U.S. patent application number 10/892238 was filed with the patent office on 2005-01-06 for method and apparatus for the coating of substrates for pharmaceutical use.
This patent application is currently assigned to Phoqus Pharmaceuticals Limited. Invention is credited to Brown, Steven R., Reeves, Linda A., Staniforth, John N..
Application Number | 20050003074 10/892238 |
Document ID | / |
Family ID | 10802890 |
Filed Date | 2005-01-06 |
United States Patent
Application |
20050003074 |
Kind Code |
A1 |
Brown, Steven R. ; et
al. |
January 6, 2005 |
Method and apparatus for the coating of substrates for
pharmaceutical use
Abstract
A method of coating a substrate includes applying an active
coating material to the substrate to form an active coating layer.
The active coating material comprises biologically active material
and the active coating layer is removable from the substrate.
Inventors: |
Brown, Steven R.; (Kent,
GB) ; Reeves, Linda A.; (Kent, GB) ;
Staniforth, John N.; (Bath, GB) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
1100 N GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
22201-4714
US
|
Assignee: |
Phoqus Pharmaceuticals
Limited
Kent
GB
|
Family ID: |
10802890 |
Appl. No.: |
10/892238 |
Filed: |
July 16, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10892238 |
Jul 16, 2004 |
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09310740 |
May 13, 1999 |
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6783768 |
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09310740 |
May 13, 1999 |
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PCT/GB97/03113 |
Nov 13, 1997 |
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Current U.S.
Class: |
427/2.24 |
Current CPC
Class: |
A61K 9/2086 20130101;
A61K 9/7007 20130101; A61K 9/2886 20130101; A61K 9/70 20130101;
A61K 9/2893 20130101 |
Class at
Publication: |
427/002.24 |
International
Class: |
A61L 002/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 13, 1996 |
GB |
9623634.4 |
Claims
1. A method of coating a substrate, the method including the steps
of applying an active coating material to the substrate to form an
active coating layer, the active coating material comprising
biologically active material, wherein the active coating layer is
removable from the substrate.
2. A method according to claim 1, wherein the active coating
material is applied electrostatically.
3. A method according to claim 1, wherein the active coating
material is applied in the form of a dry powder.
4. A method according to claim 3, wherein at least 90% by weight of
the particles of the active coating material have a particle size
between from 1 to 200 .mu.m.
5. A method according to claim 1, wherein the active coating
material further includes one or more excipients.
6. A method according to claim 1, wherein the substrate is conveyed
through a region adjacent to a source of the active coating
material.
7. A method according to claim 6, wherein the method comprises
supporting the substrate adjacent to the source of the active
coating material with a surface of the substrate maintained at such
a different electric potential from that of the active coating
material that the application of the electric potential causes the
active coating material to move from the source of the active
coating material towards the substrate, a surface of the substrate
becoming coated with the active coating material.
8. A method according to claim 6, wherein the substrate is
supported from above and the powder moves from the source upwards
towards a lower surface of the substrate.
9. A method according to claim 6, wherein the substrate is charged
when the substrate is adjacent to the source of the active coating
material.
10. A method according to claim 6, wherein the source of active
coating material is charged.
11. A method according to claim 1, wherein the method further
includes the step that after the active coating layer is applied
the active coating material is treated to form an active film
coating secured to the surface of the substrate.
12. A method according to claim 1, wherein the method further
includes the step of applying a cover coating layer onto the active
coating layer to form a cover coating layer such that the active
coating layer is substantially completely covered by the cover
coating layer.
13. A method according to claim 12, wherein the cover coating layer
is removable from the substrate.
14. A method according to claim 1, wherein the active coating
material is applied to a part of a surface of the substrate, the
active coating layer forming a first active coated region on the
surface of the substrate.
15. A method according to claim 1, wherein the method includes the
further step of applying a second active coating layer onto a
surface of the substrate, the second active coating layer forming a
second active coating region on a surface of the substrate.
16. A method according to claim 15, wherein the method further
includes the step of applying a second cover coating layer onto the
second active coating layer to form a second cover coating layer
such that the second active coating layer is substantially
completely covered by the second cover coating layer, the second
cover coating layer being substantially separate from the first
cover coating layer.
17. A method of coating a plurality of coating regions onto the
surface of a substrate, the method comprising the steps of: (a)
applying active coating material to a surface of the substrate to
form a plurality of active coating regions on the surface
comprising active coating layers, the active coating material
including biologically active material (b) applying cover coating
material to a surface of the substrate to form a plurality of cover
coating regions, the cover coating regions forming layers of cover
coating material, each active coating region being substantially
completely covered by a cover coating region, such that each region
of active coating and cover coating is removable from the surface
of the substrate.
18. A method according to claim 1, the method further including the
step of removing the active coating layer from the substrate to
form a wafer comprising active material.
19. A method according to claim 18, wherein the wafer is cut to
form wafer portions, each wafer portion including substantially a
dose of the active material.
20. Apparatus for coating a pharmaceutical substrate according to a
method as claimed in claim 1.
21. An apparatus for coating a substrate, the apparatus comprising:
(a) a source of active coating material, (b) support means for
supporting a substrate adjacent to the source of the active coating
material such that the active coating material forms an active
coating layer on the surface of the substrate.
22. An apparatus according to claim 21, further comprising: (c) a
source of a cover coating material, (d) means for conveying the
substrate having the active coating layer to a position adjacent to
the source of cover coating material such that the cover coating
material forms a cover coating layer which substantially completely
covers the active coating layer.
23. An apparatus according to claim 21, wherein the substrate
comprises a conveyor belt.
24. An apparatus according to claim 21, further including means for
applying a charge to the source of active coating material.
25. An apparatus according to claim 21, wherein the apparatus
further includes means for applying a charge to the substrate.
26. An apparatus according to claim 21, wherein the source is
arranged below the substrate.
27. An apparatus for coating a substrate, the apparatus comprising:
(a) a source of active coating material (b) means for moving the
substrate relative to the source of coating material, (c) means for
applying an active coating material onto a surface of the substrate
to form a plurality of active coating regions (d) means for
applying a cover coating material onto the surface of the substrate
to form a plurality of cover coating regions such that each active
coating region is substantially completely covered by a cover
coating region, the coating materials being applied such that the
active coating material is removable from the surface of the
substrate.
