MXPA01003614A - Flow resistance modulated aerosolized active agent delivery - Google Patents

Abstract

The present invention is directed to methods and devices for delivering an active agent formulation to the lung of a human patient. The active agent formulation may be in dry powder form, it may be nebulized, or it may be in admixture with a propellant. The active agent formulation is delivered to a patient at a low inspiratory flow rate for an initial period of time to increase bioavailability of the active agent.

Description

ADMINISTRATION OF AEROSOLIZED ACTIVE AGENT MODULATED BY FLOW RESISTANCE Field of the Invention The present invention relates to the pulmonary administration of a formulation of an active agent. More particularly, it is a method and apparatus for the pulmonary administration of a formulation of an active agent for the increased systemic bioavailability of the active agent by means of drug absorption in the deep lung. The bioavailability is increased by modulating the flow of the aerosolized active agent in a manner that is independent of the patient's instruction and the monitoring of the flow range.

BACKGROUND OF THE INVENTION Effective administration to a patient is a critical aspect of successful drug therapy. There are several routes of administration and each has its own advantages and disadvantages. Oral administration of drugs in the form of pills, capsules, elixirs and the like is perhaps the most convenient method, but many drugs are degraded in the digestive tract before they can be absorbed. Frequently, the subcutaneous injection is an effective route of systemic administration of a drug, which includes the administration of proteins, but which enjoys little acceptance by the patient. As the injection of medications, such as insulin, one or more times a day, can often be a source of poor compliance on the part of the patient, a variety of alternative routes of administration, including transdermal, intranasal administration, have also been employed. , intrarectal, intravaginal and pulmonary. It is of particular interest that the pulmonary administration of the drugs depends on the inhalation of a formulation of an active agent by the patient, so that the active drug within the dispersion can reach the distant (alveolar) regions of the lung. This can be accomplished by using a patient operated apparatus where the inspiratory flow is the one that aerosolizes the active agent formulation, or by using a drug dispersion or an aerosol apparatus that uses a compressed gas or propellant to aerosolize and administer the formulation of the active agent.

It has been discovered that certain drugs are easily absorbed directly into the bloodstream, through the alveolar region. Pulmonary administration is particularly promising for the administration of proteins and polypeptides, which are difficult to administer by other routes of administration. Such pulmonary administration is effective, both for systemic administration, and for localized administration to treat diseases of the lungs. Elliot and associates, Aust. Paediatr. J. (1987) 23: pages 293 to 297 described the nebulized administration of semi-synthetic human insulin, for the respiratory devices of six diabetic children and determined that it was possible to control the diabetes of these children, although the efficiency of the absorption was low (20 to 25%) compared to subcutaneous administration. In U.S. Patent No. 5,320,094, Laube et al., Mentioning Elliot and a number of other studies, emphasized that although insulin had been administered to the lung, none of the patients had responded sufficiently to pulmonary insulin therapy, decreasing blood glucose levels to within normal ranges. Laube and associates hypothesized that this problem was the result of the loss of the medicine in the delivery system and / or the oropharynx as a result of the administration method and that the maximization of delivery within the lungs should improve the control of blood glucose. In order to achieve maximum administration, Laube and associates controlled the range of inspiratory flow at the time of inhalation of the aerosol, in flow ranges less than 30 liters / minute and, preferably about 17 liters / minute. The administration system included a medication chamber to receive the insulin, an exit opening through which the insulin was withdrawn and a flow range, which limited the opening to control the inspiratory flow range. Commonly assigned US Patent Application No. 60 / 078,212, tested the above hypothesis and indicated that pulmonary administration of insulin in amounts of less than 17 liters per minute produced increased levels of insulin in the blood, in a shorter period of time , than in higher inspiratory flow ranges. In U.S. Patents Nos. 5,364,838 and 5,672,581, Rubsamen et al. Describe the administration of a measured quantity of aerosolized insulin. Insulin is released automatically into the inspiratory flow path in response to information obtained from the determination of the inspiratory flow range, and the inspiratory volume of a patient. An apparatus that continuously monitors, sends information to a microprocessor, and when the microprocessor determines that an optimum point has been reached in the respiratory cycle, the microprocessor operates the opening of a valve, allowing the release of insulin. The inspiratory flow range is in the range of approximately 0.1 to 2.0 liters / second and the volume is in the range of approximately 0.1 to 0.8 liters. Document WO97 / 40819 describes slow inspiratory flow rates, as the key to the increased administration of the drug and the deposit of drugs administered via the pulmonary route. In order to obtain the target flow ranges (15 to 60 liters per minute), the resistance of the apparatus was designed to be within 0.12 to 0.21 (cm H20) 1/2. EPO Patent 692,990 Bl discloses deagglomerators for dry powder inhalers and indicates that it is desirable to reduce the dependence on the amount of air flow of the dose of administration and / or the respirable fraction of an inhaled powder aerosol. Deagglomerators respond to increasing flow ranges, to vary the geometry of a channel through which airborne dust passes, resulting in a lower increase in pressure drop than would have been seen in the absence of Variable geometry and they provide more effective deagglomeration in a variety of flow ranges. We have now determined that, in order to effectively administer an active agent, via the pulmonary route, in a comfortable and reproducible manner, it is desirable to maintain an initial low flow range, followed by a higher flow period.

