MXPA98008976A - Methods for inhalation of dusts se - Google Patents

Abstract

A method for inhaling a dry powder drug includes the steps of providing a dry powder drug composition having a drug particle size of about 1-7 microns and a mass mean aerodynamic diameter of the aerosol assortment around 3.5 to 5.5 microns, this composition is loaded into an inhaler that is generally independent of the flow rate, and the inhaler has an inspiratory flow resistance of 0.12 to 0.21 (cm H2O) 1/2 in the surrounding range from 15-60 L / min: the patient inhales the drug composition of the inhaler with an inspiratory flow rate of about 15-60 L / min, resulting in an assortment efficiency measured by respirable fraction greater than 2.

Description

METHODS FOR INHALATION OF DRY POWDERS DESCR PTIVA MEMORY Considerable information regarding the performance in vi tro and in vi o of metered dose inhalers and dry powder inhalers have been reported in the literature. In general, metered dose inhalers are independent of the flow rate of inhalation * but require significant coordination and therefore only about 20% of the nominal dose will be delivered to the lungs. Radiolabeled deposition studies of metered dose inhalers typically demonstrate the deposition of common 3-micron particles mainly in the more central air passages. Recent 3M Corporationr Minneapolisr MNr E.U.A. r has presented data indicating that if the particle size can be reduced to an average mass mean aerodynamic diameter < DMIA) of 1.5 icrasr can result in an increase in the total amount of particles and peripheral deposition. This result seems to confirm the more uniform belief that smaller particles are required to maximize peripheral deposition (ie, particles on the size scale of 2 microns). However in the case of dry powder inhalers * most studies have shown that the main problem around the dry powder assortment is related to the dependence of the flow velocity. The performance of dry powder inhalers now in use varies significantly with inhalation flow rates ranging from 15 to 120 li / min of inspiration effort. In general »at least 60 liters / minute of inspiration flow have been required to consistently disintegrate a dry powder sufficiently to produce particles that can be inhaled. For some products »inhalation flow rates are significantly greater than 60 liters / minute before sufficient disaggregation can occur. Both the total amount of formulation of the drug supplied to the patient and the aerodynamic size of the particle are affected by the increase in the inhalation flow rate. For example? at 30 liter / minute »the aerodynamic sizes of the active particles can be as large as from ß to 10 microns but above 60 liters / minutes the same formulation of metered dose inhaler can be from 2 to 4 microns . Even more »the variation from dose to dose can be significantly greater as the flow rate is reduced. Unfortunately »asking the patient to breathe forcefully when using a metered dose inhaler is in direct opposition to maximizing the deposit. Traditionally it is thought that 30 liters / minute is a well-controlled inhalation flow rate. And »data has now been presented showing that using the existing metered-dose inhaler technology» a significant and uniform peripheral particle reservoir »has been created at any flow velocity. Finally, it is now generally believed that for a protein to be efficiently supplied in a systematic way through the lungs, a very small particle size is required to facilitate peripheral deposition, preferably in the alveoli. The size often considered necessary for this purpose is in the interval of one miera. Using the dry powder inhalation system described in PCT / US93 / 09751 »published on April 28, 1994» and incorporated by reference (referred to herein as the system SPIROS) »have the following observations been made in vitro and i vivo? 1. The in vitro assortment of various drug / lactose mixtures has been shown to be independent of the flow rate on a flow scale of 15 to 60 liters / minute. Both the size of the active particles and the quantity of drug assortment were independent of the flow velocity. 2. Using a radionuclide technique, it was confirmed that the in vitro assortment system is independent of the flow rate in vivo (15 to 60 liters / minute). In addition »this study clearly indicated that even with a low inhalation speed (less than 60 liters / minute)» the drug was uniformly delivered through the lung »including the periphery. In fact »there is a tendency to have a high peripheral deposit of the lung at a low flow rate.

