U.S. patent application number 16/158937 was filed with the patent office on 2019-02-14 for perfusion dosage form.
This patent application is currently assigned to SUN PHARMACEUTICAL INDUSTRIES LIMITED. The applicant listed for this patent is SUN PHARMACEUTICAL INDUSTRIES LIMITED. Invention is credited to Subhas Balaram BHOWMICK, Ashish Anilrao DUBEWAR, Kirti GANORKAR, Prashant KANE, Samarth KUMAR, Nishit PATEL, Umeshkumar Mukeshbhai PATEL.
Application Number | 20190046398 16/158937 |
Document ID | / |
Family ID | 54106163 |
Filed Date | 2019-02-14 |
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United States Patent
Application |
20190046398 |
Kind Code |
A1 |
KUMAR; Samarth ; et
al. |
February 14, 2019 |
PERFUSION DOSAGE FORM
Abstract
The present invention relates to a method for enabling hospitals
or clinics to administer a dose of a drug to patients in need
thereof while avoiding steps of manipulation, dilution,
reconstitution, dispensing, sterilization, transfer, handling or
compounding before intravenous administration. The present
invention further relates to a perfusion system comprising
different sets of perfusion containers, each container comprising a
ready-to-infuse, stable, sterile, aqueous perfusion solution of a
drug, wherein the set of perfusion containers alone or in
combination provides for direct intravenous administration of a
desired dose of the drug to a patient in need thereof, such that
the delivered dose is equal to or within .+-.5% of the calculated
dose.
Inventors: |
KUMAR; Samarth; (Vadodara,
IN) ; KANE; Prashant; (Vadodara, IN) ;
BHOWMICK; Subhas Balaram; (Vadodara, IN) ; GANORKAR;
Kirti; (Vadodara, IN) ; PATEL; Nishit;
(Vadodara, IN) ; DUBEWAR; Ashish Anilrao;
(Vadodara, IN) ; PATEL; Umeshkumar Mukeshbhai;
(Vadodara, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUN PHARMACEUTICAL INDUSTRIES LIMITED |
MUMBAI |
|
IN |
|
|
Assignee: |
SUN PHARMACEUTICAL INDUSTRIES
LIMITED
MUMBAI
IN
|
Family ID: |
54106163 |
Appl. No.: |
16/158937 |
Filed: |
October 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14843296 |
Sep 2, 2015 |
10098813 |
|
|
16158937 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/14 20130101; A61J
1/16 20130101; A61K 47/26 20130101; G06F 19/00 20130101; A61J 1/10
20130101; B65B 55/04 20130101; G16Z 99/00 20190201; A61M 5/1408
20130101; A61K 31/4745 20130101; G16H 20/17 20180101; A61K 9/0019
20130101; A61P 35/00 20180101; G06F 19/3456 20130101; G16H 20/13
20180101; B65D 81/266 20130101 |
International
Class: |
A61J 1/10 20060101
A61J001/10; A61J 1/16 20060101 A61J001/16; A61M 5/14 20060101
A61M005/14; A61K 31/4745 20060101 A61K031/4745; A61K 47/26 20060101
A61K047/26; G16H 20/13 20060101 G16H020/13; B65D 81/26 20060101
B65D081/26; B65B 55/04 20060101 B65B055/04; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 3, 2014 |
IN |
2804/MUM/2014 |
Claims
1. A method for enabling hospitals or clinics to administer a dose
of a drug to patients in need thereof while avoiding steps of
manipulation, dilution, reconstitution, dispensing, sterilization,
transfer, handling or compounding before intravenous
administration, the method comprising: (a) manufacturing a first
set of perfusion containers containing a ready-to-infuse, stable,
sterile, aqueous perfusion solution of the drug at a first higher
concentration, and a second set of top-up perfusion containers
containing a ready-to-infuse, stable, sterile, aqueous perfusion
solution of the drug at a second concentration and optionally a
third set of top-up perfusion containers having a ready-to-infuse,
stable, sterile, aqueous perfusion solution of the drug at a third
concentration, the first concentration of drug being higher than
the second and third concentrations, the containers within each set
of perfusion containers ranging in volume from a lower to a higher
volume, (b) calculating the dose to be administered to patients
according to at least one patient parameter and providing
instructions for selecting one or more perfusion container(s) from
the first set and if required one or more top-up perfusion
container(s) from the second or third set and for directly
administering the drug from the selected perfusion containers such
that the delivered dose is equal to or within .+-.5% of the
calculated dose, (c) supplying to the distributors or hospitals or
clinics, the first set of perfusion containers and second or third
set of top-up containers along with the instructions.
2. The method as claimed in claim 1, wherein the drug is selected
from irinotecan, topotecan, pemetrexed, docetaxel, paclitaxel,
gemcitabine, cisplatin, oxaliplatin, carboplatin, leukovorin,
etoposide, doxorubicin, daunonibicin, epirubicin, idarubicin,
vincristine, vinblastine, vinorelbine, 5-fluorouracil, ifosfamide,
cyclophosphamide, mechlorethamine, carmustine, dacarbazine,
cladribine, fulvestrant, pegfilgrastim, pamidronate, mitoxantrone,
streptozocin, mitomycin, gentamicin, teniposide, vancomycin,
methicillin, daptomycin, tobramycin, amikacin, midazolam, propofol,
fentanyl, remifentanil, rocuronium, vecuronium, atracurium,
voriconazole or acyclovir.
3. The method as claimed in claim 1, wherein drug is irinotecan or
its pharmaceutically acceptable salt.
4. The method as claimed in claim 3, wherein irinotecan or its
pharmaceutically acceptable salt is irinotecan hydrochloride and
wherein the ready-to-infuse, stable, sterile, aqueous perfusion
solution of irinotecan hydrochloride has a pH ranging from about
3.0 to 4.5, and wherein irinotecan hydrochloride is present in the
first set of infusion containers at concentration ranging from
about 1.0 mg/ml to 3.0 mg/ml and in the second or third set of
infusion containers at a concentration ranging from about 0.1 mg/ml
to 0.6 mg/ml.
5. The method as claimed in claim 4, wherein irinotecan
hydrochloride is present in the first set of infusion containers at
a concentration of 1.5 mg/ml and at a volume ranging from about 50
ml to about 300 ml, in the second set of infusion containers at a
concentration of 0.4 mg/ml and at a volume ranging from about 10 ml
to about 100 ml and in the third set of infusion containers at a
concentration of 0.2 mg/ml and at a volume ranging from about 10 ml
to about 100 ml.
6. The method as claimed in claim 1, wherein the perfusion
containers filled with the aqueous solution of drug are terminally
sterilized.
7. The method as claimed in claim 1, wherein the perfusion
containers are packaged in a secondary packaging, comprising an
overwrap pouch and an oxygen scavenger in between the perfusion
container and the pouch.
8. The method as claimed in claim 7, wherein at least one of
perfusion container or the secondary packaging is designed to
protect the solution of drug from light.
9. The method as claimed in claim 4, wherein the ready-to-infuse,
stable, sterile, aqueous perfusion solution of irinotecan
hydrochloride comprises an osmotic agent in an amount sufficient to
make the solution isoosmolar and a pH adjusting agent or a buffer
to adjust and maintain the pH in the range of 3.0 to 4.5.
