Note: Descriptions are shown in the official language in which they were submitted.
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BACKGROUND OF THE INYENTION
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Field of the Inven_ion
The present invention relates to methods of preparing products by
freeze-drying.
Description of the Pri_r Art
Freeze-drying is a well known method of drying heat-sensitive
materials in order to protect them from thermal damage. In the past,
preparations containing active ingredients, such as pharmaceuticals,
nutrients, diagnostics, f~rtilizers and insecticides, have been prepared by
freeze-drying aqueous solutions or suspensions containing these active
ingredients. One problem that has arisen, however, with the use of known
freeze-drying processes is cracking of the freeze-dried preparations.
Typically, cracking is caused by the stresses set up during ice
crystallization. Though cracking is never desirable, it is especially
undesirable where drop methods of freezing are employed. In such cases,
cracking of the frozen droplets usually results in unusable and inelegant
remnants of fractured droplets.
Another problem encountered by use of known freeze-drying methods
is a phenonomen called meltback. Meltback occurs when the heat required
during the drying process me]ts the frozen material. As such, meltback
defeats the whole purpose of freeze-drying--the removal of water through
sublimation as opposed to evaporation. To avoid meltback in conventional
freeze-drying methods, only limited amounts of material of limited
thickness can be dried at one time. Even ulith these limitations,
conventional freeze-drying methods are not always rapid enough to prevent
meltback.
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In the area of pharmaceu-ticals, knoi~n freeze-dried
closage forms do no-t always exhibit fast dissolution rates ~.7hen
broucJht into contact with appropriate solvents, such as water,
saliva o.r gastrointestinal ~luids. P~apid dissolution of
pharmaceutical dosage forms can be of critical importance in
instances where it is desirable that the pharmaceutical enker the
physiological system as soon as possihle.
Thus, there is a need for a method of producing freeze-
dried prepara~ion6 tha~ avoids cracking and meltback duriny the
freeze-drying process In addition, there is a need for freeze-
dried pharmaceukical dosage forms that exhibik rapid dissolution
upon inge~tion.
SllMMARY OF THE INVENTION
It is an object of the present invention to provide a
method of freeze-drylng an aqueous solution or suspension that
prevents or reduces the incidence of crac~king of the freeze-dried
preparation.
It is an additional object of the present invention to
provide a method of freeze-drying whereby the incidence of
meltback during the freeze-drying process is reduced or
eliminatecl.
It is a further object of the present invention to
provide a method of preparing freeze-dried pharmaceutical dosage
forms that exhibit rapid dissolution in appropriate solvents.
It is a further additional object of the present
invention to provide freeze-dried foams ~hat include active
inyredients, such as pharmaceukicals, nutrients, diagnostics,
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~ertilizers and insecticides.
It is a specific object of the present invention ~o
provide a method of preparing an effective unit dosage form of an
active ingredient, said active ingredient being selected from the
group consisting of pharmaceuticals, nutrients, vitamins,
minerals, diagnostic ayents, fertilizers and insecticides,
comprising the following steps in combination:
a. ~orming a dispersion of a yas and a solution or
suspension, said solution or suspension containing said active
ingredient dissolved or suspended therein;
b. maintaining said gas in a dispersed state within said
dispersion; and
c. freeze-drying a unit volume of said dispersion to form a
freeæe-dried ~oam containing said active ingredient dispersed
therethrough, said freeze-dried unit volume containing an
effective unit dosage of said a~tive ingredient.
In order to maintain the dispersion of the gas within
the solution or suspension, it is preferable to include one or
more sur~actants within the solution or suspension. In addition,
it is preferable to include a bulk-forming agent within the
suspension or solution such that both the gas and the active
ingredient are maintained in a dispersed state within the solution
or suspension. Any suitable conventional method of freeze-drying
may be employed.
The resulting freeze-dried ioams prevent or reduce the
incidence of cracking during the ~reeze-drying process. This is
because the s~resses that normally build up during the free~ing
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61368-7~4
process are harmlessly released due to the porosity of the foam.
In addition, the presence of the dispersed yas with the solution
or suspension results in a more rapid freeze-drying process, sinse
during both the freeziny and the drying steps, vapors are more
readily able to penetrate into the interior of the preparation
being freeze-dried. Because of this more rapid rate of freeze-
drying, the chance of meltback during the freeze-drying process is
greatly reduced or eliminated.
In the realm of pharmaceutical use, freeze-dried
pharmaceutical dosage forms prepared according to the present
invention exhibit rapid dissolution upon contact with
physiological solvents, such as water, saliva, or gastrointestinal
fluids. Therefore, the present inventive pharmaceutical freeze-
dried foams provide a more rapid dispersion of the pharmaceutical
within the body upon ingestion.
