U.S. patent application number 14/576179 was filed with the patent office on 2015-08-20 for drug mixing and delivery system and method.
The applicant listed for this patent is Windgap Medical, Inc.. Invention is credited to Brent A. Buchine, Adam R. Standley, Christopher J. Stepanian.
Application Number | 20150231334 14/576179 |
Document ID | / |
Family ID | 53403885 |
Filed Date | 2015-08-20 |
United States Patent
Application |
20150231334 |
Kind Code |
A1 |
Buchine; Brent A. ; et
al. |
August 20, 2015 |
DRUG MIXING AND DELIVERY SYSTEM AND METHOD
Abstract
The present disclosure provides methods of preparing a medical
solution. In some aspects, the medical solution can be prepared
from mixing a first liquid with a second liquid or mixing a solid
component with a liquid in an autoinjector. In some aspects, the
heat released from the mixing can promote solubility of a dry
medicament in the solution.
Inventors: |
Buchine; Brent A.;
(Watertown, MA) ; Standley; Adam R.; (Cambridge,
MA) ; Stepanian; Christopher J.; (Somerville,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Windgap Medical, Inc. |
Somerville |
MA |
US |
|
|
Family ID: |
53403885 |
Appl. No.: |
14/576179 |
Filed: |
December 18, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61917925 |
Dec 18, 2013 |
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62016260 |
Jun 24, 2014 |
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Current U.S.
Class: |
514/11.7 ;
514/415; 514/654; 604/92 |
Current CPC
Class: |
A61K 38/26 20130101;
A61M 2205/364 20130101; A61K 38/00 20130101; A61M 5/19 20130101;
A61M 5/3294 20130101; A61K 9/0019 20130101; A61M 5/44 20130101;
A61M 2205/366 20130101; A61P 25/06 20180101; A61K 45/06 20130101;
A61M 5/2046 20130101; A61M 5/1409 20130101; A61K 31/4045 20130101;
A61P 3/08 20180101; A61P 9/02 20180101; A61K 31/137 20130101; A61M
5/2448 20130101; A61M 5/284 20130101 |
International
Class: |
A61M 5/24 20060101
A61M005/24; A61M 5/28 20060101 A61M005/28; A61K 31/4045 20060101
A61K031/4045; A61K 31/137 20060101 A61K031/137; A61K 38/26 20060101
A61K038/26 |
Claims
1. A method of preparing a medical solution comprising mixing a dry
medicament and a first liquid, wherein the first liquid comprises a
pH optimizing agent, and the dry medicament is readily solubilized
upon mixing with the first liquid.
2-11. (canceled)
12. The method of claim 1, wherein the dry medicament is located in
a first chamber of a medical device.
13. The method of claim 12, wherein the first liquid is located in
a second chamber of the medical device.
14. The method of claim 13, wherein the medical device is an
automatic injection device, prefilled syringe, or a needle
assembly.
15. (canceled)
16. The method of claim 1, wherein the dry medicament is
epinephrine, glucagon, or sumatriptan.
17-19. (canceled)
20. A method for forming an epinephrine solution in an automatic
injection device, prefilled syringe, or needle assembly, comprising
the steps of: placing dry epinephrine into a chamber in the
automatic injection device, prefilled syringe, or needle assembly;
placing into a separate chamber within the automatic injection
device, prefilled syringe, or needle assembly, a pH optimized
solution; activating the automatic injection device, prefilled
syringe, or needle assembly, and causing the dry epinephrine to be
dissolved by the pH optimized solution, wherein an epinephrine
solution is formed inside the automatic injection device.
21. The method of claim 20, wherein the pH optimized solution
includes an acid.
22-23. (canceled)
24. The method of claim 20, wherein the dry epinephrine is
epinephrine freebase or an epinephrine salt.
25-26. (canceled)
27. The method of claim 20, wherein the final concentration of the
epinephrine solution is between 0.7 and 1.3 mg/ml.
28. The method of claim 20, wherein the final pH of the epinephrine
solution is between 1-5.
29. The method of claim 20 further comprising placing into a third
chamber within the automatic injection device, prefilled syringe,
or needle assembly a pH adjusting solution.
30. (canceled)
31. The method of claim 29, where the pH adjusting solution is a
base.
32-33. (canceled)
34. The method of claim 24, wherein the epinephrine salt is a
maleate, malate, fumarate, tartrate, bitartrate, sulfate,
hydrochloride, or borate salt of epinephrine.
35-51. (canceled)
52. A method of preparing a medical solution comprising mixing a
first liquid with a second liquid to generate a mixture, wherein
the mixing generates heat to promote solubility of a dry medicament
in the mixture.
53. (canceled)
54. The method of claim 52, wherein the dry medicament is
subsequently added to the mixture.
55. The method of claim 52, wherein the dry medicament is added to
the first liquid prior to mixing with the second liquid.
56. The method of claim 52, wherein the dry medicament is amorphous
or crystalline.
57-58. (canceled)
59. The method of claim 52, wherein the dry medicament comprises
one or more therapeutic agents.
60-178. (canceled)
179. A method of preparing a medical solution comprising mixing a
dry medicament and a first liquid, wherein the first liquid
comprises an aqueous solution, and the dry medicament is a salt and
readily solubilized upon mixing with the first liquid.
180. A method for forming an epinephrine solution in an automatic
injection device, prefilled syringe, or needle assembly, comprising
the steps of: placing dry epinephrine salt into a chamber in the
automatic injection device, prefilled syringe, or needle assembly;
placing into a separate chamber within the automatic injection
device, prefilled syringe, or needle assembly, a liquid; activating
the automatic injection device, prefilled syringe, or needle
assembly, and causing the dry epinephrine to be dissolved by the
liquid.
Description
RELATED APPLICATIONS
[0001] The present invention claims priority under 35 U.S.C.
.sctn.119(e) to U.S. provisional patent applications, U.S. Ser. No.
61/917,925, filed Dec. 18, 2013, and U.S. Ser. No. 62/016,260,
filed Jun. 24, 2014, the entire contents of each of which are
incorporated herein by reference.
BACKGROUND OF INVENTION
[0002] Individuals who suffer from certain medical conditions are
often required to keep an auto-injector or prefilled syringe nearby
in order to address a medical need. A few examples of this are
insulin pens for people with diabetes, epinephrine autoinjectors
for those with food and insect stings allergies, and antidotes for
soldiers at risk of exposure to chemical and/or biological toxins
in the field.
[0003] Exposure to certain substances, such as, for example,
peanuts, shellfish, bee venom, certain drugs, toxins, and the like,
can cause allergic reactions in sensitive individuals. Such
allergic reactions can lead to anaphylactic shock. This can cause a
sharp drop in blood pressure, hives, and/or severe airway
constriction and can be a life-threatening condition. The response
of a sensitive individual to an allergen can either gradually or
abruptly increase or decrease over time, making a large portion of
those sensitive individuals needful of a solution to mitigate the
effects of anaphylactic shock. Responding rapidly to mitigate the
effects from such exposures can prevent injury and/or death. For
example, in certain situations, an injection of epinephrine (i.e.,
adrenaline) can provide substantial and/or complete relief from the
allergic reaction.
[0004] With regards to allergies, for example, an allergic reaction
may occur in a location physically distant from the nearest
hospital or medical facility. For example, bee stings, are more
likely to occur outside than indoors. Food containing peanuts are
more likely to be supplied to the individual away from a controlled
home environment like at a baseball park.
[0005] Because emergency medical facilities may not be available
when an individual is suffering from an allergic reaction, some
individuals carry a medicament delivery device, such as, for
example, an auto-injector, to rapidly self-administer the
epinephrine in response to an allergic reaction. Having an
epinephrine auto-injector nearby enables emergency intervention
after an exposure to an allergen to reduce and/or reverse the
side-effects of life threatening anaphylaxis.
[0006] For patients that are required to carry epinephrine
autoinjectors with them, the thermal stability profile of the
medication can present an issue. Patients must care for their
medications in a way that prevents them from being exposed to
excessive heat or cold outside of controlled room temperature. Not
doing so can degrade the medication rapidly and result in a drug
that doesn't have the recommended potency to deal with the onsets
of anaphylactic shock.
SUMMARY
[0007] In some embodiments, aspects of the invention relate to dry
drug compositions (e.g., dry powder compositions) that can be
dissolved and/or reconstituted rapidly for delivery to a patient
(e.g., a human patient). According to aspects of the invention, dry
compositions have several advantages over liquid compositions,
including increased stability (e.g., a long shelf life, potency
and/or chiral stability) over time and upon exposure to changes in
temperature.
[0008] In some embodiments, a dry drug composition comprises an
epinephrine free base. In some embodiments the dry drug composition
comprises an L-epinephrine freebase. In some embodiments, a dry
drug composition comprises an epinephrine salt. In some
embodiments, the epinephrine salt is a maleate, malate, fumarate,
acid tartrate, hydrogen tartrate, or sulfate salt of epinephrine.
In some embodiments, the epinephrine salt is epinephrine
hydrochloride. In some embodiments, the epinephrine salt is
epinephrine bitartrate. In some embodiments, the epinephrine salt
is epinephrine borate. In some embodiments, the epinephrine is
L-epinephrine. In some embodiments, the dry drug composition
further comprises a salt and/or an antioxidant. In some
embodiments, the dry drug composition comprises sodium
metabisulfite and/or manitol.
[0009] In some embodiments, a dry drug composition is prepared by
drying a drug solution (e.g., by vacuum drying, freeze drying,
lyophilizing, or any suitable drying technique, as aspects of the
invention are not limited in this respect). In some embodiments the
dry drug is placed inside the autoinjector as a dry powder. In some
embodiments, a dry composition may have any suitable particle size
that allows for efficient and rapid reconstitution. In some
embodiments, the particle size of the dry drug can be controlled by
drying a drug solution within a confined volume. For example, in
some embodiments, a drug solution is dried within the confines of
an autoinjector (e.g., within one or more microfluidic channels of
an autoinjector). As a result, the particle size of a dried drug
composition may be one the order of the diameter of a microfluidic
channel (e.g., from about 1 micron to about 500 microns in
diameter). However, smaller or larger particle sizes may be used in
some embodiments.
[0010] It should be appreciated that a dried drug composition may
include the drug alone and/or any other molecules that were present
in the drug solution (e.g., one or more salts, stabilizers,
anti-oxidants, etc., or any combination thereof).
[0011] It also should be appreciated that the composition can be
dried to different extents depending on the conditions used and the
nature of the composition (e.g., the drug and other components of
the composition). In some embodiments, a dry composition has less
than 50% water by weight, less than 40% water by weight, less than
30% water by weight, less than 20% water by weight, less than 10%
water by weight, less than 5% water by weight, less than 1% water
by weight, less than 0.1% water by weight, less than 0.01% water by
weight, or less.
[0012] It also should be appreciated that a dry drug composition
can be dissolved and/or mixed and/or reconstituted by exposure to
water or any suitable solvent (aqueous or non-aqueous), with or
without salts and/or other buffers or components.
