Note: Descriptions are shown in the official language in which they were submitted.
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PARENTERAL PHARMACEUTICAL COMPOSITIONS CONTAINING GF120918A
FIEI,D OF THE INVF.~TION
The present Invention relates to novel pharmaceutical compositions that
5 are useful in ~r~v~nling malignant cells from becoming resistant to a diverse
variety of chemotherapeutic agents.
BACKGROUND OF THE INVENTION
The multidrug-resistance inhibitor, chemirAlly known as N-{4-[2-1,2,3,4-
10 tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-
9-oxo-4-acridine carbox~mi~l~ and its physiologically acceptable salts and solvates is
described and ~ e~ in World Patent Application WO 92/12132 filed in the
name of Laboratires Glaxo S.A. and published July 23, 1992. Multidrug-resistanceis a process whereby tumor cells become resistant to structurally diverse
15 chemotherapeutic agents following exposure to treatment with anti-tumor drugs.
This acquired drug resistance can be a major obstacle in the clinical treatment and
management of malignant disease. It has been shown that this type of resistance
can be reversed by GF120918, resensitizing multidrug-resistant tumor ceIls to
various chemotherapeutic agents. It has also been seen that certain tumors are
20 intrinsically multidrug-resistant and the use of multidrug-resistance inhibitors are
also beneficial in treating tumors of this type.
GF120918A, the hydrochloride salt of N-{4-[2-1,2,3,4-tetrahydro-6,7-
dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo 4
25 acridine carboxAmi~l~, to be safely and effectively administered to patients
parenlerally by either intravenous injection or intravenous infusion must be
adequately miscible in the blood. Therefore, any combination of the drug and thevarious excipients, in a liquid form, must be sllffl~iPntly compatible with the
physiological composition of the blood to allow sufficient admixing. This mixing30 with the blood allows the compound to be distributed throughout the body in an
unr~m~rk~hle fashion. However, problems exist with the parental administration
of GF120918A due to the compounds poor solubility- GF120918A is a weak base
and therefore exhibits a higher solubility at a pH less than about 4. Since the pH of
the blood is approximately 7-4, the c~pound alone in solution precipitates upon
35 injection or infusion into the blood stream.
An object of the present Inventionis to provide a parenteral formulation
that when injected or infused into the blood stream remains miscible and allows
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the active drug to be distributed throughout the body in an unremarkable fashion.
A further object of the present Invention is to provide a parenteral formulationand method of use that will improve or increase the efficacy of a
chemotherapeutic agent or restore sensitivity of a tumor to chemotherapeutic
5 agent or reverse or reduce resistance of a tumor to a chemotherapeutic agent;
subsequently abating tumor cell multidrug-resistance and decreasing morbidity.
Publications such as In Vitro Method for l~etecting Precipitation of
parenteral Forml~lAtion~ After Injections Journal of Pharmaceutical Sciences, Vol.
72, No. 9, September 1983; Pluronic SllrfActAnts Affecting Diazepam Solubility,
Compatibility, and Adsorption From i.v. Admixture Solutions, Journal of Surface
Sciences, Vol. 11, No. 4, 1988, Taiwan, Republic of China, Precipitation of the
Renin Inhibitor Ditekiren Upon iv Infusion: in Vitro Studies and Their
Relation~l~ip to in VivQ Precipitation in the Cynomolgus Monkey Pharmaceutical
Research, Vol. 8, No. 1, 1991; Intravenous premedication with diazepam A
comparison between two vehicles Anesthesia, 1984, Vol. 39, p. 879-882;
Precipitation of Solub;1i7~d Drugs due to Injection or Dilution Drug Intelligence
and t~linic~l Pharmacy, Vol. 11, July 77; and U.S. Patents 4 205 089 and 4 296 131
issued May 27, 1980 and October 20, 1981 both to Ladage et al., teach how to increase
the solubility of a compound in a formulation. These publications advocate the
use of: cosolvents, complexing agents, hydrotropic agents, liposomes, fat
~m~ ions, polyaphrons, dimethylsulfoxide and surfactants. However, even
though GF120918A is soluble in the standardized formulations utilized for
parenlelal administration, precipitation nevertheless occurs upon injection or
infusion into the blood stream. This precipitation on infusion occurs as the
formulation, a weak base, mixes within the pH neutral blood stream. The novel
compositions of the present Invention maintain solubility within the blood
stream and prevent precipitation of the drug upon injection or infusion into theblood stream.
SUMMARY OF THE INVENTION
The present Invention relates to pharmaceutical compositions that prevent
or minimize precipitation upon injection or infusion; comprising:
a) a safe and therapeutically effective amount of N-{4-[2-1,2,3,4-tetrahydro-
6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-
oxo-4-acridine carboxamide and its physiologically acceptable salts and
solvates;
b) a safe and effective amount of a surfactant;
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c) a buffer; and
d) a p~ArmAceutically acceptable carrier or diluent.
