WO2001076560A1

WO2001076560A1 - Physically stabilized dry powder formulations

Info

Publication number: WO2001076560A1
Application number: PCT/US2001/009711
Authority: WO
Inventors: Gary Ward; Sarvajna Dwivedi
Original assignee: Dura Pharmaceuticals, Inc.
Priority date: 2000-04-11
Filing date: 2001-03-27
Publication date: 2001-10-18
Also published as: EP1274400A1; JP2004515260A; AU2001249479A1; CA2404645A1

Abstract

In a method for making a dry powder formulation for inhalation, a hydrophilic pharmaceutical compound is processed to remove particles having a diameter of less than about 3 microns. A hydrophilic excipient is similarly processed to remove excipient particles having a diameter of less than about 10 microns. The processed pharmaceutical compound and excipient are optionally separately ripened, by exposure to high humidity. They are then blended together to create the formulation, and ripened again, if desired. The removal of fine particles physically stabilizes the formulation. The formulation accordingly provides a consistent respirable dose, even after exposure to high humidity conditions, for long periods of time, such as when a patient opens the packaging of the pharmaceutical, and then uses it over weeks or months.

Description

PHYSICALLY STABILIZED DRY POWDER FORMULATIONS

BACKGROUND OF THE INVENTION

The field of the invention is dry powder pharmaceutical formulations.

Dry powder inhalers are widely used to treat pulmonary diseases, such as asthma, as well as other diseases and conditions. Various dry powder inhaler designs have been proposed and used. In virtually all dry powder inhalers, a dose of dry powder is released from a container, such as a blister disk, gelatin capsule, etc., or a dose is metered out from bulk storage.

The dry powder is formulated either as a pure active pharmaceutical, or an active pharmaceutical and an excipient carrier. In virtually all dry powder inhalers now in use, the patient's inspiratory effort is required to remove and disperse the powder into inhalable primary particles. With most dry powder inhalers, dispersion of particles of from about 1- 5 or 1-10 microns is believed to be necessary for good pulmonary deposition, i.e., to allow the active drug particles to be inhaled deep into the lungs, where they are better absorbed by the body.

Various proposals have been made on improving the efficiency or dispersibility of dry powder formulations. These proposals include using smooth excipient or carrier particles, use of ternary agents, or the addition of fine particles, for example, having diameters of less than about 3 microns. These techniques intend to, at least in part, compensate for the passive dispersion mechanism of current dry powder inhalers, which requires forceful patient inhalation, to achieve adequate dispersion. Generally, having a highly dispersible formulation, including a high percentage of fine particles has been considered to be desirable.

However, one disadvantage with most dry powder formulations is their sensitivity to sorbed moisture. When dry powder formulations are exposed to high relative humidity conditions, for a sufficient time, physical changes can occur in the formulation. These changes may result in particle fusion, sintering, or particle size growth. The end result is often a decrease in dispersibility, and a reduced dose delivered to the patient

These physical changes, in the past, have been attributed to the micronized active pharmaceutical particles present in the formulation. It is well known that the particle size reduction processes, used for making inhalable formulations, may induce disorder in the crystal lattice of the active pharmaceutical particles. This disorder, typically resulting from physical impact, dislocations, etc., creates the so-called amorphous regions. It is also well known that water in the gaseous state may readily enter an amorphous material or region, and act as a plasticizer. This results in enhanced molecular mobility of the amorphous material, leading to a decrease in the glass temperature (Tg), which under certain circumstances (e.g., where Tg approaches ambient temperature) may result in an amorphous to crystalline phase transition. This re-crystallization event may result in inter- particle fusion, potentially leading to a decrease in the fine particle fraction of the dry powder formulation, when the formulation is stored unsealed at elevated relative humidities.

