DESC:Field of the Invention

The present invention relates to a micronization of fluticasone for deep lung delivery. Particularly the present invention relates to micronization of fluticasone propionate by High pressure homogenization (HPH) technique. There is also provided a pharmaceutical formulation in dry powder form comprising fluticasone propionate.

Background of the Invention

Fluticasone is used in the treatment of respiratory tract diseases such as asthma and COPD. Fluticasone which has the chemical name of S-(fluoromethyl) (6S, 8S, 9R, 10S,11S, 13S,14S, 16R, 17R)-6,9-difluoro- 11,17-dihydroxy- 10,13,16-trimethyl-3 - oxo-6,7,8, 11, 12,14,15, 16-octahydrocyclopenta[a]phenanthrene-17-carbothioate belongs to the group of corticosteroids. Fluticasone was first disclosed in the patent numbered US 4,335,121.

Fluticasone propionate is the active ingredient of FLONASE, FLOVENT DISKUS and FLOVENT HFA Nasal Sprays, is a synthetic corticosteroid with the chemical name of S-fluoromethyl 6a, 9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1, 4-diene-17ß-carbothioate and the following chemical structure of Formula (I).

Formula-I

Fluticasone propionate is indicated for the management of the nasal symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric patients 4 years of age and older.

Drugs used in the treatment of respiratory tract diseases are administered through various routes (e.g. inhalation, oral, or parenteral routes). However, the preferred route of administration of these drugs is inhalation, since the drugs are directly delivered to the affected sites (airways) in high doses via this route, have a short onset time, and they lack or have minimal systemic side effects. For this reason, main the inhalation devices, metered dose inhalers, nebulizers and dry powder inhalers have a widespread use.

A combination of intrinsic physiochemical properties, particle size, shape, surface area and morphology affects the forces interaction and aerodynamic properties, which in turn determine fluidization, dispersion, delivery to the lungs and deposition in peripheral ways.

Manufacturing of drug inhalation powder and the deposition of drug particles in the lung are affected by electrostatic charges present on the powder. Therefore it is very important factor in handling pharmaceutical powders.

Amount of the specific charge on the powder is inversely related to particle size fraction.

Particle size is the single most important design variable of aerosol formulation. There is substantial evidence from the literature that links aerodynamic size and size distribution to the probability of deposition in specific lung sites.

Since the aerosol particles are small, a large surface are renders the particles subject to greater potential for charging and moisture uptake.

The size of the drug particles used in inhalation therapy is closely related to the influence of the respective drug on the respiratory tract disease. In order to gain a therapeutic benefit from the inhaled drug particles, they have to be absorbed in the lungs, i.e. at the bronchial and alveolar sites. For this reason, dry powder formulations prepared for inhalation therapy are formulated using drug particles of a micron size range between 0.1 to 7 microns. If the particles are larger than that, they are deposited in the upper airways and in the mouth. If they are smaller, they cannot be deposited in the lungs, therefore they are exhaled.

The most common technique for the preparation of micron-size drugs is the mechanical combination (e.g. by crushing, grinding and milling).

Conventional crushing, grinding as well as wet and dry milling processes are often associated with more or less severe operational problems or poor product quality due to e.g. heavy metal contamination when organic pharmaceutical compounds and active agents are handled.

For example, milling techniques are frequently used in industrial practice to reduce particle size of solids. However, dry milling techniques may cause unacceptable levels of dust which require sophisticated safety precautions to be taken during milling operation.

The micron size particles, particularly those resulting from high energy operations such as jet milling, have high surface areas and surface energies, which result in poor flow and high tendency to aggregate.

U.S. 5,510,118 discloses process of preparing therapeutic compositions containing nanoparticles by dispersing active agent particles in a liquid dispersion medium in which active agent is poorly soluble, followed by subjecting the dispersion to homogenization to reduce the particle size of active agent to the desired effective average particle size. The active agent particles can be reduced in size in the presence of surface modifiers.

U.S. 8,182,792 B2 discloses process of micronizatin of active pharmaceutical agent by high pressure homogenization in presence of gaseous propellant or compressed gas.

U.S. 2004/0208833 A1 discloses homogenization to obtain nanoparticulate fluticasone composition in presence of at least one surface stabilizer.

U.S. 2013/0203717 A1 discloses process of reducing the particle size of an active pharmaceutical ingredient while maintaining its polymorphic form, comprising a step of processing the API by cavitation at elevated pressure and then subject to spray drying to obtain the product as a dry powder.

