U.S. patent application number 14/725714 was filed with the patent office on 2015-09-17 for intrathecal baclofen pharmaceutical dosage forms and related delivery system.
The applicant listed for this patent is Mallinckrodt LLC. Invention is credited to John J. Foster, Thomas R. Prentice, Angela S. Strantz.
Application Number | 20150258279 14/725714 |
Document ID | / |
Family ID | 54067817 |
Filed Date | 2015-09-17 |
United States Patent
Application |
20150258279 |
Kind Code |
A1 |
Foster; John J. ; et
al. |
September 17, 2015 |
INTRATHECAL BACLOFEN PHARMACEUTICAL DOSAGE FORMS AND RELATED
DELIVERY SYSTEM
Abstract
According to the subject invention, there is disclosed, a dosage
and packaging configuration which includes the use of color-coded
pre-filled syringes and vials to fill and refill infusion systems
with existing and new dosage forms of intrathecal baclofen.
Inventors: |
Foster; John J.;
(Stillwater, MN) ; Prentice; Thomas R.; (Lake
Elmo, MN) ; Strantz; Angela S.; (Hazelwood,
MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mallinckrodt LLC |
Hazelwood |
MO |
US |
|
|
Family ID: |
54067817 |
Appl. No.: |
14/725714 |
Filed: |
May 29, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12403190 |
Mar 12, 2009 |
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14725714 |
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|
14574733 |
Dec 18, 2014 |
|
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|
12403190 |
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|
12701342 |
Feb 5, 2010 |
8969414 |
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14574733 |
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61037544 |
Mar 18, 2008 |
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61150337 |
Feb 6, 2009 |
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Current U.S.
Class: |
604/189 ;
514/567 |
Current CPC
Class: |
A61K 31/197 20130101;
A61M 2005/3125 20130101; A61K 47/02 20130101; A61M 2205/6081
20130101; A61M 2005/3114 20130101; A61K 9/0019 20130101; A61K
9/0085 20130101; A61M 5/31535 20130101; A61M 2205/6009 20130101;
A61M 5/315 20130101; A61M 5/31 20130101 |
International
Class: |
A61M 5/31 20060101
A61M005/31; A61M 5/315 20060101 A61M005/315; A61K 9/00 20060101
A61K009/00; A61K 31/197 20060101 A61K031/197; A61K 47/02 20060101
A61K047/02 |
Claims
1. A drug delivery system comprising a labeled pre-filled syringe
containing a sterile aqueous solution of baclofen that is suitable
for intrathecal delivery, wherein the sterile aqueous solution of
baclofen was sterilized by heating at 121.degree. C. for a F.sub.0
value of 7 minutes.
2. The drug delivery system of claim 1, wherein the sterile aqueous
solution of baclofen contains no more than 0.5% of
4-(4-chlorophenyl)-2-pyrrolidone by weight of baclofen.
3. The drug delivery system of claim 1, wherein the sterile aqueous
solution of baclofen further comprises sodium chloride.
4. The drug delivery system of claim 1, wherein the sterile aqueous
solution of baclofen is substantially free of any particulates.
5. The drug delivery system of claim 1, wherein the sterile aqueous
solution of baclofen has a baclofen concentration from about 0.5
mg/mL to about 4.0 mg/mL.
6. The drug delivery system of claim 5, wherein the labeled
pre-filled syringe contains from 5 mL to 40 mL of the sterile
aqueous solution of baclofen.
7. The drug delivery system of claim 5, further comprising a
color-coding system indicative of the concentration of baclofen in
the labeled pre-filled syringe, size of the pre-filled syringe, or
both.
8. The drug delivery system of claim 7, further comprising a
plunger, wherein the color-coding system is on the plunger, on a
label of the labeled pre-filled syringe, or both.
9. The drug delivery system of claim 1, wherein the labeled
pre-filled syringe further comprises a leur-lock tip.
10. A drug delivery system comprising a labeled pre-filled syringe
containing a sterile aqueous solution of baclofen that is suitable
for intrathecal delivery, wherein the sterile aqueous solution of
baclofen contains no more than 0.5% of
4-(4-chlorophenyl)-2-pyrrolidone by weight of baclofen.
11. The drug delivery system of claim 10, wherein the sterile
aqueous solution of baclofen further comprises sodium chloride.