One known approach to resolving this problem is to reduce or eliminate the unstable amorphous phase, by conditioning or by exposing the powder containing the amorphous phase to controlled humidity, prior to packaging. This conditioning process intends to effectively reduce Tg to ambient conditions, changing the immobile amorphous glassy state, to a mobile amorphous rubbery state. The mobile amorphous state readily converts to a more physically stable crystalline state. After conditioning and drying, the powder is then ready for packaging for use in a dry powder inhaler. The intended result of using conditioned powder is to have the powder become more physically stable, upon exposure to elevated relative humidity, when the package is opened. The objective of the conditioning is to convert amorphous phase to a crystalline phase, without producing a significant change in the particle size distribution of the powder. Figure 1 shows an example of micronized albuterol sulfate, before and after conditioning. As shown in Fig. 1, no significant change in particle size distribution is observable after conditioning.

However, it has now been discovered, in connection with powder formulations, that this known conditioning technique of exposing powder to controlled humidity, and then drying it prior to packaging, does not appear to sufficiently improve the physical stability of the formulation, as measured by decreases in the respirable dose of the aerosolized powder formulation, when exposed to high humidity. As an example, Fig. 2 is a graph of respirable dose ( fine particle fraction ) for micronized albuterol sulfate, blended with α-lactose monohydrate, versus storage time in months. The powder formulation, conditioned as is well known in the field, shows a significant decrease in respirable dose, over time. In fact, the respirable dose for the conditioned formulation is almost as rapid as for the unconditioned formulation. This will result in a decrease in the dose received by a patient, when the formulation is stored unpackaged (i. e. , in an opened package ) at common environmental conditions ( for example, 25°C and 75% RH ) over time.

As a result, it has now understood that another previously undiscovered mechanism controls or contributes significantly to the physical instability of dry powder formulations, when exposed to high humidity.

Accordingly, there remains a need for improved inhaled dry powder pharmaceutical formulations, which are more physically stable, even in the presence of high humidity.

BRIEF STATEMENT OF THE INVENTION

In a method for making a dry powder formulation for inhalation, having a hydrophilic pharmaceutical compound, and a hydrophilic excipient, the hydrophilic pharmaceutical compound is processed to remove particles having a diameter of less than about 3 microns. The hydrophilic excipient is also processed to remove excipient particles having a diameter of less than about 10 microns. The processed pharmaceutical compound and processed excipient are mixed or blended. The mixture is then ripened by exposing it to a ripening environment. The ripening environment preferably has relatively high humidity and temperature. During ripening, remaining fine particles tend to fuse to other particles, stabilizing the formulation. The processed hydrophilic pharmaceutical compound, and the processed excipient, may be separately ripened, before they are blended together.

In a method for making a dry powder formulation for inhalation, having a hydrophobic pharmaceutical compound, and a hydrophilic excipient, the hydrophilic excipient is processed to remove particles having a diameter of less than about 10 microns. The processed excipient is blended with the hydrophobic pharmaceutical compound, and the blend is then ripened, by exposure to a high humidity and high temperature environment. The hydrophilic excipient may be separately ripened before blending.

The formulations are more physically stable than prior formulations. As a result, the respirable dose provided by the formulation remains relatively constant over time, even with exposure to high humidity conditions. Consequently, patients using unsealed dry powder inhalers and pharmaceutical powder containers, can continue to receive a consistent and proper dose of inhaled pharmaceutical formulation, even though the inhaler and container may have been unsealed and exposed to humidity in the environment for several weeks or months.

Accordingly, it is an object of the invention to provide an improved dry powder pharmaceutical formulation, methods for making the formulation, and methods for using the formulation.

The foregoing description does not necessarily describe only the essential features or steps of the invention. The invention may reside as well in subcombinations of the above-described features and steps.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph showing the particle size distribution of micronized albuterol sulfate before and after conditioning to remove the amorphous phase, as is known in the art, without changing the particle size distribution.

Fig. 2 is a graph of data for micronized albuterol sulfate formulations in lactose, showing respirable dose per actuation, over time, for albuterol sulfate, conditioned as is known in the art, and also for unconditioned micronized albuterol sulfate.