28. A coated substrate comprising an active coating layer on a
surface of the substrate, the active coating layer including
biologically active material and in which the active coating layer
is removable from the surface of the coated substrate.
29. A coated substrate according to claim 28, the substrate further
including a cover coating layer on a surface of the substrate, the
cover coating layer substantially completely covering the active
coating layer in which the cover coating layer is removable from
the surface of the substrate.
30. A coated substrate according to claim 28, wherein the substrate
includes a plurality of active coating layers forming active
coating regions on a surface of the substrate.
31. A coated substrate according to claim 30, wherein each active
coating region includes a cover coating region comprising a layer
of cover coating material in which each active coating region is
substantially completely covered by a cover coating region.
32. A coated substrate when made according to a method as claimed
in claim 1.
33. An intermediate product for use in producing a plurality of
solid dosage forms, the intermediate product comprising a substrate
and an active coating layer deposited on the substrate, the amount
of active coating material deposited on a given area of the
substrate being controlled such that the product can subsequently
be divided into portions with each portion containing a
predetermined amount of active coating material, each predetermined
amount being one dose of the active material.
34. A wafer for administration to a patient, the wafer comprising
biologically active material and having a thickness of less than 2
mm.
35. A wafer produced by a method according to claim 18.
36. A method of coating a substrate, the method comprising applying
an active coating material to a surface of the substrate to form an
active coating layer, the active coating material comprising
biologically active material, applying a cover coating layer over
the exposed surfaces of the active coating layer and dividing the
layered product to form layered portions, each layered portion
including substantially one dose of the active material.
Description
[0001] The present invention relates to methods of coating
substrates, to apparatus for coating substrates and to coated
substrates for pharmaceutical use. In particular, but not
exclusively, the invention relates to the coating of pharmaceutical
substrates to produce solid dosage forms.
[0002] It is to be understood that the term "solid dosage form" is
to be interpreted in a broad sense as covering a wide variety of
pharmaceutical products. Thus the term covers pharmaceutical
products to be taken orally, for example, pharmaceutical tablets of
conventional shape as well as capsules and spherules and tablets of
unconventional shape. The term also covers pharmaceutical products
not taken orally, for example, a pessary, a bougie, a suppository
or a patch for application to the skin. Also, where reference is
made to "pharmaceutical substrate" it is to be understood that the
term covers the substrates of the solid dosage forms indicated
above. The term "solid dosage form" does not, however, include
pharmaceutical products such as small pellets and granules, for
example small pellets which are filled into capsule shells for
administration and granules which are compressed to form tablets;
such pellets or granules are not themselves each solid dosage forms
but rather, when combined together in a capsule or tablet, define
in combination a solid dosage form.
[0003] It will be understood that the term "active material" and
"active component" used throughout the specification includes
material which is biologically active and will comprise one or a
mixture of pharmaceutical materials. The pharmaceutical materials
include those materials which are administered for the prevention
and/or treatment of disease.
[0004] Active materials are conventionally administered in the form
of tablets.
[0005] In a conventional method of producing a pharmaceutical
tablet, a mixture containing the biologically active ingredient
together with diluents such as lactose and other ingredients is
mixed and portions of the mixture are formed into discrete tablets
by, for example, pressing samples of the mixture.
[0006] A problem with the method of producing tablets described
above is that, due to inhomogeneity of the mixture from which the
tablet cores are made, the amount of active ingredient in the
resulting tablet cores varies from one tablet to the next. While
that is a problem for all types of tablet core produced in that
way, it is a particularly serious problem when the amount of active
ingredient in each core is low, for example for active compounds of
high activity. In that case a small absolute variation in the
percentage amount of active ingredient in the cores corresponds to
a significant variation in the dose contained in each tablet which
is clearly most undesirable.
[0007] In one known method, a coating solution containing active
material is applied to the surfaces of small beads using
conventional spray coating techniques, for example by spraying the
coating solution towards the beads as they are tumbled in a
revolving drum. The coated beads are filled into capsule shells for
administration. Such a method is not appropriate for use where
accuracy in the amount of the active material applied to the cores
is required because there is little control over the amount of
coating material applied to each core using that method.
[0008] Active components are often administered in tablet form. As
indicated above, conventional tablets include a small amount of
active component and a large amount of diluent such as lactose so
that the tablet is a convenient size. The tablet is a convenient
way for the active component to be administered because each tablet
contains a predetermined metered dose of the active material.
[0009] However, some patients find the taking of tablets difficult,
for example because of their size or because of the presence of the
other ingredients in the tablet composition. Thus an alternative
dosage form would be desirable.
[0010] GB 1 561 100 describes the coating of a web with material
containing an active ingredient. The coated web is processed to
internalize the active coating by, for example, lamination and
winding to provide a dosage form.
[0011] It is an object of the invention to overcome or mitigate one
or more of the above mentioned disadvantages.
[0012] In accordance with the invention, there is provided a method
of coating a substrate, the method including the steps of applying
an active coating material to the substrate to form an active
coating layer, the active coating material comprising biologically
active material, wherein the active coating layer is removable from
the substrate.
[0013] In accordance with the invention, the active material is
applied as a coating to a substrate from which it can be
removed.
[0014] In one alternative embodiment of the invention, the coating
material is applied directly onto a surface of the coating
apparatus, the coating formed in the process being removed from the
apparatus as a wafer containing the active material.
[0015] In a second alternative embodiment of the invention, the
coating material is applied onto a substrate, the coating being
removed from the substrate as a wafer, for example by a patient
prior to the administration of the material. The substrate may be,
for example, a sheet comprising plastics material, for example low
adhesion plastics material.
[0016] The surface of the substrate may be precoated with one or
more coating layers.
[0017] Preferably, the active coating material is applied
electrostatically. There are various advantages in applying coating
materials electrostatically, for example, reduction in waste of
coating material, improved coating efficiency and improved coating
weight uniformity.
[0018] In one alternative of the invention, the active coating
material is applied in the form of a dry powder.
