Drugs fluticasone propionate

 

(57) Abstract:

The present invention relates to the drugs used for the delivery of drugs by inhalation, in particular, this invention relates to a drug that contains fluticasone propionate, having a particle size of mainly less than 12 microns, one or more surfactants, one or more buffer agents and water. Also described is a method of obtaining the specified drug and its container. Proposed remedies are more stable during storage and quickly redicilious. 4 C. and 14 C.p. f-crystals.

The present invention describes methods for improving pharmaceutical compositions comprising an ester of fluticasone. In particular, the invention describes new compounds for use fluticasone propionate by inhalation.

Fluticasone propionate is a common name S-vermeil 6a,9a-debtor-11b-hydroxy-16a-methyl-17a-propionyloxy-3-oxytoca - 1,4-diene 17b of carbothioate, corticosteroid with known and described [1] local anti-inflammatory action. Shows the effectiveness of the treatment of asthmatic conditions, through the application of fluticasone propionate in the form of dry powders or aerosols containing small particles that were changed using the nebulizer with a measured dose, arranged so that a fixed amount of drug delivered to the patient with each actuation of the inhaler (inhalation). However, some patients, particularly children and the elderly, have difficulty coordinating pressing the inhaler and inhale, and therefore cannot effectively use this form of medication. In addition, some patients have found inhalation dry powders difficult or unpleasant. Thus, there is a demand for a pharmaceutical composition containing fluticasone propionate in the form suitable for nebulization (spray).

According to the first aspect of the present invention is proposed suitable for nebulization composition, which includes:

(a) fluticasone propionate, represented mainly in the form of particles of size less than 12 microns,

(b) one or more surfactants,

(C) one or more buffer substances and water.

Fluticasone propionate may be prepared in known in the art methods [1] . It is clear that it is possible to make a solvate fluticasone propionate, and, accordingly, the invention extends to compositions comprising a solvate of fluticasone propionate, which is acceptable from the point of view of physiology. The particle size of cu is to allow the inhalation to the lungs of almost all of the drug when applied nebulizing composition. Convenient is the particle size in the range from 0.5 to 12 microns, for example from 1 to 6 microns. Parameter which is important for the introduction of fluticasone propionate in the lungs, is the size of the droplets in nopolizirovannoe composition. The size of the droplets depends to some extent on the type of nebulizer, whether facial mask or mouthpiece, and the pressure or flow rate of compressed gas, as well as on the physical properties of the composition for nebulization. Napolitani composition will heterodispersed, i.e., the size of the droplets will be different. Usually, the average size of the droplets is in the range from 0.5 to 15 microns, with a preferred range is from 0.5 to 10 microns, and most preferred is an amount of up to 5 microns.

It is desirable that the composition described in this invention contain fluticasone propionate in an amount of from 0.5 to 10 % by weight of the total solid ingredients of the composition, and it is preferable for the content of fluticasone propionate from 1 to 9%, and most preferred from 1.5 to 6.5%.

The surfactants used in the compositions described in this invention must be physiologist who eat (SpanR85), sorbitan monooleate, sorbitan monolaurate, polyoxyethylene(20) sorbitan monolaurate, polyoxyethylene(20) sorbitan monooleate, natural lecithin, alerby ether of polyoxyethylene(2), stearyl ester of polyoxyethylene(2), lauric ester of polyoxyethylene(4), block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol of dioleate, tetrahydrofurfuryl the oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glycerol monolaurate.

Particularly preferred surfactants for use described in this invention the compositions are sorbitan monolaurate and polyoxyethylene(20) sorbitan monolaurate (also known as Polysorbate 20).

Convenient is that the composition described in this invention contain surfactants from 0.25 to 0.6% by weight of the total solid ingredients of the composition, preferably the content of surfactants from 0.4 to 0.6%, and most preferred is from 0.45 to 0.55%.

Preferably, the composition described in this invention, contained sorbitan monolaurate and polyoxyethylene(20) sorbitan monolaurate in the ratio from 1:7.5 to 1:8,25, for example from 1:7.7 to 1:8,1.

The compositions described in this invention, buffered to the volumes for inhalation use. Such buffers include citrate and phosphate, and phosphate are preferred. Particularly preferred buffers for use described in this invention the compositions are monosodium phosphate dihydrate and dibasic anhydrous sodium phosphate.

It is desirable that the compositions described in this invention were isotonic. Isotonicity composition can be adjusted by adding acceptable salts, for example sodium chloride.

Thus, the compositions described in this invention, in its preferred embodiment additionally contain sufficient to create an isotonic composition amount of sodium chloride or other convenient, acceptable from a pharmaceutical point of view of salt.

