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Dry powder formulationsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Effervescent Or Pressurized Fluid Containing, Organic Pressurized Fluid, Powder Or Dust ContainingDry powder formulations description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070071690, Dry powder formulations. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention is concerned with dry powder formulations for use in dry powder inhalers. [0002] Dry Powder inhalers (DPIs) represent an alternative to Metered Dose Inhalers (MDIs) for the administration of medicaments to the lung. [0003] Active substances for use in dry powders for inhalation must be provided in the form of very fine particles in order that they can penetrate deep within the lung. Indeed, if the lung is to be used to administer drug substances systemically, the active substance must be sufficiently fine that it penetrates into the alveolar ducts and sacs whereupon it can be most efficiently absorbed into the blood. [0004] However, fine particulates can present major formulation difficulties. For example such particulates possess strong adhesive and cohesive properties that can cause the active particles to aggregate and can lead to poor bulk properties of the powder such as poor flowability. [0005] The mechanical properties of dry powders can be improved by mixing the fine particles of active substance with relatively coarser particles of an inert carrier material. The ordered mixture of carrier and active enables the dry powder to be handled more easily during manufacture and during filling of the powder into DPI devices. Additionally, the active substance is maintained in a relatively dispersed state on the surface of the carrier particles. However, the adhesive force between carrier and active must not be so great that upon actuation of the DPI the efficient and reproducible re-dispersion of the active into fine dispersible particles is prevented. [0006] A common approach used by formulators to achieve an appropriate balance between the competing forces of adhesion and re-dispersion is to treat the carrier with a ternary component in order to cover or coat the carrier particles and thereby modulate the adhesive force between the active particles and the carrier surface. [0007] Numerous ternary components have been suggested in the art. There are still further suggestions in the prior art as to the amount of ternary component that should be employed, and the extent to which the ternary component must coat or cover the carrier surface in order to achieve an appropriate compromise between adhesion and re-dispersion such that active particles are not liable to prematurely segregate from the carrier surface (e.g. during storage and handling), but are readily released upon actuation initiated and driven in passive dry powder inhalers by a patient's inspiration. [0008] U.S. Pat. No. 6,521,260 describes the use of ternary components in dry powder formulations containing active and carrier. The nature and amount of ternary component is selected in order to alter the surface properties of the carrier with the purpose of promoting release of active particles upon actuation of an inhaler. However, the amount of ternary component must not be so great such that active and carrier particles prematurely segregate during storage. [0009] This reference mentions that surface active materials may be employed as ternary components. In this regard magnesium stearate may be used but it is stated clearly that it is not preferred. This reference does not state how much magnesium stearate should be employed to achieve the purpose of promoting release of the active upon actuation. We are told only that 1.5% by weight of magnesium stearate is too much as it promotes premature segregation. The only other comment relating to the use of magnesium stearate is that it is highly surface active and should be used only in "particularly small amounts". By contrast, phosphatidyl cholines, being less surface active than magnesium stearate can be used in higher quantities. Conspicuously, this reference exemplifies a formulation employing lecithin (a natural mixture of phosphatidyl cholines) in an amount of 0.5% by weight. [0010] Insofar as the skilled person would be motivated to use magnesium stearate despite the clear prejudice towards its use, it would be employed in only a "particularly small amount" relative to the 0.5% by weight suggested for lecithin and other less surface active materials [0011] Indeed in a paper (J. Pharm. Pharmacol. 1982, 34: 141-145, a named inventor on U.S. Pat. No. 6,521,260 teaches that magnesium stearate can affect the adhesion of active substances to carrier particles, and that its use in amounts of 0.5% to 4.0% by weight de-stabilises formulations to the extent that significant segregation occurs. [0012] The benefits of using magnesium stearate in dry powders is taught in U.S. Pat. No. 6,528,096. Specifically it teaches that it can be used to alter the surface properties of carrier particles and thereby improve the properties of dry powder formulations. However, the skilled person is informed that it should be used in amounts of less than 0.5% by weight, and no significant improvement in the fine particle fraction of a delivered dose is achieved with concentrations above 0.25% by weight. Additionally, this reference reports an "advantageous relationship" between the degree of carrier surface coating by magnesium stearate and the respirable fraction of a delivered dose. Critical to the working of this invention is the need to ensure a continuous coating of magnesium stearate over more than 10% of the surface of the carrier particles. The requisite coating can be achieved by conventional blending of carrier and magnesium stearate, or alternatively higher shear mixing techniques can be employed. High shear mixing can achieve the requisite coating within about 0.5 hours, however; the skilled person is clearly taught that if conventional blending is to be