U.S. patent application number 09/144718 was filed with the patent office on 2001-11-08 for method for preventing crystal formation in a dispersion of a liquid in a matrix.
Invention is credited to BURA, SCOTT A., DOHNER, JOHN W., FORD, RICHARD E..
Application Number | 20010038850 09/144718 |
Document ID | / |
Family ID | 24262030 |
Filed Date | 2001-11-08 |
United States Patent
Application |
20010038850 |
Kind Code |
A1 |
DOHNER, JOHN W. ; et
al. |
November 8, 2001 |
METHOD FOR PREVENTING CRYSTAL FORMATION IN A DISPERSION OF A LIQUID
IN A MATRIX
Abstract
An improved method for the manufacture of transdermal drug
delivery devices comprising liquid dispersions of a liquid in an
aqueous or nonaqueous matrix is disclosed. More particularly, the
invention relates to preventing the formation of a crystalline
structure in such liquid dispersions by annealing films and
laminates in-line immediately following film formation and/or
lamination during the manufacture of these devices.
Inventors: |
DOHNER, JOHN W.; (PORTOLA
VALLEY, CA) ; BURA, SCOTT A.; (SAN JOSE, CA) ;
FORD, RICHARD E.; (MT. VIEW, CA) |
Correspondence
Address: |
ALZA CORPORATION
P O BOX 7210
INTELLECTUAL PROPERTY DEPARTMENT
MOUNTAIN VIEW
CA
940397210
|
Family ID: |
24262030 |
Appl. No.: |
09/144718 |
Filed: |
September 1, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09144718 |
Sep 1, 1998 |
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08951943 |
Oct 17, 1997 |
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08951943 |
Oct 17, 1997 |
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08566228 |
Dec 1, 1995 |
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Current U.S.
Class: |
424/443 ;
424/448; 424/449 |
Current CPC
Class: |
A61K 9/7053 20130101;
A61F 2013/0296 20130101; A61K 9/7084 20130101 |
Class at
Publication: |
424/443 ;
424/448; 424/449 |
International
Class: |
A61K 009/70; A61K
009/14; A61F 013/00 |
Claims
We claim:
1. An improved method for manufacturing delivery devices for the
transdermal administration of a liquid drug capable of forming a
crystalline structure, the method comprising: a) heating, to a
predetermined temperature, each individual film or laminate of a
transdermal delivery device which comprises a dispersion of said
liquid drug in a matrix immediately following film formation or
lamination; b) maintaining each film or laminate at the desired
temperature for a period of time sufficient to prevent the
formation and/or growth of a crystalline structure in any film or
laminate; and c) allowing each film or laminate to cool to ambient
conditions.
2. The method according to claim 1 further comprising the step of
providing that each dispersion of said liquid drug in a matrix is
placed between two non-porous substrates prior to heating.
3. The method according to claim 2 further comprising the steps of:
c) laminating the individual films or laminates to form a final
laminate; d) heating the final laminate to said predetermined
temperature immediately following lamination and maintaining the
final laminate at the temperature for a period of time sufficient
to prevent formation and/or growth of a crystalline structure in
the final laminate; and e) allowing the final laminate to cool to
ambient conditions.
4. The method according to claim 3 further comprising the steps of:
e) cutting subunits from said final laminate and forming said
delivery devices; f) packaging said delivery devices in sealed
containers; g) heating the devices in said containers to a
predetermined temperature and maintaining the devices at the
temperature for a period of time sufficient to prevent formation
and/or growth of a crystalline structure in the devices; and h)
allowing the sealed devices to cool to ambient conditions.
5. The method according to claim 3 wherein the predetermined
temperature is above the melting point of the crystalline structure
and the period of time is sufficient to melt any crystals present
in the dispersion.
6. The method according to claim 1 wherein the device comprises an
impermeable backing lamina, a drug reservoir layer, a release rate
controlling layer, and adhesive layer, and a release liner layer
and said dispersion forms said drug reservoir layer.
7. The method of claim 6 wherein the dispersion forms said adhesive
layer.
8. The method of claim 2 wherein the drug is scopolamine.
9. The method of claim 8 wherein the predetermined temperature is
within the range of 75-90.degree. C. and the period of time is 2-10
minutes.
10. The method of claim 4 wherein the liquid drug is scopolamine
and the devices sealed within the containers are heated to a
temperature of about 75.degree. C. for a period of approximately
4-24 hours.
