Pharmaceutical composition for inhalation (options) and how you can get

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to a pharmaceutical composition for use in powder inhalers. The invention consists in that the composition consists of the carrier, the particles of which are covered drug or mixture of drugs. The composition is easily redispersible and breaks up into particles that can penetrate into the lungs of the patient. The composition may be used for the preparation of drugs and a method of its receipt. The invention provides for obtaining oldservername the amount of the mixture to enter into the lungs of the patient. 3 S. and 12 C.p. f-crystals, 2 tab.

The invention relates to the manufacture of pharmaceutical compositions for inhalation using fine biologically active substances or fine mixture of biologically active substances on the media without a binder material.

Biologically active substances used for inhalation, penetrating deep into the lungs and to provide General or local action. To achieve this effect it is necessary that the diameter of the particles of biologically active ve is a specially manufactured device, the so-called nebulizer. It is necessary to pre-attirbute active substance, for example, in the form of capsules or blisters, or put more into the inhaler, and then with the breath of the patient to direct the active substance into the metering device and into the dispersing device, for example, in truevue chamber, which is redispersible mixture. Thus, the obtained oldservername the amount of the mixture is absorbed into the lungs of the patient.

In most cases, a fine of biologically active substances used for inhalation, are characterized by high specific surface of the particles, which leads to the resulting distribution of forces of interaction and in turn increase the adhesion and cohesion of the particles. This raises the need for re-grinding of such powders and, accordingly, the problem of development of technical processing. The processing methods include mixing the biologically active substances, storage and transportation of the obtained powder, the filling capsules, blisters or inhalers, as well as therapeutic dosage amounts.

Conventional agglomeration in the pharmaceutical industry, for example, granulirovanie particles with each other, what this leads to a significant reduction in the number of particles of biologically active substances that can penetrate into the lungs. In addition, currently it is prohibited to employ a large number of excipients for inhalation, as the toxic properties of these substances when introduced into the lungs is not yet known.

To solve the above problems, for example, in European patent EP 0398631 described a method of obtaining a mixture for inhalation by grinding biologically active substances to particles with an average diameter of 5 µm and 10 µm, followed by processing in one of two ways: by mixing with a solid, conventional pharmaceutical carriers, and the average diameter of the obtained particles is 30 to 80 μm or manufacturer of spherical agglomerates of particles of biologically active substances (so-called soft pills), the latter inhalation again break down into primary particles. The method of obtaining soft pills are also described in patents great Britain GB 1,569,612 and GB 1,520,247. However, when receiving soft pills, you need to adjust the amount of moisture in the biologically active substance. In patents DE Germany 25 35 258 and GB 1,520,247 described method of capsule filling, soft pills. The experts 50% of the biologically active substance, contained in the capsule.

However, the percentage of dispersion (the number of particles of the active substance can penetrate into the lungs after emptying capsules with soft pills, divided by the total number of particles present in the capsules before emptying) soft pills, obtained according to the above methods is not high enough.

When using commercial cascading impinger (four stage liquid impinger) at a flow rate of 60 l/min percent dispersion 13.8 - 29.5% of the nominal dose.

Another known method (DE 22 29 981) consists of mixing a bioactive substance with a water-soluble media, pharmaceuticals, and the size of the carrier is from 80 to 150 μm. The disadvantage of this method is poor fluidity of the compositions.

In the German patent DE 41 40 689 described inhalation powder, which consists of a physiologically compatible excipient with an average particle size of approximately 20 μm and the second component with particles of smaller size about 10 microns. With this mixture fill the capsules and spend inhalation through the device, the principle of which is described in the patent GE Is In the European patent EP 258 356 described microparticles for inhalation, representing the agglomerate of the excipients, for example lactose, xylitol and mannitol, and the size of the agglomerate is 30 to 150 μm. The disadvantage of this method is relatively complicated process of obtaining a conglomerate of auxiliary substances with a specific particle size.

In German patent DE 28 51 489 A1 describes a composition including beclomethasone, 90% (wt.) particles which have a size less than 10 microns and the powder-carrier, 90% (wt.) which are particles with a size less than 400 microns and at least 50% (wt.) - larger than 30 μm. To obtain this composition, along with the biologically active compound in beclomethasone you can also use other bronchodilatory with similar beclomethasone particle size. As a bronchodilator use ortsiprenalin, terbutaline or salbutamol.

Obtaining pharmaceuticals is carried out by simple mixing.

