Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1996-07-10
2001-04-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S499000, C514S951000
Reexamination Certificate
active
06221398
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a process for preparing a pharmaceutical powder for inhalation, which powder comprises crystalline particles of an inhalation compound, in particular particles of mass median diameter 10 &mgr;m or less.
BACKGROUND OF THE INVENTION
Inhalation of dry powders has been recognized as a valuable method for the administration of pharmacological agents and in particular those which are useful in the treatment of diseases of the respiratory tract. However, the utility of the method has been limited by the difficulty in making appropriate doses available to the lower respiratory tract of the patient. In general only a relatively small proportion of any nominal dose will reach the lower respiratory tract of the inhaling patient; the remainder may remain in the inhaler device or be deposited in the mouth and throat of the patient.
One major factor determining the proportion of inhalable drug which will reach the lower respiratory tract of a patient is the particle size distribution of the particles emerging from the inhaler device. This particle size distribution is in turn dependent both on the construction and function of the inhaler, and the powder fomuation. The present application is concerned with the nature of the powder formulation. This should have a high integrity of the crystal structure, or crystal habit (as may be measured using X-ray crystallography techniques, for example), high purity and stability, and a particle size within the respirable particle range.
In order to achieve a desired crystal structure and particle sum powder formulations of respirable particles are in general obtained by processes including crytallization from solution followed by micronization However, optimum crystal structure formation and optimum purity may not be obtained in this process, and micronization has associated problems. Prolonged comminution rests in a high energy powder and crystal lattice defects which may be manifested for example in lower stability, and/or hygroscopicity. As micronization results in some amorphous character on the surface of the obtained particles, a “conditioning” step is necessary in order to obtain a particle considered to be completely crystalline. International patent applications PCT/SE91/00186 (WO 92/18110) and PCT/SE94/00780 (WO 95/05805) describe methods of conditioning substances in order to obtain crystalline products. It is an object of the present invention to provide a process for the production of crystalline respirable particles which avoids the necessity for post-crystallisation micronization.
European Patent No. 437451 discloses a process for producing finely divided solid crystalline powders, comprising dissolving the solid to be finely divided in a liquid carrier solvent to form an injection solution and adding the injection solution to a volume of anti-solvent, which is a supercritical fluid, liquefied compressed gas or dense vapour, sufficient to precipitate or crystallise the solid.
European patent application, publication number 0 542 314 A1, discloses a method of forming microparticles of a material, involving bringing a supercritical anti-solvent gas into contact with a solution of said material in a solvent at a controlled rate operable to expand the solution and precipitate the material. Needles and globules are formed.
Neither of the above are directed to powders for inhalation per se, and as they use supercritical media the use of compressed gases and heavy, expensive apparatus is necessitated.
U.S. Pat. No. 5,314,506, again not related to powders for inhalation, describes impinging a jet stream of an organic pharmaceutical compound and a jet stream of an anti-solvent, to precipitate small crystals of the organic pharmaceutical compound. Pressurised blow-cans and elevated temperatures are employed, and the crystals obtained range from flakes of up to 25 microns, to needles, and cubes of less than 3 microns.
EP 0169618 discloses a method for the preparation of water-insoluble organic compounds such as may be used in suspensions for intravenous injection, as non-crystalline particles. The method involves preparing a solution of the compound in a water-miscible organic solvent and infusing an aqueous precipitating liquid into the organic solution, in most cases in the presence of surfactant.
The process of the present invention aims to provide a powder for inhalation comprising crystalline particles of an inhalation compound of mass median diameter less than 10 &mgr;m, irrespective of the substance concerned. Thus the process does not require the use of supercritical media nor the processes of micronizing and conditioning.
According to the present invention there is provided a process for producing a pharmaceutical powder for inhalation comprising crystalline particles of an inhalation compound, comprising dissolving an inhalation compound to be provided in crystalline particle form in a solvent; and introducing the solution containing the inhalation compound, in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation, under non-supercritical conditions.
There is also provided according to the present invention a pharmaceutical powder and a crystalline inhalation compound obtainable by the process of the invention.
Preferably the particles of the inhalation compound of the present invention have a mass median diameter of at least 0.1 &mgr;m, more preferably at least 1 &mgr;m. Where the powder is intended particularly for oral inhalation, preferably the particles have a mass median diameter of 10 &mgr;m or less, preferably 7 &mgr;m or less. Most preferably the particles have a mass median diameter of 1-6 &mgr;m. By “mass median diameter” is meant that half of the mass of the inhalation compound is made up of particles having a diameter less than the mass median diameter and half of the mass of the inhalation compound is made up of particles having a diameter greater than the mass median diameter. Preferably as much as possible of the powder consists of particles of diameter 10 &mgr;m or less; for example at least 75% or at least 90% of the powder consists of particles of diameter 10 &mgr;m or less.
The pharmaceutical powder of the present invention may be administered orally or nasally. Where nasal administration is intended the particles of the inhalation compound may have a mass median diameter outside the above preferred ranges.
The pharmaceutical powder may comprise a water-soluble inhalation compound, or a water-insoluble inhalation compound.
The solution containing the inhalation compound is introduced into the anti-solvent in droplet form or as a jet-stream, for example through a porous filter or one or more nozzles.
Through the present invention it is possible to control the size of particles obtained by controlling any or all of parameters such as the concentration of the compound in the solvent, the rate of addition of the solution into the anti-solvent and the intensity of the agitation such that particles within a specific desired particle size range may be obtained. A powder formulation having good physicochemical stability and needing no mechanical micronization or conditioning is obtained.
Medically useful compounds which may be provided in respirable particle form according to the present invention include &bgr;2-adrenoteceptor agonists, for example salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol procaterol, broxaterol, picumeterol, TA-2005 ([8-hydroxy-5-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)]-2(1H)quinolone), mabuterol; anticholineigic bronchodilators, for example ipratropium bromide; glucocorticosteroids, for example betamethasone, fluticasone, budesonide, tipredane, dexamethasone, beclomethasone, fluocinolone, triamcinolone acetonide, mometasone and rofleponide; peptides and proteins, for example insulin, immunomodulators, anti-allergic drugs for example sodium cromoglycat
Jakupovic Edib
Trofast Jan
Astra Aktiebolag
Fish & Richardson P.C.
Page Thurman K.
Seidleck Brian K.
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