U.S. patent application number 13/453353 was filed with the patent office on 2012-08-16 for stable pharmaceutical formulations.
This patent application is currently assigned to Baxter Healthcare S.A.. Invention is credited to James E. Kipp, Reagan Miller, Lakshmy Nair, Barrett E. Rabinow, Joseph Chung Tak Wong.
Application Number | 20120207762 13/453353 |
Document ID | / |
Family ID | 40941781 |
Filed Date | 2012-08-16 |
United States Patent
Application |
20120207762 |
Kind Code |
A1 |
Kipp; James E. ; et
al. |
August 16, 2012 |
STABLE PHARMACEUTICAL FORMULATIONS
Abstract
Stable pharmaceutical formulations and methods of making same
are provided. In a general embodiment, the present disclosure
provides a method of making a stable pharmaceutical formulation
comprising adding one or more vitrifying additives to an aqueous
pharmaceutical solution to raise the glass transition temperature
of the aqueous pharmaceutical solution. The aqueous pharmaceutical
solution can be cooled to a temperature of about -50.degree. C. to
about -10.degree. C. The vitrifying additive enhances the formation
of a glass or amorphous solid of the aqueous pharmaceutical
solution at cryogenic temperatures (-50 to -10.degree. C.), and the
pharmaceutical formulation can be thawed to liquid form and
administered to a mammalian subject.
Inventors: |
Kipp; James E.; (Wauconda,
IL) ; Wong; Joseph Chung Tak; (Long Grove, IL)
; Nair; Lakshmy; (Vernon Hills, IL) ; Miller;
Reagan; (Wildwood, IL) ; Rabinow; Barrett E.;
(Skokie, IL) |
Assignee: |
Baxter Healthcare S.A.
Glattpark (Opfikon)
IL
Baxter International Inc.
Deerfield
|
Family ID: |
40941781 |
Appl. No.: |
13/453353 |
Filed: |
April 23, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12437679 |
May 8, 2009 |
8183233 |
|
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13453353 |
|
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61053301 |
May 15, 2008 |
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Current U.S.
Class: |
424/141.1 ;
514/210.13; 514/3.6 |
Current CPC
Class: |
A61P 31/10 20180101;
A61K 47/36 20130101; A61P 31/04 20180101; A61P 31/00 20180101; A61K
47/40 20130101; A61K 9/0019 20130101 |
Class at
Publication: |
424/141.1 ;
514/3.6; 514/210.13 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61P 31/00 20060101 A61P031/00; A61P 31/10 20060101
A61P031/10; A61K 31/407 20060101 A61K031/407; A61K 39/395 20060101
A61K039/395 |
Claims
1. A method of stabilizing a pharmaceutical agent without
lyophilization, the method comprising: combining a pharmaceutical
agent with water and at least one vitrifying additive to form an
aqueous pharmaceutical solution, the vitrifying additive being
present in an amount ranging from about 1% to about 30% effective
to enhance the formation of an amorphous solid of the aqueous
pharmaceutical solution when the aqueous pharmaceutical solution is
cooled to a temperature below a glass transition temperature of the
aqueous pharmaceutical solution; and cooling the aqueous
pharmaceutical solution to a temperature of about -25.degree. C. to
about -10.degree. C. to form the amorphous solid of the aqueous
pharmaceutical solution.
2. The method of claim 1, wherein the vitrifying additive is a
polyalcohol selected from polyethylene glycol, mannitol, sorbitol,
and combinations thereof.
3. The method of claim 1, wherein the vitrifying additive is a
disaccharide selected from the group consisting of sucrose,
trehalose, lactose, and combinations thereof.
4. The method of claim 1, wherein the vitrifying additive is
raffinose.
5. The method of claim 1, wherein the vitrifying additive is a
dextran with an average molecular weight of about 40,000.
6. The method of claim 1, wherein the pharmaceutical agent is an
echinocandin antifungal agent.
7. The method of claim 1, wherein the pharmaceutical agent
comprises an antifungal agent selected from caspofungin,
micafungin, anidulafungin, or a salt thereof.
8. A method of making a shelf-stable pharmaceutical agent without
lyophilization, the method comprising: combining a carbapenem with
water and a dextran to form an aqueous carbapenem solution, the
dextran being present in an amount ranging from about 1% to about
30% effective to give the carbapenem a shelf-life of at least 1
month; and cooling the aqueous carbapenem solution to a temperature
of about -25.degree. C. to about -10.degree. C. to form the
amorphous solid of the aqueous carbapenem solution.
9. The method of claim 8, wherein the shelf-stable carbapenem has a
shelf-life of least 3 months.
10. The method of claim 8, wherein the shelf-stable carbapenem has
a shelf-life of least 6 months.
11. A pharmaceutical formulation comprising: an aqueous
pharmaceutical solution comprising water and a pharmaceutical agent
that is unstable in aqueous solution at room temperature, and at
least one vitrifying additive, the vitrifying additive being
present in an amount effective to enhance the formation of an
amorphous solid of the aqueous pharmaceutical solution when the
aqueous pharmaceutical solution is cooled to a temperature below a
glass transition temperature of the aqueous pharmaceutical
solution.
12. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive is selected from the group consisting of
polyalcohols, polysaccharides, monosaccharides, disaccharides,
trisaccharides, aminosugars, amino derivatives of saccharides, and
combinations thereof.
13. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive comprises a polyalcohol selected from
polyethylene glycol, mannitol, sorbitol, and combinations
thereof.
14. The pharmaceutical formulation of claim 11 wherein the
vitrifying additive comprises a monosaccharide selected from the
group consisting of dextrose, fructose, and combinations
thereof.
15. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive comprises a disaccharide selected from the
group consisting of sucrose, trehalose, lactose and combinations
thereof.
16. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive comprises raffinose.
17. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive is a polysaccharide selected from the group
consisting of dextrans, cyclodextrins, and combinations
thereof.
18. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive is a 2-hydroxypropyl-beta-cyclodextrin.
19. The pharmaceutical formulation of claim 11, wherein the
vitrifying additive is a dextran with an average molecular weight
of about 40,000.
20. The pharmaceutical formulation of claim 11, wherein the
pharmaceutical agent is selected from the group consisting of
antibiotics, antifungal agents, monoclonal antibodies, plasma
proteins, and combinations thereof.
21. The pharmaceutical formulation of claim 11, wherein the
pharmaceutical agent is an antibiotic selected from the group
consisting of trimethoprims, polymyxin B sulfate, beta-lactams,
monobactams, oxazolidinones, macrolides, ketolides, tetracyclines,
streptogramins, and combinations thereof.
22. The pharmaceutical formulation of claim 20, wherein the
antibiotic is a beta-lactam antibiotic selected from the group
consisting of cephalosporins, penicillins, thienamycins,
carbapenems, penems, cephems, trinems, and combinations
thereof.
23. The pharmaceutical formulation of claim 11, wherein the
pharmaceutical agent is a carbapenem antibiotic.
24. The pharmaceutical formulation of claim 11, wherein the
pharmaceutical agent is an echinocandin antifungal agent.
25. The pharmaceutical formulation of claim 20, wherein the
antifungal agent comprises caspofungin, micafungin, anidulafungin,
or a salt thereof.
26. A pharmaceutical formulation comprising: an aqueous
pharmaceutical solution comprising water and a pharmaceutical agent
that is unstable in aqueous solution at room temperature, the
pharmaceutical agent selected from the group consisting of
antibiotics, antifungal agents, monoclonal antibodies, plasma
proteins, and combinations thereof, and at least one vitrifying
additive selected from the group consisting of polyalcohols,
polysaccharides, monosaccharides, disaccharides, trisaccharides,
aminosugars, amino derivatives of saccharides, and combinations
thereof, the vitrifying additive being present in an amount
effective to enhance the formation of an amorphous solid of the
aqueous pharmaceutical solution when the aqueous pharmaceutical
solution is cooled to a temperature below a glass transition
temperature of the aqueous pharmaceutical solution.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 12/437,679, filed May 8, 2009, and claims the
benefit of U.S. Provisional Patent Application Ser. No. 61/053,301
filed May 15, 2008, the entire disclosures of which are expressly
incorporated herein by reference.
BACKGROUND
[0002] The present disclosure relates generally to pharmaceutical
formulations. More specifically, the present disclosure relates to
stable pharmaceutical formulations and methods of making the stable
pharmaceutical formulations.
[0003] The use of freezing in the preservation of pharmaceutical
agents is known. One example of a frozen pharmaceutical agent is
ceftriaxone sodium, which is stable for at least 18 months if
stored at or below -20.degree. C. The advantage of a frozen
pharmaceutical, compared to a lyophilized or powdered drug for
reconstitution, lies in its ease of use. The frozen formulation can
be thawed and administered as is to the patient without need for
further dilution. This also reduces the potential for medication
errors and contamination due to manipulation by the clinician.
Nonetheless, for some very unstable drugs, freezing a drug solution
can cause degradation of the drug. This is particularly the case
with beta-lactam antibiotics such as ampicillin and amoxicillin,
carbapenems such as imipenem and meropenem, and large molecular
biologics such as some monoclonal antibodies and blood factors. In
many cases, this instability arises from high concentration of drug
in the unfrozen liquid remaining between ice crystals, and shifts
in pH, ionic strength, dielectric strength and other physical
properties of this unfrozen liquid.
SUMMARY
[0004] The present disclosure is directed to stable pharmaceutical
formulations and methods of making the stable pharmaceutical
formulations. In a general embodiment, the present disclosure
provides a method of stabilizing a pharmaceutical agent. The method
comprises combining a therapeutically effective amount of a
pharmaceutical agent with water, preferably providing a drug
concentration of 0.1 to 100 mg/mL, and one or more vitrifying
additives to form an aqueous pharmaceutical solution. The
vitrifying additive is present in an amount (for example about 1 to
about 30%) effective to enhance the formation of an amorphous solid
of the aqueous pharmaceutical solution when the aqueous
pharmaceutical solution is cooled to a temperature below a glass
transition temperature of the aqueous pharmaceutical solution. The
method also comprises cooling the aqueous pharmaceutical solution
to a temperature of about -50.degree. C. to about -10.degree. C. to
form the amorphous solid, which is the pharmaceutical agent as a
stable pharmaceutical formulation.
[0005] In an embodiment, the method further comprises aseptically
filling the aqueous pharmaceutical solution in a container before
cooling. The cooled aqueous pharmaceutical solution can be stored
at a temperature of about -10.degree. C. to about -50.degree. C.
for a period of at least about three months.
[0006] In an embodiment, the aqueous pharmaceutical solution
exhibits less than about ten percent degradation after storing. The
method can further comprise thawing the aqueous pharmaceutical
solution and administering the thawed aqueous pharmaceutical
solution to a patient.
[0007] In an embodiment, the vitrifying additive is one more
polyalcohols, polysaccharides, monosaccharides, disaccharides,
trisaccharides, aminosugars, amino derivatives of saccharides, or a
combination thereof. The polyalcohol can be, but is not limited to,
polyethylene glycol, poloxamers, mannitol, sorbitol, or a
combination thereof. The disaccharide can be, but is not limited
to, sucrose, trehalose, lactose, or a combination thereof. The
trisaccharide can be, but is not limited to, raffinose.