10. A perfusion system comprising: a first set of perfusion
containers comprising a ready-to-infuse, stable, sterile, aqueous
perfusion solution of a drug at a first higher concentration, and a
second set of top-up perfusion containers comprising a
ready-to-infuse, stable, sterile, aqueous perfusion solution of the
drug at a second concentration and optionally a third set of top-up
perfusion containers comprising a ready-to-infuse, stable, sterile,
aqueous perfusion solution of the drug at a third concentration,
the first concentration of drug being higher than the second and
third concentrations, the first to the third sets of perfusion
containers ranging in volume from a higher volume to a lower
volume, instructions for selecting one or more perfusion
container(s) from the first set and if required one or more top-up
perfusion container(s) from the second or third set and for
directly administering the drug from the selected perfusion
containers such that the delivered dose is equal to or within
.+-.5% of a dose calculated according to at least one patient
parameter, wherein the set of perfusion containers alone or in
combination provides for direct intravenous administration of a
desired dose of the drug to a patient in need thereof, such that
the delivered dose is equal to or within .+-.5% of the calculated
dose.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation application of U.S.
patent application Ser. No. 14/843,296, filed on Nov. 18, 2015,
which will issue as U.S. Pat. No. 10,098,813, will issue on Oct.
16, 2018, which claims priority from Indian Patent No.
2804/MUM/2014, filed on Sep. 3, 2014, the disclosures of which are
incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a method for enabling
hospitals or clinics to administer a dose of a drug to patients in
need thereof while avoiding steps of manipulation, dilution,
reconstitution, dispensing, sterilization, transfer, handling or
compounding before intravenous administration.
[0003] The present invention further relates to a perfusion system
comprising different sets of perfusion containers, each container
comprising a ready-to-infuse, stable, sterile, aqueous perfusion
solution of a drug, wherein the set of perfusion containers alone
or in combination provides for direct intravenous administration of
a desired dose of the drug to a patient in need thereof, such that
the delivered dose is equal to or within .+-.5% of the calculated
dose.
BACKGROUND OF THE INVENTION
[0004] There are drawbacks associated with most of the commercially
available parenteral dosage forms, particularly parenteral dosage
forms of chemotherapeutic agents. [0005] 1. First, these marketed
products cannot be directly administered to a patient & rather
require manipulation, the concentrated solution needs to be diluted
or the lyophilized powder needs to be reconstituted using a
suitable solvent, prior to infusion. [0006] 2. Second, besides the
inconvenience, the manipulation exposes the involved personnel
(workers, pharmacists, medical personnel, nurses) to risk of
exposure to the cytotoxic drugs. [0007] 3. Any manipulation may
compromise the sterility required in intravenous perfusions,
particularly when they are designed to be preservative free. [0008]
4. On preparation of this solution for intravenous infusion, ideal
optimum conditions such as the desired pH at which drug is most
stable, are disturbed. Therefore, if the infusion is stored, the
degradation occurs more rapidly. [0009] 5. Human manipulation is
associated with medication/dosing errors. Antineoplastic drugs, in
particular have a low therapeutic index. Medication errors in
dosing or dosing rate can have highly undesirable consequences and
result in an unfavorable therapeutic outcome.
[0010] The present invention provides a method which enables
accurate dosing of the drug to the patients while avoiding the
above mentioned errors. The method of the present invention avoids
steps of manipulation, dilution, reconstitution, dispensing,
sterilization, transfer, handling or compounding before intravenous
administration of desired dose of drug.
SUMMARY OF THE INVENTION
[0011] The present invention provides a method for enabling
hospitals or clinics to administer a dose of a drug to patients in
need thereof while avoiding steps of manipulation, dilution,
reconstitution, dispensing, sterilization, transfer, handling or
compounding before intravenous administration, the method
comprising: [0012] (a) manufacturing a first set of perfusion
containers containing a ready-to-infuse, stable, sterile, aqueous
perfusion solution of the drug at a first higher concentration, and
a second set of top-up perfusion containers containing a
ready-to-infuse, stable, sterile, aqueous perfusion solution of the
drug at a second concentration and optionally a third set of top-up
perfusion containers having a ready-to-infuse, stable, sterile,
aqueous perfusion solution of the drug at a third concentration,
the first concentration of drug being higher than the second and
third concentrations, the containers within each set of perfusion
containers ranging in volume from a lower to a higher volume,
[0013] (b) calculating the dose to be administered to patients
according to at least one patient parameter and providing
instructions for selecting one or more perfusion container(s) from
the first set and if required one or more top-up perfusion
container(s) from the second or third set and for directly
administering the drug from the selected perfusion containers such
that the delivered dose is equal to or within .+-.5% of the
calculated dose, [0014] (c) supplying to the distributors or
hospitals or clinics, the first set of perfusion containers and
second or third set of top-up containers along with the
instructions.
[0015] According to a further aspect of the present invention,
there is provided a perfusion system comprising: [0016] a first set
of perfusion containers comprising a ready-to-infuse, stable,
sterile, aqueous perfusion solution of a drug at a first higher
concentration, and a second set of top-up perfusion containers
comprising a ready-to-infuse, stable, sterile, aqueous perfusion
solution of the drug at a second concentration and optionally a
third set of top-up perfusion containers comprising a
ready-to-infuse, stable, sterile, aqueous perfusion solution of the
drug at a third concentration, the first concentration of drug
being higher than the second and third concentrations, the first to
the third sets of perfusion containers ranging in volume from a
higher volume to a lower volume, [0017] instructions for selecting
one or more perfusion container(s) from the first set and if
required one or more top-up perfusion container(s) from the second
or third set and for directly administering the drug from the
selected perfusion containers such that the delivered dose is equal
to or within .+-.5% of a dose calculated according to at least one
patient parameter, [0018] wherein the set of perfusion containers
alone or in combination provides for direct intravenous
administration of a desired dose of the drug to a patient in need
thereof, such that the delivered dose is equal to or within .+-.5%
of the calculated dose.
DESCRIPTION OF FIGURES
[0019] FIG. 1 represents the configuration of the perfusion dosage
form, wherein 1 is perfusion bag filled with ready-to-infuse,
stable, sterile aqueous solution of a drug, 2 is the secondary
package--an overwrap aluminum pouch and 3 is a single exit port for
delivering of the solution by intravenous route.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0020] The term "perfusion" as used herein in the present
invention, refers to the passage of fluid through the lymphatic
system or blood vessels to an organ or tissue, in particular this
term refers to the slow or prolonged intravenous infusion or
administration of a solution of active ingredient to a patient.
[0021] The term "ready-to-infuse" or `directly administering` or
`direct intravenous infusion` or `direct delivery` as used herein
refers to direct intravenous infusion of the aqueous drug solution
to the patient without involving any intermediate steps of
manipulation, dilution, reconstitution, dispensing, sterilization,
transfer, handling or compounding before intravenous parenteral
administration of the drug solution. The aqueous drug solution can
be directly administered parenterally from the perfusion
container.
[0022] The term `calculated dose` as used herein means the dose of
the drug that is to be administered to the patient depending upon
the disease condition or in other terms indication and the patient
parameters such as body surface area, body weight, renal clearance
or hepatic function and other factors, that may affect the dose
calculation.
[0023] The term `delivered dose` as used herein means the dose of
the drug that is delivered to the patient from the perfusion
container of the first set and optionally the perfusion container
from the second and the third set. The delivered dose according to
the method of the present invention is equal to or within .+-.5% of
the calculated dose. The % variation may be calculated as the % of
difference between the delivered dose and the calculated dose,
divided by the calculated dose.
[0024] The term `top-up perfusion containers` refer to the
perfusion containers containing the aqueous solution of the drug at
a concentration lower than the concentration of the aqueous
solution of the drug present in the primary or the first set of the
containers.
[0025] The term "sterile" or `sterilized` as used in the context of
the invention, means a solution that has been brought to a state of
sterility and has not been subsequently exposed to microbiological
contamination, i.e. the sterility of the aqueous solution present
in the perfusion container has not been compromised.