11. A process for preventing the formation of the crystalline
structure of a liquid drug dispersed within a matrix which
comprises: a) forming a laminate wherein each individual film or
lamina comprising a dispersion of said liquid drug in a matrix is
heated to a predetermined temperature immediately following
formation or lamination; b) maintaining each film or lamina at the
desired temperature for a period of time sufficient to prevent the
formation and/or growth of a crystalline structure in any film or
lamina; and c) allowing each film or lamina to cool to ambient
conditions.
12. A process according to claim 11 further comprising the step of
providing that each dispersion of said liquid drug in a matrix is
placed between two non-porous substrates prior to heating.
13. A process according to claim 12 wherein the predetermined
temperature is above the melting point of the crystalline structure
and the period of time is sufficient to melt any crystals present
in the dispersion.
14. An improved method of manufacturing delivery devices for the
transdermal administration of a liquid drug capable of forming a
crystalline structure, comprising: a) forming a drug
reservoir/backing film, said drug reservoir comprising a liquid
drug capable of forming a crystalline structure; b) immediately
following forming the drug reservoir/backing film, performing a
first annealing step wherein the drug reservoir/backing film is
heated to a predetermined temperature for a period of time
sufficient to prevent formation and/or growth of a crystalline
structure and thereafter allowed to cool to ambient conditions; c)
forming a contact adhesive/release liner film, said contact
adhesive comprising a liquid drug capable of forming a crystalline
structure; d) immediately following forming the contact
adhesive/release liner film, performing a second annealing step
wherein the contact adhesive/release liner film is heated to a
predetermined temperature for a period of time sufficient to
prevent formation and/or growth of a crystalline structure and
thereafter allowed to cool to ambient conditions; e) laminating the
drug reservoir surface of the drug reservoir/backing film to the
contact adhesive surface of the contact adhesive/release liner film
to form a final laminate; f) immediately following forming the
final laminate, performing a third annealing step wherein the final
laminate is heated to a predetermined temperature and maintaining
the temperature for a period of time sufficient to prevent the
formation and/or growth of a crystalline structure in the final
laminate and thereafter allowing the final laminate to cool to
ambient conditons.
15. The method according to claim 14 further comprising the steps
of: placing a non-porous substrate on the drug reservoir surface of
said drug reservoir/backing film prior to said first annealing
step; placing a non-porous substrate on the contact adhesive
surface of said contact adhesive/release liner laminate prior to
said second annealing step; and removing the non-porous substrates
from said drug reservoir/backing film and said contact
adhesive/release liner film prior to laminating the drug reservoir
surface of the drug reservoir/backing film to the contact adhesive
surface of the contact adhesive/release liner film to form the
final laminate.
16. The method according to claim 15 wherein the predetermined
temperature is above the melting point of the crystalline structure
and the period of time is sufficient to melt any crystals present
in the dispersion.
17. The method according to claim 16 further comprising the steps
of: cutting subunits from said final laminate and forming said
delivery devices; packaging said delivery devices in sealed
containers; heating the devices in said containers to a
predetermined temperature and maintaining the devices at the
temperature for a period of time sufficient to prevent formation
and/or growth of a crystalline structure in the devices; and
allowing the sealed devices to cool to ambient conditions.
18. The method according to claim 14 further comprising the step of
laminating a rate control membrane to the contact adhesive surface
of the contact adhesive/release liner film to form a rate control
membrane/contact adhesive/release liner laminate prior to said
second annealing step.
19. The method according to claim 18 further comprising the steps
of placing a non-porous substrate on the drug reservoir surface of
said drug reservoir/backing film prior to said first annealing
step; placing a non-porous substrate on the surface of the rate
control membrane prior to said second annealing step; and removing
the non-porous substrates from said drug reservoir/backing film and
said rate control membrane/contact adhesive/release liner laminate;
and laminating the drug reservoir surface of the drug
reservoir/backing film to the surface of the rate control membrane
of the rate control membrane/contact adhesive/release liner
laminate to form the final laminate.
20. The method according to claim 19 wherein the predetermined
temperature is above the melting point of the crystalline structure
and the period of time is sufficient to melt any crystals present
in the dispersion.
21. The method according to claim 20 further comprising the steps
of: cutting subunits from said final laminate and forming said
delivery devices; packaging said delivery devices in sealed
containers; heating the devices in said containers to a
predetermined temperature and maintaining the devices at the
temperature for a period of time sufficient to prevent formation
and/or growth of a crystalline structure in the devices; and
allowing the sealed devices to cool to ambient conditions.