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Further objects and embodiments of the present invention will be
made known in the following description of the preferred embodiments and
claims. Though the following description of the preferred embodiments
focuses on the inclusion of pharmaeeuticals as the active ingredien~, it is
to be understood that the desirable properties of the inventive methods and
foams may be advantageously used in connection with many different types
of active ingredients including, by way of example, nutrients, vitamins,
minerals, diagnostics, fertilizers flnd insecticides.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The starting point for preparation of the inventive freeze-dried
foams is the solution or suspension to be freeze-dried. This solution or
suspension should be primarily aqueous in nature and should contain the
desired active ingredient dissolved or suspended therein. Examples of
pharmaceutical compositions that can be successfully utilized in
2 o connection with the present invention are benzodiazapine, oxazepam,
temazepam and lorazepam. However, any pharmaceutical composition
that can be freeze-dried conventionally with success may be used in
connection with the present invention.
In addition to incorporation of pharmaceutieal compositions as the
active ingredient, nutritional, diagnostic or other chemical agents may be
advantageously incorporated into the inventive freeze-dried foam.
Examples of nutritional agents that may be used with the present invention
are vitamins, minerals, and food supplements. Diagnostic agents, such as
monoclonal antibodies, may be successfully incorporated into the present
freeze-dried foams. Other types of active chemical agents may also be
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used with the present invention, for example, fertilizers and insecticides.
Whatever active ingredient is incorporated into the freeze-dried foam, it
should be present in the resulting freeze-dried foam in an effecti~re
concentration per unit volume.
The selected gas may be incorporated into the solution or suspension
by bubbling the gas through the solution or suspension. The gas may be
selected from any gas that will not adversely react with the active
ingredient. Suitable gases include air, oxygen, nitrogen and argon. It is
aclvantageous to incorporate bubbles of minute, uniform size into the
1~ solution or suspension. Preferably, the majority of bubbles range from
approximately 50 microns to approximately 500 microns in size. Most
preferably, the bubbles are substantially uniform in size and have an
average diameter of approximately l00 microns. The advantage of small,
uniform bubbles is that it is easier to maintain the gas in a dispersed state
within the solution or suspension. To obtain this desirable result, the gas
may be first passed through sintered glass immediately before bubbling the
gas through the solution or suspension. Alternatively, gas may be
incorporated into the solution or suspension by means of high speed mixing.
At least some portion of the gas dispersed within the solution or
suspension must be maintained in a dispersed state during the freeze-drying
process, since the dispersed gas is necessary to formation of the foam-like
structure of the resulting freeze-dried foam. One means for maintaining a
sufficient dispersion of the gas within the solution or suspension is to
employ a rapid freezing technique. In the use of such techniques, the
dispersed gas bubbles are "trapped" within the solution or suspension as it is
frozen, thus forming the foam-like structure. Alternatively, one or more
surfactant compositions may be incorporated into the solution or
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suspension. Surfactants aid in maintaining the gas in its dispersed state
throughout the suspension or solution during the freezing process.
~lthough any conventional surfactant may be used, preferred surfactant
agents include sodium lauryl sulfate, polyoxyethylene sorbitan esters
,~ 5 ~commercially available under the ~en~,~ween), sorbitan esters
(commercially available under the~ Span) lecithin and sodium
dioctylsulphosuccinate. The surfactar.t compositions, if used, should be
present in an amount sufficient to effectively maintain the dispersion of
the gas within the solution or suspension.
One or more bulk-forming agents may also be incorporated into the
solution or suspension prior to freezing. The bulk-forming agent may be
present in addition to a surfactant or to the exclusion of a surfactant. The
primary purpose of the bulk-forming agent is to aid in maintaining the
dispersion of the active ingredient within the so]ution` or suspension This
is especially helpful in the case of active ingredients that are not aqueously
soluble enough such that they must be suspended, rather than dissolved.
Additionally, bulk-forming agents aid the maintenance of the dispersion of
the gas within the solution or suspension prior to and during the freezing
process. Any suitable, conventional bulk-forming agent may be used in
2 o connection with the present invention. Preferred bulk-forming agents
include long chain polymers, e.g., polypeptides such as gelatin or
hydrolyzed gelatin, cellulose derivatives, alginate derivatives, polyvinyl
pyrrolidone, polyethylene glycols, polysaccharides, such as dextran,
mannitol, sugars and starches, and gums such as acacia, xanthan, and
tragacanth. The bulk-forming agents may be incorporated into the solution
or suspension in concentrations sufficient to aid in the maintenance of the
dispersion of the active ingredient or gas within the solution or suspension.
