U.S. patent application number 10/936075 was filed with the patent office on 2005-05-19 for stabilized azithromycin compositions.
Invention is credited to Hrakovsky, Julia, Khondo, Lev, Lessen, Tania, Mathivanan, Mathi, Pesachovich, Michael, Schwarz, Joseph, Singer, Claude, Tenengauzer, Ruth.
Application Number | 20050106239 10/936075 |
Document ID | / |
Family ID | 27406829 |
Filed Date | 2005-05-19 |
United States Patent
Application |
20050106239 |
Kind Code |
A1 |
Tenengauzer, Ruth ; et
al. |
May 19, 2005 |
Stabilized azithromycin compositions
Abstract
Compositions and methods of stabilizing azithromycin
compositions are described. Stabilized azithromycin compositions
comprise an intimate admixture of azithromycin and a
stabilizing-effective amount of an antioxidant to improve the
resistance of the azithromycin to degradation. Coprecipitation or
co-milling of azithromycin and an antioxidant are particularly
preferred means of achieving an intimate admixture. Pharmaceutical
formulations comprising a stabilized azithromycin composition and
methods of making such formulations are also described.
Inventors: |
Tenengauzer, Ruth; (Hod
Hasharon, IL) ; Schwarz, Joseph; (Toronto, CA)
; Hrakovsky, Julia; (Rosh-H-Ayin, IL) ; Lessen,
Tania; (Toronto, CA) ; Khondo, Lev; (Toronto,
CA) ; Mathivanan, Mathi; (Markham, CA) ;
Singer, Claude; (Kfar Saba, IL) ; Pesachovich,
Michael; (Ramat Gan, IL) |
Correspondence
Address: |
KENYON & KENYON
One Broadway
New York
NY
10004
US
|
Family ID: |
27406829 |
Appl. No.: |
10/936075 |
Filed: |
September 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10936075 |
Sep 7, 2004 |
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10822773 |
Apr 13, 2004 |
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10822773 |
Apr 13, 2004 |
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10274097 |
Oct 18, 2002 |
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6764997 |
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60336346 |
Oct 18, 2001 |
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60331931 |
Nov 21, 2001 |
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60341295 |
Dec 17, 2001 |
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Current U.S.
Class: |
424/464 ;
514/28 |
Current CPC
Class: |
A61P 31/04 20180101;
A61K 9/0095 20130101; A61K 9/2077 20130101; A61K 9/1617 20130101;
A61K 31/7052 20130101; A61K 9/145 20130101 |
Class at
Publication: |
424/464 ;
514/028 |
International
Class: |
A61K 031/7052; A61K
009/20 |
Claims
1-150. (canceled)
151. A dry blend, used for forming azithromycin tablets by direct
compression, comprising: (a) azithromycin; and (b) at least one
pharmaceutically acceptable excipient, wherein said azithromycin is
not azithromycin dihydrate.
152. A dry blend, used for forming azithromycin tablets,
comprising: (a) azithromycin; and (b) at least one pharmaceutically
acceptable excipient, wherein said azithromycin is not azithromycin
dihydrate.
153. The dry blend of claim 151 or 152 wherein said azithromycin
comprises azithromycin ethanolate monohydrate.
154. The dry blend of claim 151 or 152 wherein the azithromycin is
non-granulated.
155. The dryblend of claim 151 or 152 comprising from about 58% to
about 64%, by weight, of the azithromycin.
156. The dry blend of claim 151 or 152 comprising from about 11% to
about 31%, by weight, of a diluent.
157. The dry blend of claim 151 or 152 comprising (a) from about
58% to about 64%, by weight, of the azithromycin; and (b) from
about 11% to about 31%, by weight, of the diluent.
158. The dry blend of claim 157 wherein the diluent is dibasic
calcium phosphate dihydrate.
159. The dry blend of claim 151 or 152 wherein the diluent is
selected from the group consisting of spray dried lactose,
anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch,
cellulose, microcrystalline cellulose, dibasic calcium phosphate
anhydrous, dibasic calcium phosphate dihydrate, calcium carbonate
and calcium sulfate.
160. The dry blend of claim 151 or 152 comprising from about 4.1%
to about 5.6%, by weight, of a disintegrant.
161. The dry blend of claim 151 or 152 comprising: (a) from about
4.1% to about 5.6%, by weight, of the disintegrant; and (b) from
about 1.7% to about 2.4%, by weight, of a lubricant.
162. The dry blend of claim 151 or 152 comprising from about 1.7%
to about 2.4%, by weight, of a lubricant.
163. The dry blend of claim 151 or 152 comprising about 0.5% to
7.0%, by weight, of a lubricant.
164. The dry blend of claim 151 or 152 wherein the lubricant is
selected from the group consisting of magnesium stearate, talc,
stearic acid, glyceryl behenate, polyethylene glycol, ethylene
oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate,
sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal
silica.
165. The dry blend of claim 151 or 152 further comprising a
glidant.
166. The dry blend of claim 151 or 152 wherein the glidant is
selected from the group consisting of colloidal silicon dioxide and
talc.
167. The dry blend of claim 151 or 152 comprising: (a) from about
58% to about 64%, by weight, azithromycin; (b) from about 4.1% to
about 6.7%, by weight, binder; (c) from about 11% to about 31%, by
weight, diluent; (d) from about 4.1% to about 5.6%, by weight,
disintegrant; and (e) from about 1.7% to about 2.4%, by weight,
lubricant.
168. The dry blend of claim 167 wherein the azithromycin is
non-granulated.
169. An azithromycin tablet comprising azithromycin and at least
one pharmaceutically acceptable excipient, wherein said
azithromycin is not azithromycin dihydrate.
170. The azithromycin tablet of claim 169 wherein the azithromycin
comprises azithromycin ethanolate monohydrate.
171. An azithromycin tablet of claim 169 wherein said tablet is
produced by: (a) forming a dry blend of azithromycin and at least
one pharmaceutically acceptable excipient; and (b) direct
compressing said dry blend to form the azithromycin tablet.
172. An azithromycin tablet of claim 171 wherein the azithromycin,
in the dry blend, is non-granulated.
173. An azithromycin tablet of claim 171 wherein the dosage of
azithromycin in said tablet is 500 mg.
174. The azithromycin tablet of claim 173 wherein the azithromycin,
in the dry blend, is non-granulated.
175. A method of forming an azithromycin tablet, comprising: (a)
mixing particles of azithromycin and at least one pharmaceutically
acceptable excipient to form a dry blend; and (b) direct
compressing said dry blend to form the azithromycin tablet, wherein
the azithromycin is not azithromycin dihydrate.
176. The method of claim 175 wherein the azithromycin comprises
azithromycin ethanolate monohydrate.
177. The method of claim 175 wherein the azithromycin is
non-granulated.
178. The method of claim 175 further comprising the step of mixing
a lubricant with the dry blend prior to direct compressing.
179. The method of claim 177 further comprising the step of
precompressing the dry blend.
180. The method of claim 177 further comprising the step of force
feeding the dry blend into a tabletting means.
181. The method of claim 177 wherein the dry blend comprises: (a)
from about 58% to about 64%, by weight, azithromycin; (b) from
about 4.1% to about 6.7%, by weight, binder; (c) from about 11% to
about 31%, by weight, diluent; (d) from about 4.1% to about 5.6%,
by weight, disintegrant; and (e) from about 1.7% to about 2.4%, by
weight, lubricant.
182. A method of treating a bacterial infection in a human or
non-human animal comprising administering to said human or
non-human animal an azithromycin tablet of any of claims 169, 170,
171, 172, 173 or 174.
183. A method of forming azithromycin granules, comprising: a)
mixing (i) a granulating amount of a granulating liquid, (ii)
optionally, one or more pharmaceutically acceptable excipients, and
(iii) azithromycin particles to form wet granules, wherein the wet
granules comprise azithromycin and the granulating liquid; and b)
drying the wet granules to remove the granulating liquid and
thereby form azithromycin granules, wherein the azithromycin is not
azithromycin dihydrate.
184. The method of claim 183 wherein the azithromycin comprises
azithromycin ethanolate monohydrate.
185. The method of claim 183 wherein the azithromycin particles
comprise azithromycin powder.
186. The method of claim 183 wherein the azithromycin is
crystalline.
187. The method of claim 183 wherein the granulating liquid is a
non-aqueous liquid
188. The method of claim 187 wherein the non-aqueous liquid is
denatured alcohol.
189. The method of claim 183 further comprising the step of
dissolving a binder in the granulating liquid prior to mixing the
granulating liquid with the azithromycin.