SUMMARY OF THE INVENTION Accordingly, in one aspect, the present invention is directed to an apparatus for the administration of an aerosolized formulation of an active agent to the lungs of a human patient. The apparatus comprises a flow resistance modulator that modulates the flow resistance of the aerosolized active agent formulation to produce an initial target flow range of the aerosolized active agent formulation. The flow resistance modulator modulates the resistance in a way that is independent of the flow rate monitoring and patient instruction. In another aspect, the present invention relates to a method for administering a formulation of an active agent to the lungs of a human patient. The method comprises the provision of an aerosolized active agent formulation with a high flow resistance, for an initial period, followed by a period of lower flow resistance.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic view of one embodiment of an apparatus for the administration of a dry powder active agent formulation of the present invention. Figure 2 is a graph of the concentration of the aerosol administered by the apparatus of Figure 1.

Figure 3 is a graph of the resistance of the flow resistance modulator of the apparatus of Figure 1 as a function of time. Figure 4 is a graph of the resistance of the flow range corresponding to the resistance shown in Figure 3. Figure 5 are superimposed graphs of a flow modulator of the present invention and the corresponding flow range of the associated apparatus. Figure 6 is a graph of the inhalation ranges of patients using the apparatus of Figure 1 in variable flow resistances, using a maximum inhalation effort. Figure 7 is a graph of the patient inhalation volumes, using the apparatus of Figure 1 in variable flow resistances, using maximum inhalation effort. Figure 8 is a graph of the comfortable inhalation ranges of the patients, using the apparatus of Figure 1 in variable flow resistances. Figure 9 is a graph of patient inhalation volumes, using the apparatus of Figure 1 in variable flow resistances in a comfortable inhalation range.

