Download PREPARATION AND UTILITY OF SUB-MICRON LACTOSE, A

PREPARATION AND UTILITY OF SUB-MICRON LACTOSE, A NOVEL
EXCIPIENT FOR HFA MDI SUSPENSION FORMULATIONS
Phil Jinks
3M HealthCare Ltd, Loughborough, Leicestershire, LEII 1EP
Summary
HFA MDI formulations fall into two categories; solutions and suspensions. Drugs formulated
as solutions have the advantage of being fully homogeneous and are likely to provide the best
dosing uniformity. However, due to solubility constraints most drugs are formulated as
suspensions and these typically have better chemical stability than their solution counterparts
but are likely to exhibit some degree of inconsistency of dosing behaviour. The latter
inconsistencies arise from a variety of processes such as deposition of particles onto the MDI
can and valve surfaces and rapid flocculation and creaming/sedimentation leading to
inconsistent sampling of the formulation by the valve.
One way to overcome the latter drawbacks of suspension formulations is to include a bulking
agent. This poster describes the preparation and characteristics of a novel bulking agent, which
is a sub-micron dispersion of lactose, prepared by high-pressure homogenisation of
concentrated lactose/ethanol dispersion. Examples are shown of improved MDI dosing
performance achieved by the use of this novel excipient.
Introduction
For many years lactose has been widely utilised as an excipient in Dry Powder Inhalers to
improve both the dosing consistency and the drug respirability from the device(1). In MDIs, the
requirements for dosing consistency and respirability are still paramount, however the use of
bulking agents in the latter systems has never been exploited to any great extent, presumably
due to the formulator perceiving there to be little benefit in their use.
With the advent of potent bronchodilators such as formoterol and salmeterol, certain limitations
of the MDI became more pronounced. In particular, drug deposition and dosing variability
effects can be amplified many fold when one is considering a product with a dose of only 6mcg
per actuation compared with a previously more common dose of 100 to 200mcg.
One way to address the challenges of highly potent suspension formulations in MDIs is to
incorporate a bulking agent with wide compatability with both formulation and hardware
components. The following paper describes the preparation and utility of sub-micron lactose as
a bulking agent with the latter characteristics.
Experimental
1. Preparation of sub-micron lactose(2)
Micronised lactose monohydrate (100g) was dispersed in anhydrous ethanol (840g) using a
Silverson high shear mixer. The dispersion was added to the product reservoir of an Avestin
Emulsiflex C50 homogenizer and recirculated for 20 minutes at a processing pressure of
10,000 psi. The dispersion was then passed out of the homogenizer at 20,000 psi. A viscous
ethanolic slurry of sub-micron lactose was formed.
2. Coflocculation behaviour of sub-micron lactose
sub-micron lactose with
micronised brilliant blue
(E133) 20:1 weight ratio
sub-micron
lactose alone
Figure 1
In Figure 1 above, the vial on the right shows the appearance of sub-micron lactose at a level of
2.64mg/ml in a formulation comprising P134a/ethanol at a weight ratio of 98:2. The
formulation on the left is identical to the formulation on the right with the addition of
micronised brilliant blue (E133) at a level of 0.132mg/ml.
The flocculation and sedimentation dynamics for both systems appeared identical and after
initial settling, the brilliant blue appeared evenly dispersed throughout the formulation
indefinitely, despite being of significantly lower density (1.3g/ml) than lactose (1.6g/ml). This
latter observation was considered highly favourable with regard to the potential for sub-micron
lactose to coflocculate strongly with a drug in suspension and thereby enhance the homogeneity
of the suspension.
3. Size differential between sub-micron lactose and micronised drug
Figure 2
Figure 2 above shows a scanning electron micrograph of the emitted spray from a MDI
incorporating sub-micron lactose in combination with a micronised drug. The micrograph
allows an appreciation of the enormous size differential between sub-micron lactose seen in the
background and the micronised drug particle seen in the centre of the image. Further chemical
and physical characterisation of sub-micron lactose has been performed(3).
4. Pharmaceutical performance of sub-micron lactose containing MDI formulations
4a Through life medication delivery performance of high potency beta agonist HFA MDI
formulation with and without sub-micron lactose
System with no lactose
6
5
4
mcg
3
2
Start Mean : 3.4 mcg
RSD : 41.2%
Middle Mean : 3.8mcg
RSD : 26.3%
1
End Mean : 3.7mcg
RSD : 18.9%
Overall Mean : 3.7mcg
Overall RSD : 27.0%
0
11
12
13
58
59
60
61
118
119
120
Shot Number
Unit 1
Mean
Unit 2
+/-20%
Unit 3
+/-25%
Unit 4
+/-35%
Unit 5
Label Claim
With sub-micron lactose (10:1 sub-micron lactose:drug by weight)
7
6
5
mcg
4
3
Start Mean : 4.7 mcg
RSD : 6.4%
2
Middle Mean : 4.7mcg
RSD : 6.4%
End Mean : 4.6mcg
RSD : 4.4%
Overall Mean : 4.7mcg
Overall RSD : 6.4%
1
0
11
12
13
58
59
60
61
118
119
120
Shot Number
Unit 1
Mean
Unit 2
+/-20%
Unit 3
+/-25%
Unit 4
+/-35%
Unit 5
Label Claim
The above charts show the benefit in terms of dosing consistency derived from the addition of
sub-micron lactose to the formulation.
4b Loss of dose performance of high potency beta agonist HFA MDI formulation with and
without sub-micron lactose
System with no lactose
7
6
5
mcg
4
3
Mean = 3.9mcg
2
1
RSD = 31.3%
Average retained dose (Single Shot): 43.94%
Average retained dose (Double Shot): 78.03%
0
T0 - First Shot
Unit 1
Mean
T0 - Second Shot
Unit 2
+/-20%
T24 - First Shot
Unit 3
+/-25%
Unit 4
+/-35%
T24 - Second Shot
Unit 5
Label Claim
System with sub-micron lactose
7
6
5
mcg
4
3
Mean = 4.4mcg
2
1
RSD = 6.5%
Average retained dose (Single Shot): 89.87%
Average retained dose (Double Shot): 93.61%
0
T0 - First Shot
Unit 1
Mean
T0 - Second Shot
Unit 2
+/-20%
T24 - First Shot
Unit 3
+/-25%
Unit 4
+/-35%
T24 - Second Shot
Unit 5
Label Claim
In the above charts the T0 shots are initial baseline shots and the two T24 shots are fired in
succession after 24 hours and with no priming. The data indicate a substantial reduction in
“loss of dose” with the incorporation of sub-micron lactose.
Conclusions
A novel excipient has been prepared which is a sub-micron dispersion of lactose. The submicron lactose when incorporated into high potency suspension MDI formulations, has been
found to markedly improve system dosing performance.
References
(1) Byron Peter R (1990) Respiratory Drug Delivery. p169 CRC Press Inc.
(2) International patent application no WO0230394A2 page 17
(3) Blatchford C. (2003). Chemical and physical characterisation of sub-micron lactose, a
bulking agent for suspension MDI products. Conference proceedings from Drug
Delivery to the Lungs XIV.