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The resulting solution or suspension having gas dispersed therethrough
may be freeze-dried by any conventional freeze-drying process. For
examp]e, the solution or suspension may be frozen by dispensing the
solution or suspension into preformed molds and subsequently freezing such
molds on refrigerated shelves or in refrigerated chambers. Alternatively,
the molds containing the solution or suspension may be passed through
stream of cold gas or ~apor, such as liquid nitrogen in a freezing tunnel.
~s an alternative to the use of molds, the solutions or suspensions
having gas dispersed therein may be frozen in dropwise ~ashion. ~or
example, the solution or suspension may be pumped or fed under gravity
through an orifice in order to form drops, spheres or a spray of small
particles. These drops can then be frozen by pass~ge through a cold gas or
liquid, for example, liquid nitrogen or liquid nitrogen vapor. Another
possibility is that drops of the solution or suspension may be frozen in a
chilled liquid that is incompatible with the solution or suspension. In such
cases, the relative densities of the liquid and the solution or suspension are
controlled such that the drops can either pass through the chilled
incompatible liquid as it freezes or, alternatively, the frozen droplet may
float on the surface of the chiUed incompatible liquid. This latter flotation
feature facilitates the collection of the frozen droplets. An example of a
liquid that may be chilled and that is incompatible with most primarily
aqueous solutions or suspensions is trichlorethylene.
The use of dropwise forms of freezing is particularly advantageous in
the preparation of the inventive freeze-dried foams since it allows for the
rapid freezing of the solution or suspension. This in turn limits the amount
of gas that can escape from its dispersed state within the solution or
suspension. In addition, the presence of the gas in the solution or
suspension being frozen decreases the freezing time and virtually
eliminates cracking because of the porosity of the solution or suspension.
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The frozen solution or suspension is then dried on heated shelves in a
partiaUy or completely evacuated chamber in accordance with
convention~l freeze drying methods. In the case of frozen molded forms of
the solution or suspension, these forms may be forced through an extrusion
device such that the frozen solution or suspension is cut or formed into
appropriately sized segments prior to drying. The drying process is
relatively rapid due to the porous nature of the frozen droplets or molded
forms. Furthermore, because the drying process is relatively rapid, the
phenomenon of meltback is completely avoided or substantially reduced.
The resultlng freeze-dried product hRs a foam-like structure and includes
the active ingredient dispersed therethrough. In the case of
pharmaceutical freeze-dried dosage forms, the resulting dosage forms
exhibit extremely rapid dissolution when placed in water or in the human
mouth. Such rapid dissolution is desirable in order to introduce the
pharmaceutical into the physiological system as soon as possible.
Of course, secondary components such as flavorings, preservatives or
colorings may also be incorporated in the freeze-dried foams in accordance
with conventional practices.
COMPARATIVE EXAMPLES 1-6
2 o In Examples 1-6, the BOC freezing machine described in United
Kingdom Patent No. 2117222A was used to accomplish freezing of the
solutions or suspensions. In each example, a solution containing 4% by
weight of gelatin and 3% by weight of mannitol in water was dispersed
dropwise into the liquid nitrogen flowing down the V-shaped channel of the
2 5 BOC freezing machine. The solutions frozen in Examples 4-6 also
contained 6.67% by weight of oxazepam as the active pharmaceutical
ingredient. The drops rolling along this channel froze from the outside to
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the center. A typical residence time for the drops in the freezing channel
WQS about ~-10 seconds. During this time, the surface of the drops froze,
but not the core of the drops. Complete freezing occured after the sphere
had been separated from the liquid nitrogen in the freezing machine and
was left exposed to the cold nitrogen exhaust gas. The resulting frozen
drops were then freeze-dried on heated shelves in an evacuated chamber.
The mean diameters, dosage weights, disintegration times, cracking rates,
and drying times for Examples 1-6 are shown below in Table I.
TA~LE I
Exemple .UeQn DoYR~e Dl3integration 96 Drying
Dilmet~r Weight time ~t 37C CracWng tim~.
(mm.) (g.) (mins.)
5.5 0.1 4.i ~ec. I00 ~33
2 6.9 0.175 5.6 gec. ~00 280
3 7.9 0.25 6.5 sec. 100 260
4 i.8 0.1 ~.5 sec. I00 293
7.2 0.175 6.3 sec. I00 300
6 8.~ O.ZS 7.0 s~c. I00 300
The disintergration times noted are the times taken to wet the
2 0 freeze-dried droplet dosage form. In all cases, the dispersion of the
disintergrated dosage form in water was poor.
