Azithroraycin Powder for Oral Suspension Compositions
FIELD OF THE INVENTION
This invention relates to non-caking azithroraycin powder for oral suspension (POS) compositions and methods of making such compositions.
BACKGROUND OF THE INVENTION
Azithromycin is marked in the United States by Pfizer, Inc., under the tradename ZITHROMAX®.
U.S. Patent No. 5,605,889, incorporated in its entirety herein by reference, discloses azithromycin powder for oral suspension compositions. US. Patent No. 4,963,531, incorporated in its entirety herein by reference, is cited by the '889 patent and discloses in Example 2 an azithromycin powder for oral suspension. U.S. Patent No. 6,861,413 and PCT publication no. WO 2005/002592 A2, both of which are incorporated in their entireties herein by reference, also disclose azithromycin POS compositions.
There exists a need for an improved azithromycin powder for oral suspension composition that is non-caking and a method of manufacturing such a composition.
SUMMARY OF THE INVENTION
The present invention is directed, in one embodiment, to a non-caking azithromycin powder for oral suspension composition comprising azithromycin and a hydrated buffer. In a preferred embodiment, the hydrated buffer is a hydrate of sodium phosphate, preferably tribasic sodium phosphate dodecahydrate.
In another embodiment, the present invention is directed to a method for making a non-caking azithromycin powder for oral suspension composition comprising the steps of: a) dry mixing azithromycin and a pharmaceutically acceptable excipient to form a first mixture; b) adding to the first mixture and mixing therewith a hydrattsd buffer and a pharmaceutically acceptable excipient to form a second mixture; c) adding to the second
mixture and mixing therewith a phannaceutically acceptable excipient to form a third mixture; and, d) adding to the third mixture and mixing therewith a pharmaceutically acceptable excipient to form a fourth mixture. In a preferred embodiment, separate portions of a suitable diluent or sweetener, such as sucrose, are mixed in each of steps a), b), c) and d). In yet another embodiment, the present invention is directed to non-caking azithromycin powder for oral suspension compositions made by the foregoing process as more fully described hereinbelow.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Unless otherwise indicated, the term azithromycin includes the salts, hydrates, solvates and physiologically functional derivatives and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous. Preferred forms of azithromycin include azithromycin dihydrate and azithromycin monohydrate hetniethanolate, such as disclosed in U.S. Patent No. 6,365,574, incorporated by reference herein in its entirety. The azithromycin component can also be in the form of a stabilized azithromycin composition such as disclosed in U.S. Patent No. 6,764,997, incorporated by reference herein in its entirety. The term "non-caking," used herein means that when constituted in aqueous media, for example, the formed suspension has a smooth consistency and doesn't contain any caking or clumping particles, by visual inspection. Also, the powder for oral suspension in accordance with the present invention does not cake or clump during manufacture, i.e., when mixed with excipients. Nor does it cake or clump upon storage, even under relatively humid conditions, e.g., a relative humidity of about 75% or greater and when stored for relatively long periods such as about 6 months or longer and even at elevated temperatures of about 40°C or greater, or at any combination of such humidity, time and temperature parameters. Thus, the powders for oral suspension in accordance with the present invention will remain free flowing and non-caking during typical storage and use conditions.
All percentages mentioned herein, unless otherwise indicated, are on a w/w basis, i.e., as a percentage of the total weight of the powder for oral suspension composition.
In a first embodiment, the present invention is directed to a non-caking
azithromycin powder for oral suspension composition comprising azithromycin and a hydrated buffer.
The hydrated buffer is preferably a hydrate of sodium phosphate, such as tribasic sodium phosphate dodecahydrate. Other phannaceutically acceptable hydrated sodium phosphate buffers such as, for example, tribasic sodium phosphate hexabydrate; tribasic sodium phosphate hemihydrate; tribasic sodium phosphate octahydrate; and, dibasic sodium phosphate dihydrate and dibasic sodium phosphate heptahydrate may also be used.