[0026] The term `stable` as used herein means that the aqueous
perfusion solution filled in the container is physically as well as
chemically stable as demonstrated by compliance to acceptable
specification, when the dosage form is stored at room temperature
(about 25.degree. C. and 40% relative humidity) for twelve months,
preferably eighteen months, more preferably 24 months or
longer.
[0027] According to the method or system of the present invention,
there is provided a first set of perfusion containers containing a
ready-to-infuse, stable, sterile, aqueous perfusion solution of the
drug at a first higher concentration. This solution is generally
administered at a higher concentration and in higher volumes than
solutions of the drug from the other set(s) of perfusion
containers. The second or the third sets of perfusion containers
include the aqueous perfusion solution of the drug at a
concentration lower than the first concentration of drug (as
provided in the first set of perfusion containers). The first to
third sets of perfusion containers range in volume from a higher to
a lower volume. The sets of sterile perfusion containers filled
with sterile aqueous solutions of drug are particularly,
manufactured in a pharmaceutical manufacturing site and not in
hospital premises where there may be intermediate steps of
dispensing or mixing of the aqueous solution which has been
manufactured separately in a manufacturing plant or site and
supplied in bulk volumes to the hospital or pharmacy. The perfusion
containers are filled with the aqueous perfusion solution of the
drug and the perfusion containers are subjected to sterilization
process in the pharmaceutical manufacturing facility.
[0028] Generally the volume of a container from the first set of
containers is greater than the volume of a container from the
second and third sets of containers, and the volume of a container
from the second set of containers is generally greater than the
volume of a container from the third set of containers.
[0029] According to an embodiment of the invention, the volume of a
container from the first set of containers is greater than the
volume of a container from the second and third sets of containers,
and the volume of a container from the third set of containers is
around the same as the volume of a container from the second set of
containers. Each container in a set of containers may have the same
volume or a different volume. Generally each container in a set has
a different volume. According to one embodiment, the second and
optionally the third set of containers have an associated volume of
10% to 90% of the volume of a container of the first set of
containers having the lowest associated volume; generally 50% to
75%.
[0030] Generally the concentration of the solution of the drug in
the first set of containers is greater than the concentration of
the solution of the drug in the second and third sets of
containers. The concentration of the solution of the drug in the
second set of containers may be greater than or the same as the
concentration of the drug in the third set of containers. According
to one embodiment, the concentration of the solution of the drug in
the second and optionally the third set of containers is 10% to 95%
less than the concentration of the solution of the drug in the
first set of containers; generally 75% to 95% less. Typically, the
concentration of the solution of the drug in the second set of
containers is 10% to 30% of the concentration of the solution of
the drug in the first set of containers. Typically, the
concentration of the solution of the drug in the third set of
containers is 5% to 15% of the concentration of the solution of the
drug in the first set of containers.
[0031] A dose to be administered to patients may be calculated
according to at least one patient parameter. Instructions, in
particular written instructions are provided for selecting one or
more perfusion container(s) from the first set and if required one
or more top-up perfusion container(s) from the second or third set
and for directly administering the drug from the selected perfusion
containers such that the delivered dose is equal to or within
.+-.5% of the calculated dose. Suitably, the patient parameter
according to which the dose to be administered to the patient is
calculated may be selected from the group consisting of one of
patient's body surface area, body weight or ideal body weight,
hepatic function or renal function. In some preferred embodiments,
the patient parameter is patient's body surface area.
[0032] Further, the present invention may include supplying to the
distributors or hospitals or clinics the first set of perfusion
containers and second or third set of top-up containers along with
the instructions, generally in the form of written
instructions.
[0033] The method or system of the present invention avoids steps
of manipulation, dilution, reconstitution, dispensing,
sterilization, transfer, handling or compounding before intravenous
administration of desired dose of drug. Suitably, the method avoids
any manipulation, any step of reconstituting or dilution such as
those involved in conventional lyophilized or concentrated
products. The method further does not involve any step of transfer
of infusion solution from one container to another before
administration or any volume adjustment, i.e. addition or
withdrawal of the aqueous solution from the perfusion container,
before administration. The method of the present invention thus
eliminates the risk of any potential calculation or dilution error
as well as risk of microbiological contamination prior to
administration. The method of the present invention also eliminates
or minimizes contact of the drugs by hospital personnel, thus
avoiding any potential side effects associated with the drug,
especially with cytotoxic anti-cancer drugs.
[0034] The drug according to the method or system of the present
invention is an active ingredient selected from the group
consisting of anti-cancer/chemotherapeutic agents, antibiotics or
antibacterial agents, analgesic or anaesthetic agents, alpha
adrenergic agonists, beta-adrenergic agonists, muscle relaxants,
antifungal agents, antiviral agents. Suitably, the drug may be
selected from the group consisting of anti-cancer
drugs/chemotherapeutic agents such as, but not limited to
irinotecan, topotecan, pemetrexed, docetaxel, paclitaxel,
gemcitabine, cisplatin, oxaliplatin, carboplatin, leukovorin,
etoposide, doxorubicin, daunonibicin, epirubicin, idarubicin,
vincristine, vinblastine, vinorelbine, 5-fluorouracil, ifosfamide,
cyclophosphamide, mechlorethamine, carmustine, dacarbazine,
cladribine, fulvestrant, pegfilgrastim, pamidronate, zoledronic
acid, mitoxantrone, streptozocin, mitomycin, gentamicin,
teniposide; Antimicrobial agents such as, but not limited to
vancomycin, methicillin, daptomycin, tobramycin, amikacin,
ticarcillin; Analgesics or anesthetic agents such as, but not
limited to midazolam, propofol, fentanyl, remifentanil, thiopental;
Muscle relaxants such as, but not limited to rocuronium,
vecuronium, atracurium; Antifungal agents such as, but not limited
to voriconazole, Antiviral agents such as, but not limited to
acyclovir.
[0035] In preferred embodiments, the drug is selected from the
group consisting of anticancer agents. In one preferred embodiment,
the drug is irinotecan or its pharmaceutically acceptable salt.
Preferably, the salt is hydrochloride salt. Irinotecan or its
pharmaceutically acceptable salt, for example irinotecan
hydrochloride may be used in the method of the present invention at
a concentration ranging from about 0.1 mg/ml to about 3.0 mg/ml;
preferably, from about 0.2 mg/ml to about 2.0 mg/ml.
[0036] Suitably, according to one preferred embodiment of the
present invention, the first set of perfusion containers contains a
ready-to-infuse, stable, sterile, aqueous perfusion solution of
drug, irinotecan hydrochloride, at a first higher concentration,
which first higher concentration may range from about 1.0 mg/ml to
about 3.0 mg/ml. Preferably, the first higher concentration is 1.5
mg/ml. According to this embodiment, the second or third set of
infusion container contain a ready-to-infuse, stable, sterile,
aqueous perfusion solution of irinotecan hydrochloride at a
concentration ranging from about 0.1 mg/ml to 0.8 mg/ml, preferably
from about 0.1 mg/ml to 0.6 mg/ml. Preferably, the second and third
set of infusion containers contain the ready-to-infuse, stable,
sterile, aqueous perfusion solution of irinotecan hydrochloride, at
a concentration of 0.4 mg/ml and 0.2 mg/ml respectively.
[0037] Preferably, the set of perfusion containers according to the
present invention may range in volume from a lower to a higher
concentration. The volume of the aqueous solution filled in the
first set of perfusion containers may vary from about 50 ml to
about 1000 ml, preferably from about 60 ml to about 800 ml, more
preferably from about 80 ml to about 500 ml. Suitably, the volume
of the aqueous solution filled in the second and third set of
perfusion containers may vary from about 10 ml to about 100 ml,
preferably from about 25 ml to about 80 ml, more preferably from
about 40 to 60 ml.