[0019] Advantageously, at least 90% by weight of the particles of
the active coating material have a particle size less than 200
.mu.m.
[0020] Advantageously, at least 90% by weight of the particles of
the active coating material have a particle size between from 1 to
200 .mu.m. Preferably, at least 90% by weight of the particles of
the active coating material have a particle size between from 1
.mu.m to 100 .mu.m. The term "particle size" refers to the
equivalent particle diameter of the particles and may be measured
using, for example, laser light diffraction. The particle size of
the powder is an important factor in powder coating techniques. If
the particles of the powder are very small, the powder will often
be too cohesive for successful powder application using many powder
coating techniques. However, large particles can be disadvantageous
because they are often more difficult to coat onto a surface and,
if the coating material is to be fused after application to the
surface, longer fusing times may be required, leading to increased
risk of damage to the substrate and to the active component.
[0021] Where reference is made to % by weight of particles, for
example the % by weight of particles having a particular size, the
particles will also preferably have that % by volume of particles
of that size.
[0022] Alternatively, the coating material may be applied in the
form of a liquid.
[0023] Advantageously, the active coating material further includes
one or more excipients. The formulation will usually consist of the
active component and a mixture of excipients that will aid in the
coating of the material. The formulation may also include other
components, for example, colorants and/or flavourings and/or agents
to control the rate of release of the active component.
[0024] Advantageously, the substrate is conveyed through a region
adjacent to a source of the active coating material. That allows
the method to be continuous.
[0025] In one advantageous embodiment of the invention, the method
comprises supporting the substrate adjacent to the source of the
active coating material with a surface of the substrate maintained
at such a different electric potential from that of the active
coating material that the application of the electric potential
causes the active coating material to move from the source of the
active coating material towards the substrate, a surface of the
substrate becoming coated with the active coating material.
[0026] Preferably, the substrate is supported from above and the
powder moves from the source upwards towards a lower surface of the
substrate.
[0027] Preferably, the substrate is charged when the substrate is
adjacent the source of the active coating material. Alternatively,
or in addition, the source of active coating material may be
charged.
[0028] The method may further include the step that after the
active coating layer is applied the active coating material is
treated to form an active film coating secured to the surface of
the substrate. Where the coating material is in the form of a
powder material, the treatment advantageously comprises a heating
step, preferably by infra red radiation, but other forms of
electromagnetic radiation may be used. Usually, the change in the
coating upon heating will simply be a physical change from a powder
to a liquid and then, on cooling, to a solid coating, but there are
other possibilities: for example, the powder coating may comprise a
polymer which is cured during the treatment step, for example by
irradiation with energy in the gamma, ultra violet or radio
frequency bands, to form a cross-linked polymer coating.
[0029] The method may further include the step of applying a cover
coating layer onto the active coating layer to form a cover coating
layer such that the active coating layer is substantially
completely covered by the cover coating layer.
[0030] The active coating material applied to the surface of the
substrate might not be treated to form an active film coating. A
cover coating layer applied subsequently over the active coating
material could be used to seal the active coating on the surface of
the substrate.
[0031] Where the coating material is in the form of a liquid, the
treatment advantageously comprises drying the coating material with
a heater although other methods could be used.
[0032] The coating material containing the active component is
susceptible to damage at high temperatures and it is therefore
particularly important that the temperature of treatment is not
high. Advantageously, the temperature of treatment is less than
250.degree. C., preferably less than 200.degree. C. and more
preferably less than 150.degree. C. Where the higher treatment
temperatures are used, the duration of the treatment is
advantageously short to reduce the possibility of damage of the
coating material.
[0033] Preferably, the cover coating material is applied
electrostatically. The cover coating material may be in the form of
a powder. The cover coating material may also include active
material. The active material in the cover coating may be the same
as or different from the active material in the active coating
layer.
[0034] Advantageously, at least 90% by weight of the particles of
the cover coating material have a particle size between from 1 to
200 .mu.m.
[0035] Preferably, the substrate is conveyed through a region
adjacent to a source of the cover coating material.
[0036] In one advantageous embodiment of the invention, the method
comprises supporting the substrate adjacent to the source of the
cover coating material with a surface of the substrate maintained
at such a different electric potential from that of the cover
coating material that the application of the electric potential
causes the cover coating material to move from the source of the
cover coating material towards the substrate, a surface of the
substrate becoming coated with the cover coating material.
[0037] Advantageously, the substrate is supported from above and
the powder moves from the source upwards towards a lower surface of
the substrate.
[0038] Preferably, the substrate is charged when the substrate is
adjacent to the source of the cover coating material.
Alternatively, or in addition, the source of cover coating material
may be charged.
[0039] Advantageously, the method further includes the step that
after the cover coating layer is applied the cover coating material
is treated to form a film coating secured to the surface of the
substrate. The treatment of the cover coating layer may be similar
to that of the active coating layer described above.
[0040] In an embodiment of the invention the active coating layer
covers only part of a surface of the substrate. In that embodiment,
the cover coating layer may cover only part of a surface of the
substrate, or alternatively may cover the whole surface of the
substrate.
[0041] The cover coating layer may be applied by depositing powder
which thereafter forms a layer over the active coating layer or by
applying a preformed sheet or film over the active coating
layer.
[0042] The method may further include the step of applying a
further coating material to a surface of the substrate to form a
further coating layer. The further coating material may include
biologically active material, the further coating layer forming a
further active coating layer and the method may further include the
step of applying a further cover coating material onto the further
active coating layer to form a further cover coating layer such
that the further active coating layer is substantially completely
covered by the further cover coating layer.
[0043] Thus substrates having two or more different active
components may be produced. The cover coating material covering the
first active coating may be different from that covering the second
active coating so that the rate of release of the first active
component may be different from that of the second active
component. Alternatively, the two active components may be the same
and the cover coatings may be the same or different materials. One
or more of the cover coating materials may contain active
material.
[0044] Advantageously, the method is continuous. In practice, there
are considerable advantages in being able to operate the coating
process continuously rather than as a batch process.