190. The method of claim 189 wherein the binder is
polyvinylpyrrolidone
191. The method of claim 189 wherein the binder is selected from
the group consisting of acacia, cellulose derivatives, 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.
192. The method of claim 183 further comprising the step of
preblending the azithromycin with at least one pharmaceutically
acceptable excipient prior to mixing with the granulating
liquid.
193. A granule comprising azithromycin and, optionally, one or more
excipients wherein said granule is formed by a wet granulation
process and the azithromycin is not azithromycin dihydrate.
194. The granule of claim 193 wherein said azithromycin comprises
azithromycin ethanolate monohydrate.
195. The granule of claim 193 comprising about 82%, by weight,
azithromycin, about 5.7% binder, about 9.0% filler, and about 2.8%
disintegrant.
196. A granule comprising 98-100%, by weight, azithromycin and
0-2%, by weight, of one or more pharmaceutically acceptable
excipients.
197. A pharmaceutical composition comprising granules of
azithromycin, wherein said granules are formed by a wet granulation
process, and at least one pharmaceutically acceptable excipient,
wherein said azithromycin is not azithromycin dihydrate.
198. The pharmaceutical composition of claim 197 wherein the
azithromycin comprises azithromycin ethanolate monohydrate.
199. A pharmaceutical formulation, comprising: a tablet, capsule,
sachet or powder for suspension which comprises a) granules of
azithromycin; and b) at least one pharmaceutically acceptable
excipient, wherein said azithromycin is not azithromycin
dihydrate.
200. The pharmaceutical formulation of claim 199 wherein said
azithromycin comprises azithromycin ethanolate monohydrate.
201. The pharmaceutical formulation of claim 199 wherein the dosage
of azithromycin is 500 mg.
202. A pharmaceutical formulation, comprising: a) a capsule; b)
granules of azithromycin; and c) at least one pharmaceutically
acceptable excipient, wherein said azithromycin is not azithromycin
dihydrate.
203. The pharmaceutical formulation of claim 202 wherein said
azithromycin comprises azithromycin ethanolate monohydrate.
204. A pharmaceutical formulation, comprising a) granules of
azithromycin, wherein said granules consist essentially of 98-100%,
by weight, azithromycin and 0-2%, by weight, of one or more
pharmaceutically acceptable excipients; and b) at least one
pharmaceutically acceptable excipient, wherein said azithromycin is
not azithromycin dihydrate.
205. The pharmaceutical formulation of claim 204 wherein said
azithromycin comprises azithromycin ethanolate monohydrate.
206. A method of treating a bacterial or protozoal infection in a
mammal, comprising administering to said mammal an effective amount
of a pharmaceutical formulation of any of claims 199, 202 or
204.
207. A pharmaceutical formulation, comprising: a tablet, capsule,
sachet or powder for suspension which comprises a) dry granulated
particles of azithromycin; and b) optionally, one or more
pharmaceutically acceptable excipients, wherein said azithromycin
is not azithromycin dihydrate.
208. The pharmaceutical formulation of claim 207 wherein said
azithromycin comprises azithromycin ethanolate monohydrate.
209. The pharmaceutical formulation of claim 207 wherein the dosage
of azithromycin is 500 mg.
210. The pharmaceutical formulation of claim 207 comprising a
tablet containing about 64%, by weight, azithromycin.
211. An azithromycin tablet comprising (a) from about 58 to about
64 wt % azithromycin; (b) from about 4.1 to about 6.7 wt % binder;
(c) from about 11 to 31 wt % filler; (d) from about 4.1 to about
5.6 wt % disintegrant; and (e) from about 1.7 to about 2.4 wt %
lubricant, wherein said azithromycin is not azithromycin
dihydrate.
212. The azithromycin tablet of claim 211 wherein said azithromycin
comprises azithromycin ethanolate monohydrate.
213. A pharmaceutical formulation in a tablet dosage form, wherein
said tablet is produced by: (a) forming a blend of dry granulated
particles of azithromycin and at least one pharmaceutically
acceptable excipient; and (b) compressing said blend to form the
azithromycin tablet, wherein said azithromycin is not azithromycin
dihydrate.
214. The pharmaceutical formulation of claim 213 wherein the
azithromycin comprises azithromycin ethanolate monohydrate.
215. The pharmaceutical formulation of claim 213 wherein the dosage
of azithromycin is 500 mg.
216. The pharmaceutical formulation of claim 213 further comprising
the step of precompressing said blend prior to compressing said
blend to form the tablet.
217. The pharmaceutical formulation of claim 216 comprising a
tablet containing about 64%, by weight, azithromycin ethanolate
monohydrate.
218. The pharmaceutical formulation of claim 216 wherein the dosage
of azithromycin is 500 mg.
219. A pharmaceutical composition comprising dry granulated
particles of azithromycin and at least one pharmaceutically
acceptable excipient, wherein said azithromycin is not azithromycin
dihydrate.
220. The pharmaceutical composition of claim 219 wherein said
azithromycin comprises azithromycin ethanolate monohydrate.
221. The pharmaceutical composition of claim 219 further comprising
a capsule.
222. The pharmaceutical composition of claim 221 wherein said
pharmaceutically acceptable excipients comprise a diluent, a
disintegrant and a lubricant.
223. A dry granulated azithromycin particle, comprising: (a)
azithromycin; and (b) at least one pharmaceutically acceptable
excipient, wherein said azithromycin is not azithromycin
dihydrate.
224. The dry granulated azithromycin particle of claim 223 wherein
said azithromycin comprises azithromycin ethanolate
monohydrate.
225. The dry granulated azithromycin particle of claim 223 wherein
said pharmaceutically acceptable excipients comprise a diluent, a
disintegrant and a lubricant.
226. The dry granulated azithromycin particle of claim 225 wherein
the diluent is dibasic calcium phosphate dihydrate.
227. The dry granulated azithromycin particle of claim 225 wherein
the diluent is selected from the group consisting of spray dried
lactose, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol,
starch, cellulose, microcrystalline cellulose, dibasic calcium
phosphate anhydrous, dibasic calcium phosphate dihydrate, calcium
carbonate and calcium sulfate.
228. A method of preparing an azithromycin pharmaceutical
formulation, in a tablet, capsule, sachet or powder for suspension
dosage form, comprising: a) forming a blend of azithromycin and at
least one pharmaceutically acceptable excipient; b) compressing the
blend to produce a compressed material; c) milling the compressed
material to produce granules; d) processing the granules into a
tablet, capsule, sachet or a powder for suspension, wherein said
azithromycin is not azithromycin dihydrate.
229. The method of claim 228 wherein said azithromycin comprises
azithromycin ethanolate monohydrate.
230. The method of claim 228 further comprising the step of
blending at least one pharmaceutically acceptable excipient with
the granules to form a blend prior to forming the dosage form.
231. A method of preparing an azithromycin pharmaceutical
formulation, in capsule dosage form, comprising: a) forming a blend
of azithromycin and at least one pharmaceutically acceptable
excipient; b) compressing the blend to produce a compressed
material; c) milling the compressed material to produce granules;
d) processing the granules into a capsule, wherein said
azithromycin is not azithromycin dihydrate.
232. The method of claim 231 wherein said azithromycin comprises
azithromycin ethanolate monohydrate.
233. The method of claim 231 further comprising the step of
blending at least one pharmaceutically acceptable excipient with
the granules to form a blend prior to forming the dosage form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. provisional application Ser. No. 60/336,346, filed
Oct. 18, 2001; No. 60/331,931, filed Nov. 21, 2001; and, No.
60/341,295, filed Dec. 17, 2001. The entire content of each of
these applications is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to stabilized azithromycin
compositions, methods of preparing stabilized azithromycin
compositions, pharmaceutical formulations containing the stabilized
azithromycin compositions and methods of making such
formulations.
BACKGROUND OF THE INVENTION
[0003] The first of the macrolide antibiotics, erythromycin, was
discovered in 1952 among the metabolic products of Streptomyces
erythreus. Erythromycin is most effective against Gram-positive
bacteria. Erythromycin has low acid stability which reduces its
oral bioavailability and necessitates enteric coating of the
drug.
[0004] Azithromycin,
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-
-3-C-methyl-3-O-methyl-.alpha.-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-tr-
ihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethyl
amino)-.beta.-D-xylo-hexopyranosyl]oxy]-1-Oxa-6-azacyclopentadecan-15-one-
, may be considered a second generation macrolide antibiotic.
