Title of Invention	PHARMACEUTICAL COMPOSITION FOR ADMINISTRATION BY NHALATION
Abstract	A pharmaceutical composition, characterized in that an active substance such as herein described or active substance blend with a mean particle size of 0.1 µm to 10 µm is blended with a physiologically acceptable carrier such as herein described or carrier blend with a mean particle size of between 200 µm and 1000 µm.

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The present invention relates to a pharmaceutical composition for administration by inhalation, the micronized active substance or the micronized active substance blend being applied to a carrier without the use of binders. To exhibit a topical or systemic effect, active substances which are administered by inhalation must penetrate deep into the lung. To achieve this, the diameter of the active substance particles must not exceed about 5 µm - 10 µm. In addition, the active substance or active substance blend is administered to the patient with the aid of a special device called an inhaler. Here the active substance must initially be either made up into doses beforehand, for example in capsules or blisters, or stored in sizeable amounts in the inhaler so that it can then be withdrawn from a measuring device by the patient's inspiration process and redispersed with a dispersing device, for example a swirl chamber, into the fine primary particles, entrained with the inspiration and thereby made accessible to the lung. Because of the particle size, the very finely particulate active substances used for this purpose have a high specific surface area and a very pronounced adhesive and cohesive properties, which in turn results in the fact that the technological processing of such powders runs into difficulties. Such technological steps are the blending of the active substances where active substance blends are involved, the storage and transport of the powders, the filling of capsules, blisters or inhalers and the dosing of the therapeutic amounts. 2 The agglomeration processes conventionally used in pharmacy, e.g. granulation, cannot be used because this binds the particles together so strongly that active substance particles accessible to the lung are no longer present or can no longer be generated. Moreover, the majority of excipients commonly used in pharmacy cannot be used at the present time in pharmaceutical forms for inhalation because the toxicological behaviour of these excipients when administexed to the lung is still largely unknown. To solve the abovementioned problems, it was proposed, for example in EP 0 398 631, to grind the active substance to a mean particle diameter of 5 µm to 10 µm and then either to blend it with a solid carrier conventional pharmaceutically acceptable, said carrier having a mean particle diameter of 30 µm to 80 µm, or else to prepare round agglomerates of the active substance particles (so-called soft pellets), the latter disintegrating into the primary particles again during inhalation. A process for the preparation of such soft pellets is also described (GB 1,569,612 and GB 1,520,247). It is necessary here to adjust the moisture content of the active substance prior the preparation of the soft pellets. The soft pellets can be filled into capsules, for example as described in DE 25 35 258 and GB 1,520,247. in vitro tests showed that when these capsules were discharged with the aid of an inhaler, at least 50% of the material introduced was discharged. 94 146 PH 3 However, these soft pellets prepared according to the instructions given above still have an unsatisfactory dispersion rate (= proportion of active substance particles accessible to the lung after discharge, based on the amount filled into the capsule). With a volumetric flow rate of 60 1/min, dispersion rates of 13.8-29.5% of the nominal dose were found for commercially available systems in the four-stage liquid impinger. In another process (DE 22 29 931), the active substance is blended with a pharmaceutically applicable, water-soluble carrier, said carrier having a particle size of 80 µm to 150 - µm. The poor flow properties of the pharmaceutical composition are a disadvantage here. DE 41 40 689 describes inhalation powders consisting of a physiologically acceptable excipient with a mean particle size of about 2 0 µm and a second component excipient with smaller particles having a size of about 10 µm. This blend can be filled into capsules and is inhaled with the aid of devices described in DE 33 45 72,2. Here too the poor flow properties are a disadvantage. EP 258 356 describes microparticles for inhalation purposes which consist of a agglomerate' of excipients, for example lactose, xylitO'l and mannitol, with a size of between 30 µm and 150 µm. The problem with this process is the relatively complex step for preparing the excipient agglomerates with a specific particle size x 94 146 PH 4 The object is thus to develop, a powder for inhalation purposes which is easy to prepare, does not require expensive in-process controls of the moisture content of thn% active substances and/or the excipients, and exhibits a high degree of redispersion. The pharmaceutical