In the studies on metered dose inhaler "where the DMMA determined in vitro is between 2 and 3 microns» the in vivo deposition is typically referred to as a value between 10 to 20% of the nominal dose. The albuterol deposition of the Spirss system was shown to be equal to or better than what was expected from the metered dose inhalers »even though the aerodynamic particle size of the active particle was approximately 4.5 microns. 4. Recent pharmacokinetic (blood level) data from a comparison of beta-ethasone assorted from a metered-dose inhaler compared to Spiros »indicated that twice the same amount of drug was delivered to the lung from the Spiros system. Again, the particle size of the active particle in the dry powder inhaler system was between 4 and 5 microns »while the formulation of the metered dose inhaler was between 3 and 4 microns. 5. Using calcium chloride as a model peptide for the systematic assortment it has been estimated that the bioactivity that follows the dose with the Spiros system is greater than 20% compared to a subcutaneous injection. On the contrary »an approved nasal product has only 3% bioavailability. Surprisingly, "the particle size of caleitonin in the calci tonina / lactose mixture was 4 to 5 microns", however, an excellent systemic availability O207 was achieved.). Using the above observations, the following conclusions can now be made in relation to the assortment of dry powder. Until a dry powder inhaler was developed that adequately disaggregated the powder at insipirate or low flow rates it was not possible to separate the performance of the dry powder inhaler from the patient's handling of inhalation. Thus »the relationship between the particle size and the deposition of the same was confused with the performance of the dry powder inhaler miemo. With the development of the Spiros system it has now been shown that under conditions of low flow velocities the particle sizes that would be considered at the upper end of achieving good deposition in the lung can actually provide uniform deposition through the respiratory tract. . Importantly »the assortment of dry powder from the Spiros system has no longer been degraded by the speed of inhalation by the patient» as is the case with existing dry powder inhalers. A slow deep inspiration is key to the increase of the drug assortment and its peripheral deposition. Thus »the assortment system must operate efficiently under these conditions. With the deagglomeration of the dry powder at a low inhalation flow surprisingly good results were obtained on what could be expected for commercially available metered dose inhalers or dry powder inhalers. The results that were obtained in vivo were possible because 1) Spiros ee independent of the inhalation flow velocity "and 2) Spiros efficiently disbuds the powder. Therefore »the patients were able to be trained and benefit from the maneuver of slow and deep inhalation. The slow and deep inhalation allows more particles to pass through the throat (and not be deposited by impaction) and are available to be deposited in the lung. Secondly, the deep and slow inhalation maneuver dilates the lungs completely, "driving the particles further into the lung" and inhibits the premature impaction of the larger particles in the upper air passages. To facilitate slow inhalation, some resistance of the device is required. If resistance is not found »then it is difficult for a patient to inhale slowly. This is what is often observed for metered dose inhalers and some dry powder inhalers such as Rotohaler and Spinhaler. If the flow resistance is too high, the result is the discomfort of the patient when the Inhaler is used at an optional flow rate. A higher air velocity in the ducts and passages can also be obtained as a result. The increase in speed increases the deposition by impaction in the upper air passages. Less deposited drug is then available in the lower regions of the lung. The drug can be a systemic or topical drug for the treatment of asthma. The drug can be a protein »a polypeptide or a hormone» for the treatment of the lungs or other conditions. i.- A dry powder inhalation system consists of a micronized drug in the range of 1 to 7 microns »alone or in mixtures of lactose or some other suitable inert carrier (for example "sugars" salts). 2.- The inhalation system must be independent of the flow velocity over the range of interest »that is» from 10 to 15-60 L / min. 3.- Average mass aerodynamic diameter (DMMA) of the spray assortment (waterfall impact 26.3 L / min) for throat UPS) should be 3.5 - 7 preferably 3 - 6 microns.

In addition, the respirable fraction (fraction of particles that penetrate the entrance of the impactor with a particle size smaller than 5.8 microns) must be greater than 20%. The most preferred level could be greater than 30 to 40%. This describes the efficiency of the device to deagglomerate the powder. Such a co-rotating device (Ratohaler) of beta-etasone that could be considered independent of the flow velocity in this scale gives an aerosol of 10 microns and a respirable fraction of 2.6%. The resistance of the device (slope of the flow curve against pressure drop (in units of (cm H ^ 0 'must be 0.12 to 0.21 with the most preferred scale of 0.12 to

Claims (11)

NOVELTY OF THE INVENTION R IVINDIATIONS

1. - An inhaler system for inhaling a dry powder drug composition »comprising? a dry powder drug composition having a drug particle size of about 1 to 7 microns and an average aerodynamic diameter of the aerosol assortment of about 3 to 6 microns »an inhaler that is loaded with the powder composition dry which is generally independent of the speed "and with the inhaler having an inspiratory flow resistance of around 0.12 to 0.21 (cmHz0 ^) in the range of about 10 to 60 L / min; characterized in that the drug composition of the inhaler is inhaled with an inspiratory flow rate of about 15 to 60 L / min. resulting in an assortment efficiency measured by respirable fraction of at least 20%.

2. The inhaler system according to claim 1 »further characterized in that the drug composition includes active particles and the aerodynamic particle size of the active particles is about 4.5 microns.

3. The inhaler seventh according to claim 1 »further characterized in that the drug comprises a topical or systemic drug for the treatment of asm.

4. The inhaler system according to claim 1 »further characterized in that the drug comprises a protein» a polypeptide or a hormone.

5. The inhaler system according to claim 1, characterized in that the percentage of the particles greater than 5 microns ee is around 30 to 90%.

6. The inhaler system according to claim 1 »further characterized in that the inhaler has a flow resistance of about 0.12 to .018 (cm H20) -i.

7. The inhaler system according to claim 1 »further characterized in that the composition of the drug includes an inert carrier.

8. The inhaler system according to claim 1 »further characterized in that the drug comprises beclametaeone.

9. The inhaler system according to claim 1 »further characterized in that the respirable fraction (fraction of the particles are introduced by the entrance of the impactor with the particle size smaller than about 5.8 microns) is at least 20 %.

10. The inhaler system according to claim 1 »further characterized in that the flow resistance is around 0.12 to 0.21 (cm H20) -l in the range of 15-60 L / min.

11. - The inhaler system according to claim 1 »further characterized in that the average aerodynamic diameter of the mass of the aerosol assortment is around 3.5 to 5.5.