[0045] Advantageously, the active coating material is applied to a
part of a surface of the substrate, the active coating layer
forming a first active coated region on the surface of the
substrate. Where, for example, a plurality of coating layers are to
be applied to each substrate, each coating layer forms a coated
region on a part of the substrate.
[0046] Thus the method may include the further step of applying a
second active coating layer onto a surface of the substrate, the
second active coating layer forming a second active coated region
on a surface of the substrate.
[0047] Preferably, the method further includes the step of applying
a cover coating material onto the active coating layer to form a
cover coating layer such that the active coating layer is
substantially completely covered by the cover coating layer and
such that the cover coating layer is removable from the substrate.
Depending on the nature of the cover coating material, the cover
coating layer may be removable together with the active coating
layer or may be removable separately. The cover coating layer
provides a cosmetic coating and may also protect the active coating
material. The cover coating material may also include active
material which may be the same as or different from the active
material of the active coating layer. The cover coating may
comprise a preformed film or sheet of material which is applied
over the active coating.
[0048] Where more than one active coating layer is applied to the
substrate, the method preferably further includes the step of
applying a second cover coating layer onto the second active
coating layer to form a second cover coating layer such that the
second active coating layer is substantially completely covered by
the second cover coating layer, the second cover coating layer
being substantially separate from the first cover coating
layer.
[0049] The invention also provides a method of coating a plurality
of coating regions onto the surface of a substrate, the method
comprising the steps of:
[0050] (a) applying active coating material to a surface of the
substrate to form a plurality of active coating regions on the
surface comprising active coating layers, the active coating
material including biologically active material
[0051] (b) applying cover coating material to a surface of the
substrate to form a plurality of cover coating regions, the cover
coating regions forming layers of cover coating material, each
active coating region being substantially completely covered by a
cover coating region,
[0052] such that each region of active coating and cover coating is
removable from the surface of the substrate.
[0053] Advantageously, the method further includes the step of
removing that active coating layer from the substrate to form a
wafer comprising active material. Each wafer may comprise a single
dose of active component. Alternatively, the wafer may be
subsequently cut to form wafer portions, each wafer portion
including substantially a dose of active material.
[0054] Where reference is made to the quantity of active coating
material being substantially equal to a dose of the active
material, it will be understood that the quantity may be a fraction
of the single standard dose, for example 1/2 or 1/3 of a single
standard dose of the active material. It will be understood that
the quantity of active material will depend on the active component
used and the number of solid dosage forms to be taken by the
patient for each dose. Where more than one layer of the active
coating material is to be applied to each substrate, the quantity
of active component in each layer will be chosen accordingly.
[0055] The invention also provides apparatus for coating a
substrate according to a method as described above.
[0056] The first aspect of the invention also provides an apparatus
for coating a substrate, the apparatus comprising:
[0057] (a) a source of active coating material,
[0058] (b) support means for supporting a substrate adjacent to the
source of the active coating material such that the active coating
material forms an active coating layer on a surface of the
substrate.
[0059] Advantageously, the apparatus further comprises:
[0060] (c) a source of a cover coating material,
[0061] (d) means for conveying the substrate having the active
coating layer to a position adjacent to the source of cover coating
material such that the cover coating material forms a cover coating
layer which substantially completely covers the active coating
layer.
[0062] The apparatus advantageously includes means for applying the
active coating material and/or the cover coating material
electrostatically. As indicated above, the coating material may be
applied in the form of a dry powder or in the form of a liquid.
[0063] Advantageously, the substrate comprises a conveyor belt.
[0064] Advantageously the apparatus further includes means for
applying a charge to the source of active coating material. The
charge can be adjusted to change the amount of coating material
applied to the substrate.
[0065] Advantageously, the apparatus further includes charging
means for applying a charge to the substrate. The charge may be
applied using a corona charge wire adjacent to the substrate or by
arranging a charged plate adjacent to the substrate. The charged
substrate attracts coating material from the source onto the
surface of the substrate. Thus it is possible to obtain a very thin
uniform layer of coating material on the substrate surface.
[0066] Preferably, the source is arranged below the conveyor.
[0067] Also provided by the present invention is an apparatus for
coating a substrate, the apparatus comprising:
[0068] (a) a source of coating material
[0069] (b) means for moving the substrate relative to the source of
coating material,
[0070] (c) means for applying an active coating material onto a
surface of the substrate to form a plurality of active coating
regions,
[0071] (d) means for applying a cover coating material onto the
surface of the substrate to form a plurality of cover coating
regions such that each active coating region is substantially
completely covered by a cover coating region,
[0072] the coating materials being applied such that the active
coating material is removable from the surface of the
substrate.
[0073] The invention also provides a coated substrate comprising an
active coating layer on a surface of the substrate, the active
coating layer including biologically active material and in which
the active coating layer is removable from the surface of the
coated substrate.
[0074] In one embodiment of the invention, each active coating
layer comprises a quantity of biologically active material which is
substantially equal to one dose or, for example, one half dose of
the biologically active material. It will be understood that the
quantity of active component will depend on the active material
used and the required dose.
[0075] Alternatively the active coating layer may subsequently be
cut into small portions.
[0076] Preferably, the substrate further includes a cover coating
layer on a surface of the substrate, the cover coating layer
substantially completely covering the active coating layer in which
the cover coating layer is removable from the surface of the
substrate. As indicated above, the cover coating layer may be
removable separately from the active coating layer.
[0077] The substrate may include a plurality of active coating
layers forming active coating regions on a surface of the
substrate.
[0078] Preferably, each active coating region includes a cover
coating region comprising a layer of cover coating material in
which each active coating region is substantially completely
covered by a cover coating region.
[0079] In one alternative embodiment of the present invention, for
example where the active coating material is applied as a liquid,
the active coating material is applied as a metered dose to a
surface of the substrate, to form an active coating layer on the
surface.
[0080] Very accurate application of the coating material on each
surface can be obtained.
[0081] This is to be contrasted with the known methods where
coating material is sprayed towards the cores. In that case the
amount of coating material applied to each substrate depends on
many factors all of which would require close control if accurate
application is to be achieved. It will be understood that whilst
reference is made to applying a metered dose, that should not be
taken to imply that there is necessarily any measurement of the
amount of material applied. A metered volume of liquid may be
applied to each substrate.
