U.S. patent application number 16/633048 was filed with the patent office on 2020-07-02 for liquid dosage forms of imatinib.
This patent application is currently assigned to FTF PHARMA PRIVATE LIMITED. The applicant listed for this patent is FTF PHARMA PRIVATE LIMITED. Invention is credited to Jayanta Kumar MANDAL, Sandip MEHTA, Vijay PATEL, Manish UMRETHIA.
Application Number | 20200206223 16/633048 |
Document ID | / |
Family ID | 63517936 |
Filed Date | 2020-07-02 |
![](/patent/app/20200206223/US20200206223A1-20200702-C00001.png)
United States Patent
Application |
20200206223 |
Kind Code |
A1 |
MEHTA; Sandip ; et
al. |
July 2, 2020 |
LIQUID DOSAGE FORMS OF IMATINIB
Abstract
Imatinib is approved and marketed in solid oral dosage forms
which may be dispersed in water or apple juice for patients having
swallowing difficulty. Dispersion of Imatinib solid dosage forms in
apple juice may increase palatability and patient compliance but
apple juice may not be available all the time for administration.
Further, dispersion of Imatinib solid oral dosage forms may not
administer correct and consistent dose of medicine every time. The
present invention therefore provides liquid dosage forms of
Imatinib which correctly and consistently administers correct dose
of drug to the patients.
Inventors: |
MEHTA; Sandip; (AHMEDABAD,
IN) ; PATEL; Vijay; (AHMEDABAD, IN) ;
UMRETHIA; Manish; (AHMEDABAD, IN) ; MANDAL; Jayanta
Kumar; (AHMEDABAD, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FTF PHARMA PRIVATE LIMITED |
Ahmedabad, Gujarat |
|
IN |
|
|
Assignee: |
FTF PHARMA PRIVATE LIMITED
Ahmedabad, Gujarat
IN
|
Family ID: |
63517936 |
Appl. No.: |
16/633048 |
Filed: |
July 26, 2018 |
PCT Filed: |
July 26, 2018 |
PCT NO: |
PCT/IB2018/055583 |
371 Date: |
January 22, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 47/26 20130101; A61K 9/0095 20130101; A61K 47/10 20130101;
A61K 31/506 20130101; A61K 47/12 20130101; A61K 47/36 20130101;
A61K 9/0053 20130101; A61K 47/02 20130101; A61K 9/08 20130101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 47/10 20060101 A61K047/10; A61K 47/26 20060101
A61K047/26; A61K 47/12 20060101 A61K047/12; A61K 47/02 20060101
A61K047/02; A61K 9/00 20060101 A61K009/00; A61K 9/08 20060101
A61K009/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 26, 2017 |
IN |
201721026519 |
Mar 21, 2018 |
IN |
201823010403 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. (canceled)
22. (canceled)
23. (canceled)
24. (canceled)
25. (canceled)
26. A liquid dosage form of imatinib comprising: about 0.01% w/v to
about 25% w/v of imatinib mesylate; about 25% w/v to about 60% w/v
of glycerin; about 0.01% w/v to about 10% w/v of sodium benzoate;
about 0.01% w/v to about 10% w/v of liquid maltitol; citric acid in
a quantity sufficient to adjust the pH of the liquid dosage form to
a desired pH; and water in a quantity sufficient to bring the final
volume of the liquid dosage form to the desired volume.
27. The liquid dosage form of claim 26, further comprising: about
0.01% w/v, to about 5% w/v of acesulfame or the potassium salt
thereof.
28. The liquid dosage form of claim 26, further comprising about
0.01% w/v to about 5% w/v of strawberry flavour.
29. The liquid dosage form of claim 26, wherein the pH is from
about 2.0 to about 7.0.
30. The liquid dosage form of claim 26 is ready to use oral
solution.
31. The liquid dosage form of claim 26 is stable liquid dosage form
characterized in that any individual impurity present in the liquid
dosage form is not more than 2.0% and the total impurities present
in the liquid dosage form are not more than 5.0%.
32. (canceled)
33. The liquid dosage form of claim 26, wherein the dosage form
has: (a) a C.sub.max for imatinib, or a salt thereof, when assayed
in the plasma of a mammalian subject following administration that
is at least about 70% to about 143% greater than the C.sub.max for
an imatinib marketed or known formulation, administered at the same
dose; (b) an AUC for imatinib, or a salt thereof, when assayed in
the plasma of a mammalian subject following administration that is
at least about 80% to about 125% greater than the AUC for an
imatinib marketed or known formulation, administered at the same
dose; (c) a T.sub.max for imatinib, or a salt thereof, when assayed
in the plasma of a mammalian subject following administration that
is less than about 6 hours to about 8 hours; or (d) any combination
of (a), (b), and (c).
34. The liquid dosage form of claim 26 is packaged in the
pharmaceutically acceptable packaging material selected from the
group comprising ofcontainers, pumps, bottles with spray pump,
bottles with dropper assembly, bottles, collapsible tubes, glass
ampoules, stoppered vials, pre-filled syringes, wherein the bottles
and containers are clear or transparent or opaque or amber colored
glass bottles and containers or clear or transparent or opaque or
amber colored plastic bottles and containers made from
polyethylene, low-density polyethylene, high-density polyethylene,
polyamide, polyolefin, polycarbonate, acrylic multipolymers,
polypropylene, polyethylene terephthalate, polyvinyl chloride,
polystyrene.
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. A liquid dosage form of imatinib comprising: about 0.01% w/v to
about 25% w/v of imatinib or a pharmaceutically acceptable salt
thereof having d.sub.90 between about 10 .mu.m and about 200 .mu.m;
about 0.01% w/v to about 10% w/v of a suspending agent; about 10%
w/v to about 90% w/v of a solvent or co-solvent; and a vehicle in a
quantity sufficient to bring the final volume of the liquid dosage
form to the desired volume.
42. The liquid dosage form of claim 41, wherein the suspending
agent is selected from the group consisting of acacia, agar,
alginic acid, carbomer, carmellose sodium, dextrin, gelatin, veegum
or gel white, gellan gum, sodium alginate, methylcellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxypropyl starch, hypromellose,
maltodextrin, methylcellulose, modified starch, pectin, poloxamer,
polycarbophil, polyethylene glycol, polyvinyl acetate, poly (vinyl
alcohol), potassium alginate, polyvinyl pyrrolidone, pregelatinized
starch, propylene glycol alginate, sodium alginate, carboxymethyl
cellulose or an alkali metal salt thereof, microcrystalline
cellulose, gum arabic, karaya gum, sterculia gum, tragacanth,
xanthan gum, bentonite, carageenan, guar gum, colloidal silicon
dioxide or any combination thereof.
43. (canceled)
44. (canceled)
45. The liquid dosage form of claim 41, wherein the solvent or
co-solvent is selected from the group consisting of
dichloromethane, acetonitrile, ethyl acetate, acetone, propylene
carbonate, glycerin, coconut fatty acid diethanolamide, medium
and/or long chain fatty acids or glycerides, monoglycerides,
diglycerides, triglycerides, structured triglycerides, soyabean
oil, peanut oil, corn oil, corn oil monoglycerides, corn oil
diglycerides, corn oil triglycerides, polyethylene glycol,
caprylocaproyl macrogol-8 glycerides, caproyl 90, propylene glycol,
polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor
oil derivatives, castor oil, cottonseed oil, olive oil, safflower
oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic
acid, methanol, ethanol, isopropyl alcohol, butanol, acetone,
methyl isobutyl ketone, methyl ethyl ketone or any combination
thereof.