12. The drug delivery system of claim 10, wherein the sterile
aqueous solution of baclofen is substantially free of any
particulates.
13. The drug delivery system of claim 10, wherein the sterile
aqueous solution of baclofen has a baclofen concentration from
about 0.5 mg/mL to about 4.0 mg/mL.
14. The drug delivery system of claim 13, wherein the labeled
pre-filled syringe contains from 5 mL to 40 mL of the sterile
aqueous solution of baclofen.
15. The drug delivery system of claim 13, further comprising a
color-coding system indicative of the concentration of baclofen in
the labeled pre-filled syringe, size of the pre-filled syringe, or
both.
16. The drug delivery system of claim 15, further comprising a
plunger, wherein the color-coding system is on the plunger, on a
label of the labeled pre-filled syringe, or both.
17. The drug delivery system of claim 10, wherein the labeled
pre-filled syringe further comprises a leur-lock tip.
Description
[0001] This application is a continuation-in-part application of
U.S. patent application Ser. No. 12/403,190, filed Mar. 12, 2009,
which claims the benefit of priority of U.S. Provisional
Application No. 61/037,544, filed Mar. 18, 2008, and a
continuation-in-part application of U.S. patent application Ser.
No. 14/574,733, filed Dec. 18, 2014, which is a continuation of
U.S. patent application Ser. No. 12/701,342 (now U.S. Pat. No.
8,969,414), filed Feb. 5, 2010, which claims the benefit of
priority of U.S. Provisional Application No. 61/150,337, filed Feb.
6, 2009, the disclosure of which are hereby incorporated by
reference in their entireties.
[0002] The present invention relates generally to a syringe vial or
vial that is filled in advance with a liquid to be injected. More
specifically, the present invention is directed to pre-filled
syringes and vials to fill and refill infusion systems with
existing and new forms of intrathecal baclofen.
[0003] Baclofen is a skeletal muscle relaxant and antispastic
agent. Baclofen is a structural analog of the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA), and may exert its
effects by stimulation of the GABA.sub.B receptor subtype. Baclofen
is the generic (USAN) name (USP Dictionary of USAN and
International Drug Names 2003) for
4-amino-3-(p-chlorophenyl)butyric acid, a derivative of
.gamma.-aminobutyric acid. Its structural formula is:
##STR00001##
Baclofen is a white to off-white, odorless or practically odorless
crystalline powder, with a molecular weight of 213.66 g/mol. It is
slightly soluble in water, very slightly soluble in methanol, and
insoluble in chloroform. Baclofen can be administered orally, but
when injected directly into the intrathecal space of a patient
effective cerebrospinal fluid (CSF) concentrations are achieved
with resultant plasma concentrations 100 times less than those
occurring with oral administrations.
[0004] As indicated in US patent application 2006/0009523, which is
hereby incorporated by reference, baclofen solutions having
concentrations in the range of about 3 to about 8 mg/mL can be
obtained by mixing the appropriate quantity of baclofen with an
aqueous diluent and heating the solution to a temperature of at
least about 30.degree. C., at least about 40.degree. C., at least
about 5.degree. C., preferably at least about 60.degree. C., and
most preferably at least about 70.degree. C. and a temperature of
less than about 90.degree. C., less than about 95.degree. C., less
than about 100.degree. C., less than about 121.degree. C., or most
preferably less than the temperature at which baclofen thermal
degrades to a significant degree. The heat is applied while
simultaneously subjecting the solution to intense agitation, e.g.
sonication, high-speed stirring, etc. The temperature range of at
least about 60.degree. C. to at less than about 100.degree. C. is
most preferred. Further, it is generally preferable, although not
required, that the aqueous solution be heated to a temperature
lower than its boiling point to prevent significant evaporation of
the aqueous solvent during dissolution. Dissolution temperatures of
100.degree. C. or higher that do not boil off the aqueous solvent
can be obtained by means known to those of skill in the art, such
as by increasing the atmospheric pressure that the solution is
subjected to during heating. One common means of achieving this
result is by autoclaving the solution.