[0005] Azithromycin is subject to degradation that can occur during
manufacture and storage. In particular, the amine group of
azithromycin is susceptible to oxidation. For example, azithromycin
is susceptible to degradation if exposed to elevated temperatures
and/or air during manufacturing processes, including processes of
formulating pharmaceutical dosage forms of azithromycin. This could
cause the drug product to deviate from regulatory purity
requirements even before the product reaches doctors and patients.
Additionally, once formulated, azithromycin has a tendency to
degrade under normal storage conditions, which may result in an
unacceptable level of impurities at the time of administration.
[0006] Thus, there exists a need for improved azithromycin
compositions and methods of manufacturing such compositions in
which the tendency for degradation of the azithromycin is reduced,
resulting in azithromycin compositions with a higher degree of
purity.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 is an HPLC chromatogram depicting elution profiles of
azithromycin standards.
[0008] FIG. 2 is an HPLC chromatogram depicting typical elution
profiles of azithromycin impurities.
SUMMARY OF THE INVENTION
[0009] One embodiment of the invention is directed to stabilized
azithromycin compositions. A stabilized azithromycin composition
preferably includes an intimate admixture of azithromycin and a
stabilizing-effective amount of an antioxidant. Coprecipitation and
co-milling of azithromycin and an antioxidant are particularly
preferred methods of achieving an intimate admixture.
[0010] Another embodiment of the invention is directed to a method
for preparing a stabilized azithromycin composition. The method
comprises dissolving azithromycin and a stabilizing-effective
amount of an antioxidant in a solvent and co-precipitating the
azithromycin and antioxidant, and, recovering a stabilized
azithromycin composition.
[0011] Stabilized azithromycin compositions can also be prepared by
dissolving azithromycin and a stabilizing-effective amount of an
antioxidant in a first solvent to form a mixture; drying the
mixture; redissolving the mixture in a second solvent;
co-precipitating azithromycin and the antioxidant and recovering a
stabilized azithromycin composition.
[0012] Yet another method for making a stabilized azithromycin
composition in accordance with the present invention includes
co-milling azithromycin and a stabilizing-effective amount of an
antioxidant. In this embodiment, co-milling may be achieved by, for
example, grinding the azithromycin and antioxidant together by
conventional means such as using a mortar and pestle or
co-micronization processes as are generally known in the art.
[0013] Once a stabilized azithromycin composition is prepared in
accordance with the present invention, it is preferably formulated
into pharmaceutical formulations such as conventional dosage forms,
including tablets, capsules (e.g., hard and soft gelatin capsules),
suspensions, sachets, dragees, suppositories, etc. Tablets are
preferred dosage forms. Tablets may be made with the stabilized
azithromycin compositions and optional excipients by processes
including, e.g., wet granulation, dry granulation such as slugging
or compaction, or direct compression, followed by shaping into
tablets.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] Definitions
[0015] As used herein, the term "AZT" refers to azithromycin. The
term "DMAZT" refers to azaerythromycin A (USP), desmethyl
azithromycin. DMAZT is an intermediate used in the synthesis of
azithromycin. The term "TAZT" refers to tosyl azithromycin. The
term "BH" refers to butylated hydroxyanisole. The term "BHT" refers
to butylated hydroxytoluene. The term "PG" refers to propyl
gallate. The term "PVP" refers to polyvinylpyrrolidone. The term
"SLS" refers to sodium lauryl sulfate. The term "APr" refers to
active pharmaceutical ingredient. The term "LOD" refers to loss on
dry.
[0016] Unless otherwise indicated, the term "azithromycin" includes
the salts, hydrates, solvates and physiologically functional
derivatives thereof. The term also includes all polymorphous
forms.
[0017] The term "stabilizing-effective amount," used in reference
to the amount of antioxidant in the stabilized azithromycin
composition, means (1) an amount such that no more than about 3.8%,
preferably no more than about 1.2%, and, most preferably, no more
than about 0.86% by weight of azithromycin in the stabilized
azithromycin composition is degraded upon exposure to 55.degree. C.
for seven days or, (2) an amount such that no more than about
1.25%, preferably no more than about 0.8%, and, most preferably, no
more than about 0.35% by weight of azithromycin in the stabilized
azithromycin composition is degraded upon exposure to 50.degree. C.
for 20 hours.
[0018] Azithromycin degrades when exposed to temperatures above
about 25.degree. C. It has now been found that the addition of
antioxidants to azithromycin protects azithromycin from degradation
at elevated temperatures, which may be due to oxidation and/or
other means.
[0019] In one aspect, the present invention is directed to a
stablized azithromycin composition. In several embodiments, the
azithromycin used is azithromycin ethanolate monohydrate.
Azithromycin ethanolate monohydrate is a stable azithromycin
compound disclosed in U.S. Pat. No. 6,365,574, which is
incorporated herein by reference.
[0020] In one embodiment, the stabilized azithromycin composition
comprises azithromycin and an stabilizing-effective amount of an
antioxidant. As used herein, "antioxidant" refers to a substance
known to inhibit oxidation. Among preferred antioxidants suitable
for use in accordance with the present invention are included
ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic
palmitate, butylated hydroxyanisole, butylated hydroxytoluene,
2,4,5-trihydroxybutyrophenone,
4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum
guaiac, propyl gallate, thiodipropionic acid, dilauryl
thiodipropionate, tert-butylhydroquinone and tocopherols such as
vitamin E, and the like, including pharmaceutically acceptable
salts and esters of these compounds. Preferably, the antioxidant is
a food grade antioxidant, however any antioxidant which is
generally recognized as pharmaceutically acceptable may be
used.
[0021] More preferably, the antioxidant is butylated
hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic
acid, pharmaceutically acceptable salts or esters thereof, or
mixtures thereof. Most preferably, the antioxidant is butylated
hydroxytoluene or sodium ascorbate.
[0022] Preferably, the antioxidant is present in the stabilized
azithromycin compositions in an effective amount to retard or
prevent degradation of azithromycin, thereby stabilizing the
azithromycin. Preferably, the amount of antioxidant is in the range
of about 0.01-10% by weight azithromycin. More preferably, the
amount of antioxidant is in the range of about 0.1-5% by weight
azithromycin. In preferred embodiments, (1) the amount of
antioxidant used is such that no more than about 3.8%, preferably
no more than about 1.2%, and, most preferably, no more than about
0.86% by weight of azithromycin in the stabilized azithromycin
composition is degraded upon exposure to 55.degree. C. for seven
days, or (2) the amount of antioxidant used is such that no more
than about 1.25%, preferably no more than about 0.8%, and, most
preferably, no more than about 0.35% by weight of azithromycin in
the stabilized azithromycin composition is degraded upon exposure
to 50.degree. C. for 20 hours.
[0023] In another aspect, the present invention is directed to a
method for manufacturing a stabilized azithromycin composition.
[0024] In one embodiment, the stabilized azithromycin composition
is made by the addition of an antioxidant to a solution of
azithromycin before crystallizing the azithromycin from the
solution. Upon crystallization, a co-precipitate of azithromycin
and antioxidant is formed and recovered from the solution. The
co-precipitate comprises azithromycin and antioxidant in intimate
admixture. The stabilized composition of azithromycin may then be
formulated into suitable dosage forms with conventional
excipients.
[0025] In another embodiment, the stabilized azithromycin
composition is made by the addition of an antioxidant to an
azithromycin solution at the onset of crystallization of
azithromycin from the solution. A co-precipitate of azithromycin
and antioxidant is formed and recovered from the solution. The
co-precipitate comprises azithromycin and antioxidant in intimate
admixture. The stabilized composition of azithromycin may then be
formulated into suitable dosage forms with conventional
excipients.
[0026] In yet another embodiment, a stabilized azithromycin
composition is made by addition of an antioxidant to an
azithromycin solution and the partial or total evaporation of the
solvent. Preferably, this embodiment comprises the steps of: 1)
dissolving azithromycin and an antioxidant in a first solvent; 2)
evaporating the first solvent to form a dry residue; 3)
redissolving the dry residue in a second (not necessarily
different) solvent; 4) crystallizing azithromycin and 5) adding
additional antioxidant at the onset of crystallization. A
co-precipitate of azithromycin and antioxidant is formed and
recovered from the solution. The co-precipitate comprise
azithromycin and antioxidant in intimate admixture. The stabilized
composition of azithromycin may then be formulated into suitable
dosage forms with conventional excipients.
[0027] The preferred solvent in the disclosed methods is an
alcohol. More preferably, the solvent is a lower straight or
branched-chain alkanol such as ethanol, propanol, isopropanol,
etc.
[0028] In still another embodiment, a stabilized azithromcyin
composition is made by co-milling azithromycin and antioxidant to
form an intimate admixture. Co-milling may be done by grinding the
azithromycin and antioxidant using conventional methods such as
with a mortar and pestle or by co-micronizing the azithromycin and
antioxidant.