Fig. 3 is a graph for an albuterol sulfate in lactose formulation, where the formulation was processed according to the invention, to reduce the level of hydrophylic fine albuterol sulfate particles in the formulation, and without similarly processing the lactose, versus an equivalent control formulation, in which neither the albuterol sulfate or the lactose was so processed.

Fig. 4 is a graph showing processing of lactose to remove fine particles, by controlled sieving.

Fig. 5 is a graph showing reduction of fine particles of lactose, by exposure to a high humidity ripening process.

Fig. 6 is a graph showing reduction of fine particles of albuterol sulfate by controlled milling.

Fig. 7 is a graph of physical stability, similar to Fig. 3 but for a micronized beclamethasone dipropianate in lactose formulation, where the lactose fine particles were removed by sieving, and the active drug-lactose formulation was exposed to a high humidity ripening environment.

DETAILED DESCRIPTION

Small particles in a powder are inherently likely to remain highly energetic, even after the amorphous to crystalline phase transition is complete, due to their high surface to volume ratio. These particles are likely to interact with each other, and with other larger particles, which they are in contact with, in an effort to reduce their surface energy, and therefore shift the powder to a more stable state. Such a phenomenon is commonly observed during crystallization from solutions, and is known as Ostwald ripening, or the Kelvin effect. In general, large particles grow in size, at the expense of smaller particles, which fuse or are absorbed into the larger particles.

This phenomenon is believed to also occur in the solid state, in the presence of high levels of atmospheric moisture. This effect appears to be the primary cause of the reduction in the respirable fine particle dose observed for dry powder formulations, after exposure to high relative humidity. If such complete change could be introduced into the dry powder formulation, in a controlled manner during manufacturing, then the formulation would be more physically stable, when exposed to high humidity, after the inhaler or pharmaceutical powdered package is opened and unsealed by the patient. Generally, the respirable fine particle dose or fraction here means particles having an aerodynamic diameter of less than about 6 microns.

For formulations including hydrophilic substances, whether an excipient or carrier, or an active pharmaceutical, the most energetic hydrophilic fines are preferably removed. For active pharmaceutical powders, used in an inhaled formulation, particles of less than 3 microns in diameter, and preferably less than 1 micron in diameter, are removed, to increase stability. In many known formulations, the intent has been to maximize the amount of fine particles, to achieve high efficiency, i.e., good dispersal of the powder, with the available inspiratory force of the patient. Consequently, in the past, the presence of fines (active pharmaceutical particles of less than about 1 micron in diameter) in the formulation, was considered advantageous, as it improved efficiency. Removing fines, as in the step described above, reduces efficiency, and is contrary to the principles of most prior dry powder inhaler formulations.

The removal of fines increases stability, while decreasing efficiency. However, for certain inhalers, and specifically newer inhalers in development, which do not rely on the patient's inspiratory force for powder dispersion, a reduction in efficiency is not critical, and is significantly outweighed by the advantages of improved stability.

The same principal of removing fines for improved stability applies to carriers or excipients in a dry powder formulation. Commonly used excipients are sugars, such as sucrose, fructose, trehalose, and especially lactose. These excipients are hydrophilic or polar. Like hydrophilic active pharmaceutical particles, hydrophilic excipient particles, which have previously undergone particle size reduction (by, for example, milling, spray drying, grinding, controlled crystallization, etc.) will also undergo ripening, where the smaller particles tend to fuse to each other, and to larger particles, thus reducing the particle count and shifting size distribution toward larger particles. Consequently, it is advantageous to remove the hydrophilic excipient fines as well. The function of the excipient is to act as a carrier and/or bulking agent. Particles below about 10 microns do not significantly contribute to this purpose. Consequently, sub- 10 micron particles are preferably removed. Removing them improves the physical stability of the excipient, without degrading the functions performed by the excipient. Even powders which have not been size reduced may have a significant amount of fines present, due to particle attrition during packaging and handling. Fig. 3 graphs the improved stability of albuterol sulfate, via the methods of the invention.