22. The method according to claim 18 wherein the rate control
membrane is a microporous polypropylene membrane saturated with
mineral oil.
23. The method according to claim 21 wherein the liquid drug is
scopolamine base.
24. The method according to claim 23 wherein the predetermined
temperature in the first, second, and third annealing steps is
approximately 75-90.degree. C. and the period of time is about 2-10
minutes.
25. The method according to claim 24 wherein the devices sealed
within the containers are heated to a temperature of about
75.degree. C. for a period of approximately 4-24 hours.
26. A drug delivery device for the transdermal administration of
scopolamine manufactured by the method according to any one of
claims 1,14, or 25.
Description
FIELD OF THE INVENTION
[0001] This invention relates to the manufacture of dispersions of
a liquid in an aqueous or non-aqueous matrix and to drug delivery
devices which utilize these liquid dispersions. More particularly,
the invention relates to preventing the formation and/or growth of
a crystalline structure in films or laminates comprising such
liquid dispersions by annealing the films and/or laminates
immediately following film formation and/or lamination. The
crystal-free films and laminates may then be formed into various
articles, such as drug delivery devices.
BACKGROUND OF THE INVENTION
[0002] As used herein, "annealing" refers to a process of
subjecting the liquid dispersion or article formed therefrom to a
specified, elevated temperature for a predetermined minimum period
of time and then allowing the dispersion or article to cool to
ambient conditions.
[0003] Transdermal delivery devices comprising a dispersion of a
drug or other biological agent in various aqueous or non-aqueous
matrices are known in-the art as described in U.S. Pat. Nos.
3,598,122, 3,598,123, 4,031,894, 4,144,317, 4,201,211, 4,262,003,
4,379,454, and 4,436,741, all of which are incorporated herein in
their entirety by reference. As disclosed in these patents, aqueous
matrices typically comprise water or water/ethanol and 1-5 wt. % of
a gelling agent such as hydroxyethylcellulose. Non-aqueous matrices
are typically comprised of a polymeric material such as copolymers
of ethylene vinyl acetate or blends of low molecular weight and
high molecular weight polyisobutene. The drug may be in solid form
or in the form of a liquid dispersion. This invention relates to
such liquid drug dispersions.
[0004] In addition to the above mentioned patents, U.S. Pat. No.
5,370,924, incorporated herein in its entirety by reference,
discloses methods for manufacturing transdermal drug delivery
devices. The methods disclosed in this patent describe a process
whereby the various elements of a transdermal device may be
fabricated separately and joined together in a final manufacturing
step.
[0005] Although this invention will be described hereafter
specifically with respect to scopolamine delivery devices, it
should be recognized that it is applicable to dispersions of any
other drug or biological agent in matrices where a crystalline
structure may be formed. Such drugs or agents such as nicotine,
secoverine, and benztropine, for example, may, to the extent they
form crystalline structures, be treated in a manner similar to the
methods by which dispersions of scopolamine base are treated
according to this invention.
[0006] Transdermal delivery devices for the administration of
scopolamine of the type disclosed in U.S. Pat. No. 4,031,894 cited
above are used extensively for the prevention of motion sickness.
The original manufacture of the product is described in the patent
by solvent casting of chloroform solutions of scopolamine base in
polyisobutene (PIB) and mineral oil (MO) onto impermeable webs to
form drug reservoir and contact adhesive films. Upon evaporation of
the chloroform, a dispersion of liquid scopolamine base in the
PIB/MO matrix is formed. The drug reservoir and contact adhesive
films are then laminated to opposite sides of a release rate
controlling membrane, formed from a mineral oil impregnated
microporous film, to produce a final laminate comprising a
removable release liner layer, an adhesive layer, a rate
controlling membrane layer, a drug reservoir layer, and an
impermeable backing lamina. The final laminate is then die cut into
individual systems and packaged in individual heat sealed
pouches.
[0007] The manufacture of the product in this manner was carried
out for approximately five years without any indication of the
formation of crystals in either the drug reservoir or the adhesive.
After that time, small crystals of scopolamine hydrate were
observed infrequently but this did not present a problem because
the release rate of the drug from the device was not affected by
the presence of the small number of small crystals then occurring.
