, similar to those described in W096 / 09085. DDE is defined as the percentage of the administered dose contained in the package and out of the aerosol mucus device and was received in glass vial (Gelman, 47 mm diameter) for induction of air intake was reduced (30L / min) for 2.5 seconds after the device had arrived .

The pre-post and post-production insulin integrity is measured with reference to the human insulin standard of control by dissolving the weighted part of the powder in distilled water and comparing the redissolved solution to the initial solution placed on the spray drier. Table times and spikes of spikes with HPLC and HPLC are used to determine if the insulin molecule has been altered chemically or fragmented in the process. LTV absorbance was used to determine the insulin strength (at 278 nm) and confirmation of the absence of insoluble clusters (at 400 nm). Furthermore, the pH is starting and reconstituted solutions are measured. The formless nature of the insulin powder is confirmed by a microscope with polarization.

Testing in live Ukama In order to examine the effect of change in the rate of injection on insulin insufficiency, 24 subjects dose 2 mg of insulin by using a systemic device shown in Figure 1. Each behavior consists of two inhalations that amount to 1 mg each. The aerosols are Inhale Therapeutic Systems Inhalers (San Carbs, CA) as disclosed in U.S. Pat. 5,740,794, which is incorporated herein by reference. Medhdndlanimar are:

A. Inhalation of insulin with an agnastasis of 3.6 μ MMAD (large PSD), using normal respiratory and aerosol devices (no barrier).

B. Inhalation of insulin with an agnastasis of 3.6 μm MMAD (large PSD), with an inhalation rate limited to approximately 10 liters per minute with the system shown in Figure 1 (barrier).

C. Inhalation of insulin with agnastasis 2.6 μ MMAD (small PSD), with inhalation rate limited to approximately 10 l / min with the system shown in Figure 1 (barrier).

The compositions of the insulin dry powder have a median particle diameter of less than 5 microns. The spraying device distributes the powder and a powdered vial (vial) stored in a volume of about 240 ml in a storage compartment. The volume of HHS is a part of deep breath (> 2 lft). The compartment is designed like this while during the injection of the medication floor, air from the environment drains into the compartment, pushing the air outlet out of the compartment and deeply into the pan.

The blood was sufficient to provide a minimum of 1 ml of blood water was collected from 24 conjugates in glos with heparin at 30 and 15 minutes for insulin dosing and 0 (just prior to insulin excretion), 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes after inhalation. The incidence of insulin in samples taken over 360 minutes is shown in TUFlu I in pU.min / mL (microenvironment of insulin per milblood of plasma). These images show a low initial flow rate followed by a higher flow rate, providing a greater prevalence of insulin than a steady high flow rate (mean 11% increase in incidence in comparison with case A). The combination of low initial flux rash and tiny bait paste increased the prevalence (a mean of 242% increase in case C ί compared with case B).

Table I

AUG36Q (uUminM)

<td>Hðnwr VMfangs</td>

<td>50180001</td>

<td>50180002</td>

<td>50180003</td>

<td>50180004</td>

<td>S0I8M0S</td>

<td>50180006</td>

<td>5ÖÍ8QÖ07</td>

<td>50180008</td>

<td>50180009</td>

<td>50180010</td>

<td>50180011</td>

<td>50180ÓI2</td>

<td>50180013</td>

<td>'50180014'</td>

<td>50180015</td>

<td>501800IÍ</td>

<td>50180018</td>

<td>50I8Ö01 *</td>

<td>50180020</td>

<td>5oieooif ~</td>

<td>5oTOT ' "</td>

<td>50180023</td>

<td>50180024</td>

<td>50180028</td>

<td>Maftattal</td>

<td>Staðalfrávili</td>

<td>Share St frv</td>

<td>A mglnhindrur stir PSD</td><td>a barrier rtórPW</td><td>c barrier MMP8O</td>

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

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

<td>944</td><td>1191</td><td>3490 ......¹</td>

<td>...... 1'973 '</td><td>737</td><td></td>

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

<td>2217 -</td><td>2948</td><td>"5®" ""</td>

<td></td><td>1017</td><td>25 «</td>

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

<td>2447</td><td>22ÍO</td><td>3593</td>

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

<td>1714</td><td>441</td><td>2206 .......</td>

<td>523</td><td></td><td>2602</td>

<td></td><td>1129</td><td>1794</td>

<td>2823</td><td>28Í4</td><td>4468</td>

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

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

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

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

<td>W "</td><td>..................&gt; '* »' ..................</td><td>JÓÆT "</td>

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

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

<td>Ι93Ϊ</td><td>....... Í8F "</td><td>509 *</td>

<td>2ÍÍ</td><td>134</td><td>183 _</td>

<td>73Ϊ</td><td>&amp;</td><td></td>

<td>1644</td><td>1767 "</td><td>39W</td>

<td>1158 '</td><td></td><td>2440</td>

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

AUC360

Hhitiall

<td>WA</td><td>dB</td>

<td>AM</td><td>Am</td>

<td>inhibition</td><td>PSD</td>

<td>$ 11</td><td>1.91</td>

<td>147</td><td>1.94</td>

<td>IJF .......</td><td>2.93</td>

<td>12:37</td><td>153</td>

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

<td>-T3J ~</td><td>"| B ~</td>

<td>047</td><td>2.51</td>

<td>U5</td><td>1.91</td>

<td>0.92</td><td>"Ί, ϊο</td>

<td>0.99</td><td>Ϊ22</td>

<td>Ú26</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>"ÓÍ0</td><td>2.74</td>

<td>1.22</td><td>"I5F"</td>

<td>1.96</td><td>167</td>

<td>1.12</td><td>2:36</td>

<td>12:53</td><td>137</td>

<td>142 ............ '</td><td>1.98</td>

<td>141</td><td>242</td>

<td>12:58</td><td>1.20</td>

<td>52</td><td>....... 'io</td>