The target preferred minimum particle size cutoff for the excipient particles may vary with the formulation and application, but typically will be less than 50 microns, and preferably will be less than 20 microns, and more preferably less than 10 microns. Similarly, the minimum particle diameter cutoff size for an active pharmaceutical may vary depending on the properties of the pharmaceutical and the specific application. Typically, for an active pharmaceutical, the minimum desirable particle size cutoff is 4, 3, 2, and more preferably one micron in diameter. For many inhaled pharmaceuticals, intended for delivery into the deep lung, the preferred particle size is from 1-10 microns in diameter, or 1-5 microns in diameter. As a result, there is overlap between size range for deep lung deposition, and the range of undesirable fine particles (typically 3 microns or less) which are preferably removed to improve stability. While these factors may have to be balanced in making any specific formulation, depending upon the stability desired, and the deep lung deposition desired, in general, preferably fine active pharmaceutical particles of less than 3 microns are removed, to improve stability.

The fine hydrophilic particles, excipient or active pharmaceutical, can be removed using various known techniques, including controlled milling, sieving, air classification, controlled crystallization or controlled ripening under high humidity. Fig. 4 shows reduction in sub 10 micron lactose particles, by controlled sieving. Fig. 6 shows reduction in sub one micron albuterol sulfate particles, by controlled milling. Fig. 5 shows reduction in sub 10 micron lactose particles by exposure to high humidity.

In formulations intended for inhalation, containing pure active pharmaceutical powder, and no excipient, the initial active bulk powder must undergo particle size reduction, so that the particles are in the preferred respirable range of diameters, typically about 1-10 microns. This size reduction by milling, spray drying, grinding, etc., is thought to create the amorphous areas on the particles, as described above, tending to make these particles unstable. Active hydrophilic pharmaceuticals are accordingly preferably processed to remove the fine particles (typically, less than 3 micron in diameter). The processed hydrophilic pharmaceutical may then also, optionally, be ripened, by exposing it to high humidity before packaging. This results in a more stable neat dry powder. Where the active hydrophilic pharmaceutical is to be prepared in a formulation including a hydrophilic excipient, such as lactose, the pharmaceutical and excipient are initially separately processed to remove the active pharmaceutical fine particles (less than 3 microns), and the excipient is also separately processed to remove the excipient fine particles ( typically less than 10 microns in diameter). The processed active pharmaceutical and the processed excipient may then be separately ripened, by separately exposing them to high humidity. After this separate ripening, the pharmaceutical and excipient are blended, with the blend then preferably further ripened by exposing it to high humidity. Alternatively, the processed pharmaceutical and the processed excipient may be blended (without separate ripening), with the blend then ripened by exposure to high humidity.

The ripening preferably is performed by placing the powder in an air environment at 15-60°C, and a relative humidity of 50-99%, and more preferably in an environment at

20-30°C, and a relative humidity of 50-70%. The duration of the ripening may range from 1-72 hours, and typically the 4-48 hrs. After ripening, the formulation is preferably packaged directly, with no further processing or drying steps.

Hydrophobic, or non-polar active pharmaceutical compositions have been found to be much less subject to the physical instability characteristic of hydrophilic compositions.

However, in formulations where a hydrophobic active pharmaceutical is blended with a hydrophilic excipient, the excipient is preferably processed and ripened, as described above.

Fig. 7 shows data for the hydrophobic pharmaceutical beclomethasone dipropianate and lactose. As shown, by processing the formulation to remove fines, stability is improved.

The amount of fines removed may vary, with fewer fines providing better stability.

Preferably, at least 80%, or 90%, or more preferably, 99%, of the active fines of less than 1 micron in diameter, and of the excipient fines of less than 10 microns in diameter, are removed, before packaging.

Claims

CLAIMS.