In its most preferred embodiment of the invention is suitable for use by nebulization composition, consisting of:

(a) 0.5 to 2.2 mg fluticasone propionate (micronized),

(b) 0,12 - 0,18 mg and polyoxyethylene(20) sorbitan of monolaurate,

(C) 0,015 - 0,025 mg sorbitan of monolaurate,

(d) of 18.5 - 19 mg monosodium phosphate dihydrate,

(e) a 3.2 - 3.7 mg dibasic anhydrous sodium phosphate,

(f) to 9.4 and 9.8 mg of chloride is edocfile embodiment of the invention consist of:

(a) 0,25 - 1,1 mgml fluticasone propionate (micronized),

(b) 0.06 to 0.09 mg/ml and polyoxyethylene(20) sorbitan of monolaurate,

(C) 0,0075 - of 0.0125 mg/ml sorbitan of monolaurate,

(d) a 9.25 - 9.5 mg/ml monosodium phosphate dihydrate,

(e) 1,6 - of 1.85 mg/ml dibasic anhydrous sodium phosphate,

(f) 4,7 - 4,9 mg/ml sodium chloride and water.

The compositions described in this invention, form during storage clariflocculators suspension, which, however, surprisingly quickly redicilious under mild shaking and form a slurry with excellent transport characteristics suitable for use in conventional nebulizers even after prolonged storage.

Chemical and physical stability, and pharmaceutical acceptability of the compositions described in this invention can be determined by methods well known in the art. For example, the chemical stability of the components after long-term storage can be determined using chromatography (HPLC).

The size distribution of particles in the compositions described in this invention after nebulization can be measured by conventional means, for example by using a cascaded inactionable or analytical journal is the location of the released dose inhalation under pressure using the apparatus A". Such methods allow to calculate the "respirable fraction" of the composition. Here, the term "respirable fraction" means the number of the active substance collected in the lower impingement the camera at one operation, expressed as a percentage of the total amount of active substance to be delivered during a single actuation of the inhaler when using the above analytical process "Twin Impinger". It is shown that the "respirable fraction" of the compositions described in this invention is 10% or more by weight of the drug, for example from 10 to 50%, or from 15 to 35%.

The compositions described in this invention can be prepared by ordinary methods of preparation of suspensions. As a rule, fluticasone propionate treated with a small amount of surfactant for "wetting" it before adding to the total liquid containing the remaining components. Constant agitation is necessary to maintain the homogeneity of the suspension. The entire suspension is sterilized, usually by means of steam heat sterilization. Portions of the suspension are then typically packaged in sterile containers, such as containers containing one dose, such as vials or ampoules, which are conveniently made of Isani, such as asthma, consisting in, inhalation applying effective amounts described herein stock.

The compositions described in this invention can thus be applied with the help of a nebulizer, in which case the suspended portion of the composition is preferably packaged in sterile containers as described above. The compositions described in this invention can also be applied in the form of nasal drops. In this case, it is desirable to package them in sterile containers of small size, suitable for such usage.

Further, the invention is illustrated by the following examples without limiting the scope of this invention:

Example 1. Composition mg:

fluticasone propionate (micronized) - 0,525

polyoxyethylene(20) sorbitan of monolaurate - 0,14

sorbitan of monolaurate - 0,018

monosodium phosphate dihydrate - 18,80

dibasic anhydrous sodium phosphate - 3,50

sodium chloride - 9,60

water for injection to, ml - 2,00

It is clear that the composition prepared in accordance with example 1, consists of:

about 0.26 mg/ml fluticasone propionate (micronized),

about 0.07 mg/ml and polyoxyethylene(20) sorbitan monolaurate 1.75 mg/ml dibasic anhydrous sodium phosphate,

about 4.8 mg/ml sodium chloride and water.

The composition prepared in accordance with example 1, was poured into the nebulizer. The size distribution of particles in nebulization was measured as the percentage of fluticasone propionate in stage 2 (the fraction of small particles) apparatus "Twin Impinger" and as a percentage of fluticasone propionate on stages 2-7 (fraction of small particles) cascade impactor. Were the values obtained, respectively, of 18.5% and 18.2%.

Example 2 . Composition mg:

fluticasone propionate (micronized) - 2,10

polyoxyethylene(20) sorbitan of monolaurate - 0,16

sorbitan of monolaurate - 0.02

monosodium phosphate dihydrate - 18,80

dibasic anhydrous sodium phosphate - 3,50

sodium chloride - 9,60

water for injection to, ml - 2,00

It is clear that the composition prepared in accordance with example 2, consists of:

about 1,05 mg/ml of fluticasone propionate (micronized),

about 0.08 mg/ml and polyoxyethylene(20) sorbitan of monolaurate,

about 0.01 mg/ml sorbitan of monolaurate,

around 9.4 mg/ml monosodium phosphate dihydrate,

about 1.75 mg/ml dibasic anhydrous sodium phosphate,

about 4.8 mg/ml sodium chloride and water.