[0029] In another aspect, the present invention is directed to
pharmaceutical formulations comprising a stabilized azithromycin
composition as described herein and methods for making such
pharmaceutical formulations. The pharmaceutical formulations
typically contain, in addition to the stabilized azithromycin
composition, one or more pharmaceutically acceptable excipients,
such as binders, fillers, disintegrants, carriers, lubricants,
glidants, flavorants, colorants, buffers, thickening agents, etc.
Some excipients can serve multiple functions, for example as both
binder and disintegrant.
[0030] The pharmaceutical formulations comprising a stabilized
azithromycin composition include dosage forms such as tablets,
granulates, dragees, hard or soft capsules, powders, solutions,
emulsions, suspensions, or the like. Tablets are particularly
preferred dosage forms of the pharmaceutical formulations in
accordance with the present invention. Among the methods for
forming preferred tablet dosage forms are included, e.g., wet
granulation, dry granulation, e.g., compaction and slugging, and
direct compression.
[0031] Examples of tablet disintegrants useful in accordance with
the present invention are starch, pregelatinized starch, sodium
starch glycolate, sodium carboxymethylcellulose, cross inked sodium
carboxymethylcellulose (sodium croscarmellose; crosslinked starch
available under the registered trademark Ac-Di-Sol from FMC Corp.,
Philadelphia, Pa.), clays (e.g. magnesium aluminum silicate),
microcrystalline cellulose (of the type available under the
registered trademark Avicel from FMC Corp. or the registered
trademark Emcocel from Mendell Corp., Carmel, N.Y.), alginates,
gums, surfactants, effervescent mixtures, hydrous aluminum
silicate, cross-linked polyvinylpyrrolidone (available commercially
under the registered trademark PVP-XL from International Specialty
Products, Inc.), and others as known in the art.
[0032] Among preferred disintegrants are sodium croscarmellose
(Ac-Di-Sol), sodium starch glycolate (available commercially under
the registered trademarks Primojel from Avebe (Union, N.J.) or
Generichem, (Little Falls, N.J.), pregelatinized starch and
Explotab from Mendell Corp.), microcrystalline cellulose (Avicel),
and cross-linked polyvinylpyrrolidone (PVP-XL).
[0033] Examples of binders include, e.g., acacia, cellulose
derivatives (such as methylcellulose and carboxymethylcellulose,
hydroxypropylmethylcellulose, 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.
[0034] Flavors incorporated in the composition 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, and 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. The amount of flavoring may depend on a number of factors
including the organoleptic effect desired. Generally the flavoring
will be present in an amount of from 0.5 to about 3.0 percent by
weight based on the total tablet weight, when a flavor is used.
[0035] A variety of materials may be used as fillers or diluents.
Examples are spray-dried or anhydrous lactose, sucrose, dextrose,
mannitol, sorbitol, starch (e.g. starch 1500), cellulose (e.g.
microcrystalline cellulose; Avicel), dihydrated or anhydrous
dibasic calcium phosphate (available commercially under the
registered trademark Emcompress from Mendell or A-Tab and Di-Tab
from Rhone-Poulenc, Inc., Monmouth Junction, N.J.), calcium
carbonate, calcium sulfate, and others as known in the art. A
preferred filler in accordance with the present invention is
dibasic calcium phosphate dihydrate or anhydrous.
[0036] Lubricants can also be employed herein in the manufacture of
certain dosage forms, and will usually be employed when producing
tablets. Examples of lubricants are magnesium stearate, talc,
stearic acid, glycerylbehenate, polyethylene glycol, ethylene oxide
polymers (for example, available under the registered trademark
Carbowax from Union Carbide, Inc., Danbury, Conn.), sodium lauryl
sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl
fumarate, DL-leucine, colloidal silica, and others as known in the
art. Preferred lubricants are magnesium stearate, and mixtures of
magnesium stearate with sodium lauryl sulfate. Lubricants generally
comprise 0.5 to 7.0% of the total tablet weight.
[0037] Other excipients such as glidants and coloring agents may
also be added to azithromycin tablets. Coloring agents 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 coloring agent is an optional
ingredient in the compositions of this invention, but when used
will generally be present in an amount up to about 3.5 percent
based on the total tablet weight.
[0038] As known in the art, tablet blends may be dry-granulated or
wet granulated before tableting. Alternatively, tablet blends may
be directly compressed. The choice of processing approach depends
upon the properties of the drug and chosen excipients, for example
particle size, blending compatibility, density and flowability. For
azithromycin tablets, granulation is preferred, with wet
granulation being most preferred. The stabilized azithromycin
composition may be wet-granulated, and then other excipients may be
added extragranularly. Alternatively, the stabilized azithromycin
composition and one or more excipients may be wet-granulated. Dry
granulation, such as compaction and/or slugging with or without an
intragranular excipient may also be used to make the tablets,
followed by tabletting with or without extragranular excipients. In
addition, tablets may also be coated, with a coating that exhibits
little or no effect on or interference with tablet dissolution, to
assure ease of swallowing or to provide an elegant appearance.
[0039] Tablets may be film-coated to provide ease of swallowing and
an elegant appearance. Many polymeric film-coating materials are
known in the art, including, e.g., hydroxypropylmethylcellulose
(HPMC). HPMC may be obtained commercially, for example from
Colorcon Corp., in coating formulations containing excipients which
serve as coating aids, under the registered trademark Opadry.
Opadry formulations may contain lactose, polydextrose, triacetin,
polyethyleneglycol, polysorbate 80, titanium dioxide, and one or
more dyes or lakes. Other suitable film-forming polymers also may
be used herein, including, hydroxypropylcellulose, and
acrylate-methacrylate copolymers.
[0040] Conventional tableting processes are employed, e.g., by
forming a tablet from a desired blend or mixture of ingredients
into the appropriate shape using a conventional tablet press.
Tablet formulation and conventional processing techniques have been
widely described, for Example in Pharmaceutical Dosage Forms:
Tablets; Edited By Lieberman, Lachman, and Schwartz; Published by
Marcel Dekker, Inc., 2d Edition, Copyright 1989, the text of which
is herein incorporated by reference.
[0041] The azithromycin dosage forms of this invention also include
powders to make oral suspensions, and also the oral suspensions
themselves. Generally the powder is a non-caking, free flowing
powder which is sold direct to pharmacies or other retail outlets
and then made up into the actual suspension by a pharmacist. The
oral suspension is thus the actual dosage form ingested by
patients.
[0042] Azithromycin suspensions may contain, e.g., in addition to a
stabilized azithromycin composition, one or more thickening agents,
a buffer or pH-altering agent. Dispersing agents may also be used
to facilitate formation of a suspension.
[0043] Suitable thickening agents function as suspending agents and
include, for example, hydrocolloid gums known for such purpose,
examples of which include xanthan gum, guar gum, locust bean gum,
gum tragacanth, and the like. Alternatively, synthetic suspending
agents may be used such as sodium carboxymethylcellulose,
polyvinylpyrrolidone, hydroxypropylcellulose and the like.
Dispersing agents include colloidal silicon dioxide, available from
Cabot Corporation, Boston, Mass. under the trade designation
Cab-O-Sil.
[0044] A powder used to make a suspension may also contain
conventional optional ingredients such as (1) wetting agents such
as sorbitan monolaurate, polysorbate 80, and sodium lauryl sulfate;
(2) anti-foaming agents and (3) sweeteners and fillers such as
glucose. The powder may also contain a buffer to maintain a high pH
upon reconstitution, as discussed above. Suitable buffers and
pH-altering agents include tribasic sodium phosphate, anhydrous
sodium carbonate, glycine, and the like. Suitable preservatives are
well known, for example sodium benzoate and the like.
[0045] A stabilized azithromycin composition in accordance with the
present invention may be formulated in a unit dose packet dosage
form or sachet. Such a packet will typically contains a blend of
azithromycin and excipients which is thus reconstituted. In
addition to a stabilized azithromycin composition in accordance
with the present invention, the packet may contain, for example, a
dispersing agent which makes the sachet powder free flowing, for
example colloidal silicon dioxide such as Cab-O-Sil from Cabot. The
dispersing agent may also serve as a glidant. The formulation may
also optionally contain ingredients including (1) a filler or
sweetener (e.g. glucose); (2) a buffer (e.g. sodium phosphate); (3)
a wetting agent such as a surfactant, for example sodium lauryl
sulfate, and (4) flavors such as any of those enumerated herein,
and the like. The powder in the packet flows freely and disperses
quickly, essentially immediately upon stirring when
reconstituted.
