U.S. patent application number 10/725845 was filed with the patent office on 2004-06-10 for preparation of powder agglomerates.
Invention is credited to Yang, Tsong-Toh.
Application Number | 20040109828 10/725845 |
Document ID | / |
Family ID | 27365838 |
Filed Date | 2004-06-10 |
United States Patent
Application |
20040109828 |
Kind Code |
A1 |
Yang, Tsong-Toh |
June 10, 2004 |
Preparation of powder agglomerates
Abstract
The invention relates to a method of producing an agglomerate of
drug and solid binder. The process involves producing individual
agglomerate particles and then converting the convertible amorphous
content of same, following agglomeration, by the application of,
for example, moisture. Agglomerates capable of conversion as well
as the finished agglomerates and oral and nasal dosing systems
including same are also contemplated. The process produces
agglomerates which are rugged but which will produce an acceptable
fine particle fraction during dosing.
Inventors: |
Yang, Tsong-Toh; (Warren,
NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
27365838 |
Appl. No.: |
10/725845 |
Filed: |
December 2, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10725845 |
Dec 2, 2003 |
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10238423 |
Sep 10, 2002 |
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10238423 |
Sep 10, 2002 |
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09901205 |
Jul 9, 2001 |
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6495167 |
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09901205 |
Jul 9, 2001 |
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09824377 |
Apr 2, 2001 |
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6503537 |
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09824377 |
Apr 2, 2001 |
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09042973 |
Mar 17, 1998 |
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60041055 |
Mar 20, 1997 |
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Current U.S.
Class: |
424/46 ;
514/172 |
Current CPC
Class: |
A61K 31/58 20130101;
A61K 9/0043 20130101; A61K 9/1623 20130101; A61K 47/183 20130101;
A61K 9/0075 20130101; A61P 11/06 20180101; A61K 9/1617 20130101;
A61K 47/26 20130101 |
Class at
Publication: |
424/046 ;
514/172 |
International
Class: |
A61L 009/04; A61K
009/14; A61K 031/58 |
Claims
What is claimed is:
1. A process of producing agglomerates comprising the steps of: (a)
providing particles of at least one first material and particles of
at least one solid binder, at least one of said first material and
said solid binder having a preselected amount of convertible
amorphous content which is capable of being converted to
crystalline form upon exposure to a preselected stimulus, said
convertible amorphous content being provided in an amount which is
sufficient to allow for the formation of agglomerates; (b)
agglomerating said particles of said first material and said solid
binder while maintaining said preselected amount of convertible
amorphous content; and thereafter (c) exposing said convertible
amorphous content within said agglomerates to said preselected
stimulus so as to convert said convertible amorphous content to a
crystalline form.
2. The process of claim 1 wherein said first material comprises a
pharmacologically active agent.
3. The process of claim 2 wherein said pharmacologically active
agent comprises at least one member selected from the group
consisting of corticosteroids, .beta.-agonists, anticholinergics,
leukotriene antagonists and inhalable proteins or peptides.
4. The process of claim 2, wherein said pharmacologically active
agent comprises at least one member selected from the group
consisting of: mometasone furoate; beclomethasone dipropionate;
budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone;
salbutamol; albuterol; terbutaline; salmeterol; bitolterol;
ipratropium bromide; oxitropium bromide; sodium cromoglycate;
nedocromil sodium; zafirlukast; pranlukast; formoterol;
eformoterol; bambuterol; fenoterol; clenbuterol; procaterol;
broxaterol;
(22R)-6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alp-
ha.,17.alpha.-propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005;
tipredane; insulin; interferons; calcitonins; parathyroid hormones;
and granulocyte colony-stimulating factor.
5. The process of claim 2, wherein said pharmacologically active
agent comprises mometasone furoate.
6. The process of claim 2, wherein said particles of said
pharmacologically active agent have an average particle size of 10
.mu.m or less.
7. The process of claim 1, wherein said solid binder comprises at
least one member selected from the group consisting of polyhydroxy
aldehydes, polyhydroxy ketones, and amino acids.
8. The process of claim 1, wherein said solid binder comprises a
hydrated or anhydrous saccharide.
9. The process of claim 1, wherein said solid binder comprises
anhydrous lactose or a hydrated lactose.
10. The process of claim 1 wherein said solid binder comprises
anhydrous lactose.
11. The process of claim 2, wherein said particles of said solid
binder have an average particle size of 10 .mu.m or less.
12. The process of claim 2, wherein said agglomerate contains
between about 1% and about 50% convertible amorphous content.
13. The process of claim 2, wherein said agglomerate contains
between about 3% and about 30% convertible amorphous content.
14. The process of claim 2, wherein said agglomerate contains
between about 5% and about 25% convertible amorphous content.
15. The process of claim 2, further comprising the step of mixing
said particles of pharmacologically active agent and said solid
binder prior to said agglomerating step.
16. The process of claim 14, wherein said particles of
pharmacologically active agent and said solid binder are mixed to
substantial homogeneity.
17. The process of claim 2, wherein said particles of
pharmacologically active agent and said solid binder are
agglomerated in a pan rotated with an eccentric motion.
18. The process of claim 2, wherein said agglomerates have an
average size of between about 300 and about 1000 .mu.m.
19. The process of claim 2, wherein said agglomerates have a range
in size from between about 100 and about 1500 .mu.m.
20. The process of claim 1 wherein said preselected stimulus is
atmospheric moisture.
21. The process of claim 1, wherein said solid binder is maintained
at a moisture content of less than or equal to that of a relative
humidity of 25% when measured at 21.degree. C., prior to
crystallization.
22. The process of claim 1, wherein said solid binder is maintained
at a moisture content of less than or equal to that of a relative
humidity of 20% when measured at 21.degree. C., prior to
crystallization.
23. The process of claim 2, further comprising converting said
convertible amorphous content of said agglomerate into a
crystalline form by exposure of said agglomerates to an atmosphere
having a moisture content equal to that of a relative humidity of
between about 30% and about 80% when measured at 25.degree. C.
24. The process of claim 23, wherein said convertible amorphous
content is converted into a crystalline form by exposure of said
agglomerates to an atmosphere having a moisture content equal to
that of a relative humidity of between about 40% and about 60% when
measured at 25.degree. C.
25. The process of claim 2, wherein said particles of said
agglomerate are more strongly bound to one another after conversion
of said amorphous content to a crystalline form than before
conversion.
26. The process of claim 2, wherein said agglomerates have a crush
strength of between about 50 mg and about 5,000 mg after conversion
of said convertible amorphous content.
27. The process of claim 2, wherein said agglomerates have a crush
strength of between about 200 mg and about 1,500 mg after
conversion of said convertible amorphous content.
28. The process of claim 1, further comprising the step of
micronizing said solid binder and/or said first material to impart
thereto a preselected amount of amorphous content to the resulting
particles prior to the step of providing said particles.
29. The process of claim 28, wherein said solid binder is
micronized using jet milling with a substantially anhydrous
gas.
30. The process of claim 2, wherein said pharmacologically active
agent and said solid binder are mixed at a weight ratio of between
about 1000:1 to 1:1000.
31. The process of claim 2, wherein said pharmacologically active
agent and said solid binder are mixed at a weight ratio of between
about 100:1 to 1:500.
32. The process of claim 2, wherein said pharmacologically active
agent and said solid binder are mixed at a weight ratio of between
about 100:1 to 1:300.
33. The process of claim 2, wherein said pharmacologically active
agent and said solid binder are agglomerated at a weight ratio of
between about 20:1 to about 1:20.
34. The process of claim 2, wherein said pharmacologically active
agent and said solid binder are agglomerated at a weight ratio of
between about 1:3 to about 1:10.
35. The product of the process of claim 1.
36. The product of the process of claim 2.
37. The product of the process of claim 3.
38. A process for producing agglomerates containing a
pharmacologically active agent, comprising the steps of: (a)
providing at least one pharmacologically active agent having an
average particle size of below about 10 .mu.m; (b) providing at
least one solid binder having an average particle size of about 10
.mu.m or below; at least one of said pharmacologically active agent
and said solid binder having a preselected amount of convertible
amorphous content which is sufficient to allow for the formation of
agglomerates upon conversion; (c) forming a homogeneous mixture of
said particles of said pharmacologically active agent and said
solid binder while maintaining said preselected amount of
convertible amorphous content; (d) agglomerating said mixture of
said particles of said pharmacologically active agent and said
solid binder while maintaining said preselected amount of
convertible amorphous content of said solid binder; and (e)
thereafter allowing said convertible amorphous content of said
agglomerates to convert to a crystalline form; to form (f)
agglomerates which are free-flowing, have bridges and are
characterized by having a strength of between 50 mg and 5000
mg.
39. The process of claim 38 wherein said pharmacologically active
agent comprises at least one member selected from the group
consisting of corticosteroids, .beta.-agonists, anticholinergics,
leukotriene antagonists and inhalable proteins or peptides.
40. The process of claim 38, wherein said pharmacologically active
agent comprises mometasone furoate
41. The process of claim 38, wherein said solid binder comprises
anhydrous lactose or a hydrated lactose.
42. The process of claim 38, wherein said agglomerate contains
between about 1% and about 50% convertible amorphous content prior
to conversion.