[0013] Accordingly, in some embodiments, the present disclosure
provides pharmaceutical compositions comprising a medicament as a
dry component. The medicament can be kept out of the liquid phase
and stored as a dry medication, for example, as a lyophilized,
spray dried, vacuum dried or chemical derived powder. The dry
medicament has the advantages of an extended shelf-life, reduced
temperature susceptibility, a greater efficacy and potency to
endure over a longer period of time and through a wider range of
temperature environments.
[0014] In some embodiments, aspects of the invention relate to a
sealed container comprising a dry drug composition (e.g., a dry
drug powder) as described herein. In some embodiments, the sealed
container is incorporated into the housing of an injector. In some
embodiments, the sealed container is a microfluidic channel in an
injector and wherein the channel is connected to a liquid
reservoir. In some embodiments the dry drug is placed inside the
microfluidic channel.
[0015] In some embodiments, aspects of the invention relate to an
injector comprising a dry drug composition.
[0016] In some embodiments, dry drug compositions can be prepared
and/or delivered in injector devices. In some embodiments, an
injector device also contains a liquid reservoir that can be
accessed to deliver a fluid to the dry composition in order to
solubilize and/or rehydrate and/or dissolve the drug immediately
prior to injection. In some embodiments, the injector is an
autoinjector that automatically mixes the dry drug composition with
the fluid when the injector is activated.
[0017] In some embodiments the dry drug is placed within the
confines of an autoinjector as a dry powder, for example, the
loading of L-epinephrine freebase. In some embodiments the dry
drug, for example, L-epinephrine freebase is ground using a mortar
and pestle to decrease the particle size and improve the
dissolution rate. In some embodiments the L-epinephrine freebase is
ground using another means.
[0018] In some embodiments, aspects of the invention relate to a
method of delivering a drug (e.g., epinephrine) to a subject by
dissolving and/or rehydrating and/or mixing a dry composition
(e.g., a dry epinephrine) with a solution sufficient to dissolve
the dry drug (e.g., to dissolve at least 50%, at least 60%, at
least 70%, at least 80%, at least 90%, around 95%, or 90-100% of
the dry drug), and delivering the dissolved drug (and, in some
embodiments, some quantity of undissolved drug) to a subject via
injection (e.g., immediately after dissolving the drug). In some
embodiments, this can be accomplished by preloading an autoinjector
with a dry drug and a solution to dissolve the dry drug and causing
mixing and dissolution of the drug by activating the autoinjector.
In some embodiments, the solution to dissolve the dry drug is pH
optimized with a buffer. Where pH optimized means a pH that will
result in the dissolution of the various forms of epinephrine. In
some embodiments the buffer is an acid. In some embodiments the
buffer is hydrochloric acid. In some embodiments and epinephrine
solution is administered. In some embodiments, an L-epinephrine
solution is administered. In some embodiments, an epinephrine salt
solution is administered. In some embodiments, the epinephrine salt
is a maleate, malate, fumarate, acid tartrate, hydrogen tartrate,
or sulfate salt of epinephrine. In some embodiments, the
epinephrine salt is epinephrine HCl, epinephrine bitartrate, or
epinephrine borate. In some embodiments, the mixing is performed in
an autoinjector prior to injection. In some embodiments, the mixing
is performed in a prefilled syringe prior to injection. In some
embodiments, the subject is a human subject. In some embodiments,
the subject is non-human.
[0019] In another aspect, the present disclosure provides methods
to prepare a medical solution by utilizing the energy released from
the ingredients of the solution to dissolve the therapeutic
compounds.
[0020] In one aspect, provided herein is a method of preparing a
medical solution from a dry medicament composition. Such method
comprises mixing a first liquid with a second liquid to generate a
mixture. In some embodiments, the mixing of the two liquids
generates heat to promote solubility of a dry medicament in the
mixture. In some embodiments, the first and second liquids are
mixed together before contacting the dry medicament composition.
However, it should be appreciated that in some embodiments, one of
the liquids can be contacted to the dry medicament composition
before being mixed with the other liquid, or both liquids and the
dry medicament composition can all be mixed together simultaneously
as aspects of the disclosure are not limited in this respect.
[0021] In another aspect, provided herein is a medical kit
comprising a dry medicament, a first liquid, and a second liquid.
In some embodiments, heat is produced from mixing the first liquid
and the second liquid to promote solubility of the dry medicament
in the mixture.
[0022] In another aspect, provided herein is a method of preparing
a medical solution comprising mixing a solid component with a
liquid to generate a solution. The mixing of the solid component
and the liquid would generate heat to promote solubility of a dry
medicament in the solution.
[0023] In another aspect, provided herein is a medical kit
comprising a dry medicament and a liquid. Heat would be produced
from mixing the dry medicament with the liquid to promote
solubility of the dry medicament in the mixture.
DETAILED DESCRIPTION OF FIGURES
[0024] FIG. 1 illustrates a method for a single-stage mixing and
injection process.
[0025] FIGS. 2A-B illustrate a two-step mixing and then injecting
the mixed or dissolved solution.
[0026] FIG. 3 illustrates a multi-step dissolution method including
a fast dissolution step followed by a pH adjusting step causing the
solution to be suitable for injecting.
[0027] FIG. 4 shows a non-limiting embodiment of an injection
system 20 using the inventive methods.
[0028] FIGS. 5A and 5B illustrate a non-limiting embodiment of a
dual wet chamber injection device configured to hold the first
liquid and the second liquid that combine to form an exothermic
reaction to aid in dissolving the dry medicament in a fluidic
channel.
[0029] FIG. 6 shows a non-limiting embodiment of an injection
system 300 using the inventive methods.
[0030] FIG. 7 is a non-limiting embodiment of a sectional view of
an enlarged portion of an exemplified mixer.
[0031] FIG. 8 shows a non-limiting embodiment of an injection
device equipped with a heat exchanger in the form of the tube coil
around the dry medicament vial. Heat may be activated via mixing
multiple liquids and/or mixing at least one liquid with at least
one solid component.
[0032] FIG. 9 shows a non-limiting embodiment of an injection
device equipped with a heat exchanger having a jacket around the
vial containing the dry medicament. Heat may be activated via
mixing multiple liquids and/or mixing at least one liquid with at
least one solid component.
[0033] FIG. 10 shows a non-limiting embodiment of an injection
device equipped with a microfluidic heat exchanger. Heat may be
activated via mixing multiple liquids and/or mixing at least one
liquid with at least one solid component through a microfluidic
channel. The microfluidic channel is in the form of a closed loop,
separate from the mixing channel of the medicament constituents.
The exemplified injection device shows heat generated from mixing
two liquid reactants. It is understood that the exemplified
microfluidic heat exchanger can also be applied to transferring the
heat generated from mixing at least one liquid with at least one
solid component. A plurality of vials may be added to accommodate
more heat-generating components.
[0034] FIG. 11 shows a non-limiting embodiment of an injection
device equipped with a microfluidic heat exchanger. Heat may be
activated via mixing multiple liquids and/or mixing at least one
liquid with at least one solid component through a microfluidic
channel. The exemplified injection device shows heat generated from
mixing the liquid and the solid component. It is understood that
the exemplified microfluidic heat exchanger can also be applied to
transferring the heat generated from mixing liquids. A plurality of
vials may be added to accommodate more heat-generating
components.
DETAILED DESCRIPTION
[0035] Provided herein are methods of preparing a medical solution
comprising a therapeutic agent. In some embodiments, aspects of the
invention relate to stabilizing a drug and making it less
susceptible to temperature-induced degradation, by preparing a dry
composition (e.g., a dry salt form) of the drug that can be readily
reconstituted (e.g., in the context of an autoinjector) for
delivery to a patient.
[0036] The dry composition can be prepared from any suitable method
as used in the pharmaceutical formulation. For example, a drug may
be chemically derived, lyophilized (freeze-dried) and/or spray
dried and/or using any other technique to put the drug and/or
medicament into a dry form. However, in some embodiments, it is
important that the dried drug be easily and rapidly soluble so that
the dry composition can be used in an autoinjector that also
contains a liquid component that can be mixed with the dry drug to
solubilize it upon activation of the autoinjector (e.g.,
immediately prior to or at the time of injection).
[0037] There are many common drug formulations that contain
epinephrine in some form, including those used to treat cardiac
arrest as well as anaphylaxis. Due to the insolubility of
epinephrine freebase, finished dosage forms of epinephrine used in
healthcare are typically formulated using an acid to form
hydrochloride, bitartrate, or borate salts.
[0038] Epinephrine freebase is only sparingly soluble in water,
while some epinephrine salts dissolve readily. Epinephrine
freebase, however, becomes more soluble when properly pH adjusted
with an acid, like with hydrochloric acid, to a pH below 6, a pH
below 5, a pH between 2-5, a pH between 1-5. Adding metabisulfite
to the solution also helps epinephrine freebase dissolve more
readily into solution. When used in drug applications, epinephrine
is usually administered as a salt dissolved in water, or the
equivalent, to form a solution.
[0039] In some embodiments, aspects of the invention relate to a
dried epinephrine composition. In some embodiments, a composition
includes a chemically derived, lyophilized, spray dried, vacuum
dried or other method for making a dry composition of matter that
includes one or more or all of the following components:
epinephrine, an acid or epinephrine along with an acid, sodium
chloride or other salt or compound added to adjust tonicity, sodium
metabisulfite or other antioxidant and/or manitol. The acid can be
of a number of embodiments like hydrochloric acid, sulfuric acid,
phosphoric acid, maleic acid and others.
[0040] In some embodiments, a dried (e.g., freeze dried) form of
(-)-epinephrine Hydrochloride (EpiHCl) is used. It should be
appreciated that (-)-epinephrine is also referred to as
L-epinephrine. By drying (e.g., freeze-drying) the active
ingredient it may be readily soluble in water. Free-base
Epinephrine formulated in medical solutions utilizes hydrochloric
acid for dissolution, which effectively converts the free base into
a soluble salt in solution. The reconstitution of (-)-Epinephrine
Hydrochloride as described herein (e.g., in the context of an
autoinjector) is therefore equivalent to a formulation of
epinephrine base using hydrochloric acid.
[0041] In one embodiment, L-epinephrine freebase is placed inside
an autoinjector, for example, in one chamber. A solution that is pH
optimized with HCl, or any other acid is placed in another chamber.
In one embodiment, the HCl solution is of 1M or higher. In some
embodiments, the HCl solution is of 0.1M or higher. In some
embodiments, the HCl solution is of 0.01M or higher. In some
embodiments, the HCl solution is of 0.001M or higher. In some
embodiments, the HCl solution is of 0.0001M or higher. In some
embodiments, the HCl solution is of 0.00001M or higher. In some
embodiments, the HCl solution is of 0.000001M or higher.