U.S. 2015/0080355 A1 discloses process for preparing of pharmaceutical composition comprising fluticasone and ebastine in nanosize form by High pressure Homogenization in presence of surfactant.

WO 2015/114320 A1 discloses scalable process to control the particle size distribution of the active pharmaceutical ingredients by suspension preparation in a mixture of solvents in which the Active pharmaceutical Ingredient is partially soluble in one of the solvent and the other solvent is anti-solvent followed by particle size reduction by high pressure homogenization.

“Preparation of nanosized fluticasone propionate nasal spray with improved stability and uniformity” by Jiajia Dai et al, College of pharmaceutical sciences, Zhejiang University of Technology, HanZhou, China, Jan 2015 discloses the process for preparation of nanosized fluticasone propionate by high pressure homogenization in the presence of surfactant.

Surfactant is used for droplet size disruption and stabilization in mechanical emulsification process. The surfactant is capable of adsorbing at newly formed droplets between subsequent disruption steps. Thus the total disruption process can be facilitated by surfactants.

The inventors of the present invention have developed micronization of fluticasone by high pressure homogenization to attain the desired particle size for high deposition of drug particles into lungs.

Summary of the Invention

In one general aspect, there is provided a process for micronization of fluticasone propionate for deep lung delivery, said process comprising the steps of:
a) dispersing the fluticasone propionate in a solvent in which it is practically insoluble without stabilizer or surfactant modifier;
b) processing the dispersion of step (a) by high-pressure homogenizer; and
c) removing the solvent from micronized dispersion of step (b) to obtain dry powder.

In another general aspect, there is provided micronized fluticasone propionate for deep lung delivery having comprises one or more of the following properties:
i. an average particle size of about 3 microns;
ii. a specific surface area of about 3 m2/g ;
iii. a specific surface energy of less than 45 mJ/m2; and
iv. an aspect ratio of about 0.7.

Detailed Description of the Invention

All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about" and "general" are to be construed as modifying a term or value such that it is not an absolute. This includes, at the very least, a degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein, the term “fluticasone” is used in broad sense to include, not only “fluticasone” per se, but also their pharmaceutically acceptable esters, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, etc.

The term "derivative" includes, but is not limited to, pharmacologically active metabolites and prodrugs.

The ester of fluticasone is selected from fluticasone propionate, fluticasone furoate, or fluticasone valerate.

As used herein, the term “average particle size” refers to Dv50. Dv50 is also known as volume median or volume average particle size, it physically represents that each volume of particles greater or smaller than such value takes account of 50% of total particles volume.

As used herein, the term “microns” refers to symbol µm.

In one general aspect, there is provided a process for micronization of fluticasone propionate for deep lung delivery, said process comprising the steps of: (a) dispersing the fluticasone propionate in solvent without stabilizer or surfactant modifier (b) processing the dispersion of step (a) by high-pressure homogenizer and (c) removing the solvent from micronized dispersion of step (b) to obtain dry powder.

In another general aspect, the fluticasone propionate can be suspended in any suitable solvent, such as water or any other inorganic or organic solvent, where they are practically insoluble. The solvent comprises one or more of water, an alcohol, a hydrocarbon, a ketone or mixture thereof. The alcohol selected from methanol, ethanol or isopropyl alcohol; the hydrocarbon selected from toluene, n-hexane, benzene or heptane; the ketone is selected from acetone, methylethylketone, or methylisobutylketone.

In general, the micronized dispersion of fluticasone propionate of step (b) may be subjected to filtration, spray drying, conventional solvent evaporation techniques such as recrystallization using solvent evaporation, liquid antisolvent technique to obtain dry powder.

In general, spray drying is a conventional chemical processing unit operation used to produce dry powder from a variety of liquid and slurry starting materials.

In general, high-pressure homogenization is based on the principle of cavitations (i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid).
In general, the high-pressure homogenizer may operate as follows: The homogenizer which has an inlet and an outlet relies on a high pressure pump which is designed to supply the desired pressure at a constant rate to the product stream. The pump delivers the product at constant pressure through defined fixed geometry microchannels within the interaction chamber. Particle size reduction and homogenization of the suspension formed previously in the stirred pressure vessel occur within the interaction chamber. The jet interaction chamber block makes use of three different forces: shear, impaction and cavitation. The high pressure homogenization provides rather uniform particle size reduction e.g. micronization and deagglomeration of the pharmaceutically active agent.

Accordingly, the process of spray drying involves supplying the feed solution at room temperature and pumping it through the nozzle where it is atomized by the nozzle gas. The atomized solution is then dried by preheated drying gas in a special chamber to remove water moisture from the system, thus forming dry particles of drug.