46. (canceled)
47. (canceled)
48. (canceled)
49. The liquid dosage form of claim 41, optionally comprising pH
modifying agent or buffering agent selected from the group
consisting of acetic acid, adipic acid, ammonium carbonate,
ammonium hydroxide, ammonium phosphate, boric acid, citric acid,
diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric
acid, propionic acid, potassium acetate, potassium bicarbonate,
Potassium chloride, potassium citrate, potassium metaphosphate,
potassium phosphate, sodium acetate, sodium bicarbonate, sodium
borate, sodium carbonate, sodium chloride, sodium citrate, sodium
glycolate, sodium hydroxide, sodium lactate, odium phosphate,
sodium proprionate, succinic acid, sulfuric acid, tartaric acid,
triethylamine, triethanolamine, tromethamine, trolamine or any
combination thereof in a quantity sufficient to adjust the pH of
the liquid dosage form to a desired pH.
50. (canceled)
51. (canceled)
52. The liquid dosage form of claim 41, further comprising one or
more of the following, about 0.01% w/v to about 50% w/v of a
sweetening agent selected from the group consisting of glucose,
sucralose, trehalose, fructose, xylose, dextrose, galaxies,
tagatose, maltose, sucrose, glycerol, dulcitol, mannitol, lactitol,
sorbitol solution, xylitol, liquid maltitol, saccharine or the
corresponding sodium, potassium or calcium salt, cyclamate or the
corresponding sodium or calcium salt, aspartame, or acesulfame or
the potassium salt thereof, dulcin or ammonium glycyrrhizinate,
alitame, linulin, lisomalt, neohesperidin dihydrochalcone,
thaumatin or any combination thereof; about 0.01% w/v to about 5%
w/v of a flavoring agent selected from the group consisting of
synthetic flavor oils and flavoring aromatics and/or natural oils,
extracts from plant leaves, flowers, fruits, cinnamon oil, oil of
wintergreen, peppermint oils, clove oil, bay oil, anise oil,
eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage,
oil of bitter almonds, cassia oil, citrus oil, vanilla, lemon,
orange, grape, lime, grapefruit flavors, apple, banana, pear,
peach, strawberry, raspberry, cherry, plum, pineapple, apricot
essences or any combination thereof; 0% w/v to about 10% w/v of an
anti-foaming agent selected from the group consisting of
simethicone, organic phosphates, alcohols, paraffin oils,
stearates, glycols or any combination thereof; 0% w/v to about 10%
w/v of a surfactant selected from the group consisting of sodium
lauryl sulfite, docusate sodium, cocamidopropyl amino betaine,
polyoxyethylene sorbitan fatty acid esters (polysorbate,
Tween.RTM.), polyoxyethylene 15 hydroxystearate (macrogol 15
hydroxystearate, Solutol HSI15)), polyoxyethylene castor oil
derivatives (Cremophor.RTM. EL, ELP, RH 40), polyoxyethylene
stearates (Myrj.RTM.), sorbitan fatty acid esters (Span.RTM.),
polyoxyethylene alkyl ethers (Brij.RTM., polyoxyethylene
nonylphenol ether (Nonoxynol.RTM. or any combination thereof; 0%
w/v to about 10% w/v of an anti-oxidant selected from the group
consisting of .alpha.-tocopherol acetate, ascorbic acid, erythorbic
acid, butylated hydroxytoluene (BHT), d-.alpha.-tocopherol natural,
monothioglycerol, sodium bisulfite, sodium sulfite, sodium
metabisulfite, potassium metabisulfite, acetone sodium bisulfite,
ascorbyl palmitate, cysteine, d-.alpha.-tocopherol synthetic,
nordihydroguaiaretic acid, sodium formaldehyde sulfoxylate, sodium
thiosulfate, acetylcysteine, ascorbyl palmitate, butylated
hydroxyanisole (BHA), cysteine hydrochloride, dithiothreitol,
propyl gallate, thiourea or any combination thereof; and 0% w/v to
about 10% w/v of a preservative selected from the group consisting
of ethanol, chlorobutanol, phenoxyethanol, potassium benzoate,
benzyl alcohol, benzoic acid, potassium sorbate, sorbic acid,
benzalkonium chloride, benzethonium chloride, cetrimonium bromide,
cetylpyridinium chloride, bronopol, chlorbutol, chlorocresol,
cresol, butylparaben or salt thereof, methylparaben or salt
thereof, propylparaben or salt thereof, ethylparaben or salt
thereof, phenol, thymol, phenylethanol, sodium benzoate, propylene
glycol, glycerin, ghloroform or any combination thereof.
53. (canceled)
54. (canceled)
55. (canceled)
56. (canceled)
57. (canceled)
58. (canceled)
59. (canceled)
60. (canceled)
61. (canceled)
62. (canceled)
63. (canceled)
64. (canceled)
65. The liquid dosage form of claim 41, wherein the pH is from
about 4.0 to about 9.0.
66. (canceled)
67. The liquid dosage form of claim 41, wherein the vehicle is
selected from the group consisting of water, medium chain
triglyceride and combination thereof.
68. (canceled)
69. The liquid dosage form of claim 41 is ready to use oral
suspension.
70. The liquid dosage form of claim 41 is stable liquid dosage form
characterized in that any individual impurity present in the liquid
dosage form is not more than 2.0% and the total impurities present
in the liquid dosage form are not more than 5.0%.
71. (canceled)
72. (canceled)
73. The liquid dosage form of claim 41, wherein the dosage form
has: (a) a C.sub.max for imatinib, or a salt thereof, when assayed
in the plasma of a mammalian subject following administration that
is at least about 70% to about 143% greater than the C.sub.max for
an imatinib marketed or known formulation, administered at the same
dose; (b) an AUC for imatinib, or a salt thereof, when assayed in
the plasma of a mammalian subject following administration that is
at least about 80% to about 125% greater than the AUC for an
imatinib marketed or known formulation, administered at the same
dose; (c) a T.sub.max for imatinib, or a salt thereof, when assayed
in the plasma of a mammalian subject following administration that
is less than about 6 hours to about 8 hours; or (d) any combination
of (a), (b), and (c).
74. The liquid dosage form of claim 41 is packaged in the
pharmaceutically acceptable packaging material selected from the
group comprising of containers, pumps, bottles with spray pump,
bottles with dropper assembly, bottles, collapsible tubes, glass
ampoules, stoppered vials, pre-filled syringes, wherein the bottles
and containers are clear or transparent or opaque or amber colored
glass bottles and containers or clear or transparent or opaque or
amber colored plastic bottles and containers made from
polyethylene, low-density polyethylene, high-density polyethylene,
polyamide, polyolefin, polycarbonate, acrylic multipolymers,
polypropylene, polyethylene terephthalate, polyvinyl chloride,
polystyrene.
75. (canceled)
76. (canceled)
77. (canceled)
78. (canceled)
79. (canceled)
80. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates, in general, to the
pharmaceutical field, and more precisely it relates to the liquid
dosage forms of protein-tyrosine kinase inhibitor such as Imatinib
or pharmaceutically acceptable salt thereof. In particular, the
present invention relates to ready to use, liquid dosage forms of
Imatinib or pharmaceutically acceptable salt thereof and to the
processes for the preparation thereof.
BACKGROUND OF THE INVENTION
[0002] Imatinib, chemically known as
N-(4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino)phenyl)-4-[(4-methylp-
iperazin-1-yl)methyl]benzamide having an empirical formula
C.sub.29H.sub.31N.sub.7O and a molecular weight of 493.6 gm/mol has
a following structural formula:
##STR00001##
[0003] Imatinib mesylate is a protein-tyrosine kinase inhibitor; it
inhibits the abnormal functioning Bcr-Abl tyrosine kinase, which is
produced by the Philadelphia chromosome abnormality, found in
chronic myeloid leukemia (CML). Imatinib inhibits cell
proliferation and induces apoptosis (programmed cell death) in the
Bcr-Abl cell lines and in the leukemic cells generated by CML.