In addition to the small number and size of the crystals, another
reason that the release rates were not affected is attributed to
the observation that the crystal size did not change appreciably
(i.e. minimal if any crystal growth) with time in the pouch.
[0008] Approximately two years later, larger numbers of rapidly
propagating crystals were observed in the drug reservoir, with a
lower incidence observed in the contact adhesive layer which
contained a lower concentration of scopolamine base. At that time,
the size of the crystals and their frequency of occurrence had
increased to the point where they produced a significant adverse
effect on the release rate of scopolamine from the device.
Thereafter, every lot manufactured developed unacceptably high
crystal size and frequency and commercial production had to be
halted until the problem could be solved.
[0009] Crystallization was most noticeable after the step in which
the final laminate film was cut into individual devices. After the
final laminate film was fed through the die-cutting machine for the
formation of individual transdermal delivery units, crystallization
began around the edges of the cut product and crystalline growth
thereafter propagated rapidly throughout the mass of the reservoir
and in some cases the adhesive layer. Visually observable crystals
were not necessarily apparent immediately after the cutting step;
instead they would typically develop over a period of days. These
crystals were identified as a hydrate form of scopolamine base.
[0010] Various attempts to eliminate the problem were tried over
the next several months, all to no avail. For example, the drug
reservoir film, adhesive film, and the final laminate film were
heated overnight, yet crystallization after die-cutting still
occurred. Similarly, the casting solutions were heated and allowed
to stand for extended periods also with no effect. Attempts to
reduce the amount of residual water in the chloroform solution of
the scopolamine base by drying with extra amounts of drying agents
such as anhydrous sodium sulfate and magnesium sulfate were also
unsuccessful as crystallization still occurred. Extensive cleaning
of contacting surfaces reduced but did not eliminate the presence
of crystals after die-cutting.
[0011] A successful process for the prevention of the formation of
the scopolamine hydrate crystals was ultimately discovered and is
described in U.S. Pat. No. 4,832,953, incorporated in its entirety
herein by reference. According to that invention, formation of
crystalline hydrates in a liquid dispersion of a hydratable liquid
in a non-aqueous, typically polymeric, matrix can be prevented if,
after they have been placed in their packages, the articles are
heated to a temperature above the melting point of the crystalline
hydrate, are maintained at that temperature for a period of time,
and then are allowed to cool to ambient conditions. For this
process to be successful, holding times for cast films and
laminates, prior to die-cutting, pouching, and annealing, were
minimized in an effort to outrace the kinetics of crystal growth.
It was found that when so treated, crystals initially present
disappeared, did not reform upon cooling to ambient conditions, and
there were no additional signs of crystal formation or growth after
storage at ambient conditions and under accelerated aging
conditions for several months.
[0012] The commercial manufacture of the product including the step
of annealing the pouched systems as described in U.S. Pat. No.
4,832,953 was then-carried out for approximately seven years before
the current crystallization problem developed and commercial
production again had to be halted. The measures employed to prevent
formation of the hydrate as taught in the U.S. Pat. No. 4,832,953
patent are not effective in preventing the formation of the newly
observed crystals because: 1) the new crystals do not melt at the
annealing temperatures specified therein; and 2) the kinetics of
the new crystal growth are significantly faster, such that films
cannot practically be moved through the manufacturing process fast
enough to eliminate significant crystal growth. Crystals have been
observed only four hours after film casting and have been observed
in the final product.
[0013] An extensive investigation was undertaken, including
examination of raw materials, process equipment, and procedures to
isolate a source of crystallization, during which it was determined
that crystal formation could not be attributed to any specific
feature of the procedures, equipment, or raw materials used to
produce the product. It was confirmed that rapid crystallization
could start after any manufacturing step involving the scopolamine
films and laminates. Production was halted until the problem was
solved according to this invention.
SUMMARY OF THE INVENTION
[0014] The new crystal has been identified as a crystalline form of
anhydrous scopolamine base. The cause of the change from the
previous hydrate form to a more stable anhydrous crystal form is
unknown. The inventors have found that the annealing of all the
individual scopolamine-containing films and laminates, in addition
to the final laminate and pouched system, successfully prevents the
formation and growth of the currently observed scopolamine
crystalline structure. The invention provides a method to
effectively beat the crystal growth kinetics in a practical
manner.