[0042] In one embodiment, additional components like metabisulfite,
sodium chloride and other materials may also be included in the
solution for dissolving the epinephrine. In one embodiment, the
autoinjector is activated and/or fluid communication is created
between the pH optimized solution and the epinephrine freebase
causing the epinephrine freebase to dissolve readily into solution
and be injected into the patient, all in one step (FIG. 1).
[0043] In another embodiment, the dissolving of epinephrine
freebase happens in one step and the dissolved solution is held
inside the autoinjector or prefilled syringe until a subsequent
step and/or input from the user causes the liquid dose of
epinephrine to be injected into the body (FIGS. 2A and 2B).
[0044] In one embodiment, the epinephrine freebase is dissolved
into solution using a first solution (e.g., a pH optimizing
solution) so the pH of the dissolved material is below a pH of 6,
is below a pH of 5, is below a pH of 4, is below a pH of 3, is
below a pH of 2, is between a pH of 2-5. In one embodiments, the
dissolved epinephrine solution is secondly adjusted with a second
solution (e.g., a pH adjusting solution) so the final pH is
physiologically acceptable for administration.
[0045] In certain embodiments, the first solution (e.g., the pH
optimizing solution) has a pH that is capable of dissolving or
solubilizing a medicament dry power (e.g., an epinephrine dry
powder). In certain embodiments, the first solution comprises an
acid. In certain embodiments, the first solution comprises a base.
In certain embodiments, the first solution comprises a buffer.
[0046] In certain embodiments, the second solution (e.g., the pH
adjusting solution) is capable of adjusting the pH of the
medicament solution (e.g., the epinephrine solution), for example
to result in a pH that is physiologically acceptable. In certain
embodiments, the second solution comprises an acid. In certain
embodiments, the second solution comprises a base. In certain
embodiments, the second solution comprises a buffer.
[0047] In some embodiments, a buffer for adjusting the pH of the
dissolved solution is contained inside a reservoir to receive the
dissolved solution. For example, this buffer may exist to increase
the pH of the dissolved solution above a pH of 2 if a pH upon
dissolution drops below a pH of 2. In one embodiment, the pH
adjusting solution is water. In one embodiment the pH adjusting
solution is a base. In one embodiment, the pH adjusting solution is
sodium hydroxide. By adjusting the pH through the pH adjusting
buffer, the solution becomes suitable for injection.
[0048] In some embodiments, the components of each solution are
weighed and measured so that the final concentration of therapeutic
agent or medicament (e.g., L-epinephrine) in solution is 1 mg/ml.
In one embodiment, the final concentration of therapeutic agent or
medicament (e.g., L-epinephrine) is between 0.8 mg/ml and 1.2
mg/ml. In one embodiment, the final concentration of therapeutic
agent or medicament (e.g., L-epinephrine) is between 0.7 mg/ml and
1.3 mg/ml. In some embodiments, the final concentration of
therapeutic agent or medicament (e.g., L-epinephrine) is less than
0.8 mg/ml, for example less than 0.7 mg/ml. In some embodiments,
the final concentration of therapeutic agent or medicament (e.g.,
L-epinephrine) is greater than 1.2mg/ml, for example greater than
1.3 mg/ml.
[0049] In some embodiments, the concentration of one or more
components (e.g., one or more acids, bases, buffers, salts,
excipients, therapeutic agents, medicaments, drugs, or other
components described herein) ranges from 1 nM to 1 M, for example
from 1 nM to 1 .mu.M, from 1 .mu.m to 1 mM, from 1 mM to 10 mM,
from 10 mM to 100 mM, from 100 mM to 500 mM, from 500 mM to 1M,
about 1 mM, about 5 mM, about 10 mM, about 50 mM, about 100 mM,
about 500 mM, about 1M, or higher or lower depending on the
component and/or the application.
[0050] In some embodiments, aspects of the invention are useful for
preparing a dry drug form that a) is stable for extended periods of
time and b) can be rapidly dissolved and/or mixed and/or
reconstituted into a liquid form for injection. In some
embodiments, the dry drug composition is stored in an injector
housing along with a liquid that is separated from the dry
composition until activation. Activation can bring the liquid and
dry phases into contact using any suitable technique or combination
of channels, reservoir, seals, and/or electromechanical elements
that can be used to control the storage and mixing of the dry and
liquid phases.
[0051] In some embodiments, aspects of the invention relate to dry
epinephrine compositions. Like all medications, drugs or antidotes,
epinephrine has a lifetime over which it's acceptably effective,
beyond which it has potentially degraded and lost an unacceptable
amount of its potency. In addition, degradation of epinephrine can
be accelerated when subjected to large temperature fluctuations,
especially when the temperature exceeds its acceptable storage
temperature. According to aspects of the invention, epinephrine in
solution is particularly vulnerable to changes in environmental
conditions. For example, in order to maintain potency of an
epinephrine solution, a typical epinephrine auto-injector
manufacturer recommends that the device be stored at controlled
room temperature (20.degree. C.-25.degree. C. with allowable
temperature excursions as low as 15.degree. C. and as high as
30.degree. C.). If this temperature range is maintained accurately,
the epinephrine can remain stable for up to 20 months from the date
of manufacture. Any deviation of the epinephrine and/or
auto-injector outside of this recommended temperature range may
cause the epinephrine to lose potency resulting in an epinephrine
that is less effective and potentially insufficient for reversing
the effects of anaphylactic shock. In addition to thermal
instability, epinephrine may also degrade when exposed to light,
oxygen, and certain materials.
[0052] As used herein, a pH optimizing solution refers to a
solution that has the capacity to change the pH of a mixture. In
certain embodiments, a pH optimizing solution facilitates
dissolution of the dry medicament. In certain embodiments,
optimizing solution is an acid as generally described herein. In
certain embodiments, the optimizing solution is a base as generally
described herein. In certain embodiments, the pH optimizing
solution is a buffer.
[0053] As used herein, a pH adjusting solution is a solution that
can alter the pH value of a solution. In certain embodiments, the
pH adjusting solution adjusts the pH of the solution
physiologically acceptable pH suitable for administration. In
certain embodiments, the pH adjusting solution is an acid as
generally described herein. In certain embodiments, the pH
adjusting solution is a base as generally described herein. In
certain embodiments, the pH adjusting solution is a buffer as
generally described herein. In certain embodiments, the pH
adjusting solution is a salt.
[0054] As generally defined herein, an acid is a chemical substance
that dissociates in aqueous solution to give H.sup.+. In certain
embodiments, the acid is an organic acid. In certain embodiments,
the acid is an inorganic acid. Examples of the acids include, but
are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid,
4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic
acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic
acid, camphoric acid, camphor-10-sulfonic acid, capric acid,
caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric
acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic
acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, glycerophosphoric acid,
glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,
isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic
acid, malic acid, malonic acid, mandelic acid, methanesulfonic
acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic
acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic
acid, salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic
acid, or undecylenic acid. In some embodiments, the acid is
hydrochloric acid;, sulfuric acid;, phosphoric acid;, maleic acid;
1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid;
2-hydroxyethanesulfonic acid; 2-oxoglutaric acid;
4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic
acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid;
benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+);
capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic
acid (octanoic acid); carbonic acid; cinnamic acid; citric acid;
cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid;
ethanesulfonic acid; formic acid; fumaric acid; galactaric acid;
gentisic acid; glucoheptonic acid (D); gluconic acid (D);
glucuronic acid (D); glutamic acid; glutaric acid;
glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic
acid; hydrochloric acid; isobutyric acid; lactic acid (DL);
lactobionic acid; lauric acid; maleic acid; malic acid (-L);
malonic acid; mandelic acid (DL); methanesulfonic acid;
naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid;
nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic
acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic
acid (-L); salicylic acid; sebacic acid; stearic acid; succinic
acid; sulfuric acid; tartaric acid (+L); thiocyanic acid;
toluenesulfonic acid (p); or undecylenic acid. In some embodiments,
the acid is sulfuric acid, hydrochloric acid, hydrobromic acid,
nitric acid, phosphoric acid, perchloric acid, formic acid, acetic
acid, propionic acid, oxalic acid, maleic acid, citric acid,
succinic acid, malonic acid, tartaric acid, or combinations
thereof. In certain embodiments, the acid is hydrochloric acid,
nitric acid, sulfuric acid, phosphoric acid, tartaric acid, malic
acid, malonic acid, maleic acid, fumaric acid, succinic acid, or
formic acid.
[0055] As generally defined herein, a base is a chemical substance
that dissociates in aqueous solution to give OH.sup.-. In certain
embodiments, the base is an organic base. In certain embodiments,
the base is an inorganic base. In certain embodiments, the base is
an alkaline base. Examples of the bases include, but are not
limited to, sodium citrate, sodium acetate, sodium hydroxide,
potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium
hydroxide, magnesium hydroxide, iron hydroxide, zinc hydroxide,
copper hydroxide, manganese hydroxide, aluminum hydroxide,
isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, ethanolamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine,
histidine, caffeine, procaine, hydrabamine, choline, betaine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
purines, piperazine, piperidine, N-ethylpiperidine, tromethamine,
N-methylglucamine, or combinations thereof. In some embodiments,
the base is sodium hydroxide or potassium hydroxide.
[0056] As used herein, the term "buffer" refers to either a
buffering agent or a buffering solution comprising one or more
buffering agents. As generally defined herein, a buffering agent is
a weak acid or base used to maintain the pH of a solution near a
chosen value after the addition of another acid or base. The
function of a buffering agent is to prevent a rapid change in pH
when acids or bases are added to the solution. Exemplary buffering
agents include but are not limited to citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, and
mixtures thereof. In certain embodiments, the buffer is a sodium
salt, a calcium salt, a potassium salt, or an ammonium salt. In
certain embodiments, the buffer is a citrate, acetate, phosphate,
sulfate, nitrate, tartrate, succinate, malate, or maleate. In
certain embodiments, the buffer is sodium citrate, sodium acetate,
potassium hydroxide, potassium citrate, potassium acetate, sodium
succinate, or potassium succinate.
[0057] As used herein, the first liquid can be a solvent or a
solution. In some embodiments, the first liquid is a single
solvent. In some embodiments, the first liquid is a solution
comprising a pH optimizing agent and a single solvent. In some
embodiments, the first liquid comprises water. In some embodiments,
the first liquid comprises water and a pH optimizing agent. In some
embodiments, the pH optimizing agent is an acid as generally
defined herein. In some embodiments, the pH optimizing agent is
HCl. In some embodiments, the first liquid is an aqueous solution
comprising HCl. In some embodiments, the pH optimizing agent is a
base as generally defined herein. In some embodiments, the pH
optimizing agent is an alkaline base.