[0038] In one preferred embodiment, wherein the drug is irinotecan
or its pharmaceutically acceptable salt, the volume of the aqueous
solution filled in the first set of perfusion containers may vary
from about 50 ml to about 500 ml, preferably from about 80 ml to
about 300 ml. In specific embodiments, the first set of container
may incorporate 90 ml, 100 ml, 120 ml, 150 ml, 180 ml, 200 ml, 210
ml, 240 ml, 270 ml or 300 ml of the aqueous solution of irinotecan
or its pharmaceutically acceptable salt. In this preferred
embodiment, the volume of the aqueous solution filled in the second
and third set of top-up perfusion containers may vary from about 10
ml to about 100 ml, preferably from about 25 ml to about 75 ml. In
specific embodiments, the second and third set of top up perfusion
containers may incorporate about 50 ml of the aqueous solution of
irinotecan or its pharmaceutically acceptable salt. In one
embodiment, the different set of perfusion containers having
different volumes may be distinguished. In particular the different
sets of perfusion containers may be visually distinguished, for
example through the use of different patterns or colours on some or
all of the containers. In particular different colours may be used
for labeling.
[0039] In one preferred embodiment, the drug is irinotecan
hydrochloride and the ready-to-infuse, stable, sterile, aqueous
perfusion solution of irinotecan hydrochloride has a pH ranging
from about 3.0 to 4.5, and irinotecan hydrochloride is present in
the first set of infusion containers at concentration ranging from
about 1.0 mg/ml to 3.0 mg/ml and in the second or third set of
infusion containers at a concentration ranging from about 0.1 mg/ml
to 0.6 mg/ml. In one preferred particularly embodiment irinotecan
hydrochloride is present in the first set of infusion containers at
a concentration of 1.5 mg/ml and at a volume ranging from about 50
ml to about 300 ml, in the second set of infusion containers at a
concentration of 0.4 mg/ml and at a volume ranging from about 10 ml
to about 100 ml and in the third set of infusion containers at a
concentration of 0.2 mg/ml and at a volume ranging from about 10 ml
to about 100 ml.
[0040] In one preferred embodiment, wherein the drug is Irinotecan
hydrochloride, the currently approved product of Irinotecan
hydrochloride (Camptosar.RTM.) is indicated for the treatment of
metastatic colorectal cancer with following two treatment regimens,
(colorectal combination regimens and colorectal single-agent
regimens) wherein the target dose of irinotecan to be delivered is
based on body surface area (BSA).
[0041] a) Colorectal Combination Regimens: [0042] 125 mg/m.sup.2
intravenous (i.v.) infusion over 90 minutes on Days 1, 8, 15, 22 in
6-week cycles with 5-flourouracil and leucovorin [0043] 180
mg/m.sup.2 i.v. infusion over 90 minutes on Days 1, 15, 29 in
6-week cycles with 5-flourouracil and leucovorin
[0044] b) Colorectal Single-Agent Regimens [0045] 125 mg/m.sup.2
i.v. infusion over 90 minutes on Days 1, 8, 15, 22 followed by a
2-week rest [0046] 350 mg/m.sup.2 i.v. infusion over 90 minutes
once every 3 weeks
[0047] Essentially, the approved dose is either 125 mg/m.sup.2 or
180 mg/m.sup.2 or 350 mg/m.sup.2 based on the body surface area for
different dosage regimens. For a patient having a body surface area
of 1.8 m.sup.2, the single daily target dose that is needed can be
calculated which comes to be 225 mg or 324 mg or 630 mg,
respectively. This dose can be delivered within .+-.5% variance by
the method of the present invention by selecting first set of
infusion containers and if required selecting one or more infusion
containers from the second and third sets of infusion containers of
the present invention. For instance, to deliver a 225 mg dose, one
can select a first set of perfusion container that have 150 ml of
aqueous solution of irinotecan hydrochloride at a concentration of
1.5 mg/ml. For delivering 324 mg, one can select a first set of
perfusion container that have 210 ml of aqueous solution of
irinotecan hydrochloride at a concentration of 1.5 mg/ml and
additionally a second set of perfusion container that have 50 ml of
aqueous solution of irinotecan hydrochloride at a concentration of
0.2 mg/ml. The dose delivered by these containers is 325 mg, i.e.
0.3% more than the calculated desired dose of 324 mg and is within
.+-.5% variance limit.
[0048] In this illustrative embodiment, wherein the drug is
Irinotecan hydrochloride, suitable instructions may be provided
according to the method or system of the present invention to
calculate the dose to be administered based on one of patient's
parameters, such as patient's body surface area and for selecting
one or more perfusion container(s) from the first set and if
required one or more top-up perfusion container(s) from the second
or third set and for directly administering the drug from the
selected perfusion containers such that the delivered dose is equal
to or within .+-.5% of the calculated dose. Such instructions for
example are illustrated below in Tables a, b and c.
[0049] According to one embodiment of the method or system of the
present invention, there is provided calculation of dose and
instructions for selecting one or more perfusion containers for
administering drug, irinotecan hydrochloride at a dose of 125
mg/m2, in accordance with body surface area as the patient
parameter in table (a) below:
TABLE-US-00001 TABLE (a) First set of Perfusion Top-up Top-up
container perfusion containers - perfusion Drug Second set
containers - Third set concentration - Drug concentration - Drug
concentration - 1.5 mg/ml: 0.4 mg/ml: 0.2 mg/ml: Volume Volume
Volume % Total delivered Dose delivered from Dose delivered Dose
Variation** Target from delivered second delivered from third
delivered from Dose to first from first top up from top- top up
from top- Total dose delivered be perfusion perfusion perfusion up
perfusion up delivered dose Vs BSA delivered container container
container container container container (mg) calculated (m.sup.2)
(mg) D (ml) (a) (mg) (ml) (b) (mg) (ml) (c) (mg) (a + b + c) dose
1.3 162.5 90 135 50 ml 20 mg 50 ml 10 mg 165 1.5 1.4 175 120 180 0
0 0 0 180 2.86 1.5 187.5 120 180 0 0 50 ml 10 mg 190 1.3 1.6 200
120 180 50 ml 20 mg 0 0 200 0 1.7 212.5 120 180 50 ml 20 mg 50 ml
10 mg 210 -1.2 1.8 225 150 225 0 0 0 0 225 0 1.9 237.5 150 225 0 0
50 ml 10 mg 235 -1.1 2.0 250 150 225 50 ml 20 mg 0 0 245 -2.0 2.1
262.5 180 270 0 0 0 0 270 2.86 2.2 275 180 270 0 0 0 0 270 -1.8 2.3
287.5 180 270 50 ml 20 mg 0 0 290 0.9 2.4 300.0 180 270 50 ml 20 mg
50 ml 10 mg 300 0 **% Variation from delivered dose Vs calculated
dose = [((a + b + c) - D]D .times. 100
[0050] One or more perfusion containers may be suitably selected
from first, second and third set of perfusion containers to deliver
the calculated target dose within .+-.5% of variation.