43. The process of claim 38, wherein said agglomerate contains
between about 3% and about 30% convertible amorphous content prior
to conversion.
44. The process of claim 38, wherein said agglomerate contains
between about 5% and about 25% convertible amorphous content prior
to conversion.
45. The process of claim 38, wherein said agglomerates have a
strength of between 200 mg and about 1500 mg.
46. A dosage form of a pharmacologically active agent useful for
administration by oral inhalation therapy consisting essentially
of: agglomerates of particles of a pharmacologically active agent
and particles of crystalline solid binder, said particles having an
average particle size of 10 .mu.m or less and being provided in a
weight ratio of between 100:1 to 1:500, said agglomerates having an
average size of between 400 and 700 .mu.m, a bulk density of
between about 0.2 and about 0.4 g/cm.sup.3 and a crush strength of
between 200 mg and about 1500 mg.
47. The dosage form of claim 46, wherein said crystalline solid
binder comprises lactose.
48. The dosage form of claim 47, wherein said crystalline lactose
comprises anhydrous lactose.
49. The dosage form of claim 46, wherein said agglomerates have a
bulk density of between about 0.29 and about 0.38 g/cm.sup.3.
50. The dosage form of claim 46 wherein said pharmacologically
active agent comprises at least one member selected from the group
consisting of corticosteroids, .beta.-agonists, anticholinergics,
leukotriene antagonists and inhalable proteins or peptides.
51. The dosage form of claim 46, wherein said pharmacologically
active agent comprises at least one member selected from the group
consisting of: mometasone furoate; beclomethasone dipropionate;
budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone;
salbutamol; albuterol; terbutaline; salmeterol; bitolterol;
ipratropium bromide; oxitropium bromide; sodium cromoglycate;
nedocromil sodium; zafirlukast; pranlukast; formoterol;
eformoterol; bambuterol; fenoterol; clenbuterol; procaterol;
broxaterol; (22R)-6.alpha.,9.alpha.-difluoro-11.beta.,21-dihy-
droxy-16.alpha.,17.alpha.-propylmethylenedioxy-4-pregnen-3,20-dione;
TA-2005; tipredane; insulin; interferons; calcitonins; parathyroid
hormones; and granulocyte colony-stimulating factor.
52. The dosage form of claim 46 wherein said agglomerate includes
no binder other than said solid binder.
53. An intermediate agglomerate useful for producing a free-flowing
crystalline agglomerate dosage form of a pharmacologically active
agent useful for administration by oral or nasal inhalation
therapy, said intermediate agglomerates comprising: particles of
said pharmacologically active agent and particles of solid binder,
said pharmacologically active agent or said solid binder having a
preselected amount of convertible amorphous content which is
sufficient to allow for the formation of crystalline agglomerates
upon exposure to moisture, said particles of said pharmacologically
active agent and said particles of said solid binder having an
average particle size of 10 .mu.m or less, and said particles being
provided in a weight ratio of between 1000:1 to 1:1000.
54. The intermediate agglomerate of claim 53 having an average size
of between 300 and 1000 .mu.m, and a bulk density of between about
0.2 and about 0.4 g/cm.sup.3.
55. The intermediate agglomerate of claim 53, wherein said lactose
comprises anhydrous lactose.
56. The dosage from of claim 53, having a bulk density of between
about 0.29 and about 0.38 g/cm.sup.3.
57. The intermediate agglomerate of claim 53, having an average
size of between 400 and about 700 .mu.m.
58. The intermediate agglomerate of claim 53 wherein said
pharmacologically active agent comprises at least one member
selected from the group consisting of corticosteroids,
.beta.-agonists, anticholinergics, leukotriene antagonists and
inhalable proteins or peptides.
59. The intermediate agglomerate of claim 53, wherein said
pharmacologically active agent comprises at least one member
selected from the group consisting of: mometasone furoate;
beclomethasone dipropionate; budesonide; fluticasone;
dexamethasone; flunisolide; triamcinolone; salbutamol; albuterol;
terbutaline; salmeterol; bitolterol; ipratropium bromide;
oxitropium bromide; sodium cromoglycate; nedocromil sodium;
zafirlukast; pranlukast; formoterol; eformoterol; bambuterol;
fenoterol; clenbuterol; procaterol; broxaterol;
(22R)-6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha-
.-propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005; tipredane;
insulin; interferons; calcitonins; parathyroid hormones; and
granulocyte colony-stimulating factor.
60. The intermediate agglomerate of claim 63, having a convertible
amorphous content of between about 1 and about 50% by weight.
61. A dosing system comprising: (a) an inhaler, said inhaler
including a storage reservoir for storing an amount of a
pharmacologically active agent in the form of a crystalline
agglomerate, sufficient to provide a plurality of individual doses
thereof, a metering device for measuring and metering a preselected
amount of said pharmacologically active agent from said storage
reservoir, and a nozzle for conveying said pharmacologically active
agent from said metering device to the mouth or nose of a patient;
and (b) an amount of a pharmacologically active agent sufficient to
provide a plurality of individual doses thereof, said
pharmacologically active agent being stored within said storage
reservoir, being provided as an agglomerate of particles of said
pharmacologically active agent and particles of a crystalline
binder, wherein said particles have an average particle size of 10
.mu.m or less and the components thereof are provided in a weight
ratio of between 1000:1 to 1:1000, said agglomerates having an
average size of between 300 and 1000 .mu.m and a bulk density of
between about 0.2 and about 0.4 g/cm.sup.3; and said agglomerate
and said inhaler, when used in combination, being capable of
producing a fine particle fraction of at least 10%, at an inhaled
air flow rate about 60 L/min.
62. The dosing system of claim 61, wherein said crystalline
agglomerates have a strength of between about 50 mg and about 5000
mg and wherein said inhaler is designed such that it will impart to
said agglomerated pharmacologically active agent an amount of force
which is sufficient to produce a fine particle fraction of at least
10%, at an inhaled air flow rate about 60 L/min.
63. The dosing system of claim 61, wherein said crystalline
agglomerates have a strength of between about 200 mg and about
1,500 mg and wherein said inhaler is designed such that it will
impart to said agglomerated pharmacologically active agent an
amount of force which is sufficient to produce a fine particle
fraction of at least 10%, at an inhaled air flow rate about 60
L/min.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates broadly to the formation of
agglomerates. More specifically, the present invention relates to
the field of pharmaceutical dosage form design and, in particular,
the production of unique agglomerated dosage forms for
administration of pharmacologically active agents to patients. The
formulations in accordance with this invention are particularly
well suited for oral and/or nasal inhalation.
INTRODUCTION TO THE INVENTION
[0002] There are several known methods of treating diseases and
conditions of the upper and lower airway passages and the lungs.
These conditions include, for example, asthma and rhinitis. One
such technique involves administering certain pharmacologically
active agents or drugs such as, for example, mometasone furoate,
topically to the airway passages or lungs in an immediately useable
form. Mometasone furoate is a topically effective, steroidal
anti-inflammatory.
[0003] Oral inhalation therapy is one method of delivering such
topically active drugs. This form of drug delivery involves the
oral administration of a dry powdered drug directly to the
afflicted area in a form which is readily available for immediate
benefit.
[0004] However, inhalation therapy is a particularly demanding
dosing system and it involves its own set of unique design and
performance problems. Amongst those problems is a concern over the
accuracy and repeatability of dosing. One must try to ensure that
the same amount of drug is administered each and every time.
Moreover, unlike pills, capsules and creams, oral inhalation
therapy must concern itself with not only the dosage form itself,
but also a drug delivery device and the interaction between them.
One has only to consider over-the-counter nasal sprays to
understand this problem. When one squeezes a conventional squeeze
bottle, it is difficult to apply the same amount of force each and
every time. With even a slight difference in force, differences in
the amount of drug administered can result. Even with somewhat more
consistent pump style spray applicators, variations in dosing can
occur. While such variation is usually not a problem when
administering OTC nasal sprays, variation should be minimized where
possible when administering prescription medications for such
serious conditions as asthma. The dangers of over-medicating or
under-medicating and the consequences of such unwanted deviation
can be profound. The problem becomes even more complex when the
size of the doses are as small as they often are in oral inhalation
therapy.
[0005] To help mitigate these problems, companies such as Schering
Corporation have developed complex and highly accurate inhaler
systems for administering powdered medications such as those
described in PCT International Publication No. WO 94/14492, which
was published on Jul. 7, 1994, the text of which is hereby
incorporated by reference. Such inhaler systems were designed to
meter out an exact dose of a powdered medication using a dosing
hole of a specific size. The hole is completely filled with drug
prior to administration and the entire contents of the dosing hole
are then delivered to the patient through a nozzle. The dosing hole
is then filled again for the next dose. These devices have been
specifically designed to remove, as much as possible, human error
and mechanically induced variability in dosing.
