U.S. patent application number 10/383351 was filed with the patent office on 2003-09-18 for fast melt multiparticulate formulations for oral delivery.
Invention is credited to McEntee, Nicholas Joseph Patrick, Simpson, David Bradley Brook, Staniforth, John Nicholas, Tobyn, Michael John.
Application Number | 20030175355 10/383351 |
Document ID | / |
Family ID | 27791705 |
Filed Date | 2003-09-18 |
United States Patent
Application |
20030175355 |
Kind Code |
A1 |
Tobyn, Michael John ; et
al. |
September 18, 2003 |
Fast melt multiparticulate formulations for oral delivery
Abstract
A drug formulation for gastrointestinal deposition, said
formulation comprising a free flowing plurality of particles
comprising an active agent and a water-soluble excipient, wherein
the particles have a mean diameter of greater than about 10 .right
brkt-bot.m to about 1 mm, and the formulation is capable of
dissolving or dispersing in a patient's mouth within 1 minute after
administration without the co-administration of a fluid.
Inventors: |
Tobyn, Michael John; (Wilts,
GB) ; Staniforth, John Nicholas; (Bath, GB) ;
Simpson, David Bradley Brook; (Bath, GB) ; McEntee,
Nicholas Joseph Patrick; (Bath, GB) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
27791705 |
Appl. No.: |
10/383351 |
Filed: |
March 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60366710 |
Mar 22, 2002 |
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60362307 |
Mar 7, 2002 |
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Current U.S.
Class: |
424/489 ;
424/490 |
Current CPC
Class: |
A61J 3/005 20130101;
A61J 7/0076 20130101; A61K 31/341 20130101; A61K 9/1623 20130101;
A61K 9/0007 20130101; A61J 1/03 20130101; A61K 31/661 20130101;
A61J 7/0061 20130101; A61K 31/4045 20130101; A61K 31/454 20130101;
A61K 31/167 20130101; A61K 31/4402 20130101; A61K 9/5047 20130101;
A61K 9/0056 20130101; A61K 9/1617 20130101; A61K 9/5078 20130101;
A61K 31/44 20130101; A61K 9/5073 20130101; A61K 31/165
20130101 |
Class at
Publication: |
424/489 ;
424/490 |
International
Class: |
A61K 009/14; A61K
009/16; A61K 009/50 |
Claims
1. A drug formulation for gastrointestinal deposition, said
formulation comprising a free flowing plurality of particles
comprising an active agent and a water-soluble excipient, wherein
the particles have a mean diameter of greater than about 10 .mu.m
to about 1 mm, and the formulation is capable of dissolving or
dispersing in a patient's mouth within 1 minute after
administration without the co-administration of a fluid.
2. A drug formulation for gastrointestinal deposition, said
formulation comprising a free flowing plurality of particles and
including an active agent and a water-soluble excipient, wherein
the particles have a mean diameter of greater than about 10 .mu.m
to about 1 mm, and the excipient has a negative heat of
solution.
3. A drug formulation as claimed in claim 2, wherein said particles
each include both active agent and water-soluble excipient.
4. A drug formulation as claimed in claim 3, wherein the particles
comprise a core and a coating that includes a quantity of the
excipient.
5. A drug formulation as claimed in claim 1, wherein the particles
are formed by melt-coating core particles with a coating material
that includes a quantity of the excipient, at a temperature below
the melting point or decomposition temperature of the active
agent.
6. A drug formulation as claimed in claim 4, wherein a quantity of
the active agent is included in the core or core particles.
7. A drug formulation as claimed in claim 6, wherein the coating or
coating material is substantially free of active agent.
8. A drug formulation as claimed in claim 4, wherein a quantity of
the active agent is included in the coating or coating
material.
9. A drug formulation as claimed in claim 8, wherein the core or
core particles are substantially free of active agent.
10. A drug formulation as claimed in claims 4, wherein the coating
or coating material further comprises a water soluble or
hydrophilic binder.
11. A drug formulation as claimed in claim 10, wherein the binder
melts or softens sufficiently to melt-coat the core particles at a
temperature below the melting point or decomposition temperature of
the active agent.
12. A drug formulation as claimed in claim 1, wherein the excipient
melts or softens sufficiently to melt-coat the core particles at a
temperature below the melting point or decomposition temperature of
the active agent.
13. A drug formulation as claimed in claim 11, wherein the binder
melts or softens sufficiently to melt-coat the core particles at a
temperature below the melting point or decomposition temperature of
the excipient.
14. A drug formulation as claimed in claims 4, wherein the coating
or coating material substantially completely covers the surface of
the core or core particles.
15. A drug formulation as claimed in claim 1, wherein the core or
core particles include a quantity of the water-soluble excipient
and/or an additional, optionally, water soluble excipient.
16. A drug formulation as claimed in claim 15, wherein, the core or
each core particle comprises a granulation of said an additional
excipient and active agent, or a particle of additional excipient
coated with active agent.
17. A drug formulation as claimed in claim 1, formed by a process
in which the active agent is not raised to or above its melting
point, or a temperature at which a significant proportion thereof
is caused to decompose.
18. A drug formulation as claimed in claim 1, wherein the melting
point of the water-soluble excipient is equal to or below 150, 120
or 110.degree. C.
19. A drug formulation as claimed in claim 18, wherein the melting
point of the water-soluble excipient is at least 40 or 50.degree.
C.
20. A drug formulation as claimed in claim 1, wherein the melting
point of the binder is equal to or below 150, 120 or 110.degree.
C.
21. A drug formulation as claimed in claim 20, wherein the melting
point of the binder is at least 40 or 50.degree. C.
22. A drug formulation as claimed in claim 1, wherein the melting
point of the excipient exceeds that of the binder.
23. A drug formulation as claimed in claim 1, wherein the
water-soluble excipient has a heat of solution equal to or below -7
KCal/Kg.
24. A drug formulation as claimed in claim 23, wherein the heat of
solution of the water-soluble excipient is equal to or below -10,
--15, -20, -25, or -30 KCal/Kg.
25. A drug formulation as claimed in claim 1, wherein the
solubility in water of the water-soluble excipient is at least 20,
30 or 40% w/w at 25.degree. C.
26. A drug formulation as claimed in claim 1, wherein the
water-soluble excipient is a sugar, sugar alcohol, polyethylene
glycol (PEG), polyethylene oxide, gelatin, partially hydrolyzed
gelatin, hydrolyzed dextran, dextrin, alginate or a mixture of any
of the foregoing.
27. A drug formulation as claimed in claim 26, wherein the
water-soluble excipient is a sugar alcohol or combination of sugar
alcohols.
28. A drug formulation as claimed in claim 27, wherein the sugar
alcohol or sugar alcohols is or are sorbitol, mannitol, maltitol,
reduced starch saccharide, xylitol, reduced paratinose, erythritol,
or any combination thereof.
29. A drug formulation as claimed in claim 1, wherein the binder
includes a polyethylene glycol (PEG) and/or a polyethylene
oxide.
30. A drug formulation as claimed in claim 1, wherein the core or
core particles include an additional excipient for controlling or
delaying the release of the active agent.
31. A drug formulation as claimed in claim 30, wherein the core or
core particles include a layer or coating of said additional
excipient encapsulating an inner core comprising the active
agent.
32. A drug formulation as claimed in claim 30, wherein said
additional excipient provides an enteric or sustained release
coating.
33. A drug formulation as claimed in claim 32, wherein said
additional excipient is selected from the group consisting of
cellulose acetate phthalate, hydroxypropyl-methylcelluose
phthalate, polymethacrylates, Shellac, ethylcellulose,
hydroxypropyl-celluose, and hydroxypropylmethylcelluose.
34. A drug formulation as claimed in claim 1, wherein said
formulation dissolves in a patient's mouth within 30 or 15 seconds
after administration without the coadministration of a fluid.
35. A drug formulation as claimed in claim 1, wherein the particles
comprise at least about 50%, 60%, or 75% drug.
36. A drug formulation as claimed in claim 1 further comprising a
salivary stimulant.
37. A drug formulation as claimed in claim 1, wherein said
formulation further comprises an excipient selected from the group
consisting of polyvinyl alcohol, polyvinylpyrrolidine, acacia and
combinations thereof.
38. A drug formulation as claimed in claim 1 further comprising a
water-soluble artificial sweetener.
39. A drug formulation as claimed in claim 38, wherein said water
soluble artificial sweetener is selected from the group consisting
of soluble saccharin salts, such as sodium or calcium saccharin
salts, cyclamate salts, acesulfam-K, the free acid form of
saccharin and mixtures thereof.
40. A drug formulation as claimed in claim 1 further comprising a
dipeptide based sweetener.
41. A drug formulation as claimed in claim 40, wherein said
dipeptide based sweetener is L-aspartyl L-phenylalanine methyl
ester.
42. A drug formulation as claimed in claim 36, wherein said
salivary stimulant is selected from the group consisting of citric
acid, tartaric acid, malic acid, fumaric acid, adipic acid,
succinic acid, acid anhydrides thereof, acid salts thereof and
combinations thereof.
43. A drug formulation as claimed in claim 36, wherein said
salivary stimulant is an effervescent agent.
44. A drug formulation as claimed in claim 43, wherein said
effervescent agent is the result of a reaction of a soluble acid
source and an alkali metal carbonate or carbonate source.
45. A drug formulation as claimed in claim 2, wherein the
formulation is capable of dissolving or dispersing in a patient's
mouth within 1 minute after administration without the
co-administration of a fluid.
46. A drug formulation as claimed in claim 1, arranged for direct
un-encapsulated administration to the oral cavity.
47. A drug formulation as claimed in claim 1, wherein the particles
are non-compressed.
48. A method of preparing a drug formulation as claimed in claim 1,
comprising forming the particles by melt-coating core particles
with a coating material that includes a quantity of the
water-soluble excipient and, optionally, a quantity of the binder,
at a temperature below the melting point or decomposition
temperature of the active agent.
49. Use of a drug formulation as claimed in claim 1, or a drug
formulation is prepared by a method as claimed in claim 48, for the
preparation of a medicament for treating a human or animal patient,
wherein the formulation is administered directly and in an
un-encapsulated form to the patient's oral cavity.
50. A method of treating a human or animal patient, wherein a
formulation as claimed in claim 1, is administered in a
un-encapsulated form directly into the patient's oral cavity.