The amount of the hydrated buffer present in the powder for oral suspension composition is in the range of from about 0.2% to about 2.0% w/w based on the total weight of the powder for oral suspension. More, preferably, the amount of the hydrated buffer present in the powder for oral suspension composition is in the range of from about 0.4% to about 1.2% w/w. In a particularly preferred embodiment, the hydrated buffer is tribasic sodium phosphate dodecahydrate, which is present in the powder for oral suspension composition in an amount of about 0.8% w/w.
The non-caking azithromycin powder for oral suspension compositions also may contain one or more phannaceutically acceptable excipients. Any phannaceutically acceptable excipient known in the art as useful in powder for oral suspension compositions may be included, such as one or more members selected from the group consisting of diluents (fillers), sweeteners, binders, suspending (thickening) agents, buffers, glidants, flavorants and colorants. An excipient can serve multiple functions, for example, as both a filler and a sweetener.
A variety of materials maybe used as diluents. Examples are spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, soibitol, starch (e.g. starch 1500), cellulose (e.g. microcrystalh'ne cellulose; AVICEL®), and others as known in the art. A preferred diluent in accordance with the present invention, which also functions as a sweetener hi the powder for oral suspension compositions, is sucrose. The amount of the diluent used in the powder for oral suspension compositions of the present invention is typically in the range of from about 50% to about 98% w/w based on the total weight of the powder for oral suspension.
Sweeteners may include, for example, sucrose, glucose, aspartame, saccharin mannitol and any other phannaceuticalty acceptable sweetener or combination thereof. The amount of the sweetener used in the powder for oral suspension compositions of the present invention is typically in the range of from about 50% to about 98% w/w based on the total weight of the powder for oral suspension.
Examples of binders are acacia, cellulose derivatives (such as methylcellulose and carboxymethylcellulose, hydroxypropylmethyleellulose, hydroxypropylcellulose, hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites, and the like. The amount of the binder used in the powder for oral suspension compositions of the present invention is typically in the range of from about 0.1% to about 10% w/w based on the total weight of the powder for oral suspension.
Suitable suspending agents include, for example, hydrocolloid gums such as xanthan gum, guar gum, locust bean gum, gum tragacanth, veegum, sodium alginate and the like. Alternatively, synthetic suspending agents may be used such as sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like. The amount of the suspending agent used in the powder for oral suspension compositions of the present invention is typically in the range of from about 0.1% to about 10% w/w based on the total weight of the powder for oral suspension.
Dispersing agents may also be used to facilitate formation of a suspension. Among suitable dispersing agents are included, for example, colloidal silicon dioxide and other pharmaceutically acceptable dispersing agents. In preferred embodiments, a dispersing agent is not included in the powder for oral suspension. Flavorants incorporated in the powder for oral suspension compositions may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants leaves, flowers, fruits, and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of
nutmeg, oil of sage, oil of bitter almonds, arid cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. Solid forms, such as spray-dried forms of flavorants, are particularly useful in the powder for oral suspension compositions disclosed herein. The amount of flavoring may depend on a number of factors including the organoleptic effect desired. The amount of the flavorant used in the powder for oral suspension compositions of the present invention is typically in the range of from about 0.1% to about 4%, based on the total weight of the powder for oral suspension.
Colorants may include titanium dioxide and/or dyes suitable for food such as those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. A colorant is an optional ingredient in the powder for oral suspension compositions disclosed herein but, when used, will generally be present in an amount up to about 0.005% to about 0.15% based on the total weight of the powder for oral suspension.
The powder for oral suspension may also contain wetting agents such as sorbitan monolaurate, polysorbate 80, and sodium lauryl sulfate; the amount of wetting agent, when employed, is typically in the range of from about 0.3% to about 3% based on the total weight of the powder for oral suspension and may also include an anti-foaming agent such as simethicone or dimethicone in amounts typically of from about 0.1% to about 4% based on the total weight of the powder for oral suspension.