COMPARATIVE EXAMPLES 7 AND 8
In Examples 7 and 8, placebo freeze-dried dosage forms made from
solutions without incorporated gas were di~persed dropwise into a flask
25 containing liquid nitrogen. The resulting drops floated on the surface of
liquid nitrogen initially. However, the droplets sank immediately once the
temperature of the drop had reached the approximate temperature of
liquid nitrogen, i.e., -196C. The frozen droplets were collected by
decanting the liquid nitrogen. The frozen droplets were freeze-dried on
30 heated shelves in an evacuated chamber. In Example 7, the placebo dossge
form included 4% hydro]yzed gelatin and 3% mannitol by weight in water.
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The mean diameters, dosage weights, disintegration times, cracking rates
and drying times for Examp]es 7 and 8 are shown below in Table II.
TABLE ~
Ex~mple ~le~n no3sge Disinte~Rtion ~ Drying
Di Imeter Weight time at 37~C Crackin~ time
(mm.) ~.) (mins.)
7 5.0 0.07Inst~ntaneou~ 100 Dried
overni~ht
8 4.5 0.07Inst~ntaneous 100 IjO
EXAMPLES 9-18
10Examples 9-18 represent freeze-dried foam dosage forms prepared in
accordance with the present invention. In each case, solutions containing
4% by weight gelatin and 3% mannitol in water were prepared. Additional
components were added as noted in Table III. Air bubbles were
incorporated into the solutions and suspensions by use of a Silverson~
~` homogenizer. All of the air bubbles incorporated into the solution and
suspension were of relatively uniform size and had an average diameter of
approximately 100 microns. The resulting solutions and suspensions were
dispensed dropwise into a flask containing liquid nitrogen. The spheres
floated not only during freezing, but also continued to float once
20 completely frozen. This facilitated the removal OI the frozen droplets
from the liquid nitrogen. The mean diameters, dosage weights,
disintegration times, cracking rates and drying times for Examples 9-18 are
shown below in Table III. Dispersion of each of the dosage forms in
Examples 9-18 was excellent upon disintegration in water.
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T~BLE nl
Example Addi~ionalUeQn Dos~ge t)isinte6rstion ~ Dr~in~
ComponentsOi~meter~1eight time at 37~C Craeking~ ~ima
(mm.) (g,) ~ n.)
9 3~6 T~cen 806.50,09-0.10 0.5 5ec, O IjO
16 30dium dioctyl 6.3 0.0~0.10 0.3 sec. 0 180
~phosu~cinate
Il 1~6 sodium dioctyl6.3 ~.09-0.10 tnstantaneous 0 llO
sulphosuccinate
6.676 Oxez~pam
12 0.25~ 30dium dioctyi 6.i 0.09-0.10 Instantaneous ~).8 )~]
su)phosucc1nate
)3 1S sodlum lauryl 6.31 0.09-0.!0 Inst~ntQneous O lij
14 0.259t iodium l~uryl ,.i 0.09-0.10 Instant~neous ~ 120
1 5 5ulphate
6.676 Oxazep~m 7.5 0.09-0.10 Instantaneous ~ 135
O.ZS~ sodium 13U~
sulph~te
16 0.67~ Lorazep~m 7.3 0.09-0.~0 Inst~ntaneous 16.8 137
2 0 0.25~ sodlum l~uryl
su)phute
17 6.67S Oxazepsrn 7.7 0.09-0.10 Instant~neous 0 135
18 0.67aS Lorazeparn a.o o.o~oso Instantlneou3 0.4
As can be seen by a comparison of Tables I and II to the inventive
25 compositions shown in Table III, the freeze-dried dosage forms produced
according to the present invention are superior to the dosage forms
prepared According to the prior art in several respects. First, the drying
time for the inventive formulations is in most cases significantly shorter.
This is believed to be due to the increased porosity of the foamed solutions
30 or suspensions. Second, the inventive formulations exhibit far less cracking
then the .ree2e-dried forrnulations prepared according to prior a~t. This is
believed due to the ability of the foamed solutions or suspensions to
harmlessly release the tensions that build up during the freezing process.
Third, the disintegration rates of the inventive formulations are noticably
35 shorter in some cases than the droplet formulations prepared according to
the prior art. In the area of pharmaceutical formulations, rapid
disintegration time is desirable since it can often enhance the onset of the
pharmacoloE;ical properties of the drug being administered.
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It is to be understood that the preceeding description of the preferred
embodiments has emphasized certain embodiments by way of example.
Numerous other embodiments not specifically discussed may fall within the
spirit and scope of the present invention and the following claims.
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