[0015] It is accordingly an aspect of this invention to prevent the
formation and/or growth of a crystalline structure in a dispersion
of a liquid in an aqueous or nonaqueous matrix.
[0016] It is another aspect of this invention to prevent the
formation and/or growth of a crystalline structure of scopolamine
in dispersions of scopolamine base in a non-aqueous matrix.
[0017] It is another aspect of this invention to manufacture
transdermal therapeutic systems for the controlled delivery of
scopolamine base which are free from crystals of scopolamine.
[0018] It is yet another aspect of this invention to provide an
improved method of manufacture of transdermal therapeutic systems
which prevents the formation and/or growth of a crystalline
structure in dispersions of a liquid in an aqueous or nonaqueous
matrix.
[0019] These and other aspects of this invention will be readily
apparent from the following description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a flow diagram depicting the process of forming
the drug reservoir/backing layer according to a preferred
embodiment of this invention.
[0021] FIG. 2 is a flow diagram depicting the process of forming
the rate control membrane/contact adhesive layer according to a
preferred embodiment of this invention.
[0022] FIG. 3 is a flow diagram depicting the process of forming
the final laminate according to a preferred embodiment of this
invention.
[0023] FIG. 4 is an isometric view of an in-line annealing oven
useful for the purposes of the present invention.
DISCLOSURE OF THE INVENTION
[0024] According to this invention, formation and/or growth of a
crystalline structure in a dispersion of a liquid in an aqueous or
non-aqueous matrix can be prevented if, immediately following the
formation of each and every film or laminate of the dispersion, the
layer(s) containing the liquid dispersion is (are) sandwiched
between non-porous films and subjected to an annealing process
wherein they are heated to a sufficient temperature for a
sufficient time and then allowed to cool. Preferably, the following
conditions are satisfied at each annealing step: 1) the melting
point temperature of the crystal is exceeded; 2) sufficient time is
provided to allow the crystal to melt; 3) the dispersion is
protected from environmental exposure until the next manufacturing
(and annealing) step; and 4) the annealing step begins promptly
after film formation and/or lamination. Films and laminates treated
by this annealing process are stable and have been observed to
remain crystal-free after storage at ambient conditions for at
least 90 days.
[0025] A preferred embodiment of this invention is directed to the
manufacture of transdermal delivery devices. It has been found that
transdermal delivery devices manufactured according to this
invention are free from crystals and exhibit release rates within
applicable specifications for the product. Although this invention
will be described with respect to a specific example relating to
the manufacture of transdermal delivery devices for the controlled
delivery of scopolamine, it should be recognized that this
invention is applicable to the processing of dispersions of any
liquid agent capable of forming a crystalline structure.
[0026] According to this preferred embodiment, individual films and
laminates of a transdermal therapeutic system which comprise a
dispersion of a liquid in a matrix, as well as the final laminate
and pouched system, are subjected to an annealing process
immediately following the formation of the films or laminates. The
annealing process is performed immediately after the film is placed
between two non-porous substrates in order to minimize exposure of
the film to the atmosphere. The film or laminate thus treated is
stable with respect to crystal growth until the next processing
step, assuming exposure of the annealed film to the environment is
controlled.
[0027] In a particularly preferred embodiment directed to the
manufacture of transdermal delivery devices containing scopolamine,
the rate control membrane/contact adhesive films, drug reservoir
films, and final laminate films are protected between two
non-porous substrates and are subjected to an annealing process,
immediately following lamination, and are heated to a sufficient
temperature, for a sufficient time, and then allowed to cool to
ambient conditions in order to prevent subsequent crystal formation
and growth. The final laminate is then cut into individual systems,
placed into sealed containers, and then subjected to an additional
annealing step.
[0028] The formation of the films and laminates may be achieved by
any means known in the art. Although this invention will be
described with respect to an example wherein a solvent casting
procedure is utilized to form the various films, it should be
recognized that other procedures for forming the films, such as
extrusion or reverse roll coating, may be used in the practice of
this invention. For example, if an extrusion process is used to
form the various films, it would not be necessary to use the drying
ovens in the manufacturing processing line and the extruded films
would proceed directly to the annealing oven or to a lamination
stage immediately followed by the annealing step of this
invention.
[0029] The annealing of the films and laminates can be achieved by
various means. For example, when the films are formed by solvent
casting, annealing can be performed by a second pass through the
drying ovens that are used to dry the initial film. This requires
that by the time the last portion of film has exited the ovens for
the first time, the portion of film that first exited the ovens has
not already begun to crystallize. Alternatively, the film casting
may be broken up into small sublots so that any film or laminate is
subjected to annealing within a few hours of casting or lamination.