The specifically mentioned suitable diluents, sweeteners, binders, suspending agents, buffers, glidants, flavorants, colorants and wetting agents in the foregoing lists are intended to be exemplary, not exhaustive, of specific excipients that may be used in the practice of the disclosed invention. It is further understood that more than one of any particular type of excipient may be used in the powder for oral suspension compositions described herein. For example, the compositions may include more than one flavorant, colorant, etc. Also, a single excipient may provide multiple functions, as mentioned hereinabove.

The powder for oral suspension compositions of the present invention are non-caking as defined hereinabove. Generally, the powder for oral suspension compositions are sold as powders, i.e., before constitution in a suspending medium. The actual suspension is typically prepared by a pharmacist. The oral suspension is thus the actual dosage form ingested by patients.
An azithromycin powder for oral suspension composition in accordance with the present invention maybe supplied in bottles containing for example, 300 mg, 600 mg, 900 mg or 1200 mg azithromycin. Upon constitution in, for example, aqueous media, the suspensions will typically contain either 100 mg azithromycin/S mjL or 200 mg azhhromvcdn/5 mL. The powders for oral suspension may also be supplied in unit dosage packets or sachets that, upon constitution in aqueous media, provide a unit dosage of azithromycin.
In another embodiment, the present invention is directed to a method for making a non-caking azithromycin powder for oral suspension composition comprising the steps of: a) dry mixing azithromycin and a pharmaceutically acceptable excipient to form a first mixture; b) adding to the first mixture and mixing therewith a hydrated buffer and a pharmaceutically acceptable excipient to form a second mixture; c) adding to the second mixture and mixing therewith a pharmaceutically acceptable excipient to form a third mixture; and, d) adding to the third mixture and mixing therewith a pharmaceutically acceptable excipient to form a fourth mixture. In a preferred embodiment, separate portions of a suitable diluent or sweetener, such as sucrose, are mixed in each of steps a), b),c)andd).
It has been surprisingly discovered that non-caking azithromycin powder for oral suspension compositions, particularly those which employ a hydrated buffer as described hereinabove, can be made in accordance with mis method.
In a first step, the azithromycin is combined with pharmaceutically acceptable excipients and mixed, for example, in a high-shear mixer such as a DIOSNA®. This step results in a first mixture. The excipients included in the first mixture may be any of those described hereinabove. Preferred excipients include a glidant, such as colloidal silicon dioxide; a suspending agent, such as xanthan gum; a binder such as hydroxypropyl
cellulose; spray-dried artificial flavorants; and a diluent/sweetening agent, such as sucrose. It is preferred that only a first portion of the total amount of sucrose or other pharmaceuticalry acceptable sweetener used to make the composition is mixed in the first step with any other excipients and the azithromycin. In the foregoing description, the method of making the non-caking powder for oral suspension will be described using sucrose as the primary sweetener. However, it is understood that the method may be employed with other pharmaceutically acceptable sweeteners and/or mixtures thereof. Similarly, the process is not to be construed as United to other specific excipients named in the following discussion.
Thus, the sucrose is preferably added portion-wise to the mixture. The amount of sucrose mixed in the first step is preferably in the range of from about 1% to about 10% w/w based on the total amount of the sucrose used in the powder for oral suspension product. Preferably, the sucrose is milled using a FITZ-MILL® fitted with a 0.84 mm
screen.
i
In a second step, the hydrated buffer is added to the high-shear mixer and mixed therein, resulting in a second mixture. Prior to adding it to the first mixture, the hydrated buffer is preferably milled along with a second part of sucrose, preferably an amount of from about 5% to about 15% w/w based on the total weight of the sucrose used in the powder for oral suspension, using, for example, a FITZ-MHX® preferably fitted with a 0.84 mm screen.