employed the blending time must be in excess of 2 hours. [0013] In The Journal of Aerosol Medicine Vol 11, No. 3, 1998 at 143-152, an inventor of U.S. Pat. No. 6,528,096 teaches that pre-treatment of lactose particles with 0.25% magnesium stearate significantly improves the disaggregation of beclamethasone dipropionate without causing segregation during filling, transport or use. [0014] It is clear from the prior art that any beneficial properties that derive from the use of magnesium stearate are predicated on its apparent ability to alter the surface properties of carrier particles. In this regard, the skilled person is taught that in order to advantageously influence the fine particle fraction of a delivered dose, as high a surface coating should be obtained with as little magnesium stearate as possible. [0015] Certain mixing techniques are taught for achieving this result, which involve either high energy mixing, or long duration low energy mixing. Other suggestions involve combining low energy blending coupled with carrier treatment steps involving high energy milling or mixing. [0016] The problem with the suggestions made in the prior art is that no consideration is given to the nature of the active substance employed, and the constraints that the physical and chemical properties can impose on the amounts of magnesium stearate that can be used in practice. For example, it is known that dry powders are sensitive to atmospheric humidity, and are difficult to use for that reason in multi-dose dry powder inhaler devices. It is also known that many active substances can be hygroscopic and can exacerbate the moisture sensitivity of dry powders. Dry powders for inhalation should be excluded from humid conditions to the greatest extent possible. Moisture sensitivity is often manifested in a dramatic reduction of the inhalable proportion of an emitted dose (the so-called "fine particle fraction"), which can be determined according to in-vitro measurements described below. Moisture can also influence adversely the accuracy and reproducibility of shot weight and emitted dose content uniformity. [0017] The use of magnesium stearate to improve the moisture resistance of dry powders is described in WO 00/28979. [0018] It is not only the hygroscopic nature of certain active substances that can have a destabilsing effect on dry powders. The amount of active substance that needs to be delivered in a single inhalation by from a DPI device is dictated by the medical condition that is intended to be treated, and in certain situations the drug loading can be quite high. This can also adversely affect the mechanical properties of dry powders, e.g. flowability, absent the use of sufficient magnesium stearate, e.g. for lubricating purposes. [0019] Accordingly, whereas the prior art teaches the skilled person that only small amounts, i.e. less than 0.5% magnesium stearate can be tolerated in dry powder formulations, this is generally an unacceptably low amount taking into consideration the demands imposed by the quantity and properties of the active substance employed. [0020] Applicant has surprisingly found that the effect of surface coverage of magnesium stearate on the performance of dry powders appears to be minor compared to the moisture protection and lubricating properties of this substance, in terms of the uniformity of the delivered dose and the fine particle fraction of the delivered dose. Accordingly, provided one ensures that during the preparation a dry powder for inhalation the surface coverage of the carrier particles by magnesium stearate is kept low, one can employ relatively large amounts of magnesium stearate and yet obtain reproducibly high fine particle fraction, even after prolonged periods of storage, and through life of a device. [0021] Accordingly, in a first aspect the invention provides a dry powder for inhalation comprising active particles and carrier particles for supporting active particles, the formulation further containing magnesium stearate in an amount of at least 0.5% by weight of the formulation, and wherein particles of magnesium stearate are disposed on the surface of the carrier particles such that the surface coverage of carrier particles is less than 10%. [0022] The amount of magnesium stearate employed should be at least 0.5% by weight. The upper limit depends on the toxicological acceptability of large amounts of magnesium stearate delivered to the lungs. A level of up to 2.0% is preferred. Within these limits, the amount of magnesium stearate employed will depend on the nature of the active substance, and the amount to be employed. The skilled person will have regard the physical and chemical properties of the active substance and be able to select an appropriate amount without undue burden or without having to resort to inventive activity. [0023] In a particular embodiment the magnesium stearate may be employed in an amount of 0.5 to 2.0% by weight, more particularly 0.5 to 1.5% by weight, still more particularly 0.5 to 1.0% by weight, even more particularly 0.6 to 1.0% by weight. [0024] The extent to which the magnesium stearate covers the surface of the carrier particles can be determined from scanning electron microscope (SEM) images. Scanning electron microscopy is one of the most versatile analytical techniques and it is well known in the art. Compared to conventional optical microscopes, an electron microscope offers advantages including high magnification, large depth of focus, great resolution and ease of sample preparation and observation. Electrons generated from an electron gun enter a surface of a sample and generate many low energy secondary electrons. The intensity of these secondary electrons is governed by the surface topography of the sample. An image of the sample surface is therefore constructed by measuring secondary electron intensity as a function of the position of the scanning primary electron beam. Continue reading about Dry powder formulations... 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