Imatinib also inhibits proliferation and induces apoptosis in
gastrointestinal stromal tumor (GIST) cells, which express an
activating c-kit mutation. More recently, the drug has been
approved for the treatment of mesenchymal cell neoplasms of the
intestinal tract.
[0004] It has now been discovered that Imatinib mesylate can be
used as a treatment for patients suffering from hepatic fibrosis
based on its ability to downregulate stellate cell activation in
culture and in vivo.
[0005] Imatinib mesylate is well absorbed after oral administration
with Cmax achieved within 2-4 hours post-dose. It was also reported
that mean absolute bioavailability is 98%. Biotransformation of
Imatinib mesylate is via hepatic metabolism and cytochrome P450
enzymes (especially CYP3A4). Imatinib mesylate is converted to its
main circulating active metabolite, a N-desmethylated piperazine
derivative. This derivative, in vitro, has potency similar to
Imatinib mesylate and comprises about 15% of the AUC (area under
the curve) for Imatinib mesylate. When imatinib mesylate is orally
administered, the elimination half-lives of Imatinib mesylate and
its major active metabolite, the N-desmethyl derivative, are
approximately 18 and 40 hours, respectively and the time to reach
peak concentration is 2 to 4 hours.
[0006] Imatinib mesylate is presently available as tablet form of
100 mg and 400 mg. The approved dosage range for imatinib mesylate
in the treatment of CML is 400 mg to 800 mg (400 mg twice a day)
and 600 mg per day for gastrointestinal stromal tumors (GIST).
[0007] It was reported that amounts of imatinib mesylate effective
to treat hepatic fibrosis would broadly range between about 50 mg
and about 600 mg per day and preferably between about 50 mg and
about 200 mg per day administered orally.
[0008] Prior art reveals that Imatinib or pharmaceutically
acceptable salt thereof has been formulated into solid dosage
forms. Liquid dosage forms of Imatinib or pharmaceutically
acceptable salt thereof are not much explored by the formulation
scientists. The prior arts mentioned in the forthcoming paragraphs
are incorporated herein by references for all the purposes.
[0009] EP 1895984 and US 20060275372 describes a stable
nanoparticulate composition of imatinib mesylate, or a salt thereof
and at least one surface stabilizer. EP 2009008 discloses a
pharmaceutical composition comprising imatinib mesylate having less
than about 0.09% area HPLC percent units of desmethyl-imatinib
mesylate and at least one pharmaceutically acceptable cxcipients.
EP 2120877 and US 2010087444 describes a solid dispersion of
imatinib mesylate comprising imatinib mesylate and a
pharmaceutically acceptable carrier, wherein said carrier is a
cellulose derivative.
[0010] US 2016143850 and EP 3019159 describes a granulate
composition of imatinib mesylate comprising of imatinib mesylate,
binder and of disintegrant.
[0011] US 2008119479 discloses a pharmaceutical composition which
comprises ZD6474 or a pharmaceutically acceptable salt thereof, and
imatinib, in association with a pharmaceutically acceptable
cxcipient or carrier. EP 2782560 and US 2015125534 discloses a
pharmaceutical powder formulation comprising granules of a tyrosine
kinase inhibitor, wherein the granules of the tyrosine kinase
inhibitor are coated with an enteric coating, wherein the tyrosine
kinase inhibitor is present in an amount of up to 23% by weight
based on the total weight of the pharmaceutical powder
formulation.
[0012] WO 2006132930 discloses a pharmaceutical combination
comprising a pyrimidylaminobenzamide compound and Imatinib.
[0013] U.S. Pat. No. 8,653,093. U.S. Pat. No. 7,767,688. EP 1893213
and WO 2006132930 discloses a medicament for the treatment of
gastrointestinal stromal tumours by use of a pharmaceutical
combination comprising of
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imida-
zol-1-yl)-3-(trifluoromethyl)phenyl]benzamide or a pharmaceutically
acceptable salt thereof, and imatinib or a pharmaceutically
acceptable salt thereof.
[0014] WO 2014041551 (hereinafter referred as '551 publication)
discloses oral aqueous solution comprising Imatinib or
pharmaceutically acceptable acid addition salts or polymorphs
thereof, process for preparing such solution and their use in the
treatment of chronic myeloid leukemia, gastrointestinal stromal
tumors. The specification of '551 publication teaches oral aqueous
solution which essentially comprises viscosity regulating agent
that is used to stabilize the active ingredient (i.e. Imatinib
mesylate) or increase the viscosity of the oral solution. Preferred
viscosity regulating agents according to the specification of '551
publication are polyvinyl pyrrolidone and hypromellose. Such
preferred viscosity regulating agent has not been used in the oral
solutions of the present invention being the first major difference
between the present invention and the invention disclosed in the
specification of '551 publication. Thus, the stability achieved by
the oral solution of the present invention and results provided in
the present specification are without using (i) viscosity
regulating agents preferred in the specification of '551
publication, and (ii) any additional stabilizing agent.
[0015] Further, the specification of '551 publication does not
provide stability results of the oral solution prepared therein.
Upon reading the specification of '551 publication, a skilled
person cannot have an idea regarding stability and shelf life of
the Imatinib oral solution disclosed therein. What the
specification provides is mere statement that "the formulation is
found to be stable throughout the period of the stability study."
(See page 19; lines 13-14) The specification of '551 does not
define what should be considered as "stable" and also that what is
the period of"stability study". Therefore it is difficult for a
skilled person to envisage stability of the oral solution disclosed
in the specification of '551 publication.
[0016] Another major difference between the invention disclosed in
the specification of '551 publication and the present invention is
that the oral solution of Imatinib disclosed in the specification
of '551 publication is shown supra-bioavailable (which means the
AUC and Cmax of the oral solution disclosed in the specification of
'551 publication is higher than either the acceptable values or
values shown by Imatinib tablets) when tested in rats against
Imatinib tablets, whereas the oral solution of the present
invention has been found bioequivalent (which means all the
pharmacokinetic parameters such as AUC, Cmax is within the
acceptable limits when compared with Imatinib tablets) to the
marketed Gleevec (Imatinib) tablets during clinical studies in
humans. Further, supra-bioavailability may not be advantageous as
sometimes it may lead to toxicity and/or other side effects.
Furthermore, just because the oral solution disclosed in the
specification of '551 publication is supra-bioavailable in rats
does not necessarily mean that it can be administered to humans.
Thus, the oral solution of Imatinib according to the present
invention is ready to use for human administration.
[0017] Currently available preparations of Imatinib are solid oral
preparations e.g. tablets, and capsules. These preparations have
their own disadvantages and limitations, for example they are not
suitable for all types of patient populations. Therefore there is
an existing need for liquid dosage forms of Imatinib having
prolonged stability and palatability.
[0018] Compared to the conventional tablets and capsules, oral
liquid dosage forms including solutions, syrups, suspensions,
elixirs, and concentrates offer unique advantages to many patients.
For example, liquids may provide better patient compliance for
those with swallowing difficulties and better dosage control versus
a fixed tablet dose. Hence, liquid dosage forms are generally
formulated for use in geriatric and pediatric patients. However,
there are also a number of "challenges" surrounding the formulation
and development of these forms.
[0019] Children generally reject taking medicine which does not
have a favorable shape, taste, flavor, etc. However, if a child who
needs to take a medicine, rejects taking it, he might never recover
from his condition. When a child is unable to take medicine orally,
it is intravenously administered, and he and his caregivers then
may experience stress. Syrups and suspensions are considered as
favorable types of dosage forms in which to orally administer
medicine to infants and children. However, they may have
disadvantages such as solubility, a bad taste, portability problems
or required refrigerator storage. Palatability is one of the main
elements of patient acceptability of an oral pediatric medicine.