[0046] Although the following examples illustrate the practice of
the present invention in some of its embodiments, the examples
should not be construed as limiting the scope of the invention.
Other embodiments will be apparent to one skilled in the art from
consideration of the specification and examples.
EXAMPLES
[0047] General
[0048] The dibasic calcium phosphate dihydrate used was
Emcompress.RTM., which is available from Penwest Pharmaceuticals
Co., Cedar Rapids, Iowa. The sodium starch glycolate used was
Explotab.RTM., which is also available from Penwest
Pharmaceuticals. Sodium lauryl sulfate was used as received from
Cognis (Henkel). The povidone used was povidone K-25 as received
from ISP Pharmaceuticals. The colloidal silicon dioxide used was
either Cab-O-Sil.RTM., available from Astro Chemicals Inc.,
Springfield, Mass., or Aerosil 200.RTM., available from Degussa.
The dibasic calcium phosphate used was A-Tab, which is available
from Rhodia (Rhone Poulenc). The pregelatinized starch used was
Starch 1500.RTM., which is available from Colorcon. The
croscarmellose sodium used was Ac-Di-Sol.RTM., which is available
from Farma International. The tablet coating used was Opadry.RTM.,
which is available from Colorcon. The xanthan gum used is available
from Kelco.
[0049] Quantitation Method Used in Accelerated Stability
Studies
[0050] The quantity of impurities present before and after
oxidative stress were quantified by high performance liquid
chromatography, employing the following conditions:
1 Column: RP18, 5.mu., 150 .times. 4.6 mm Eluent: 40% 0.05M of
potassium hydrogen phosphate (K.sub.2HPO.sub.4) adjusted to pH 8.2
with 20% phosphoric acid; 60% acetonitrile Flow rate: 0.9 ml
min.sup.-1 Detection: UV, .lambda. = 210 nm Column Temp.:
30.degree. C. Sample Volume: 50 .mu.l Diluent: Same as Eluent
Sample solutions were freshly prepared from azithromycin and
injected on column.
[0051] The percentages of impurities were calculated from the
integrator output.
[0052] Performance Evaluation
[0053] The performance of the HPLC system was tested using
standardized solutions of AZT and DMAZT.
Example 1
Admixtures of Azithromycin and BHT
[0054] Mixtures of azithromycin and BHT were prepared using various
methods of admixing to assess their effectiveness at inhibiting
degradation of azithromycin.
[0055] Preparative
Preparation 1 [CS Ex. 1: precipitated]
[0056] Technical grade azithromycin (10 g, 13 mmol) and BHT (0.18
g, 0.82 mmol, 6.1 mole %) were dissolved in absolute ethanol (30
ml) at 20.degree. C. in a 250 ml three-necked flat flanged jacketed
vessel equipped with a mechanical stirrer, a condenser and
thermometer. Water (3 ml) was added at 20.degree. C. and the
solution was heated at a constant 9.degree. C. h.sup.-1 temperature
gradient to 55.degree. C. over about 4 hours. More water (11 ml)
was slowly added to the vessel at between 35.degree. C. and
55.degree. C., which caused a precipitate to form. The resulting
suspension was maintained at 55.degree. C. for another two hours.
During this time interval more water (49 ml) was added to the
suspension. The suspension was then cooled at a constant
temperature gradient from 55.degree. C. to 20.degree. C. over 2
hours and filtered at 20.degree. C. After drying, a stable dry
product (9 g, 90%) was obtained.
Preparation 2 [CS Ex. 2: Added at Cloudiness]
[0057] Technical grade azithromycin (10 g, 13.35 mmol) was
dissolved in absolute ethanol (30 ml) at 20.degree. C. in a 250 ml
three-necked flat flanged jacketed vessel equipped with a
mechanical stirrer, a condenser and thermometer. Water (3 ml) was
added at 20.degree. C. and the solution was heated at a constant
9.degree. C. h.sup.-1 temperature gradient to 55.degree. C. over
about 4 hours. More water (11 ml) was slowly added to the vessel at
between 35.degree. C. and 55.degree. C. Azithromycin began to
precipitate from the solution at 46.degree. C. BHT (0.18 g, 0.82
mmol, 6.1 mole %) was added at the first sign of cloudiness. After
reaching 55.degree. C., the suspension was maintained at that
temperature for another two hours, over which time more water (49
ml) was added. The suspension was then cooled at a constant
18.degree. C. h-1 temperature gradient from 55.degree. C. to
20.degree. C. over about 2 hours and then filtered at 20.degree. C.
A stable dry product (9 g, 90%) was obtained after drying.
Preparation 3 [CS Ex. 3: Portion Evaporated Portion Added at
Cloudiness]
[0058] Technical grade azithromycin (10 g, 13 mmol), and BHT (0.12
g, 0.54 mmol, 4.1 mole %) were dissolved in absolute ethanol (30
ml) at 20.degree. C. in a 250 ml three-necked flat flanged jacketed
vessel equipped with a mechanical stirrer, a condenser and
thermometer. The ethanol was evaporated and the dry residue was
taken up in fresh absolute ethanol (20 ml). Water (3 ml) Was added
at 20.degree. C. and the solution was heated at a constant
9.degree. C. h.sup.-1 temperature gradient to 55.degree. C. over
about 4 hours. More water (11 ml) was slowly added to the vessel at
between 35.degree. C. and 55.degree. C. Azithromycin began to
precipitate from the solution at 46.degree. C. BHT (180 mg, 0.82
mmol, 6.1 mole %) was added at the first sign of cloudiness. After
reaching 55.degree. C., the suspension was maintained at that
temperature for another two hours, over which time more water (49
ml) was added. The suspension was cooled at a constant temperature
gradient of 18.degree. C. h.sup.-1 from 55.degree. C. to 20.degree.
C. over about 2 hours and then filtered at 20.degree. C. A stable
dry product (9 g, 90%) was obtained after drying.
Preparation 4 [Milling]
[0059] Azithromycin (1 g, 1.3 mmol) was weighed out and set aside.
BHT (12 mg, 0.054 mmol, 4.1 mole %) was finely milled with a mortar
and pestle. The azithromycin was added portionwise to the BHT. Each
portion was thoroughly milled with the BHT using the mortar and
pestle.
Preparation 5 [Comparative]
[0060] In this example, no antioxidant was used. In other respects,
the azithromycin was processed according to Preparation 1 and the
resulting product was used as a control sample against which to
compare the degradation rates of stabilized azithromycin
compositions.
[0061] Methodology
[0062] Samples of azithromycin admixtures prepared according to
preparations 1-5 were analyzed by HPLC for impurity content
immediately after their preparation by mixing with an appropriate
quantity of eluent to give an approximately 4 mg/ml clear solution.
Another sample of each of the preparations was stored at 55.degree.
C. The vial contents were analyzed by HPLC seven days after being
placed in the oven.
[0063] Results
[0064] The results of the accelerated stability study on stabilized
azithromycin are recorded in Table 1.
2TABLE 1 Comparison of Degradation of Azithromycin stabilized with
BHT and without Stabilization Upon Exposure to 55.degree. C. Total
Total Impurities Exposure Impurities After BHT Before Exposure Time
Exposure Percent Preparation (mole %) (% Area) (Days) (% Area)
Change Method of Admixing 1 6.1 0.66 7 1.16 0.50 AZT and BHT
co-precipitated from solution 2 6.1 0.88 7 0.98 0.10 Precipitation
of AZT from a suspension of BHT 3 4.1 0.66 7 0.86 0.20
Co-precipitation of AZT and BHT from a suspension of BHT 4 4.1 0.25
16 1.03 0.78 Milling 5 -- 0.27 7 3.76 3.49 No BHT was used
[0065] The four different techniques of intimately admixing
azithromycin and BHT used in Preparations 1-4 led to a significant
reduction in impurity content, relative to the control, after the
admixture was subjected to oxidative stress. The stability results
suggest that degradation occurs by an oxidation pathway because of
the general inhibition achieved by adding the free radical
inhibitor BHT. The degrees of inhibition observed using the
different techniques of admixing are significantly different.