1. A method for making a dry powder formulation for inhalation, having a hydrophilic pharmaceutical compound, and a hydrophilic excipient, comprising the steps of:

processing the hydrophilic pharmaceutical compound to remove pharmaceutical particles having a diameter of less than about 3 microns;

processing the hydrophilic excipient to remove excipient particles having a diameter of less than about 10 microns;

blending the processed hydrophilic pharmaceutical and excipient, to make a formulation; and

ripening the formulation by exposing it to a ripening environment.

2. The method of claim 1 wherein the hydrophilic pharmaceutical compound is processed to remove particles having a diameter of less than 1 micron.

3. The method of claim 1 where the pharmaceutical compound is processed by controlled milling, spray drying, air classification, controlled crystallization, or sieving.

4. The method of claim 1 further including the step of separately ripening the at least one of the pharmaceutical compound and the excipient, before blending it, by exposing it to a ripening environment.

5. The method of claim 1 where the ripening environment is air at 15-60°C and a relative humidity of 50-99%.

6. The method of claim 1 wherein the excipient comprises a member selected from mannitol, sucrose, fructose, trehalose, and lactose.

7. The method of claim 1 where at least 10% of the excipient particles (by particle count) having a diameter of less than 10 microns are removed in the excipient processing step.

8. The method of claim 1 where at least 10% of the pharmaceutical compound particles ( by particle count ) having a diameter of less than 1 micron are removed in the pharmaceutical compound processing step.

9. The method of claim 5 where the ripening step is performed for from 4 to

48 hours.

10. A dry powder formulation for inhalation, comprising:

a hydrophilic excipient powder having a reduced number of particles of less than 10 microns in diameter; and

an active pharmaceutical powder blended with the excipient.

11. The formulation of claim 10 where the active pharmaceutical powder comprises a hydrophilic compound having a reduced number of particles of less than 1 micron in diameter.

12. A method for treating a patient with an inhaled dose of a dry powder formulation, comprising the steps of:

preparing a dry powder formulation including a hydrophilic excipient processed to remove fine particles having a diameter of less than 10 microns, and an active pharmaceutical blended with the excipient;

sealing the formulation within at least one container;

storing the at least one container;

delivering the at least one container to a patient;

having the patient unseal the at least one container; and

having the patient inhale a dose of the formulation, from the opened at least one container, at least 15 days after opening the at least one container.

13. The method of claim 12 where the dose delivered after at least 15 days comprises at least 80% of a dose delivered within one day of opening the container.

14. The method of claim 1 wherein the formulation is exposed to the ripening environment until a majority of remaining excipient particles under 10 microns are fused to larger excipient particles.

15. The method of claim 1 wherein the ripening environment is at about 30° C and a relative humidity of about 90%.

16. A dry powder pharmaceutical formulation comprising: a hydrophilic excipient having less than 10% of particles with diameters less than 10 microns; and

a dry active pharmaceutical powder having less than 10% of particles with diameters less than 1 micron.

17. The dry powder pharmaceutical of claim 16 wherein the excipient comprises at least 75% w/w of the formulation.

18. A method of making a dry powder formulation for inhalation, having a hydrophobic pharmaceutical compound, and a hydrophilic excipient, comprising the steps of:

processing the hydrophilic excipient to remove particles having a diameter of less than about 10 microns;

blending the processed excipient with the hydrophobic pharmaceutical compound; and

ripening the blended pharmaceutical compound and excipient by exposing it to a ripening environment.

19. The method of claim 1 where a sufficient number of the excipient and/or pharmaceutical particles are removed, to provide improved physical stability.

20. A method for making a dry powder formulation for inhalation, having a hydrophilic pharmaceutical compound, and a hydrophilic excipient, comprising the steps of:

processing the hydrophilic pharmaceutical compound to remove pharmaceutical particles having a diameter of less than 1 micron; processing the hydrophilic excipient to remove excipient particles having a diameter of less than 10 microns;

ripening the formulation by exposing it to a ripening environment.

21. The formulation of claim 10 wherein the number of particles of the active pharmaceutical compound is reduced by at least 10% by processing the compound before it is combined with the excipient.