[0005] Stable baclofen solutions can be produced by acidification
and back titration. Baclofen solutions having concentrations up to
about 10.0 mg/mL can be prepared by dissolving baclofen in an
acidic solution, preferably one having a pH lower than the
pKa.sub.1 of baclofen. For example, pH values lower than about
3.87, lower than about 3.0, lower than about 2.0, lower than about
1.5, or even lower than a pH of about 1.0 can be used
advantageously. Surprisingly, once the baclofen has been dissolved
in the acidic solution, and prior to pharmaceutical administration,
the baclofen solution can be back titrated to a pH of 4.0 to 8.5
without precipitation of baclofen particulates. The titration is
carried out by adding a base to the acidic solution until the pH is
adjusted to a pH in the desired range. A final pH of 5.0 to 7.0 is
currently preferred for baclofen solutions intended for
pharmaceutical uses such as intrathecal injection, but pH ranges of
4.5 to 8.0 and of 4.0 to 8.5 can also be suitable for such uses.
These pH ranges are intended to be illustrative of appropriate
values for uses such as intrathecal injection. The appropriate pH
ranges for any particular pharmaceutical application will be
readily apparent to those skilled in the art, and the final pH of
the baclofen solution can be any pharmaceutically acceptable pH
appropriate for a given use. In addition, baclofen solutions
prepared by this method can be stored at a pH that is not
appropriate for a given pharmaceutical use so long as the solution
is titrated to a pharmaceutically acceptable pH prior to
administration.
[0006] Alternately, stable baclofen solutions can be produced by
alkalinization and back titration. That is, solutions having
concentrations of baclofen of about 10.0 mg/mL or lower can be
prepared by dissolving baclofen in a basic solution, preferably one
having a pH higher than the pKa.sub.2 of baclofen. For example,
solutions of pH higher than about 9.62, higher than about 10.0,
higher than about 11.0, higher than about 12.0, and even higher
than the pH of about 13.0 can be used advantageously. Once the
baclofen is dissolved in the basic solution the pH can be back
titrated to a pH of about 4.0 to 8.5, or preferably can be titrated
to a pH of 5.0 to 7.0, or to other pH values appropriate for
pharmaceutical uses such as intrathecal injection, as discussed
above. For use in other applications, pharmaceutical or otherwise,
or during storage prior to use the baclofen solution can be
titrated to a lower pH or can be maintained for some period of time
at the original basic pH.
[0007] Presently, intrathecal baclofen is stored in ampoules.
Typical procedure for filling infusion systems includes breaking
the ampoules to open them, removing the drug from the ampoule and
filtering it using a syringe with an in-line filter and needle,
removing the needle from the syringe and replacing it with a
catheter that includes a second in-line filter and needle. The
needle is then inserted through the skin into the implanted pump
reservoir and the fluid is dispensed and filtered, filling the
infusion system reservoir with the drug. This process may need to
be done from 1 to 4 times for a single filling, depending on the
reservoir size and the ampoule configuration selected. There are
multiple issues with the current process and the need to enhance
safety with intrathecal drugs is paramount.
[0008] As used herein, the terms below have the meanings
indicated.
[0009] The term "pre-filled," as used herein, means containing an
exact, pre-determined dose of a sterile pharmaceutical
composition.
[0010] The present invention implements a pre-filled syringe that
is ready for immediate delivery to the infusion system. The
packaging system includes a syringe with a leur-lock tip filled
with intrathecal baclofen, a color coding system (label) for the
various concentrations of the drug product and size of syringe, a
package, a label, and instructions for use.
[0011] Since the drug in the syringe is already prepared, the
process of drawing up and filtering the drug into a syringe prior
to refilling the infusion system is eliminated. Eliminating this
process makes filling and refilling the infusion system safer and
easier. The pre-filled syringe is easier to use because the
practitioner does not have to draw up and filter the drug while
administering the therapy to the patient. The syringe's label or
plunger is color coded by concentration and syringe sizes, thereby
reducing practitioner error and increasing safety to the recipient.
Higher concentration formulations will be available to reduce the
number of times the recipient must be injected with the needle. The
pre-filled syringe also eliminates the potential of contamination
of the drug with glass particles from the ampoule, bacteria and the
like.
[0012] Further features and advantages of the invention, as well as
the structure and operation of various embodiments of the
invention, are described in detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is an illustration of the pre-filled syringe
according to an exemplary embodiment.
[0014] FIG. 2 is an illustration of the pre-filled syringe as used
with an infusion system.