Detailed Description of the Invention The present invention provides a method and apparatus for the pulmonary administration of an active agent formulation wherein the flow resistance of the active agent formulation is varied over time. The present invention is surprising in that it provides increased blood levels of the active agent in a comfortable and reproducible manner. Definitions . "Active agent" as described in the present invention includes an agent, medicament, compound, composition of materials or mixtures, which provide some pharmacological and often beneficial effect. This includes food, food supplements, nutrients, medicines, vaccines, vitamins and other beneficial agents. As used in the present invention, the term further includes any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. The active agent that can be administered includes antibiotics, antiviral agents, aneleptics, analgesics, anti-inflammatory agents and bronchodilators, and can be organic or inorganic compounds including, without limitation, drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, muscles of the skeleton, the cardiovascular system, soft muscles, the blood circulatory system, synoptic sites, neuroefector binding sites, endocrine and hormone systems, the immune system, the reproductive system, the skeletal system, the autacoid systems, food systems and excretory, histamine systems for the central nervous system, the appropriate agents can be selected from, for example, polysaccharides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, anti-peptide agents, analgesics, anti-inflammatories, muscle contractors, antimicrobials, anti-malaria, hormonal agents including contraceptives, sympathomimetics, polypeptides, and proteins with the ability to elicit physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitic agents, neoplastic, antineoplastic, hypoglycemic, nutritional agents and supplements, Growth supplements, fats, antiteteritis agents, electrolytes, vaccines and diagnostic agents. Examples of the useful active agents of the present invention, include but are not limited to, insulin, calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, cererase, cerezyme, cyclosporine, granulosite colony stimulating factor (GCSF), alpha-1 proteinase inhibitors, elcatonin, granulolytic macrophage colony-stimulating factor (GMCSF), growth hormones, human growth hormone (HGH), growth hormone-releasing hormone (GHRH), heparin, low-weight heparin molecular (LMWH), interferon alpha, interferon beta, interferon gamma, interlukin-2, luteinizing hormone-releasing hormone (LHRH), somatostatin, somatostatin analogs including ocreotide, vasopressin analogues, follicle simulating hormones (FSH), factor insulin-like growth, insulintropine, interleukin 1 receptor antagonist, interleukin 3, interleukin 4, interleukin 6, interleukin 10, colony simulating factor s of macrophages (M-CSF), nerve growth factor, parathyroid hormones (PTH), thymosin alpha 1, inhibitor of Ilb / IIIa, antitrypsin, alpha 1, respiratory syncytial virus antibody, cystic fibrosis membrane regulatory gene ( CFTR) deoxyribonuclease (Dnase), protein for bactericidal increase / permeability (BPI), antibody. CMV, interleukin-1 receptor, 13-cis retinoic acid, pentamidine isethioate, albuterol sulfate, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, ipatropium bromide, flunisolide, cromolyn sodium, tartrate ergotamine and the analogues, agonists and antagonists of the above. The active agents can additionally comprise nucleic acids, present as simple nucleic acid molecules, viral vectors, associated viral particles, nucleic acids associated or incorporated within lipids and / or lipid-containing material, plasmids of DNA or RNA or other acid constructions. nucleic acids of a type suitable for transvection or cell transformation, particularly cells of the alveolar regions of the lungs. The active agents can be in various forms, such as soluble and insoluble molecules, charged or uncharged, molecular complex components or pharmacologically acceptable salts. The active agents can be molecules that occur naturally or can be produced recombinantly, or they can be analogues of the naturally occurring active agents produced or that are recombined with one or more amino acids added or deleted. In addition, the active agent may comprise dead or live viruses, attenuated for use as vaccines. "Formulation of aerosolized active agent" means the active agent as defined above, in a formulation that is suitable for pulmonary administration. The formulation of the aerosolized active agent can be in the form of a dry powder, it can be a solution, suspension or paste to be nebulized, or it can be a mixture with a highly volatile propellant with a suitable low boiling point. It must be understood, that more than one active agent may be incorporated into the aerosolized formulation of the active agent and that the use of the term "agent" in no way precludes the use of two or more such agents. The "inspiratory flow range" is the flow range, in which the aerosolized formulation of the active agent is administered. The amount of active agent in the aerosolized formulation will be the amount necessary to administer a therapeutically effective amount of the active agent to achieve the desired result. In practice, this amount will vary widely depending on the particular agent, the severity of the condition and the desired therapeutic effect. However, the apparatus is generally useful for active agents that must be administered in doses 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 observation that when an active agent is administered to a patient in a range of initially low inspiratory flow, the bioavailability of the active agent increases, in opposite manner to when the agent Active is administered in a range of constant inspiratory flow, but higher. Formulations of the active agent suitable for use in the present invention include dry powders, solutions, suspensions or pastes for nebulization and particles suspended or dissolved within a propellant. The dry powders 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 active agent contains a particle size selected to allow penetration of the pulmonary alveoli, ie, preferably of an average mass diameter of 10 μm (MMD) or less, preferably less than 7.5 μm, and more preferably smaller of 5 μm being generally in the range of 0.1 μm to 5 μm in diameter. The efficiency of the administered dose (DDE) of this powder is >30%, generally > 40% preferably > 50% and frequently > 60%, and the particle size distribution of the aerosol is about a mean aerodynamic mass diameter of about 1.0 to 5.0 μm (MMAD) generally, from 1.5 to 4.5 μm MMAD and preferably from 1.5 to 4.0 μm MMAD. These dry powder active agents have a lower moisture content of about 10% by weight, generally less than about 5% by weight and preferably less than about 3% by weight. Said powders of active agents are described in WO 95/24183 and W096 / 32149, which are incorporated herein by reference. However, it may be possible to administer larger sized particles, such as those with MMAD 's between 10 and 30 μm, to the extent that the MMAD' s of the particles are less than 5.0 μm. Such particles are described, for example, in PCT publications WO 97/44013 and WO 98/31346 whose descriptions are incorporated herein by reference. Formulations of the dry powder active agent are preferably prepared by spray drying under conditions which result in a substantially amorphous powder. The active agent in bulk, generally in crystalline form, is dissolved in a physiologically acceptable aqueous regulator, generally a citrate regulator having a pH in the range of about 2 to 9. The active agent