Palatability is defined as the overall appreciation of an oral
medicinal product in relation to its smell, taste, aftertaste and
feeling in the mouth. Design of the formulation of an oral
pediatric medicine should be considered together with its
palatability.
[0020] According to Gleevec.RTM. prescribing information,
Gleevec.RTM. tablets can be dissolved in water or apple juice for
patients having swallowing difficulty but in any treatment an
important consideration is to ensure that the patient receives the
correct dose of medicine. Administration of Gleevec.RTM. tablets by
dissolving in water or apple juice may not administer correct and
consistent dose every time. Disadvantages associated with such an
administration is that (i) Gleevec tablets take much longer time to
get dispersed in water or apple juice and (ii) it leaves behind
lots of residues in the container after administration resulting
into the administration of incorrect dose. Further, Imatinib has
bitter taste and administration with apple juice may mask its taste
and increase the palatability and patient compliance. But apple
juice or any other flavored beverage may not be available all the
time while administering a drug to the patient. It may therefore
happen that patients have to take medicines with water which
creates cloying sensation in their mouth. Ii will therefore be
desirable to have Imatinib containing dosages in liquid forms which
also contain sweeteners and flavors which makes such dosage forms
palatable and more patient compliant. Further, liquid dosage forms
provide assurance of dosage uniformity upon administration to
patients and eliminates difficulty of administration. Liquid dosage
forms can also provide physicians more flexibility in designing
dosage regimens for patients. Such liquid dosage forms are
advantageous to pediatric patients, geriatric patients and those
patients who are unable to take oral therapy.
OBJECTS OF THE INVENTION
[0021] Because of their liquid character, liquid dosage forms
represent an ideal dosage form for patients who have difficulty
swallowing tablets or capsules. This factor is of particular
importance in administration of drugs to children and aged
patients. Further, as mentioned above, administration of Imatinib
tablets by dispersing in water or apple juice is also not preferred
because of administration of incorrect and inconsistent dose every
time. It is therefore principal object of the present invention to
provide liquid dosage forms of Imatinib or pharmaceutically
acceptable salt thereof. The liquid dosage forms of the present
invention are useful for administering to pediatric, geriatric
patients and other patients who are unable to take solid oral
therapy. The liquid dosage forms according to the present invention
include liquids, liquid dispersions, suspensions, solutions,
emulsions, sprays, spot-on, syrups, elixirs, drops, gels,
solution-gels, concentrates and the like.
[0022] Liquid dosage forms are designed as ready to use liquids and
as powder for reconstitution into liquid orals like syrups,
solutions, suspensions and emulsions. Powder for reconstitution may
require skills & expertise and needs to be prepared by a
healthcare provider and may not be prepared by the patient or
caregiver. The reconstitution process may also he a time consuming
process and the patient cannot be benefited by the immediate dose
of Imatinib as and when required. In such a situation, ready to
use, liquid dosage forms of Imatinib may be very useful and the
patients can be given required doses immediately using ready to
use, liquid dosage forms of Imatinib. Therefore, a yet another
object of the present invention is to provide ready to use, liquid
dosage forms of Imatinib or pharmaceutically acceptable salt
thereof.
[0023] The solution dosage form can be a viable alternative for
patients who have problems in swallowing the tablet or capsule
dosage form. It provides assurance of dosage uniformity upon
administration to patients and eliminates difficulty of
administration. A solution can also provide physicians more
flexibility in designing dosage regimens for patients. Imatinib
solution dosage form is suitable for administration to both
pediatric and geriatric patients while also compensating for a good
organoleptic properties and remaining suitably stable. Hence, the
development of a liquid formulation is therefore desirable since it
offers improved patient compliance. A yet another object of the
present invention is therefore to develop solution dosage forms of
Imatinib or pharmaceutically acceptable salt thereof. The solution
dosage forms according to the present invention comprises Imatinib
or pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients or additives selected from
the group comprising of vehicles, solvents/co-solvents,
solubilizers, surfactants, pH adjusting agents and/or pH1 modifying
agents and/or buffering agents or any combination thereof. The
solution dosage forms according to the present invention may
further comprise one or more agents selected from the group
comprising of preservatives, sweetening agents, flavoring agents
and coloring agents or any combination thereof.
[0024] Suspensions possess certain advantages over other liquid
dosage forms. Some drugs are insoluble in all acceptable media and
must, therefore, be administered as a tablet, capsule, or as a
suspension. In addition, disagreeable tastes can be masked by a
suspension of the drug or a derivative of the drug. Drugs in
suspension are chemically more stable than in solution. In another
object, the present invention therefore provides suspension dosage
forms of imatinib or pharmaceutically acceptable salt thereof. The
suspension dosage forms according to the present invention
comprises lmatinib or pharmaceutically acceptable salt thereof and
one or more pharmaceutically acceptable excipients or additives
selected from the group comprising of vehicles,
solvents/co-solvents, solubilizers, suspending agents/thickening
agents/viscosity modifying agents, anti-foaming agents, anti-caking
agents, wetting agents, surfactants, pH adjusting agents and/or pH
modifying agents and/or buffering agents or any combination
thereof. The suspension dosage forms according to the present
invention may further comprise one or more agents selected from the
group comprising of preservatives, sweetening agents, flavoring
agents and coloring agents or any combination thereof.
[0025] A yet another object of the present invention is to provide
liquid dosage forms of Imatinib or pharmaceutically acceptable salt
thereof having palatability, prolonged stability and improved
and/or comparable pharmacokinetic profile or bioavailability when
compared to the known or marketed Imatinib formulations. The liquid
dosage forms of the present invention comprise sweetener(s) and
flavoring agent(s) which masks the bitter taste of Imatinib and
provides pleasant taste.
[0026] A yet another object of the present invention is to provide
process for the preparation of liquid dosage forms of Imatinib or
pharmaceutically acceptable salt thereof.
[0027] A yet another object of the present invention is to provide
use of the liquid dosage forms of the present invention in the
manufacture of a medicament.
[0028] A yet another object of the present invention is to provide
liquid dosage forms of the present invention for use as a
medicament.
[0029] A yet another object of the present invention is to provide
method for the treatment of a disease or disorder that can be
treated by inhibiting protein-tyrosine kinase comprising
administering to a patient, such as human, an effective dosage
amount of a liquid dosage form comprising Imatinib or
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients or additives as disclosed
and described herein. A yet another object of the present invention
is to provide method for the treatment of a tumor disease or cancer
disease comprising administering to a patient, such as human, an
effective dosage amount of a liquid dosage form comprising Imatinib
or pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients or additives as disclosed
and described herein. A yet another object of the present invention
is to provide method for the treatment of at least one disease or
condition selected from the group comprising of chronic myeloid
leukemia, acute lymphoblastic leukemia, myeldysplastic diseases,
mycloproliferative diseases, aggressive systemic mastocytosis,
hypereosinophilic syndrome and/or chronic eosinophilic leukemia,
unresectable, recurrent and/or metastatic dermatofibrosarcoma
protuberans, and unresectable and/or metastatic malignant
gastrointestinal stromal tumors comprising administering to a
patient, such as human, an effective dosage amount of a liquid
dosage form comprising Imatinib or pharmaceutically acceptable salt
thereof and one or more pharmaceutically acceptable excipients or
additives as disclosed and described herein.
[0030] A yet another object of the present invention is to use the
liquid dosage forms of the present invention for the treatment of a
disease or disorder that can be treated by inhibiting
protein-tyrosine kinase. A yet another object of the present
invention is to use the liquid dosage forms of the present
invention for the treatment of a tumor disease or a cancer disease.