In patent WO 91/11179 A1 describes the use as a material of the carrier lactose, polysaccharides and other compounds. According to the description of the particle size of the carrier is 5 to 1000 μm, and the roughness coefficient is less than about 1.75. For the S="ptx2">

Thus, the aim of the invention was to develop a simple method of obtaining powder for inhalation, do not require humidity control in a biologically active substance and/or auxiliary substance in the process of obtaining a composition characterized by a high degree of redispersible. The resulting composition should have a satisfactory amount of fluidity in the process of inhalation to break down into particles that easily penetrates into the lungs. Under equal conditions inhalation degree of redispersible should be at least 40%.

The essence of the invention consists in a suitable mixing biologically active substances or their mixtures with pharmaceuticals carrier with an average particle size of 200 to 1000 μm, preferably 300 to 600 μm, and the coefficient of roughness of the obtained particles is more than about 1.75, and the particle size of the biologically active substances should be 0.01 to 10 μm. The particles of biologically active substances cover the surface of the carrier and formed almost all of the particles of the medium with a layer of biologically active substances on the surface. According to the invention upon receipt of this composition can exclude is este particles of media you can use commercial products or obtained by fractionation using sieves, with a particle size corresponding to the specified range.

Determination of the particle size of the carrier was performed by analysis of images obtained using a scanning electron microscope and/or by using sieve analysis. The particle size of the biologically active substance has been determined using scanning electron microscope and/or a laser diffraction spectrometry.

The proposed method of producing such powder compositions is a simple and effective method, and the resulting composition has better fluidity as compared with the original powder biologically active substances, and with soft pills. The results are shown in table experience 1. The smaller the height of the layer of granular material means better fluidity of the composition. The closer the values of bulk and printed volumes, the better the fluidity. However, emptying and redispersion obtained according to the invention the composition is much better compared to known compositions (mixtures soft pills, made under the United Kingdom patents GB 1 569 612 or 1 GB 520 247 or raw biologically active powder), then there is less residual amount of powder in Inga the ranks of biologically active substances, such as analgesics, anti-allergic drugs, antibiotics, antiholinergicescoe, anti-histamine, anti-inflamatory drugs, corticoid, steroids, antitussive, bronchodilator drugs, diuretics, enzymes, cardiovascular drugs, hormones, proteins and peptides. For example, as analgesics can be used: codeine (codein), diamorphine (diamorphin), dihydromorphine (dihydromorphin), ergotamine (ergotamin), fentanyl (fentanyl) and morphine (morphin); as antiallergic drugs - krenolinova acid (cromoglicinsaure) and nedocromil (nedocromil); as antibiotics - cephalosporins (cephalosporine), fusafungine (fusafungin), neomycin (neomycin), penicillins (penicilline), pentamidine (pentamidin), streptomycin (streptomycin), sulfa drugs (sulfonamide) and tetracyclines (tetracycline); as antiholinergiceski drugs - atropine (atropin), tropenmedizin (atropinmethonitrat), ipratropium (ipratropiumbromid), oxitropium (oxitropiumbromid), tropinone (trospiumchlorid); as antihistaminics drugs - azelastin (azelastin), fileselection (flezelastin), methapyrilene (methapyrilen); as a fever-reducing drugs - beclomethasone (beclometason), budesonide (budesonid), dexamethasone (dexamethason), flunisolide (flunisolid), fluticasone (fluticason), tipredane (tipredane) and naliticheskoj drugs - bambuterol (bambuterol), bitolterol (bitolterol), carbuterol (carbuterol, clenbuterol (clenbuterol, ephedrine (ephedrin), epinephrine (epinephrin), formoterol (formoterol), fenoterol (fenoterol), geksoprenalin (hexoprenalin), ibuterol (ibuterol), izoprenalin (isoprenalin), isoproterenol (isoproterenol), metaproterenol (metaproterenol), ortsiprenalin (orciprenalin), phenylephrine (phenylephrin), phenylpropanolamine (phenylpropanolamin), pirbuterol (pirbuterol), procaterol (procaterol), reproterol (reproterol), rimiterol (rimiterol), the salbutamol (salbutamol), salmeterol (salmeterol), sulfonterol (sulfonterol, terbutaline (terbutalin) and tulobuterol (tolobuterol); as diuretics - amiloride (amilorid) and furosemide (furosemid); enzyme, trypsin; as cardiovascular drugs diltiazem (diltiazem) and nitroglycerin (nitroglycerin); as hormones, cortisone, hydrocortisone and prednisolone; as proteins and peptides - cyclosporine (cyclosporine), cetrorelix (cetrorelix), glucagon (glucagon and insulin. As other biologically active substances can be used adrenochrome (adrenochrom), colchicine, heparin, scopolamine. These biologically active substances can be used in the form of free acids or bases or as pharmaceutically compatible salts. As the counterions can be used, for example, physiologically compatible Selo the rat, bromide, chloride, iodide, carbonate, citrate, fumarate, malate, maleate, gluconate, lactate, pamoate and sulfate. You can also use the esters, for example, acetate, acetonide, propionate, dipropionate, valerate.