51. A drug delivery system comprising a dosing device comprising a
housing and an actuator, said device containing at least one unit
dose of a drug formulation as claimed in claim 1, said device upon
actuation delivering a unit dose of said drug formulation such that
an effective dose of said drug cannot be delivered into the lower
lung of a human patient.
52. The drug delivery system of claim 51 wherein said at least one
unit dose is contained in a reservoir.
53. The drug delivery system of claim 51 further comprising a
metering component to meter a unit dose from said reservoir upon
actuation of said system.
54. The drug delivery system of claim 51 comprising multiple unit
doses, wherein said unit doses are individually metered prior to
said actuation.
55. The drug delivery system of claim 51 further comprising
sachets, each sachet containing said individually metered unit
dose.
56. The drug delivery system of claim 55 wherein said sachets are
aligned linearly in the form of a strip.
57. The drug delivery system of claim 56 wherein said strip is in
the form of a roll.
58. The drug delivery system of claim 57 further comprising
blisters on a substrate base, each blister containing said
individually metered unit dose, said blisters covered by a
seal.
59. The system of claim 58 wherein said blisters are aligned
linearly in the form of a strip.
60. The system of claim 59 wherein said strip is in the form of a
roll.
61. A method of treating a patient with an active agent for
gastrointestinal deposition comprising administering a formulation
comprising a non-compressed free flowing plurality of particles
comprising an active agent and a water-soluble excipient, said
particles having a mean diameter of greater than 10 .mu.m to about
1 mm, and said formulation dissolving in a patient's mouth within 1
minute after administration without the co-administration of a
fluid.
62. A method of treating a patient with an active agent for
gastrointestinal deposition comprising formulating a drug
formulation comprising a non-compressed free flowing plurality of
particles comprising an active agent and a water-soluble excipient,
said particles having a mean diameter of greater than 10 .mu.m to
about 1 mm, and said formulation dissolving in a patient's mouth
within 1 minute after administration without the co-administration
of a fluid, containing said drug formulation in a drug delivery,
said device upon actuation delivering a unit dose of said drug
formulation such that an effective dose of said drug cannot be
delivered into the lower lung of a human patient; and administering
a unit dose of said particles to the oral cavity.
63. A method of preparing a drug delivery system for
gastrointestinal deposition of an active agent comprising
formulating a drug formulation comprising a non-compressed free
flowing plurality of particles comprising an active agent and a
water-soluble excipient, said particles having a mean diameter of
greater than 10 .mu.m to about 1 mm, and said formulation
dissolving in a patient's mouth within 1 minute after
administration without the coadministration of a fluid, containing
said drug formulation in a drug delivery, said device upon
actuation delivering a unit dose of said drug formulation such that
an effective dose of said drug cannot be delivered into the lower
lung of a human patient.
64. The system of claim 51 wherein said active agent is an
antibiotic.
65. The system of claim 64 wherein said antibiotic is a macrolide
antibiotic.
66. The system of claim 65 wherein said macrolide antibiotic is
selected from the group consisting of erythromycin, dirithromycin,
josamycin, midecamycin, kitasamycin, tylosin, roxithromycin,
rokitamycin, oleandomycin, miocamycin, flurithromycin, rosaramicin,
azithromycin, clarithromycin, and pharmaceutically acceptable salts
thereof.
67. The system of claim 65 wherein said macrolide antibiotic is
selected from the group consisting of erythromycin, clarithromycin,
and pharmaceutically acceptable salts thereof
68. A method of treating a patient with a macrolide antibiotic for
gastrointestinal deposition comprising administering a drug
formulation for gastrointestinal deposition comprising a
non-compressed free flowing plurality of particles comprising a
macrolide antibiotic and a water-soluble excipient, said particles
having a mean diameter of greater than 10 .mu.m to about 1 mm, said
formulation dissolving in a patient's mouth within 1 minute after
administration without the coadministration of a fluid.
69. The method of claim 68 wherein said formulation dissolves in a
patient's mouth within 30, or 15 seconds after administration
without the coadministration of a fluid.
70. The method of claim 68 wherein said particles comprise at least
about 50%, 60% or 75% drug.
71. A macrolide antibiotic formulation for gastrointestinal
deposition comprising a non-compressed free flowing plurality of
particles comprising a macrolide antibiotic and a water-soluble
excipient, said particles having a mean diameter of greater than 10
.mu.m to about 1 mm, said formulation dissolving in a patient's
mouth within 1 minute after administration without the
coadministration of a fluid.
72. A formulation for gastrointestinal deposition comprising a
non-compressed free flowing plurality of particles comprising an
active agent and a water-soluble excipient, said particles having a
mean diameter of greater than 10 .mu.m to about 1 mm, said
formulation dissolving in a patient's mouth within 1 minute after
administration without the co-administration of a fluid, said
particles comprising less than 5% hydrophobic material.
73. The formulation of claim 72 wherein said particles are prepared
by a process comprising melt granulating said water soluble
excipient and the active agent to form a homogenous mixture.
74. The formulation of claim 72 wherein said particles are prepared
by a process comprising melt coating said water soluble excipient
onto said active agent.
75. The formulation of claim 73 which is prepared without the use
of an aqueous fluid.
76. A drug formulation as claimed in claim 1, wherein the
water-soluble excipient is xylitol
77. A drug formulation as claimed in claim 1, wherein the active
agent is paracetamol.
78. A drug formulation as claimed in claim 1, being adapted to
provide both immediate release and controlled release of the active
agent.
79. A drug formulation as claimed in claim 78, comprising a free
flowing plurality of particles comprising an active agent and a
water-soluble excipient, wherein at least a portion of the
particles comprise active agent and at least one delayed release
excipient.
80. A drug formulation as claimed in claim 78, wherein a first
portion of the particles comprises at least one delayed release
excipient, to provide controlled release of active agent, and a
second portion of the particles does not include any delayed
release excipients, to provide immediate release of active
agent.
81. A method of treating a human or animal patient, wherein a
formulation as claimed in claim 2, is administered in a
un-encapsulated form directly into the patient's oral cavity.
82. A drug delivery system comprising a dosing device comprising a
housing and an actuator, said device containing at least one unit
dose of a drug formulation as claimed in claim 2, said device upon
actuation delivering a unit dose of said drug formulation such that
an effective dose of said drug cannot be delivered into the lower
lung of a human patient.
83. A method of treating a human or animal patient, wherein a
formulation prepared by a method as claimed in claim 48, is
administered in a un-encapsulated form directly into the patient's
oral cavity.
84. A drug delivery system comprising a dosing device comprising a
housing and an actuator, said device containing at least one unit
dose of a drug formulation that was prepared by a method as claimed
in claim 48, said device upon actuation delivering a unit dose of
said drug formulation such that an effective dose of said drug
cannot be delivered into the lower lung of a human patient.
Description
[0001] This application claims priority from U.S. Provisional
Application No. 60/362,307 filed on Mar. 7, 2002 and No. 60/366,710
filed Mar. 22, 2002, the entire disclosures of which are hereby
incorporated by reference.
DESCRIPTION
[0002] The present is directed to fast melt multiparticulate
formulations for oral use. The multiparticulates can be used in a
multiple dose delivery device which dispenses a unit dose of the
powder upon actuation, or can be packaged for dispensation in
sachets or like unit dose containers.
[0003] The most prominent mode of delivery of therapeutic agents is
by the oral route by means of solid dosage forms such as tablets
and capsules. Oral administration of solid dosage forms is more
convenient and accepted than other modes of administration, e.g.,
parenteral administration. However, the manufacture, dispensing and
administration of solid dosage forms are not without associated
problems and drawbacks.
[0004] With the manufacture of solid dosage forms, in addition to
the active agent, it is necessary to combine other ingredients in
the formulations for various reasons, such as to enhance physical
appearance, to provide necessary bulk for tableting or capsuling,
to improve stability, to improve compressibility or to aid in
disintegration after administration. However, these added
excipients have been shown to adversely influence the release,
stability and bioavailability of the active ingredient. The added
excipients are a particular problem with drugs which require a high
dose in order to provide a therapeutic effect, e.g., biphosphonate
drugs. The inclusion of the additional excipient can make the final
tablet extremely large which could result in esophogeal damage due
to the physical characteristics of the dosage form if it is not
swallowed properly. Esophogeal damage can also be caused by
toxicity caused by the drug itself, if the tablet becomes lodged in
the throat or has an increased transit time through the esophagus,
due to its increased size.
[0005] Further, the tableting of certain drugs has many associated
production problems. In particular, many drugs, e.g., paracetamol
(acetaminophen), have poor compressibility and cannot be directly
compressed into solid dosage forms. Consequently, such drugs must
either be wet granulated or manufactured in a special grade in
order to be tableted which increases manufacturing steps and
production costs.
[0006] The adherence to good manufacturing practices and process
controls is essential in order to minimize dosage form to dosage
form and batch to batch variations of the final product. Even
strict adherence to these practices still is not a guarantee that
acceptable variation will occur.
[0007] With the high cost of industrial scale production and
governmental approval of solid dosage forms, such formulations are
often available in a limited number of strengths, which only meet
the needs of the largest sectors of the population. Unfortunately,
this practice leaves many patients without acceptable means of
treatment and physicians in a quandary with respect to
individualizing dosages to meet the clinical needs of their
patients.
[0008] The dispensing of oral solid dosage forms also makes the
formulations susceptible to degradation and contamination due to
repackaging, improper storage and manual handling.
[0009] There are also many patients who are unable or unwilling to
take conventional orally administered dosage forms. For some
patients, the perception of unacceptable taste or mouth feel of a
dose of medicine leads to a gag reflex action that makes swallowing
difficult or impossible. Other patients, e.g., pediatric and
geriatric patients, find it difficult to ingest typical solid oral
dosage forms, e.g., due to tablet size.
[0010] Other patients, particularly elderly patients, have
conditions such as achlorhydria which hinders the successful use of
oral solid dosage forms. Achlorhydria is a condition wherein there
is an abnormal deficiency or absence of free hydrochloric acid in
the gastric secretions of the stomach. This condition hinders the
disintegration and/or dissolution of oral solid dosage forms,
particularly dosage forms with high or insoluble excipient
payloads. Thus, as the present dosage form is in fast melt
multiparticulate form, it does not need to undergo disintegration
and/or dissolution to the same extent as solid dosage forms
[0011] Flavoured solutions/suspensions of some therapeutic agents
have been developed to facilitate the oral administration of oral
agents to patients normally having difficulty ingesting
conventional solid oral dosage forms. While liquid formulations are
more easily administered to the problem patient, liquid/suspension
formulations are not without their own significant problems and
restrictions. The liquid dose amount is not as easily controlled
compared with tablet and capsule forms and many therapeutic agents
are not sufficiently stable in solution/suspension form. Indeed,
most suspension type formulations are typically reconstituted by
the pharmacist and then have a limited shelf life even under
refrigerated conditions. Another problem with liquid formulations
which is not as much a factor with tablets and capsules is the
taste of the active agent. The taste of some therapeutic agents is
so unacceptable that liquid formulations are not a viable option.