The composition prepared in which the manual, described in example 1. Were obtained value, equal to 22.1% for the device "Twin Impinger" and 21.6% for cascade impactor.

REFERENCES

1) GB 2088877.

2) the British Pharmacopoeia 1988, page A204-207, Annex XVII C.

1. Suitable for nebulization pharmaceutical composition in the form of a suspension for administration to the lungs of an effective amount of a composition comprising: (a) fluticasone propionate, represented mainly in the form of particles of size less than 12 microns, (b) one or more surfactants, (C) one or more buffering agents, and (d) water.

2. Suitable for nebulization pharmaceutical composition in the form of a suspension for administration to the lungs of an effective amount of a composition essentially consisting of: (a) fluticasone propionate, represented mainly in the form of particles of size less than 12 microns, (b) one or more surfactants, (C) one or more buffer agents, (d) pharmaceutically acceptable salts, are suitable for establishing isotonicity, and (d) water.

3. The pharmaceutical composition under item 1 or 2, where the particle size fluticasone propionate is from 1 to 6 μm.

4. The pharmaceutical composition according to any one of paragraphs.1 to 3, where the content of fluticasone propionate is from p. 1 - 4, where the composition contains two surfactant.

6. The pharmaceutical composition according to any one of paragraphs.1 - 5, where the content of the surfactant is 0.4 - 0.6% of the total weight of the solid ingredients of the composition.

. The pharmaceutical composition according to any one of paragraphs.1 - 6, where the surfactants selected from the group consisting of sorbitan of Triolet, sorbitan of monooleate, sorbitan of monolaurate, polyoxyethylene (20) sorbitan of monolaurate, polyoxyethylene (20) sorbitan of monooleate, natural lecithin, olejowego ether of polyoxyethylene (2), stearyl ester of polyoxyethylene (2), lauric ester of polyoxyethylene (4), block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol of dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glycerol of monolaurate.

8. The pharmaceutical composition according to p. 7, where the surfactants are sorbitan monolaurate and polyoxyethylene (20) sorbitan monolaurate.

9. The pharmaceutical composition according to p. 8, where sorbitan monolaurate and polyoxyethylene (20) sorbitan monolaurate contained in a ratio of from 1 : 7.5 to 1 : 8,25.

10. The pharmaceutical composition according to any one of paragraphs.1 to 9, which is buffered to a pH from about 5 to about 7.

11. Farmatsevticheskii: (a) 0.25 to 1.1 mg/ml fluticasone propionate (micronized); (b) 0.06 to 0.09 mg/ml polyoxyethylene (20) sorbitan of monolaurate; (C) 0,0075 - of 0.0125 mg/ml sorbitan of monolaurate; (g) a 9.25 - 9.5 mg/ml monosodium phosphate dihydrate; (e) 1,6 - of 1.85 mg/ml dibasic anhydrous sodium phosphate; (e) 4,7 - 4,9 mg/ml sodium chloride, and (f) water.

13. The pharmaceutical composition according to p. 12, containing: (a) 0.26 mg/ml fluticasone propionate (micronized); (b) 0.07 mg/ml of polyoxyethylene (20) sorbitan of monolaurate; (C) 0,009 mg/ml sorbitan of monolaurate; (g) to 9.4 mg/ml monosodium phosphate dihydrate; (d) 1.75 mg/ml dibasic anhydrous sodium phosphate; (e) to 4.8 mg/ml sodium chloride, and (f) water.

14. The pharmaceutical composition according to p. 12, containing: (a) of 1.05 mg/ml fluticasone propionate (micronized); (b) 0.08 mg/ml of polyoxyethylene (20) sorbitan of monolaurate; (C) 0.01 mg/ml sorbitan of monolaurate; (g) to 9.4 mg/ml monosodium phosphate dihydrate; (d) 1.75 mg/ml dibasic anhydrous sodium phosphate; (e) to 4.8 mg/ml sodium chloride, and (f) water.

15. The pharmaceutical composition according to any one of paragraphs.1 - 14 for use in the nebulizer to form multiple droplets of the composition suitable for inhalation.

16. The preparation method of the pharmaceutical composition sweat the resulting solution of the drug and surfactant with a mixture of one or more buffer agents and water.

17. The method according to p. 16, characterized in that the mixture additionally contains a pharmaceutically acceptable salt, suitable for establishing isotonicity.

18. The container containing the composition according to any one of paragraphs.1 - 14.

 

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