[0058] In some embodiments, the pH of the first liquid is from
about 0.1 to about 6.9. In some embodiments, the pH of the first
liquid is from about 0.5 to about 5.0. In some embodiments, the pH
of the first liquid is from about 1.0 to about 5.0. In some
embodiments, the pH of the first liquid is from about 2.0 to about
5.0. In one embodiment, the pH of the first liquid is from about
0.1 to about 6.0. In one embodiment, the pH of the first liquid is
from about 0.1 to about 5.0. In one embodiment, the pH of the first
liquid is from about 0.1 to about 4.0. In one embodiment, the pH of
the first liquid is from about 0.1 to about 3.0. In one embodiment,
the pH of the first liquid is from about 0.1 to about 2.0. In one
embodiment, the pH of the first liquid is from about 0.1 to about
1.0. In one embodiment, the pH of the first liquid is from about
0.01 to about 2.2 and the dry medicament is epinephrine.
[0059] In some embodiments, the pH of the first liquid is from
about 7.0 to about 13.5. In some embodiments, the pH of the first
liquid is from about 8.0 to about 13.5. In some embodiments, the pH
of the first liquid is from about 9.0 to about 13.5. In some
embodiments, the pH of the first liquid is from about 9.5 to about
13.5. In some embodiments, the pH of the first liquid is from about
9.5 to about 13.5 and the dry medicament is glucagon.
[0060] The disclosure further provides compositions of a medical
solution and methods for preparing a medical solution from a
therapeutic agent in a solid form over a short period of time
(e.g., a few minutes to a few seconds). Aspects of the disclosure
relate to generating energy (e.g., in the form of a change in
temperature) from mixing two or more ingredients of a medical
preparation and using that energy to help to prepare a solution of
a medicament that is suitable for administration to a subject.
[0061] Methods provided herein are advantageous in situations where
a drug in solid form does not dissolve readily upon contact with a
liquid. In such situations, typical preparative methods involve
additional time and energy (e.g., vigorous shaking over many
minutes) to dissolve and/or reconstitute a drug prior to
administration. This shaking may be detrimental in cases where
immediate drug delivery is required in an emergency setting. In
other cases, it may be difficult to produce a solution suitable for
administration within a prefilled syringe or an auto-injector,
e.g., where this type of reconstitution of a solid drug may produce
a foam or other form unsuitable for injection, or in cases where
the drug degrades during reconstitution. The present disclosure
overcomes disadvantages of shaking by utilizing energy (e.g., heat)
generated from mixing two or more ingredients (e.g., one liquid
component with another liquid component or solid component) of a
medical solution. The energy (e.g., heat) can be reabsorbed to
promote the dissolution of a dry medicament. The medical solutions
prepared from the methods described herein can be administered in
any route or by any device, for example, a prefilled syringe or an
autoinjector device (e.g., an EpiPen).
[0062] In one aspect, the invention provides a method of preparing
a medical solution from a dry medicament, comprising mixing a first
liquid with a second liquid to generate a mixture. The mixing of
the two liquids generates heat to promote solubility of the dry
medicament in the mixture. In certain embodiments, the invention
provides a method of preparing a medical solution from a dry
medicament, comprising mixing a first liquid, a second liquid, and
at least another liquid to generate a mixture. The mixing of at
least two liquids generates heat to promote solubility of the dry
medicament in the mixture.
[0063] In some embodiments, the heat is released from an exothermic
chemical reaction from mixing the first liquid and the second
liquid. As used herein, an exothermic reaction is a chemical
reaction that releases energy in the form of light or heat. In some
embodiments, the heat is released in the range of about 0 kcal to
5000 kcal per mol of the therapeutic agent. In some embodiments,
the heat is released in the range of about 0 kcal to 3000 kcal per
mol of the therapeutic agent. In some embodiments, the heat is
released in the range of about 0 kcal to 1000 kcal per mol of the
therapeutic agent. In some embodiments, the heat is released in the
range of about 0 kcal to 500 kcal per mol of the therapeutic agent.
In some embodiments, the heat is released in the range of about 0
kcal to 300 kcal per mol of the therapeutic agent. In some
embodiments, the heat is released in the range of about 0 kcal to
100 kcal per mol of the therapeutic agent. In some embodiments, the
heat is released in the range of about 0 kcal to 50 kcal per mol of
the therapeutic agent. In some embodiments, the heat is released in
the range of about 0 kcal to 30 kcal per mol of the therapeutic
agent. In some embodiments, the heat is released in the range of
about 0 kcal to 20 kcal per mol of the therapeutic agent. In some
embodiments, the heat is released in the range of about 0 kcal to
10 kcal per mol of the therapeutic agent. In some embodiments, the
released heat is at least about 1 kcal per mol of the therapeutic
agent. In some embodiments, the released heat is at least about 5
kcal per mol of the therapeutic agent. In some embodiments, the
released heat is at least about 10 kcal per mol of the therapeutic
agent. In some embodiments, the released heat is at least about 20
kcal per mol of the therapeutic agent. In some embodiments, the
released heat is at least about 30 kcal per mol of the therapeutic
agent. In some embodiments, the released heat is at least about 40
kcal per mol of the therapeutic agent. In some embodiments, the
released heat is at least about 50 kcal per mol of the therapeutic
agent. In some embodiments, the released heat is at least about 1
kcal per mol of the therapeutic agent and at most about 100 kcal
per mol of the therapeutic agent. In some embodiments, the released
heat is at least about 5 kcal per mol of the therapeutic agent and
at most about 100 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 10 kcal per mol of
the therapeutic agent and at most about 100 kcal per mol of the
therapeutic agent. In some embodiments, the released heat is at
least about 20 kcal per mol of the therapeutic agent and at most
about 100 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 30 kcal per mol of
the therapeutic agent and at most about 100 kcal per mol of the
therapeutic agent. In some embodiments, the released heat is at
least about 40 kcal per mol of the therapeutic agent and at most
about 100 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 50 kcal per mol of
the therapeutic agent and at most about 100 kcal per mol of the
therapeutic agent. It should be appreciated that the amount of
energy released per mol of the therapeutic agent can be determined
by providing an appropriate ratio of heat generating reagents
(e.g., first and second solutions or a liquid and a solid
component) to the therapeutic agent. The heat or energy is released
from mixing of the heat generating reagents (e.g., first and second
solutions or a liquid and a solid component) as described herein.
In some embodiments, the heat is reabsorbed in dissolution of the
dry medicament in the mixture.
[0064] In some embodiments, the dry medicament is subsequently
added to the mixture formed by the first liquid and the second
liquid. In some embodiments, the dry medicament is added to the
first liquid before the first liquid is mixed with the second
liquid.
[0065] As used herein, the dry medicament can be of any solid form.
In some embodiments, the dry medicament is a powder. In some
embodiments, the powdered form of the dry medicament is prepared
from lyophilizing a liquid medication. In some embodiments, the
powdered form of the dry medicament is prepared from spray-drying,
vacuum drying, or chemically precipitating out of a medical
solution. In some embodiments this dry medicament is amorphous. In
another embodiment this dry medicament is crystalline. In some
embodiments the dry medicament can form a porous matrix. In some
embodiments the dry medicament can form a loose assemblage of
powder. In some embodiments the dry medicament can form a loose
assemblage of porous matrix. In some embodiments the dry medicament
can form a loose assemblage of powder with particles (e.g., in the
size of about 1 nm to about 1000 .mu.m). In some embodiments, the
dry medicament can form a loose assemblage of powder with the
particle size ranging from about 1 nm to about 500 .mu.m. In some
embodiments, the dry medicament can form a loose assemblage of
powder with the particle size ranging from about 1 nm to about 100
.mu.m. In some embodiments, the dry medicament can form a loose
assemblage of powder with the particle size ranging from about 1 nm
to about 50 .mu.m. In some embodiments, the dry medicament can form
a loose assemblage of powder with the particle size ranging from
about 1 nm to about 10 .mu.m. In some embodiments, the dry
medicament can form a loose assemblage of powder with the particle
size ranging from about 1 nm to about 1 .mu.m. In some embodiments,
the dry medicament can form a loose assemblage of powder with the
particle size ranging from about 1 nm to about 500 nm. In some
embodiments, the dry medicament can form a cake consisting of a
porous matrix with particles (e.g., in the size of about 1 nm to
about 1000 .mu.m). In some embodiments, the dry medicament can form
a cake consisting of a porous matrix with the particle size ranging
from about 1 nm to about 500 .mu.m. In some embodiments, the dry
medicament can form a cake consisting of a porous matrix with the
particle size ranging from about 1 nm to about 100 .mu.m. In some
embodiments, the dry medicament can form a cake consisting of a
porous matrix with the particle size ranging from about 1 nm to
about 50 .mu.m. In some embodiments, the dry medicament can form a
cake consisting of a porous matrix with the particle size ranging
from about 1 nm to about 10 .mu.m. In some embodiments, the dry
medicament can form a cake consisting of a porous matrix with the
particle size ranging from about 1 nm to about 1 .mu.m. In some
embodiments, the dry medicament can form a cake consisting of a
porous matrix with the particle size ranging from about 1 nm to
about 500 nm. In some embodiments, the dry medicament can form a
cake consisting of a porous matrix with the particle size ranging
from about 1 nm to about 100 nm.
[0066] In some embodiments, the dry medicament comprises one
therapeutic agent. In some embodiments, the dry medicament
comprises two or more therapeutic agents. In some embodiments, the
dry medicament comprises one therapeutic agent and a
pharmaceutically acceptable excipient. In some embodiments, the dry
medicament comprises two or more therapeutic agents and a
pharmaceutically acceptable excipient.
[0067] As used herein, a therapeutic agent refers to a substance
used for the treatment, prevention, cure or mitigation of disease
or illness, by affecting the structure or function of the body. The
therapeutic agents include pro-drugs, which become biologically
active or more active after they have been placed in a
predetermined physiological environment. Examples of therapeutic
agents include, but are not limited to, small-molecule drugs,
peptides, proteins, antibodies, sugars, polysaccharides,
nucleotides, oligonucleotides, aptamers, siRNA, nucleic acids, and
combinations thereof.
[0068] In some embodiments, the therapeutic agent is an
anti-inflammatory agent, an antimicrobial agent, an antifungal
agent, an anti-parasitic agent, an anti-inflammatory agent, an
anti-cancer agent, an agent for treatment of a cardiovascular
disease, an agent for treatment of an allergy reaction, or a
pain-relieving agent. In some embodiments, the therapeutic agent is
an agent for treatment of an allergy reaction. In some embodiments,
the agent is for treatment of anaphylaxis. In some embodiments, the
agent is epinephrine.