[0082] Advantageously, a predetermined number of droplets of active
coating material are applied to the surface of the substrate. Thus
where the droplets are of the same size, the number of droplets
applied to the substrate surface determines the amount of active
material applied. By altering the number of droplets applied, the
apparatus can easily be adapted to apply the required quantity of
active material.
[0083] Advantageously the coating method is such that the
coefficient of variation of the quantity applied to each substrate
or region of the substrate is not more than 15%.
[0084] As indicated above, where the coating material includes
active material, the accuracy and reproducibility of the
application of the material to the substrates is of particular
importance. For known spraying techniques such as those described
above, the coefficient of variation can be 50% or more. Whilst that
is acceptable where the coating is a cosmetic coating, it is not
acceptable where the coating contains active material. Preferably
the coefficient of variation is not more than 10%, and most
preferably 3% or less.
[0085] Advantageously, the active coating material is applied in
the form of individual liquid droplets which are propelled from the
supply directly towards a surface of the substrate.
[0086] As indicated above, where the material is applied as a
plurality of individual droplets, it is more simple to alter the
dose of active material applied to the substrate by changing the
number of droplets applied. Thus advantageously, the number of
droplets applied is controllable.
[0087] An ink jet head may be used in the coating of the substrates
with active coating material. A conventional ink jet head, for
example those used for ink jet printers, can be used to apply an
easily controllable amount of material from the head onto a
substrate.
[0088] In one embodiment of the invention, the area of the surface
of the substrate covered by the active coating layer is less than
40% of the total surface area of the substrate. The area covered by
the active coating layer may be less than 25% of the total surface
area of the substrate. The active coating may form a plurality of
small coated regions on the surface of the substrate.
[0089] Thus the active coating layer may cover only a part of the
exposed surface of the substrate.
[0090] Where the quantity of active material to be administered
using each solid dose is small, as indicated above, it is
advantageous for the proportion of active component in the active
coating material to be large.
[0091] By covering a smaller proportion of the surface of the
substrate, a smaller amount of coating material may be used. Thus
the proportion of active component in the coating material may be
increased.
[0092] The active coating material may be applied to a plurality of
individual regions of the surface of the substrate.
[0093] The invention also provides a method of coating a substrate,
the method comprising applying an active coating material to a
surface of the substrate to form an active coating layer, the
active coating material comprising biologically active material,
applying a cover coating over the exposed surfaces of the active
coating layer and dividing the substrate to form substrate
portions, each substrate portion including substantially one dose
of the active material.
[0094] The invention also provides a pharmaceutical solid dosage
form comprising a substrate and an active coating layer covering
less than 25% of the surface area of the substrate the active
coating layer comprising biologically active material.
[0095] The coating layer may be shaped, for example to form a
pattern, a picture, symbols, letters or numerals.
[0096] The invention also provides a wafer for administration to a
patient, the wafer comprising biologically active material and
having a thickness of less than 2 mm. Preferably the thickness is
less than 1 mm.
[0097] The invention further provides an intermediate product for
use in producing a plurality of solid dosage forms, the
intermediate product comprising a substrate and an active coating
layer deposited on the substrate, the amount of active coating
material deposited on a given area of the substrate being
controlled such that the product can subsequently be divided into
portions with each portion containing a predetermined amount of
active coating material, each predetermined amount being one dose
of the active material.
[0098] In accordance with a further aspect of the invention, there
is provided a method of coating a substrate, the method comprising
applying an active coating material to a surface of the substrate
to form an active coating layer, the active coating material
comprising biologically active material, applying a cover coating
layer over the exposed surfaces of the active coating layer and
dividing the layered product to form layered portions, each layered
portion including substantially one dose of the active
material.
[0099] In accordance with the further aspect of the invention, the
active coating material can be such that it is not removed from the
substrate. For example, the active material might be applied to an
edible film which can be administered orally.
[0100] It will be understood that the method of coating may further
include features of the method of the first aspect of the invention
described herein. Furthermore, it will be appreciated that the
apparatus and coating materials described in respect of the first
aspect of the invention could be used in the method in accordance
with the further aspect of the invention, with minor modifications
where necessary.
[0101] Embodiments of the invention will now be described by way of
example having reference to the drawings of which:
[0102] FIG. 1 shows schematically a side view of an apparatus for
coating a tablet core;
[0103] FIG. 2 shows schematically a side view of a part of the
apparatus of FIG. 1; and
[0104] FIG. 3 shows schematically a side view of an apparatus for
coating a substrate in accordance with the invention.
[0105] The apparatus shown in FIG. 1 is for coating both faces of
pharmaceutical tablet cores. The apparatus comprises an inclined
tablet core feed chute 1 leading to a first rotatable wheel 2
having circular depressions 3 in its outer surface. The cores 4 are
fed from the chute 1 into the depressions 3 where they are held by
suction by means of a suction line 5 in communication with the base
of the depression 3 via an opening. The first drum is rotated in
the direction shown by the arrow A. Adjacent to the outer surface
of the wheel 2 downstream from the feed chute 1 is an active
coating station 6 and a cover coating station 7. Downstream from
the active coating station is an active coating fusing station 8 at
which the active coating is fused and downstream from the cover
coating station 7 is a cover coating fusing station 9 at which the
cover coating is fused. A cooling station (not shown) may be
provided downstream from each of the fusing stations 8, 9 where
cool air is directed at the core to cool the fused coating.
[0106] A second wheel 10 similar to the first wheel 2 is arranged
adjacent to the first wheel 2, the nip between the wheels being
downstream of the fusing station 9. The second wheel 10 rotates in
an opposite sense to that of the first wheel 2 as shown by the
arrow B. Arranged adjacent to the outer edge of the second wheel 10
downstream from the nip of the two wheels are a second cover
coating station 11 and a second fusing station 12.
[0107] FIG. 2 shows the active coating device 6 in more detail.
FIG. 2 shows a portion of the wheel 2 together with a core 4 in a
depression 3 on the surface of the wheel 2. As described below, the
apparatus of FIG. 2 can be used to form wafers of coating material
in accordance with the present invention.