[0006] While such devices represent a significant advance in oral
inhalation therapy, there are still some circumstances in which
problems may remain. These problems often center on the properties
of the pharmacologically active agent and their interaction with
the inhaler. For example, certain drugs are not "free-flowing" and
that may make it difficult to move the drug from storage in a
reservoir, to measurement in a dosing hole, to delivery from the
inhaler. Other drugs may suffer from electrostatic charge problems
or may exhibit an unacceptable degree of cohesive force. Such drugs
may be "sticky," even when in powdered form. These drugs may clog
the inhaler/applicator, affecting its ability to properly meter the
intended amount of medication. Such powders may also adhere to the
nozzle of the applicator, thus reducing the amount of medication
actually delivered. This is often referred to as "hang up." Drugs
may also be "fluffy" which makes handling and loading sufficient
drug into a dosing hole a real challenge. To make matters even
worse, these and other physical properties of various
pharmacologically active agents may vary within a single batch of
material. This can defeat attempts to compensate.
[0007] Related problems may also result based upon the small size
of the particles which are generally used in inhalation therapy.
Inhalation therapy commonly involves drug particles which are on
the order of 10 .mu.m or below. This ensures adequate penetration
of the medicament into the lungs of the patient as well as good
topical coverage. In order to provide adequate dispensing of such
medicines, tight control must be maintained on the size of the
particles of the drug. However, powders of this size can be
extremely difficult to work with, particularly when small dosages
are required. Such powders are typically not free-flowing and are
usually light, dusty or fluffy in character, creating problems
during handling, processing, and storing. In addition, it can be
difficult to repeatedly and accurately load such materials into the
dosing hole of an inhaler. Thus not only the properties of the
drug, but also the required size of the therapeutic particulate,
can combine to cause considerable problems in terms of handling and
dosing.
[0008] One method of improving the ability to administer fine
powdered medicaments is by the inclusion of dry excipients such as,
for example, dry lactose. However, it has been determined that when
particularly small doses of medication are required, such as under
about 100-200 .mu.g of drug, the inclusion of conventional
excipients may not adequately compensate for the problems
associated with the use of fine drug particles. In addition, dry
excipients as commonly used, generally have particle sizes which
are significantly larger than the particle size of the drug.
Unfortunately, the use of such large particles can have a
significant impact on the amount of drug delivered from dose to
dose. Moreover, the intended benefits of the use of such excipients
begins to diminish as the size of the dose decreases. Therefore,
drug hang up or retention within the metering device or the
inhalation nozzle and other handling issues can become an
increasing problem.
[0009] Alternatively, drug products can be processed to form
agglomerates or pellets which are generally more free-flowing and
bulky. One method of agglomerating drugs is described in PCT
International Publication No. WO 95/09616, published on Apr. 13,
1995. As described therein, agglomerates of finely divided powder
medicaments, such as micronized powders having a particle size
smaller than 10 .mu.m, can be produced which require no binders.
However, they can be formed with excipients. These agglomerates can
then be administered through an inhaler for powdered
medications.
[0010] The ability to create particles without a binder is
significant to inhalation therapy and can pose a great advantage
over other techniques which use water or other traditional binders
in agglomerate formation. Agglomerates of pure drug can provide
great advantages when formulating and handling powders. It has been
found, however, that at doses of about 100-200 .mu.g, of a drug
such as mometasone furoate, and below, agglomerates of pure drug
can suffer from hang up and dosing variability can be a genuine
concern. Even in dosing systems designed to provide relatively
larger doses of pharmacologically active agent, such as about 400
.mu.g or above, the resulting agglomerates of pure drug can still
suffer from integrity problems. These agglomerates are still
relatively soft and can be crushed during metering thereby
providing variability in dosing. The material can also be broken
fairly readily by, for example, dropping an inhaler from a height
of about four feet. This would prematurely result in the formation
of smaller particles which are more difficult to handle. In fact,
it is the handling difficulties of the fine drug particles that
necessitated agglomeration in the first place.
[0011] If binder-containing agglomerates are to be used, such
agglomerates can be made by the methods described in, for example,
U.S. Pat. No. 4,161,516 and GB Patent 1,520,247 which disclose the
use of certain binding materials, including water, for the
production of agglomerates for oral inhalation. According to the
processes described therein, prior to agglomeration, the moisture
content of certain "self agglomerating" or hygroscopic micronized
drugs are elevated. After the micronized powder has been elevated
to the desired water content level, it is agglomerated.
Non-hygroscopic materials must be bound with more traditional
binders as described therein. Similarly, WO 95/05805 discloses a
process for forming agglomerates where a mixture of homogeneous
micronized materials are treated with water vapor to eliminate any
convertible amorphous content which may destabilize at a later
point. After treatment with water vapor, the now crystalline
material is agglomerated. However, this application warns that if
the vapor exposure is conducted after agglomeration, the product is
"useless in an inhalation device."
[0012] The effect of moisture on the tableting characteristics of
anhydrous lactose is discussed in Sebhatu, Elamin and Ahlneck,
"Effect of Moisture Sorption on Tableting Characteristics and Spray
Dried (15% Amorphous) Lactose," Pharmaceutical Research, Vol. 11,
No. 9, pages 1233-1238 (1994). The article does not, however,
discuss the formation of agglomerates, or the production of
agglomerates which can yield an acceptable "fine particle
fraction," also known as a "respirable fraction" when administered
as part of oral inhalation therapy.
[0013] The Sebhatu et al. article uses a method for determining
amorphous content which is more fully described by T. Sebhatu, M.
Angberg and C. Ahineck, "Assessment of the Degree of Disorder in
Crystalline Solids by Isothermal Microcalorimetry," International
Journal of Pharmaceutics, Vol. 104, pages 135-144 (1994). An
isothermal microcalorimeter is used to determine the specific heat
of crystallization for totally amorphous lactose, and then the
"percent disorder" (denoted herein, for purposes of the present
invention, "percent convertible amorphous content") is determined
by dividing the specific heat of crystallization for a partially
amorphous sample by the value previously obtained for the totally
amorphous material, then multiplying by 100. The equipment
described for making these measurements is satisfactory for use in
the present invention.
SUMMARY OF THE INVENTION
[0014] The present invention provides an improved agglomerate and a
process for making same. By design, the present invention takes
advantage of the use of a solid binder in combination with fine
drug particles and the amorphous characteristics which can be
imparted to the solid binder and/or the drug. This occurs just when
others would seek to eliminate such characteristics. The present
invention also results in unique crystalline agglomerates of a
first material and a solid binder which are free-flowing,
sufficiently bulky and sufficiently stable to be handled, metered
and delivered, even in extremely small doses. At the same time, the
interparticulate bond strength of the agglomerates is sufficiently
fragile to allow the agglomerates to break apart during
administration through an inhaler so as to provide an acceptable
fine particle fraction. All of this is accomplished substantially
without the use of an additional, more conventional binder.
[0015] In particular, the present invention provides a process of
producing agglomerates. The process includes providing particles of
at least one first material, generally a pharmacologically active
agent, and providing particles of at least one solid binder. At
least one of these two particles, the drug or the solid binder,
includes as part thereof, a preselected amount of a convertible
amorphous content which is sufficient to, upon crystallization
thereof, allow for the formation of generally crystalline,
agglomerates. The predetermined convertible amorphous content of
the binder and/or the drug is capable of being converted to a
crystalline form upon exposure to a preselected stimulus which
includes, among other things, humidity.
[0016] The particles are then agglomerated while maintaining the
preselected or predetermined amount of convertible amorphous
content. After agglomeration is complete, the convertible amorphous
content within the agglomerates is exposed to the preselected
stimulus and is converted to a crystalline form. By "crystalline,"
it is understood that the agglomerates of the present invention can
still contain some amorphous content, predominantly non-convertible
amorphous phase with or without some amount of unconverted
convertible amorphous content. The latter is to be minimized.
Without wishing to be bound by any particular scientific theory, it
is believed that the conversion of the convertible amorphous
content creates crystalline bonds between the particles. These
bonds are strong enough to preserve the integrity of the
agglomerates during handling, storage and metering. However, they
are soft enough to be overcome by commercially available inhalers
so as to provide an acceptable fine particle fraction upon
dosing.
[0017] It is an important aspect of the present invention that the
agglomerates contain a certain content of convertible amorphous
content during formation. "Convertible" means that the amorphous
content, when exposed to certain predetermined or preselected
stimuli, will convert from amorphous to crystalline form. This
convertible amorphous content can be present as part of the drug,
part of the solid binder, or both. The distribution of the
amorphous content on the particles is generally unimportant so long
as sufficient convertible amorphous content is present, preferably
substantially homogeneously, throughout the system.
[0018] The fact that the solid binder may or may not contain any
convertible amorphous content is not important in and of itself. In
such instances, the solid binder still imparts certain advantageous
properties to the resulting agglomerates in terms of their ability
to flow freely, their bulk density, their strength and the ability
to retard hang-up.