Further, solution/suspension type formulations are typically not
acceptable where the active agent must be provided with a
protective coating, e.g. a taste masking coating or an enteric
coating to protect the active agent from the strongly acidic
conditions of the stomach.
[0012] Fast melt drug formulations have also been developed to
facilitate the oral administration of oral agents to patients
normally having difficulty ingesting conventional solid oral dosage
forms. Fast melt formulations are typically in the form of tablets
or lozenges that dissolve or disperse in a patient's mouth within a
minute without the need of water or chewing. Drug delivery
formulations which exhibit fast melt properties can improve patient
compliance due to the ease of swallowing as well as the absence of
a need for the co-administration of water or another fluid.
Further, fast melt systems can be formulated as to have a superior
taste and improved accuracy of dosing as compared to liquid
preparations.
[0013] Other formulations which have been contemplated in order to
facilitate the oral administration of oral agents and to avoid the
associated problems of solid dosage forms are multiparticulate
dosage forms as disclosed in WO 01/64182, the contents of which are
hereby incorporated by reference.
[0014] According to a first aspect of the present invention, there
is provided a drug formulation for gastrointestinal deposition,
said formulation comprising a free flowing plurality of particles
comprising an active agent and a water-soluble excipient, wherein
the particles have a mean diameter of greater than about 10 .mu.m
to about 1 mm, and the formulation is capable of dissolving or
dispersing in a patient's mouth within 1 minute after
administration without the co-administration of a fluid.
[0015] Thus, the present invention, in its first aspect, provides a
formulation which exhibits the benefits of fast melt formulations
as well as the benefits of multiparticulate formulations. It also
facilitates the delivery of a wide range of therapeutic agents for
gastrointestinal deposition and minimizes pulmonary deposition of
materials having undesirable or unknown pulmonary toxicology but
which are approved for oral delivery. In some embodiments, the
formulation can contain minimal excipient and be used in a multiple
dose delivery device which dispenses a unit dose of the formulation
upon actuation. Such delivery devices are disclosed in WO
01/64182.
[0016] In a second aspect, the present invention provides a drug
formulation for gastrointestinal deposition, said formulation
comprising a free flowing plurality of particles and including an
active agent and a water-soluble excipient, wherein the particles
have a mean diameter of greater than about 10 .mu.m to about 1 mm,
and the excipient has a negative heat of solution.
[0017] A significant advantage of formulations in accordance with
the second aspect of the invention is that, when administered via
the oral cavity, the local cooling caused by the water-soluble
excipient dissolving in saliva serves to mask the taste of the
active agent in a manner which does not delay the release, or
dissolution of the active agent itself.
[0018] Preferably, formulations in accordance with the second
aspect of the invention are capable of dissolving or dispersing in
a patient's mouth within one minute after administration, without
the co-administration of a fluid. Such preferred formulations,
therefore, are also examples of the first aspect of the invention
and will provide all of the aforementioned benefits associated with
the first aspect of the invention.
[0019] Drug formulations in accordance with either the first or the
second aspect of the invention are preferably arranged for direct,
un-encapsulated administration to a patient's oral cavity. It is
also preferred for the particles to be non-compressed.
[0020] In embodiments, the particles each include both active agent
and water-soluble excipient. The particles can comprise a core and
a coating, with the coating including a quantity of the
water-soluble excipient.
[0021] Preferably, and in accordance with either aspect of the
invention, the particles are formed by melt-coating core particles
with a coating material that includes (and may consist of) a
quantity of the excipient, at a temperature below that at which the
active agent melts or decomposes. Forming the particles in this
manner is considered to provide them with surface properties that
render them easily wetted and capable of rapidly absorbing water
from their environment and, thus, able to facilitate the rapid
dissolution or dispersion of the formulation, especially the active
agent, when the formulation is exposed to an aqueous environment,
such as in the oral cavity.
[0022] A quantity of the active agent can be included in the core
or core particles and/or in the coating or coating material. In
some preferred embodiments, the coating or coating material is
substantially free of active agent, whereas in others, the core is
substantially free of active agent.
[0023] In further embodiments of either aspect of the invention,
the coating or coating material comprises a water-soluble or
hydrophilic binder. Preferably, the binder melts or softens
sufficiently to melt-coat the core particles at a temperature below
that at which the active agent melts or decomposes. In further
embodiments, the water-soluble excipient melts or softens
sufficiently to melt-coat the core particles at a temperature below
that at which the active agent melts or decomposes. In further
preferred arrangements, the binder melts or softens sufficiently to
melt-coat the core particles at a temperature below that at which
the water-soluble excipient melts or decomposes. In some
embodiments of the invention, the coating or coating material
substantially completely covers the surface of the core or core
particles.
[0024] Thus, particles in accordance with the present invention can
comprise a core that consists substantially or entirely of active
agent surrounded by a coating that comprises water-soluble
excipient either alone, or in combination with a water-soluble or
hydrophilic binder. When the water-soluble excipient is employed
alone in such particles, it is preferred for it to be capable of
melting or softening sufficiently to melt-coat the core particles
at a temperature below that at which the active agent melts or
decomposes. Where a binder is employed, the water-soluble excipient
need not be capable of melting or softening at a temperature below
the melting or decomposition temperature of the active agent.
However, when such a high melting point water-soluble excipient is
employed, the binder should be capable both of melting or softening
sufficiently to melt-coat the core particles at a temperature below
that at which the active agent melts or decomposes, and of binding
the water-soluble excipient in the coating.
[0025] The core or core particles, in addition to including active
agent, can also include a quantity of the water-soluble excipient
and/or an additional excipient, which may also be water soluble,
but which does not necessarily qualify as a water-soluble excipient
in accordance with the present invention. For example, the core can
comprise a granulation of such an additional excipient (e.g.
polyvinyl alcohol, or polyvinylpyrrolidine) and active agent, or
consist of a particle (e.g. a microcrystalline cellulose sphere) of
additional excipient coated with active agent.
[0026] In other embodiments in accordance with the invention, the
core can consist entirely of water-soluble excipient. In such
embodiments, the coat or coating material comprises active agent
and either an additional quantity of water-soluble excipient, or a
binder. When the coat or coating material comprises active agent
and binder, additional water-soluble excipient can also be present
in therein.
[0027] It is preferred that formulations in accordance with either
aspect of the present invention are formed by a process in which
the active agent is not raised to or above its melting point, or a
temperature at which a significant proportion thereof is caused to
decompose.
[0028] The melting point of the water-soluble excipient is
preferably equal to or below 150, 120 or 110.degree. C., and is
preferably at least 40 or 50.degree. C. Preferably, the excipient
melts at around or below 100.degree. C. The melting point of the
binder, if employed, is preferably equal to or below 150, 120 or
110.degree. C., and is preferably at least 40 or 50.degree. C.
[0029] More preferably, the binder melts at around or below
100.degree. C. In certain embodiments, the melting point of the
excipient exceeds that of the binder.
[0030] The water-soluble excipient, preferably, has a heat of
solution equal to or below -7 KCal/Kg. More preferably, the heat of
solution of the water-soluble excipient is equal to or below -10,
-15, -20, -25, or -30 KCal/Kg. The solubility in water of the
water-soluble excipient is preferably at least 20, 30 or 40% w/w at
25.degree. C.
[0031] The water-soluble excipient is preferably a sugar, sugar
alcohol, polyethylene glycol (PEG), or polyethylene oxide, and is
preferably not lactose. Formulations in accordance with the
invention, preferably, are lactose free. The preferred
water-soluble excipients are the sugar alcohols including, but not
limited to sorbitol, mannitol, maltitol, reduced starch saccharide,
xylitol, reduced paratinose, erythritol, and combinations thereof.
The preferred sugar is glucose. Other suitable water-soluble
excipients include gelatin, partially hydrolyzed gelatin,
hydrolyzed dextran, dextrin, alginate and mixtures thereof.
[0032] Preferred binders include polyethylene glycols (PEG) and
polyethylene oxides.
[0033] In further preferred embodiments, the core or core particles
include an additional excipient for controlling or delaying the
release of the active agent. In this regard, the core or core
particles can include a layer or coating of such an additional
excipient encapsulating an inner core comprising the active agent.
The additional excipient can be selected from those known to
persons skilled in the art to be capable of controlling the release
of an encapsulated active agent. Such excipients include those
commonly used to provide enteric and sustained release coatings.
Examples of the former include cellulose acetate phthalate,
hydroxypropyl-methylcelluose phthalate, polymethacrylates, such as
Eudragit.RTM. L 100-55 or L 30 D-55, and Shellac. Examples of the
latter include ethylcellulose, hydroxypropyl-celluose,
hydroxypropylmethylcelluose, and polymethacrylates, such as
Eudragit.RTM. RL and RS film-coating systems.
[0034] In alternative embodiments, formulations in accordance with
the invention can provide rapid release of the active agent. In
this regard, the term "rapid release" should be understood to mean
that such formulations release at least 80% of their active agent
within 45 minutes in standard dissolution tests. In the case of
poorly soluble active agents, such formulations typically release
at least 80% of their active agent within 40, 30, 20, 15 and
preferably 10 minutes after being administered to a patient's oral
cavity. In the case of more soluble active agents, such
formulations typically release at least 80% of their active agent
within 10, 7 and preferably 5 minutes after being administered to a
patient's oral cavity. In particularly preferred embodiments of the
invention, the active agent will dissolve into an aqueous
environment more rapidly from a formulation in accordance with the
invention than it would if it had not been incorporated in such a
formulation.
[0035] In a third aspect, the present invention provides a method
of preparing a drug formulation in accordance with the first or
second aspect of the invention, comprising forming the particles by
melt-coating core particles with a coating material that includes a
quantity of the water-soluble excipient, at a temperature below the
melting point or decomposition temperature of the active agent.
