THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
A PROCESS OF ADMINISTERING AEROSOLS OF MACROLIDE ANTIBIOTICS TO THE RESPIRATORY TRACT
M/S. ALEMBIC LIMITED, ALEMBIC ROAD, VADODARA - 390 003, GUJARAT, an Indian Company incorporated under the Companies Act, 1956.
The following composition, manufacturing process and claims particularly describes and ascertains the nature of this invention, and the manner in which it is to be performed.

COMPLETE SPECIFICATION
TITLE OF THE INVENTION : A PROCESS OF ADMINISTERING AEROSOLS OF MACROLIDE ANTIBIOTICS TO THE RESPIRATORY TRACT
What we claim :
1. A process for preparation of Dry Powder Inhalation of Macrolides comprising of the following steps,
a. Mill Roxithromycin (Macrolide antibiotic) using a jet mill to obtain a
mean particle size below 2 micron and 90% particles below 10
micron.
b. Dissolve sodium saccharin (Sweeteners) into a buffered solution of
citric acid - sodium citrate.
c. Separately dissolve Poloxamer 188 (Wetting agent) in water.
d. Wet the milled Roxithromycin obtained in step (a) with the solution of
step (c) and mix thoroughly.
e. Suspend the wet mass of step (d) into the solution of step (b) and
homogenize.
f. Disperse/ dissolve Hydroxypropyl Methylcellulose (coating polymer)
into the formed solution of step (e).
g. Spray-dry the formed suspension of step (f).
h. Blend the collected material of step (g) with lactose (Carrier) in a V-blender.
2. The dosage form of claim 1, wherein the effective amount of the physiologically acceptable Macrolide is administered as 0.6 microgram to 60 mg per dose.
3. The macrolide according to claim 2, which includes Roxithromycin, Azithromycin, Clarithromycin, Erythromycin, Telithromycin or their salts.
4. The dosage form of claim 1, wherein Bulk Sweetener described in step (b) is used in the range of 0.001% to 2.5% w/w.

5. The dosage form of claim 1, wherein the buffered solution described in step (b) is prepared by the using either single or a mixture of citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, potassium hydrogen phosphate, sodium hydrogen phosphate and sulfuric acid.
6. The dosage form of claim 1, wherein Wetting agent described in step (c) may constitute of Poloxamer 188, Lecithin or Polysorbate 80, and is used in the range of 0.001% to 3 % w/w.
7. The dosage form of claim 1, wherein the coating polymer as described in step (f) may constitute of Hydroxypropyl Methylcellulose, Serum Albumin or a mixture thereof and the polymer is used in the range of 0.001% to 10% w/w.
8. The dosage form of claim 1, wherein carrier described in step (h) may constitute of Lactose, Mannitol, Sorbitol and Sucrose or a mixture thereof and the carrier is used in the range of 2.5 % to 99.99% w/w.
9. The dosage form of claim 1, which may contain in addition to the ingredients described above, sodium chloride to impart tonicity and is present in the range of 0.001 % to 1 % w/w.
10. The dosage prepared by the process described in claim 1, due to its
excellent flowability it is suitable to be administered as a Dry Powder for
Inhalation either as a unit dosage form or in a multi-dosage form.

EXAMPLE 1:
Dry Powder for Inhalation of Roxithromycin.

Sr. No. Ingredients Microgram / Dose
1 Roxithromycin 10,000
2 Poloxamer 188 400
3 Citric acid 14
4 Sodium citrate 281
5 Hydroxypropyl Methylcellulose 2,600
6 Sodium Saccharin 1,300
7 Lactose 85,405
Total 100,000
8 Hard Gelatin Capsule "Size 3" 1 unit