[0008] In an embodiment, the polysaccharide can be dextran,
cyclodextrin, or a combination thereof. For example, the vitrifying
additive can be 2-hydroxypropyl-beta-cyclodextrin. The vitrifying
additive can also be a dextran with an average molecular weight of
about 1,000 to 70,000, for example about 40,000.
[0009] In an embodiment, the pharmaceutical agent is one or more
antibiotics, antifungal agents, monoclonal antibodies, plasma
proteins, or a combination thereof. The pharmaceutical agent can
also be one that is unstable in aqueous solution at room
temperature. The antibiotic can be one or more trimethoprims,
polymyxin B sulfate, beta-lactams, monobactams, oxazolidinones,
macrolides, ketolides, tetracyclines, streptogramins, one or more
salts of any of the above, or a combination thereof. The
beta-lactams can be cephalosporins, penicillins, thienamycins,
carbapenems, penems, cephems, trinems, one or more salts of any of
the above, or a combination thereof. The antifungal agent can be an
echinocandin antifungal, caspofungin or a salt thereof.
[0010] In another embodiment, the present disclosure provides a
method of making a shelf-stable pharmaceutical agent. The method
comprises combining a pharmaceutical agent with water and at least
one vitrifying additive to form an aqueous pharmaceutical solution.
The vitrifying additive is present in an amount effective to give
the pharmaceutical agent a shelf-life of at least 3 months, for
example at least 6 months. The aqueous pharmaceutical solution is
then cooled to a temperature of about -50.degree. C. to about
-10.degree. C. to form the amorphous solid of the aqueous
pharmaceutical solution.
[0011] In an embodiment, the shelf-stable pharmaceutical agent has
a shelf-life of least 3 months. In another embodiment, the
shelf-stable pharmaceutical agent has a shelf-life of least 6
months.
[0012] In an alternative embodiment, the present disclosure
provides a pharmaceutical formulation comprising an aqueous
pharmaceutical solution comprising water and a pharmaceutical agent
that is unstable in aqueous solution at room temperature
(15-30.degree. C.) or refrigerated storage (0-15.degree. C.), and
one or more vitrifying additives. The vitrifying additive is
present in an amount effective to enhance the formation of an
amorphous solid of the aqueous pharmaceutical solution when the
aqueous pharmaceutical solution is cooled to a temperature below a
glass transition temperature of the aqueous pharmaceutical
solution. The pharmaceutical formulation can be frozen.
[0013] An advantage of the present disclosure is to provide
improved stable pharmaceutical formulations.
[0014] Another advantage of the present disclosure is to improved
frozen pharmaceutical formulations.
[0015] Yet another advantage of the present disclosure is to
provide an improved method for making stable pharmaceutical
formulations.
[0016] Still another advantage of the present disclosure is to
provide an improved method for making pharmaceutical formulations
having a long shelf-life.
[0017] Additional features and advantages are described herein, and
will be apparent from the following Detailed Description and the
figures.
BRIEF DESCRIPTION OF THE FIGURES
[0018] FIG. 1 illustrates the structure of dextrans. Dotted lines
indicate continuations of polymer chain.
[0019] FIG. 2 illustrates the structure of beta-cyclodextrin and
some of its derivatives (see R groups).
[0020] FIG. 3 illustrates the carbapenem structure (see R groups
for identification of different carbapenems).
[0021] FIG. 4 is a graph showing the concentration of meropenem
formulations through intervals up to 6 months at -25.degree. C.
[0022] FIG. 5A is a graph showing the concentration of meropenem in
10% Dextran 40, pH 7.9, versus control without 10% Dextran 40 after
20 weeks at -25.degree. C.
[0023] FIG. 5B is a graph showing the concentration of meropenem in
10% Dextran 40, pH 7.3, versus control without 10% Dextran 40 after
20 weeks at -25.degree. C.
[0024] FIG. 6A is a graph showing the percent of initial drug with
13.3% 2-hydroxypropyl beta-cyclodextrin versus storage period
(weeks) at -25.degree. C.
[0025] FIG. 6B is a graph showing the percent of initial drug with
13.3% 2-hydroxypropyl beta-cyclodextrin versus storage period
(weeks) at -20.degree. C.
[0026] FIG. 7A is a graph showing the percent of initial drug with
9% 2-hydroxypropyl beta-cyclodextrin and trehalose versus storage
period (weeks) at -25.degree. C.
[0027] FIG. 7B is a graph showing the percent of initial drug with
9% 2-hydroxypropyl beta-cyclodextrin and trehalose versus storage
period (weeks) at -20.degree. C.
[0028] FIG. 8A is a graph showing the percent of initial drug with
9% 2-hydroxypropyl beta-cyclodextrin and mannitol versus storage
period (weeks) at -25.degree. C.
[0029] FIG. 8B is a graph showing the percent of initial drug with
9% 2-hydroxypropyl beta-cyclodextrin and mannitol versus storage
period (weeks) at -20.degree. C.
[0030] FIG. 9A is a graph showing the percent of initial drug with
9% 2-hydroxypropyl beta-cyclodextrin and sucrose versus storage
period (weeks) at -25.degree. C.
[0031] FIG. 9B is a graph showing the percent of initial drug with
9% 2-hydroxypropyl beta-cyclodextrin and sucrose versus storage
period (weeks) at -20.degree. C.
DETAILED DESCRIPTION
[0032] The present disclosure is directed to stable pharmaceutical
formulations and methods of making the stable pharmaceutical
formulations. In a general embodiment, one or more vitrifying
additives are added to an aqueous pharmaceutical solution. The
aqueous pharmaceutical solution can be cooled to a temperature of
about -50.degree. C. to about -10.degree. C. Inclusion of the one
or more vitrifying or "glass-forming" additives increases the
stability of the pharmaceutical agent, for example, in a frozen
form.