[0036] In a further aspect, the invention provides the use of a
drug formulation in accordance with the first or second aspect of
the invention, or a drug formulation prepared by a method in
accordance with the third aspect of the invention, for the
preparation of a medicament for treating a human or animal patient,
wherein the formulation is administered directly and in an
un-encapsulated form to the patient's oral cavity. The invention
also provides a method of treating a human or animal patient,
wherein a formulation in accordance with the first or second aspect
of the invention, or prepared by a method in accordance with a
third aspect of the invention, is administered in a un-encapsulated
form directly into the patient's oral cavity.
[0037] It is also possible for formulations in accordance with
either the first aspect or the second aspect of the invention to
include additional particles with different properties to those
described above. For example, the additional particles may not
include any active agent.
[0038] Certain embodiments of the invention comprise a fast melt
multiparticulate formulation which contains a salivary stimulant to
facilitate hydration of the formulation and the swallowing of a
unit dose of the multiparticulates upon oral delivery.
[0039] Certain embodiments of the invention comprise a fast melt
multiparticulate formulation which has a desired particle range in
order to minimize pulmonary aspiration of particles.
[0040] Fast melt multiparticulate formulations in accordance with
the invention are, preferably, divisable into unit doses (e.g. with
the use of a multiple unit dosing device) with a weight uniformity
which is within the acceptable range of weight uniformity for
tablets or capsules. A detailed discussion of weight uniformity can
be found in the USP/NF 23/18 section 905, which is hereby
incorporated by reference in its entirety for all purposes.
[0041] The invention also provides methods of preparing fast melt
multiparticulate dosage forms and systems disclosed herein. The
invention further provides methods of preparing fast melt
multiparticulate dosage forms without the use of an aqueous fluid
as a processing aid.
[0042] The invention additionally provides methods of preparing
multiple unit delivery systems containing fast melt
multiparticulate dosage forms in accordance with the invention.
[0043] The invention also provides methods of preparing fast melt
multiparticulate dosage forms having a desired particle size
range.
[0044] The invention further provides methods of administering an
active agent comprising administering a fast melt multiparticulate
dosage form.
[0045] The invention additionally provides methods of administering
an active agent comprising administering a fast melt
multiparticulate dosage form via the use of a multiple unit
delivery system.
[0046] In certain embodiments, the present invention is directed to
a drug formulation for gastrointestinal deposition comprising a
non-compressed free flowing plurality of particles comprising an
active agent and a water-soluble excipient, the particles having a
mean diameter of greater than 10 .mu.m to about 1 mm, the particles
comprising at least about 50% drug and the formulation dissolving
in a patient's mouth within 1 minute after administration without
the co-administration of a fluid.
[0047] In certain embodiments, the invention is directed to a
method of treating a patient with an active agent for
gastrointestinal deposition comprising administering a formulation
comprising a non-compressed free flowing plurality of particles
comprising an active agent and a water-soluble excipient, the
particles having a mean diameter of greater than 10 .mu.m to about
1 mm, and the formulation dissolving in a patient's mouth within 1
minute after administration without the co-administration of a
fluid.
[0048] In certain embodiments, the invention is directed to a drug
delivery system for delivery of a drug for gastrointestinal
deposition. The system comprises a multiple unit dosing device
comprising a housing and an actuator, the device containing
multiple doses of a fast melt multiparticulate formulation, the
device upon actuation delivering a unit dose of the fast melt
multiparticulates for gastrointestinal deposition, the
multiparticulates having a mean particle size of greater than 10
.mu.m and preferably less than about 1 mm in order to minimize
pulmonary deposition of the multiparticulates and such that an
effective dose of the drug cannot be delivered into the lower lung
of a human patient. The drug delivery system can be used to
administer the unit dose of fast melt multiparticulates into the
oral cavity of the patient (in-vivo) or to dispense the unit dose
into an intermediate receptacle (ex-vivo) for subsequent
gastrointestinal deposition. Oral drug delivery systems and devices
for oral powders are disclosed in WO01/64182, hereby incorporated
by reference in its entirety for all purposes.
[0049] In certain embodiments, the invention provides a method of
preparing a drug delivery system for delivering multiple doses of a
drug for gastrointestinal deposition comprising preparing a fast
melt multiparticulate drug formulation in a manner wherein the drug
particles when placed in the oral cavity are not deposited in any
substantial amount to the lungs; and placing multiple unit doses of
the fast melt drug formulation in a device which meters a single
unit dose for delivery.
[0050] In certain embodiments, the invention provides a method of
treating a patient in need of multiple doses of a drug for
gastrointestinal deposition comprising preparing fast melt
multiparticulates in a manner wherein the drug particles when
placed in the oral cavity are not deposited in any substantial
amount to the lungs and dissolve or disperse in the mouth within 1
minute after administration, placing multiple unit doses of the
fast melt multiparticulates in a device which meters a single unit
dose for delivery and either (a) administering the unit dose into
the oral cavity of a patient or(b) dispensing the unit dose into an
intermediate receptacle and thereafter administering the unit dose
into the oral cavity of the patient.
[0051] In certain embodiments, the particles of the invention
comprise at least about 50% drug; at least about 60% drug; at least
about 70% drug; at least about 80% drug; or at least about 90%
drug. In others, low doses of up to 20%, 10% or 5% of drug or
active agent are carried by the inventive particles. In certain
embodiments, the invention provides a method for delivery of a drug
comprising delivering fast melt multiparticulates comprising drug
particles via the use of a multiple unit dosing device comprising a
housing and an actuator, the device upon actuation delivering a
unit dose of the fast melt multiparticulates, and thereafter
re-using the device to deliver additional unit doses of the fast
melt multiparticulates at appropriate dosing intervals.
[0052] In preferred embodiments of the invention, the unit dose
comprises a discreet collection of fast melt multiparticulates. For
purposes of the invention, a "discreet collection" means that the
fast melt multiparticulates are in the form of a non-compressed
free flowing unit and not dispersed in a cloud or mist, which
effectively minimizes inhalation of the active agent into the lungs
of the patient. The unit dose can be include from about 0.01 mg to
about 1.5 g of active agent. For example, the dose of active agent
can be from about 1 mg to about 100 mg, or from about 10 mg to
about 50 mg.
[0053] In certain embodiments of the invention, the mean diameter
of the fast melt multiparticulates is of a size which minimizes
their capacity to be inhaled into the lower lung. Typically, the
mean particle size of the drug particles (or agglomerates) is
greater than 10 .mu.m, preferably greater than about 50 .mu.m or
greater than about 75 .mu.m. In certain embodiments of the
invention, the mean particle size range of the drug particles is
from about 100 .mu.m to about 1 mm, preferably from about 50 .mu.m
to about 500 .mu.m. In preferred embodiments, greater than 80% of
the particles have the above disclosed diameter (not mean
diameter), e.g. 80% of the drug particles have a diameter of
greater than 10 .mu.m, or a diameter of from about 100 .mu.m to
about 1 mm. In other embodiments, greater than about 90% of the
particles have the above disclosed diameter.
[0054] In certain embodiments of the invention, the mean diameter
of the fast melt multiparticulates does not vary by greater than
about 20%, preferably not greater than about 15% and most
preferably not greater than about 10%.
[0055] In certain embodiments of the invention, the multiple doses
of the fast melt formulation are contained in a reservoir. The
reservoir can contain an amount of multiparticulates to provide any
number of unit doses, e.g. from about 2 doses to about 400 doses.
For ease in patient compliance, the reservoir has a sufficient
quantity of to provide e.g. a days supply, a months supply or a
years supply of doses, e.g. 30 or 365 for once daily dosing for a
month or year, respectively.
[0056] In order to aid in patient compliance, certain embodiments
of the invention include a counter or indicator to display the
number of doses remaining in the system or the number of doses
actuated.
[0057] In certain embodiments of the invention, the unit doses are
individually metered prior to actuation, e.g., in the form of
capsules or blisters or preferably in the form of sachets, wherein
each sachet contains one individual unit dose. The system can be
capable of containing any multiple of pre-metered unit doses, e.g.
from about 2 to about 400 sachets.
[0058] For purposes of the present invention, the term "device"
refers to an apparatus capable of delivering a unit dose of
drug.
[0059] The term "system" refers to a drug delivery device in
combination with a fast melt multiparticulate formulation having
the specifications disclosed herein, e.g. drug particle size,
excipient type, etc.
[0060] The term "discreet collection" refers to a non-compressed
free flowing unit of multiparticulates with minimal particulate
matter being dispersed in the surrounding environment (e.g., as a
cloud or mist).
[0061] The term "drug" refers to any agent which is capable of
providing a therapeutic effect to a patient upon gastrointestinal
deposition. This encompasses all drugs which are intended for
absorption for a systemic effect (regardless of their actual
bioavailability) as well as drugs intended for a local effect in
the gut and/or oral cavity, e.g. nystatin, antibiotics or local
anaesthetics.
[0062] The term "particle size" refers to the diameter of the
particle.
[0063] The term "deposition" means the deposit of the unit dose at
the intended point of absorption and/or action. For example,
gastrointestinal deposition means the intended deposit of the unit
dose in the gastrointestinal system for e.g., absorption for a
systemic effect or to exert a local effect. Pulmonary deposition
means the intended deposit of drug into the lungs in order to
provide a pharmaceutical effect, regardless that the unit dose may
enter the oral cavity prior to pulmonary deposition.
[0064] The term "dispense", when used in connection with the
devices and systems of the present invention, means that the device
or system delivers the unit dose ex vivo with the intent of
subsequent administration to a mammal. For example, the device or
system can dispense the unit dose into a food, a liquid, a spoon,
or another intermediate receptacle.
[0065] The term "administer", when used in connection with the
devices and systems of the present invention, means that the device
or system delivers the unit dose in vivo, i.e., directly into the
gastrointestinal tract of a mammal.
[0066] The term "deliver" is meant to cover all ex vivo and in vivo
delivery, i.e., dispensing and administering, respectively.
[0067] The term "patient" refers to humans as well as other mammals
in need of a therapeutic agent, e.g., household pets or livestock.
This term also refers to humans or mammals in need of or receiving
prophylactic treatment.
[0068] The term "fast melt" means a formulation which dissolving or
disperses in a patient's mouth within 1 minute after administration
without the co-administration of a fluid. Preferably, the
formulation dissolving or disperses in a patient's mouth within 30
seconds, or 15 seconds after administration without the
co-administration of a fluid
[0069] The term "disperses" means that the administered formulation
becomes hydrated in the mouth and the particles of the formulation
become suspended is saliva, such that the multiparticulate
formulation is wetted and easily swallowed.