[0015] The barrel 14 is made of glass or plastic having two open
ends. The pre-filled syringe 10 can have sizes of 5 milliliters, 20
milliliters, or 40 milliliters. One end of the barrel 14 is closed
off by a plunger 11 that forces the medical liquid (not shown) to
the other end of the barrel 14 when dispensing. A gasket 12 is
attached to the plunger 11 for sealing the medical liquid in the
barrel 14. The gasket 12 is made of a rubbery elastic material,
such as natural rubber or synthetic rubber. The dispensing end of
the barrel 14 is dosed off by a leur-lock tip 13. The leer-lock tip
13 mates with the infusion system for dispensing the medical
liquid.
[0016] The pre-filled syringe 10 is filled with a medical fluid, in
particular, intrathecal baclofen. The solution comprises baclofen
USP, Sodium Chloride, and water and is approved by the Food and
Drug Administration, The solution is formed aseptically, is
terminally sterilized as described below, and inserted into
sterilized syringes. The dosages of intrathecal baclofen are 2.5
milligrams per 5 milliliters, 40 milligrams per 20 milliliters, 80
milligrams per 40 milliliters, 80 milligrams in 20 milliliters, or
160 milligrams in 40 milliliters. The available high concentrations
and large syringe sizes eliminate the need for multiple operations
to fill the pump reservoir, thus reducing the potential of
practitioner error and thereby increasing the safety of the
recipient. Further, the syringes have minimal head space, which
leads to a decrease in degradation of the baclofen solution via
oxidation. The label or plunger 11 of each pre-filled syringe 10
has a distinct color for identifying the dosages. The color-coded
system further helps to eliminate practitioner error of injecting
the wrong dose. The product is packaged, labeled, and
sterilized.
[0017] FIG. 2 displays the pre-filled syringe 10 as used with the
pump system. Pump refill kits are commercially available from
Medtronic.RTM. and include a catheter 23 for connecting the
pre-filled syringe to the pump 21. Intrathecal baclofen may be
dispensed from the pre-filled syringe 10, through the catheter 23,
into the pump 21 without the baclofen being drawn and filtered. The
pump 21 then pumps the intrathecal baclofen through a second
catheter 22 to a desired location in the body. The pre-filled
syringe can be used with the Medtronic SynchroMed Infusion
System.RTM., the Johnson and Johnson Codman.RTM. division pumps,
and InSet.RTM. technologies pumps.
[0018] In an alternative embodiment, the baclofen may be stored in
a vial. The vial can be made of glass or plastic. It may be closed
off at the top by a stopper with crimp top. Flip off tops may be
used for tamper proof and color coding. Color coding is done by
concentration and syringe sizes, thereby reducing practitioner
error and increasing safety to the recipient. Types of stopper that
may be used include rubber and plastic. The size of the vial may be
20 milliliters or 40 milliliters. In the 20 milliliter vial, the
concentration of intrathecal baclofen may be 500 micrograms per
milliliter, 2000 micrograms per milliliter, or 4000 micrograms per
milliliter. In the 40 milliliter vial, the concentration of
baclofen may be 2000 micrograms per milliliter or 4000 micrograms
per milliliter.
[0019] The baclofen solution is aseptically inserted into vials and
the vials are terminally sterilized. Common sterilization protocols
call for heating the solution to 121.1.degree. C. with a
sterilization time (F.sub.0) of about 30 minutes. Baclofen,
however, is heat-sensitive and forms a poorly soluble degradation
product, 4-(4-chloropheyl)-2-pryyolidone (4-CPP), upon exposure to
heat. For example, baclofen solutions sterilized by moist heat
contain up to 1.4 wt % of 4-CPP, which is higher than the
permissible level for the marketed product (Sigg et al., Solubility
and Stability of Intrathecal Baclofen Solutions at High
Concentrations: Implications for Chronic Use in the SynchroMed
Infusion System, White Paper 2007, Minneapolis: Medtronic
Neurological). Therefore, it is desirable to find and implement a
sterilization method that utilizes less harsh conditions in order
to prevent this thermal degradation from taking place, while
continuing to meet sterility standards. Accordingly, vials
containing baclofen solutions are steam heated at 121.1.degree. C.
for a F.sub.0 of 7 minutes. Said terminally sterilized baclofen
solutions contain less than 0.5 wt % of 4-CPP. The level of 4-CPP
in said terminally sterilized baclofen solutions is less than that
in previous formulations. For example, Lioresal Intrathecal
(Medtronic) contains 0.6 wt % of 4-CPP.