In a third step, another portion of excipients is added to the high-speed mixer and mixed therein, resulting in a third mixture. In a preferred embodiment, this portion of excipients comprises a third portion of the total amount of sucrose used to make the composition. Prior to adding it to the second mixture, the sucrose is preferably milled, for example using a FITZ-MILL®, preferably fitted with a 0.84 mm screen. The amount of sucrose mixed in this step is preferably in the range of from about 20% to about 50% w/w based on the total weight of the sucrose used in the powder for oral suspension.
In a fourth step, a remaining portion of excipients is combined with the third mixture to form a fourth mixture, which is blended in, for example a Y-Conc blender. In a
preferred embodiment, this portion of excipients comprises a fourth portion of the total amount of sucrose used to make the composition. Prior to adding it to the third mixture, the sucrose is preferably sieved through a 16 mesh screen. The amount of sucrose mixed in this step is preferably in the range of from about 30% to about 70% w/w based on the total weight of the sucrose used in the powder for oral suspension.
Upon completion of blending, the final blend which comprises the powder for oral suspension has a particle size such that about 70% to about 80% of the particles are retained on a 60 mesh screen. The bulk density of the final blend will typically be about 0.75 to about 0.95 g/ml, more preferably about 0.85 g/ml.
In yet another embodiment, the present invention is directed to non-caking azithramycin powder for oral suspension compositions made by any of the foregoing processes.
The non-caking azithromycin powder for oral suspension compositions described herein may be administered to a mammal, preferably a human, in a phannaceutically effective amount for the treatment of infection.
The present invention is further exemplified by the following non-limiting examples:
EXAMPLES
Example 1
A non-caking azithromycin powder for oral suspension composition as set forth below in Table 1 was made as described below.
Table 1

(Table 1 Removed)
The non-caking azithromycin powder for oral suspension formulation described in Table 1, was made as follows:
1) The azithromycin, colloidal silicon dioxide, xanthan gum, hydroxypropyl cellulose,
flavor and 1-10% of the sucrose (milled with a FTTZ-MILL® fitted with a 0.84 mm screen
were mixed in a high-shear mixer for 2 minutes.
2) The trisodium phosphate dodecahydrate and 5-15% of the sucrose were milled with
a FTTZ-MILL® fitted with a 0.84 mm screen and mixed with the material from 1) in the
high-shear mixer for 2 minutes.
3) A portion comprising 20-50% of the sucrose was milled through the F1TZ-MILL®
fitted with a 0.84 mm screen and added to the high-shear mixer and mixed for 2 minutes.
4) The remainder, comprising 40-70% of the sucrose was sieved through a 16 mesh
screen, added to the mixture from 3) and blended in a Y-Cone for an additional 20
minutes.
The stability of the powder composition prepared as described above was studied by placing the powder in 60ml HDPE bottles and storing them at room temperature/humidity, i.e., about 25°C/60% relative humidity (RH) and at accelerated conditions, i.e., about 40°C/75% RH. The bottles were capped with child resistant plastic caps. Two packaging configurations were tested for stability. One packaging configuration contained 27.5 g of powder per bottle and the other packaging configuration contained!6.5 g of powder per bottle. No caking or clumping was observed during this stability monitoring, including in powders stored for 6 months at the accelerated conditions
discussed above.
The redispersibility of two batches of the powder composition prepared as described above was tested during storage at room temperature and at accelerated conditions and their suspendability was found to be successful. Redispersability testing was carried out by adding the required amount of water to the powder contained in the bottle. The bottle is shaken well and placed in an incubator at room temperature for 10 days. At the end of the 10-day period, the bottle is again shaken. The suspension was observed to have a smooth consistency with no caking or clumping observed. This demonstrates that the powder for oral suspension formulations in accordance with the present invention also do not cake or clump upon constitution in an aqueous media, as would be done prior to administration.
Example 2
A non-caking azhhromycin powder for oral suspension composition as set forth below in Table 2 was made as described below.
Table!

(Table 2 Removed)
1) Color and Sucrose (Part I materials) were milled through the 0.84 ram
screen and place into the high-shear mixer.
2) Part n materials were transferred to the high-shear mixer from step 1.