[0070] In certain embodiments, the particulates are defined
functionally with respect to the fact that they are of a size such
that an effective dose cannot be delivered into the lower lung of a
human patient. However, this definition should be understood to
mean that a small percentage of drug (but not an amount effective
to render a therapeutic effect) may in fact be inadvertently
delivered to the lungs of the patient. Also, this definition is
meant to define the particles, but not to limit the use of the
invention to the treatments of humans only. The invention may be
used for delivering doses of drugs to other mammals as well.
[0071] In this specification, there are references to the
temperature at which the active agent or the water-soluble
excipient decomposes. This temperature should be understood to be
the temperature at and above which the active agent or excipient
would decompose to a significant extent, if held there for
sufficient time for the active agent or excipient to be processes
by melt granulation.
[0072] In general, it has been recognized in the art that dry
powder inhalation or insufflation formulations must consist of
particles of a size of about 2 microns in diameter in order for the
particles, when inhaled, to reach the peripheral or "deep" lung,
including alveoli. Particles larger than 10 microns in diameter are
not able to reach the deep lung when inhaled because they are
collected on the back of the throat and upper airways in humans.
Therefore, known powder delivery systems have been formulated with
particle sizes of less than 10 microns in order for the particles
to reach the intended site of action, the pulmonary system. Known
powder delivery devices have not contemplated delivery of particles
from a multi-dose delivery device to achieve gastrointestinal
deposition, and therefore have avoided the use of drug particles
having a large size, e.g. greater than 10 microns. By virtue of the
invention disclosed in Applicants co-pending application,
WO01/64182, it has been a surprising discovery that drug particles
greater than 10 microns can be delivered from a multi-use drug
delivery device for gastrointestinal deposition in a patient in
order to minimize the inhalation of the drug particles into the
lungs, in order to have substantially all of the dose deposited in
the gastrointestinal system. By virtue of the present invention,
powders that can be used in such devices can exhibit fast melt
properties in order to provide the benefits of such formulations.
The powders can be used in the device or can be administered
without the use of the device, e.g., by using a sachet.
[0073] As the fast melt multiparticulates of the present invention
are not intended to be compressed, a high load formulation of the
active agent is ascertainable. This is due to the fact that
excipients which must be included in prior art fast melt tablets
(e.g., fillers in order to provide bulk for tableting and
disintegrants to provide a breakdown of the tablet upon
administration) need not be included in the present formulations,
or included to a lesser extent. As the fast melt formulations can
have lower excipient and a higher drug load, the resultant unit
dose is smaller which decreases the necessary time for the
dissolution or dispersion of the formulation upon oral
delivery.
[0074] The water-soluble excipient of the formulation can be a
sugar alcohol including, but not limited to sorbitol, mannitol,
maltitol, reduced starch saccharide, xylitol, reduced paratinose,
erythritol, and combination thereof. Other suitable water-soluble
excipients include gelatin, partially hydrolyzed gelatin,
hydrolyzed dextran, dextrin, alginate and mixtures thereof.
[0075] The formulations of the present invention preferably include
a salivary stimulant including, but not limited to citric acid,
tartaric acid, malic acid, fumaric acid, adipic acid, succinic
acid, acid anhydrides thereof, acid salts thereof and combinations
thereof.
[0076] The salivary stimulant can also be an effervescent agent,
such as wherein the effervescence is the result of a reaction of a
soluble acid source and an alkali metal carbonate or carbonate
source. The carbonate sources can be selected from the group
consisting of dry solid carbonate and bicarbonate salts such as
sodium bicarbonate, sodium carbonate, potassium bicarbonate and
potassium carbonate, magnesium carbonate and sodium
sesquicarbonate, sodium glycine carbonate, L-lysine carbonate,
arginine carbonate and amorphous calcium carbonate.
[0077] The drug formulations of the present invention preferably
comprise a sweetener such as a water-soluble artificial sweetener,
including but not limited to soluble saccharin salts, such as
sodium or calcium saccharin salts, cyclamate salts, acesulfam-K,
the free acid form of saccharin and mixtures thereof. The sweetener
can also comprise a dipeptide based sweetener such as L-aspartyl
L-phenylalanine methyl ester.
[0078] The formulations of the present invention can also comprise
further pharmaceutical excipients such as polyvinyl alcohol,
polyvinylpyrrolidine, acacia or a combination thereof.
[0079] The dissolution or dispersion of the formulation can be
improved with the use of a surfactant, such as sodium lauryl
sulphate (Texapon K 12), various polysorbates known under the trade
name Tween, ethers of polyhydroxy ethylene fatty acids known under
the trade name Brij, esters of polyhydroxy ethylene fatty acids
known under the trade name Myrj, sodium desoxycholate, glycerol
polyethylene glycol ricinoleate (Cremophor EL),
polyoxyethylene-polyoxypropylene polymers known under the trade
name Pluronic, and various polyalkoxy alkylene sterol ethers.
[0080] The fast melt formulations of the present invention can also
comprise starches, e.g., corn starch, or modified starches, e.g.,
sodium starch glycolate or mixtures thereof, in any proportions.
Starches can provide increased salivation due to the porous nature
of the starch. Increased salivation favours rapid dissolution or
dispersion of the formulation upon oral administration.
[0081] When a starch is present in the formulation, the formulation
can further comprise a starch degrading enzyme will have a
synergistic effect with the starch with respect to dissolution or
dispersion. The enzymes upon being contacted with an aqueous
solution will initiate conversion of the starch to mono and
polysaccharides which quickly dissolve in the aqueous environment
and further contribute to improving the taste of the
multiparticulate formulation and increasing salivation.
[0082] The enzymes can be chosen for their degradation effect on
the starch and also for their stability over time, i.e. during the
shelf-life of the fast melt multiparticulate formulation.
Advantageously, the enzyme will be chosen from the group of starch
degrading enzymes comprising alpha-amylase, beta-amylase,
amyloglucosidase, debranching enzymes and glucose-fructose
isomerase. In certain embodiments, the enzymes can be an equal
mixture of amyloglucosidase and a-amylase.
[0083] In certain embodiments, drug formulations in accordance with
the invention are prepared by a process comprising melt granulating
the water soluble excipient and the active agent to form a
homogenous mixture. In an alternate embodiment, the process
comprises melt coating the water-soluble excipient onto the active
agent which can be optionally pregranulated with a pharmaceutically
acceptable excipient.
[0084] In such processes, the water-soluble excipient is preferably
a water-soluble alcohol such as xylitol.
[0085] The melt granulation and melt coating processes are
particularly preferred processes of the present invention as it is
not necessary to use an aqueous fluid as a processing aid. This
results in a process which can be used for a wide variety of active
agents, including those agents which would be susceptible to
degradation upon contact with water. Accordingly, such processes
provide advantages over many prior art processes for making fast
melt systems which rely on water as a processing aid. These prior
art processes would not be suitable for water liable drugs as such
processes would result in degradation of the drug during the
manufacturing process and during storage due to residual moisture
in the final product.
[0086] In certain embodiments, formulations in accordance with the
invention can be prepared by subliming solvent from a composition
comprising the active agent and the water soluble excipient and
reducing the sublimed composition to the particles. In such
embodiments, the composition can further comprises an excipient
selected from the group consisting of polyvinyl alcohol,
polyvinylpyrrolidone, acacia or a combination thereof. The
sublimation is preferably by freeze-drying and the solvent can be
an aqueous solvent or a co-solvent comprising an aqueous solvent
and an alcohol. A surfactant can also be included in such a
formulation.
[0087] In certain embodiments, fast melt formulations in accordance
with the invention can be prepared by a process which comprises
preparing a mixture comprising the active agent, the water soluble
excipient and a solvent, freezing the mixture, vacuum drying the
frozen mixture above a collapse temperature of the mixture to form
a partially collapsed matrix network and reducing the sublimed
composition to the particles. Preferably, the mixture comprises the
active agent, a gum, a carbohydrate base, and a solvent, wherein
the gum is selected from the group consisting of acacia, guar,
xanthan, tragacanth gum, and mixtures thereof, and the carbohydrate
is selected from the group consisting of mannitol, dextrose,
sucrose, lactose, maltose, maltodextrin, corn syrup solids, and
mixtures thereof.
[0088] In certain embodiments, fast melt formulations in accordance
with the invention can be prepared by a process which comprises
preparing a mixture comprising the active agent, the water soluble
excipient and an agar aqueous solution, solidifying the mixture
into a jelly form, drying the jelly and reducing the dried
composition into the particles. The drying can be effected by
reduced pressure drying, aeration drying or freeze-drying.
[0089] In certain embodiments, fast melt formulations in accordance
with the invention can be prepared by a process which comprises
melt spinning the active agent with the saccharide to form a mass
of spun fibres and reducing the spun fibres to the particles. The
saccharide can be sucrose or glucose.
[0090] In order to achieve the desired lower limit of the particles
size of the fast melt multiparticulate formulation of the
invention, air jet sieving can be used to remove fine particles. In
particular embodiments, the invention is directed to a method of
preparing a multiparticulate drug formulation for gastrointestinal
deposition comprising preparing a non-compressed free flowing
plurality of particles comprising a core comprising a drug and a
pharmaceutically acceptable excipient as disclosed herein and air
jet sieving the particles to separate the cores from fine
particles; and thereafter overcoating the core with a functional
coating as disclosed herein.
[0091] The invention is also directed to compositions obtained
using these methods.
[0092] The compositions of multiparticulates obtained using air jet
sieving and methods thereof are not limited to the particular
embodiments disclosed herein. The use of an air jet sieve is
beneficial as the standard sieving techniques used with screens and
meshes may not separate all of the desired fine particles as the
fine particles may adhere to the surface of larger particles and
thus not separate during the sieving process. The air jet sieving
process utilizes a negative pressure to draw particles below a
particular size range down through an appropriate screen or mesh.
In another embodiment, there is a combination of a downward
negative pressure and an upward positive pressure which facilitates
the de-agglomeration of the different particle sizes. In other
embodiments, the upward pressure can be introduced upwards from a
rotating wand. An apparatus utilizing a negative downward pressure
and an upward positive pressure through a rotating wand is a Micron
Air Jet Sieve MAJS I/II manufactured by Hosakawa.
[0093] The effect of humidity can have a negative impact of the
flowability of particles (e.g., due to cohesiveness). This can be a
particular problem with the present invention, which is directed to
fast melt multiparticulates which are designed to absorb water.
Accordingly, in preferred embodiments, the unit doses of fast melt
multiparticulates are premetered prior to actuation of the device.