Comparison of the results from Preparations 1 and 2 shows that
oxidation is inhibited somewhat more effectively by adding the
stabilizer as soon as the azithromycin begins to precipitate from
the ethanolic solution, rather than before, but that both
techniques are highly effective. It is believed that addition of
the stabilizer at the time that the azithromycin begins to
precipitate from the solution may be more effective relative to
addition of the stabilizer before precipitation because the
stabilizer or antioxidant (such as BHT) is more effectively
entrapped within the already formed crystals and consequently has
increased protective activity. If the crystals are not yet formed,
the stabilizer or antioxidant is more easily washed out by the
solvent. Comparison of the results from Preparations 2 and 3 shows
that the anti-oxidant inhibiting effect of BHT did not diminish
over time. The best results of azithromycin stabilization were
achieved by forming a stabilized azithromycin composition by
co-milling of azithromycin and an antioxidant such as BHT.
Example 2
Admixtures of Azithromycin and Food Grade Antioxidants
[0066] The inhibiting effect of food grade antioxidants was
explored at yet lower concentrations and with other mixing
methods.
[0067] Preparative
Preparation 6 [M 2206]
[0068] Technical grade azithromycin was recrystallized from
ethanol. No anti-oxidants were added.
Preparation 7 [T 582-02]
[0069] Technical grade azithromycin (300 g, 400 mmol) was
recrystallized from ethanol. BHT (1.2 g, 5.4 mmol, 1.4 mole %) was
dissolved in ethanol and the solution was sprayed onto the
azithromycin with thorough mixing.
Preparation 8 [T 592-03]
[0070] Technical grade azithromycin (300 g, 400 mmol) was
recrystallized from ethanol. BHT (1.2 g, 5.4 mmol, 1.4 mole %) and
PG (1.2 g, 5.7 mmol, 1.4 mole %) were dissolved in ethanol and the
solution was sprayed onto the azithromycin with thorough
mixing.
Preparation 9 [T 582-04]
[0071] Technical grade azithromycin (300 g, 400 mmol) was dissolved
in ethanol and a solution of BHT (1.2 g, 5.4 mmol, 1.4 mole %) in
ethanol was combined with the azithromycin solution. The ethanol
was then evaporated leaving a residue of azithromycin and BHT in
intimate admixture.
Preparation 10 [T 582-05]
[0072] Technical grade azithromycin (300 g, 400 mmol) was dissolved
in ethanol and a solution of BHT (1.2 g, 5.4 mmol, 1.4 mole %) and
PG (1.2 g, 5.7 mmol, 1.4 mole %) was combined with the azithromycin
solution. The ethanol was then evaporated leaving a residue of
azithromycin, BHT and PG in intimate admixture.
[0073] Methodology
[0074] Preparations 6-10 were incubated at 25.degree. C. and
50.degree. C. for 20 hours under open cap conditions.
[0075] Results
[0076] The results of the accelerated stability study comparing
azithromycin stabilized by co-precipitation with an antioxidant and
granulation with an antioxidant-containing solution are reported in
Table 2.
3TABLE 2 Comparison of Degradation of Unstabilized Azithromycin,
Azithromycin Stabilized by Wet Granulation with Antioxidant and
Azithromycin Stabilized by Co-precipitation with an Antioxidant
After Twenty Hours at Ambient or Elevated Temperature Temp
Antioxidant % Impurity 1 % Impurity 2 % Impurity 3 % Impurity 4
Total Preparation (.degree. C.) (mole %) (RRT.sup.a .apprxeq. 0.23)
(RRT.sup.a .apprxeq. 0.30) (RRT.sup.a .apprxeq. 0.34) (RRT.sup.a
.apprxeq. 0.76) Impurity Method of Mixing 6.sup.b 25 -- 0.07 0.19
0.09 0.03 0.38 Antioxidant was not added. (unstabilized) 50 0.30
0.50 0.16 0.16 1.12 7 25 BHT (1.4.sup.b) 0.07 0.24 0.08 0.05 0.44
Azithromycin granulated with an 50 0.32 0.52 0.22 0.16 1.22
ethanolic solution of antioxidant. 8 25 BHT (1.4) 0.06 0.21 0.06
0.04 0.37 Azithromycin granulated with 50 & PG (1.4) 0.28 0.38
0.27 0.15 1.08 an ethanolic solution of antioxidant. 9 25 BHT (1.4)
0.09 0.22 0.07 0.03 0.41 Co-precipitation of AZT and 50 0.08 0.22
0.08 0.06 0.44 antioxidant 10 25 BHT (1.4) 0.08 0.20 0.08 0.03 0.39
Co-precipitation of AZT and 50 & PG (1.4) 0.08 0.22 0.08 0.06
0.44 antioxidants .sup.aRRT = relative retention time .sup.b1.4
mole % corresponds to approximately 0.4 weight percent for both BHT
and PG
[0077] As can be seen by comparison of the results obtained from
Preparations 9 and 10 with those obtained from Preparations 6 and
7, the use of antioxidants resulted in less degradation when the
antioxidants were co-precipitated with azithromycin versus
granulating azithromycin with an ethanolic solution containing the
antioxidants. Degradation of the untreated azithromycin was most
significant at elevated temperature, yet elevated temperature had
little effect upon the degradation rate of azithromycin that was
coprecipitated with an antioxidant (Preparations 9 and 10). In
addition, the mode of application of the antioxidant is more
important to achieving the inhibiting effect than the amount of
antioxidant used (compare the total impurity content of
Preparations 8, 9 and 10 after twenty hours at 50.degree. C.).
Example 3
Wet Granulated Tablet of Stabilized Azithromycin
[0078] In addition to studying the stability of mixtures highly
concentrated in azithromycin (Le., mixtures of azithromycin and an
antioxidant), we studied the stability of azithromycin in
representative pharmaceutical compositions and dosage forms
containing antioxidant mixed with AZT in various ways.
[0079] Formulations
Formulation 1 [T 582-02]
[0080] Stabilized azithromycin resulting from Preparation 7 was
formulated into a wet granulated tablet following the stepwise
procedure below using the components in Table 3.
4TABLE 3 mg/ Per No Components Tablet Wt. % Batch (g) 1 Preparation
7 (AZT granulated with 270 58.35% 219.12 BHT soln.) 2 Dibasic
Calcium phosphate dihydrate 30 6.48 24.28 3 Sodium starch glycolate
9.4 2.03 7.61 4 Sodium lauryl sulfate (SLS) 3.13 0.68 2.54 5
Povidone K-25 (PVP) 19 4.11 15.36 6 Dibasic Calcium Phosphate
Dihydrate 115 24.90 92.95 7 Sodium starch glycolate (SSG) 9.4 2.03
7.61 8 Magnesium stearate 4.75 1.03 3.82 9 Colloidal silicon
dioxide 2.09 0.45 1.69 (Cab-O-Sil .RTM.) Total 462.7 100.00 347.98
10 BHT in Azithromycin: 1.08 0.23 0.88 11 Alcohol 2A (removed in
processing) 40
[0081] 1. A solution of SLS (2.54 g) and PVP K-25 (15.36 g) was
prepared in denatured alcohol formula 2A (40 g) (see USP).
[0082] 2. Preparation 7 (220.0 g) was mixed in a polyethylene bag
with dibasic calcium phosphate dihydrate and sodium starch
glycolate.
[0083] 3. The product of step 2 was transferred into a Hobart
planetary mixer and granulated with the PVP-SLS solution of step 1
at low speed for 1 minute.
[0084] 4. The granulate was passed through a hand screen (#8 mesh)
and dried at 45.degree. C. for 6 hours in a forced air oven.
[0085] 5. The dried granulate of step 4 was passed through a hand
screen (# 16 mesh). The loss on drying (LOD) of the granulate was
2.9% (90.degree. C.).
[0086] 6. The screened granulate was additionally dried at
50.degree. C. for 50 minutes at which point LOD=1.6-1.9%.
[0087] 7. The dried granulation of step 6 was mixed with the
dibasic calcium phosphate dihydrate and SSG in a polyethylene bag
for 2 minutes.
[0088] 8. In a separate bag colloidal silicon dioxide was mixed
with about 100 g of the granulate of step 7 and then passed through
a hand screen (# 16 mesh) and then combined with the remaining
quantity of the granulate of step 7 and mixed for 1 minute in a
polyethylene bag.
[0089] 9. The magnesium stearate was combined with about 100 g of
the granulate of step 8, passed through a hand screen (#16 mesh)
and then combined with remaining quantity of step 8 and mixed for 1
minute in polyethylene bag.
[0090] Capsule-shape tablets were prepared from the granulate
obtained after step 9 using 0.248.times.0.560 inch punches on a B3B
Manesty tablet press.
Formulation 2 [T 582-03]
[0091] Formulation 2 was prepared using the same inactive
ingredients and processing as per Formulation 1 but substituting
Preparation 8 containing AZT granulated with an ethanolic solution
containing 1.4 mole % of BHT and PG for Preparation 7. The
formulation thus contained 0.23 wt. % of each of BHT and PG.