[0069] Exemplified therapeutic agents include, but are not limited
to, anti-inflammatory, antipyretic, anti-spasmodics or analgesics
such as indomethacin, diclofenac, diclofenac sodium, codeine,
ibuprofen, phenylbutazone, oxyphenbutazone, mepirizole, aspirin,
ethenzamide, acetaminophen, aminopyrine, phenacetin,
butylscopolamine bromide, morphine, etomidoline, pentazocine,
fenoprofen calcium, naproxen, selecxip, valdecxip, and tolamadol,
anti-rheumatism drugs such as etodolac, anti-tuberculoses drugs
such as isoniazide and ethambutol hydrochloride, cardiovascular
drugs such as isosorbide dinitrate, nitroglycerin, nifedipine,
barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole,
amrinone, indenolol hydrochloride, hydralazine hydrochloride,
methyldopa, furosemide, spironolactone, guanethidine nitrate,
reserpine, amosulalol hydrochloride, lisinopril, metoprolol,
pilocarpine, and talcetin, antipsychotic drugs such as
chlorpromazine hydrochloride, amitriptyline hydrochloride,
nemonapride, haloperidol, moperone hydrochloride, perphenazine,
diazepam, lorazepam, chlorodiazepoxide, adinazolam, alprazolam,
methylphenidate, myrnasipran, peroxetin, risperidone, and sodium
valproate, anti-emetics such as metoclopramide, lamocetron
hydrochloride, granisetron hydrochloride, ondansetron
hydrochloride, and azacetron hydrochloride, antihistamines such as
chlorpheniramine maleate and diphenhydramine hydrochloride,
vitamins such as thiamine nitrate, tocopherol acetate,
cycothiamine, pyridoxal phosphate, cobarnamide, ascortic acid, and
nicotinamide, anti-gout drugs such as allopurinol, colchicine, and
probenecide, anti-Parkinson's disease drugs such as levodopa and
selegrine, sedatives and hypnotics such as amobarbital, bromuralyl
urea, midazolam, and chloral hydrate, antineoplastics such as
fluorouracil, carmofur, acralvidine hydrochloride,
cyclophosphamide, and thiodepa, anti-allergy drugs such as
pseudoephedrine and terfenadine, decongestants such as
phenylpropanolamine and ephedorine, diabetes mellitus drugs such as
acetohexamide, insulin, tolbutamide, desmopressin, and glipizide,
diuretics such as hydrochlorothiazide, polythiazide, and
triamterene, bronchodilators such as aminophylline, formoterol
fumarate, and theophylline, antitussives such as codeine phosphate,
noscapine, dimorfan phosphate, and dextromethorphan,
anti-arrhythmics such as quinidine nitrate, digitoxin, propafenone
hydrochloride, and procainamide, topical anesthetics such as ethyl
aminobenzoate, lidocaine, and dibucaine hydrochloride,
anti-convulsants such as phenyloin, ethosuximide, and primidone,
synthetic glucocorticoids such as hydrocortisone, prednisolone,
triamcinolone, and betamethasone, antiulceratives such as
famotidine, ranitidine hydrochloride, cimetidine, sucralfate,
sulpiride, teprenone, plaunotol, 5-aminosalicylic acid,
sulfasalazine, omeprazole, and lansoprazol, central nervous system
drugs such as indeloxazine, idebenone, thiapride hydrochloride,
bifemelane hydrocide, and calcium homopantothenate,
antihyperlipoproteinemics such as pravastatin sodium, simvastatin,
lovastatin, and atorvastatin, antibiotics such as ampicillin
hydrochloride, phthalylsulfacetamide, cefotetan, and josamycin, BPH
therapeutic agents such as tamsulosin hydrochloride, doxazosin
mesylate, and terazosin hydrochloride, drugs affecting uterine
motility such as branylcast, zafylcast, albuterol, ambroxol,
budesonide, and reproterol, peripheral circulation improvers of
prostaglandin I derivatives such as beraprost sodium,
anticoagulants, hypotensives, agents for treatment of cardiac
insufficiency, agents used to treat the various complications of
diabetes, peptic ulcer therapeutic agents, skin ulcer therapeutic
agents, agents used to treat hyperlipemia, tocolytics, etc.
[0070] In certain embodiments, the therapeutic agent is selected
from the group consisting of Agrylin (anagrelide HCl), Akten
(lidocaine hydrochloride), Apokyn (apomorphine hydrochloride),
Arestin (minocycline hydrochloride), Avandamet (rosiglitazone
maleate and metformin HCl), Avelox I.V. (moxifloxacin
hydrochloride), Cardizem (R) (Diltiazem HCl for injection),
Contrave (naltrexone HCl and bupropion HCl), Gemzar (gemcitabine
HCL), Hycamtin (topotecan hydrochloride), Lamisil (terbinafine
hydrochloride), Metozolv ODT (metoclopramide hydrochloride),
Namenda (memantine HCl), Paxil (paroxetine hydrochloride), Oxecta
(oxycodone HCl), Quillivant XR (methylphenidate hydrochloride),
Redux (dexfenfluramine hydrochloride), Relpax (eletriptan
hydrobromide), Reminyl (galantamine hydrobromide), Renagel
(sevelamer hydrochloride), Requip (ropinirole hydrochloride),
Ritalin LA (methylphenidate HCl), Savella (milnacipran
hydrochloride), Strattera (atomoxetine HCl), Tasigna (nilotinib
hydrochloride monohydrate), Tiazac (diltiazem hydrochloride),
Valcyte (valganciclovir HCl), Valtrex (valacyclovir HCl), VERSED
(midazolam HCI), Zanaflex (tizanidine hydrochloride), Zingo
(lidocaine hydrochloride monohydrate), Ziprasidone (ziprasidone
hydrochloride), Zoloft (sertraline HCl), Zometa (zoledronic acid),
Zyrtec (cetirizine HCl), glucagon, or sumatriptan.
[0071] Pharmaceutically acceptable excipients include any and all
diluents, dispersions, suspension aids, surface active agents,
isotonic agents, thickening or emulsifying agents, preservatives,
solid binders, lubricants, and the like, as suited to the
particular dosage form desired. General considerations in
formulation and/or manufacture of pharmaceutical compositions
agents can be found, for example, in Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980), and Remington: The Science and Practice of
Pharmacy, 21st Edition (Lippincott Williams & Wilkins,
2005).
[0072] As used herein, the first liquid can be a solvent or a
solution. In some embodiments, the first liquid is a single
solvent. In some embodiments, the first liquid is a solution
comprising a solute and a single solvent. In some embodiments, the
first liquid is a solution comprising two or more solvents. In some
embodiments, the first liquid comprises a solvent and a cosolvent.
In some embodiments, the first liquid comprises water. In some
embodiments, the first liquid is water. In some embodiments, the
first liquid is an aqueous solution. In some embodiments, the first
liquid comprises a non-aqueous solvent, for example, a polar
solvent (e.g., dimethyl sulfoxide, ethyl acetate, n-butanol,
ethanol, isopropanol, or n-propanol), or a non-polar solvent (e.g.,
alkane hydrocarbons such as hexane). In some embodiments, the first
liquid comprises water and a cosolvent. Examples of cosolvent that
can be used with water are PEG 300, propylene glyco or ethanol.
[0073] In some embodiments, the first liquid can further comprise a
non-therapeutic agent. In some embodiments, the first liquid is an
aqueous solution comprising a non-therapeutic agent. The
non-therapeutic agent acts to modify the solubility of at least one
therapeutic agent. In some embodiments, the non-therapeutic agent
is an acid. In some embodiments, the non-therapeutic agent is a
pharmaceutically acceptable acid. In some embodiments, the
non-therapeutic agent is a pharmaceutically acceptable organic
acid. In some embodiments, the non-therapeutic agent is a
pharmaceutically acceptable inorganic acid. Examples of the acids
for the non-therapeutic agents include, but are not limited to,
1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,
2-hydroxyethanesulfonic acid, 2-oxoglutaric acid,
4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic
acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic
acid, camphoric acid, camphor-10-sulfonic acid, capric acid,
caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric
acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic
acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, glycerophosphoric acid,
glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,
isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic
acid, malic acid, malonic acid, mandelic acid, methanesulfonic
acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic
acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic
acid, salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic
acid, or undecylenic acid. In some embodiments, the acid is
sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid,
phosphoric acid, perchloric acid, formic acid, acetic acid,
propionic acid, oxalic acid, maleic acid, citric acid, succinic
acid, malonic acid, tartaric acid, or combinations thereof.
[0074] In some embodiments, the pH of the first liquid is less than
about 0.1. In some embodiments, the pH of the first liquid is from
about 0.1 to about 6.9. In some embodiments, the pH of the first
liquid is from about 0.5 to about 5.0. In some embodiments, the pH
of the first liquid is from about 1.0 to about 5.0. In some
embodiments, the pH of the first liquid is from about 2.0 to about
5.0. In some embodiments, the pH of the first liquid is from about
2.0 to about 4.0.
[0075] As used herein, the second liquid can be a solvent or a
solution. In some embodiments, the second liquid is a single
solvent. In some embodiments, the second liquid is a solution
comprising a solute and a single solvent. In some embodiments, the
second liquid is a solution comprising two or more solvents. In
some embodiments, the second liquid comprises a solvent and a
cosolvent. In some embodiments, the second liquid comprises water.
In some embodiments, the second liquid is water. In some
embodiments, the second liquid is an aqueous solution. In some
embodiments, the second liquid comprises a non-aqueous solvent, for
example, a polar solvent (e.g., dimethyl sulfoxide, ethyl acetate,
n-butanol, ethanol, isopropanol, or n-propanol), or a non-polar
solvent (e.g., alkane hydrocarbons such as hexane). In some
embodiments, the second liquid comprises water and a cosolvent.
Examples of cosolvent that can be used with water are PEG 300,
propylene glycol or ethanol.
[0076] In some embodiments, the second liquid further comprises a
non-therapeutic agent. In some embodiments, the second liquid is an
aqueous solution comprising a non-therapeutic agent. In some
embodiments, the non-therapeutic agent in the second liquid acts to
modify the pH of the first liquid upon mixing. In some embodiments,
the non-therapeutic agent in the second liquid is a base. In some
embodiments, the non-therapeutic agent in the second liquid is a
pharmaceutically acceptable base. In some embodiments, the
non-therapeutic agent is a pharmaceutically acceptable organic
base. In some embodiments, the non-therapeutic agent is a
pharmaceutically acceptable inorganic base. In some embodiments,
the base is an alkaline base. Examples of the base that can be used
in the second liquid include, but are not limited to, sodium
hydroxide, potassium hydroxide, lithium hydroxide, ammonium
hydroxide, calcium hydroxide, magnesium hydroxide, iron hydroxide,
zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum
hydroxide, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, ethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,
lysine, arginine, histidine, caffeine, procaine, hydrabamine,
choline, betaine, ethylenediamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
tromethamine, N-methylglucamine, or combinations thereof. In some
embodiments, the base is LiOH, KOH, or NaOH.
[0077] In some embodiments, the pH of the second liquid is from
about 7.0 to about 14.0. In some embodiments, the pH of the second
liquid is from about 7.0 to about 12.0. In some embodiments, the pH
of the second liquid is from about 7.0 to about 10.0. In some
embodiments, the pH of the second liquid is from about 8.0 to about
10.0.
[0078] In some embodiments, the first liquid is an aqueous solution
comprising hydrochloric acid and the second liquid is an aqueous
solution comprising NaOH. In some embodiments, the first liquid is
an aqueous solution comprising hydrochloric acid and a dry
medicament, and the second liquid is an aqueous solution comprising
NaOH.