[0033] Non-limiting examples of suitable pharmaceutical agents
useful in embodiments of the present disclosure include small
molecule drugs such as beta-lactam antibiotics, macrocyclic
antibiotics, macrocyclic antifungals, and biologics such as
monoclonal antibodies and blood factors such as antihemophilia
factor VIII. Preferred beta-lactams include highly unstable drugs
such as ampicillin, and carbapenems such as imipenem, meropenem,
ertapenem, doripenem and panipenem. Preferred macromolecular
antibiotics include erythromycin, azithromycin, dalfopristin and
quinupristin. The combination of the latter two is provided in the
commercial product, SYNERCID.RTM. (by Monarch Pharmaceuticals).
Preferred macromolecular antibiotics include echinocandins,
including but not limited to caspofungin (CANCIDAS.RTM., by Merck),
micafungin (MYCAMINE.RTM., by Astellas), and anidulafungin
(ERAXIS.RTM., by Pfizer). These pharmaceutical agents will be
discussed in more detail below.
[0034] It has surprisingly been found that the stability of
pharmaceutical agents can be enhanced by freezing a liquid solution
of the pharmaceutical agents to form a solid glass or amorphous
solid of the pharmaceutical agents. This can be accomplished by
combining with the liquid pharmaceutical solutions at least one
vitrifying additive in an amount that raises the glass transition
temperature of the liquid pharmaceutical solutions, or otherwise
enhances the formation of a glass or amorphous solid at cryogenic
temperatures (-50.degree. C. to -10.degree. C.). The resultant
frozen pharmaceutical solutions can be thawed to liquid form and
administered to a mammalian subject. Inclusion of one or more
vitrifying additives increases the stability of the pharmaceutical
agent beyond that which would have been attained in the absence of
the additive under the same storage conditions.
[0035] Vitrifying additives that can raise the glass transition
temperature above the standard pharmaceutical agent storage
temperature may enhance chemical stability of the pharmaceutical
agent. Sugars such as trehalose, sucrose, or raffinose, or a high
molecular weight polysaccharide such as dextran can be used as
vitrifying agents that effectively raise the glass transition
temperature.
[0036] As used herein, the term "shelf-life" is defined as the
period from the time of manufacture within which 10% drug loss
occurs. The inclusion of one or more vitrifying additives increases
the shelf-life of the pharmaceutical formulation beyond that which
would have been attained in the absence of the additive to the
pharmaceutical formulation under the same storage conditions. For
example, these vitrifying additives may be used in combination with
storage temperatures from about -50.degree. C. to about -10.degree.
C. to achieve desired shelf lives of the pharmaceutical agent in
the frozen state.
[0037] In an embodiment, the vitrifying additive is a polyalcohol,
monosaccharide, disaccharide, polysaccharide, aminosugar,
aminopolysaccharide, or a combination thereof. Non-limiting
examples of polyalcohols include polyethylene glycol, mannitol and
sorbitol. Glucose and fructose are examples of monosaccharides.
Non-limiting examples of disaccharides are sucrose, trehalose and
lactose. Non-limiting examples of polysaccharides include raffinose
(a trisaccharide), maltotetraose, dextran, and cyclodextrins such
as alpha- or beta-cyclodextrins and their derivatives.
Pharmaceutical-grade dextrans include Dextran 40 (MW=40,000),
Dextran 1 (MW=1,000), and Dextran 70 (MW=70,000). Dextran solutions
are used as plasma expanders. Cyclodextrins that are in prevalent
pharmaceutical use include alpha-cyclodextrin,
sulfobutylether(7)-beta-cyclodextrin (CAPTISOL.RTM., manufactured
by Cydex, Inc.), and 2-hydroxypropyl-beta-cyclodextrin.
Sulfobutylether(7)-beta-cyclodextrin is used in several
pharmaceutical products such as voriconazole (VFEND.RTM., by
Pfizer) and ziprasidone HCl (GEODON.RTM., by Pfizer).
2-Hydroxypropyl-beta-cyclodextrin is used in itraconazole for
intravenous injection (SPORANOX.RTM. IV, by Janssen Pharmacetica).
An example of an aminosugar is N-methylglucamine.
[0038] Dextrans are high molecular weight polysaccharides that are
cross linked by .alpha.-1,6 glycosidic linkages and crosslinked at
the C-3 hydroxy groups. FIG. 1 illustrates the structure of
dextrans. Dextran 40 has an average molecular weight of 40,000
(range 10,000 to 90,000) and is used pharmaceutically as a
plasma-volume expander. Therapeutic examples include (1) the
adjunctive treatment of shock or impending shock due to hemorrhage,
burns, surgery or other trauma, (2) use as a priming fluid, either
as the sole primer or as an additive, in pump oxygenators during
extracorporeal circulation, (3) the treatment of deep venous
thrombosis ("DVT"), and (4) prophylaxis of pulmonary embolism
("PE") and DVT in patients undergoing procedures associated with a
high incidence of thromboembolic complications, such as hip
surgery.
[0039] Pharmaceutical agents that are normally unstable in solution
above freezing can be lyophilized (i.e. freeze-dried) if they are
not damaged by the freezing process. The protection of biological
molecules by lyophilization is a subject of considerable practical
importance, particularly in the pharmaceutical industry. Much work
has been conducted on the use of a wide variety of compounds as
cryoprotectants for these types of processes. Saccharides are often
used in this capacity and have been found to protect proteins
during lyophilizing stresses. They have also been shown to prevent
damage to cells during lyophilization. Trehalose, a disaccharide of
glucose, has been found to be a highly effective. Simple
lyophilization generally occurs in three phases: (a) cooling phase,
(b) sublimation (primary drying), (c) desorption (final drying or
secondary drying). Often, it is desirable to obtain a glass, below
the glass transition, by the end of the cooling phase, prior to
water removal by sublimation. Typically, the final temperature
reached is well below -20.degree. C., and quite often is lower than
-35.degree. C. Embodiments of the present disclosure provide
preservation methods that do not dry the material, therefore
ambient pressure reduction to remove water and the attendant use of
complicated lyophilization apparatuses are not needed.