Formulation 3 [T 582-04]
[0092] Formulation 3 was prepared using the same inactive
ingredients and processing as per Formulation 1 but substituting
Preparation 9, a co-precipitate of AZT and 1.4 mole % BHT from an
ethanolic solution, for Preparation 7. The formulation thus
contained 0.23 wt. % of BHT.
Formulation 4 [T 582-05]
[0093] Formulation 4 was prepared using the same inactive
ingredients and processing as per Formulation 1 but substituting
Preparation 110, a co-precipitate of AZT, 1.4 mole % BHT, and 1.4
mole % PG, from an ethanolic solution, for Preparation 7. The
formulation thus contained 0.23 wt. % of BHT and PG.
[0094] Methodology
[0095] All tablets were stressed under "open cap" conditions at
50.degree. C. for. 184 h.
[0096] Results
[0097] The results of the accelerated stability study on tablets
formulated with stabilized azithromycin are reported in Table
4.
5TABLE 4 Comparison of Stability of Wet-Granulated Tablets
Containing 250 mg Stabilized Azithromycin Prepared by Different
Methods of Admixing The Azithromycin and Antioxidant Upon Exposure
to 50.degree. C. Antioxidant Total Impurities (%) (Wt. % of Before
Percent Change Formulation Preparation Tablet) Exposure 66 h 184 h
66 h 184 h Method of Admixing 1 7 BHT (0.23%) 0.47 1.51 2.55 1.04
2.08 AZT granulated with ethanolic solution containing antioxidant.
2 8 BHT (0.23%) 0.37 1.20 2.10 0.83 1.73 AZT granulated with
ethanolic PG (0.23%) solution containing antioxidant. 3 9 BHT
(0.23%) 0.38 0.71 1.17 0.33 0.79 Co-precipitation of AZT and
antioxidant. 4 10 BHT (0.23%) 0.34 0.40 0.58 0.20 0.24
Co-precipitation of AZT and PG (0.23%) antioxidant.
[0098] The results recorded in Table 4 show that an intimate
admixture of AZT and antioxidant obtained by co-precipitation is
more effective at inhibiting degradation in a wet granulated tablet
formulation than the application of the antioxidant during wet
granulation of the AZT with other excipients.
Example 4
Azithromycin Tablet Prepared By Dry Granulation
[0099] The stability of dry granulated tablet formulations of
azithromycin that were pre-compressed by roller compaction was also
assessed in formulations with and without an added food grade
antioxidant.
[0100] Formulations
[0101] Azithromycin was formulated into dry granulated 500 mg
tablets following the stepwise procedure below using the excipients
in Table 5.
6 TABLE 5 Formulations(mg/Tablet) Stage Ingredients 5 6 7 8 9 Part
I Azithromycin 525.3* 525.3* 525.3* 525.3* 525.3* Colloidal
Sio.sub.2 (Aerosil 200 .RTM.) 8.0 8.0 8.0 8.0 8.0 Propyl Gallate --
0.8 -- -- -- BHT -- 0.8 -- 0.4 0.8 Sodium Ascorbate -- -- 1.6 -- --
Part II Dibasic Calcium Phosphate 90.7 89.1 89.1 90.3 89.9
Pregelatinized Starch 55.0 55.0 55.0 55.0 55.0 Croscarmellose
Sodium 18.0 18.0 18.0 18.0 18.0 Talc 32.0 32.0 32.0 32.0 32.0
Magnesium Stearate 2.0 2.0 2.0 2.0 2.0 Part III Colloidal SiO.sub.2
(Aerosil 200 .RTM.) 10.0 10.0 10.0 10.0 10.0 Sodium Lauryl Sulfate
2.4 2.4 2.4 2.4 2.4 Croscarmellose Sodium 28.0 28.0 28.0 28.0 28.0
Talc 13.6 13.6 13.6 13.6 13.6 Magnesium Stearate 15.0 15.0 15.0
15.0 15.0 Coating Opadry .RTM. 24.0 24.0 24.0 24.0 24.0 Theoretical
End Weight 824.0 824.0 824.0 824.0 824.0 *525.3 mg of Azithromycin
solvate is equivalent to 500 mg Azithromycin (based on the specific
API potency of the particular lot used)
Formulation 5 [K-28201]
[0102] 1. Part I materials were blended in a polyethylene bag and
passed through an oscillating granulator (Frewitt.RTM.) equipped
with a 1 mm aperture screen and loaded into a twin shelled Y-cone
dry blender.
[0103] 2. Part II materials were added to the Y-cone blender and
mixed.
[0104] 3. The mix was passed through a roller compactor.
[0105] 4. The compact was twice passed through the oscillating
granulator. In the first pass, the granulator was equipped with a 2
mm aperture screen. In the second pass, the granulator was equipped
with a 1 mm aperture screen. The milled granulate was loaded into a
Y-cone blender.
[0106] 5. The Part III materials were added to the Y-cone blender
and mixed.
[0107] 6. Oval tablets 9.times.17 mm were pressed from the mixture
on a Kilian RLS rotary tablet press.
[0108] 7. A portion of the compressed tablets were coated with
Opadry.RTM. II White. This formulation did not contain
stabilizers.
Formulation 6 [K-28202]
[0109] Formulation 6 was processed using the same inactive
ingredients and processing as per Formulation 5 except that 0.8
mg/tablet BHT and 0.8 mg/tablet PG were added in Step 1 and the
amount of dibasic calcium phosphate used was reduced to give a
tablet of identical theoretical end weight. Formulation 6 contained
0.1 wt. % BHT and 0.1 wt. % Propyl Gallate.
Formulation 7 [K-28483]
[0110] 1. Part I materials were blended in a Diosna.RTM. P-10 high
shear mixer.
[0111] 2. Part II materials were added to the mixer and mixed.
[0112] 3. The mix was passed through a roller compactor.
[0113] 4. The compact was twice passed through a Frewitt. In the
first pass, the Frewitt was equipped with a 2 mm aperture screen.
In the second pass, the Frewitt was equipped with a 1 mm aperture
screen. The milled granulate was loaded into a Y-cone blender.
[0114] 5. The Part III materials were added to the Y-cone blender
and mixed.
[0115] 6. Oval tablets 9.times.17 mm were pressed from the mixture
on a Kilian RLS rotary tablet press.
[0116] 7. A portion of the compressed tablets were coated with
Opadry.RTM. II White.
[0117] The formulation contained 0.2 wt. % of Sodium Ascorbate.
Formulation 8 [K-28484]
[0118] Formulation 8 was processed using the same inactive
ingredients and processing as per Formulation 7 except that 0.4
mg/tablet BHT was added to the Part I materials in lieu of 1.6
mg/tablet sodium ascorbate and the amount of dibasic calcium
phosphate was adjusted to yield a tablet of identical weight.
Formulation 8 contained 0.05 wt. % of BHT.
Formulation 9 [K-28485]
[0119] Formulation 9 was processed using the same inactive
ingredients and processing as per Formulation 8 except that 0.8
mg/tablet BHT was added in Step I and the amount of dibasic calcium
phosphate was reduced by 0.4 mg/tablet. Formulation 9 contained 0.1
wt. % of BHT.
[0120] Methodology
[0121] Tablets were stressed under a variety of storage conditions:
in blister packs, in high density polyethylene (HDPE) bottles, and
in aluminum laminated bags. The containers were filled and then
sealed under ordinary atmosphere. The tablets were stored for five
or seven days at 55.degree. C.
[0122] Results
[0123] The results of the accelerated stability study on tablets
prepared by dry granulation with pre-compression by roller
compaction are reported in Table 6.
7TABLE 6 Stability of Dry-Granulated 500 mg Azithromycin Tablets
Pre-Compressed by Roller Compaction to Storage at 55.degree. C. in
Conventional Pharmaceutical Packaging and with or Without Different
Food Grade Antioxidants Formulated in the Tablets Storage
Stabilizer Exposure Time Total Impurities By HPLC (% Area)
Formulation Conditions (Wt. % of Tablet) (Days) Before Exposure
After Exposure Change 5 (coated) Blister Pack -- 5 0.7 1.3 0.6 5
(coated) HDPE Bottle -- 5 0.7 1.9 1.2 6 (coated) Blister Pack BHT
(0.1) & PG (0.1) 5 0.4 0.6 0.2 6 (coated) HDPE Bottle BHT (0.1)
& PG (0.1) 5 0.4 0.6 0.2 7 (coated) Aluminum Laminate Bag SA
(0.2) 7 0.3 0.8 0.5 7 (uncoated) Aluminum Laminate Bag SA (0.2) 7
0.6 0.9 0.3 8 (coated) Aluminum Laminate Bag BHT (0.05) 7 0.2 0.6
0.4 8 (uncoated) Aluminum Laminate Bag BHT (0.05) 7 0.4 0.7 0.3 9
(coated) Aluminum Laminate Bag BHT (0.1) 7 0.2 0.5 0.3 9 (uncoated)
Aluminum Laminate Bag BHT (0.1) 7 0.3 0.5 0.2
[0124] A significant reduction in the degradation rate of tablets
stored in blister packs and HDPE bottles was observed when 0.2 wt.
percent antioxidant was included in the formulation (compare the
results for Formulations 5 and 6). BHT (alone) and mixtures of BHT
and PG were more effective at inhibiting degradation than SA, but
all three antioxidants provide an inhibiting effect relative to
untreated azithromycin.