[0079] Upon medication administration, the dry medicament is often
dissolved and/or rehydrated into its liquid form before delivering
to a human or non-human patient. In some embodiments, the dry
medicament is subsequently added to the mixture formed by the first
liquid and the second liquid. In some embodiments, the dry
medicament is added to the first liquid prior to mixing with the
second liquid. In some embodiments, the dry medicament is added to
the second liquid prior to mixing with the first liquid. In some
embodiments, the first liquid is a solution comprising a dry
medicament. In some embodiments, the first liquid is an aqueous
solution comprising the dry medicament. In some embodiments, the
first liquid is an aqueous solution comprising a dry medicament and
an acid (e.g., sulfuric acid, hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, perchloric acid,
formic acid, acetic acid, propionic acid, oxalic acid, maleic acid,
citric acid, succinic acid or malonic acid, tartaric acid, or
combinations thereof). In some embodiments, the first liquid is a
solution comprising a dry medicament, a solvent and a cosolvent. In
some embodiments, the first liquid is a solution comprising a dry
medicament, a non-therapeutic agent, a solvent and a cosolvent.
[0080] The present invention overcomes the disadvantages of shaking
by utilizing the heat generated from mixing some ingredients of the
medical solution. In some embodiments, heat is released from mixing
the first liquid and the second liquid. In some embodiments, heat
is released from the exothermic reaction between the first liquid
and the second liquid. The exothermic reaction may be capable of
causing a change in the temperature of the solution(s). In some
embodiments, the exothermic reaction raises the temperature of the
solution(s) by about 1.degree. C., by about about 1.degree. C. to
about 2.degree. C., by about 2.degree. C., by about 2.degree. C. to
about 3.degree. C., by about 3.degree. C., by about 3.degree. C. to
about 4.degree. C., by about 4.degree. C., by about 4.degree. C. to
about 5.degree. C., by about 5.degree. C., by about 5.degree. C. to
about 10.degree. C., about 10.degree. C., by about 10.degree. C.,
or above 10.degree. C. relative to the temperature of the
solution(s) prior to mixing.
[0081] In some embodiments, heat is released from a first liquid
comprising an acid with a second liquid comprising a base. In some
embodiments, heat is released from mixing a first liquid comprising
a strong acid with a second liquid comprising a strong base. In
some embodiments, heat is released from mixing a first liquid
comprising a strong acid with a second liquid comprising a weak
base. In some embodiments, heat is released from mixing a first
liquid comprising a weak acid with a second liquid comprising a
strong base. In some embodiments, this would be accomplished by
mixing a first liquid comprising a weak acid with a second liquid
comprising a weak base. In some embodiments, this would be
accomplished by mixing a first liquid comprising an acid with a
second liquid comprising a buffer. In some embodiments, this would
be accomplished by mixing a first liquid comprising a buffer with a
second liquid comprising a base.
[0082] In some embodiments, the provided method mixes a first
liquid comprising an aqueous HCl solution with a second liquid
comprising an aqueous NaOH solution to promote solubility of
epinephrine freebase. Epinephrine freebase is not particularly
soluble in water. The solubility of epinephrine increases in an
acidic environment. In some embodiments, epinephrine freebase is
dissolved in an aqueous solution comprising HCl. Epinephrine
freebase can be protonated and fully dissolved upon adjustment of
the pH value of the solution.
[0083] In some embodiments, addition of a second liquid comprising
NaOH to the first liquid comprising epinephrine and HCl can further
increase the solubility of epinephrine. In certain embodiments,
addition of a second liquid comprising NaOH to the first liquid
comprising epinephrine and HCl can further increase the solubility
of epinephrine by increasing the temperature and thus increase the
solubility of the epinephrine at a higher pH than would normally be
achievable by adding HCl alone.
[0084] Relative amounts of the therapeutic agent and/or the
pharmaceutically acceptable excipient will vary, depending upon the
identity, size, and/or condition of the subject treated and further
depending upon the route by which the medical solution is to be
administered. By way of example, the medical solution may comprise
between 0.1% and 100% (w/w) one or more therapeutic agents.
[0085] The medical solution provided herein may comprises a
buffering agent. In some embodiments, the buffering agent is in the
first liquid. In some embodiments, the buffering agent is in the
second liquid. In some embodiment, the buffering agent is added
after the first liquid is mixed with the second liquid. Exemplary
buffering agents include citrate buffer solutions, acetate buffer
solutions, phosphate buffer solutions, ammonium chloride, calcium
carbonate, calcium chloride, calcium citrate, calcium glubionate,
calcium gluceptate, calcium gluconate, D-gluconic acid, calcium
glycerophosphate, calcium lactate, propanoic acid, calcium
levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric
acid, tribasic calcium phosphate, calcium hydroxide phosphate,
potassium acetate, potassium chloride, potassium gluconate,
potassium mixtures, dibasic potassium phosphate, monobasic
potassium phosphate, potassium phosphate mixtures, sodium acetate,
sodium bicarbonate, sodium chloride, sodium citrate, sodium
lactate, dibasic sodium phosphate, monobasic sodium phosphate,
sodium phosphate mixtures, tromethamine, magnesium hydroxide,
aluminum hydroxide, alginic acid, pyrogen-free water, isotonic
saline, Ringer's solution, ethyl alcohol, and mixtures thereof.
[0086] The provided medical solution can be delivered by
intradermal, intramuscular, intranasal, intravenous, oral, rectal,
subcutaneous, topical, or vaginal administration. In certain
embodiments, the provided medical solution is administered
intradermally or intramuscularly. Suitable devices for use in
delivering intradermal or intramuscular medical solution described
herein include conventional syringes or short needle devices such
as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;
5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and
5,417,662.
[0087] In some embodiments, the amount of a therapeutic agent in
the medical solution is an effective amount sufficient to elicit
the desired biological response, i.e., treat the condition. In some
embodiment, the amount of a therapeutic agent in the medical
solution is a therapeutically effective amount sufficient to
provide a therapeutic benefit in the treatment of a condition or to
delay or minimize one or more symptoms associated with the
condition. The term "therapeutically effective amount" can
encompass an amount that improves overall therapy, reduces or
avoids symptoms or causes of the condition, or enhances the
therapeutic efficacy of another therapeutic agent. In some
embodiments, the effective amount is prophylactically effective
amount sufficient to prevent a condition, or one or more symptoms
associated with the condition or prevent its recurrence.
[0088] As used herein, the effective amount of a therapeutic agent
will vary from subject to subject, depending, for example, on
species, age, and general condition of a subject, severity of the
side effects or disorder, identity of the particular compound(s),
mode of administration, and the like. The desired dosage can be
delivered three times a day, two times a day, once a day, every
other day, every third day, every week, every two weeks, every
three weeks, or every four weeks. In certain embodiments, the
desired dosage can be delivered using multiple administrations
(e.g., two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, or more administrations).
[0089] In certain embodiments, an effective amount of a compound
for administration one or more times a day to a 70 kg adult human
may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to
about 2000 mg, about 0.0001 mg to about 1000 g, about 0.001 mg to
about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to
about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100
mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg,
of a compound per unit dosage form.
[0090] In certain embodiments, the compounds of the invention may
be at dosage levels sufficient to deliver from about 0.001 from
about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg
to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from
about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1
mg/kg to about 25 mg/kg, of subject body weight per day, one or
more times a day, to obtain the desired therapeutic effect.
[0091] It will be appreciated that dose ranges as described herein
provide guidance for the administration of provided pharmaceutical
compositions to an adult. The amount to be administered to, for
example, a child or an adolescent can be determined by a medical
practitioner or person skilled in the art and can be lower or the
same as that administered to an adult.
[0092] In certain embodiments, provided herein is a medical kit
comprising a dry medicament, a first liquid, and a second liquid,
wherein mixing the first liquid and the second liquid produces heat
to promote solubility of the dry medicament in the mixture. In some
embodiments, provided kit may optionally further include a second
container comprising a pharmaceutical excipient for dilution or
suspension of the therapeutic agent. In some embodiments, the first
liquid, the second liquid, and the dry medicament are combined to
form one unit dosage form.
[0093] The invention provides a method of preparing a medical
solution from a dry medicament, comprising mixing a solid component
with a liquid to generate a solution. The mixing of the solid
component with a liquid generates heat to promote solubility of a
dry medicament in the solution.
[0094] In some embodiments, the heat is released from an exothermic
chemical reaction from mixing the solid component with the liquid.
In some embodiments, the heat is released in the range of about 0
kcal to 5000 kcal per mol of the therapeutic agent. In some
embodiments, the heat is released in the range of about 0 kcal to
3000 kcal per mol of the therapeutic agent. In some embodiments,
the heat is released in the range of about 0 kcal to 1000 kcal per
mol of the therapeutic agent. In some embodiments, the heat is
released in the range of about 0 kcal to 500 kcal per mol of the
therapeutic agent. In some embodiments, the heat is released in the
range of about 0 kcal to 300 kcal per mol of the therapeutic agent.
In some embodiments, the heat is released in the range of about 0
kcal to 100 kcal per mol of the therapeutic agent. In some
embodiments, the heat is released in the range of about 0 kcal to
50 kcal per mol of the therapeutic agent. In some embodiments, the
heat is released in the range of about 0 kcal to 30 kcal per mol of
the therapeutic agent. In some embodiments, the heat is released in
the range of about 0 kcal to 20 kcal per mol of the therapeutic
agent. In some embodiments, the heat is released in the range of
about 0 kcal to 10 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 1 kcal per mol of
the therapeutic agent. In some embodiments, the released heat is at
least about 5 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 10 kcal per mol of
the therapeutic agent. In some embodiments, the released heat is at
least about 20 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 30 kcal per mol of
the therapeutic agent. In some embodiments, the released heat is at
least about 40 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 50 kcal per mol of
the therapeutic agent. In some embodiments, the released heat is at
least about 1 kcal per mol of the therapeutic agent and at most
about 100 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 5 kcal per mol of
the therapeutic agent and at most about 100 kcal per mol of the
therapeutic agent. In some embodiments, the released heat is at
least about 10 kcal per mol of the therapeutic agent and at most
about 100 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 20 kcal per mol of
the therapeutic agent and at most about 100 kcal per mol of the
therapeutic agent. In some embodiments, the released heat is at
least about 30 kcal per mol of the therapeutic agent and at most
about 100 kcal per mol of the therapeutic agent. In some
embodiments, the released heat is at least about 40 kcal per mol of
the therapeutic agent and at most about 100 kcal per mol of the
therapeutic agent. In some embodiments, the released heat is at
least about 50 kcal per mol of the therapeutic agent and at most
about 100 kcal per mol of the therapeutic agent. It should be
appreciated that the amount of energy released per mol of the
therapeutic agent can be determined by providing an appropriate
ratio of heat generating reagents (e.g., first and second solutions
or a liquid and a solid component) to the therapeutic agent. The
heat or energy is released from mixing of the heat generating
reagents (e.g., first and second solutions or a liquid and a solid
component) as described herein. In some embodiments, the heat is
reabsorbed in the dissolution of the dry medicament in the
mixture.