Preferably, annealing occurs in-line, immediately following film
formation and/or lamination. Most preferably, an annealing oven is
placed immediately after the lamination stage.
[0030] The manufacture of transdermal delivery devices using a
solvent casting procedure will now be described with reference to
the drawings. The process for the formation of the drug reservoir
layer is shown in FIG. 1. The drug reservoir casting solution is
cast onto impermeable backing layer 21 fed from source roll 11 to
form a film comprising drug reservoir layer 22 on impermeable
backing layer 21. The film is then passed through the drying ovens
20 to evaporate the solvent. The dried film is then passed through
a laminator 30 where non-porous interleaving layer 32 is applied to
the surface of drug reservoir layer 22. The laminate is then passed
through in-line annealing oven 40, shown in detail in FIG. 4. After
exiting the annealing oven, the laminate is wound up on take-up
roll 31 of the laminator.
[0031] The rate control membrane/contact adhesive layer is formed
by a similar process as shown in FIG. 2. The contact adhesive
solution 51 is cast onto release liner 50 and passed through the
drying ovens 20. Rate control membrane 52 and non-porous
interleaving layer 53 are then laminated to the surfaces of the
contact adhesive and rate control membrane, respectively. The
laminate is then passed through the in-line annealing oven 40
before being taken up on the take-up roll 31 of the laminator.
[0032] The final laminate is produced as shown in FIG. 3. The drug
reservoir laminate and rate control membrane/contact adhesive
laminate rolls are set up in the laminator. Interleaving layer 53
is removed from the rate control membrane/contact adhesive laminate
and interleaving layer 32 is removed from the drug reservoir
laminate, exposing the rate control membrane 52 and drug reservoir
22, respectively, which are then laminated together to form the
final laminate. The final laminate, comprising impermeable release
liner 50, contact adhesive layer 51, rate control membrane 52, drug
reservoir layer 22, and impermeable backing layer 21, is then
passed through in-line annealing oven 40 before being taken up once
again on take-up roll 31 of the laminator. In a final processing
step (not shown), individual systems are die cut from the final
laminate. The systems are placed in individual pouches, the pouches
are heat sealed and the pouched systems are then placed in an
in-line annealing oven for a final annealing process.
[0033] FIG. 4 depicts annealing oven 40 in greater detail. The
laminate first enters the annealing oven where it contacts heated
roll 41 which provides immediate heating to the laminate. The
laminate passes over idler rolls 42 and tension roll 43 and is
passed through the annealing chamber 44 which is preheated to a
predetermined temperature. The dwelling time of the laminate in the
annealing chamber may be adjusted by setting an appropriate line
speed for the laminate. Annealing oven 40 is also provided with air
handler 45 and access door 46.
[0034] As seen in the above description, at each film
forming/laminating step, the adhesive is sandwiched between
non-porous substrates so that after annealing is performed,
additional contamination by crystal seeds is not possible until the
next processing operation. After each intermediate film or laminate
is annealed, that product is stable until the next operation, as
long as it is not exposed to the atmosphere.
[0035] The use of an in-line annealing oven offers several
advantages to alternative methods of annealing individual films and
laminates. First, it eliminates the need for breaking the
production down into small sublots in order to reduce film exposure
time, thus allowing for production at the previous full lot
capacity. Such a method also reduces the film exposure time more
effectively to only a matter of seconds. Additionally, the use of
an in-line annealing oven allows for better utilization of the
casting ovens and avoids the difficulty in handling the laminates
as would be required if they were to be run through the casting
ovens a second time. With the in-line annealing method of this
invention, better prevention of crystal formation is observed
because only seconds elapse between the time that the film leaves
the casting ovens and enters the annealing oven, effectively
beating crystal growth kinetics by eliminating any time available
for crystal formation and/or growth.
[0036] The temperature and time are not critical provided they are
adequate to prevent the formation of crystals after cooling and are
not so high as to cause damage to the individual films or laminas.
If crystals are initially present, the temperature must be at, and
preferably above, the melting point of the crystal and the time
should be sufficient to cause melting of all the crystals present.