In another general aspect, the dispersion of step (a) may be passed through high-pressure homogenizer at high pressure between in the range of 500 to 2000 bar. The pressure creates powerful disruptive forces such as cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles. More particularly, the operating pressure of vessel in high-pressure homogenizer is between in the range of 800 to 1250 bar.

In another general aspect, the temperature of high-pressure homogenizer is reduced less than
30° C by heat exchange process. Particularly the temperature is reduced to 10°C to 20°C.

According to another general aspect, there is provided micronized fluticasone propionate for deep lung delivery having average particle size of about 3 microns.

In another general aspect, the advantage of this embodiment of the invention is a more efficient control of the average particle size by controlling the residence time through the number of passes through the equipment. Average particle size of the fluticasone is controlled by the total number of passes through the homogenizer, and typical numbers of passes in practice range from about 3 to 25 to reach an average particle size of about 3 microns. If the total number of passes through the homogenizer is reached, the dispersion may be stored in a storage tank. In this embodiment of the invention both static interaction geometries and dynamic high pressure relaxation valves may be used for homogenization.

In another general aspect, the recirculation of dispersion of step (a) may be performed from 2-30 times. Preferably the number of passes of recirculation is less than 10 times. More preferably the number of passes is 7 times.

In another general aspect, the particle size distribution of fluticasone propionate has Dv10 ranges from 0.75 to 1.5 microns. Particularly Dv10 ranges from 1 microns to 1.2 microns.

In another general aspect, the particle size distribution of fluticasone propionate has Dv90 ranges from 4 to 6 microns. Particularly Dv90 ranges from 4.5 to 5.5 microns.

In another general aspect, the particle size distribution of fluticasone propionate has Dv50 ranges from 2 to 3 microns. Particularly Dv10 ranges from 2.5 to 3 microns.

In another general aspect, there is provided a process for micronization of fluticasone furoate for deep lung delivery, said process comprising the steps of: (a) dispersing the fluticasone furoate in solvent without stabilizer or surfactant modifier (b) processing the dispersion of step (a) by high- pressure homogenizer and (c) removing the solvent from micronized dispersion of step (b) to obtain dry powder.

In another general aspect, the micronized fluticasone furoate obtained according to the present invention has average particle size of about 3 microns.

It is well known that the two main clearance mechanisms active in the lung are mucillary clearance (MCC) in the central and small airways and macrophage phagocytosis in the alveolar region. As used herein the term “deep lung delivery” relates to drug particles which are preferably engulfed by alveolar macrophages in the alveoli and are not cleared by MCC.
In another general aspect, the micronized fluticasone propionate obtained according to the present invention having one or more of the following properties:
i. an average particle size of about 3 microns;
ii. a specific surface area of about 3 m2/g;
iii. a specific surface energy of less than 45 mJ/m2; and
iv. an aspect ratio of about 0.7,
has several advantages; improved flow properties, improved fluidisability and deep lung delivery from dry powder formulations.

In general, the morphology of fluticasone propionate is remaining same after homogenization.

In general, the morphology of fluticasone propionate before and after homogenization is amorphous form.

In general, the morphology of the fluticasone propionate before and after homogenization is polymorphic Form-I characterized by X-ray diffraction peaks at about 7.9°, 10.0°, 11.5°, 12.4°, 13.1°, 14.9°, and 15.8 ° ± 0.2 ° 2?.

In another general aspect, the dry powder inhalation formulation comprising micronized fluticasone obtained according to present invention can be delivered to the patient. Said dry powder formulations further comprise at least one physiologically and pharmaceutically acceptable excipient along with the active agent. This excipient is composed of fine grained excipient, coarse grained excipient or a combination thereof, preferably a combination of fine grained excipient and coarse grained excipient. This excipient can be selected from monosaccharides (glucose etc.), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, anhydrates or a combination thereof etc.), oligosaccharides and polysaccharides (dextrant etc.), polyalcohols (sorbitol, mannitol, xylitol etc.), salts (sodium chloride, calcium carbonate etc.) or a combination thereof. Same or different substances are used as fine grained excipient and coarse grained excipient, though preferably the same substance is used. Fine grained and coarse grained excipients are preferably lactose, more preferably lactose anhydrate.
On the other hand, along with the particle size of the excipient comprised in the dry powder formulations of the present invention, the average particle size of the fluticasone used is quite important in order that the formulation to be obtained has good flow characteristics and therefore an effective inhalation is performed.