This reduces the contamination of the unit doses as compared to
having the formulation in a multiple dose reservoir. Preferably,
the premetered unit doses are contained in sachets which minimize
the effect of humidity and moisture on the formulation.
[0094] Other multiple unit oral dosing devices, adapted contain the
formulation in a reservoir or as premetered unit doses, which are
useful in the present invention are disclosed in WO01/64182 hereby
incorporated by reference.
[0095] Classes of drugs which are suitable in the present invention
include antacids, anti-inflammatory substances, coronary dilators,
cerebral dilators, peripheral vasodilators, anti-infectives,
psychotropics, anti-manics, stimulants, anti-histamines, laxatives,
decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal
preparations, anti-anginal drugs, vasodilators, anti-arrhythmics,
anti-hypertensive drugs, vasoconstrictors and migraine treatments,
anti-coagulants and anti-thrombotic drugs, analgesics,
anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants,
anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic
agents, thyroid and anti-thyroid preparations, diuretics,
anti-spasmodics, uterine relaxants, mineral and nutritional
additives, anti-obesity drugs, anabolic drugs, erythropoietic
drugs, anti-asthmatics, bronchodilators, expectorants, cough
suppressants, mucolytics, drugs affecting calcification and bone
turnover and anti-uricemic drugs. Specific drugs include
gastro-intestinal sedatives such as metoclopramide and
propantheline bromide; antacids such as aluminum trisilicate,
aluminum hydroxide, ranitidine and cimetidine; anti-inflammatory
drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen,
flurbiprofen, diclofenac, dexamethasone, prednisone and
prednisolone; coronary vasodilator drugs such as glyceryl
trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate;
peripheral and cerebral vasodilators such as soloctidilum,
vincamine, naftidrofuryl oxalate, co-dergocrine mesylate,
cyclandelate, papaverine and nicotinic acid; anti-infective
substances such as erythromycin stearate, cephalexin, nalidixic
acid, tetracycline hydrochloride, ampicillin, flucloxacillin
sodium, hexamine mandelate and hexamine hippurate; neuroleptic
drugs such as flurazepam, diazepam, temazepam, amitryptyline,
doxepin, lithium carbonate, lithium sulfate, chlorpromazine,
thioridazine, trifluperazine, fluphenazine, piperothiazine,
haloperidol, maprotiline hydrochloride, imipramine and
desmethylimipramine; central nervous stimulants such as
methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine
sulfate and amphetamine hydrochloride; antihistamic drugs such as
diphenhydramine, diphenylpyraline, chlorpheniramine and
brompheniramine; anti-diarrheal drugs such as bisacodyl and
magnesium hydroxide; the laxative drug, dioctyl sodium
sulfosuccinate; nutritional supplements such as ascorbic acid,
alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugs
such as dicyclomine and diphenoxylate; drugs affecting the rhythm
of the heart such as verapamil, nifedipine, diltiazem,
procainamide, disopyramide, bretylium tosylate, quinidine sulfate
and quinidine gluconate; drugs used in the treatment of
hypertension such as propranolol hydrochloride, guanethidine
monosulphate, methyldopa, oxprenolol hydrochloride, captopril and
hydralazine; drugs used in the treatment of migraine such as
ergotamine; drugs affecting coagulability of blood such as epsilon
aminocaproic acid and protamine sulfate; analgesic drugs such as
acetylsalicylic acid, acetaminophen, codeine phosphate, codeine
sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone,
morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine
hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine
and mefenamic acid; anti-epileptic drugs such as phenytoin sodium
and sodium valproate; neuromuscular drugs such as dantrolene
sodium; substances used in the treatment of diabetes such as
tolbutamide, disbenase glucagon and insulin; drugs used in the
treatment of thyroid gland dysfunction such as triiodothyronine,
thyroxine and propylthiouracil, diuretic drugs such as furosemide,
chlorthalidone, hydrochlorthiazide, spironolactone and triamterene;
the uterine relaxant drug ritodrine; appetite suppressants such as
fenfluramine hydrochloride, phentermine and diethylproprion
hydrochloride; anti-asthmatic and bronchodilator drugs such as
aminophylline, theophylline, salbutamol, orciprenaline sulphate and
terbutaline sulphate; expectorant drugs such as guaiphenesin; cough
suppressants such as dextromethorphan and noscapine; mucolytic
drugs such as carbocisteine; anti-septics such as cetylpyridinium
chloride, tyrothricin and chlorhexidine; decongestant drugs such as
phenylpropanolamine and pseudoephedrine; hypnotic drugs such as
dichloralphenazone and nitrazepam; anti-nauseant drugs such as
promethazine theoclate; haemopoietic drugs such as ferrous
sulphate, folic acid and calcium gluconate; uricosuric drugs such
as sulphinpyrazone, allopurinol and probenecid; and calcification
affecting agents such as biphosphonates, e.g., etidronate,
pamidronate, alendronate, residronate, teludronate, clodronate and
alondronate.
[0096] Particularly preferred agents include antibiotics such as
clarithromycin, amoxicillin erythromycin, ampicillin, penicillin,
cephalosporins, e.g., cephalexin, pharmaceutically acceptable salts
thereof and derivatives thereof.
[0097] A particularly preferred agent is paracetamol
(acetaminophen). Other preferred agents are NTHES such as
ibuprofen, indomethacin, aspirin, diclofenac and pharmaceutically
acceptable salts thereof.
[0098] In certain preferred embodiments, however, formulations in
accordance with the invention do not include any non-steroidal
anti-inflammatory drug (NSAID).
[0099] The size of the unit dose is dependent on the amount of drug
needed to provide the intended therapeutic effect and the amount of
any pharmaceutically acceptable excipient which may be necessary.
Typically, a unit dose of from about 0.01 mg to about 1.5 g would
be sufficient to contain a therapeutically effective amount of the
drug to be delivered, however, this range is not limiting and can
be smaller or higher, depending on the amount of drug and excipient
that is necessary.
[0100] The following examples serve to illustrate the invention,
but should not be understood to be limiting in any respect.
EXAMPLE 1
[0101] The following materials were employed in this example.
1 Material % Composition Paracetamol 75 Xylitol 24 Aspartame 0.5
Acesulphame K 0.5
[0102] Method
[0103] Granular paracetamol, aspartame fine, acesulphame potassium
and 12% xylitol were accurately weighed into a glass jar and
blended at 42 rpm for 30 minutes using an inversion low shear
mixer. The blend was transferred to a jacketed vessel maintained at
a temperature of 95.degree. C. The blend was mixed at an impeller
speed sufficient to keep the whole powder bed moving (i.e. 222 RPM)
using an overhead mixer for a time sufficient to allow homogenous
distribution of the molten binder in the blend. The remaining melt
binder was added to the blend and the impeller speed increased to
provide continuous movement of the powder bed (i.e. 250 RPM). The
formulation was cooled and then sieved using a 710 micron sieve to
remove any large agglomerates, once distribution of the melt binder
was complete.
[0104] Results
[0105] The formulation had a sweet taste and good mouthfeel. The
dissolution of the paracetamol from the formulation was measured
using a modified version of the standard USP test for measuring
paracetamol (acetaminophen) dissolution. The test conditions
involved stirring 333 mg of the formulation in 900 ml of water,
buffered to pH 5.8 with a potassium phosphate buffer, at 37.degree.
C., using a paddle speed of 100 RPM (the standard USP paddle speed
is 50 RPM). The results are set out below.
EXAMPLE 2
[0106] The following materials were employed in this example.
2 Material % Composition Paracetamol 77 Xylitol 20 Aspartame 0.5
Acesulphame K 0.5 Maltodextrin M100 2
[0107] Method
[0108] Granular paracetamol, aspartame fine, maltodextrin M100,
acesulphame potassium and 10% xylitol were accurately weighed into
a glass jar and blended at 42 rpm for 30 minutes using an inversion
low shear mixer. The blend was transferred to a jacketed vessel
maintained at a temperature of 95.degree. C. The blend was mixed at
an impeller speed sufficient to keep the whole powder bed moving
(i.e. 222 RPM) using an overhead mixer for a time sufficient to
allow homogenous distribution of the molten binder in the blend.
The remaining melt binder was added to the blend and the impellar
speed increased to provide continuous movement of the powder bed
(i.e. 250 RPM). The formulation was cooled and then sieved using a
710 micron sieve to remove any large agglomerates, once
distribution of the melt binder was complete.
[0109] Results
[0110] It was found that incorporation of certain grades
maltodextrin improved mouthfeel and reduced aftertaste without
impeding drug release. The dissolution of the paracetamol from the
formulation was measured using the same test as that employed in
Example 1, and the results are set out below.
EXAMPLE 3
[0111] The tastemasking properties of xylitol result from its
negative heat of solution, which confers a cooling effect on
dissolution on the oral cavity. This example details the use of
erythritol, which has a greater negative heat of solution, to
improve the degree of tastemasking. Formulations were prepared
using erythritol as the melt binder from the following
materials.
3 Material % Composition Paracetamol 87 Erythritol 10 Aspartame 0.5
Acesulphame K 0.5 Maltodextrin M100 2
[0112] Method
[0113] Granular paracetamol, aspartame fine, maltodextrin M100,
acesulphame potassium and 5% erythritol were accurately weighed
into a glass jar and blended at 42 rpm for 30 minutes using an
inversion low shear mixer. The blend was transferred to a jacketed
vessel maintained at a temperature of 121.degree. C. The blend was
mixed at an impellar speed sufficient to keep the whole powder bed
moving (i.e. 222 RPM) using an overhead mixer for a time sufficient
to allow homogenous distribution of the molten binder in the blend.
The remaining melt binder was added to the blend and the impellar
speed increased to provide continuous movement of the powder bed
(i.e. 250 RPM). The formulation was cooled and then sieved using a
710 micron sieve to remove any large agglomerates, once
distribution of the melt binder was complete.
[0114] Results
[0115] Upon melt granulation it was observed that the formulation
developed a slight brown discoloration. This was attributed to the
thermal degredation of Maltodextrin M100. This was confirmed by the
preparation of Example 4 in which there was no evidence of
browning.
EXAMPLE 4
[0116] The following materials were employed in this example.