is dissolved in a concentration of 0.01% in weight at 1% by weight, generally 0.1% 0.2%. Subsequently, the solutions can be spray-dried in a conventional spray dryer which can be obtained with commercial suppliers such as Niro A / S (Denmark), Buchi (Switzerland) and the like, resulting in a substantially amorphous powder. These amorphous powders can also be prepared by lyophilization, vacuum drying or evaporative drying, of a solution of the suitable active agent, under conditions to produce the amorphous structure. The formulation of the amorphous active agent produced in this manner can be milled to produce particles within the desired size range. The dry powder active agents can also be in crystalline form. The crystalline dry powders can be prepared by grinding, or by jet grinding the crystalline active agent in bulk. The active agent powders of the present invention can be optionally combined with pharmaceutical carriers or excipients, which are suitable for respiratory and pulmonary administration. Such vehicles can simply serve as bulking agents, when desired, to reduce the concentration of the active agent in the powder being administered to the patient, but can also serve to improve the dispersibility of the powders within an apparatus of dispersion of powder, in order to provide a more efficient and reproducible administration of the active agent and to improve the handling characteristics of the active agent, such as the flowability and consistency to facilitate the manufacture and filling of the powder. Such excipients include, but are not limited to, (a) carbohydrates, for example monosaccharides such as fructose, galactose, glucose D-mannose, sorbose and the like; disaccharides, such as, lactose, trehalose, cellobiose and the like, cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; 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 prepared from acids and organic 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 and the like, and (e) alditols, such as mannitol, xylitol, and similar. A preferred group of vehicles includes lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, human serum albumin and mannitol. Dry powder active agent formulations can be administered using Inhale Therapeutic Systems dry powder inhalers, such as those described in WO 96/09085 which is incorporated herein by reference, but adapted to control the strength of flow as will be described below. The dry powders can also be administered using a metered dose inhaler, as described by Laube and associates in U.S. Patent No. 5,320,094 which is incorporated herein by reference or by a patient operated apparatus, such and such. as described in U.S. Patent No. 4,338,931, which is incorporated herein by reference. The nebulized solutions can be prepared by commercially available aerosolizing solutions of active agent formulations. These solutions can be administered by a dosimeter, which is a nebulizer that delivers an aerosol in a bolus controlled dose, such as Raindrop, produced by Puritan Bennett, whose use is described by Laube and associates. Other methods for the administration of solutions, suspensions or pastes are described by Rubsamen et al., In US Pat. No. 5,672,581. An apparatus using a vibratory piezoelectric member is described in U.S. Patent No. 5,586,550 issued to Ivri et al., Which is incorporated herein by reference. The propellant systems may include an active agent dissolved in a propellant or particles suspended in a propellant. Both of these types of formulations are described in the Patent North American No. 5,672,581 to Rubsamen y asociados which is incorporated herein by reference. In order to obtain the bioavailability increases of the active agent, the apparatuses described above must be modified in order to restrict the initial inspiratory flow range of the active agent formulation. We have discovered that, once the initial period of the inspiratory flow range has been established, the restriction can be released, and a higher flow range is permissible. If the highest flow range has not been established, the patient may become frustrated and stop inhaling. According to the present invention, a flow range of less than about 15 liters per minute, preferably less than 10 liters per minute and frequently between 5 and 10 liters per minute, will be established for a period of less than about 10 seconds, preferably less of 5 seconds and frequently between approximately 3 and 5 seconds. After this initial period of limited flow range, the restriction of flow range will be released, and the flow range will be the patient's normal inspiratory flow range. This flow range is between about 15 and 80 liters per minute, generally between about 15 and 60 liters per minute and frequently between about 15 and 30 liters per minute. In order to achieve this, a flow resistance modulator will be incorporated into the apparatus. A pressure sensor in the device will determine the presentation of the inhalation. The flow resistance modulator will be set to a high resistance between approximately 0.4 and 2 (cm H20) 1/2 / SLM (where SLM stands for liters per minute in temperature and standard pressure), generally between approximately 0.4 and 1.5 (cm H20) 1/2 / SLM and frequently between approximately 0.5 and 1.0 (cm H20) 1/2 / SLM, to obtain the flow range described above. Once the limited initial flow period, determined by the pressure sensor and the previously established time period, has passed, the flow resistance modulator will be readjusted, so that it will provide little or no resistance to flow. This resistance will be between approximately 0 and 0.3 (cm H20) 1/2 / SLM, generally between 0 and 0.25 (cm H20) 1 2 / SLM and frequently between 0 and 0.2 (cm H20) 1/2 / SLM. Accordingly, the comfortable normal inspiratory flow range of the patient will be established. An exemplary system for modulating the flow range is illustrated in Figure 1. In this system, the flow rate modulator is a valve (100) placed in the air inlet manifold (102) to the apparatus (104). ) to control the flow range of the air inlet. The fluidometer (106) and the computer (108) are used only to evaluate the patient's behavior, in response to the flow restriction for research purposes. The pressure sensor (110) measures the presentation of the inhalation and detonates the opening of the valve (100) although the modulator of the flow range, in this case, is illustrated as a valve operated by a microprocessor, simple mechanical valve systems can also be used. In addition, in order to detect the presentation of the inhalation, either a flow sensor or a pressure sensor could be used. According to a further feature of the present invention, it has been found that the impact on the throat of the particles is proportional to the flow range and to the square of the aerodynamic diameter according to the following equation: 1 = k2Q 1 = number of particles that impact on the throat k = proportionality constant d = MMAD of the particles Q = flow range. According to the above equation, it is possible to administer larger particles, using the lower initial flow ranges of the present invention, without raising the number of particles impacting the throat, because most of the active agent is administered during the period under the flow range. Then, initially, when the flow range is low and the concentration of the aerosol is high, that is, the number of particles in the aerosol is at its peak, the particles will be preferably administered to the deep lung, instead of being impacted in the throat and the bioavailability of the active agent will be increased. The concentration of the aerosol leaving the apparatus of Figure 1 is illustrated in Figure 2.