If crystals are not present at the time of the heating step,
temperatures lower than the melting point of the crystal may be
effective. Nevertheless, it is preferable from the point of quality
assurance and uniformity of processing conditions to heat above the
melting point of the crystal, the formation of which it is desired
to prevent.
[0037] In the preferred embodiment of this invention directed to
the prevention of the formation of scopolamine crystals during the
manufacture of transdermal therapeutic systems containing
scopolamine, the temperature to which the individual and final
laminates were heated is preferably within the range of
75-90.degree. C., for a duration of 2-10 minutes. The final pouched
systems are preferably heated to a temperature of 75.degree. C. for
a period of 4-24 hours. The actual temperature for other materials
is easily determined by measuring the melting point of the
crystal.
[0038] Having thus generally described our invention, the following
specific example is provided to illustrate the invention. The
example is not intended to limit the scope of the invention in any
way. Unless otherwise indicated, parts are by weight.
EXAMPLE 1
[0039] Preparation of Scopolamine Base Solution
[0040] Scopolamine base was formed by dissolving scopolamine
hydrobromide in an aqueous sodium bicarbonate-sodium carbonate
buffer solution. Sodium hydroxide was added until a pH of about 9.6
was reached at which point the scopolamine base precipitated from
solution and was extracted with chloroform.
[0041] Preparation of Casting Solutions
[0042] 20.0 parts high molecular weight PIB (Vistanex L-100,
1,200,000 viscosity average molecular weight), 26.1 parts low
molecular weight PIB (Vistanex LM-MS, 35,000 viscosity average
molecular weight), 41.7 parts mineral oil (10 cp at 25.degree. C.)
and 11.3 parts of scopolamine base were dissolved in chloroform in
a mixer to prepare the drug reservoir casting solution used in
forming the drug reservoir film.
[0043] To prepare the contact adhesive casting solution, a solution
of 23.1 parts of said high molecular weight PIB, 28.8 parts of said
low molecular weight PIB, 46.1 parts of said mineral oil, and 2.0
parts of said scopolamine base were dissolved in chloroform in a
mixer.
[0044] Preparation of Films and Laminates
[0045] The drug reservoir casting solution was then solvent cast to
form a drug reservoir film approximately 50 micrometers dry
thickness on an approximately 65 micrometer backing of aluminized
polyethylene terephthalate (Scotchpak.RTM.). The drug reservoir
film was passed through an oven to evaporate the chloroform,
leaving behind a drug containing adhesive film on a backing
substrate. After leaving the oven, the film was moved to a
laminator where an interleaving film was applied. The laminate was
then passed into a second oven placed immediately following the
laminator, where the laminate was heated to a temperature of
80-85.degree. C. for 9-10 minutes. Thereafter, the laminate is
returned to the take-up roll on the laminator.
[0046] The rate control membrane/contact adhesive laminate was
similarly prepared by solvent casting a 50 micrometer dry thickness
adhesive layer of the contact adhesive casting solution onto a 75
micrometer siliconized, polyethylene terephthalate film. After
casting, the films were passed through the ovens to evaporate the
chloroform solvent, leaving behind a drug containing adhesive on a
release liner. This film was moved to a laminator, where a
microporous polypropylene rate controlling membrane, with the pores
saturated with mineral oil, was laminated to the adhesive surface.
An interleaving film was added to protect the top of the control
membrane and the entire laminate was introduced into the second
oven immediately thereafter and was heated to a temperature of
80-85.degree. C. for 5-6 minutes.
[0047] The rate control membrane surface of the rate control
membrane/contact adhesive laminate was then laminated to the drug
reservoir surface of the drug reservoir laminate to yield a final
laminate. This final laminate was then also passed through the
annealing oven immediately following the laminator and heated to a
temperature of 80-85.degree. C. for approximately 2 minutes. 2.5
cm.sup.2 circular disk-shaped systems were punch-cut from the
resulting five layer laminate. The individual systems were then
packaged within heat-sealed foil-lined pouches. The pouches were
then treated by heating in an additional annealing oven to
75.degree. C. for 4-24 hours and thereafter allowed to cool to
ambient conditions.
[0048] None of the systems made according to the invention were
observed to contain crystals. Additionally, systems made according
to the invention exhibited release rates within the applicable
specifications for the product.
[0049] Having thus described our invention, it is readily apparent
that various modifications can be made by workers skilled in the
art without departing from the scope of this invention. It is
intended that the invention embrace these equivalents within the
scope of the claims that follow.
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