composition should also have satisfactory flow properties and be easily capable of disintegrating in the inhaler to give particles accessible to the lung. Under the same conditions, at least 40% should be redispersed. It has now been found, surprisingly, that by appropriate blending of the active substance or active substance blend with a pharmaceutically applicable carrier having a mean particle size of 200 µm to- 1000 µm, preferably of between 300 µm and 600 \µm, the active substance particles having a size of 0.01 µm to 10 µm adhere to the carrier particles, thereby forming almost round carrier particles coated with active substance. The pharmaceutical composition according to the invention makes it possible to dispense with the conditioning, for example additional purification processes, of the carrier used. The carrier particles are commercially available or can be obtained by fractionation (screening) in a specific particle size or particle size range. The size of the carrier particles was determined by the measurement of scanning electron micrographs and/or by screen analysis. The size of the active substance particles was determined by scanning electron microscopy and/or by laser diffraction spectrometry . 94 146 PH 5 This powder pharmaceutical composition is easy and economic to prepare and possesses appreciably better flow properties than either the untreated active substance powder or the soft pellets. This is shown by the results in Table 1. A lower bulk height signifies better flow properties of the pharmaceutical composition. The more similar the bulk volume and tapped volume, the better the flow properties are. However, the discharge and subsequent redispersion is also better than that of the pharmaceutical compositions known hitherto (blends, soft pellets according to GB 1 569 612 or GB 1 520 247, or untreated active substance powder), i.e. there are less residues in the inhaler and there is a greater yield of particles accessible to the lung. The pharmaceutical composition can contain a variety of active substances, for example analgesics, antiallergics, antibiotics, anticholinergics, antihistamines, antiinflammatory substances, antipyretics, corticoids, steroids, antitussives, bronchodilators, diuretics, enzymes, cardiovascular substances, hormones, proteins and peptides. Examples of analgesics are codeine, diambrphine, dihydromorphine, ergotamine, fent'anyl and morphine; examples of antiallergics are cromoglycic acid and nedocromil; examples of antibiotics are cephalosporins, fusafungin, neomycin penicillins, pentamidine, streptomycin, sulphonamides and tetracyclines; examples of anticholinergics are atropine, atropine methonitrate, ipratropium bromide, oxytropium bromide and trospium chloride; examples of antihistamines are azelastin, flezelastin and methapyrilene; examples of antiinflammatory substances are beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, tipredanes and triamcinolone; examples of antitussives are narcotine and 94 146 PH 6 noscapine; examples of bronchodilators are bambuterol, bitolterol, carbuterol, clenbuterol, ephedrine, epinephrine, formoterol, fenoterol, hexoprenaline, ibuterol / isoprenaline, isoproterenol, metaproterenol, orciprenaline, phenylephrine, phenylpropanolamine, pirbuterol, procaterol, reproterol, rimiterol, salbutamol, salmeterol, sulfonterol, terbutaline and tolobuterol; examples of diuretics are amiloride and furosemide; an example of enzymes is trypsin; examples of cardiovascular substances are diltiazem and nitroglycerol; examples of hormones are cortisone, hydrocortisone and prednisolone; examples of proteins and peptides are cyclosporins n cetrorelix,) glucagon and insulin. Other active substances which can be used are adrenochrome, colchicin, heparin and scopolamine. The active substances cited as examples can be used as free bases or acids or as pharma-ceutically compatible salts. Examples of counterions which can be used are physiologically compatible alkaline earth or alkali metals or amines, as well as, for example, acetate, benzenesulphonate, benzoate, hydrogencarbonate, hydrogen-tartrate, bromide, chloride, iodide, carbonate, citrate, fumarate, malate, maleate, gluconate, lactate, pamoate and sulphate. It is also possible to use esters, for example acetate, acetonide, propionate, dipropionate and valerate. The pharmaceutical composition according to the invention can also consist of a blend of several finely ground active substances, for example sodium cromoglycate and reproterol hydrochloride. As already described,' 100% of the active substance particles should-be smaller than 10 µm\ and preferably in the range 1 um to 5 µm. 94 146 PH 7 The carrier used is a non-toxic material having a mean particle size of 200 µm to 1000 µm and preferably of between 300 µm and 600 µm. Carriers according to the invention can be inorganic salts such as sodium chloride and calcium carbonate, organic salts such as, for example, sodium lactate, and organic compounds such as, for example, urea, monosaccharides such as, for example, glucose and derivatives thereof such as sorbitol polyacohols, mannitol and xylitol, disaccharides such as, for example, lactose, maltose