[0019] In a more preferred embodiment, the present invention
provides a method of producing agglomerates of a pharmacologically
active agent including the steps of providing of at least one
pharmacologically active agent having an average particle size of
below about 10 .mu.m and at least one solid binder. Preferably, the
majority of the solid binder also exists as particles of less than
about 10 .mu.m. Generally, the binder has a preselected amount of
convertible amorphous content which is sufficient to allow for the
formation of agglomerates with the pharmacologically active agent
upon crystallization by exposure to a preselected stimulus such as
atmospheric moisture. The next step involves forming a
substantially homogeneous mixture of the particles while
maintaining the preselected amount of convertible amorphous
content. The mixture is then agglomerated while still maintaining
the preselected amount of amorphous content. Finally, the
convertible amorphous content of the solid binder and/or drug
within the agglomerates is converted to a crystalline form by
exposure to the preselected stimulus. The resulting agglomerates
are free-flowing and are characterized by bridges or bonds between
the particles such as, for example, between the pharmacologically
active agent and the solid binder, (or even between the particles
of the solid binder themselves), which are strong enough to
withstand handling, but weak enough to allow for the delivery of an
acceptable fine particle fraction of free particles of the
pharmacologically active agent.
[0020] The result of this preferred aspect of the present invention
is the creation of a dosage form of a pharmacologically active
agent useful as part of oral and/or nasal inhalation therapy. The
dosage form includes agglomerates of particles of the
pharmacologically active agent and particles of crystalline solid
binder. The particles preferably have an average particle size of
10 .mu.m or less.
[0021] The ratio of drug to binder in the agglomerate can vary
widely depending upon the amount of drug to be administered, the
fine particle fraction desired and the amount of and relative
distribution of, convertible amorphous content present as part of
the drug and/or binder. In fact, the ratio of drug to binder can
range from between about 1000:1 to 1:1000 (drug:binder). However,
preferably, the drug and binder are present in a ratio of between
100:1 to 1:500 and even more preferably between 100:1 to 1:300.
[0022] The agglomerates generally range in sizes from between about
100 to about 1500 .mu.m and an average size of between 300 and 1000
.mu.m. The bulk density of the resulting agglomerates is between
about 0.2 and about 0.4 g/cm.sup.3. Preferably the ratio of drug to
solid binder ranges from between about 20:1 to about 1:20 and most
preferably 1:3 to 1:10. The agglomerates also preferably have an
average size of between about 300 and about 800 .mu.m and more
preferably between about 400 and about 700 .mu.m.
[0023] In another aspect of the present invention there is provided
an intermediate agglomerate useful for producing a free-flowing
crystalline agglomerate dosage form of a pharmacologically active
agent. The intermediate agglomerate includes particles of a
pharmacologically active agent and particles of solid binder,
preferably anhydrous lactose. The binder and/or the drug particles
include a preselected amount of convertible amorphous content which
is sufficient to allow for the formation of crystalline
agglomerates upon exposure to a preselected stimulus. The particles
of pharmacologically active agent and particles of the binder have
an average particle size of about 10 .mu.m or below, and each is
provided in a ratio of between about 100:1 and about 1:500 and even
more preferably between about 100:1 and about 1:300. The resulting
agglomerates range in size from between about 100 .mu.m to about
1500 .mu.m and have an average size of between 300 and 1000 .mu.m.
Their bulk density generally ranges from between about 0.2 and
about 0.4 g/cm.sup.3.
[0024] These intermediate agglomerates are too weak to withstand
normal handling and thus they are not suitable for a dosage form.
They also have a relatively high rate of hang up in the nozzle of
an inhaler. Such agglomerates are also not stable. Over time, they
will convert, in an uncontrolled manner, to a crystalline form.
This yields a higher level of variability in terms of bond strength
and dosing uniformity. However, these amorphous agglomerates are
very useful in the formation of crystalline dosage forms in which
at least substantially all of the convertible amorphous content is
converted to a crystalline form by exposure to a preselected
stimulus.
[0025] A particularly preferred aspect of the present invention is
the provision of a method of ensuring a higher level of dosing
uniformity for very small doses of orally inhaled pharmacologically
active agents or drugs (about 400 .mu.g of drug or below). The
method includes metering a dose of an agglomerated
pharmacologically active agent as previously described and
administering that dose of agglomerated pharmacologically active
agent to a patient in need thereof.
[0026] The present invention also provides a metered dose of a
pharmacologically active agent useful for administration by oral
inhalation therapy. The metered dose can vary widely in size;
including up to about 50,000 .mu.g of the pharmacologically active
agent per inhalation. The ability to accommodate such a wide range
of dosing levels is a direct result of the advantages which inure
from the use of the present invention to manufacture agglomerates.
However, the present invention is most useful in the context of
very small doses including up to about 400 .mu.g of particulate
pharmacologically active agent with the balance being lactose
binder. More particularly, the dose contains about 100 .mu.g of
pharmacologically active agent or less. It is these smaller dosing
levels which are the most demanding on dosage forms.
[0027] Oral inhalation of a pharmacologically active agent, as
previously noted, can be demanding, not only on dosing equipment,
but also on formulations. The dosage form appears to need to
simultaneously meet a number of criteria, many of which were
thought to be mutually exclusive. For example, it is very important
that the agglomerates be formed in a highly repeatable, consistent
manner with very little variation in terms of size, drug content
and interparticle bond strength. The agglomerates must also be
sufficiently solid to allow them to be worked, sieved, spheronized
and otherwise manipulated without falling apart. At the same time,
the agglomerates must be sufficiently weak so as to allow them to
break apart during inhalation and yield, to the extent possible,
small, free particles of drugs in a manner which is therapeutically
effective. For another example, the agglomerates must be
sufficiently free-flowing to allow them to be loaded into an
inhaler, and metered through the inhaler and delivered, with as
little residue being retained as possible. However, forming
agglomerates of inherently free-flowing materials can be
difficult.
[0028] One of the most interesting aspects of the present invention
is the realization that attempting to balance these often competing
performance criteria is neither possible nor necessary. Instead,
the invention uses certain properties when those properties are
advantageous. Then, just when those same attributes would become
liabilities, the agglomerate is changed fundamentally to eliminate
those properties entirely. In their place, a new crystalline
agglomerate is realized. This new agglomerate retains none of those
properties of the former agglomerates which were useful for
agglomerate formation, but detrimental to handling, measuring and
administering.
[0029] Instead, the new agglomerates, after conversion of the
convertible amorphous content of the solid binder and/or the drug,
are free flowing and very consistent in terms of agglomerate size
and size distribution. Furthermore, the agglomerates are
sufficiently rugged to allow them to be handled, metered, and even
dropped while within an inhaler without the adverse consequences
found in the prior art. At the same time, when used in combination
with an inhaler that can generate sufficient force, the structural
integrity of these rugged agglomerates can be interrupted
sufficiently so as to provide an acceptable fine particle
fraction.
[0030] Therefore, in accordance with another aspect of the present
invention, there is provided a crystalline agglomerate of a drug
with an average particle size of 10 .mu.m or less and particles of
a solid binder. These particles are bound together as a result of
the conversion at a portion of a convertible amorphous region of
either the drug, the binder, or both. No additional binder is
required. These agglomerates are provided in combination with a
nasal or oral inhaler which is configured so as to provide a fine
particle fraction of drug particles of at least 10%. In general,
the agglomerates which result have a crush strength of between
about 50 mg and about 5,000 mg. More preferably, the crystalline
agglomerates in accordance with the present invention have a crush
strength of between about 200 mg and about 1500 mg. Thus, the
inhaler used for dosing these agglomerates will have to provide, as
a minimum, sufficient force to overcome the inherent strength of
the agglomerate so as to result in a fine particle fraction of at
least about 10% or more. This means that at least 10% of the drug
will be reduced to a fine particle fraction of particles having a
size of 6.8 .mu.m or less. It should come as no surprise that if an
inhaler is configured to provide at least a 10% fine particle
fraction of the drug when the agglomerate strength is 5,000 mg, the
same inhaler will provide a much greater fine particle fraction if
used in combination with agglomerates in accordance with the
present invention having a strength of, for example, 500 mg.
[0031] It has also been found that by providing a solid binder
having a similar range of particle sizes when compared to the
particle size of the particles of drug, it is possible to obtain a
substantially homogeneous distribution of drug in each metered
dose, even when the metered doses of drug are as small as about 400
.mu.g or below.
[0032] In sum, it has been found that by converting the amorphous
content of the binder or drug to a crystalline form within the
pre-formed agglomerate, once agglomeration is complete, one can
impart desirable properties. When the amorphous content of the
agglomerates is converted to crystalline form, the agglomerates
become stable. They are, indeed, less sensitive to factors such as
humidity and temperature. The crystalline material is also
free-flowing and exhibits reduced hang up relative to the same
agglomerates prior to conversion. It is easier to load into and
empty from a dose hole and, therefore, provides for consistent
metering. This coupled with high stability and homogeneity makes
consistent dosing of very small doses possible.
[0033] Thus it has been found that, through the present invention,
it is possible to provide materials which are ideally suited for
agglomeration just when it is necessary to agglomerate such
materials and it is also possible to produce agglomerates which are
ideally suited for administering pharmacologically active
substances through an oral inhalation system.
[0034] Another important aspect of the present invention is a
change in the conventional perception of the amorphous content of
particles. The industry has long known of the amorphous character
imparted to certain materials by such processes as micronizing,
spray drying, freeze drying and ball milling. Some degree of
amorphous character is unavoidably imparted upon materials when the
particle size is reduced using such techniques. However, because of
the variability that can result from such amorphous materials, the
industry has long sought a way to minimize or eliminate the
creation of amorphous content during microparticle formation.