For a spray of 0.5 liters, the graph shows that the concentration of the first 0.1 to 0.2 liters, is the highest and then that concentration drops. Therefore, it is important to administer the initial portion of the aerosol at a low flow to avoid impact on the throat and increase bioavailability. The resistance profile of the flow range modulator to perform this is illustrated in Figure 3. The resistance is high (0.65 (cm H20) 1/2 / SLM) for an initial time period of 3 seconds, then the valve it is open and the resistance transitions to the normal resistance of the apparatus (in this case 0.15 (cm H20) 1 2 / SLM). As will be appreciated from the flow ranges of Figure 4, the inspiratory flow range in the initial period is about 10 SLM and then transits up to about 25-30SLM. The resistance profile of an additional flow range modulator of the present invention and its associated flow range profile are illustrated in Figure 5. The resistance transitions from high to low (0.9 to 0.20 (cm H20) 1/2 / SLM) for an initial time period of 5 seconds. As can be seen from the flow ranges of Figure 5, the inspiratory flow range in the initial period of 3 seconds is less than 20 SLM and then, increases to approximately 30 SLM. In both of these cases, as the concentration of the aerosol in the first 0.1 to 0.2 liters is the highest, most of the active agent is administered in the initial time period of 30 seconds. This increases the administration to the deep lung and in this way, the bioavailability of the active agent. The following examples are illustrative of the present invention, should not be construed as limiting the scope of the invention. Those skilled in the art will appreciate variations and equivalents of the examples, in light of the present disclosure, the drawings and the appended claims.