[0108] The active coating station 6 comprises a conveyor 13
arranged in a loop in a vertical plane so that the upper surface 14
faces the surface of the wheel and the cores 4 which pass the
device 6 as the wheel rotates. The contour of the upper surface 14
of the conveyor 13 is chosen to match the contour of the outer
surface of the wheel so that the distance between the core and the
upper surface of the conveyor is unchanged as the wheel rotates.
The direction of rotation C of the conveyor 13 is such that the
direction of movement of the upper surface of the conveyor is
opposite to that of the movement of the core over the upper surface
of the conveyor. Alternatively, the direction of movement of the
upper surface of the conveyor and the core may be the same.
[0109] As shown in FIG. 2, a corona charge wire 15 and powder
source 16 are arranged beneath the conveyor immediately below the
lower surface 17 of the conveyor.
[0110] The corona charge wire 15 sprays charge onto the lower
surface 17 of the conveyor. It will be appreciated that a different
method could be used to apply charge to the conveyor.
[0111] The powder source 16 uses an archimedes screw to form a
small mound of powder beneath the lower surface of the conveyor.
The source 16 comprises a hopper 18 containing the powder including
the biologically active component, and an Archimedes screw 19 which
in use passes through the powder material 20 in the hopper 18 and
through a vertical barrel 21. Thus, the powder material 20 is
circulated from the lower regions of the hopper 18 to the top of
the barrel 21 where a moving heap of powder is formed. The heap
will be of substantially constant size and shape as excess powder
overflows from the top of the barrel 21 and is returned to the
hopper 18.
[0112] Stirrers 22 are provided in the hopper 18 to help to improve
the flow of the powder and break up any agglomerates.
[0113] Thus a small moving heap of powder of substantially constant
size and shape is formed beneath the lower surface of the conveyor
17.
[0114] It will be appreciated that a device other than the
Archimedes screw could be used to form the heap of powder.
[0115] The powder source 16 is located downstream from the charge
spraying device 15 and powder from the heap of powder is attracted
to the surface of the charged conveyor 17 where it forms a thin,
uniform layer which is transported to the upper surface 14 of the
conveyor.
[0116] The tablet core 4 passing over the upper surface of the
conveyor is held at a different potential from that of the conveyor
13, either by earthing the core or applying a charge to the core,
and powder on the conveyor moves from the conveyor to the exposed
surfaces of the tablet core 4 to form a powder coating.
[0117] The active coating station 6 is enclosed in a housing (not
shown) to reduce the risk of powder loss of the active powder. In
use the housing has an opening above the upper surface of the
conveyor 14 so that the tablet core 4 is exposed to the active
powder coating material as it passes the station 6.
[0118] It will be appreciated that the thickness of the powder
layer formed on the surface of the tablet core depends on several
factors including the amount of charge sprayed onto the conveyor,
the magnitude of the charge applied to the core, the size of the
heap of powder produced, the size of the opening in the housing and
the speed of the conveyor. Those factors will be varied to give the
desired coating depending on the type of powder and core used.
[0119] The composition of the active coating material used will of
course depend on the active ingredient to be used and the amount of
the coating to be applied.
[0120] Active materials most suitable to be applied to the tablet
include those materials having a high therapeutic activity, for
example those where the usual prescribed dose is about 1 mg or
less, and which have a good stability to degradation due to heat
where the coating material containing active material is to be
heated.
[0121] An active material which may be applied to a tablet core in
accordance with the invention is Diltiazem HCL.
[0122] The amount of active ingredient to be coated onto each core
or other substrate will generally be small and the active
ingredient will usually be diluted with one or more excipients. The
excipients used will be chosen so that they aid the coating of the
active material onto the cores by, for example improving the
electrostatic properties of the powder and its physical properties
and aiding the formation of the fused active coating, for example
the excipient may be a material which melts at a low temperature to
aid the formation of a film.
[0123] Where the active coating material is a powder, the particle
size will be an important factor with regard to the transfer of the
active coating material from the conveyor to the tablet core and to
the subsequent fusing of the material. Usually a particle size
range of 1 to 200 .mu.m will be used (at least 90% of the particles
of the powder having a size within that range).
[0124] One example of an active coating material is as follows:
1 Xylitol 45% wt Diltiazem HCL (active) 45% wt TiO.sub.2 9% wt
Colloidal silica 1% wt
[0125] It is thought that in at least one embodiment of the
invention, the active composition will comprise three main
components together with additives.
[0126] The components may, for example, comprise the following
[0127] i) a continuous phase component, for example Xylitol or PEG
6000,
[0128] ii) the active component,
[0129] iii) a particle seed and/or charge modifying component, for
example TiO.sub.2 or silica,
[0130] iv) a flow aid, for example colloidal silica or magnesium
stearate.
[0131] Each component may comprise one or more different
materials.
[0132] The active coating material of the above example was in the
form of a powder and had a particle size distribution such that at
least 90% wt of the particles had a size in the range of from 5 to
25 .mu.m.
[0133] It is often preferred that at least 90% by weight of the
particles have a size in the range of from 1 to 45 .mu.m. In one
preferred embodiment 90% by weight of the particles have a size
less than 70 .mu.m, 50% by weight have a size less than 40 .mu.m
and 10% by weight of the particles have a size less than 10
.mu.m.
[0134] The active powder coating material may be produced using one
or a combination of the following processing steps:
[0135] a) precipitation of two or more of the components to form
composite particles
[0136] b) spray drying of two or more of the components to form
composite particles
[0137] c) granulation
[0138] d) extrusion
[0139] e) micronisation.
[0140] For example, all of the components of the composition may be
co-micronised to give a powder material having the desired particle
size.
[0141] An example of a powder cover coating material is as is
follows:
2 39.75% Eudragit RS (ammonio- methacrylate copolymer) 39.75%
Klucel (hydroxy propyl cellulose) 15.0% Titanium dioxide 5.0%
Aluminium lake 0.5% Aerosil 200 (colloidal silicon dioxide)
[0142] The cover coating material was prepared by the following
method:
[0143] a) A sample containing the % wt of components listed above
was premixed in a high shear mixer. Water was added to the mixture
in a high shear mixer for a few minutes to give a granulated
mixture which was dried in a fluid bed drier at a temperature of
about 45.degree. C. for 20 to 30 minutes to give a material having
a moisture content (measured as loss on drying) below 3% by weight.