According to the invention, the composition may consist of finely ground mixture of several biologically active substances, for example, from kromolin-sodium (natriumcromoglicat) and reprotonated (reproterolhydrochlorid). As mentioned previously, 100% of the biologically active substance is a particle size less than 10 μm, preferably from 1 to 5 microns.

As media use non-toxic material with an average particle size of 200 to 1000 μm, preferably from 300 to 600 μm. According to the invention as a carrier can be applied inorganic salts such as sodium chloride and calcium carbonate, organic salts, such as sodium lactate and organic compounds, for example, urea, monosaccharides, such as glucose, and derivatives thereof, such as sorbitol, polyalcohol, sorbitol, mannitol, xylitol, disaccharides, such as lactose, maltose, and their derivatives, and polysaccharides, such as starch and their derivatives, oligosaccharides such as cyclodextrin and dextrin. Can t and carrier depends on the used compounds. As indicated in the examples, the mixing of the biologically active substances (5 - 80% (wt.)) with the carrier (20 - 90% (wt.)), preferably 30 to 70% (wt.) biologically active substances and 30 - 70% (wt.) media allows to obtain satisfactory results.

The composition can also optionally include other components, such as flavorings, for example, saccharin or peppermint. In the song, you can add 10 - 20% (wt.) such components in relation to biologically active substance and, accordingly, to the mixture of biologically active substances.

A composition is carried out by mixing the components in a suitable mixer, for example, vibrational, rotational, and in high-speed mixers or mixer fluidized bed. As a vibratory mixer using a vortex mixer production W. A. Bachoven AG, Basel, CH; as a high-speed mixer using the mixer Diosna production Dierks und Sohne, Osnabruck BRD. The mixer serves parts and mix up until crystals of the media will not be covered with a thin layer of biologically active substances or mixtures of biologically active substances, and the fraction of small particles gradually disappears and the other ways, such as vibration or vortex mixing, to obtain a powder composition in accordance with the invention. The particles of the carrier are mixed in the vessel during rotation. This results in the precipitation of the biologically active substance on the carrier particles, the result is the composition described in the present invention.

To demonstrate the advantages of the proposed composition compared with a simple mixture of two biologically active substances or with soft pills, obtained according analogues (GB 1,569,612 and GB 1,520,247) identified some of the physical characteristics of the compositions according to the present invention. Getting a simple mixture of two biologically active substances was performed using a vibration mixer (the turbula mixer; W. A. Bachofen AG, Basel). Soft pills were obtained by placing powdered biologically active substance on the bottom of the main column, which is used to determine particle size (Retisch, BRD), and the vibration is carried out until, until it forms a spherical agglomerates of biologically active substances.

Some parameters of the composition obtained according to the invention, compared with a simple mixture of two biologicheskiye patents GB 1,569,612 and GB 1/520/247.

100 g of the composition is carefully poured into the measuring cylinder. Read the volume is the bulk volume. Filled cylinder was placed in the device for tamping and spent 20 hits, read the volume is printed volume (see R. Voigt, Lehrbuch der pharmazeutischen Technologie, Verlag Chemie, 5. Edition, Page 148).

Hausner-Faktor - ratio of bulk volume to the printed volume.

The height of the layer of granular material were determined using a cylinder with a diameter of 42 mm, and the powder slowly poured until then, it was not formed until the heap with a maximum height, the value of which is the height of the layer of bulk material. Redispersion was determined using the inhaler and cascading impinger, it was determined the amount of powder deposited on the cascades from the second to the fourth, in relation to the total sample in percent. This experience was carried out at two different flow rates.

Example 1

to 266.8 g fine kromolin-sodium and 133,2 g fine reprotonated sodium sieved using sieves with openings 0.125 mm and then placed in a mixer (Diosna PWC Dierks und Sohne, Osnabruck BRD). In addition, the download of 600.0 g of a commercial preparation of lactose, with the following distribution of particle size: 100% < 800 μm, 12-35% <according to the invention are characterized by good fluidity and can be used to fill the inhaler. The parameters of the obtained agglomerate is shown in table experience 1.

Example 2

3000 g of fine kromolin-sodium and 200 g of fine reprotonated sieved using sieves with openings 0.125 mm and then were placed in a vibrating mixer (the turbula: W. A. Bachofen AG, Basel). In addition, it was loaded with 500 g of a commercial preparation of lactose, with the following distribution of particle size: 100% < 800 μm, 12-35% < 400 μm and a maximum of 7% < 200 μm. Then the mixture was stirred for 30 minutes the resulting agglomerates (composition according to the invention are characterized by good fluidity and can be used to fill the inhaler. The parameters of the obtained agglomerate is shown in table experience 2.