Examples Example 1. In order to determine the relationship of the flow resistance to the flow range, 10 volunteers, 5 men (M) and 5 women (F) were asked to breathe against 3 different resistances and they were instructed to inhale, both in a maximum way and in a comfortable range. The results are illustrated in Figures 6 through 9. Figures 6 and 7 are the flow ranges for the maximum and comfortable inhalation ranges for men and women. Figures 8 and 9 show the aerosol volumes inhaled in the maximum and comfortable inhalation ranges and the resistances described above. The resistance to maintain a comfortable flow rate of 10 liters per minute is approximately 0.3 (cm H20) 1 / SLM. In addition, the inspiratory volume of the aerosol administered at higher flow resistances decreases because inspiration becomes increasingly difficult and less comfortable, as resistance increases. In fact, if the resistance is decreased after the initial period of administration of the high-strength aerosol, the inspiratory volume will not significantly decrease over the administered volume over a constant administration range of low-flow resistance.

Example 2 Materials and Methods. Materials . Insulin of crystalline human zinc was obtained, 26. 3 U / mg from Eli Lilly and Company, Indianapolis, IN and it was discovered that it was > 99% pure measured by reverse phase HPLC. USP mannitol was obtained from Roquette Corporation (Gurnee, IL). The glycine was purchased from Sigma Chemical Company (St, Louis, Missouri). Sodium citrate dihydrate USP was obtained from J. T. Baker (Phillipsburg, NJ).

Powder Production Insulin powders are made by dissolving crystalline insulin in bulk, in sodium citrate regulators containing mannitol and glycine to produce a final solids concentration of 7.5 mg / ml and a pH of 6.7 ± 0.3. The spray dryer is operated with an inlet temperature between 110 ° C and 120 ° C and the liquid feed range of 5 ml / min, resulting in an outlet temperature between 70 ° C and 80 ° C. Subsequently, the solutions are filtered through a 0.22 μm filter and spray-dried in a Buchi spray dryer to form a fine amorphous white powder. The resulting powders are stored in hermetically sealed containers in a dry environment (<10% RH).

Analysis of Dust The particle size distribution is measured by centrifugal liquid sedimentation in a Horiba CAPA-700 particle size analyzer, after the dispersion of the powders in a Sedisperse A-ll (Micrometrics, Norcross, GA). The moisture content of the powders is measured by the Karl Fischer technique, using a Mitsubishi CA-06 moisture meter. The decrease in the size of the aerosol particles is measured using a cascade impactor (Graseby Andersen, S yrna, GA). The efficiency of the administered dose (DDE) is evaluated using Inhale Therapeutic Systems aerosol apparatuses, similar to those described in WO96 / 09085. The DDE is defined as the percentage of nominal dose contained within a bubble pack that came out of the buccal part of the aerosol apparatus and was captured in a fiberglass filter (Gelman, diameter of 47 mm) through which, it was produced a vacuum (30L / min) for 2.5 seconds after the activation of the device. The DDE is calculated by dividing the mass of dust collected in the filter between the mass of dust in the bubble pack. The integrity of the insulin before and after the powder processing is measured against a reference standard of human insulin by re-dissolving heavy portions of the powder in distilled water and comparing the dissolved solution again with the original solution placed in the dryer Dew. The retention time and peak area by rpHPLC are used to determine if the insulin molecule had been chemically modified or degraded in the process. The UV absorbance was used to determine the insulin concentration (at 278 nm) and the presence or absence of insoluble aggregates (at 400 nm). In addition, the pHs of the starting and reconstituted solutions were measured. The amorphous nature of the insulin powder is confirmed by means of a polarized light microscope.

Live tests. In order to examine the effect of changes in the range of inhalation on the bioavailability of inhaled insulin, 24 individuals were administered a dose of 2 mg of insulin, using the system illustrated in Figure 1. Each treatment will consist of two inhalations of 1 mg each. Inhalers are inhalers of Inhale Therapeutic Systems (San Carlos CA) as described in US Pat. No. 5,740,794, which is incorporated herein by reference. The treatments are: Administration by inhalation of insulin with a particle size of 3.6 μm MMAD (large PSD), using the standard breathing maneuver and the inhaler (without inclination). B. Administration by inhalation of insulin with a particle size of 3.6 μMADD (large PSD), with an inhalation range limited to approximately 10 liters per minute, by the system shown in Figure 1 (tilt). C. Inhalation administration of insulin with a particle size of 2.6 μMADM (small PSD) with an inhalation range limited to approximately 10 liters per minute, using the system shown in Figure 1 (tilt). Dry powder insulin formulations have average particle diameters less than 5 μ. The inhaler disperses the powders and produces aerosol clouds (bursts) of the drug, which are maintained in a volume of approximately 240 ml in a holding chamber. The volume of the holding chamber is a smaller fraction of a deep inspiratory breath (> 2 liters). The chamber is designed so that by inhaling the burst, the air is pulled into the chamber, thus pushing the aerosol out of the chamber and deep into the lungs.