3) Part m materials were milled through the 0.84 mm screen, placed into
the high-shear mixer from step 2 and mixed for 2 minutes.
4) Sucrose Caster (Part IV) was milled through the O.S4 mm screen, placed
into the high-shear mixer from step 3 and mixed for 2 minutes.
5) The mixed materials from step 4 were transferred to the blender and
blended with Part V Sucrose Caster sieved through the 16 mesh sieve.
Redispersability testing was carried out by adding the required amount of water to the powder contained in the bottle. The bottle is shaken well and placed in an incubator at room temperature for 10 days. At the end of the 10-day period, the bottle is again shaken. The suspension was observed to have a smooth consistency with no caking or clumping observed.

What is claimed is:
1. A non-caking azithromycin powder for oral suspension composition comprising
azithromycin and a hydrated buffer.
2. The composition according to claim 1, wherein the hydrated buffer comprises a
hydrate of sodium phosphate.
3. The composition according to claim 2, wherein the hydrated buffer comprises
tribasic sodium phosphate dodecahydratc, tribasic sodium phosphate hexahydrate,
tribasic sodium phosphate octahydrate, tribasic sodium phosphate hemihydrate,
dibasic sodium phosphate dihydrate or dibasic sodium phosphate heptahydrate,
4. The composition according to claim 3, wherein the hydrated buffer comprises
tribasic sodium phosphate dodecahydrate.
5. The composition according to claim 4, wherein the tribasic sodium phosphate
dodecahydrate is present in an amount of from about 0.2 to about 2% w/w.
6. The composition according to claim 2, further comprising a pharmaceutically
acceptable excipient.
7. The composition of claim 6, wherein the pharmaceutically acceptable excipient
comprises one or more members selected from the group consisting of diluents,
sweeteners, binders, suspending agents, buffers, glidants, flavorants and colorants.
8. The azithromycin composition according to claim 7, comprising azithromycin,
colloidal silicon dioxide, sucrose, xanthan gum, hydroxypropyl cellulose, artificial
flavors and tribasic sodium phosphate dodecahydrate.
9. The azithromycin composition according to claim 8, comprising about 4.86% w/w
azithromycin (as anhydrous base), about 0.49% w/w colloidal silicon dioxide,
about 93% w/w sucrose, about 0.16% w/w xanthan gum, about 0.12% w/w
hydroxypropyl cellulose, about 0.49% w/w artificial flavors and about 0.8% w/w
tribasic sodium phosphate dodecahydrate.
10. The azithromycin composition according to claim 1, wherein the azithromycin is
azithromycin monohydrate hemiethanolate.
11. A method for making a non-caking azithromycin powder for oral suspension
composition comprising the steps of:
a) dry mixing azithromycin and a pharmaceutically acceptable excipient to
form a first mixture;
b) adding to the first mixture and mixing therewith a hydrated buffer and a
pharmaceutically acceptable excipient to form a second mixture;
c) adding to the second mixture and mixing therewith a pharmaceutically
acceptable excipient to form a third mixture; and,
d) adding to the third mixture and mixing therewith a pharmaceutically
acceptable excipient to form a fourth mixture.

12. The method according to claim 11, wherein the hydratcd buffer comprises a
hydrate of sodium phosphate.
13. The method according to claim 11, wherein the-hydrated buffer comprises tribasic
sodium phosphate dodecahydrate, tribasic sodium phosphate hexahydrale, tribasic
sodium phosphate octahydrate, tribasic sodium phosphate hemihydrate, dibasic
sodium phosphate dihydrate or dibasic sodium phosphate heptahydrate.
14. The method according to claim 13, wherein the hydrated buffer comprises tribasic
sodium phosphate dodecahydrate.
15. The method according to claim 14, wherein the tribasic sodium phosphate
dodecahydrate is milled prior to adding to the first mixture.
16. The method according to claim 14, wherein the tribasic sodium phosphate
dodecahydrate is present in an amount of from about 0.2 to about 2% w/w.