[0040] Embodiments of the present disclosure do not entail the
partial or complete dehydration and lyophilization of unstable
pharmaceutical agents, but rather the long-term storage of such
pharmaceutical agents in an aqueous matrix that is frozen at a high
sub-zero temperature (e.g., -20.degree. C.), which enables storage
in commercial freezers that are generally found in a hospital
setting. Typically, biological tissues are frozen to extreme
cryogenic temperatures such as that of liquid nitrogen (-70.degree.
C.). Certain frozen aqueous pharmaceutical formulations of the
present disclosure have an advantage in that they can be thawed to
a liquid state and used as is in a therapeutic drug regimen. In an
alternative embodiment, certain frozen formulations of the present
disclosure contain concentrated drug solutions that may be diluted
with a pharmaceutically acceptable diluent after thawing.
[0041] Cyclodextrins are polysaccharides in which the sugar
subunits are concatenated in a ring. FIG. 2 illustrates the
structure of beta-cyclodextrin and some of its derivatives (see R
groups). Cyclodextrins are nearly always used in the pharmaceutical
art and elsewhere to enhance solubility. Far less common is their
use to stabilize drugs in solution. Solubility and stability
enhancement is due to the formation of inclusion complexes, in
which a poorly soluble, hydrophobic drug is partially encapsulated
on a molecular level by the cyclodextrin molecule, which possesses
a hydrophobic cavity. Because the outside surface of the
cyclodextrin can interact with water molecules, aqueous solubility
is usually improved. By a similar encapsulation mechanism, reaction
of a drug molecule with water may be impeded, although this
stabilization is not usually dramatic because water molecules can
still diffuse into the open cyclodextrin cavity to interact with
the drug.
[0042] It has surprisingly been found that Dextran 40 and
2-hydroxypropyl-beta-cyclodextrin are excellent vitrifying agents
for the enhancement of chemical stability of drugs in the frozen
state at -25 to -20.degree. C. A high-degree of stabilization by
2-hydroxypropyl beta-cyclodextrin was not expected because
generally the glass transition temperature ("Tg") of
polysaccharides is proportional to their molecular weight, and
2-hydroxypropyl beta-cyclodextrin has a low molecular weight
(approximately 1400) relative to the high molecular weight
dextrans, such as Dextran 40.
[0043] The stable pharmaceutical formulations in embodiments of the
present disclosure can allow for the use of freezers at
conventional sub-zero temperature (-20 to -25.degree. C.) rather
than using ultra-cold (-80 to -50.degree. C.) or cryogenic (-180 to
-80.degree. C.) storage in the clinical setting. Storage at higher
temperature saves energy and cost, as compared to lower cryogenic
temperatures. Many hospital freezers are set at -20 to -25.degree.
C. in order to accommodate commercially available pharmaceutical
products, such as frozen premixed infusion products, and therefore
current hospital infrastructures and protocols can be followed. The
stable pharmaceutical formulations can be thawed and used directly
as is. In contrast, in the case of lyophilized products, the powder
must be reconstituted with an aqueous diluent that is acceptable
for injection. This reconstitution procedure must be conducted
under aseptic conditions, usually under a laminar-flow hood.
[0044] As previously discussed, there are many pharmaceutical
agents that are highly unstable in solution and would benefit from
the addition of glass-transition modifiers as covered by
embodiments of the present disclosure. Such pharmaceutical agents
include, but are not limited to, beta-lactams such as carbapenems,
some penicillins such as ampicillin, other antibiotics such as
SYNERCID.RTM. (quinupristin-dalfopristin), antifungal agents such
as caspofungin (CANCIDAS.RTM., by Merck), micafungin
(MYCAMINE.RTM., by Astellas), and anidulafungin (ERAXIS.RTM., by
Pfizer) and biologics such as monoclonal antibodies, and blood
factors such as antihemophilia factor VIII.
[0045] The instability of carbapenems having the structure shown
below arises from ring strain created by the carbon-carbon double
bond that is endocyclic to the 5-membered ring (FIG. 3 shows
various R groups).
[0046] This ring system is more strained than that of other
beta-lactams such as various penicillins and cephalosporins. The
rate of hydrolytic cleavage of the beta-lactam ring of the
carbapenem is thereby enhanced. Meropenem (MERREM.RTM., by
AstraZeneca, see FIG. 3) is one example of a beta-lactam antibiotic
of the carbapenem class. Other carbapenems include imipenem,
ertapenem, panipenem, and doripenem.
[0047] The stability and degradation kinetics of meropenem have
been studied. Meropenem is predicted to have a shelf-life (t90) of
about 0.5 day at 0.degree. C. Extrapolated to -25.degree. C., the
predicted shelf-life is less than one month. Meropenem also
polymerizes at higher drug concentration by a second-order
mechanism. If one requires a meropenem formulation that is
ready-to-use, there is value in being able to stabilize these
compounds in frozen aqueous media.
[0048] Another class of drugs used in embodiments of this
disclosure is the echinocandin class of antifungals, as represented
by caspofungin (CANCIDAS.RTM., by Merck), micafungin
(MYCAMINE.RTM., Astellas) and anidulafungin (ERAXIS.RTM., by
Pfizer). Caspofungin acetate (CANCIDAS.RTM., by Merck) is shown
below:
##STR00001##
[0049] Caspofungin is unstable in liquid form. It is available
commercially as a lyophilized powder for reconstitution. Prior to
use, the powder is dissolved in 10.5 mL of diluent (e.g., 0.9%
Sodium Chloride Injection) to prepare a concentrate that is only
stable for up to one hour at .ltoreq.25.degree. C. Ten mL of this
concentrate is aseptically transferred to an intravenous ("IV") bag
(or bottle) containing 250 mL of infusion diluent (e.g., 0.9%
Sodium Chloride Injection). This infusion solution must be used
within 24 hours if stored at .ltoreq.25.degree. C.