Procedure (EXAMPLE 1):
1. Mill Roxithromycin using a jet mill at the rate of 3 Kg per hour with a compressed air pressure of 5.4 Kg/cm2.
2. Prepare a buffered solution by dissolving citric acid 0.14 g and sodium citrate 2.81 g in 280 ml of water. Dissolve 13 g of Sodium saccharin in the formed buffer.
3. Separately dissolve 4 g of Poloxamer 188 in 20 ml of water.
4. Wet the milled Roxithromycin obtained in step (1) with the solution of step (3).
5. Suspend the wet mass of step (4) into the solution of step (2) using a high shear cutter-rotter Homogeniser and mix thoroughly for 2 hrs.
6. Disperse 26 g of Hydroxypropyl Methylcellulose using a triple blade stirrer into the suspension of step 5. The addition should be at the vortex to avoid any lump formation. Once dispersed, reduce the speed of the stirrer and give a gentle agitation for 30 minutes.
7. Spray-dry the formed suspension at an inlet temperature of 80 degree C and atomization air pressure of 3.5 Kg/ cm2 using a twin cyclone system based spray drier (JISL, Mumbai)
8. Blend the dried material of step (7) with 854.05 g of lactose in a V-blender for 2 hrs. The quantity of the lactose is proportionately adjusted depending upon the combined yield in both the cyclones.
9. Fill the individual units (Size 3 capsules) using semi automatic capsule filling machine.

EXAMPLE 2:
Dry Powder for Inhalation of Azithromycin dihydrate.

Sr. No. Ingredients Microgram / Dose
1 Azithromycin 5,000
2 Lecithin 1,200
3 Sodium Hydroxide 6
4 Potassium hydrogen orthophosphate 276
5 Serum Albumin 3,500
6 Sodium Saccharin 700
7 Lactose 39,318
Total 50,000
8 Hard Gelatin Capsule "Size 3" 1 unit

Procedure (EXAMPLE 2):
1. Mill Azithromycin dihydrate using a jet mill at the rate of 2 Kg per hour with a compressed air pressure of 3.5 Kg/cm .
2. Prepare a buffered solution by dissolving Sodium hydroxide 0.06 g and Potassium hydrogen phosphate 2.76 g in 280 ml of water. Dissolve 7 g of Sodium saccharin in the formed buffer.
3. Separately dissolve 12 g of Lecithin in 120 ml of water by the aid of gentle agitation for about 48 hrs.
4. Wet the milled Azithromycin dihydrate obtained in step (1) with the solution of step (3).
5. Suspend the wet mass of step (4) into the solution of step (2) using a high shear cutter-rotter Homogeniser and mix thoroughly for I hr.
6. Dissolve 35 g of Serum Albumin using a triple blade stirrer into the suspension of step 5.
7. Spray-dry the formed suspension at an inlet temperature of 50 degree C and atomization air pressure of 4 Kg/ cm2 using spray drier.
8. Blend the dried material of step (7) with 393.18 g of lactose in a V-blender for 1.5 hrs. The quantity of the lactose is proportionately adjusted depending upon the yield.
9. Fill the individual units (Size 3 capsules) using semi automatic capsule filling machine.

Test reports

Sr.
No. Parameters TEST RESULTS
Example 1 Example 2
1 Description White to off white, free flowing powder, filled in size 3 hard gelatin capsules. White to off white, free flowing powder, filled in size 3 hard gelatin capsules.
2 Average weight 105.29 mg 50.42 mg
3 Bulk density 0.258 g /cc 0.313 g/cc
4 Moisture 0.17% w/w 0.26 % w/w
5 In-vitro deposition*
(Cascade Impactor)
Adaptor
Port
Cone
Stage 0(5.3-10)
Stage 1(4.1-5.3)
Stage 2 (3.2-4.1)
Stage 3 (2.1-3.2)
Stage 4 (1.4-2.1)
Stage 5 (0.62-1.4)
Stage 6 (0.36-0.62)
Stage 7 (0.16-0.36)
Filter (<0.16) (%)
12.4 12.7 0.4 14.1
1
3.0 14.8 26.8 12.0 2.21 0.59
0 (%)
18.6 11.5 0.5 12.6 1.3 2.1 11.7 28.5 10.9 1.5 0.8 0
6 Assay 101.55 %w/w 99.55 % w/w

Respirable fraction (In-vitro deposition) was determined by an Andersen 8-stage cascade impactor operating at 60 L/minute, equivalent to an approximately 4 kPa pressure drop across the inhaler.