[0051] According to another embodiment of the method or system of
the present invention, there is provided calculation of dose and
instructions for selecting one or more perfusion containers for
administering drug, irinotecan hydrochloride at a dose of 180
mg/m2, in accordance with body surface area as the patient
parameter in table (b) below:
TABLE-US-00002 TABLE (b) First set of Perfusion Top-up Top-up
container perfusion containers - perfusion Drug Second set
containers - Third set concentration - Drug concentration - Drug
concentration - 1.5 mg/ml: 0.4 mg/ml: 0.2 mg/ml: Volume Volume
Volume % Total delivered Dose delivered from Dose delivered Dose
Variation** Target from delivered second delivered from third
delivered from Dose to first from first top up from top- top up
from top- delivered be perfusion perfusion perfusion up perfusion
up Total dose dose Vs BSA delivered container container container
container container container delivered calculated (m.sup.2) (mg) D
(ml) (a) (mg) (ml) (b) (mg) (ml) (c) (mg) (a + b + c) dose 1.3 234
mg 150 ml 225 mg 0 0 50 ml 10 mg 235 mg 0.4% 1.4 252 mg 150 ml 225
mg 50 ml 20 mg 50 ml 10 mg 255 mg 1.2% 1.5 270 mg 180 ml 270 mg 0 0
0 0 270 mg 0% 1.6 288 mg 180 ml 270 mg 50 ml 20 mg 0 0 290 mg 0.7%
1.7 306 mg 210 ml 315 mg 0 0 0 0 315 mg 2.9% 1.8 324 mg 210 ml 315
mg 0 0 50 ml 10 mg 325 mg 0.3% 1.9 342 mg 210 ml 315 mg 50 ml 20 mg
50 ml 10 mg 345 mg 0.88% 2.0 360 mg 240 ml 360 mg 0 0 0 0 360 mg 0%
2.1 378 mg 240 ml 360 mg 50 ml 20 mg 0 0 380 mg 0.5% 2.2 396 mg 270
ml 405 mg 0 0 0 0 405 mg 2.27% 2.3 414 mg 270 ml 405 mg 0 0 50 ml
10 mg 415 mg 0.2% 2.4 432 mg 270 ml 405 mg 50 ml 20 mg 50 ml 10 mg
435 mg 0.7% **% Variation from delivered dose Vs calculated dose =
[((a + b + c) - D]D .times. 100
[0052] One or more perfusion containers may be suitably selected
from first, second and third set of perfusion containers to deliver
the calculated target dose within .+-.5% of variation.
[0053] According to another embodiment of the method or system of
the present invention, there is provided calculation of dose and
instructions for selecting one or more perfusion containers for
administering drug, irinotecan hydrochloride at a dose of 350
mg/m2, in accordance with body surface area as the patient
parameter in table (c) below:
TABLE-US-00003 TABLE (c) First set of Perfusion Top-up Top-up
container perfusion containers - perfusion Drug Second set
containers - Third set concentration - Drug concentration - Drug
concentration - 1.5 mg/ml: 0.4 mg/ml: 0.2 mg/ml: Volume Volume
Volume % Total delivered Dose delivered from Dose delivered Dose
Variation** Target from delivered second delivered from third
delivered from Dose to first from first top up from top- top up
from top- delivered be perfusion perfusion perfusion up perfusion
up Total dose dose Vs BSA delivered container container container
container container container delivered calculated (m.sup.2) (mg) D
(ml) (a) (mg) (ml) (b) (mg) (ml) (c) (mg) (a + b + c) dose 1.3 455
mg 270 ml 405 mg 100 ml 40 mg 0 0 445 mg -2.2% (50 .times. 2) 1.4
490 mg 240 ml 360 mg 0 0 0 0 495 mg 1.0% 90 ml 135 mg 0 0 0 0 1.5
525 mg 240 ml 360 mg 0 0 0 0 515 mg -1.9% 90 ml 135 mg 50 ml 20 mg
0 0 1.6 560 mg 270 ml 405 mg 50 ml 20 mg 0 0 560 mg 0% 90 ml 135 mg
0 0 0 0 1.7 595 mg 270 ml 405 mg 0 0 0 0 585 mg -1.7 120 ml 180 mg
0 0 0 0 1.8 630 mg 270 ml 405 mg 0 0 0 0 630 mg 0% 150 ml 225 mg 0
0 0 0 1.9 665 mg 270 ml 405 mg 0 0 0 0 675 mg 1.5% 180 ml 225 mg 0
0 0 0 2.0 700 mg 270 ml 405 mg 50 ml 20 mg 0 0 695 mg -0.7% 180 ml
225 mg 0 0 2.1 735 mg 270 ml 405 mg 50 ml 20 mg 0 0 740 mg 0.7% 210
ml 270 mg 0 0 0 0 2.2 770 mg 270 ml 405 mg 0 0 0 0 765 mg -0.65%
240 ml 360 mg 0 0 0 0 2.3 805 mg 270 ml 405 mg 0 0 0 0 810 mg 0.62%
270 ml 405 mg 0 0 0 0 2.4 840 mg 270 ml 405 mg 50 ml 20 mg 0 0 830
mg -1.2% 270 ml 405 mg 0 0 0 0 **% Variation from delivered dose Vs
calculated dose = [((a + b + c) - D]D .times. 100
[0054] One or more perfusion containers may be suitably selected
from first, second and third set of perfusion containers to deliver
the calculated target dose within .+-.5% of variation.
[0055] The method and system of the present invention is
particularly advantagenous as it avoids the complex and error prone
delivery of intravenous infusions that use concentrated solutions
which require prior dilution before intravenous administration. For
example, a comparison is made between the method of delivery of a
specific dose of irinotecan using currently marketed concentrated
product Camptosar.RTM. as against the system/method of the present
invention. For illustrative purposes, in order to deliver a total
dose of, 225 mg, Camptosar.RTM. being available at a concentration
of 20 mg/mL in three sizes i.e 2 ml, 5 ml and 15 mL; following are
the alternatives that can be followed. [0056] 2 ml vial (each vial
contains 40 mg irinotecan hydrochloride)--Solutions from 5 vials
and 1.25 ml from the 6.sup.th vial to be transferred to another
container followed by dilution to 150 ml using a diluent such as
dextrose solution. (the remaining 0.75 ml solution from 6.sup.th
vial to be discarded) [0057] 5 ml vial (each vial contains 100 mg
irinotecan hydrochloride)--Solutions from 2 vials and 1.25 ml from
the 3.sup.rd vial to be transferred to another container followed
by diluted to 150 ml (remaining 3.75 ml solution from 3.sup.rd vial
to be discarded) [0058] 15 ml (each vial contains 300 mg irinotecan
hydrochloride)--11.25 ml solution to be withdrawn from a 15 ml vial
and further diluted q.s to 150 ml. (remaining 3.75 ml solution to
be discarded).
[0059] The steps of dilution and administering a dose using
Camptosar.RTM. is complex, requires manipulation (dilution) and is
prone to errors and also involve wastage of drug solution. In
contrast, the method of the present invention provides for
convenient delivery of the desired dose avoiding the aforesaid
disadvantages. Thus, it is apparent that the method/system of the
present invention conveniently provides different sets of perfusion
containers containing ready-to-infuse, stable, sterile aqueous
solution of the irinotecan hydrochloride and instructions for
selecting the appropriate concentration using combination of the
two or more perfusion container from either first and/or second or
third set of perfusion containers so that accurate dose is
delivered. For instance, to deliver a total dose of 225 mg, the
method of the present invention provides a first set of perfusion
bag having 150 ml of 1.5 mg/ml irinotecan hydrochloride and
instructions for selecting the same.
[0060] The aqueous solution of drug in containers of the first set
and containers of the second and third sets in one preferred
embodiment, is similar in excipients except their concentrations.
The pharmaceutically acceptable excipients or adjuvants that may be
used in formulating the ready-to-infuse, stable, sterile, aqueous
perfusion solution of drug include, but are not limited to pH
adjusting and/or buffering agents, tonicity adjusting agents,
chelating agents, solvents etc. In one embodiment, the aqueous
perfusion solution of drug is preservative free.