[0035] In fact, that is the very point of WO 95/05805. That PCT
application seeks to form, as much as possible, a homogenous
mixture of particles of as uniform characteristics as possible so
as to insure the production of agglomerates having a more tightly
controlled size. The theory appears to be that if one can insure a
homogeneity in terms of particle size, mixture of particles and
crystallinity, is easier to control the resulting size and
composition of agglomerates. Therefore, moisture is added to the
particles, prior to agglomeration, to insure that their entire
convertible amorphous content is converted to crystalline form.
[0036] In accordance with the present invention, however, it has
been found that the amorphous character of the drug and/or binder
can be harnessed to the formulator's advantage. By using the
amorphous content of the mixture as the binder, one can eliminate
the need for additional binders. This can only be accomplished,
however, where agglomeration occurs prior to exposure of
significant quantities of atmospheric moisture. Once the
particulate has been exposed to moisture, the conversion of the
convertible amorphous content will prevent a solid state
agglomeration and a formation of direct intercrystalline bonds.
[0037] Moreover, it has been found that merely imparting such
amorphous content upon particles is not sufficient. Certainly, it
has long been known to micronized drugs. However, because of many
drugs' natural stability, they cannot be readily transformed to
crystalline agglomerates as discussed herein. Rather, it has been
discovered that by imparting a certain amount of amorphous
character to a solid binder, a binder which is capable of being
readily re-converted to a crystalline form, the advantages of the
present invention can be realized. It has been discovered that the
use of a solid metastable material as a binder provides advantages
both when the binder is in its amorphous form and again when it is
in its crystalline form, so long as the various forms are
intentionally used at the right time.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 is a graph illustrating the water uptake of
agglomerates of the present invention when exposed to humidity
before and after being subjected to conversion.
[0039] FIG. 2 is a block diagram illustrating a manufacturing
scheme for agglomerates of either lactose alone or mometasone
furoate and lactose.
[0040] FIG. 3 is a graph illustrating the results of a 122 cm (48
inch.) drop test wherein: .smallcircle. is inhaler 1, .cndot. is
inhaler 2, .gradient. is inhaler 3, .tangle-soliddn..quadrature. is
inhaler 4, .quadrature..quadrature. is inhaler 5, .box-solid. is
inhaler 6, .DELTA. is inhaler 7, .tangle-solidup. is inhaler 8,
.diamond. is inhaler 9, and .diamond-solid. is inhaler 10.
[0041] FIG. 4 is a graph illustrating the results of a control for
a 122 cm (48 inch.) drop test wherein: .smallcircle. is inhaler 1,
.cndot. is inhaler 2, .gradient. is inhaler 3, .tangle-soliddn. is
inhaler 4, .quadrature..quadrature. is inhaler 5, .box-solid. is
inhaler 6, .DELTA. is inhaler 7, .tangle-solidup. is inhaler 8,
.diamond. is inhaler 9, and .diamond-solid. is inhaler 10.
DETAILED DESCRIPTION OF THE INVENTION
[0042] An agglomerate in accordance with the present invention is a
bound mass of small particulates. The agglomerates include at least
one first material and at least one solid binder. The first
material, in accordance with the present invention can be anything
as, indeed, the present invention can be used broadly to make
free-flowing agglomerates for any application including, medicine,
cosmetics, food and flavoring, and the like. However, preferably,
the first material is a pharmacologically active agent or drug
which is to be administered to a patient in need of some course of
treatment. The pharmacologically active agent may be administered
prophylactically as a preventative or during the course of a
medical condition as a treatment or cure.
[0043] Most preferably, in accordance with the present invention,
the pharmacologically active agent or drug is a material capable of
being administered in a dry powder form to the respiratory system,
including the lungs. For example, a drug in accordance with the
present invention could be administered so that it is absorbed into
the blood stream through the lungs. More preferably, however, the
pharmacologically active agent is a powdered drug which is
effective to treat some condition of the lungs or respiratory
system directly and/or topically. Particularly preferred
pharmacologically active agents in accordance with the present
invention include, without limitation, corticosteroids such as:
mometasone furoate; beclomethasone dipropionate; budesonide;
fluticasone; dexamethasone; flunisolide; triamcinolone;
(22R)-6.alpha.,9.alpha.-difluo-
ro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.-propylmethylenedioxy-4-pregne-
n-3,20-dione; tipredane and the like. .beta.-agonists (including
.beta..sub.1 and .beta..sub.2-agonists) including, without
limitation, salbutamol (albuterol), terbutaline, salmeterol, and
bitolterol may also be administered. Formoterol (also known as
eformoterol) e.g., as the fumarate or tartrate, a highly selective
long-lasting .beta..sub.2-adrenergic agonist having
bronchospasmolytic effect, is effective in the treatment of
reversible obstructive lung ailments of various genesis,
particularly asthmatic conditions. Another long-acting
.beta.-agonist which can be administered in accordance with the
present invention is known as TA-2005, chemically identified as
2(1H)-Quinolinone,
8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxyphenyl)-1-meth-
ylethyl]amino]ethyl]-monohydrochloride, [R--(R*,R*)]-- also
identified by Chemical Abstract Service Registry Number 137888-11-0
and disclosed in U.S. Pat. No. 4,579,854, the text of which is
hereby incorporated by reference. Anticholinergics such as
ipratropium bromide and oxitropium bromide may be used. So, too can
sodium cromoglycate, nedocromil sodium and leukotriene antagonists
such as zafirlukast and pranlukast. Bambuterol (e.g. as
hydrochloride), fenoterol (e.g. hydrobromide), clenbuterol (e.g. as
hydrochloride), procaterol (e.g. as hydrochloride), and broxaterol
are highly selective .beta..sub.2-adrenergic agonists can be
administered. Several of these compounds could be administered in
the form of pharmacologically acceptable esters, salts, solvates,
such as hydrates, or solvates of such esters or salts, if any. The
term is also meant to cover both racemic mixtures as well as one or
more optical isomers. The drug in accordance with the present
invention can also be an inhalable protein or a peptide such as
insulin, interferons, calcitonins, parathyroid hormones,
granulocyte colony-stimulating factor and the like. "Drug" as used
herein may refer to a single pharmacologically active entity, or to
combinations of any two or more, an example of a useful combination
being a dosage form including both a corticosteroid and a
.beta.-agonist. A preferred pharmacologically active agent for use
in accordance with the present invention is mometasone furoate.
[0044] To be topically effective in the lungs or the upper and/or
lower airway passages, it is important that the pharmacologically
active agent be delivered as particles of about 10 .mu.m or less.
See Task Group on Lung Dynamics, Deposition and Retention Models
For Internal Dosimetry of the Human Respiratory Tract, Health
Phys., 12, 173, 1966. The ability of a dosage form to actually
administer free particles of these therapeutically effectively
sized particles is the fine particle fraction. Fine particle
fraction is, therefore, a measure of the percentage of bound drug
particles released as free particles of drug having a particle size
below some threshold during administration. Fine particle fraction
can be measured using a multi-stage liquid impinger manufactured by
Copley Instruments (Nottingham) LTD using the manufacturer's
protocols. In accordance with the present invention, an acceptable
fine particle fraction is at least 10% by weight of the drug being
made available as free particles having an aerodynamic particle
size of 6.8 .mu.m, or less, measured at a flow rate of 60 liters
per minute.
[0045] The amount of drug administered will vary with a number of
factors including, without limitation, the age, sex, weight,
condition of the patient, the drug, the course of treatment, the
number of doses per day and the like. For mometasone furoate, the
amount of drug delivered per dose, i.e. per inhalation, will
generally range from about 10.0 .mu.g to about 10,000 .mu.g. Doses
of 25 .mu.g, 50 .mu.g, 75 .mu.g, 100 .mu.g, 125 .mu.g, 150 .mu.g,
175 .mu.g, 200 .mu.g, 250 .mu.g, 300 .mu.g, 400 .mu.g and/or 500
.mu.g are preferred.
[0046] The drug may include some or all of the convertible
amorphous content of the agglomerates as discussed herein.
[0047] The solid binder in accordance with the present invention
can be any substance which can be provided in, or reduced to, a
particle size which is roughly congruent with the size of the
particles of the pharmacologically active agent as previously
described. For example, agglomerates of mometasone furoate
anhydrous USP will preferably be provided having particles of at
least 80%.ltoreq.5 .mu.m and at least 95%.ltoreq.10 .mu.m (measured
by volume distribution). The solid binder, such as anhydrous
lactose, NF will be provided having particles of at least
60%.ltoreq.5 .mu.m, at least 90% under 10 .mu.m, and at least
95%.ltoreq.20 .mu.m. The average particle size is roughly the same
for both and is less than 10 .mu.m.
[0048] When in a crystalline form, i.e. when all, or almost all of
the convertible amorphous content of the solid binder converted to
a crystalline form, the binder must be stable, capable of
supporting and maintaining an agglomerate and binding particles of
therapeutically active agents such that same can be released as a
fine particle fraction of particles. The binder must also impart to
the crystalline agglomerate a desired range of properties including
bulk density, strength, a free-flowing character, and storage
stability.