D~AT~.Fn DESCRII~IlQN OF IHE INVENTION
By "safe and therapeutically effective amount," as used herein, means a
sufficient amount of a drug or pharmaceutical agent to abate or reverse a
multidrug-resistance response of a tissue, system or animal that is being sought by
the researcher or clinician without ~Arming the tissues of a mammal, including ahuman to which the drug is administered.
The compositions of the present Invention employ a safe and
therapeutically effective amount of the compound N-{4-[2-1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl] -phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-
acridine carboxamide (GF120918) and its physiologically acceptable salts and
solvates, a safe and effective amount of a surfactant, a safe and effective amount of
a buffer and a carrier or diluent suitable for pharmaceutical use. These
compositions are suitable for administration to mAmmAl.s, including humans
through various parenleral routes. These various parenteral routes particularly
include both intravenous bolus injection and intravenous infusion.
Persons who treat cancer and other diseases which become resistant to
chemotherapeutic, anti-tumor compounds would use the compositions of the
present Invention to resensitize multidrug-resistant cells to chemotherapeutic
agents thus abating multidrug-resistance. Therefore, compositions of the presentInvention may be administered in conjunction with an antitumor drug.
Examples of suitable antitumor drugs for use in conjunction with compositions ofthe present include, but are not limited to, Vinca AlkAloifls (e.g. vincristine,vinblastine and vinorelbine, anthracyclines (e.g. daunorubincin, doxorubicin andaclarubincin, taxol, and derivatives thereof (e.g. taxotere), podophyllotixins (e.g.
etoposide and VP16), mitoxantrone, actinomycin, colchicine, gramidine D,
cisplatin, cyclophosphamide, amsacrine or any other chemotherapeutic, antitumor
type compounds.
Compositions of the present Invention while being given in conjunction
with an antitumor drug, could also be given simultaneously with an anti-tumor
drug. This type of administration is acceptable as long as the components of thecomposition of the present Invention and any antitumor compound given
simultaneously are both physically and chemically compatible. In this instance
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"simultaneously" means, sequentially with little or no delay or given together
from a common single container where the composition of the present Invention
and the antitumor drug are physically mixed.
The ~er~ic~Al community, particularly oncologists and other me-1icAl
professionals who treat persons afflicted with tumor disease recognize that
patients suffer various adverse side-effects from the administration of
chemo~erapeutic anti-tumor drugs. One of the most serious side effects produced
by chemotherapeutic anti-tumor drugs is nausea and vomiting. Nausea and
vomiting can result in severe consequences leading to increased morbidity and
mortality. Compositions of the present Invention may also be administered with
various drug formulations to combat side-effects produced by anti-tumor
chemotherapy. These other drug formulations may be given either
simultaneously or in conjunction with formulations of the present Invention. If
given simllltAneously by either being admixed in the same syringe for injection or
admixed in the same intravenous bag or bottle for infusion the various
formulations must be both physically and chemically compatible with
compositions of the present Invention. If, however, the formulation given in
conjunction with compositions of the present Invention or given together at the
same time, but from a different container or is given by another route or given
intravenously either prior to or subsequently to compositions of the present
Invention physical and ch~micAl reactivity should not be problematic.
Parenteral compositions of the present Invention must be in a sterile form.
Any of the various methods known to persons skilled in the art employed to
prepare sterile parenteral preparations that will nct degrade components of the
present Invention are suitable for use in the compositions sterile preparation.
Parenleial compositions of the present Invention may be packaged, produced or
contained in packaging materials such as single use ampoules, vials or
intravenous bottles or bags or alternatively in multidose or multiuse vials or
containers.
Compositions of the present Invention may also be packaged as articles of
manufacture comprising a safe and therapeutically effective amount of GF120918
and its physiologically acceptable salts and solvates; a safe and effective amount of
a surfactant; a buffer; and a pharmaceutically acceptable carrier or diluent, packaged
as described above. The packaging material may also have labeling and
information relating to the pharmaceutical composition printed thereon.
.
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Additionally an article of manufacture may have a brochure, report, notice,
pamphlet, or leaflet containing product information. This form of pharmaceuticalproduct information is sometimes, in the pharmaceutical industry, called the
"package insert." A package insert may be attached to or included with a
5 ph~rmAceutical artide of manufacture. The package insert and any article of
manufacture labeling provides information relating to the pharmaceutical
composition. This information and labeling provides various forms of
information tltili7e-1 by health care professior~Al~ and patients that describes the
composition, its dosage and various other parameters required by regulatory
10 agencies, such as the United States Food and Drug Administration.