[0095] In some embodiments, the solid component comprises a dry
medicament as defined herein. In some embodiments, the solid
component is separate from a dry medicament as defined herein.
[0096] In some embodiments, the liquid is one solvent. In some
embodiments, the liquid is a solution comprising two or more
solvents. In some embodiments, the liquid comprises a therapeutic
agent as described herein. In some embodiments, the liquid
comprises a non-therapeutic agent as described herein. In some
embodiments, the liquid comprises a base as defined herein. In some
embodiments, the liquid comprises an acid as described herein. In
some embodiments, the liquid is an aqueous solution comprising a
non-therapeutic agent. In some embodiments, the liquid is an
aqueous solution comprising a base. In some embodiments, the liquid
is an aqueous solution comprising an acid. In some embodiments, the
liquid is an aqueous solution comprising a cosolvent (as defined
herein) and a therapeutic agent. In some embodiments, the liquid is
an aqueous solution comprising a cosolvent (as defined herein) and
a non-therapeutic agent. In some embodiments, the liquid is an
aqueous solution comprising a cosolvent (as defined herein) and a
base. In some embodiments, the liquid is an aqueous solution
comprising a cosolvent (as defined herein) and an acid.
[0097] In some embodiments, heat is released from mixing the solid
component with the liquid. In some embodiments, heat is released
from the exothermic reaction of mixing the solid component and the
liquid. In some embodiments, the exothermic reaction involves a
neutralization reaction involving combination of an acid and a
base. For example, mixing a liquid comprising hydrochloric acid
with a solid component comprising sodium hydroxide.
[0098] In some embodiments, the solid component is mixed with the
liquid before the dry medicament is added. In some embodiments, the
dry medicament is added to the solid component prior to mixing with
the liquid.
[0099] It is understood that the provided methods can be applied to
configurations such as traditional syringe, auto-injector (e.g.,
EpiPen), pumps, or infusion systems. The provided methods can also
be practiced manually with vials. It is recognized that the
configuration can have insulation to contain the heat generated in
the mixing to promote solubility of the dry medicament.
[0100] In some embodiments, the inventive methods prepare medical
solutions that can be delivered in injector devices. In some
embodiments, the mixing is performed in an auto-injector prior to
injection. In some embodiments, the mixing is performed in a
prefilled syringe prior to injection. In some embodiments, an
injector device also contains a liquid reservoir that can be
accessed to deliver a fluid to the dry medicament in order to
solubilize and/or rehydrate and/or dissolve the drug immediately
prior to injection. In some embodiments, the injector is an
auto-injector that automatically mixes the dry medicament with the
fluid when the injector is activated.
[0101] In order that the invention described herein may be more
fully understood, the exemplified auto-injector devices to practice
the inventive methods are provided in FIGS. 1-11. It should be
understood that these exemplified devices are for illustrative
purposes only and are not to be construed as limiting this
invention in any manner.
[0102] The inventive methods can be used in a device with a single
mixing compartment, for example, in the form of a channel, conduit,
or chamber (see FIG. 4). The single-mixing compartment serves to
mix a first liquid, a second liquid, with a dry medicament to
generate a solution. The single-mixing compartment can also serves
to mix a liquid with a dry medicament to generate a solution. The
inventive methods can also be practiced in a device with multiple
mixing compartments, for example, two mixing compartments or three
mixing compartments.
[0103] An exemplified injection system 20 (FIG. 4) has a syringe 40
and a mixture 22 for holding a dry medicament. The syringe 40 has a
cylindrical tube 42 defining a volume 44. The cylindrical tube 42
of the syringe 40 tapers down to an outlet port 48. The syringe 40
has a plunger 50 with a depressing handle 52, a shaft 54, and a
piston 56 for forcing the liquid component 26 out of the outlet
port 48. The injector 30 is shown as a needle 60 as a part of the
mixer 22 although it can be separate from the mixer 22. The
injector 30 can also be a nozzle or tubing for delivery of the
mixed combined medicament 28.
[0104] Another exemplified injection system (FIG. 4) having the
mixer 22 with a housing 64 that defines an interior flow chamber 66
with an inlet 68 and an outlet 70. The mixer 22 with a single
channel, such as a microchannel 124, is shown. The micro-channel
124 of the mixing device 22 is a serpentine channel, which defines
a fluid pathway between the inlet 68 and the outlet 70. Fluid may
enter in and out of the outlet 70 as well as the inlet 68. The
serpentine channel 124 has two functions: the first function
enables miniaturization of the channel structure by bending the
fluid flow direction so that the channel can double back, thus a
longer channel more efficiently utilizes a smaller area. The second
function is that the natural flow becomes disrupted every time
there is a bend or elbow in the channel, which results in mixing
dependent on the cross section of the channel. In certain
embodiments, the liquid, is pushed through the mixer 22 and out of
the needle 60.
[0105] An exemplified dual-chamber device is shown in FIG. 5A and
FIG. 5B. In one embodiment of the dual-chamber device, a first
liquid and a second liquid can be mixed with a dry medicament
concurrently or sequentially to generate a medical solution. In
another embodiment of the dual-chamber device, a first liquid is
mixed with a dry medicament, followed by addition of the second
liquid. In another embodiment of the dual-chamber device, a second
liquid is mixed with a dry medicament, followed by addition of the
first liquid. In another embodiment of the dual-chamber device, a
first liquid and a second liquid are mixed independently of the dry
medicament. In some embodiments, the mixed liquids can be
transferred to a chamber that contains the dry medicament, and in
some embodiments the dry medicament can be added to a chamber that
contains the mixed liquids, as aspects of the disclosure are not
limited in this respect.
[0106] An exemplified injection system (FIGS. 5A and 5B) 1500 has a
pair of wet component containers 1516a and 1516b that contain a
first liquid 1508a and a second liquid 1508b which are mixed
together prior to mixing with a dry medicament. The syringe of the
system 1500 has a plunger 1502 with a pair of shafts 1504 that each
drive a plunger 1506 in a respective liquid component volume. As
the respective liquid components 1508a and 1508b are pushed through
their respective valve 1510a and 1510b, the two liquid components
mix in a wet mixing volume 1512 where a liquid mixture is formed.
As the plunger 1502 continues to push, the combined mixture flows
through a fluidic channel 1530 of a mixer 1520 that contains the
dry medicament. The combined medicament, which contains the dry
medicament within the combined liquid mixture, flows through the
needle 1540.
[0107] An exemplified tri-chamber device is shown in FIG. 6. In one
embodiment of a tri-chamber device, a first liquid, a second
liquid, and a third liquid, can be mixed with a dry medicament
concurrently or sequentially to generate a medical solution. In
another embodiment of a tri-chamber device, a first liquid is mixed
with a dry medicament, followed by addition of the second liquid
and the third liquid. In another embodiment of a tri-chamber
device, a second liquid is mixed with a dry medicament, followed by
addition of the first liquid and the third liquid. In another
embodiment of a tri-chamber device, a first liquid and a second
liquid are mixed followed by addition of the dry medicament and
subsequent addition of the third liquid. In another embodiment of a
tri-chamber device, a first liquid, a second liquid, and a third
liquid are mixed followed by addition of the dry medicament.
[0108] An exemplified injection system 300 (FIG. 6) has a mixer 302
with a container 310 for holding a third liquid 312. The system 300
has a syringe 320 having a pair of liquid component containers 322
and 324 that contain a first liquid 332 and a second liquid 334
which are mixed together prior to mixing with a dry medicament 24.
The syringe 320 of the system 300 has a plunger 350 with a pair of
shafts 352 and 354 that each drive a plunger 362 and 364 in a
respective liquid volume. As the respective liquids 332 and 334 are
pushed through their respective valves 336 and 338, the liquid
components mix in a wet mixing volume 340 where a combined liquid
mixture is formed. As the plunger 350 continues to push, the
combined liquid mixture flows through a fluidic channel 124 of the
mixer 302 that contains the dry medicament 24. The combined liquid
mixture that mixes with the dry medicament 24 may have exothermic
properties. This exothermic property may result in improved mixing
with the dry medicament 24.
[0109] An exemplified drug mixing system 700 (FIG. 7) can have
multiple conduits or channels and seals. The mixer 122 has an inlet
68 which opens into an inlet void 126. A plurality of channels 124
start at the inlet void 126 and end in an outlet void 128 at the
outlet 70. Each of the channels 124 has a circuitous path 130 with
various radiuses and chaos-inducing features. Each channel 124 can
have variations in the cross sectional area and characteristics of
the walls of the channel 124 to cause the flow of the liquid 26 to
mix thoroughly with the dry medicament.
[0110] It is understood that the inventive methods can be practiced
with a device where heat is provided externally. In some
embodiments, heat is provided from an external heating system to a
mixing device to practice the inventive methods. In some
embodiments, heat is provided from an external irradiation system
to a mixing device to practice the inventive methods. In some
embodiments, heat is provided from an external pressure system to a
mixing device to practice the inventive methods. In some
embodiments, heat is provided from physical means such as rubbing
to a mixing device to practice the inventive methods.
[0111] In some embodiments, heat is provided to dissolve the dry
medicament by directly contacting the dry medicament with the first
liquid and/or second liquid. In some embodiments, heat is provided
to dissolve the dry medicament by directly contacting the dry
medicament with a liquid and a solid component. In some
embodiments, the heat is provided by an exothermic reaction between
a first liquid and a second liquid or between a liquid and a solid
component. However, it should be appreciated that in some
embodiments, heat may be generated (e.g., in addition to or instead
of) by an exothermic reaction between the dry medicament and one or
more liquid and/or solid components that are mixed with the dry
medicament.
[0112] In some embodiments, heat is provided to dissolve the dry
medicament via a heat exchanger (e.g., from a source other than the
mixture that contains the dry medicament). In certain embodiments,
the heat exchanger is a microfluidic-scale heat exchanger. In some
embodiment, the heat exchanger transfers heat from mixing the first
liquid and second liquid to the dry medicament. In some embodiment,
the heat exchanger transfers heat from mixing the liquid and the
solid component to the dry medicament. In certain embodiments, the
heat-generating components (e.g. the first liquid and the second
liquid, or the liquid and the solid component) are stored in
separate containers, and mix in separate channels from the
medicament stream. In certain embodiments, the heat generating
reaction is contained in a closed-loop system of the heat exchanger
(see FIGS. 8-11). In some embodiments, the heat exchange is
accomplished by heating the liquid storage vial prior to injection,
or by heating the mixing channel via a microfluidic heat exchanger.
Microfluidic heat exchange may increase the rate of heat transfer.