A yet another object of the present invention is to use the liquid
dosage forms of the present invention for the treatment of at least
one diseases or condition selected from the group comprising of
chronic myeloid leukemia, acute lymphoblastic leukemia,
myelodysplastic diseases, myeloproliferative diseases, aggressive
systemic mastocytosis, hypereosinophilic syndrome and/or chronic
cosinophilic leukemia, unrescctablc, recurrent and/or metastatic
dermatofibrosarcoma protuberans, and unresectable and/or metastatic
malignant gastrointestinal stromal tumors.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Characteristics of an active drug are of major concern in
developing an oral liquid dosage formulation. The major challenges
in developing oral liquid dosage forms are (i) the stability of a
drug in aqueous solution, suspension or emulsion. (ii) the
solubility of a drug at the required level, and (iii) an acceptable
taste and (iv) to be bioavailable when taken orally. It is the
effective use of excipients, which allows formulators overcome
these challenges Additionally, an excipient's compatibility with a
drug in the solid state cannot infer the same compatibility in
liquid dosage.
[0032] The decision to develop a solution, syrup or a suspension of
a drug is influenced by many factors like solubility, particle size
and the desired release profile of the drug and properties of the
base vehicle like surface tension, viscosity, boiling point, and
specific heat of solution, all of which may be affected in various
ways. In case of clear liquids, lack of solubility of the drug in
the base vehicle may demand the need for miscible pharmaceutical
co-solvents. Similarly, a miscible solvent may be needed to
decrease the solubility of the drug in a primary vehicle in
formulating a suspension.
[0033] The therapeutic utility of drugs involves the application of
dosage forms/delivery systems, which serve as carrier systems
together with several excipients to deliver the active therapeutic
agent to the site of action. Suspensions are an important class of
pharmaceutical dosage forms that may be given by many routes,
including oral, topical, parenteral, and also used in the eye for
ophthalmic purposes. Surprisingly, large proportions of new drug
candidates that are emerging are predominantly water insoluble and,
therefore, demonstrate poor bioavailability in the solution dosage
form. While suspensions present a viable formulation option for
many drugs, particularly for water insoluble, hydrophobic drug
substances, there are certain criteria that a well-formulated
suspension should meet.
[0034] The suspension dosage form has long been used for poorly
soluble active ingredients for various therapeutic indications.
Development of stable suspensions over the shelf life of the drug
product continues to be a challenge on many fronts. Drugs from
suspension formulations typically exhibit an improved
bioavailability when compared to the same drug formulated as a
tablet or capsule.
[0035] A good understanding of the fundamentals of disperse systems
is essential in the development of a suitable pharmaceutical
suspension. The development of a suspension dosage form follows a
very complicated path. The selection of the proper excipients
(surfactants, viscosity imparting agents etc.) is important. The
particle size distribution in the finished drug product dosage form
is a critical parameter that significantly impacts the
bioavailability and pharmacokinetics of the product.
[0036] The advantages of suspension dosage forms include effective
dispensing of hydrophobic drugs; avoidance of the use of
co-solvents; masking of unpleasant taste of certain ingredients;
offering resistance to degradation of drugs due to hydrolysis,
oxidation or microbial activity; easy swallowing for young or
elderly patients; and efficient intramuscular depot therapy. In
addition, when compared to solution dosage forms, relatively higher
concentration of drugs can be incorporated into suspension
products. To date, numerous theories have been introduced and
successfully used to explain the unique behavior of suspension
preparations.
[0037] An important consideration in any treatment regime is to
ensure that the patient receives the correct dose of medicine. For
many patients and many drugs there is an acceptable dose window
that allows fixed-dose medicines to be used to treat patients with
a wide range of body weights without the need to precisely adjust
the dose. However, there are other groups of patients where the
"fixed-unit-dose" model may not be appropriate, depending on the
drug's therapeutic index and pharmacokinetics. e.g. pediatric
patients, geriatric patients, patients with severe renal
insufficiency and patients with severe hepatic insufficiency. Oral
solid unit dose forms. e.g. tablets and capsules, are not
convenient under such circumstances since they are fixed strength
unit dose forms. In contrast, oral liquid dose forms do have the
in-built flexibility that allows the dose to be tailored to the
patients' needs.
[0038] Where the drug is sufficiently soluble, a solution dosage
form, e.g. a simple mixture, may be used. But not all drugs are
sufficiently soluble to allow suitable strength solution medicines
to be developed and manufactured with an acceptable shelf-life. In
such cases, an alternative approach could be to develop a stable
aqueous suspension that will allow consistent dosing of the
patient. Pharmaceutical suspensions have several advantages and
disadvantages when compared to other dosage forms. Since
suspensions are liquids, dose adjustment for patients with renal or
hepatic impairment, or for pediatric or geriatric patients, may be
more straightforward. This is an oversimplification of the
development of a dosing strategy for a drug candidate. There are
many other details that must be considered for a formulation
development project to be successful, but it does provide a simple
overview of some of the issues.
[0039] The suspension must be physically stable (no appreciable
settling) for a sufficient time, chemically stable over the
required time (shelf-life), possess a viscosity that allows it to
be used for its intended purpose, be easily reconstituted by
shaking, and be acceptable in use to the patient care-giver or
other user.
[0040] Some materials may possess a combination of properties
useful in the formulation and manufacture of stable, elegant
pharmaceutical suspensions. Formulation scientists need to consider
the totality of properties possessed by a particular excipient.
Even though it is being added for one particular characteristic,
the other properties will still be present, and will still
influence the formulation.
[0041] Many of the recently discovered active pharmaceutical
ingredients are quite hydrophobic with limited solubility. They may
also be quite distasteful. Other drugs may also have quite a high
chemical degradation precluding them to be administered as aqueous
solutions, and in this case, it may be possible to synthesize an
insoluble derivative. In other cases, some drugs are required to be
present in the gastrointestinal tract or in the pre-corneal pocket
with long residence time. For such drugs, a suspension is an ideal
delivery system as it provides better chemical stability and larger
surface area and is often more bioavailable than aqueous solutions,
tablets, and capsules.
[0042] Formulation of an elegant, stable, preserved, safe, and
effective suspension is a technically challenging task compared
aqueous solutions, tablets, and capsules. Pharmaceutical
suspensions are thermodynamically unstable systems. Thus,
preparation of such systems is often associated with problems of
physical stability, content uniformity, sedimentation, caking,
re-suspendibility, and crystal growth. Furthermore, issues related
to the masking of bitter taste and undesirable odor of the
pharmaceutical ingredient must be taken into consideration.
[0043] Some desirable attributes of a suspension are described as
follows,
1. It should be safe, effective, stable, and pharmaceutically
elegant during the shelf life of the product. 2. The drug should
not have a quick sedimentation rate. Furthermore, it should
re-suspend easily upon shaking and it must not cake. 3. Physical
attributes such as particle size, particle size distribution,
viscosity should remain fairly uniform throughout the shelf life of
the product. 4. Its viscosity must promote free and uniform flow
from the container. The product must be appropriately substantive
that it spreads freely over the affected area. 5. Re-suspension
should produce a homogeneous mix of drug particles such that there
is a content uniformity with each dose.
[0044] A quick means to identify whether or not a drug may be more
suitable for solution or suspension is to overlap the pH-stability
profile with the pH-solubility profile. This overlap creates a
window, which may suggest which dosage form might be most desirable
and subsequently the type of excipients needed.