The pH of the present compositions range from about 1 to about 5,
particularly from about 2.5 to about 4. The essential, as well as possible optional
components of the compositions of the present Invention, are described in the
15 following paragraphs.
Essential Components
One of the essential components of the present Invention is GF120918 and
its physiologically acceptable salts and solvates, described in International Patent
20 Application WO 92/12132 published 23 July 1992. GF120918 is an acridine
derivative that is able to reverse or reduce resistance to, increase or restore
sensitivity to or improve or increase the efficacy of an chemotherapeutic agent or
agents.
The amount of GF120918 administered to prevent, abate or reverse
multidrug resistance in a m~mm~l including a human will vary with the nature
of the condition being treated and the age and the condition of the patient and will
be ultimately at the discretion of the attendant physician or veterinarian. In
general, however, doses employed for adult human treatment will typically be in
the range of about 1 mg to about 10 gm per day, particularly from about 10 mg toabout 1 gm per day and more particularly from about 25 mg to about 750 mg per
day. The desired dose may conveniently be presented in a single dose or as
divided doses administered at a~rv~liate intervals, for example as two, three,
four or more sub-doses per day.
Another of the essential components of by the present Invention is a
surface-active agent or a mixture of compatible surface-active agents, sometimesreferred to as surfactants. Any compatible surface-active agent is sufficient for use
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in the present Invention, however, nonionic surface-active agents are particularly
suitable.
Nonionic surface-active agents are particularly suitable in compositions of
5 the present Invention and can be broadly defined as compounds produced by the
condensation of alkylene oxide groups (hydrophilic in nature) with an organic
hydrophobic compound which may be aliphatic or alkylaromatic in nature.
Examples of suitable nonionic surfactants include, but are not limite-l to:
pluronics, polyethylene oxide condensates of alkyl phenols, products derived from
10 the condensation of ethylene oxide with the reaction product of propylene oxide
and ethylene ~i~mine, ethylene oxide condensates of aliphatic alcohol's, long
chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain
dialkyl sulfoxides and mixtures of such materials.
The surface-active agent or mixtures of compatible surface-active agents can
be present in the compositions of the present Invention from about 0.05% to about
20.0%, parti~llArly from about 0.1% to about 10.0% and most particularly from
about 0.5% to about 5.0% by weight of the total composition.
The surface-active agents best suited for inclusion into the present
composition are: polyethylene glycol 660 hydroxystearate (SOLUTOL(~) HS-15),
polyoxyethylene castor oil derivatives (CREMOPHOR(~) EL, RH40, and RH60),
poloxamer, polyoxyethylene aL~yl ethers (CETOMACROGOL(g) 1000) and
polyoxyethylene sorbitan fatty acid esters (POLYSORBATE(3) 20, 40, 60, and 80 and
TWEEN~) 20, 40, 60 and 80). In particular polyethylene glycol 660 hydroxystearate,
polyethylene glycol, polyoxyethylene castor oil derivatives and polyoxyethylene
sorbitan fatty acid esters are useful in compositions of the present Invention.
Another essential component of the present Invention is a buffer or
mixture of buffers. Buffers are compounds or mixtures of compounds which if
present in a solution resist changes in the pH of the solution upon the addition of
small quantities of acids or bases. Further information about buffers can be found
in Remington's p~ArmAceutical Sciences, p. 243 - 45 17th ed. (1985). Examples ofbuffers suitable for use in compositions of the present Invention include: acetate,
phosphate and glutAmAte
The last essential component of the present Invention is a suitable carrier or
diluent that provides an appropriate vehicle for parenteral delivery of the
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composition without the introduction of untoward side-effects. Persons skilled in
the art will quickly realize that any carrier or diluent intended for parenteraladministration that is compatible with the essential and any optional componentsof the present Invention will be suitable. Examples of suitable carriers and
diluents include, but are not limited to: dextrose 5% in water and sterile water for
injection.
Optional Components
In ~d~lition to the above described essential components, the compositions
of the present Invention can contain a variety of optional parenteral conventional
components known to persons skilled in the art. Any optional components
included in compositions of the present Invention must be physically and
chemically compatible with the essential components of the present Invention.
Optional components include, but are not limited to: cosolvents, including but not
limited to, polyethylene glycol (PEG) grades 200 to 600, propylene glycol (1,2-
propanediol), ethanol and glycerin, preservatives and agents that adjust isotonicity
and osmolality. Further information concerning preservatives and agents to
adjust isotonicity and osmolAlity can be found in Remington's Pharmaceutical
Sciences, p. 1278 - 1280, 1455 - 1472, 17th ed. (1985)
Optional components may also include other drugs or combinations of
drugs that are physically and c~emic~lly compatible with compositions of the
present Invention. Possible optional additional drugs include, but are not limited
to antitumor chemotherapeutic agents, antinausents including, serotonin 5-HT3
receptor antagonists such as ondansetron and granisetron and various other
antinausents such as prochlorperazine, chlorpromazine, perphenazine,
thiethylperazine, trifluprom~7.ine, droperidol, methochlopramide,
trimethobenzamide, dronabinol, pherergan, nabilone and methylpredinisone.
