Title:  Stable powder inhalation dosage formulation

United States Patent:  6,482,429

Issued:  November 19, 2002

Inventors:  Etzler; Frank M. (New Milford, CT)

Assignee:  Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT)

Appl. No.:  885349

Filed:  June 20, 2001

An insufflation for the administration of a drug into a body cavity is described where the carrier for the drug is a finely divided powder selected from the group consisting of myoinositol, mannitol and cellobiose.

DETAILED DESCRIPTION OF THE INVENTION

The performance of powder, inhalation capsules is affected by a number of factors. Among such factors, exposure to high (>60% RH) humidity is known to reduce respirable mass. Cellobiose is an alternative to lactose in formulations of pharmaceutical powders for inhalation due to its lower sintering rate in high humidity. Cellobiose is a disaccharide with a structure very similar to that of lactose.

In the following work, a formulation containing cellobiose was compared to a formulation containing lactose using particle sizing and capsule retention measurements. The particle size distributions of cellobiose, lactose, a lactose/ipratropium bromide blend and a cellobiose/ipratropium bromide blend were measured using the Aerosizer (Amherst Processing Instruments). The particle size distributions of blends of cellobiose or lactose with ipratropium bromide were measured using the Aerobreather product manufactured by Amherst Processing Instruments, a device used to measure the particle size distribution of inhaled particles. Capsule retention of cellobiose or lactose blends with ipratropium bromide was determined manually by measuring the powder retained within the capsule after dumping powder out. These experiments are intended to compare some of the performance characteristics of the two formulations under normal, low humidity (<60% RH) conditions.

A sample of cellobiose lot 62H0042 (Sigma Chemical Company) was milled with a mortar and pestle and sifted with a 200 mesh screen using the Sonic Sifter UP by ATM (Serial #A3075). The cellobiose that passed through the screen was collected for experimental use. A blend of 190 mg of cellobiose and 10 mg of ipratropium bromide was made. A blend of 190 mg of lactose (Pharmatose 200M) and 10 mg of ipratropium bromide was also made. The ipratropium bromide was supplied by Boehringer Ingelheim Pharmaceuticals, Inc., of Ridgefield, Conn. Pharmatose 200 M is the commercial name for a sized product comprising lactose monohydrate.

The particle size distribution of the milled cellobiose, Pharmatose 200M and the cellobiose/ipratropium bromide blend was measured using the Aerosizer (Serial #50961117). The Pulse Jet Disperser device (Amherst Processing Instruments) was used for powder dispersion. Three measurements were made for each sample and the results were averaged. Particle size distribution measurements of a lactose(Pharmatose 200 M)/ipratropium bromide blend were used to compare with the cellobiose/ipratropium bromide blend.

Su Heung capsules were filled with 5.5 mg of the cellobiose and Pharmatose 200M blends and then locked. Particle size distributions of the inhaled particles from each blend were measured using the Aerobreather (Serial #0269904A), an instrument that attaches to the Aerosizer and simulates inhalation at different flowrates. In order to measure the particle size distribution of the inhaled particles, the capsules were placed in the a dry powder inhaler and the inhaler was placed into the mouthpiece of the Aerobreather. Each capsule was then pierced prior to inhalation by the Aerobreather. The particle size distributions of the inhaled particles were measured at three different inhalation rates: 20, 40, and 60 l/min. At each flowrate, the particle size distributions of the inhaled particles were measured in triplicate and then averaged.

Capsule retention of the cellobiose/ipratropium bromide blend and lactose/ipratropium bromide blend was measured using capsule lots 72602 (Su Heung), 27985 (Capsugel), supercritical fluid extracted 29625(Capsugel) [see U.S. Pat. No. 6,228,394, issued May 8, 2001], and 31810P(Capsugel). About 5.5 mg +/-0.5 mg of the powder blend was placed into each capsule. The capsule was closed and shaken to disperse the powder throughout the capsule. The capsule was then opened and the blend dumped out of the capsule. The amount of powder remaining in the capsule was then measured gravimetrically. This procedure was repeated ten times for each sample. The results of the ten determinations were averaged.

Table 3:1 below shows the particle size distributions and mean particle sizes of the milled cellobiose, lactose, a cellobiose/ipratropium bromide blend and a lactose/ipratropium bromide blend as measured using the Aerosizer and Pulse Jet Disperser.

 

The mean particle sizes of the cellobiose and lactose samples were almost identical, while the mean particle size of each blend was higher than that of the unblended sugar. The cellobiose sample has more particles under 2 gm and above 10 gm than did the lactose sample. The cellobiose/ipratropium bromide blend has fewer particles under 10 gm and more above 10 gm than did the cellobiose sample. The larger particle sizes for each of the blends indicate that the sugar particles are adhering to ipratropium particles to create larger composite particles. The cellobiose/ipratropium bromide blend has a higher mean particle size than the lactose/ipratropium bromide blend. This result may indicate that cellobiose has somewhat stronger adhesion to ipratropium bromide than does lactose, or alternatively, may reflect differences in the respective particle size distributions of the constituent components.

TABLE 3:2 below shows the particle size distributions and mean particle size of blends of ipratropium bromide and lactose or cellobiose, which were inhaled into the Aerobreather at 20, 40 and 60 l/min.

 

The cellobiose blend has a lower mean particle size than the lactose blend at all three inhalation rates, which is the opposite of the particle sizing results from the Aerosizer. The peaks of the distributions for the cellobiose blend are shifted to lower particle sizes than the lactose blend at all inhalation rates. The difference could reflect differences in adhesion strength, particle size distribution or size selection of retained particles.

TABLE 3:3 below shows the retention of ipratropium bromide and cellobiose or lactose blends after manual retention tests.

 

The retention tests show that lactose has slightly lower retention than cellobiose. This occurs independent of capsule type used. It is likely that cellobiose adheres somewhat more strongly to the capsule surface than does lactose.

In conclusion, cellobiose/ipratropium bromide and lactose/ipratropium bromide blends were prepared and sized. The cellobiose blend has a higher mean particle size than does the lactose blend. The difference in the mean particle size between the two tested blends may suggest a slightly greater adhesion strength between cellobiose and ipratropium bromide than between lactose and ipratropium bromide, or may merely be a consequence of the different particle size distribution of the two materials. The particle size distribution of the blends inhaled into the Aerosizer by the Aerobreather also suggests similar performance of the two blends. The small difference in mean particle size of the inhaled particles may reflect difference in adhesion strength, particle size distribution or size selection of the retained powders but do not suggest markedly different performance. The cellobiose blend was found to be retained in capsules to a greater degree than the lactose blend. This result may reflect a slightly greater adhesion strength between cellobiose and ipratropium bromide than between lactose and ipratropium bromide, or again may be a consequence of the difference in the particle size distribution of the two materials.

Accordingly, the data collected suggests that the performance of cellobiose/ipratropium bromide and Pharmatose 200M/ipratropium bromide blends is similar under low humidity (<60% RH) conditions. The usefulness of cellobiose as a powder carrier was also evaluated by comparing the sintering rates of ground cellobiose, sifted cellobiose (passed through a 200 M U.S. standard mesh sieve, but caught on a 450 M sieve) and 200 M lactose (Pharmatose 200 M).

Claim 1 of 7 Claims

What is claimed is:

1. An insufflation for the administration of a drug into a body cavity which consists of about 0.1% to about 3% by weight of a powder of ipratropium bromide, albuterol sulfate or tiotropium bromide together with a carrier, where the carrier is a finely divided powder selected from the group consisting of myoinositol, cellobiose or a mixture thereof.
 

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