In some embodiments, the closed loop system of the heat exchanger
may also evolve a gas, or heat contained gas (such as air), which
can be used to force the medicament injection process. In some
embodiments, upon initiation of the heat-producing exothermic
reaction, a byproduct from the reaction could be a gaseous species
to increase the pressure on the backside of the reactant plungers
shown in FIGS. 5-8. This gaseous byproduct would in turn provide
infusion force on the medicament plunger and thus assure that
injection is not made until heating has occurred and proper mixing
of the medicament is possible.
[0113] In some embodiments, a nurse and/or doctor would take two
vials: One of a dry medicament and one containing a solvent, for
example, sterile water for injection. The nurse and/or doctor would
then use a syringe to draw out the sterile water and subsequently
dispense the water into the vial of the dry medicament. The nurse
and/or doctor would then agitate the vial that now contains the
water and the dry medicament until all the medicament is in a
solution. The nurse and/or doctor would then draw the mixed and/or
dissolved liquid dose of the medicament into a syringe and then
inject the medical solution into the patient. In some embodiments,
the injection is carried out prior to giving medication orally. In
some embodiments, the injection is carried out prior to giving
medication through I/V. In some embodiments, the injection is
carried out prior to giving medication through the skin using a
topical delivery mechanism and/or any other method of introducing
drugs into a human and/or non-human where the compound would need
to be reconstituted before delivery.
[0114] In some embodiments, the dry medicament is prepared by
drying a drug solution e.g., by vacuum drying, freeze drying,
lyophilizing, or any suitable drying technique. In some embodiments
the dry drug is placed inside the autoinjector as a dry powder. In
some embodiments, a dry medicament may have any suitable particle
size that allows for efficient and rapid reconstitution. In some
embodiments, the particle size of the dry medicament can be
controlled by drying a drug solution within a confined volume. For
example, in some embodiments, a drug solution is dried within the
confines of a device, for example, an autoinjector. As a result,
the particle size of a dried drug composition may be one the order
of the diameter of a microfluidic channel (e.g., from about 1
micron to about 500 microns in diameter).
[0115] In some embodiments, the medical solution is administered to
a human subject. In some embodiments, the medical solution is
administered to a non-human subject.
[0116] In some embodiments, it should be appreciated that one or
more components of any injection system or device described herein
can be manufactured from any suitable material, for example
materials that are acceptable for delivery of a medicament to a
subject (e.g., a human subject). For example, one or more
components (e.g., a chamber, vial, plunger, container, channel,
tube, etc.) may be made of glass and/or biocompatible plastic or
polymer and/or metal and/or any other acceptable material and or
other materials acceptable by a regulatory body (such as the FDA)
or other approved bodies. It also should be appreciated that in
some embodiments one or more components of any injection system or
device described herein are of a size suitable for preparing and/or
injecting therapeutically acceptable volumes of medicament for
delivery to a subject (e.g., a human subject). For example, one or
more components (e.g., a chamber, vial, plunger, container,
channel, tube, etc.) may be of a size suitable for containing,
and/or preparing (e.g., mixing), and/or delivering (e.g., to a
subject, for example a human subject) between 0.01 ml and 2 ml of
solution, for example between 0.5 ml and 1 ml of solution, between
0.1 ml and 0.4 ml of solution, or around 0.1 ml, 0.2 ml, 0.3 ml,
0.4 ml, or 0.5 ml of solution.
[0117] In some embodiments, a dry composition described herein
and/or exemplified herein retains greater than 90% potency, greater
than 95% potency, between 90% and 100% potency, or between 90% and
115% potency when subjected to the following temperature exposure
of less than -30.degree. C., or between -30.degree. C. and
-25.degree. C., or less than -25.degree. C., or between -25.degree.
C. and -20.degree. C., or less than 20.degree. C., or between
-20.degree. C. and -15.degree. C., or less than -15.degree. C., or
between -15.degree. C. and -10.degree. C., or less than -10.degree.
C., or between -10.degree. C. and -5.degree. C., or less than
-5.degree. C., or between -5.degree. C. and 0.degree. C., or less
than 0.degree. C., or between 0.degree. C. and 5.degree. C., or
less than 5.degree. C., or between 5.degree. C. and 10.degree. C.,
or less than 10.degree. C., or between 10.degree. C. and 15.degree.
C., or less than 15.degree. C., or between 15.degree. C. and
20.degree. C. or less than 20.degree. C. or between 20.degree. C.
and 25.degree. C. or greater than 25.degree. C., or between
25.degree. C. and 30.degree. C., or greater than 30.degree. C. or
between 30.degree. C. and 35.degree. C., or greater than 35.degree.
C., or between 35.degree. C. and 40.degree. C., or greater than
40.degree. C., or between 40.degree. C. and 45.degree. C., or
greater than 45.degree. C., or between 45.degree. C. and 50.degree.
C., or greater than 50.degree. C., or between 50.degree. C. and
55.degree. C. or greater than 55.degree. C., or between 55.degree.
C. and 60.degree. C., or greater than 60.degree. C. for up to 1
year, 2 years, 3 years, 5 years, 7 years, for up to 10 years or for
greater than 10 years.
[0118] In some embodiments, after the L-epinephrine powder has been
dissolved in an injector device, the resulting solution retains a
potency greater than 90% potency, greater than 95% potency, between
90% and 100% potency, or between 90% and 115% potency even when the
dry L-Epinephrine has been previously subject to a temperature
exposure of less than -30.degree. C., or between -30.degree. C. and
-25.degree. C., or less than -25.degree. C., or between -25.degree.
C. and -20.degree. C., or less than -20.degree. C., or between
-20.degree. C. and -15.degree. C., or less than -15.degree. C., or
between -15.degree. C. and -10.degree. C., or less than -10.degree.
C., or between -10.degree. C. and -5.degree. C., or less than
-5.degree. C., or between -5.degree. C. and 0.degree. C., or less
than 0.degree. C., or between 0.degree. C. and 5.degree. C., or
less than 5.degree. C., or between 5.degree. C. and 10.degree. C.,
or less than 10.degree. C., or between 10.degree. C. and 15.degree.
C., or less than 15.degree. C., or between 15.degree. C. and
20.degree. C. or less than 20.degree. C. or between 20.degree. C.
and 25.degree. C. or greater than 25.degree. C., or between
25.degree. C. and 30.degree. C., or greater than 30.degree. C. or
between 30.degree. C. and 35.degree. C., or greater than 35.degree.
C., or between 35.degree. C. and 40.degree. C., or greater than
40.degree. C., or between 40.degree. C. and 45.degree. C., or
greater than 45.degree. C., or between 45.degree. C. and 50.degree.
C., or greater than 50.degree. C., or between 50.degree. C. and
55.degree. C. or greater than 55.degree. C., or between 55.degree.
C. and 60.degree. C., or greater than 60.degree. C. for up to 1
year, 2 years, 3 years, 5 years, 7 years, for up to 10 years or for
greater than 10 years.
[0119] In some embodiments, a dry composition described herein or
exemplified in the Examples retains a chiral purity greater than
60%, greater than 70%, greater than 75%, greater than 80%, greater
than 85%, greater than 90%, greater than 95%, 95% to 100%,
L-Epinephrine when subject to a temperature exposure of less than
-30.degree. C., or between -30.degree. C. and -25.degree. C., or
less than -25.degree. C., or between -25.degree. C. and -20.degree.
C., or less than -20.degree. C., or between -20.degree. C. and
-15.degree. C., or less than -15.degree. C., or between -15.degree.
C. and -10.degree. C., or less than -10.degree. C., or between
-10.degree. C. and -5.degree. C., or less than -5.degree. C., or
between -5.degree. C. and 0.degree. C., or less than 0.degree. C.,
or between 0.degree. C. and 5.degree. C., or less than 5.degree.
C., or between 5.degree. C. and 10.degree. C., or less than
10.degree. C., or between 10.degree. C. and 15.degree. C., or less
than 15.degree. C., or between 15.degree. C. and 20.degree. C. or
less than 20.degree. C. or between 20.degree. C. and 25.degree. C.
or greater than 25.degree. C., or between 25.degree. C. and
30.degree. C., or greater than 30.degree. C. or between 30.degree.
C. and 35.degree. C., or greater than 35.degree. C., or between
35.degree. C. and 40.degree. C., or greater than 40.degree. C., or
between 40.degree. C. and 45.degree. C., or greater than 45.degree.
C., or between 45.degree. C. and 50.degree. C., or greater than
50.degree. C., or between 50.degree. C. and 55.degree. C. or
greater than 55.degree. C., or between 55.degree. C. and 60.degree.
C., or greater than 60.degree. C. for up to 1 year, up to 2 years,
up to 3 years, up to 5 years, up to 7 years, up to 10 years or for
greater than 10 years.
[0120] In some embodiments, after the L-epinephrine powder has been
dissolved in an injector device, the resulting solution retains a
chiral purity greater than 60%, greater than 70%, greater than 75%,
greater than 80%, greater than 85%, greater than 90%, greater than
95%, 95% to 100%, even when the dry L-Epinephrine has been
previously subject to a temperature exposure of less than
-30.degree. C., or between -30.degree. C. and -25.degree. C., or
less than -25.degree. C., or between -25.degree. C. and -20.degree.
C., or less than -20.degree. C., or between -20.degree. C. and
-15.degree. C., or less than -15.degree. C., or between -15.degree.
C. and -10.degree. C., or less than -10.degree. C., or between
-10.degree. C. and -5.degree. C., or less than -5.degree. C., or
between -5.degree. C. and 0.degree. C., or less than 0.degree. C.,
or between 0.degree. C. and 5.degree. C., or less than 5.degree.
C., or between 5.degree. C. and 10.degree. C., or less than
10.degree. C., or between 10.degree. C. and 15.degree. C., or less
than 15.degree. C., or between 15.degree. C. and 20.degree. C. or
less than 20.degree. C. or between 20.degree. C. and 25.degree. C.
or greater than 25.degree. C., or between 25.degree. C. and
30.degree. C., or greater than 30.degree. C. or between 30.degree.
C. and 35.degree. C., or greater than 35.degree. C., or between
35.degree. C. and 40.degree. C., or greater than 40.degree. C., or
between 40.degree. C. and 45.degree. C., or greater than 45.degree.
C., or between 45.degree. C. and 50.degree. C., or greater than
50.degree. C., or between 50.degree. C. and 55.degree. C. or
greater than 55.degree. C., or between 55.degree. C. and 60.degree.
C., or greater than 60.degree. C. for up to 1 year, up to 2 years,
up to 3 years, up to 5 years, up to 7 years, up to 10 years or for
greater than 10 years.
EQUIVALENTS AND SCOPE
[0121] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The disclosure includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The disclosure includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0122] Furthermore, the disclosure encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the disclosure,
or aspects of the disclosure, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
disclosure or aspects of the disclosure consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the disclosure, to the tenth of the unit of the
lower limit of the range, unless the context clearly dictates
otherwise.
[0123] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present disclosure that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the disclosure can be excluded from any claim, for
any reason, whether or not related to the existence of prior
art.
[0124] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
disclosure, as defined in the following claims.
* * * * *