Other additional optional drugs include: antibiotics, antidepressants, antiulcercompounds, analgesics, anticholornergics, antivirals and a myriad of other drugssuitable to treat conditions that also require the administration of compositions of
the present Invention.
METHOD OF MANUFACTURE
The compositions of the present Invention can be made using methods and
techniques that are commonly employed in preparing parenteral preparations
within the pharmaceutical industry. Remington's Pharmaceutical Sciences, p.
1518 - 1541, 17th ed. (1985).
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COMPOSII~ON USE
Compositions of the present Invention in their method aspect involves
administering to a mAmmAl, including a human a safe and effective amount of
the compositions of the present Invention described herein. These safe and
5 effective amounts will vary based on the type and size of mAmn~l being treated and the results wished to be obtained.
EXAMpT.F~
The following examples further describe and demonstrate particular
10 embo~liments within the scope of the present Invention. The examples are given
solely for illustration and are not to be construed as limitations as many variations
are possible without departing from the Invention's spirit and scope.
Fxample I
Ir~gre~ nts Amounts
GP120918A 0.53 mg
(-~1A~;A1 acetic acid 2.87 microliters
TWEEN 80~) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Preparation
100 mL of 0.5 mg GF120918A/mL Intravenous Infusion, 0.05M Acetate, pH
3.75, 1% v/v TWEEN 80, qs with 5% Dextrose in water.
Pipette 286.5 IlL of glacial acetic acid into a beaker and add approximately 50
mL of D5W. Weigh 1.08 g of polysorbate 80 and add to the beaker with glacial
acetic acid and D5W. Using a spatula and rinsing with D5W if necessary, dispersethe polysorbate 80 by stirring. Weigh 53.2 mg of GF120918A and dissolve it in the
above solution. Add additional D5W until a total volume of approximately 98 mL
is achieved. Dissolve 5 g of sodium hydroxide in 30 mL of distilled, deionized
water in a separate beaker. Add the sodium hydroxide solution dropwise with
stirring to the solution until a pH of 3.75 is achieved. Pour the resulting solution
into a 100 mL volumetric flask and q.s. to 100 mL with D5W. Stir or shake the
solution to ensure homogeneity. Filter the final solution through a 0.22 ~1 filter to
ensure sterility.
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~mple TT
GF120918A 0.53 mg
l acetic acid 2.87 microliters
CREMOPHOR EL~ 10 microliters
Sodium Hydroxide adjustto pH3.75
5% Dextrose in water (USP) qs to 1 mL
~xample m
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
CREMOPHOR RH40~) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
~rnple IV
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
CREMOPHOR RH60(~) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Fxample V
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
SOLUTOL H~15(E~) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Example VI
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 60(~) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
Example VII
GF120918A 3.19 mg
PEG 300 0.4 mL
TWEEN 80(~) 100 microliters
Glacialacetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
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F.x~mple V~TT
GF120918A 3.19 mg
PEG 300 0.4 mL
CREMOPHOR EL~g) 100 microliters
Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
T~xample IX
GF120918A 3.19 mg
PEG 300 0.4 mL
TWEEN 60~) 100 microliters
Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
Fxample X
GF120918A 3.19 mg
PEG 300 0.4 mL
CREMOPHOR RH40(~) 100 microliters
Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
Example ~T
GF120918A 3.19 mg
PEG 300 0.4 mL
CREMOPHOR RH60(~) 100 microliters
Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
Example XTT
GF120918A 3.19 mg
PEG300 0.4 mL
SOLUTOL HS-15(g) 100 microliters
Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
=
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11
R~Ample X~TT
GF120918A 3.19 mg
PEG 300 0.4 mL
. TWEEN 20~) 100 microliters
Glacialacetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
RxAm,ple XTV
GF120918A 3.19 mg
PEG 300 0.4 mL
TWEEN 40~) 100 microliters
Glacial acetic acid 17.2 microliters
Sodium Hydroxide adjust to pH 3.5
Water for Injection (USP) qs to 1 mL
Rxample XV
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 20(~) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
ExAmple XVI
GF120918A 0.53 mg
Glacial acetic acid 2.87 microliters
TWEEN 40(g) 10 microliters
Sodium Hydroxide adjust to pH 3.75
5% Dextrose in water (USP) qs to 1 mL