17. The method according to claim 11, wherein the pharmaceutically acceptable
excipient in any of steps a), b), c) or d) comprises one or more members selected
from the group consisting of diluents, sweeteners, binders, suspending agents,
buffers, glidants, fiavorants and colorants.
18. The method according to claim 17, wherein the pharmaceutically acceptable
excipients in step a) comprise colloidal silicon dioxide, xanthan gum,
hydroxypropyl cellulose, sucrose and flavorant
19. The method according to claim 18, wherein step a) comprises mixing a first
portion of the total amount of sucrose used in the azithromycin composition.
20. The method according to claim 19, wherein the amount of sucrose mixed in step a)
is from about 1% to about 10% w/w based on the total weight of the sucrose.
21. The method according to claim 18, wherein step b) comprises mixing a second
portion of the total amount of sucrose used in the azithromycin composition.
22. The method according to claim 21, wherein the amount of sucrose mixed in step b)
is from about 5% to about 15% w/w based on the total weight of the sucrose.
23. The method according to claim 18, wherein step c) comprises mixing a third
portion of the total amount of sucrose used in the azithromycin composition.
24. The method according to claim 23, wherein the amount of sucrose mixed in step c)
is from about 20% to about 50% w/w based on the total weight of the sucrose.
25. The method according to claim 18, wherein step d) comprises mixing a fourth and
remaining portion of the total amount of sucrose used in the azithromycin
composition.
26. The method according to claim 25, wherein the amount of sucrose mixed in step d)
is from about 30% to about 70% w/w based on the total weight of the sucrose.
27. The method according to claim 11, wherein the azithromycin comprises
azithromycin monohydrate hemiethanolate.
28. A method for making a non-caking azithromycin powder for oral suspension
composition comprising mixing azithromycin, a pharmaceutically acceptable
excipient and a hydrated buffer in a manner such that a non-caking azithromycin
powder for oral suspension composition is produced.
29. The method of claim 28 wherein the mixing comprises mixing azithromycin and a
pharmaceutically acceptable excipient to form a first mixture and mixing the first
mixture with a hydrated buffer to form a second mixture.
30. The method of claim 29 wherein the at least one pharmaceutically acceptable
excipient is selected from the group consisting of diluents, sweeteners, binders,
suspending agents, buffers, glidants, flavorants and colorants.
31. The method of claim 29 comprising mixing azithromycin with colloidal silicon
dioxide, xanthan gum, hydroxypropyl cellulose, flavor and sucrose to form the first
mixture.
32. The method of claim 29 farther comprising adding to the second mixture and
mixing therewith a pharmaceutically acceptable excipient to form a third mixture.
33. The method of claim 32 wherein said pharmaceutically acceptable excipient added
to the second mixture comprises sucrose,
34. The method of claim 32 further comprising adding to the third mixture and mixing
therewith a pharmaceutically acceptable excipient to form a fourth mixture.
35. The method of claim 34 wherein said pharmaceutically acceptable excipient added
to the thitd mixture comprises sucrose.
36. The method of claim 29 wherein said hydrated buffer comprises a hydrate of
sodium phosphate.
37. The method of claim 36 wherein said the hydrated buffer comprises tribasic
sodium phosphate dodecahydrate, tribasic sodium phosphate hexahydrate, tribasic
sodium phosphate octahydratc, tribasic sodium phosphate hemihydrate, dibasic
sodium phosphate dihydrate or dibasic sodium phosphate heptahydrate.
38. A non-agglomerating azithroraycin powder for oral suspension composition made
the process of claim 11.
39. A non-agglomeradng azithromycin powder for oral suspension composition made
by the process of claim 18.
40. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 19.
41. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 21.
42. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 23.
43. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 25.
44. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 28.
45. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 29.
46. A non-agglomerating azithromycin powder far oral suspension composition made
by the process of claim 31.
47. A non-agglomerating azithromycin powder for oral suspension composition made
by the process of claim 36.