[0061] Suitably, a pH adjusting and/or buffering agents is used to
adjust the pH of the aqueous solution to a suitable range at which
the drug solution is stable. The pH of the solution may be adjusted
in the desired range by use of a pH adjusting agents and or a
buffering agent known in the pharmaceutical art. The pH adjusting
agents and/or buffering agents that may be used in the present
invention may be selected from, but not limited to, tromethamine,
lactic acid or its salts, acetic acid or its salts, boric acid or
its salt, phosphoric acid or its salt, citric acid or its salt,
tartaric acid or its salt, hydrochloric acid, sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium hydrogen carbonate,
and the like and mixtures thereof.
[0062] In one preferred embodiment, the aqueous perfusion solution
of irinotecan or its salts such as irinotecan hydrochloride is
adjusted to a pH in the range of about 3.0 to about 4.5,
preferably, about 3.5 to 4.25. In one specific embodiment, the pH
of the solution is adjusted to about 3.5.
[0063] Suitably, the aqueous perfusion solution of drug filled in
the perfusion containers, may contain an osmolality or tonicity
adjusting agents in an amount sufficient to make the solution
isoosmolar to blood plasma, i.e. to provide an osmolality in the
range of about 250-375 mOsm/kg, preferably 280-320 mOsm/kg. The
tonicity adjusting agents that may be used in the present invention
are selected from, but not limited to, dextrose, sucrose, sodium
chloride, potassium chloride, calcium chloride, mannitol, glycerol,
sorbitol, propylene glycol, and the like, and mixtures thereof.
Preferably, the tonicity adjusting agent is dextrose.
[0064] Suitably, the perfusion containers according to the method
of the present invention may be a perfusion bag, infusion bag,
flexible pouch or soft bag. The container is made up of a suitable
material such as plastic or other polymeric material. The container
may include one or more layers of such materials, thus the
container may be single or multiple layered. In preferred
embodiments, the material of construction of the perfusion
containers is such that it can withstand terminal sterilization,
such as autoclaving. Suitably, the material of construction of the
perfusion containers may be selected from, but not limited to,
polyolefin polymers, polyethylene, polypropylene; cyclo olefin
polymers, cyclo olefin copolymers, polypropylene based polyolefin
polymers; polycarbonates; modified polyolefin-polyethylene polymers
or styrene-polyolefin based polymers and block co-polymers thereof.
Suitably, the container may have material that contains borate or
boron. Preferably, according to one embodiment, the container does
not contain polyvinylchloride. The containers are easy to handle
and transport. The perfusion containers are not impermeable in
nature and possess some permeation characteristics and the aqueous
solution of drug remains in contact with these materials of the
container throughout the shelf life of the dosage form.
[0065] In one specific preferred embodiment, the perfusion
containers are made up of an outer layer of polyamide 11, a middle
tie of modified polyolefin and an inner layer of linear low density
polyethylene. These containers have a water vapour transmission
rate of 2 g (m.sup.2day) when measured at (40.degree. C./90%
relative humidity); oxygen transmission rate of 900 ml/(m.sup.224
houratm) when measured at (23.degree. C./0% relative humidity) and
carbon dioxide transmission rate of 600 ml/(m.sup.224 houratm) when
measured at 23.degree. C./0% relative humidity. Such containers are
available commercially and are manufactured by Hosokawa as
PolyeliteAE-1. In another preferred embodiment the perfusion
containers may be made up of a material comprising a polymer of
cyclic olefin such as cyclooolefin homopolymer or cycloolefin
copolymer or mixture thereof. Specifically, in a particular
embodiment, the container comprises an inner layer made up of a
cycloolefin polymer, a middle layer made up of linear low density
polyethylene polymer and an outer layer made up of low density
polyethylene polymer. Such containers are available commercially
and are manufactured by Hosokawa as PolyeliteEHC film bag. In
another embodiment, the perfusion containers may be made up of an
outer layer of polypropylene polymer with styrene-ethylene-butylene
(SEB) block copolymer and a middle and inner layer made up of
polypropylene based polyolefin polymer with styrene-ethylene
butylene block copolymer. Such containers are available
commercially and are manufactured by Technoflex These type of
containers have a water vapour transmission rate of 0.62 g
(m.sup.2day) when measured at 23.degree. C./60% relative humidity;
oxygen permeability of 1110 ml/(m.sup.224 houratm) when measured at
23.degree. C./40% relative humidity and carbon dioxide transmission
rate of 5149 ml/(m.sup.224 houratm). Alternatively, the perfusion
containers may be made up of multilayer polyolefin film (M312 and
M312A) with a multilayered polyolefin tubing (M916 and M916A). Such
containers are available under the brand names of Sippex.
[0066] In one embodiment, the perfusion containers have a single
outlet for withdrawal of the aqueous solution from the container
while being administered intravenously. Suitably all of the
containers have such a single outlet. This design avoids any
manipulation, such as volume adjustment (addition or removal of
aqueous solution) prior to intravenous infusion. According to one
preferred embodiment, the single outlet is a single infusion port
or connector, which in one embodiment may have three assembled
parts including a central stopper made up of chlorobutyl rubber
(latex free); an upper breakable part and a bottom part, both made
up of polycarbonate. Such ports are available under the brand names
of Minitulipe.RTM.. In one specific embodiment, the stopper is made
up of Minitulipe M95A spike port with chlorobutyl (latex free) 6321
GS joint Sippex 323. The perfusion container with single outlet
port is represented by FIG. 1. In one embodiment, the infusion port
allows for insertion of an infusion set, cannula/needle prior to
administration such that it allows a tight connection with the
infusion line and allows for single outward flow of the aqueous
solution. In one embodiment, the perfusion container and the
delivery port connecting to the infusion needle forms a system
whereby during intravenous administration of the solution to the
patient, the vacuum created by outgress of solution is accommodated
by the elasticity or flexibility of the perfusion container instead
of ingress of external non-sterile air, which advantageously
maintains and ensures sterility of the solution until it reaches
the patient.
[0067] In one embodiment, the perfusion container includes a
thermally resealable portion that is fusible in response to thermal
energy, and a container body having a sealed empty chamber in fluid
communication with the resealable portion for receiving therein the
aqueous solution of the present invention. The method of filling
the container includes penetrating the resealable portion with an
injection member and introducing the aqueous solution of the
present invention into the chamber, withdrawing the injection
member while engaging the base of the body to substantially prevent
axial movement of the body, and applying thermal energy to the
resealable portion to thermally fuse the penetrated region thereof.
Such systems are elaborated in U.S. Pat. No. 7,992,597, which is
incorporated herein by reference.
[0068] In another embodiment, the perfusion container may include a
chamber for receiving aqueous solution of the present invention and
a thermoplastic portion in fluid communication with the chamber.
The thermoplastic portion defines a penetrable region that is
penetrable by a filling member and is heat resealable to
hermetically seal an aperture therein by applying laser radiation
at a predetermined wavelength and power and in a predetermined time
period. Such systems are elaborated in U.S. Pat. No. 7,490,639,
which is incorporated herein by reference.
[0069] In yet another embodiment, the perfusion container include a
sealed chamber; a first penetrable septum in fluid communication
with the chamber that is formed of an elastic material and is
penetrable by a first injection member to fill the first chamber
with the aqueous solution of the present invention therethrough;
and a second penetrable septum movable between first and second
positions. In the first position, at least a portion of the second
septum is spaced away from the first septum to allow the injection
member to penetrate the first septum and aseptically or sterile
fill the chamber with the aqueous solution of the present invention
therethrough. In the second position, the portion of the second
septum overlies and seals a resulting injection aperture in the
first septum after withdrawal of the first injection member
therefrom, and is penetrable by a second injection member to
penetrate the first and second septums and withdraw the filled
aqueous solution of the present invention from the chamber and
through the second injection member. Such systems are elaborated in
United States patent application number US20130333796, which is
incorporated herein by reference.