Sufficient blood was collected to provide a minimum of 1 ml of plasma from 24 subjects in heparinized tubes, during the 30 and 15 minutes prior to insulin dosing and 0 (just before insulin dosing), 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes after the start of inhalation. The bioavailabilities of insulin for the samples taken in the 360 minutes are illustrated in Table 1 as uU.min / mL (microunits of insulin per milliliter of blood plasma). These figures show that an initial low flow range, followed by a higher flow rate, gave a higher bioavailability of insulin, than a constant higher flow rate (an average increase of 11% for the condition of case B). compared to case A). The combination of the initial low flow rate and the small particle size further increased the bioavailability (an average increase of 242% for case C compared to case B).

Table I AUC360 Proportion (uU.min / mL) AUC360 Subject Number 50180001 50180002 50180003 50180004 50180004 50180005 50180006 50180006 50180007 50180008 50180000 50180010 50180010 50180010 50180010 50180012 50180012 50180012 50180013 50180014 50180021 50180021 50180021 50180021 50180023 50180023 50180023 50180021 50180028 AVERAGE STD RSD The description of each publication, patent or patents mentioned in this description, is incorporated as a reference therein, to the same point, as if each individual patent publication or patent application were specifically and individually indicated to be incorporated as a reference.

Claims (20)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore it is claimed as property, what is contained in the following:
1. CLAIMS 1. An apparatus for administering an aerosolized active agent to the lungs of a human patient, said apparatus comprising a flow resistance modulator that modulates the flow resistance of the aerosolized active agent formulation to produce an initial flow range objective of the formulation of the aerosolized active agent in a manner that is independent of the monitoring of the flow range and the instruction of the patient.
2. 2. The apparatus according to claim 1, wherein the flow resistance modulator modulates the flow of the aerosolized active agent formulation over time.
3. 3. The apparatus according to claim 1, wherein the flow resistance modulator initially produces an initial target flow range of less than 15 liters per minute.
4. 4. The apparatus according to claim 3, wherein the target initial flow range is less than 10 liters per minute.
5. 5. The apparatus according to claim 1, wherein the target initial flow range is maintained for less than 10 seconds.
6. 6. The apparatus according to claim 1, wherein the aerosolized active agent formulation comprises a dry powder active agent formulation.
7. 7. The apparatus according to claim 1, wherein the aerosolized active agent formulation comprises an active agent administered in a bolus in nebulized form.
8. 8. The apparatus according to claim 1, wherein the aerosolized active agent formulation comprises an active agent mixed with a propellant.
9. 9. The apparatus according to claim 1, wherein the aerosolized agent formulation comprises a solution of the active agent.
10. 10. The apparatus according to claim 1, wherein the aerosolized active agent formulation comprises a suspension of the active agent.
11. 11. The apparatus according to claim 1, wherein the aerosolized active agent formulation comprises a paste of the active agent.
12. 12. The apparatus according to claim 1, wherein the apparatus is an apparatus operated by the patient.
13. 13. The apparatus according to claim 1, wherein the active agent is selected from a group consisting of insulin, cyclosporine, parathyroid hormone, follicle stimulating hormone, alpha-1 antitrypsin, budesonide, human growth hormone, hormone-releasing hormone Growth hormone, interferon alpha, interferon beta, colony growth stimulating factor, leutinizing hormone-releasing hormone, calcitonin, low molecular weight heparin, somatostatin, respiratory syncytial virus antibodies, erythropoietin, Factor VIII, Factor IX, cererase, cerezyme , and analogs, agonists and antagonists thereof.
14. 14. A method for administering an aerosolized active agent to the lungs of a human patient, said method comprising administering the aerosolized active agent formulation in a high flow resistance for an initial period of time.
15. 15. The method according to claim 13, wherein the high flow resistance is a resistance between 0.4 and 2 (cm H20) 1/2 / SLM.
16. 16. The method according to claim 13, wherein the low flow resistance is a resistance between 0 and 0.3 (cm H20) 1/2 / SLM.
17. 17. The method according to claim 13, wherein the high flow resistance corresponds to a flow rate of 15 liters per minute or less.
18. The method according to claim 13, wherein the low flow resistance corresponds to a flow range of 15 to 80 liters per minute.
19. 19. The method according to claim 13, wherein the initial time period is a period of less than 10 seconds.
20. 20. The method of claim 19, wherein the initial time period is a period of less than 5 seconds.