[0045] Oral liquid formulation needs a meticulous blend of
ingredients to perform various functions like wetting and
solubilization, stabilization and to impart suitable color, taste
and viscosity. The blend should be compatible, non-reactive and
stable. The common excipients generally required for any liquid
formulation are vehicles (base), viscosity builders, stabilizers,
preservatives, colors and flavors. In addition, solubilizers are
required in case of clear liquids, suspending agents are needed for
suspensions and emulsifying agents for emulsions.
[0046] Imatinib is an inhibitor of protein-tyrosine kinase and
commercially available as tablets (Gleevec.RTM.) in the United
States since 2003 and is indicated for the treatment of chronic
myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL)
that are Philadelphia chromosome-positive (Ph+) and certain types
of gastrointestinal stromal tumors (GIST), systemic mastocytosis,
and myelodysplastic syndrome. According to Gleevec prescribing
information, Gleevec.RTM. tablets can be dissolved in water or
apple juice for patients having swallowing difficulty but in any
treatment an important consideration is to ensure that the patient
receives the correct dose of medicine. Administration of
Gleevec.RTM. tablets by dissolving in water or apple juice may not
administer correct and consistent dose every time. In the principal
aspects, the present invention therefore provides liquid dosage
forms of Imatinib or pharmaceutically acceptable salt thereof.
[0047] The liquid dosage forms according to the present invention
include, but not limited to, liquids, liquid dispersions,
suspensions, solutions, emulsions, ointments, creams, sprays,
spot-on, syrups, elixirs, drops, gels, solution-gels, concentrates
and the like. Such liquid dosage forms can be prepared using
appropriate one or more pharmaceutically acceptable excipients or
additives. Such excipients or additives may be known to those
skilled in the art.
[0048] The solution dosage form can be a viable alternative for
patients who have problems in swallowing the tablet or capsule
dosage form. It provides assurance of dosage uniformity upon
administration to patients and eliminates difficulty of
administration.
[0049] A solution can also provide physicians more flexibility in
designing dosage regimens for patients. Imatinib solution dosage
form is suitable for administration to both pediatric and geriatric
patients while also compensating for a good organoleptic properties
and remaining suitably stable. Hence, the development of a liquid
formulation is therefore desirable since it offers improved patient
compliance. In one of the further aspects, the present invention
therefore provides solution dosage forms of Imatinib or
pharmaceutically acceptable salt thereof.
[0050] Suspensions possess certain advantages over other liquid
dosage forms. Some drugs are insoluble in all acceptable media and
must, therefore, be administered as a tablet, capsule, or as a
suspension. In addition, disagreeable tastes can be masked by a
suspension of the drug or a derivative of the drug. Drugs in
suspension are chemically more stable than in solution. Therefore,
in one of the further aspects, the present invention provides
suspension dosage forms of Imatinib or pharmaceutically acceptable
salt thereof.
[0051] Liquid dosage forms are designed as ready to use liquids and
as powder for reconstitution into liquid orals like syrups,
solutions, suspensions and emulsions. Powder for reconstitution may
require skills & expertise and needs to be prepared by a
healthcare provider and may not be prepared by the patient or
caregiver. The reconstitution process may also be a time consuming
process and the patient cannot be benefited by the immediate dose
of Imatinib as and when required. In such a situation, ready to
use, liquid dosage forms of Imatinib may be very useful and the
patients can be given required doses immediately using ready to
use, liquid dosage forms of Imatinib. In one of the further
aspects, the present invention therefore provides ready to use,
liquid dosage forms of Imatinib or pharmaceutically acceptable salt
thereof.
[0052] Liquid dosage forms of an active drug can be prepared using
one or more pharmaceutically acceptable excipients or additives
suitable for the preparation of liquid dosage forms. In one of the
further aspects, the present invention provides liquid dosage forms
of Imatinib or pharmaceutically acceptable salt thereof and one or
more excipients or additives suitable for preparing liquid dosage
forms.
[0053] The term "pharmaceutically acceptable excipients or
additives" as used herein refers to such pharmaceutically
acceptable excipients which are known to those skilled in the all
for the purposes of preparing liquid dosage forms of the present
invention. Such pharmaceutically acceptable excipients, without
limitation include, vehicles, solvents/co-solvents, solubilizers,
solubility enhancing agents, tonicity agents,
permeation/penetration enhancers, mucoadhesives, suspending
agents/thickening agents/viscosity modifying agents, bulking
agents/auxiliary suspending agents, wetting agents, anti-foaming
agents, anti-caking agents, stabilizing agents, anti-oxidants,
chelating agents, buffering agents/pH modifying agents/pH adjusting
agents, surfactants, preservatives, sweetening agents, flavouring
agents and the like or any combination thereof. Such
pharmaceutically acceptable excipients can be used in an amount
which provides the liquid dosage forms of the present invention
desired property for which they are intended or desired to use.
[0054] In one of the further aspects, the present invention
provides liquid dosage forms of Imatinib in the form of solution
dosage forms comprising Imatinib or pharmaceutically acceptable
salt thereof and one or more pharmaceutically acceptable excipients
or additives selected from the group comprising of vehicles,
solvents/co-solvents and/or solubilizers. pH adjusting agents
and/or pH modifying agents and/or buffering agents or any
combination thereof. One or more surfactants may also be added in
the solution dosage forms of the present invention.
[0055] In one of the further aspects, the present invention
provides liquid dosage forms of Imatinib in the form of suspension
dosage forms comprising Imatinib or pharmaceutically acceptable
salt thereof and one or more pharmaceutically acceptable excipients
or additives selected from the group comprising of vehicles,
solvents/co-solvents and/or solubilizers, suspending
agents/thickening agents/viscosity modifying agents, anti-foaming
agents, surfactants, antioxidants, pH adjusting agents and/or pH
modifying agents and/or buffering agents or any combination
thereof. One or more anti-caking agents may also be added in the
suspension dosage forms of the present invention.
[0056] Microbiological contamination presents a significant health
hazard in oral liquids. Therefore, the use of preservatives become
inevitable to prevent the growth of microorganisms during the
product's manufacture and shelf life. Therefore, in one of the
further aspects, the liquid dosage forms of the present invention
may also comprise anti-microbial agents or preserving agents or
preservatives.
[0057] Increase in the palatability of the drug formulations
increases the patient compliance and patient acceptability towards
the drug. In one of the further aspects, the present invention
therefore provides palatable liquid dosage forms comprising
Imatinib or pharmaceutically acceptable salt thereof and at least
one or both selected from sweeteners/sweetening agents and
flavouring agents.
[0058] The liquid dosage forms according to the present invention,
without limitation include, aqueous dosage forms, alcoholic and/or
hydro-alcoholic dosage forms and non-aqueous dosage forms. Aqueous
dosage forms according to the present invention may also comprise
one or more non-aqueous and/or organic solvents.
[0059] In certain aspects, the present invention provides liquid
dosage forms of Imatinib in the form of suspensions comprising
Imatinib or pharmaceutically acceptable salt thereof, vehicle(s),
solvent(s)/co-solvent(s), solubilizer(s), suspending
agent(s)/thickening agent(s)/viscosity modifying agent(s),
preservative(s), anti-foaming agent(s), wetting agent(s),
surfactant(s), pH adjusting agent(s)/pH modifier(s) or buffering
agent(s) or both, sweetener(s) and flavoring agent(s).
[0060] In certain aspects, the present invention provides liquid
dosage forms of Imatinib in the form of solutions comprising
Imatinib or pharmaceutically acceptable salt thereof, vehicle(s),
solvent(s)/co-solvent(s), solubilizer(s), preservative(s),
surfactant(s), pH adjusting agent(s)/pH modifier(s) or buffering
agent(s) or both, sweetener(s) and flavoring agent(s).
[0061] In one of the further aspects, the liquid dosage forms of
the invention may be administered orally or via the oral cavity.