The material was impact milled and then micronised using a fluid
energy mill to a powder containing particles having a size
distribution such that 50% by volume of particles were of a size
less than 20 .mu.m.
[0144] The cover coating material will usually include percent by
weight.
[0145] Powder from the powder source is attracted to the surface of
the charged conveyor where it forms a thin, uniform layer of powder
on a part of the outer surface of the conveyor belt. A heater is
positioned downstream of the powder source and the heater fuses the
powder material on the conveyor surface to form a fused film
coating on the surface. The film coating is conveyed on the
conveyor to a region where it is removed as a thin strip of
film.
[0146] A cooling station may be positioned downstream of the heater
to cool the film coating. The film strip removed from the conveyor
may be passed to a cutting station where it is divided into
portions, each of which may contain a dose of active material.
[0147] In an alternative embodiment of the invention, powder
material is deposited onto a tape, preferably of plastics
material.
[0148] In a further embodiment of the invention, the active coating
is applied as a liquid. A head for applying the liquid is
positioned such that the outlet or outlets of the head is less than
1 mm from the surface to which the material is to be applied.
[0149] The head may be an ink jet printer head, for example an
adapted Compact 200 head manufactured by Alphadot Limited. That
head has 5 outlets spread over an area of about 10 mm and can be
used to direct liquid coating material towards the exposed surfaces
of the substrate.
[0150] The liquid coating material comprises the active component
and a solvent, preferably water, and an excipient, for example PEG,
to aid in film forming. Preferably the solids content of the liquid
coating material is very low, advantageously there would be
substantially no solids content and advantageously the active
material is fully dissolved in the solvent.
[0151] While it is envisaged that where the active layer is applied
using an ink jet printer head, the active components to control the
dissolution rate of the cover coating to give controlled release of
the active material in the active coating layer. Where more than
one active coating is applied to each tablet or substrate, the
release of each active coating can be different where different
materials are used for the cover coating over each of those active
coatings.
[0152] Where one or more of the coatings are applied as liquid
coatings, a suitable liquid coating device would be used at the
active coating station 6 and/or the cover coating station 7 and the
fusing device would be replaced by, for example a drying device to
dry the liquid coating, if necessary.
[0153] In an embodiment of the invention an apparatus similar to
that shown in FIG. 2 is used to form wafers of coating
material.
[0154] The apparatus comprises a conveyor belt of chemically inert
material having a Teflon (RTM) coating. A corona charge wire is
arranged immediately below the lower surface of the conveyor and
sprays charge onto the lower surface. A powder source similar to
that shown in FIG. 2 is also arranged beneath the lower surface of
the conveyor downstream of the corona wire. The powder material in
the powder source contains an active component and may have similar
composition to the active powder described above. Preferably a
higher proportion of film-forming components are added to the
powder, for example hydroxypropylcellulose (HPC).
[0155] An example of an active coating material is as follows:
3 Eudragit RS 23% Diltiazem HCL (active) 40% HPC 25% TiO.sub.2 7%
PEG 4000 5%
[0156] The amounts of the components are expressed as material
might be applied directly to a substrate from which it can be
removed, it is thought that, in particular where the active
material is to be peelable from the substrate in the form of a
wafer, the active material would be applied to a base layer which
is removable from the substrate.
[0157] For example, a first base coating layer would be applied to
a substrate using the apparatus shown in FIG. 2. Where the base
coating material is applied to the substrate in the form of a
powder material, the base coating would usually be fused to form
the base coating layer. The base coating layer would be peelable
from the substrate. One or more regions of active coating material
would be applied to the base coating layer, for example using an
ink jet printer head.
[0158] A cover coating would be applied over the active coating
material. Where the cover coating is in the form of a powder, the
cover coating would usually be fused to form the cover coating
layer. The material would be removed from the substrate in the form
of a three-layer wafer in which the active material was sandwiched
between two layers. The wafer may subsequently be divided into
smaller portions.
[0159] In a further embodiment of the invention, the active coating
material is applied to a substrate using an ultrasonic spray head.
The ultrasonic spray head forms a cloud of liquid droplets which
are charged electrostatically. A charge may be imparted on the
droplets, for example, by applying a high voltage to the ultrasonic
spray head. The charged droplets become attracted to the substrate
which is at a potential difference from the droplets.
[0160] Examples of active liquid coating materials which may be
used are as follows
4 a) Sodium citrate 0.02 Chlorpheniramine maleate 2.48 Propylene
glycol 4.00 Water 18.50 Ethanol 75.00 b) Sodium citrate 0.02
Chlorpheniramine maleate 2.00 Methocel E15 1.00 Lactose B.P. 6.00
PEG 4000 1.00 Water 89.98
[0161] The amounts given above represent percentage by weight of
each component.
[0162] The apparatus may include heating means (not shown) for
drying the applied coating material. However, where the liquid
coating material is such that the solvent evaporates quickly, the
heater may not be required. It will be appreciated that where the
heater is used the temperature required to dry the active coating
will be significantly lower than the temperature required to fuse
powder coating material as described above.
[0163] FIG. 3 shows a further embodiment of the invention.
[0164] FIG. 3 shows a schematic view of an alternative arrangement
of the apparatus for producing wafers including active
material.
[0165] The apparatus is similar in operation to that described
above in respect of FIG. 2 and comprises a stainless steel conveyor
belt 31 (which may be coated with PTFE on its external surface)
mounted for rotation on three rollers 34, 36. A powder hopper 32 is
arranged below the conveyor 31 and wafer forming powder material is
loaded into the hopper. The hopper is arranged to produce a
recirculating powder bed either by fluidising the powder in the
hopper with dry air or by using an auger feed screw arrangement in
the hopper and vibrating the powder in the hopper.
[0166] The hopper 32 is charged to from 0.5 to 10 kV either
positively or negatively depending on the wafer forming powder
composition to be used. For the two compositions given below, the
hopper would be charged negatively.