(.ltoreq.77.degree. F.) or within 48 hours if stored refrigerated
at 2 to 8.degree. C. (36 to 46.degree. F.) (CANCIDAS.RTM. package
insert, Merck Inc.). A frozen formulation that is ready-to-use upon
thawing to a liquid may only be possible if incorporated into a
cryogenic glass. Embodiments of the present disclosure can also
provide for the development of a frozen caspofungin formulation
that can be thawed and inhaled for the treatment of pulmonary
fungal infections. The aerosolization of caspofungin preparations
can be done using conventional nebulizers.
[0050] Other unstable drugs can be formulated using this embodiment
of the present disclosure, and include, without limitation, the
following antibiotics: trimethoprims; polymyxin B sulfate;
beta-lactams, including, without limitation, cephalosporins,
penicillins, thienamycins, carbapenems, penems, cephems, and
trinems; oxazolidinones; macrolides, including without limitation,
erythromycins and erythromycin lactobionate; ketolides;
tetracyclines, including, without limitation, chlortetracyclines
and chlortetracycline hydrochloride; and streptogramins, including,
without limitation, pristinomycins such as a combination of the
pharmaceutical agents quinupristin and dalfopristin (known
commercially as SYNERCID.RTM.).
[0051] In an alternative embodiment of the present disclosure, a
pharmaceutical agent is dissolved in Water for Injection,
optionally with an excipient to adjust the osmotic strength of the
medium, and optionally with a buffer. Depending on stability of the
drug, the solution pH is adjusted to about 3 to 11. After
dissolving all ingredients, the solution is filled by an aseptic
process into glass or plastic containers. During mixing and
filling, the solution may be cooled to retard decomposition of
drug. The filled containers are then frozen to a temperature of
about -50.degree. C. to about -10.degree. C. Preferred containers
include flexible plastic bags intended for packaging of injectable
pharmaceutical products.
[0052] Such flexible plastic containers may be made of a single
polymeric layer or multiple layers bonded together, or co-extruded.
These film layers can comprise polymers such as, but not limited
to, polyolefins, polyethers, and polyamides (nylon, for example).
An example of a flexible plastic container is the GALAXY.RTM.
container system (Baxter International Inc., Deerfield, Ill.),
intended for intravenous drug infusion. The aforementioned
formulation may alternatively be aseptically filled into glass or
plastic syringes for medical use. The prepared solution, packaged
in a container approved for medical application, is then frozen,
and distributed to the customer for thawing to a liquid form at a
desired concentration and purity for administration to a mammalian
subject. The thawed formulation can be administered by parenteral
routes that include intravenous, intramuscular, subcutaneous,
intrathecal, intracerebral, intraurethral, intradermal,
intracardiac and intraosseous.
[0053] In another embodiment of this invention, the frozen solution
is thawed to a liquid state, in which form it is ready to be
administered to a mammalian subject. In another embodiment, the
frozen solution is concentrated in pharmaceutical agent and when
thawed can be diluted to the desired final concentration for
administration. This may be beneficial for the stabilization of
some pharmaceutical agents that may otherwise not be stable in the
frozen state at the final deliverable concentration, even when in
the presence of vitrifying agents that are at a clinically
acceptable concentration. However, if the same solution is reduced
in volume, the concentration of the vitrifying agent inversely
increases. It is known that increasing the concentration of many
vitrifying agents will increase the glass transition temperature of
the aqueous solution in the frozen state (Angell C A, Liquid
fragility and the glass transition in water and aqueous solutions.
Chem. Rev. 2002, 102, 2627-2650). This is beneficial in stabilizing
the pharmaceutical agent in frozen solution because it can be
stored as a concentrate at a temperature well below Tg'.
[0054] Another advantage to preparation of a concentrate is the
ability to use other vitrifying agents such as monosaccharides or
sugar alcohols. An example of a monosaccharide is glucose. An
example of a sugar alcohol is mannitol. Another example of a sugar
alcohol is sorbitol. The above vitrifying agents would have too low
a Tg' (below -20.degree. C.) for stable storage at -20.degree. C.
Increasing their concentration would shift Tg' above -20.degree.
C.
EXAMPLES
[0055] By way of example and not limitation, the following examples
illustrate the stable pharmaceutical formulations in accordance
with embodiments of the present disclosure. The percentages
described herein are weight percentages unless specified
otherwise.
Example 1
[0056] This experiment was performed to determine the glass
transition temperature ("Tg'") of frozen meropenem formulations and
simple solutions by differential scanning calorimetry. In order to
determine whether there was a correspondence between measured glass
transition temperature and drug stability, the glass transition
temperatures of simple solutions for vitrifying agents and
different formulations of meropenem with added vitrifying agents
were measured using a Q1000 differential scanning calorimeter
("DSC") equipped with a refrigerated cooling system (TA
Instruments, New Castle, Del.).
[0057] Tzero.TM. sapphire disks were used for second cell
resistance and capacitance run in the calibration process. The cell
constant and temperature calibration were determined using indium
standard. An N2-4000 nitrogen generator (Parker Hannifin,
Haverhill, Mass.) provided the purging gas at 20 psi. Each solution
sample between 15 to 30 mg of a solution was transferred inside an
aluminum DSC pan. An aluminum top was placed on the sample and
crimped in place. An empty sample container was used as a
reference.