[0070] The perfusion containers which do not have any resealable
portions may also be used according to the method or system of the
present invention. The perfusion containers filled with aqueous
solution of drug are sterilized by way of terminal sterilization.
Preferably, the terminal sterilization is done by autoclaving of
the filled perfusion containers. Preferably, the terminal
sterilization techniques used in the present invention include use
of counter pressure sterilizers such as `Super heated water
sterilizer` and `steam air mixture sterilizers`. According to one
preferred embodiment, the terminal sterilization is carried out via
autoclaving in a super heated water spray sterilizer at following
process parameters--Minimum Sterilization Temperature-121.0.degree.
C.; Maximum Sterilization Temperature--122.0.degree. C.; Control
Temperature--121.5.degree. C.; Exposure Time--15.0 minutes and
Sterilization Pressure--3.50 bar.
[0071] In one embodiment, the perfusion containers that have been
sterilized as described above, are packaged in a secondary
packaging that surrounds the perfusion container. The secondary
packaging may comprise a second container such as a pouch or
overwrap or carton. The secondary packaging may comprise a suitable
pouch, such as an aluminium pouch covering the perfusion container
of the first component. It may further comprise an oxygen scavenger
in between the perfusion container and overwrap or pouch. In one
preferred embodiment, the secondary packaging comprises both an
aluminium pouch and an oxygen scavenger. The secondary packaging
may further comprise an outer black polyethylene bag and a
fiberboard drum. Silica gel bags may optionally be placed between
the aluminum pouch and the black polyethylene bags. In one
embodiment, either the perfusion container of the first component
or the secondary packaging, is designed to protect the solution of
drug from light. Suitably, in one embodiment, the material of the
perfusion container is such that it provides light protection. The
container may be amber colored or opaque to provide protection from
light. In another embodiment, the material of construction of the
perfusion container is such that the containers are transparent
which makes it possible to carry out visual inspection of the drug
solution prior to and during administration of the drug solution,
which ensures safety. In this embodiment, the secondary
packaging--pouch or overwrap or carton is made up of a suitable
light protective material such as for example aluminum. In one
embodiment, the secondary packaging/aluminium pouch incorporates a
transparent window for visual inspection of the aqueous drug
solution. In one embodiment, the space between the perfusion
container and secondary packaging is occupied with an inert gas
such as nitrogen or argon.
[0072] The present invention in one embodiment also provides a
perfusion system comprising a first set of perfusion containers
comprising, consisting essentially or containing a ready-to-infuse,
stable, sterile, aqueous perfusion solution of the drug at a first
higher concentration, and a second set of top-up perfusion
containers comprising, consisting essentially or containing a
ready-to-infuse, stable, sterile, aqueous perfusion solution of the
drug at a second concentration and optionally a third set of top-up
perfusion containers comprising, consisting essentially or
containing a ready-to-infuse, stable, sterile, aqueous perfusion
solution of the drug at a third concentration, the first
concentration of drug being higher than the second and third
concentrations, the first to the third sets of perfusion containers
ranging in volume from a higher volume to a lower volume, wherein
the set of perfusion containers alone or in combination provide for
direct intravenous administration of desired dose of the drug to a
patient in need thereof, such that the delivered dose is equal to
or within .+-.5% of the desired dose calculated based on one of
patient's parameters.
[0073] Particularly, the present invention also relates to a
perfusion system comprising: [0074] a first set of perfusion
containers comprising a ready-to-infuse, stable, sterile, aqueous
perfusion solution of a drug at a first higher concentration, and a
second set of top-up perfusion containers comprising a
ready-to-infuse, stable, sterile, aqueous perfusion solution of the
drug at a second concentration and optionally a third set of top-up
perfusion containers comprising a ready-to-infuse, stable, sterile,
aqueous perfusion solution of the drug at a third concentration,
the first concentration of drug being higher than the second and
third concentrations, the first to the third sets of perfusion
containers ranging in volume from a higher volume to a lower
volume, [0075] instructions for selecting one or more perfusion
container(s) from the first set and if required one or more top-up
perfusion container(s) from the second or third set and for
directly administering the drug from the selected perfusion
containers such that the delivered dose is equal to or within
.+-.5% of a dose calculated according to at least one patient
parameter, [0076] wherein the set of perfusion containers alone or
in combination provides for direct intravenous administration of a
desired dose of the drug to a patient in need thereof, such that
the delivered dose is equal to or within .+-.5% of the calculated
dose.
[0077] The present invention in one embodiment also provides a
first set of perfusion containers containing a ready-to-infuse,
stable, sterile, aqueous perfusion solution of irinotecan or its
pharmaceutically acceptable salt at a first higher concentration
ranging from 1.0 mg/ml to 3.0 mg/ml, and a second set of top-up
perfusion containers containing a ready-to-infuse, stable, sterile,
aqueous perfusion solution of irinotecan or its pharmaceutically
acceptable salt at a second concentration ranging from 0.1 mg/ml to
0.6 mg/ml, and optionally a third set of top-up perfusion
containers having a ready-to-infuse, stable, sterile, aqueous
perfusion solution of irinotecan or its pharmaceutically acceptable
salt at a third concentration ranging from 0.1 mg/ml to 0.6 mg/ml,
the set of perfusion containers ranging in volume from a 10 ml to
500 ml, wherein the set of perfusion containers alone or in
combination provide for direct intravenous administration of
desired dose of the drug to a patient in need thereof, such that
the delivered dose is equal to or within .+-.5% of the desired dose
calculated based on one of patient's parameters. Generally the
volume of a container from the first set of containers is greater
than the volume of a container from the second set of containers,
and the volume of a container from the third set of containers is
generally less than the volume of a container from the second set
of containers. In one preferred embodiment, wherein the drug is
irinotecan hydrochloride, the perfusion containers are multilayered
and are flexible. The outermost layer which is not in contact with
the aqueous solution is made up of polyamide, a middle layer made
up of modified polyolefin and the innermost layer which is in
contact with the aqueous solution of irinotecan is made up of
linear low density polyethylene. The perfusion containers are same
for all the set of containers. The containers are overwrapped with
a light protective material having oxygen scavenger. The
overwrapped material may be an aluminum pouch. The ready-to-infuse
aqueous solution comprise an osmotic agent in an amount sufficient
to make the solution isoosmolar and a pH adjusting agent or a
buffer to adjust and maintain the pH in the range of 3.0 to 4.5.
The filled perfusion containers are sterilized by terminal
sterilization, such as autoclaving i.e. wet heat sterilization or
steam sterilization at 121.degree. C. for 15 minutes at 3.5 bar
pressure. These sterilized filled perfusion container are then
packed in secondary packaging which is designed to protect the
solution of drug from light. More preferably in this embodiment,
the osmotic agent is selected from dextrose, glucose, sorbitol or
mixtures thereof and the pH adjusting agent is selected from lactic
acid, hydrochloride acid, sodium hydroxide or mixtures thereof.
[0078] Suitably, according to the present invention, the perfusion
dosage form or the ready-to-infuse aqueous solution of drug filled
in the perfusion container is physically as well as chemically
stable as demonstrated by compliance to acceptable specification,
when the dosage form is stored at room temperature (20-25.degree.
C. and 40% relative humidity) for at least twelve months,
preferably eighteen months, more preferably 24 months or longer.
The dosage form also show compliance to acceptable specification
when stored at accelerated stability testing condition of
40.degree. C./25% relative humidity for 6 months, which correlate
with stability for 2 years of shelf life. Various parameters such
as the drug content (assay) and content of related substances, i.e.
known and unknown impurities remains within specified limits such
as those specified according to ICH guidelines or
pharmacopeias.