Example 3

to 266.8 g fine kromolin-sodium and 133,2 g fine reprotonated sieved using sieves with openings 0.125 mm and then placed in a mixer, a fluidized bed (Fukae Powtec Corporation, Japan). In addition, the download of 600.0 g of a commercial preparation of sodium chloride with an average particle size of 300 microns. Then the mixture was stirred for 10 minutes the resulting agglomerate is characterized by good fluidity and can be used to fill the inhaler.

Example 5

100 g fine salbutamol sieved using sieves with openings 0.125 mm and then were placed in a vibrating mixer (the turbula; W. A. Bachofen AG, Basel). In addition, downloaded 300 g of a commercial preparation of lactose, with the following distribution of particle size: 100% < 800 μm, 12-35% < 400 μm and a maximum of 7% < 200 μm. Then the mixture was stirred for 45 minutes the resulting agglomerates (composition according to the invention are characterized by good fluidity and can be used to fill the inhaler, the cartridge or blister.

Example 6

20 g of fine beclomethasone-17,21-dipropionate sieved using sieves with openings 0.125 mm and then were placed in a vibrating mixer (the turbula; W. A. Bachofen AG, Basel). In addition, downloaded 380 g of a commercial preparation of lactose with the following raspredelenie minutes The resulting agglomerates (composition according to the invention are characterized by good fluidity and can be used to fill the inhaler, the cartridge or blister.

Example 7

20 g of fine ipratropium sieved using sieves with openings 0.125 mm and then were placed in a vibrating mixer (the turbula; W. A. Bachofen AG, Basel). In addition, downloaded 380 g of a commercial preparation of lactose, with the following distribution of particle size: 100% < 800 μm, 12-35% < 400 μm and a maximum of 7% < 200 μm. Then the mixture was stirred for 45 minutes the resulting agglomerates (composition according to the invention are characterized by good fluidity and can be used to fill the inhaler, the cartridge or blister.

1. Pharmaceutical composition for inhalation containing a mixture of biologically active substances or mixtures of biologically active substances with an average particle size less than 10 microns with a physiologically compatible carrier or mixture of carriers with an average particle size of 200 to 1000 microns, wherein the biologically active substance or a mixture of biologically active substances have an average particle size of more than 0.01 μm and the specified carrier or mixture of carriers is coefficie the Cesky active substances or mixtures of biologically active substances with an average particle size of 1 - 5 μm with a physiologically compatible carrier or mixture of carriers with an average particle size of 300 to 600 μm, characterized in that a specified carrier or mixture of carriers has a roughness coefficient over 1.75.

3. The composition according to PP.1 and 2, characterized in that it consists of a biologically active substance or of a mixture of biologically active substances and media in the following ratio, wt.%: biologically active substance or mixture of biologically active substances - 5 - 80; medium - 20 - 90; preferably biologically active substance - 30 - 70; medium - 30 - 70.

4. The composition according to PP.1 and 2, characterized in that it, along with a biologically active substance, or mixture of biologically active substances and a carrier or mixture of carriers contain other physiologically compatible auxiliary substances.

5. The composition according to PP.1 and 2, characterized in that the medium contains at least one substance from the group of sugars.

6. The composition according to PP.1 and 2, characterized in that the medium contains lactose.

7. The composition according to PP. 1 and 2, characterized in that the mixture of biologically active substances consists of reproterol and chromosonally.

8. Composition opozicia on PP.1 and 2, characterized in that the biologically active substance is a salbutamol with a carrier or mixture of carriers with a particle size greater than 400 microns.

10. The composition according to PP.1 and 2, characterized in that the biologically active substance is cetrorelix.

11. The composition according to PP.1 and 2, characterized in that the biologically active substance is a beclomethasone with the carrier or mixture of carriers with a particle size greater than 400 microns.

12. The composition according to PP.1 and 2, characterized in that the biologically active substance is ipratropium.

13. A method of obtaining a pharmaceutical composition for inhalation, wherein the biologically active substance or a mixture of biologically active substances with an average particle size of 0.01 to 10.0 μm is mixed with a physiologically compatible carrier or mixture of carriers with an average particle size of 200 to 1000 μm and a coefficient of roughness over 1.75.

14. The method according to p. 13, characterized in that the biologically active substance or a mixture of biologically active substances with an average particle size of 1 to 5 μm is mixed with a physiologically compatible carrier or mixture of carriers with an average particle size of the Itza biologically active substances cover the particles of the medium.

 

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