[0058] The sample was cooled at a rate of 5.degree. C./min from
room temperature to -40.degree. C., held for 3 min for thermal
equilibration and heated at a rate of 2.degree. C./min to
10.degree. C. All glass transition temperature values were reported
as the midpoint of the transition. The results are shown below in
Table 1:
TABLE-US-00001 TABLE 1 Tg values of frozen solutions (50 mL final
diluted volume) determined by DSC # Solution Tg (.degree. C.) 1
Meropenem (1.42 g blend with sodium carbonate), -28.14 6%
hydroxyethylstarch, 0.22% NaCl, pH 7.3 2 Meropenem (1.42 blend with
sodium carbonate), -18.01 10% Dextran 40, 0.22% NaCl, pH 7.3 3
Meropenem (1.42 blend with sodium carbonate), -17.40 10% Dextran
40, 0.22% NaCl, pH 7.9 4 Meropenem (1.42 blend with sodium
carbonate), -34.16 8% Captisol, 0.22% NaCl, pH 7.3 5 Meropenem
(1.42 blend with sodium carbonate), 13.3% -20.05 2-hydroxypropyl
.beta.-cyclodextrin, 0.22% NaCl, pH 7.3 6 Control (no added
vitrifying agent): Meropenem (1.42 <-40 blend with sodium
carbonate), 0.22% NaCl, pH 7.3, 7 15% Dextran 40 -10.78 8 15%
2-Hydroxypropyl-.beta.-cyclodextrin ("HPBC") -12.62 9 15% Trehalose
-28.14 10 15% Raffinose -25.37 11 15% Sucrose -31.17 12 6%
Hetastarch -13.24 13 8% Captisol -28.01
[0059] As seen in Table 1, the absence of a vitrifying agent in the
control formulation (#6) led to a glass transition temperature less
than -40.degree. C.
Example 2
[0060] This experiment was performed to determine the meropenem
decomposition in samples stored through 6 months at -25.degree. C.
The following formulations were prepared by mixing the ingredients
shown below in a refrigerated vessel (2-8.degree. C.). The
meropenem trihydrate was received as bulk raw material (meropenem
bulk blend) that already contained added sodium carbonate
(Na.sub.2CO.sub.3). Dissolution of 1.42 g of the blended material
in 50 mL of distilled water resulted in a final concentration of 20
mg/mL meropenem and 4.16 mg/mL sodium carbonate.
TABLE-US-00002 Formulation 1A: Meropenem bulk blend Meropenem
trihydrate 20 mg/mL (as anhydrous) Sodium carbonate 4.16 mg/mL
Hydroxyethyl starch 60 mg/mL (6%) pH adjusted to 7.3 with lactic
acid and/or sodium hydroxide.
TABLE-US-00003 Formulation 1B: Meropenem bulk blend Meropenem
trihydrate 20 mg/mL (as anhydrous) Sodium carbonate 4.16 mg/mL
Sodium chloride 0.22 mg/mL Dextran 40 100 mg/mL (10%) pH adjusted
to 7.3 with hydrochloric acid and/or sodium hydroxide.
TABLE-US-00004 Formulation 1C: Meropenem bulk blend Meropenem
trihydrate 20 mg/mL (as anhydrous) Sodium carbonate 4.16 mg/mL
Sodium chloride 0.22 mg/mL Dextran 40 100 mg/mL (10%) pH adjusted
to 7.9 with hydrochloric acid and/or sodium hydroxide.
TABLE-US-00005 Formulation 1D: Meropenem bulk blend Meropenem
trihydrate 20 mg/mL (as anhydrous) Sodium carbonate 4.16 mg/mL
Sodium chloride 0.22 mg/mL Captisol 80 mg/mL (8%) pH adjusted to
7.3 with hydrochloric acid and/or sodium hydroxide.
TABLE-US-00006 Formulation 1E: Meropenem bulk blend Meropenem
trihydrate 20 mg/mL (as anhydrous) Sodium carbonate 4.16 mg/mL
Sodium chloride 0.22 mg/mL 2-hydroxypropyl .beta.-cyclodextrin 133
mg/mL (13.3%) pH adjusted to 7.9 with hydrochloric acid and/or
sodium hydroxide
TABLE-US-00007 Formulation 1F (Control): Meropenem bulk blend
Meropenem trihydrate 20 mg/mL (as anhydrous) Sodium carbonate 4.16
mg/mL 0.9% Sodium Chloride Injection, USP QS pH 7.8 (no adjustment
of pH)
[0061] Flexible plastic containers (50-mL, BAXTER GALAXY.RTM.
PL2040) were filled with the above formulations (50-mL fill
volume). Units were pulled ("Prefreeze units") and immediately
tested for meropenem concentration by high-performance liquid
chromatography ("HPLC") (test samples were maintained at 5.degree.
C. throughout the assay period. The remaining test units of each
formulation were placed in stability chambers at -25.degree. C.
[0062] After periodic intervals up to approximately 6 months at
-25.degree. C., samples were thawed to room temperature and
immediately analyzed for meropenem by HPLC. The results are shown
in FIG. 4. Samples that contained either Dextran 40 or
2-hydroxypropyl beta-cyclodextrin were the most stable over 6
months at -25.degree. C. FIG. 5A (pH 7.9) and FIG. 5B (pH 7.3) show
a comparison between the stability of Formulation 1C (10% Dextran
40) and control samples (Formulation 1F) without Dextran 40, the
vitrification additive.
Example 3
[0063] This experiment was performed to determine meropenem
decomposition in samples stored through 6 months at -20.degree. C.
and -25.degree. C., in which combinations of vitrification
additives were used. The stability of meropenem formulations was
demonstrated with various combinations of 2-hydroxypropyl
beta-cyclodextrin, trehalose, mannitol, and sucrose. Samples were
stored at -25.degree. C. (FIGS. 6A, 7A, 8A and 9A) and at a higher
frozen temperature (-20.degree. C.; FIGS. 6B, 7B, 8B and 9B).