Example: 1
The fluticasone propionate dispersed in water and transferred into the vessel of GEA-Panda plus 2000 homogenizer (HPH). The temperature was reduced to 10°C to 20°C by chilled water to heat exchanger of HPH. The operating pressure in vessel was adjusted between 80 to 125 bar and increased the pressure gradually to 800 to 1250 bar. Monitored the homogenization pressure and the total processing time is 60 minutes. Collected the processed suspension from the collection vessel and cooled if necessary. Repeat the cycles at least seven times in order to achieved the uniform particle size of fluticasone propionate. The suspension of micronized fluticasone propionate obtained was fed to spray dryer.

Spray-drying was carried out using a Buchi 290 Mini Spray Dryer fitted with a two-fluid nozzle and peristaltic pump. The processing parameters comprised an inlet temperature of 140°±5°C, an atomization pressure about 4.0±1.0 kg/cm2 and a liquid feed rate of 5%. A resulting outlet temperature of 60-70°C was observed.

The resultant powder obtained has particle size distribution as follows measured by malvern mastersizer 2000 laser diffraction particle size analyzer.
Dv10= 1.03 microns, Dv50=2.69 microns and Dv90=5.15 microns.

Specific surface area of resultant particles may be determined by conventional surface area measuring techniques such as low temperature physical adsorption of nitrogen (eg, BET nitrogen adsorption using a Surface Area Analyzer Coulter. Micronized fluticasone propionate obtained in Example: 1 have a specific surface area of 3.2 m2/g.

The specific surface energy ES of a particulate active substance can be calculated as per the following equation:
ES = 0.683 (d2/aS, V 2/3) O 1/3
where d is the Hildebrand solubility parameter, aS, V is the shape coefficient, and O is the molecular volume. Micronized fluticasone propionate obtained in Example: 1 has surface energy of 43.1 mJ/m2.

Scanning electron microscopy (SEM) is used to measure characteristic particle dimensions such as circle diameter, length, width, and morphological information such as roundness, aspect ratio and shape.

The results of fluticasone propionate of three batches obtained according to the present invention are illustrated in Table: 1.
SR NO TEST BATCH NO & RESULTS
1. Particle size (µm) Batch 1 Batch 2 Batch 3
D(0.1) 1.029 1.135 1.079
D(0.5) 2.613 2.900 2.694
D(0.9) 4.896 5.582 5.224
2. Surface area(m2/g) 3.55 3.24 3.273
3. Total Surface energy (mJ/m2) 39.92 43.33 41.14
4. Morphology
5. CE diameter (µm) 3.55 4.59 3.69
Width (µm) 3.21 4.13 3.32
Length (µm) 4.35 5.64 4.56
Circularity 0.942 0.925 0.938
Convexcity 0.989 0.981 0.990
Area (µm2) 14.17 23.18 14.32
Elongation 0.231 0.234 0.244
Aspect ratio 0.769 0.766 0.756
Solidity 0.992 0.986 0.988
HS circularity 0.892 0.871 0.878
SE volume (µm3) 77.1 227.4 75.69

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:1. A process for micronization of fluticasone propionate for deep lung delivery, said process comprising the steps of:
a) dispersing the fluticasone propionate in a solvent in which it is practically insoluble without stabilizer or surfactant modifier;
b) processing the dispersion of step (a) by a high-pressure homogenizer; and
c) removing the solvent from micronized dispersion of step (b) to obtain dry powder.
wherein the fluticasone propionate micronized by said process comprises one or more of the following properties:
i. an average particle size of about 3 microns;
ii. a specific surface area of about 3 m2/g ;
iii. a specific surface energy of less than 45 mJ/m2; and
iv. an aspect ratio of about 0.7.

2. The process according to claim 1, wherein the solvent comprises one or more of water, methanol, ethanol, isopropyl alcohol, toluene, n-hexane, benzene, heptane, acetone, methylethylketone, and methylisobutylketone or mixture thereof.

3. The process according to claim 1, wherein the operating pressure of vessel in high- pressure homogenizer is between in the range of 800 to 1250 bar.

4. The process according to claim 1,wherein the dispersion of step (a) is circulated through high- pressure homogenizer for about 5 to 10 times.

5. The process according to claim 1, wherein the operating temperature of high-pressure homogenizer is less than 20°C.

6. The process according to claim 1, wherein the micronized fluticasone propionate has particle size distribution of Dv90 ranges from 4 to 6 microns, Dv10 ranges from 0.75 to 1.5 microns and Dv50 ranges from 2 to 3 microns.