The liquid dosage forms of the present invention may also be
administered transmucosally, sublingually, via the buccal cavity,
via mucosal membranes and/or through the gastrointestinal tract. In
one of the further aspects, the liquid dosage forms of the present
invention may be administered via pulmonary, intravenous, rectal,
opththalmic, colonic, parenteral, intracisternal, intravaginal,
intraperitoneal, local, or topical administration.
[0062] In some of the aspects, the liquid dosage forms of the
present invention can be given using oral syringe to those patients
who cannot take medicine through mouth e.g. patients who have
undergone surgery.
[0063] In some of the aspects, the liquid dosage forms of the
present invention are in the form of spray and may be administered
by oral route or nasal route. Sprays are known by various names
such as aerosol sprays, liquid pump sprays, or activated mists
etc.
[0064] In some of the aspects, the liquid dosage forms of the
present invention are in the form of immediate release dosage forms
or modified release dosage forms, such as extended release,
controlled release, sustained release, prolonged release and
delayed release. In some of the aspects, the liquid dosage forms
comprise Imatinib or pharmaceutically acceptable salt thereof one
or more suitable excipients or additives for the preparation of
modified release dosage forms such as rate controlling
polymers.
[0065] The liquid dosage forms of the present invention may also be
prepared by reconstitution of dry powder in suitable diluent or
media such as water. The dry powder for reconstitution may be in
the form of immediate release forms and comprise Imatinib or
pharmaceutically acceptable salt thereof and one or more suitable
excipients selected form the group comprising of fillers, binders,
diluents, disintegrants, pore formers, lubricants, glidants,
sweeteners, stabilizing agents, antioxidants, flavoring agents,
suspending agents/thickening agents/viscosity modifying agents,
surfactants, preservatives and plasticizers. The dry powder for
reconstitution may also be in the form of modified release forms
and comprise modified release pellets, granules or particles. Such
modified release pellets, granules or particles comprise one or
more suitable excipients such as rate controlling polymers.
[0066] In one of the further aspects, the liquid dosage forms of
the invention are suitable for administration to all types of
patients' population. In particular, liquid dosage forms of the
invention are suitable for pediatric and geriatric patients. The
liquid dosage forms of the invention are also useful for the
patients who are unable to take solid oral therapy.
[0067] In some of the aspects, the pH of the liquid dosage forms of
the present invention is between about 2.0 and about 11.0. In some
of the aspects, the pH of the liquid dosage forms of the present
invention is between about 2.0 and about 7.0. In some of the
aspects, the pH of the liquid dosage forms of the present invention
is between about 3.0 and about 9.0. In some of the aspects, the pH
of the liquid dosage forms of the present invention is between
about 4.0 and about 8.0. In some of the aspects, the pH of the
liquid dosage forms of the present invention is between about 5.0
and about 7.0. In some of the aspects, the pH of the liquid dosage
forms of the present invention is between about 5.5 and about 6.5.
In some of the aspects, the pH of the liquid dosage forms of the
present invention is between about 3.5 and about 5.0.
[0068] In one of the further aspects, the pH of the liquid dosage
forms of the present invention is such that prevents the formation
of degradants in undesired amounts and provides the liquid dosage
forms of the present invention increased stability when stored
under storage conditions. In one of the non-limiting aspects, the
pH of the liquid dosage forms of the present invention which
prevents the formation of degradants in undesired amounts and
provides the liquid dosage forms of the present invention increased
stability when stored under storage conditions is in the range from
about 2.0 to about 7.0.
[0069] In one of the further aspects, the liquid dosage forms of
the present invention are stable for prolonged time when stored
under storage conditions. The term "storage conditions" as used
herein without limitation include typical storage conditions such
as 2.degree. C.-8.degree. C., 40.degree. C..+-.2.degree.
C./75.+-.5% RH, 30.degree. C..+-.2.degree. C./65.+-.5% RH,
25.degree. C..+-.2.degree. C./40.+-.5% RH, 25.degree.
C..+-.2.degree. C./60.+-.5% RH, 40.degree. C..+-.2.degree.
C..+-.2.degree. C./NMT 25% RH (NMT=not more than) and accelerated
conditions such as 40.degree. C..+-.2.degree. C./75.+-.5% RH. The
term "prolonged time" as used herein indicates that the liquid
dosage forms of the present invention are stable for at least 1
month, at least 3 months, at least 6 months or at least 12 months
when stored under storage conditions.
[0070] As used herein, the terms "stable" or "stability" encompass
any characteristic of the liquid dosage forms which may be affected
by storage conditions including, without limitation, potency, total
impurities, degradation products, specific optical rotation,
optical purity, water content, appearance, viscosity, sterility,
and colour and clarity. The storage conditions which may affect
stability include, for example, duration of storage, temperature,
humidity, and/or light exposure.
[0071] The term "degradant", "impurity", "degradation impurity" and
"related substance" as used herein represents the same meaning and
can be used interchangeably.
[0072] In some of the aspects of the present invention. "stable" or
"storage stable", or "stability" when used with reference to the
liquid dosage forms of the present invention or when used "stable
liquid dosage forms" or "stability of the liquid dosage forms" all
these terms/phrases refer to dosage forms of the present invention
which retain at least about 90%, or at least about 95%, or at least
about 96%, or at least about 98%, of the labelled concentration of
Imatinib or salt thereof contained in the said dosage form after
storage under typical and/or accelerated conditions. In further
aspects, stable liquid dosage forms or stability of the liquid
dosage forms refer to less than about 15% (area percent), or less
than about 10% (area percent), or less than about 7% (area
percent), or less than about 5% (area percent), or less than about
2% (area percent) of Imatinib-related impurities are present after
storage under typical and/or accelerated conditions.
[0073] In some of the aspects, liquid dosage forms of the present
invention contain no more than about 15% (area percent), or no more
than about 10% (area percent), or no more than about 7% (area
percent), or no more than about 5% (area percent), or no more than
about 2% (area percent), or no more than about 1% (area percent),
or no more than about 0.5% (area percent), or no more than about
0.2% (area percent), or no more than about 0.1% (area percent) any
known or unknown single Imatinib-related impurity or other impurity
after storage under typical and/or accelerated conditions.
[0074] In some of the aspects, liquid dosage forms of the present
invention contain no more than about 15% (area percent), or no more
than about 10% (area percent), or no more than about 7% (area
percent), or no more than about 5% (area percent), or no more than
about 2% (area percent), or no more than about 1% (area percent),
or no more than about 0.5% (area percent), or no more than about
0.2% (area percent), or no more than about 0.1% (area percent)
total Imatinib-related impurities or other impurities after storage
under typical and/or accelerated conditions.
[0075] Methods for determining the stability of the liquid dosage
forms of the present invention with respect to a given parameter
are well-known to those of skill in the art. For example,
individual impurities and total impurities can be assessed by
high-performance liquid chromatography (HPLC) or thin layer
chromatography (TLC). Unless otherwise indicated to the contrary, a
percentage amount of any individual impurities (known/unknown), or
total impurities reported herein in the liquid dosage forms are
determined by a peak area percent method using HPLC.
[0076] The term "comprise/comprises/comprising" as used herein mean
that other ingredients, steps, etc. are optionally present. When
reference is made herein to a method comprising two or more defined
steps, the steps can be carried in any order or simultaneously
(except where the context excludes that possibility), and the
method can include one or more steps which are carried out before
any of the defined steps, between two of the defined steps, or
after all of the defined steps (except where the context excludes
that possibility).
[0077] The term "about," as used herein, refers to any value which
lies within the range defined by a variation of up to .+-.10% of
the value.
[0078] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention (especially in
the context of the claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context.
[0079] All percentages mentioned herein, unless otherwise
indicated, are on a w/v basis. i.e. percentage ingredient
(active/inactive) present by weight in the total volume of the
liquid dosage form.