Example 5
Azithromycin Tablet Prepared By Dry Granulation--Slugging
[0125] The stability of dry granulated tablet formulations of
azithromycin that were pre-compressed by slugging was also assessed
with and without adding a food grade antioxidant to the
formulation.
[0126] Formulations
Formulation 10 [T 582-08]
[0127] Formulation 10 was prepared using the same inactive
ingredients as Formulation 5.
[0128] 1. Part I materials were blended in a polyethylene bag and
passed through an oscillating granulator (Frewitt.RTM.) equipped
with a 1 mm aperture screen into a twin shelled Y-cone dry
blender.
[0129] 2. Part II materials were added to the Y-cone blender and
mixed.
[0130] 3. The mix was slugged into slugs using a Manesty B3B tablet
press.
[0131] 4. The slugs were milled in the granulator, which was
equipped with a #16 mesh screen and passed into the Y-cone
blender.
[0132] 5. The Part III materials were added to the Y-cone blender
and mixed.
[0133] 6. Oval tablets 9.times.19 mm were pressed from the mixture
on a Manesty B3B rotary tablet press.
[0134] 7. A portion of the compressed tablets were coated with
Opadry.RTM. II White. Coating was performed by top spraying a
suspension of Opadry II.RTM. White in a Fluidized Bed
(Uniglatt.RTM.). The inlet temperature was 60.degree. C.; the
outlet temperature was 40.degree. C. Formulation 10 did not contain
an antioxidant.
Formulation 11 [T 582-09]
[0135] Formulation 11 used the same inactive ingredients as
Formulation 6 and was processed as per Formulation 10. Formulation
11 contained 0.1 wt. % BHT and 0.1 wt. % Propyl Gallate.
[0136] Methodology
[0137] Stabilized and unstabilized azithromycin tablets prepared by
dry granulation with slugging were stored at 60.degree. C. in
sealed amber glass bottles for 114 h. Another bottle of stabilized
azithromycin tablets was stored "open cap" under identical
conditions. Stabilized azithromycin tablets were also studied at
55.degree. C. in polypropylene (PP) and amber glass bottles.
[0138] Results
[0139] The results of the accelerated stability study on tablets
formulated by dry granulation with pre-compression by slugging are
recorded in Table 7.
8TABLE 7 Comparison of Degradation of Dry-Granulated Azithromycin
Tablets with And Without 0.1 Wt. % BHT and 0.1 Wt. % PG at Elevated
Temperatures Total Impurities Detected Storage Condition by HPLC (%
Area) Formulation Storage Container Temp. (.degree. C.) Time (h)
Before Exposure After Exposure Change 10 Amber glass bottle 60 114
0.66 3.86 3.20 (unstabilized) (closed cap) 11 Amber glass bottle
(open cap) 60 114 0.48 1.85 1.37 11 Amber glass bottle (closed cap)
60 114 0.48 1.44 0.96 PP bottle 11 (closed cap with small
headspace).sup.1 55 5 0.42 0.55 0.13 PP bottle 11 (closed cap with
large headspace).sup.2 55 5 0.42 1.16 0.74 amber glass bottle 11
(closed cap with small headspace).sup.1 55 5 0.42 0.49 0.07
.sup.1The bottle was filled with tablets. .sup.2Two Tablets were
added per bottle.
[0140] The results recorded in Table 7 show that including 0.1 wt.
% BHT and 0.1 wt. % PG in the formulation was effective at
inhibiting degradation of azithromycin tablets prepared by dry
granulation with slugging. The stabilized tablets showed a three
fold reduction in degradation compared to unstabilized tablets at
60.degree. C. under identical closed capped conditions. Even under
open cap conditions, the stabilized tablets underwent less than
half the degradation than unstabilized tablets stored in a sealed
bottled.
Example 6
Powder Suitable for Preparing a Liquid Suspension Dosage Form
[0141] The stability of powder formulations suitable for making
liquid dosage forms like suspensions, syrups and elixirs also was
assessed with and without adding a food grade antioxidant to the
formulation.
[0142] Formulations
[0143] Azithromycin was formulated into a powder that can be
constituted as a liquid oral dosage form following the stepwise
procedure below using the excipients in Table 8.
9TABLE 8 Formulation 12 Formulation 13 Stage Ingredients (mg per
dose) (mg per dose) Part I Azithromycin 210.12* 210.12* Aerosil 200
20.00 20.00 BHT -- 0.40 Part II Xanthan Gum 6.50 6.50 Klucel LF
5.00 5.00 Sodium Phosphate Tribasic 20.00 20.00 Part III Sucrose
3850.00 3850.00 Theoretical End Weight 4111.60 4112.00 *210.12 mg
Azithromycin is equivalent to 200 mg Azithromycin base, based on
the specific API batch potency.
Formulation 12 [K-28527]
[0144] 1. Part I materials were passed through an 18 mesh screen
and blended in a Y cone blender.
[0145] 2. Part II materials were added to the Y-cone blender and
mixed.
[0146] 3. Sucrose (milled 0.8 mm screen) was added to the Y-cone
blender and mixed.
[0147] 4. The blend was passed through Frewitt 0.8 mm screen and
blended for 5 minutes.
[0148] Formulation 12 did not contain an antioxidant.
Formulation 13 [K-28528]
[0149] Formulation 13 was prepared using the same inactive
ingredients and processing as Formulation 12, except that 0.01 wt.
% BHT was added in Step 1.
[0150] Methodology
[0151] The stability of the powder blend was studied by placing the
powder in open capped amber bottles and storing them in a vented
over for seven days. The powder also was constituted at 40 mg/ml in
water in amber bottles. The bottles were capped and stored at room
temperature for seven days.
[0152] Results.
[0153] The results of the accelerated stability study on the dry
powder and the (unaccelerated) stability study on the solution are
recorded in Table 9.
10TABLE 9 Comparison of Degradation of Azithromycin Powder
Formulation for Preparing Liquid Dosage Forms with And Without 0.01
Wt. % BHT RRT RRT RRT RRT Total Antioxidants Time T 0.28 0.36 0.38
0.83 Impurity Formulation (Wt. %) (days) (.degree. C.) (%) (%) (%)
(%) (%) 12 -- 0 -- 0.15 0.24 0.11 <0.1 0.50 12 (dry powder) -- 7
55 0.42 0.65 0.28 0.31 1.66 % Change 0.27 0.41 0.17 0.31 1.16 12
(Constituted) -- 7 RT 0.10 0.19 <0.1 <0.1 0.50 % Change.sup.a
.about.0.sup.a .about.0.sup.a .about.0.sup.a .about.0.sup.a
.about.0.sup.a 13 -- 0 -- 0.10 0.19 <0.1 <0.1 0.29 13 (dry
powder) BHT (0.01) 7 55 0.34 0.55 0.23 0.33 1.45 % Change 0.24 0.36
0.23 0.33 1.16 13 (Constituted) BHT (0.01) 7 RT 0.12 0.20 <0.1
<0.1 0.3 % Change 0.02 0.01 0.00 0.00 0.03 .sup.aThe impurity
(identified by RRT in the above table) percentage values at 0 days
and after 7 days (reconstituted) were of negligible difference,
indicating that essentially no degradation occurred during storage
of the reconstituted formulation for 7 days.
[0154] The data shows that the addition of 0.01 wt. % BHT to the
powder formulation for making liquid dosage forms did not improve
the stability of azithromycin in the powder when held at 55.degree.
C. for seven days. The results of Examples 12 and 13 show that, in
general, no additional stability is achieved when the antioxidant
is combined with the azithromycin by simple powder mixing of the
two, in contrast to forming an intimate admixture of the
azithromycin and antioxidant by, e.g., co-precipitation or
co-milling as described hereinabove.
* * * * *