[0049] Preferably, the convertible amorphous content of the solid
binder, if indeed, it contains some or all of the convertible
amorphous content of the agglomerate, will convert from its
amorphous form to its crystalline form upon exposure to a
preselected or predetermined stimulus such as atmospheric moisture
in the form of humidity. However, materials which meet all of the
foregoing criteria and will convert responsive to other preselected
stimuli such as, for example, temperature, radiation, solvent vapor
and the like may also be used. Preferred solid binders include
polyhydroxy aldehydes, polyhydroxy ketones, and amino acids.
Preferred polyhydroxy aldehydes and polyhydroxy ketones are
hydrated and anhydrous saccharides including, without limitation,
lactose, glucose, fructose, galactose, trehalose, sucrose, maltose,
raffinose, mannitol, melezitose, starch, xylitol, mannitol,
myoinositol, their derivatives, and the like.
[0050] Particularly preferred amino acids include glycine, alanine,
betaine and lysine.
[0051] Where the drug is completely crystalline, or where it
contains only non-convertible amorphous content, the solid binder
must provide all of the amorphous content of the agglomerate system
and vice versa. Neither the solid binder material, nor the drug
need naturally have such an amorphous content, so long as such an
amorphous content can be reversibly imparted thereto.
[0052] It is possible that the drug, the binder or both contains a
certain percentage of amorphous content which is non-convertible or
stable under the conditions of use and storage, as well as when the
preselected stimuli is applied. This stable amorphous content is
not part of the convertible amorphous content previously discussed.
As is generally the case, this stable amorphous content has some
role in interparticulate binding. However, it will not contribute
to the interparticulate bonding which results from the conversion
between amorphous and crystalline materials in accordance with the
present invention.
[0053] Therefore, in certain formulations such as those using, for
example, mometasone furoate, all of the convertible amorphous
content is contributed by the solid binder. As such, sufficient
solid binder must be provided to impart enough convertible
amorphous content to the agglomerate system. However, with another
drug such as, for example, albuterol sulfate, which itself can
contain convertible amorphous content, it may be possible to use a
binder with no amorphous content or to use a mixture of a solid
binder containing a certain lower percentage of amorphous content
along with albuterol. Too much convertible amorphous content can
result in agglomerates which are bound too tightly to yield the
desirable fine particle fraction. Generally, the amount of
amorphous content in the system should range from between about 1
to about 50% by weight and more preferably between about 3 and 30%
by weight. Most preferably, the amount of convertible amorphous
content in the system will range from between about 5 to about 25%
by weight. Of course, it is equally acceptable to characterize the
amorphous content of either the binder or the drug, individually,
in terms of the percent of amorphous content in the system. Thus,
where the binder contains the total convertible amorphous content,
and where the binder contains a 20% amorphous content and is
provided in the 1:1 ratio by weight with the drug, the total
convertible amorphous content in the system will be 10% by
weight.
[0054] Some convertible amorphous character can be imparted upon
certain material, during the course of reducing the particle size
thereof. Thus, for example, if anhydrous lactose is micronized in a
micronizer such as MICRON-MASTER.RTM. Jet Pulverizer available from
the Jet Pulverizer Co., Palmyra, N.J., it is possible to obtain not
only particles of the desired size, but also to impart a certain
amount of amorphous content. This can also be accomplished using
other traditional microparticle generating devices such as milling,
spray drying or ball milling. See Briggner, Buckton, Bystrom and
Darcy, "The use of isothermal microcalorimetry in the study of
changes in crystallinity induced during the processing of powders,"
International Journal of Pharmaceutics, 105 (1994), pp. 125-135.
However, where others have tried to minimize the degree of
amorphous content generated and have considered this amorphous
content to be an unfortunate, but generally unavoidable, side
effect of particle size reduction, the present invention seeks to
encourage a certain amount of amorphous content.
[0055] The present invention also seeks to control and maintain
that amorphous character of the solid binder and/or the drug until
a specified time in the agglomeration process. To this end, certain
steps are taken to impart a preselected amount of amorphous
character and to maintain the amorphous character of the solid
binder and/or the drug. For example, when anhydrous lactose is
pulverized using a Jet Pulverizer as previously discussed,
pulverization is carried out under considerable pressure such as,
for example, between about 50 and about 120 psig (3.45 to
8.27.times.10.sup.5 newton/m.sup.2). About 80-100 psig (5.51 to
6.89.times.10.sup.5 newton/m.sup.2) is preferred. The use of such
high pressures results in a particularly violent particle formation
environment and generally increases the amount of amorphous
content. Moreover, applicants preferably use dry compressed
nitrogen gas to pulverize the solid binder, as applicants have
discovered that the exposure of the amorphous content to humidity
during particle formation can act to reconvert the amorphous
content back to a crystalline form prematurely.
[0056] Of course, it is also possible to impart an amorphous
surface to particles of a solid binder and/or drug which is already
of correct particle size or to use particulate which is inherently
amorphous in character and can be converted to a crystalline
form.
[0057] Once sufficient convertible amorphous content is present,
that amorphous character must be maintained until such time as it
is desirable to convert the particles into completely crystalline
form. For solid binders or drugs, such as lactose, which are
sensitive to humidity, this can be accomplished by processing and
storing under low humidity conditions.
[0058] Preferably, the micronized materials are subsequently stored
and/or processed under conditions of less than about 30% relative
humidity ("RH") and more preferably, less than 20% RH at 21.degree.
C. By this it is meant that the micronized materials are processed
and stored at an atmospheric moisture content which is equal to
that of an atmosphere of 30% RH at 21.degree. C., or less. Exact
amounts of moisture present in the atmosphere at various
temperatures can be derived from Table 5.27, "Mass of Water Vapor
in Saturated Air," at page 5.150 of John A. Dean, Lange's Handbook
of Chemistry, Fourteenth Ed., McGraw-Hill, Inc. New York (1992). It
is particularly preferable to store any materials containing
convertible amorphous content under humidity conditions of less
than 10% RH at 21.degree. C. and, most preferably, as close to zero
relative humidity as practicable. All processing may be carried out
at any temperature. However, processing is usually more
conveniently carried out between 0.degree. C. and 38.degree. C.
[0059] Generally, any method of agglomerating the solid binder and
the pharmacologically active agent, which can be accomplished
without converting the amorphous content of the solid binder to a
crystalline form, prematurely, and which does not require the use
of additional binder, can be practiced in accordance with the
present invention. For this reason, one can generally not practice
the agglomeration processes disclosed in the aforementioned U.S.
Pat. No. 4,161,516 as water and/or moisture are added as a binder
prior to agglomeration. This would cause the premature conversion
of some or all of the amorphous content to a crystalline form which
would actually retard agglomerate formation and lead to
variability. This variability could also cause the formation of
agglomerates which are too hard and strong. Even when such
agglomerates are administered using an inhaler which provides a
particularly violent dispensing action, these agglomerates may not
yield an acceptable fine particle fraction.
[0060] It is important that the process produce agglomerates
ranging in size from between about 100 to about 1500 .mu.m. The
agglomerates generally have an average size of between about 300
and about 1,000 .mu.m. More preferably, the agglomerates have an
average size of between about 400 and about 700 .mu.m. Most
preferably, the agglomerates will have an average size of between
about 500 and 600 .mu.m. The resulting agglomerates will also have
a bulk density which ranges from between about 0.2 to about 0.4
g/cm.sup.3 and more preferably, between about 0.29 to about 0.38
g/cm.sup.3. Most preferably, the agglomerates will have a bulk
density which ranges from between about 0.31 to about 0.36
g/cm.sup.3.
[0061] It is also important to the dosing of the pharmacologically
active agent that the agglomeration process yield a relatively
tight particle size distribution. In this context, particle size
refers to the size of the agglomerates. Preferably, no more than
about 10% of the agglomerates are 50% smaller or 50% larger than
the mean or target agglomerate size. Thus for a desired agglomerate
of 300 .mu.m, no more than about 10% of the agglomerates will be
smaller than about 150 .mu.m or larger than about 450 .mu.m.
[0062] A preferred method of preparing the agglomerates in
accordance with the invention which meets all of the foregoing
criteria involves mixing preselected amounts of one or more
pharmacologically active agent(s) and the micronized, amorphous
content containing, dry solid binder in a ratio of between about
100:1 and about 1:500 and even more preferably between about 100:1
and about 1:300 (drug:binder) and preferably a ratio of between
20:1 to about 1:20. Most preferably, the drug would be provided in
an amount of 1:3 to about 1:10 relative to the amount of the solid
binder.
[0063] These particles are then preferably mixed in some form of
mechanical mixing device. Preferably, mixing will result in
substantial homogeneity. Of course, it may not be possible for one
to obtain absolute homogeneity. However, a tolerance of .+-.10% is
acceptable during blending and .+-.5% is acceptable during
agglomeration. Blending such ingredients, in fine particle form,
may be a challenge in and of itself. Blending can be accomplished,
for purposes of example only, using a Patterson-Kelly V-shape
blender having a pin intensifier bar. Preferably, the blending
procedure is carried out in the clean room, and, as previously
noted, the humidity and temperature of the room should be
controlled. At 21.degree. C. and 20% RH for example, conversion of
the amorphous content is sufficiently slow to allow blending.