[0064] The following formulations were prepared by mixing the
ingredients shown below in a refrigerated vessel (2-8.degree. C.).
The meropenem trihydrate was received as bulk raw material
(meropenem bulk blend) that already contained added sodium
carbonate (Na.sub.2CO.sub.3). Dissolution of 1.42 g of the blended
material in 50 mL of distilled water resulted in a final
concentration of 20 mg/mL meropenem and 4.16 mg/mL sodium
carbonate.
Formulation 3A: 13% 2-Hydroxypropyl beta-cyclodextrin
[0065] Each 50 mL (0.2 m Nylon Membrane Filtered) in a plastic
infusion bag
[0066] Meropenem-R=1.14 g
[0067] Sodium Carbonate, NF=0.21 g
[0068] 2-Hydroxypropyl beta-cyclodextrin=6.65 g
[0069] Sterile Water for Injection, USP=QS 50 mL
[0070] pH 7.9 (No pH Adjustment)
Formulation 3B: 9% 2-Hydroxypropyl beta-cyclodextrin+trehalose
[0071] Each 50 mL (0.2 m Nylon Membrane Filtered) in a plastic
infusion bag
[0072] Meropenem-R=1.14 g
[0073] Sodium Carbonate, NF=0.21 g
[0074] 2-Hydroxypropyl beta-cyclodextrin=4.5 g
[0075] Trehalose=2.59 g
[0076] Sterile Water for Injection, USP=QS 50 mL
[0077] pH 7.9 (No pH Adjustment)
Formulation 3C: 9% 2-Hydroxypropyl beta-cyclodextrin+mannitol
[0078] Each 50 mL (0.2 m Nylon Membrane Filtered) in a plastic
infusion bag
[0079] Meropenem-R=1.14 g
[0080] Sodium Carbonate, NF=0.21 g
[0081] 2-Hydroxypropyl beta-cyclodextrin=4.5 g
[0082] Mannitol, USP=1.19 g
[0083] Sterile Water for Injection, USP=QS 50 mL
[0084] pH 7.9 (No pH Adjustment)
Formulation 3D: 9% 2-Hydroxypropyl beta-cyclodextrin+sucrose
[0085] Each 50 mL (0.2 m Nylon Membrane Filtered) in a plastic
infusion bag
[0086] Meropenem-R=1.14 g
[0087] Sodium Carbonate, NF=0.21 g
[0088] 2-Hydroxypropyl beta-cyclodextrin=4.5 g
[0089] Sucrose, USP=2.00 g
[0090] Sterile Water for Injection, USP=QS 50 mL
[0091] pH 7.9 (No pH Adjustment)
Formulation 3E: Control
[0092] Each 50 mL (0.2 m Nylon Membrane Filtered) in a plastic
infusion bag
[0093] Meropenem-R=1.14 g
[0094] Sodium Carbonate, NF=0.21 g
[0095] 0.9% Sodium Chloride Injection, USP=QS 50 mL
[0096] pH 7.9 (No pH Adjustment)
Results for Formulation 3A (13% 2-Hydroxypropyl
beta-cyclodextrin):
[0097] No significant change in drug concentration occurred through
six months at -25.degree. C. (FIG. 6A). The concentration was also
maintained above 90% when stored at -20.degree. C. (FIG. 6B).
Results for Formulation 3B (9% 2-Hydroxypropyl
beta-cyclodextrin+trehalose):
[0098] The concentration was also maintained above 90% when stored
through 6 months at -25.degree. C. (FIG. 7A).
Results for Formulation 3C (9% 2-Hydroxypropyl
beta-cyclodextrin+mannitol):
[0099] The concentration was also maintained above 90% when stored
through 6 months at -25.degree. C. (FIG. 8A).
Results for Formulation 3D (9% 2-Hydroxypropyl
beta-cyclodextrin+sucrose):
[0100] The combination of 9% 2-Hydroxypropyl beta-cyclodextrin and
sucrose at 4% level may not be sufficient to stabilize the
meropenem frozen premix.
[0101] Formulations 3A through 3D all showed less drug degradation
than the control with 0.9% saline, which showed 12.3% drug loss
after one month and 10% loss after approximately 3 weeks (24.3
days).
Example 4
Preparation of a Drug Concentrate with Vitrifying Agent
[0102] The following formulation is prepared by mixing the
ingredients shown below in a refrigerated vessel (2-8.degree. C.).
The drug (1 g) is slowly added per 100 mL of distilled water,
resulting in a final concentration of 10 mg/mL drug. The
concentrations of all solutes are four-fold higher than in the
final solution that is administered to the patient. Flexible
plastic containers (100-mL, Baxter PL2040, Galaxy) are filled with
the above concentrate (25-mL fill volume) and quickly frozen by
placement in a freezer at -20.degree. C. or lower. Optionally, any
plastic container can be used that can withstand expansion as the
aqueous solution is frozen and is physically rugged at the desired
storage temperature.
[0103] Drug: 10 mg/mL
[0104] Vitrifying agent: 5 g dextrose monohydrate
[0105] Buffer: 10 mM phosphate
[0106] pH target: 7.0
One bag (containing 25 mg drug in 25 mL diluent) is thawed at the
time of use, and diluted with Sterile Water for Injection USP to a
final volume of 100 mL by injecting 75 mL of Sterile Water for
Injection through the bag port. The contents are mixed and the
final solution is administered to the mammalian subject.
[0107] It should be understood that various changes and
modifications to the presently preferred embodiments described
herein will be apparent to those skilled in the art. Such changes
and modifications can be made without departing from the scope of
the present subject matter and without diminishing its intended
advantages. It is therefore intended that all such changes and
modifications be covered by the appended claims.
* * * * *