[0167] A plate 33 is arranged above the portion of the conveyor
belt 31 which is adjacent to the hopper 32. The plate may be a
stainless steel plate and is charged to a potential difference from
that of the hopper 32. The plate will normally be charged to the
opposite sign to that of the hopper. The charge on the plate 33 may
be from 0.1 to 10 kV depending on the powder composition used and
the thickness of the wafer to be formed.
[0168] The thickness of the layer formed on the surface of the belt
will usually be from 0.5 to 3 mm. The charge applied to the hopper
and to the plate 33, and the speed of the belt will be chosen to
give the desired thickness.
[0169] The powder composition is attracted to the conveyor belt 31
and adheres to the exterior surface of the belt to form a powder
layer. The size of the hopper will usually be chosen so that the
whole width of the conveyor belt is coated with powder. It is
envisaged, however, that the powder might coat less than the whole
width of the conveyor belt 31. Also, the hopper 32 may comprise a
group of several hoppers each for supplying the same or different
powder compositions to the conveyor belt 31. Thus the wafer
produced using the apparatus may be a composite wafer in that it
includes portions having different compositions. For example, the
wafer might comprise a first layer including active material and a
second coating layer including no active material.
[0170] As indicated above, the wafer might comprise a first layer
including no active material, a second layer including active
material and a third layer including no active material. That
arrangement is particularly preferred because the active material
is sandwiched between two outer layers which help to protect the
active material from mechanical or chemical damage.
[0171] Such a wafer may be formed by applying a coating layer to a
substrate, applying the active material to the coating layer to
form an active layer and subsequently applying a cover coating
layer over the active layer. The first coating layer is removable
from the substrate so that a three-layer wafer is formed.
[0172] Where reference is made herein to the active material being
applied to a substrate and being removable from a substrate, it
will be understood that that includes the case in which the active
material is applied to a coating layer which has previously been
applied to the substrate, the active coating layer being removable
from the substrate together with the coating layer.
[0173] The coated portion of the conveyor belt travels from the
region of the hopper to the heated roller 34. The heated roller 34
is heated to slightly above the melting point of the powder
composition on the surface of the conveyor belt. As the conveyor
belt moves around the heated roller 34, the powder composition on
the outer surface of the conveyor belt melts and forms a fused
coating on the surface of the belt.
[0174] A chilled roller 35 is arranged above the conveyor belt 31
downstream from the heated roller 34. The fused coating layer on
the surface of the conveyor belt passes under the chilled roller 35
which smoothes the upper surface of the coating layer and cools the
coating so that it solidifies to form a wafer on the exterior
surface of the conveyor belt. It will be appreciated that other
methods could be used to cool and smooth the coating layer, for
example cool air jets arranged above the conveyor belt downstream
from the heated roller 34.
[0175] The solidified wafer is transported on the conveyor belt 31
to the doctor blade 37 where the wafer is peeled from the surface
of the belt. The conveyor belt continues around the guide rollers
36 and a further coating is deposited onto the conveyor belt as
powder material moves from the hopper to the belt as described
above. Thus the apparatus can be used to produce a continuous
wafer.
[0176] It is thought that the width of the conveyor belt would
usually be up to 50 cm. The material may be applied across the
whole width of the conveyor belt. Alternatively, the material might
be applied as several bands of material across the belt, the
material being supplied from several separate hoppers arranged
below the belt.
[0177] The wafer peeled from the conveyor passes to a cutter 38
which may be a rotary knife wafer chopper where the wafer is cut
into uniform pieces. The cut wafer portions may be of any shape or
size but will usually contain one dose of the active material
present in the wafer. It will be appreciated that while circular or
eliptical shaped wafer portions may be preferred from an aesthetic
point of view, such shapes would lead to greater wastage of wafer
material than, for example, rectangular-shaped wafer portions.
[0178] The pieces are then passed to a packaging station 39 where
they are packaged using conventional methods to form, for example,
blister packs or plasters for use as a patch on the skin.
[0179] Examples of suitable coating compositions are given above.
Particularly suitable powder compositions for use with the
apparatus are as follows:
5 Composition 1 Diltiazem HCl (active) 50% Eudragit RSPO Type C
47.5% (ammoniomethacrylate copolymer) Titanium dioxide 2% Sunset
yellow pigment 0.5%
[0180] The % given are % by weight. The components were mixed and
the mixture was extruded and micronised to give a powder having a
narrow particle size distribution below 150 .mu.m. For example, the
particle size distribution may be as follows:
[0181] 10% by weight less that 20 .mu.m
[0182] 50% by weight less than 50 .mu.m
[0183] 90% by weight less than 90 .mu.m.
6 Composition 2 Diltiazem HCl 40% Polyethylene glycol 6000 30%
Xylitol 20% Titanium dioxide 10%
[0184] The components were wet granulated together, milled and
sieved to form a powder having a narrow particle size distribution
between 75 .mu.m and 20 .mu.m.
[0185] It will be understood that other compositions containing
active material could be used. The composition will usually include
from 1% to 90% by weight of active material based on the weight of
the composition. The remainder of the formulation will usually
comprise a polymeric matrix of binder material, for example
Eudragit E100, gelatine, PVA, PVP-PVA, PEG, lactitol,
polypropylene. The compositions may additionally include
plasticisers, opacifiers, disintegrants, detacifiers and/or
pigments.
[0186] The apparatus described above may be modified so that the
powder composition is deposited on a tape of material which is fed
around the apparatus on the exterior surface of the conveyor, the
tape having a wafer coating being removed from the apparatus. The
tape may be inedible, in which case the coating material may be
removed from the tape on administration, where the active material
is to be administered orally. Alternatively, the tape may be used,
for example, as a patch. Where the tape is edible, the active
material may be administered without removal from the tape, for
example the tape and wafer portion may be swallowed together.
[0187] Furthermore, as indicated above, the coating composition may
be applied to the substrate using a different method to that
described above. For example, the coating material may be applied
in the form of a liquid using a head similar to that used in
ink-jet printing. Alternatively, the coating material may be
applied in the form of a liquid using an ultrasonic spray head.
Dots of coating composition would be applied to regions of the
substrate using the head.
* * * * *