4 Material % Composition Paracetamol 89 Erythritol 10 Aspartame 0.5
Acesulphame K 0.5
[0117] Method
[0118] Granular acetaminophen, aspartame fine, acesulphame
potassium and 5% erythritol were accurately weighed into a glass
jar and blended at 42 rpm for 30 minutes using an inversion low
shear mixer. The blend was transferred to a jacketed vessel
maintained at a temperature of 121.degree. C. The blend was mixed
at an impeller speed sufficient to keep the whole powder bed moving
(i.e. 222 RPM using an overhead mixer for a time sufficient to
allow homogenous distribution of the molten binder in the blend.
The remaining melt binder (erythritol) was added to the blend and
the impeller speed increased to provide continuous movement of the
powder bed (i.e. 250 RPM). The formulation was cooled and then
sieved using a 710 micron sieve to remove any large agglomerates,
once distribution of the melt binder was complete.
[0119] Dissolution profiles were not obtained for examples 3 and
4.
EXAMPLE 5
[0120] The following materials were employed in this example.
5 Material % Composition Paracetamol 82 Erythritol 5 Xylitol 10
Maltodextrin M100 2 Aspartame 0.5 Acesulphame K 0.5
[0121] Method
[0122] Granular acetaminophen and erythritol were accurately
weighed into a glass jar and blended at 42 rpm for 30 minutes using
an inversion low shear mixer. The blend was transferred to a
jacketed vessel maintained at a temperature of 121.degree. C. The
blend was mixed at an impeller speed sufficient to keep the whole
powder bed moving (i.e. 222 RPM) using an overhead mixer for a time
sufficient to allow homogenous distribution of the molten binder in
the blend. The temperature was then reduced to 95.degree. C. and
the xylitol, aspartame fine, acesulphame potassium and maltodextrin
added to the blend. The impeller speed was increased as required to
provide continuous movement of the powder bed (i.e. 250 RPM). The
formulation was cooled and then sieved using a 710 micron sieve to
remove any large agglomerates, once distribution of the melt binder
was complete.
[0123] Results
[0124] Example 5 exhibited improved tastemasking over example 2,
with improved masking of the slight aftertaste which was evident in
example 3 and minimal evidence of the aftertaste which was evident
in example 4. The browning of the formulation which was observed in
example 3 was not evident in this formulation due to the
incorporation of maltodextrin in the second stage of melt coating.
The dissolution of the paracetamol from the formulation was
measured using the same test as that employed in Example 1, and the
results are set out below.
[0125] The drug release profiles of the formulation of Example 5
versus that of the unformulated raw drug, i.e., granular
acetaminophen, are shown in FIG. 1. The particle size distributions
of the formulation of Example 5 ("Special Granulate APAP") versus
that of the unformulated raw drug ("Paracetamol Special Granular")
are shown in FIG. 2.
EXAMPLE 6
[0126] Example 6 describes the use of materials capable of
liberating carbon dioxide in aqueous conditions to facilitate
tastemasking. The following materials were employed in this
example.
6 Material % Composition Paracetamol 77 Xylitol 20 Sodium Glycine
Carbonate 1.2 Citric Acid Monohydrate 0.8 Acesulphame K 0.5
Aspartame 0.5
[0127] Method
[0128] Granular paracetamol, aspartame fine, sodium glycine
carbonate, citric acid monohydrate, acesulphame potassium and 10%
xylitol were accurately weighed into a glass jar and blended at 42
rpm for 30 minutes using an inversion low shear mixer. The blend
was transferred to a jacketed vessel maintained at a temperature of
95.degree. C. The blend was mixed at an impellar speed sufficient
to keep the whole powder bed moving (i.e. 222 RPM using an overhead
mixer for a time sufficient to allow homogenous distribution of the
molten binder in the blend. The remaining melt binder was added to
the blend and the impellar speed increased to provide continuous
movement of the powder bed (i.e. 250 RPM. The formulation was
cooled and then sieved using a 710 micron sieve to remove any large
agglomerates, once distribution of the melt binder was
complete.
[0129] Results
[0130] The formulation exhibited acceptable tastemasking. However,
the addition of Maltodextrin M100, as shown in example 7, improved
its mouthfeel.
EXAMPLE 7
[0131] The following materials were employed in this example.
7 Material % Composition Paracetamol 77 Xylitol 18 Maltodextrin
M100 2.0 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 0.8
Acesulphame K 0.5 Aspartame 0.5
[0132] Method
[0133] Granular paracetamol, aspartame fine, sodium glycine
carbonate, citric acid monohydrate, maltodextrin M100, acesulphame
potassium and 9% xylitol were accurately weighed into a glass jar
and blended at 42 rpm for 30 minutes using an inversion low shear
mixer. The blend was transferred to a jacketed vessel maintained at
a temperature of 95.degree. C. The blend was mixed at an impeller
speed sufficient to keep the whole powder bed moving (i.e. 222 RPM)
using an overhead mixer for a time sufficient to allow homogenous
distribution of the molten binder in the blend. The remaining melt
binder was added to the blend and the impeller speed increased to
provide continuous movement of the powder bed (i.e. 250 RPM). The
formulation was cooled and then sieved using a 710 micron sieve to
remove any large agglomerates, once distribution of the melt binder
was complete.
[0134] Results
[0135] The addition of Maltodextrin M100 was shown to improve
mouthfeel.
EXAMPLE 8
[0136] Example 8 illustrates the use of polyethylene glycols (PEGs)
as the water soluble melt binder.
[0137] The following materials were employed in this example.
8 Material % Composition Paracetamol 80 Erythritol 5 PEG6000 Powder
10 Maltodextrin M100 2.0 Sodium Glycine Carbonate 1.2 Citric Acid
Monohydrate 0.8 Acesulphame K 0.5 Aspartame 0.5
[0138] Method
[0139] Granular paracetamol, erythritol, sodium glycine carbonate
and citric acid monohydrate and 5% PEG6000 were accurately weighed
into a glass jar and blended at 42 rpm for 30 minutes using an
inversion low shear mixer. The blend was transferred to a jacketed
vessel maintained at a temperature of 70.degree. C. The blend was
mixed at an impeller speed sufficient to keep the whole powder bed
moving (i.e. 222 RPM) using an overhead mixer for a time sufficient
to allow homogenous distribution of the molten binder in the blend.
The remaining melt binder was added to the blend, along with the
maltodextrin M100, aspartame and acesulphame potassium, and the
impeller speed increased to provide continuous movement of the
powder bed (i.e. 250 RPM). The formulation was cooled and then
sieved using a 710 micron sieve to remove any large agglomerates,
once distribution of the melt binder was complete.
[0140] Results
[0141] The resulting formulation exhibited reasonable tastemasking
and a slight aftertaste, but with excellent mouthfeel and rapid
dispersibility.
EXAMPLE 9
[0142] An additional approach to drug tastemasking is described
where the citric acid monohydrate content is increased to locally
modify the pH within the oral cavity and therefore limit drug
dissolution.
[0143] The following materials were employed in this example.
9 Material % Composition Paracetamol 77.2 Erythritol 10.0 PEG6000
Powder 7.0 Sodium starch Glycolate 2.0 Sodium Glycine Carbonate 1.2
Citric Acid Monohydrate 1.5 Acesulphame K 0.5 Aspartame 0.5
Powdered Lemon Flavour 0.1
[0144] Method
[0145] Using a Diosna P1-6 mixer-granulator equipped with a 1 litre
jacketed bowl was heated at 55.degree. C. for 10 minutes before the
addition of the granular acetaminophen, erythritol, sodium starch
glycolate, sodium glycine carbonate, citric acid monohydrate,
aspartame fine, acesulphame potassium and powdered lemon flavour.
This material was blended for a further 10 minutes prior to the
addition of the PEG6000. An impeller speed of 50 RPM and a chopper
speed of 50 RPM were selected to distribute the binder through the
material. Mixing was continued at the elevated temperature for
approximately 5 minutes before the bowl was cooled to 25.degree. C.
for 10 minutes.
[0146] Results
[0147] The resulting formulation exhibited pleasant taste, good
mouthfeel and a slight bitter aftertaste; which is attributed to
the presence of additional citric acid. The dissolution of the
paracetamol from the formulation was measured using the same test
as that employed in Example 1, and the results are set out
below.
EXAMPLE 10
[0148] Sumatriptan 50 mg (Final Formulation Mass 75.7 mg) A
granulation of Sumatriptan was prepared containing 4% w/w PVP K-30
(aqueous) in a MP Micro fluid bed dryer. The drug and binder were
granulated by the addition of water, using the down-spray method.
The granulated material was dried, cooled and then screened through
a 250 .mu.m sieve and airjet sieved to remove particles below 1001
m. The resulting granules were then spray coated with an aqueous
dispersion of Eudragit RD-100 plasticised with Triacetin. The
quantity of coating was sufficient to achieve the required degree
of tastemasking of the active (approximately 15% weight gain). The
granules were then dried and cooled for hot melt coating with
xylitol. The tastemasked Sumatriptan granules were loaded into a 1
litre-jacketed bowl for a modified Diosna P1-6 mixer-granulator
(preheated at 95.degree. C. for 10 minutes) with 1% Aspartame (or
0.5% Aspartame and 0.5% Acesulfame potassium) and 10% xylitol. An
impeller speed of 50 RPM and a chopper speed of 50 RPM were
selected to distribute the binder (xylitol) through the material.
Mixing was continued at the elevated temperature for approximately
5 minutes before addition of a further 10% xylitol to the system.
After another 5 minutes mixing, the bowl was cooled to 25.degree.
C. over 10 minutes. Once cooled the formulation was tested. It was
found that improved tastemasking and drug release could be achieved
by further addition of Triacetin to the Eudragit RD100 film
coat.
EXAMPLE 11
[0149] Lansoprazole 15 mg (Final Formulation Mass 20 mg)
[0150] Using a Diosna P1-6 mixer-granulator, a melt-granulation of
75% Lansoprazole, 20% PEG 6000 and 5% Aspartame was prepared using
a one litre jacketed mixing bowl heated to a temperature sufficient
to melt the PEG 6000 binder (i.e. 70.degree. C.). The Lansoprazole
and Aspartame were equilibrated in the bowl for 10 minutes at an
impeller speed of 300 RPM and a chopper speed of 150 RPM, after
this time the PEG6000 was added and massing continued for another 3
minutes. The material was then emptied from the bowl, cooled on a
metal tray at room temperature and then stored in sealed bags. It
was found that incorporation of 5% of a low-viscosity Sodium Starch
Glycolate into the granules improved the mouthfeel of this
formulation without altering drug release or the degree of
tastemasking.