[0020] Because the vials of baclofen solution are terminally
sterilized, there is no need to filter the baclofen solution before
use. This leads to an overall reduction in time needed to
administer the baclofen solution versus the existing delivery
methods which involve cracking open the ampoules and filtering the
solution before administration to a patient in need, and
additionally reduces the potential of practitioner error and
thereby increases the safety of the recipient.
[0021] The method of processing the vials may cause baclofen to
precipitate from solution or adsorb to the surface of the glass
vial. Therefore, treating the glass vials with a coating intended
to deactivate the reactivity of the glass surface may prevent this
unwanted precipitation. This coating typically reacts with the
hydroxyl groups of the glass and forms a more stable covalent bond.
Silanization is one method of deactivating the glass surface,
wherein the glass surface is reacted with silanes. The hydroxyl
groups of the glass attack and displace the alkoxy groups on the
silane thus forming a covalent --Si--O--Si-- bond, rendering the
glass surface inert.
[0022] In another embodiment, the vial described herein is coated
with a compound that deactivates the glass surface, so possible
reactions between baclofen and the glass are eliminated. Possible
vials with this coating include vials treated with SCHOTT Type I
plus.RTM. coating technology.
[0023] In a further embodiment, the vial described herein is
silanized to prevent adsorption and precipitation of baclofen.
[0024] The presence of oxygen may lead to the oxidation of
baclofen. In order to reduce the chances of oxidation of the
baclofen solution while in vials, a blanket of nitrogen gas is laid
across the vials before they are sealed to displace any oxygen
present. Oxidation of the baclofen solution in syringes is
minimized by the lack of head space in the syringes, which limits
the presence of any gases, including oxygen, within the
syringe.
[0025] In yet another embodiment, the baclofen solution is stored
under a nitrogen atmosphere within the vial.
[0026] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
EXAMPLE 1
Preparation of 4.0 mg/mL Baclofen Solution
[0027] To 1 L of hot water was added 630.0 g sodium chloride, and
the mixture was stirred for 10.+-.2 minutes. To the resulting
solution was added 280.0 g baclofen and 2 L hot water. The mixture
was then stirred for 45 minutes. The resulting solution was diluted
to 70 L with hot water and stirred for at least an additional 10
minutes.
EXAMPLE 2
Preparation of 2.0 mg/mL Baclofen Solution
[0028] To 1 L of hot water is added 315.0 g sodium chloride, and
the mixture is stirred for 10.+-.2 minutes. To the resulting
solution is added 140.0 g baclofen and 2 L hot water. The mixture
is then stirred for 45 minutes. The resulting solution is diluted
to 70 L with hot water and stirred for at least an additional 10
minutes.
EXAMPLE 3
Preparation of 0.5 mg/mL Baclofen Solution
[0029] To 1 L of hot water was added 78.75 g sodium chloride, and
the mixture was stirred for 10.+-.2 minutes. To the resulting
solution was added 35.0 g baclofen and 2 L hot water. The mixture
was then stirred for 45 minutes. The resulting solution was diluted
to 70 L with hot water and stirred for at least an additional 10
minutes.
EXAMPLE 4
Sterilization Protocol
[0030] A baclofen solutions described above were aseptically
transferred to vials. The vials containing the solution were then
steam-heated to 121.1.degree. C. so that the F.sub.0 for the
resulting terminally sterilized solution was 7 minutes.
EXAMPLE 5
Percent 4-CPP Found in Baclofen Solutions
[0031] The percent of 4-CPP found in 0.5 mg/mL and 4.0 mg/mL
baclofen solutions prepared as described above is presented in the
tale below.
TABLE-US-00001 Baclofen solution Percent (wt %) of 4-CPP 0.5 mg/mL
(#2118-101) 0.346 0.5 mg/mL (#2118-102) 0.436 0.5 mg/mL (#2118-103)
0.39 4.0 mg/mL (#2133-101) 0.377 4.0 mg/mL (#2133-102) 0.415 4.0
mg/mL (#2137-101) 0.442
* * * * *