Depending upon the size of the batch, blending can be accomplished
within between about 3 and 15 minutes total. If the mixture of
micronized drug and solid binder will not be further processed
immediately, it should again be stored under low humidity and low
temperature conditions.
[0064] For a particularly small amount of drug as relative to the
solid binder, the conventional blending technique may not result in
an acceptably homogeneous mixture. In this case, the following
approaches may be used:
[0065] (1) blending of the drug or drugs and the solid binder
before micronization;
[0066] (2) when a mixture of pharmacologically active agents is
used, and particularly when one is present in significantly larger
amounts than the other, blending the two agents together,
micronizing the blend and then blending with micronized solid
binder having a convertible amorphous content; and/or
[0067] (3) forming microspheres by spray drying, such as: (a)
dissolving or suspending the drug in an aqueous solution of a
diluent or carrier, such as lactose, spray drying and then mixing
the resulting microspheres with micronized solid binder having a
convertible amorphous content; or (b) spray drying a nonaqueous
solution or suspension of drug, containing suspended, micronized
diluent or carrier particles, such as lactose, then mixing with
solid binder particles having a convertible amorphous content. In
fact, even with larger amounts of drug, it may be desirable to
employ the first approach.
[0068] From the blender, the mixed particles are poured into a
conventional screen/pan combination for agglomerate formation. The
particles can now be thought of as an agglomeration as they no
longer retain as much of their individual identity. They are not
"agglomerates" as described herein as they are not smaller,
individualized collections of particles of generally spherical
shape and/or greater density.
[0069] Screen and pan are then rotated in an eccentric circular
motion in a plane parallel to the ground. This can be done manually
or using a screen shaking device. An intermittent tapping is
applied perpendicularly to the top of the pan which forces or
meters materials through the screen into the pan below where the
eccentric motion of the pan encourages agglomerate formation as
defined previously. The agglomerates are also simultaneously
spheronized. Of course, this agglomeration procedure, as with any
agglomeration procedure in accordance with the present invention,
must be carried out under low humidity conditions to prevent the
unwanted, premature conversion of the amorphous content of the
solid binder to crystalline form.
[0070] After the agglomerates are formed and properly sized by, for
example, pouring through another screen, they can be exposed to a
preselected stimuli, such as higher humidity, to cause the
substantially complete conversion of the convertible amorphous
content contained within the agglomerates to a crystalline
form.
[0071] Of course, the higher the humidity, the less the amount of
time necessary for exposure. However, a somewhat gradual and
controlled conversion is preferred as the strength of the
agglomerates is to be tightly controlled. Agglomerates containing
convertible amorphous content can be exposed to relative humidity
of between about 30% and about 80% (at 25.degree. C.) for a time
period which is sufficient to convert the entire amorphous content.
More preferably, the convertible amorphous content is converted by
exposure to an atmosphere having a water content equal to a
relative humidity of between about 40% and about 60% (measuring the
relative humidity at about 25.degree. C.). This is particularly
useful when the solid binder is anhydrous such as anhydrous
lactose. The amount of time can vary dramatically with the size and
density of the agglomerates and the surface area of exposure. For
example, placing a thin layer of agglomerates on a flat open tray
will yield a much faster conversion overall than placing the same
quantity of agglomerate in a narrow jar. In certain cases, the
length of exposure need be on the order of tens of minutes. In
other instances, one to two days may be required.
[0072] Because, preferably, the exposure is controlled to relative
humidities of 65% or below (at 25.degree. C.), there is relatively
little concern about overexposure. So long as sufficient time is
provided to allow all of the convertible amorphous content of the
agglomerates to convert to crystalline form, the fact that
additional exposure may take place is generally not of any
consequence. If humidity levels above about 65% are used, however,
then the water vapor can actually act as a binder. While the use of
water as a binder is well known, it is detrimental to the ability
to generate a fine particle fraction, particularly when used in
combination with the principal mode of binding described herein;
namely crystalline binding. Therefore, it is still desirable to
limit the exposure of the agglomerates to elevated humidity levels
beyond the point necessary for complete conversion. After
conversion, the agglomerates have an interparticulate bonding
strength which is measurably greater than the interparticulate
bonding strength prior to conversion.
[0073] The agglomerates that result are, as previously described,
generally crystalline in nature, free-flowing, rugged and resistant
to hang up. These agglomerates can be stored, handled, metered and
dispensed while maintaining their structural integrity. The
agglomerates also have a very desirable and consistent size and
size distribution. Perhaps most importantly, the crystalline
agglomerates of the present invention have sufficient strength to
allow them to be handled and abused. At the same time, the
agglomerates remain soft enough to be broken sufficiently during
dosing so as to provide an acceptable fine particle fraction. In
general, the agglomerates have a strength which ranges from between
about 50 mg and about 5,000 mg and most preferably between about
200 mg and about 1,500 mg. The crush strength was tested on a Seiko
TMA/SS 120C Thermomechanical Analyzer available from Seiko
Instruments, Inc. Tokyo, Japan, using procedures available from the
manufacturer. It should be noted that strength measured in this
manner is influenced by the quality and extent of the
interparticulate crystalline bonding described herein. However, the
size of the agglomerates also plays a role in the measured crush
strength. Generally, larger agglomerates require more force to
crush than do the smaller particles.
[0074] When agglomerates produced in accordance with the protocol
reported in Example 1 were dosed at 100 .mu.g per inhalation using
a powder inhaler as described in WO 94/14492 assigned to Schering
Corporation, sufficiently violent force was generated so as to
break up the agglomerates enough to yield the desired level of free
drug particles having a size of about 6.8 .mu.m or less. Of course,
the degree of force which must be generated while the agglomerates
are dispensed is dependent upon the internal bond strength of the
agglomerates. The greater the bond strength, the greater the amount
of force which will be required to yield an acceptable fine
particle fraction. The agglomerates of the present invention, while
too strong and stable for certain inhalers are, nonetheless, useful
in other commercially available inhalers and, when dispensed from
same, an acceptable fine particle fraction results. Such inhalers
include, without limitation, Schering's inhaler as identified
above, Diskhaler (Allen & Hanburys), Accuhaler (Allen &
Hanburys), Diskus (Glaxo), Spiros (Dura), Easyhaler (Orion),
Cyclohaler (Pharmachemie), Cyclovent (Pharmachemie), Rotahaler
(Glaxo), Spinhaler (Fisons), FlowCaps (Hovione), Turbospin
(PH&T), Turbohaler (Astra), EZ Breath (Norton Healthcare/IVAX),
MIAT-HALER (Miat), Pulvinal (Chiesi), Ultrahaler (Fisons/Rhone
Poulenc Rorer), MAG-Haler (GGU), Prohaler (Valois), Taifun
(Leiras), JAGO DPI (JAGO), M L Laboratories' DPI (M L
Laboratories).
[0075] The inhaler must be capable of producing sufficient force to
break up whatever agglomerate is used so as to produce an
acceptable fine particle fraction. Therefore, an agglomerate having
a crush strength of 1,000 mg as measured in the manner described
herein, must be used in combination with an inhaler that can apply
sufficient force to ensure that at least a 10% fine particle
fraction results from each dose therefrom.
[0076] As shown in FIG. 1, mometasone:anyhydrous lactose
agglomerates of a ratio of 1:5.8 (by weight) were exposed to 50%
relative humidity at 25.degree. C. both before and after
conversion. The graph using the unbroken line (I) demonstrates the
moisture uptake of the agglomerates when exposed to humidity before
the agglomerates are converted to crystalline form. Moisture is
absorbed very quickly reaching a maximum point. At that point,
conversion to the crystalline form takes place. As the result of
that conversion, water is actually expelled and the overall
moisture content drops. By the same token, once agglomerates which
have been converted are exposed to moisture, they may absorb a
small amount of moisture, but thereafter, moisture uptake is flat.
See broken line (II). Amongst other things, FIG. 1 demonstrates the
resulting stability of the agglomerates which are formed in
accordance with the present invention.
[0077] The discovery and use of the increasing bond strength of the
crystalline agglomerates is significant for a number of reasons.
First the resulting agglomerates are free-flowing, stable, and able
to be handled and packaged appropriately. Second, the agglomerates
provide the necessary homogeneity and bulk density to allow them to
be consistently loaded into the dose hole of an inhaler, even in
particularly small doses. Thus the crystalline agglomerates can be
accurately metered, measured and delivered. This is aptly
demonstrated in FIG. 2. When the process of the present invention
was carried out on lactose alone, and when humidity was added to
the lactose prior to agglomeration, the resulting lactose
agglomerate proved to be too soft to handle. Significant problems
in repeatable dosing would thus be realized. These same results
were observed when mixtures of drug and lactose were exposed to
humidity prior to agglomeration.
[0078] In fact, in formulating a batch in accordance with the
present invention as described in Example 1, anhydrous lactose was
used that had already been converted. That fact was not known at
the time. When the resulting agglomeration protocol did not yield
the desired results, the cause was investigated. The prior
conversion of the lactose was subsequently discovered. Thus, it is
important to maintain the convertible amorphous content of the drug
and/or binder in that state until after the formation of
agglomerates as described herein.