and derivatives thereof, polysaccharides such as, for example, starch and derivatives thereof, and oligosaccharides such as, for example, cyclodextrins and dextrins. It is also possible to use blends of the excipients. The proportion of active substance to'carrier depends on the substances used. It has been found by means of the Examples that the use of 5 to 80 percent by weignt of active substance to 20 to 95 percent by weight of carrier, preferably 30 to 70 percent by weight of active substance to 3 0 to 7 0 percent by weight of carrier, gives satisfactory results. In addition to the active substance and the carrier, the pharmaceutical compositions can also contain other ingredients such as flavouring agents, for example saccharin or peppermint flavour. The ingredients can represent for example 10-20% by weight based on the active substance or active substance blend. 94 146 PH 8 The pharmaceutical composition is prepared by blending the constituents in a suitable blender, for example an tumbling blender, a rotary blender, a high-speed blender or a fluidizing blender. A possible tumbling blender is for example the Turbula blender, W.A. Bachofen AG, Basel, CH; a possible high-speed blender is the Diosna blender, Dierks und Sonne, Osnabruck, FRG. The constituents are placed in the blender and blended until the carrier crystals are coated with the fine active substance or active substance blend, the fines gradually disappearing to form round coated particles. However, it is also possible to use other processes, such as fluidized bed or vibratory processes, to prepare the powder pharmaceutical compositions according to the invention. In these processes, the carrier particles are set in rotational motion in a' container, enabling the active substance particles to deposit thereon and thus produce the pharmaceutical composition according to the invention. To demonstrate the advantages of the pharmaceutical composition according to the invention compared with the blend of the two active substances and the soft pellets according to publications GB 1,569,612 and GB 1,520,247, these pharmaceutical compositions were prepared and some physical parameters determined. The blend of the two active substances was prepared with the aid of an tumbling blender (Turbula blender; W.A. Bachofen AG, Basel). The soft pellets were prepared by placing the fine ground active substances in the bottom vessel of a sieving tower for particle size analysis (Retsch, FRG) and subjecting 94 146 PH 9 the vessel to vibrations until round active substance agglomerates had formed. The following Tables show some comparative measurement results. Experiment 1 Active substance blend: Two parts by weight of disodium cromoglycate and one part by weight of reproterol hydrochloride . Core Blend Soft pellets agglomerates Bulk volume 2.2 7.2 3.8 (ml/g) Tapped volume 2 5 3 (20 x) (ml/g) Hausner ratio 1.10 1.44 1.27 Bulk height (mm) 35 29 24 __________ __ ___ _ at 60 1/min volumetric flow rate ______________ __ _ __ at 30 1/min volumetric flow rate The soft pellets were obtained according to the instructions in GB 1,569,612 and GB 1,520,247. 94 146 PH 10 Experiment 2 Active substance blend: Three parts by weight of disodium cromoglycate and two parts by weight of reproterol hydrochloride. Core Blend Soft pellets agglomerates Bulk volume 2 7.2 3.8 (ml/g) Tapped volume 1.9 5 3 (20 x) (ml/g) __________ ___ 1.44 1.27 Bulk height 23 35 29 (mm) Flow angle (°) 48 59 54 The bulk and tapped volumes were determined by known methods: 100 g of pharmaceutical composition were carefully charged into a measuring cylinder. The volume read off represented the bulk volume. The filled measuring cylinder was placed on a tapped 'volume meter. The contents were tapped 20 times. The volume read off represented the tapped volume (see also Voigt R., Lehrbuch der pharmazeutischen Technologie {Textbook of Pharmaceutical Technology), Verlag Chemie, 5th edition, page 148). The Hausner ratio is the ratio of bulk volume to tapped 94 146 PH 11 The bulk height was determined with the aid of a cylinder of diameter 42 mm, which was filled up slowly with powder until a bed of maximum height was formed, this height being measured. The redispersion was determined with the aid of an inhaler and a four-stage liquid impinger by determining the percentage proportions, based on the sample weight, which had deposited on the second to fourth stages. This experiment was carried out with two different volumetric flow rates. 94 146 PH 12 Example 1 266.8 g of micronized disodium cromoglycate and 133.2 g of micronized reproterol hydrochloride were passed through a screen of mesh size 0.125 mm and then placed in a Diosna blender (PWC Dierks und Sonne, Osnabruck, FRG). 600.0 g of commercially available lactose with the particle size distribution 100% 3 0 min. The resulting core agglomerates had a good flowability and can be filled into an inhaler. The properties of these core agglomerates can be taken from Experiment 1 (page 9). Example 2 3000 g of micronized disodium cromoglycate and 200.0 g of micronized reproterol hydrochloride were passed through a screen of mesh size 0.125 mm and then placed in an tumbling blender (Turbula blender; W.A. Bachofen AG, Basel). 