EXAMPLE 12
[0151] Ranitidine 150 mg (Final Formulation Mass 200 mg)
[0152] Using a Diosna P1-6 mixer-granulator, a melt-granulation of
75% Ranitidine, 20% PEG 6000 and 5% Aspartame was prepared using a
one litre jacketed mixing bowl heated to a temperature sufficient
to melt the PEG 6000 binder (i.e. 70.degree. C.). The Ranitidine
and Aspartame were equilibrated in the bowl for 10 minutes at an
impeller speed of 300 RPM and a chopper speed of 150 RPM, after
this time the PEG6000 was added and massing continued for another 3
minutes. The material was then emptied from the bowl, cooled on a
metal tray at room temperature and then stored in sealed bags. It
was found that incorporation of molar equivalents of citric acid
monohydrate and sodium bicarbonate into the melt granulation
improved the degree of tastemasking and aided the dispersion of the
granules.
EXAMPLE 13
[0153] Domperidone 10 mg (Final Formulation Mass 100 mg)
[0154] A 5% w/w aqueous dispersion of maltodextrin containing 5%
w/w domperidone was prepared and spray-coated onto microcrystalline
cellulose spheres sufficient to achieve a 33% coating wt. gain
using and MP-Micro Fluid Bed Dryer. The coated spheres were then
dried and cooled for hot melt coating with xylitol. Using a
modified Diosna P1-6 mixer-granulator the domperidone-loaded
microcrystalline cellulose spheres were blended with 10% wt. gain
of xylitol using a one litre jacketed mixing bowl heated to
95.degree. C. An impeller speed of 50 RPM and a chopper speed of 50
RPM were selected to distribute the binder through the material.
Mixing was continued at the elevated temperature for approximately
5 minutes before addition of a further 10% xylitol to the system.
After another 5 minutes mixing, the bowl was cooled to 25.degree.
C. over 10 minutes. Once cooled, the formulation was tested. It was
found that the incorporation of 0.25-0.5% of
hydroxypropylmethylcellulose to the xylitol improved the stability
of the formulation.
EXAMPLE 14
[0155] Paracetamol (Acetaminophen) 500 mg (Final Formulation Mass
745 mg)
[0156] Step 1: Spray Coating With Surelease
[0157] Granular paracetamol was tastemasked by spray-coating with
an aqueous dispersion of ethylcellulose in an MP-Micro Fluid Bed
Dryer. Approximately a 15% wt. gain was required, depending on the
degree of tastemasking. Once the desired weight of ethylcellulose
had been added to the granules, the material was dried, cooled and
then screened through a 250 .mu.m sieve and airjet sieved to remove
particles below 100 .mu.m. Using a modified Diosna P1-6
mixer-granulator, the tastemasked paracetamol granules were then
blended with 1% Aspartame and 10% xylitol in a one litre jacketed
mixing bowl heated to 95.degree. C. for 10 minutes. An impeller
speed of 50 RPM and a chopper speed of 50 RPM were selected to
distribute the binder through the material. Mixing was continued at
the elevated temperature for approximately 5 minutes before
addition of a further 10% xylitol to the system. After another 5
minutes mixing the bowl was cooled to 25.degree. C. over 10
minutes. Once cooled the formulation was tested. It was found that
improved tastemasking and drug release could be achieved by further
addition of glycerol to the ethylcellulose film coat.
EXAMPLE 15
[0158] Loperamide 2 mg (Final Formulation Mass 50 mg)
[0159] A granulation of equal quantities of aspartame and
Acesulphame K was prepared using 4% w/w PVP K-30 (aqueous) in a MP
Micro fluid bed dryer. The drug and binder were granulated by the
addition of water, using the down-spray method. The granulated
material was dried, cooled and then screened through a 250 .mu.m
sieve and airjet sieved to remove particles below 100 .mu.m. The
granules were dried and cooled for hot melt coating with xylitol.
Using a modified Diosna P1-6 mixer-granulator the
aspartame/acesulphame K granules were blended with 4% Loperamide
and 10% wt. gain of xylitol using a one litre jacketed mixing bowl
heated to 95.degree. C. An impeller speed of 50 RPM and a chopper
speed of 50 RPM were selected to distribute the binder through the
material. Mixing was continued at the elevated temperature for
approximately 5 minutes before addition of a further 10% xylitol to
the system. After another 5 minutes mixing the bowl was cooled to
25.degree. C. over 10 minutes. Once cooled the formulation was
tested. It was found that the incorporation of 0.25-0.5% of
hydroxypropylmethylcellulose to the xylitol improved the stability
of the formulation.
EXAMPLE 17
[0160] Co-Beneldopa 12.5 mg/50 mg (Final Formulation Mass 164.8
mg)
[0161] A granulation of 19.2% Benserazide Hydrochloride and 76.8%
Levodopa was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro
fluid bed dryer. The drug and binder were granulated by the
addition of water, using the down-spray method. The granulated
material was dried, cooled and then screened through a 250 .mu.m
sieve and airjet sieved to remove particles below 100 .mu.m. The
granules were dried and cooled for hot melt coating with Xylitol.
Using a modified Diosna P1-6 mixer-granulator the Co-Beneldopa
granulation was blended with 10% xylitol in a one litre jacketed
mixing bowl heated to 95.degree. C. for 10 minutes. An impeller
speed of 50 RPM and a chopper speed of 50 RPM were selected to
distribute the binder through the material. Mixing was continued at
the elevated temperature for approximately 5 minutes before
addition of a further 10% xylitol to the system.
[0162] After another 5 minutes mixing the bowl was cooled to
25.degree. C. over 10 minutes. Once cooled the formulation was
tested. It was found that by adding a 5% wt. gain of glyceryl
palmitostearate and 1% wt. gain of aspartame, the degree of
tastemasking was improved without adversely impeding drug
release.
EXAMPLE 18
[0163] Enteric coated Aspirin formulation
[0164] Method
[0165] Granular Aspirin, having a particle size suitable for spray
coating (i.e., between 100 and 5001 .mu.m) was coated in an
MP-Micro fluid bed dryer, using the down-spray coating module. An
aqueous dispersion of 15% w/w Opadry.RTM. was prepared, which was
sprayed onto the granular aspirin at a product temperature of
between 40 and 45.degree. C. to a weight gain of 10%. The coated
material was dried before a 15% weight gain of an aqueous
dispersion of 15% w/w Acryl-eze was added to the granules, at a
product temperature of 25-35.degree. C. The material was dried and
cooled before being placed in a one litre jacketed bowl for the
Diosna P1-6 mixer granulator. A blend of 60% enteric coated
aspirin, 20% Mannitol, 10% Xyltiol 7% Peg 6000, 0.5% Aspartame,
0.5% Acesulfame Potassium and 2% Maltodextrin was equilibrated at
70.degree. C. whilst mixing at an impellar speed of 50 RPM and a
chopper speed of 50 RPM. Mixing was continued at the elevated
temperature for approximately 5 minutes before the bowl was cooled
to 25.degree. C. for 10 minutes.
[0166] Results
[0167] The formulation met USP requirements for acid phase drug
release, i.e., less than or equal to 10% dissolved in 2 hours in
0.1M HCl and greater than 80% released in 90 minutes in pH 6.8
phosphate buffer.
EXAMPLE 19
[0168] Controlled Release Chlorpheniramine Maleate Drug-Loaded
Spheres
[0169] Step 1: Drug Loading
[0170] Chlorpheniramine maleate was dissolved in an aqueous
dispersion of 10% Opadry.RTM.. A 15% weight gain of Opadry.RTM. was
applied to 60-40 mesh non-pariel sugar spheres, in order to obtain
an active drug content of approximately 8% w/w. The dispersion was
applied to the sugar spheres at a product temperature of between 40
and 45.degree. C. in an MP-Micro fluid bed dryer, using the
down-spray coating module.
[0171] Step 2: Sustained Release Coating
[0172] An additional 5% coat of 10% Opadry.RTM. aqueous dispersion
was added to the drug loaded spheres before the application of an
aqueous dispersion of 15% w/w Surelease was applied. A weight gain
of between 15 and 30% was applied to produce a formulation with the
required release profile.
[0173] Step 3: Melt Granulation
[0174] The dried, 65% drug-loaded spheres were blended in a one
litre jacketed bowl for the Diosna P1-6 mixer granulator with 15%
Mannitol, 10% Erythritol, 7% Peg 6000, 0.5% Aspartame, 0.5%
Acesulfame Potassium and 2% Maltodextrin and equilibrated at
70.degree. C. whilst mixing at an impellar speed of 50 RPM and a
chopper speed of 50 RPM. Mixing was continued at the elevated
temperature for approximately 5 minutes before the bowl was cooled
to 25.degree. C. for 10 minutes.
[0175] Results
10 Time (Hours) % Drug Release 2 20-30 4 35-45 6 45-55 12 60-70
EXAMPLE 20
[0176] Immediate release Chlorpheniramine Maleate
[0177] A granulation of 8% Chlorpheniramine Maleate, 4% w/w PVP
K-30 and 88% Xylitol was prepared in an MP Micro fluid bed dryer.
The materials were granulated by the addition of water, using the
down-spray method. The granulated material was dried, cooled and
then screened through a 250 .mu.m sieve and airjet sieved to remove
particles below 1001 .mu.m. A blend containing 50% Chlorpheniramine
Granules, 25% Granular Mannitol, 10% Erythritol, 0.5% Aspartame,
0.5% Acesulfame Potassium, 1.2% Citric Acid Monohydrate, 0.8%
Sodium Glycine Carbonate and 2% Maltodextrin was equilibrated at
70.degree. C. in a one litre jacketed bowl for a Diosna P1-6
mixer-granulator for 10 minutes at an impellar speed of 50 RPM and
a chopper speed of 50 RPM prior to the addition of 10% PEG6000.
Mixing was continued at the elevated temperature for approximately
5 minutes before the bowl was cooled to 25.degree. C. for 10
minutes.
EXAMPLE 21
[0178] 10 Chronotherapeutic Chlorpheniramine Maleate Blend
Method
[0179] A blend of 16.7 g of immediate-release chlorpheniramine
maleate granules (Example 20) was blended with 83.3 g
controlled-release chlorpheniramine maleate drug-loaded spheres
(Example 19) at 42 rpm for 30 minutes using an inversion low shear
mixer.
11 Results (Formulation mass 600 mg: active 24 mg) Time (Hours)
Mean Drug Release (mg) n = 6 0.5 4.2 4 9.6 6 12.1 12 15.6
* * * * *