[0079] In another experiment also illustrated in FIG. 2, mometasone
containing agglomerates were filled into an inhaler prior to
stabilization with humidity. The final product was not stable and
provided poor dose delivery due to high hang up in the nozzle of
the inhaler and elsewhere. When the same drug containing
agglomerates were stabilized by exposure to humidity as discussed
herein, the resulting agglomerates were hard, free-flowing and
easily handled. The internal bond strength was increased, allowing
for proper handling characteristics. Yet the agglomerates remained
soft enough to yield an acceptable fine particle fraction.
[0080] The present invention results in a higher degree of dosing
uniformity. As shown in Table 1, agglomerates produced in
accordance with the present invention were loaded into 10 inhalers
as described in the aforementioned WO 94/14492. The inhalers were
set to deliver 100 .mu.g of mometasone furoate per inhalation.
Mometasone furoate was provided in a ratio of 1:5.8 to anhydrous
lactose (680 .mu.g total agglomerate) and were produced as
described in Example 1.
1TABLE 1 Dose Uniformity Over the Labeled Number Of Inhalations
(Emitted Dose) Initial Unit Dose Middle Unit Dose Final Unit Dose
Inhaler Inhalation 1 Inhalation 60 Inhalation 120 Number (.mu.g)
(.mu.g) (.mu.g) 1 91 101 98 2 91 96 93 3 99 89 90 4 88 100 100 5
105 100 96 6 95 95 96 7 106 106 96 8 92 96 89 9 109 100 93 10 90 95
100 Average 97 98 95 % CV ** 7.9 4.7 4.0 * Ideal dose is 100 .mu.g
** Percent Coefficient of Variation
[0081] The emitted dose was determined using a Dosage Unit Sampling
Apparatus for Dry Powder Inhalers similar to that described in
Pharmaceutical Forum, Vol. 20, No. 3, (1994) pp. 7494. The emitted
dose was collected using a separatory funnel attached at one end to
a sintered glass filter at an air flow rate of 60 L/minute for a
total of 4 seconds. The drug was then dissolved in a solvent and
analyzed using HPLC as is known in the art. It is clearly evident
from a review of Table 1 that from a first inhalation dose, through
the 120th, there is great consistency. In addition, the consistency
from inhaler to inhaler is significantly higher than one would
normally expect. Perhaps most importantly, the average over all 120
doses for 10 inhalers shows great consistency. These numbers also
indicate that very little material is lost during dosing. Thus,
hang-up and dosing problems resulting from filling the dosing hole
are minimized.
[0082] The fine particle fraction (as a percentage of the total
dose) resulting from these emitted doses was also tested (Table 2).
The fine particle fraction (.ltoreq.6.8 .mu.m) was determined at a
60 L/minute flow rate using a multi-stage (5-stage) liquid impinger
manufactured by Copley Industries (Nottingham) LTD.
2TABLE 2 Inhaler Initial Unit Dose Middle Unit Dose Final Unit Dose
Number Inhalation 1 Inhalation 60 Inhalation 120 1 28 24 25 2 19 21
22 3 27 25 22 Average 24 23 23
[0083] The measured fine particle fraction from each inhaler was
greater than 10% and, in addition, was greatly uniform from the
first dose through dose 120.
[0084] A multi-stage impinger allows one to measure the fraction of
certain sized particles in each of its various stages. As
illustrated in Table 3, there is great uniformity between dose 1
and dose 120 in terms of the cumulative fine particle fraction
which are less than the 13 .mu.m, less than 6.8 .mu.m, less than
3.1 .mu.m and less then 1.7 .mu.m.
3TABLE 3 Particle size Initial Dose* Middle Dose* Final Dose*
(.mu.m) Inhalation 1 Inhalation 60 Inhalation 120 <13.0 28 26 26
<6.8 24 23 23 <3.1 15 16 16 <1.7 7 8 8 *Average of three
determinations.
[0085] Finally, as shown in FIGS. 3 and 4, the agglomerates of the
present invention are very durable. FIG. 4 illustrates the control.
In this case, it illustrates, graphically, the percent of weight
delivered or the emitted dose, in weight percent, of 10 inhalers
over 120 doses each. The inhalers used were the Schering powder
inhaler previously identified and the doses were 100 .mu.g of
mometasone furoate with an anhydrous lactose binder produced as
described in Example 1. FIG. 3 presents the same data, for
identically configured inhalers, after they had been dropped onto a
hard surface from a height of about 122 cm (48 inches). A
comparison of the results memorialized in FIGS. 3 and 4 show that
very little change is exhibited overall.
[0086] The present invention helps ensure an unprecedented degree
of agglomerate uniformity which significantly reduced the
variability of dosing as previously demonstrated. For example, if
moisture is added prior to or during agglomeration, a certain
percentage of the solid binder will begin to convert to a
crystalline form. The degree of crystal formation can vary greatly
from particle to particle. As a result, the size of the agglomerate
and the physical strength of the interparticulate bonding can vary
greatly. In addition, the binder can actually begin to dissolve and
this would create bonds which are too strong. This immediately
translates into dose variability during inhalation and a
variability in the terms of the fine particle fraction of drug
delivered. The present invention overcomes this problem and
efficiently provides uniform agglomerates which are easy to
produce, store, handle and administer.
EXAMPLES
Example 1
[0087] To ensure the quality and uniformity of the product, the
environmental conditions for handling and manufacturing
agglomerates in accordance with the present invention were as
follows:
[0088] Micronization of mometasone and lactose: 21.degree.
C..+-.2.degree. and 20% RH.+-.5%
[0089] Storage of micronized lactose: 21.degree. C..+-.20 and less
than 15% RH
[0090] Powder blending and agglomeration: 21.degree.
C..+-.2.degree. and 20% RH.+-.5%
[0091] Conversion of powder agglomerates: 25.degree. C..+-.20 and
50% RH.+-.5%
[0092] A Patterson-Kelley V-shape blender installed with a pin
intensifier bar was set-up in a clean room with temperature and
humidity controlled at 21.degree. C. and 20% RH, respectively. Half
of the micronized lactose anhydrous was charged into the V-blender.
The micronized mometasone furoate anhydrous was added next. Then,
the balance of the micronized lactose anhydrous was added.
[0093] The V-blender was turned on for 5 minutes at a rotation
speed of about 24 RPM. Next, the V-blender was rotated for 3
minutes with the pin intensifier bar turned on for the first 1
minute at a pin tip speed of about 9 meters/second. The blending
protocol was then repeated.
[0094] Samples were taken from right, left, and bottom of the
V-blender to test the blend uniformity using a unit-dose sampling
thieve.
[0095] To agglomerate this mixture, a screen shaker was set up in a
clean room with temperature and humidity controlled at 21.degree.
C. and 20% RH, respectively. Thirty (30) mesh screens, pans, and
stainless-steel containers were washed with 70% alcohol and
dried.
[0096] Screen/pan combinations were assembled and placed on the
shaker. Into each 12 inch, 30 mesh screen/pan set, 200 g of the
mometasone:anhydrous lactose blend in a ratio of 1:5.8
(drug:binder) was added. The powder blend was spread on the screen
so that the level of the powder blend was lower than the edge of
the sieve frame. The screen/pan was placed on the sieve support
plate of the shaker. A stainless-steel sieve cover was placed on
the top screen.
[0097] The timer was then set for 10 minutes and the device was
turned on such that an eccentric circular shaking with a one inch
eccentric orbit at a speed of about 280 rpm occurred. The
screen/pan was also tapped at a rate of 150 taps/minute to meter
material through the screen. The process was stopped and multiple
pans consolidated.
[0098] The agglomerates formed were poured onto a 20 mesh screen
and the screen was tapped lightly. The material retained on the 20
mesh screen was discarded.
[0099] The agglomerates which passed through the 20 mesh screen
were stored in the suitable containers.
[0100] When ready to convert the material, the agglomerates were
spread onto a stainless-steel tray and exposed in a clean room
having a temperature and humidity controlled at 25.degree. C. and
50% RH, for 24 hours. The agglomerates were then combined and
placed in a suitable container.
[0101] The bulk density was determined using a Vanderkamp Tap
Density Tester set for one tap. Particle size distribution of the
agglomerates was determined using a Malvern 2605L particle size
analyzer.
Example 2
[0102] Three additional batches were produced in accordance with
the process generally described in Example 1. The batch size and
drug to binder ratios are illustrated below in Table 4:
4TABLE 4 REPRODUCIBILITY OF MOMETASONE: LACTOSE AGGLOMERATES
PARTICLE SIZE DISTRIBUTION MMF: LACTOSE BULK DENSITY DIAMETER
(.mu.m) UNDER BULK SIZE RATIO (g/cm.sup.3) 10% 50% 90% mean 0.75 Kg
1:5.8 0.35 420 540 790 580 9.60 Kg 1:5.8 0.35 370 510 740 540 9.60
Kg 1:19 0.35 390 540 770 570
[0103] As will be readily appreciated, despite varying ratios of
binder and drug, as well as varying batch sizes, a high degree of
repeatability was observed in terms of bulk density and particle
size distribution. Particle size in this context refers to the size
of the agglomerate rather than that of the particulate binder
and/or drug.
* * * * *