500.0 g of commercially available lactose with the particle size distribution 100% then blended for 3 0 min. The resulting core agglomerates had a good flowability and can be filled into an inhaler. The properties of these core agglomerates can be taken from Experiment 2 {page 10). Example 3 266.8 g of micronized disodium cromoglycate and 133.2 g of micronized reproterol hydrochloride were passed through a 0.125 mm screen and then placed in a fluidizing blender (Fukae 94 146 PH 13 Powtec Corporation, Japan). 600.0 g of commercially available sodium chloride with a mean particle size of 300 µm were added. The ingredients were then blended for 10 min. The resulting core agglomerates had a good flowability and can be filled into an inhaler. Example 4 30 g of micronized budesonide were passed through a 0.125 mm screen and then placed in an tumbling blender (Turbula blender; W.A. Bachofen AG, Basel). 270 g of commercially available lactose with the particle size distribution 100% Example 5 100 g of micronized salbutamol were passed through a 0.125 mm screen and then placed in an tumbling blender (Turbula blender; W.A. Bachofen AG, Basel). 300 g of commercially available lactose with the particle size distribution 100% 14 Example 6 20 g of micronized beclomethasone 17,21-dipropionate were passed through a 0.125 µm screen and then placed in an tumbling blender (Turbula blender; W.A. Bachofen AG, Basel). 380 g of commercially available lactose with the particle size distribution 100% then blended for 45 min. The resulting core agglomerates have a good flowability and can be filled into an inhaler, a dispenser or blisters. Example 7 20 g of micronized ipratropium bromide were passed through a 0.125 mm screen and then placed in an tumbling blender (Turbula blender; W.A. Bachofen AG, Basel). 380 g of commercially available lactose with the particle size distribution 100% 45 min. The resulting core agglomerates had a good flowability and can be filled into an inhaler, a dispenser or blisters. 15 We Claim: 1. A pharmaceutical composition, characterized in that an active substance such as herein described or active substance blend with a mean particle size of 0.1 µm to 10 µm is blended with a physiologically acceptable carrier such as herein described or carrier blend with a mean particle size of between 200 µm and 1000 µm. 2. A pharmaceutical composition, wherein an active substance or active substance blend with a mean particle size of 1 urn to 5 µm is blended with a physiologically acceptable carrier or carrier blend with a mean particle size of 300 um to600µm. 3. A process for the preparation of a pharmaceutical composition for the preparation of inhaled drugs, wherein an active substance or active substance blend with a mean particle size of 0.1 µm to 10 µm is blended with a physiologically acceptable carrier or carrier blend with a mean particle size of between 200 um and 1000 µm. 4. A process for the preparation of a pharmaceutical composition for the preparation of drugs as claimed in claim 1, wherein an active substance or active substance blend with a mean particle size of 1 µm to 5 um is blended with a physiologically acceptable carrier or carrier blend with a mean particle size of 300 um to 600 µm. 16 5. A process for the preparation of a pharmaceutical composition for the preparation of drugs as claimed in claims 3 or 4, wherein the carrier particles are coated with the active substance particles. 6. A pharmaceutical composition as claimed in one of claims 1 to 5, wherein a blend of reproterol and disodium cromoglycate is used as the active substance blend. 7. A pharmaceutical composition as claimed in one of claims 1 to 6, wherein budesonide is used as the active substance. 8. A pharmaceutical composition as claimed in one of claims 1 to 7, wherein salbutamol or a physiologically acceptable salt of salbutamol is used as the active substance. 9. A pharmaceutical composition as claimed in one of claims 1 to 8, wherein cetroreiix or a physiologically acceptable salt of cetrorelix is used as the active substance. 10. A pharmaceutical composition as claimed in one of claims 1 to 9, wherein beclom eth asone or an ester of beclomethasone is used as the active substance. 17 11. A pharmaceutical composition as ciaimed in one of claims 1 to 10, wherein ipratropium bromide is used as the active substance. A pharmaceutical composition, characterized in that an active substance such as herein described or active substance blend with a mean particle size of 0.1 µm to 10 µm is blended with a physiologically acceptable carrier such as herein described or carrier blend with a mean particle size of between 200 µm and 1000 µm.

Documents:

00800-cal-1995-abstract.pdf

00800-cal-1995-claims.pdf

00800-cal-1995-correspondence.pdf

00800-cal-1995-description(complete).pdf

00800-cal-1995-form-1.pdf

00800-cal-1995-form-18.pdf

00800-cal-1995-form-2.pdf

00800-cal-1995-form-3.pdf

00800-cal-1995-form-5.pdf

00800-cal-1995-g.p.a.pdf

00800-cal-1995-letters patent.pdf

00800-cal-1995-p.a.pdf

00800-cal-1995-priority document others.pdf

00800-cal-1995-priority document.pdf