[0079] In one preferred embodiment wherein the drug is irinotecan,
the ready-to-infuse aqueous solution of irinotecan remains
physically stable, with solution being clear, free from visible
particulate matter, no precipitation or crystallization or color
change upon storage and the value of percentage transmittance of
the solution remaining greater than 90%, preferably greater than
95% upon storage at room temperature for the shelf life period of
18-24 months. Further, the solution of irinotecan remains
chemically stable when stored at room temperature (about 25.degree.
C.) for at least 12 months and at 40.degree. C./25% relative
humidity for 6 months, wherein various parameters such as the drug
content (assay of irinotecan) and content of related substances,
i.e. known and unknown impurities remains within specified limits
upon storage. Suitably, the value of assay of irinotecan remains
within the specified limit of 90%-110% by weight of the label
claim; the highest unknown impurity remains within the specified
limit of not more than 0.2%; the known impurities or related
substances remains within the specified limit of not more than 0.2%
and the total impurities remain within the specified limit of not
more than 1.0%. The sealed perfusion bags comprising aqueous
solution of Irinotecan hydrochloride remains stable for the shelf
life when stored at 20.degree. C.-25.degree. C. (68-77.degree. F.)
and that allows for excursions between 15.degree. and 30.degree. C.
(59.degree. and 86.degree. F.).
[0080] Hereinafter, the invention will be more specifically
described by way of Examples. The examples are not intended to
limit the scope of the invention and are merely used as
illustrations.
Example 1
TABLE-US-00004 [0081] TABLE 1 Set of Perfusion containers having
Irinotecan hydrochloride drug: Different sets of perfusion
containers 90 mL 120 mL 150 mL 180 mL 210 mL 240 mL 270 mL
Ingredients Amount in mg Irinotecan hydrochloride 135 180 225 270
315 360 405 trihydrate Sorbitol 303.75 405 506.25 607.5 708.75 810
911.25 Lactic acid 6.075 8.100 10.125 12.150 14.175 16.2 18.225
Dextrose (anhydrous) 4162.5 5550 6937.5 8325 9712.5 11100.0 12487.5
HCl For pH adjustment in the range of 3-5 NaOH For pH adjustment in
the range of 3-5 Concentration (mg/ml) Irinotecan hydrochloride 1.5
Sorbitol 3.375 Lactic acid 0.0675 Dextrose 46.25
[0082] The composition of ready-to-infuse aqueous solutions of
irinotecan and method of preparation is given below:
TABLE-US-00005 TABLE 2 Composition of ready-to-infuse aqueous
solutions of irinotecan Ingredient Quantity mg/mL Irinotecan
hydrochloride, USP 0.2 mg-2.0 mg Dextrose, USP (anhydrous) 40-50 mg
Sorbitol, NF 2-5 mg Lactic acid, USP 0.01-0.1 mg Sodium hydroxide,
NF and q.s. to adjust pH in the range of 3-5 Hydrochloric acid, NF
Water for injection, USP q.s. to 1 mL q.s. = quantity
sufficient
[0083] Water for injection was purged with nitrogen. Dextrose was
added and dissolved with stirring, followed by addition and
dissolution of sorbitol. Lactic acid was then added and dissolved
with stirring. Irinotecan hydrochloride was then added slowly into
the above bulk solution with continuous stirring until complete
dissolution and pH was checked. pH was then adjusted to 3 to 5 with
10% w/v hydrochloric acid or sodium hydroxide solution. The
solution was then filtered through membrane filter cartridge
(0.2.mu..times.10 in). The filtered bulk solution was filled in a
perfusion bag and the bag was then stoppered. The stoppered
perfusion container was then terminally sterilized via autoclaving
in a super heated water spray sterilizer. The perfusion bag was
then over wrapped in an aluminum pouch and an oxygen scavenger was
placed in between the container and aluminum pouch.
[0084] The process parameters at which terminal sterilization was
carried out are given below in Table 3
TABLE-US-00006 TABLE 3 Autoclaving process parameters Process
parameters Value/Level 1. Minimum Sterilization Temperature
121.0.degree. C. 2. Maximum Sterilization Temperature 122.0.degree.
C. 3. Control Temperature 121.5.degree. C. 4. Exposure Time 15.0
minute 5. Sterilization Pressure 3.50 bar
[0085] Different batches of perfusion dosage forms prepared
according to Example 1 were charged for stability testing at
varying storage conditions--i.e. long term stability testing at
controlled room temperature 25.degree. C./40% relative humidity as
well as at accelerated stability testing condition at 40.degree.
C./25% relative humidity. The observations for various parameters
for three different batches are tabulated in table 4-6.
TABLE-US-00007 TABLE 4 Chemical and physical stability results of
one batch: 25.degree. C./ 30.degree. C./ 40.degree. C./ 40% RH 35%
RH 25% RH Analytical Test Initial Six months Assay of Irinotecan
101.44 100.76 100.42 101.20 Related compound B * 0.121 0.132 0.134
0.147 (Impurity A) Highest unknown Impurity 0.097 0.114 0.135 0.139
Total Impurity 0.724 0.638 0.634 0.653 Osmolality (mOsm/Kg) 292 295
293 296 pH 3.98 3.90 3.92 3.90 % T at 650 nm 99.879 100.000 100.000
100.000 % T = percentage transmittance: RH = Relative Humidity *
Related compound B- (S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':
6,7]indolizino[1,2-b]quinoline-3,14 (4H,12H)-dione.
TABLE-US-00008 TABLE 5 Chemical and physical stability results of
second batch: 25.degree. C./40% RH 40.degree. C./25% RH Analytical
Test Initial Six months Assay of Irinotecan 100.33 101.09 100.98
Related compound B * 0.137 0.126 0.145 (Impurity A) Highest unknown
0.106 0.118 0.138 Impurity Total Impurity 0.789 0.626 0.615
Osmolality (mOsm/Kg) 291 294 293 pH 4.16 3.83 3.93 % T at 650 nm
100.0 100.0 100.0 % T = percentage transmittance: RH = Relative
Humidity * Related compound B-
(S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':
6,7]indolizino[1,2-b]quinoline-3,14 (4H,12H)-dione.
TABLE-US-00009 TABLE 6 Chemical and physical stability results of
third batch: 25.degree. C./ 40.degree. C./ 40% RH 25% RH After12
After 6 Analytical Test Limits Initial month month Assay of
Irinotecan 90%-110% 99.89 99.33 99.5 Related compound B * NMT 0.2%
BQL BQL BQL (Impurity A) Highest unknown NMT 0.2% 0.096 0.096 0.107
Impurity Total Impurity NMT 1.0% 0.192 0.196 0.253 Osmolality
(mOsm/Kg) 250-350 289 287 297 pH 3-5 3.67 3.55 3.48 % T NLT 95%
99.9 100 100 RH = Relative Humidity; BQL--Below Quantifying limit;
NMT--Not more than; % T = percentage transmittance * Related
compound B is (S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':
6,7]indolizino[1,2-b]quinoline-3,14 (4H,12H)-dione; NLT--Not less
than
[0086] It was observed that in all the batches, the assay of the
drug remains within the specified limit upon storage. All
impurities, highest unknown impurity, total impurities and related
compounds remain within specified limits upon storage. The
particulate matter remains within specification upon storage and
the solution remains clear. The percentage transmission, which is
an indicator of the clarity of the solution does not change, it
remains about 100% indicating that the solution maintains proper
clarity. There occurs no substantial change in the osmolality and
pH of the solution upon storage. Thus, it can be concluded that the
perfusion dosage form of the present invention maintains proper
stability, physical and chemical, through out the shelf life.
* * * * *