[0080] In accordance with the methods of use and administration of
medicinal products, packaging materials, closures and containers
vary a great deal and have to meet a wide variety of different
requirements. The liquid dosage forms of the present invention may
be packaged within any type of pharmaceutically-acceptable package,
containers, pumps, bottles with spray pump, bottles with dropper
assembly, bottles, collapsible tubes, glass ampoules, stoppered
vials, pre-filled syringes, low-density polyethylene (LDPE),
high-density polyethylene (HDPE), polyolefin, polypropylene
containers/bottles depending upon the quantity of the final dosage
form. The bottles or containers without limitation include
clear/transparent/opaque or amber colored glass bottles or
containers and clear/transparent/opaque or amber colored plastic
bottles or containers made from polyethylene, polyamide,
polycarbonate, acrylic multipolymers, polypropylene, polyethylene
terephthalate, polyvinyl chloride, polystyrene and the like.
Depending upon the type of the containers or bottles, closures may
have different shapes and sizes. The closure of the packaging
material may be made from polyethylene, polyamide, polycarbonate,
acrylic multipolymers, polypropylene, polyethylene tercphthalate,
polyvinyl chloride, polystyrene and the like.
[0081] Liquid dosage forms of the present invention may be packaged
in a sterile single use bottle/container that contains a unit dose
for administration to a patient. Suitable bottles/containers may
contain volumes between 1-10 ml, 10-20 ml, 20-40 ml, and 40-100 ml,
and even more. The container may typically comprise Imatinib or
pharmaceutically acceptable salt thereof in an amount of between
10-40 mg, between 40-80 mg, between 80-130 mg, and even more. Thus,
it may also be noted that the container may be a multi-use
container (i.e., retains at least one more unit dose after a first
unit dose is dispensed).
[0082] Following embodiments of the invention describe suitable
excipients which may be used to prepare liquid dosage forms of the
present invention. It is in no way the intention of the present
inventor(s)/applicant(s) to limit the scope of the liquid dosage
forms of the present invention by the description of following
embodiments. Described embodiments are for illustrative purpose
only and a skilled person may use other excipients from the same or
different classes as well which may provide liquid dosage forms of
the present invention same or improved physico-chemical properties,
palatability, stability and the like and retain or increase
patients' acceptability towards the therapy. Such other excipients,
classes of excipients and compositions resulted therefrom are also
part of the present invention and covered within the scope of the
present invention.
[0083] Vehicles may be used in the liquid compositions of the
present invention. Vehicles are the liquid bases that carry drugs
and other excipients in dissolved or dispersed state. Vehicles may
be aqueous or non-aqueous or mixture thereof. Non-aqueous
solvents/co-solvents may also be added in the liquid compositions
of the present invention to increase the solubility of poorly
soluble substances and enhance the chemical stability of a drug.
Suitable solvents/co-solvents, solubilizers or vehicles, that may
be employed, in the liquid compositions of the invention include,
but are not limited to, dichloromethane, acetonitrile, ethyl
acetate, acetone, propylene carbonate, water, glycerine, coconut
fatty acid diethanolamide, medium and/or long chain fatty acids or
glycerides, monoglycerides, diglycerides, triglycerides, structured
triglycerides, soybean oil, peanut oil, corn oil, corn oil
monoglycerides, corn oil diglycerides, corn oil triglycerides,
polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90,
propylene glycol, polyoxyethylenesorbitan fatty acid esters,
polyoxyethylene castor oil derivatives, castor oil, cottonseed oil,
olive oil, safflower oil, peppermint oil, coconut oil, palm seed
oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol,
butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone and
the like or any combinations thereof.
[0084] In some of the non-limiting aspects of the present
invention, the non-aqueous solvent is glycerin. In some of the
further aspects, the glycerin may also act as a stabilizing agent
when the liquid dosage forms of the present invention comprise
water as vehicle and provide desired stability when stored under
storage conditions. In some of the further aspects, the amount of
glycerin used to provide desired stability to the liquid dosage
forms of the present invention is at least about 25% or more, at
least about 30% or more, at least about 40% or more, at least about
50% or more, or at least about 60% or more.
[0085] Wetting agents as used herein are routinely used in
pharmaceutical formulations, especially in liquid dosage forms to
create a homogeneous dispersion of solid particles in a liquid
vehicle. This process can be challenging due to a layer of adsorbed
air on the particle's surface. Hence, even particles with a high
density may float on the surface of the liquid until the air phase
is displaced completely. The use of a wetting agent allows removal
of adsorbed air and easy penetration of the liquid vehicle into
pores of the particle in a short period of time. For an aqueous
vehicle, alcohol, glycerin, and PG are frequently used to
facilitate the removal of adsorbed air from the surface of
particles. Whereas for a non-aqueous liquid vehicle, mineral oil is
commonly used as a wetting agent. Non-limiting examples of wetting
agents are Benzalkonium chloride, Benzcehonium chloride,
Cetylpyridinium chloride, Docusate sodium, Nonoxynol 9, Octoxynol,
Poloxamer, Poloxamer 124. Poloxamer 188, 237, 338, 407, Polyoxyl 35
castor oil, Polyoxyl 40 hydrogenated castor oil. Polyoxyl 10 oleyl
ether. Polyoxyl 20 cetylstearyl ether. Polyoxyl 40 stearate.
Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80,
Sodium lauryl sulfate. Sorbitan monolaurate, Sorbitan monooleate.
Sorbitan monopalmitate. Sorbitan monostearate, Tyloxapol and the
like or any combinations thereof.
[0086] Solubility enhancing agents may include, but are not limited
to, DL-methionine, caffeine, nicotinamide, vanillin, benzyl
alcohol, ethanol and diethylene glycol monoethyl ether and the like
or combinations thereof.
[0087] Stabilizing agents may include, but are not limited to,
sodium metabisulphite, sodium bisulphite, ethylene diamine
tetraacetic acid (EDTA) or salts thereof, ascorbic acid and the
like or combinations thereof.
[0088] Penetration/permeation enhancers may include, but are not
limited to, nicotinamide, caffeine, peppermint oil, sodium
glycocholate, phospholipids, alkyl saccharides, aprotinin,
benzalkonium chloride, ceramides, cetylpyridinium chloride,
chitosan, chitosan-4-thiobutylamidine, cyclodextrins, dextran
sulfate, dodecyl azacycloheptyl-2-ketone, ether lipids
(plasmologens), glycerol, glycosylated sphingosines, lauric acid,
23-lauryl ether, lysophosphatidyl choline, menthol,
methoxysalicylate, phosphatidyl choline,
1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine, polycarbophil
cysteine, poly-L-arginine, polyoxyethylene,
polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol.
EDTA, sodium deoxycholate, sodium glycocholate, sodium
glycodeoxycholate, sodiun lauryl sulfate, sodium salicylate, sodium
taurocholate, sodium taurodeoxycholate, sodium
taurodihydrofusidate, sphingolipids, sterols and the like or
combinations thereof.
[0089] Mucoadhesives and/or suspending agents may also be added in
the compositions of the present invention. Examples of suitable
mucoadhesives include, but are not limited to, hydroxypropyl
cellulose, gelatin, crosslinked polyacrylic acid, polymethacrylic
acid, polyhydroxyethyl methacrylic acid, hydroxypropyl methyl
cellulose, polyethylene glycol, sodium carboxymethyl cellulose,
hyaluronic acid, chitosan, polycarbophil, pectin, xanthan gum,
alginate, copolymers of dextran, polyacrylamide, acacia, copolymer
of caprolactone and ethylene oxide, carbopol 934, tragacanth,
eudragit and the like or combinations thereof.
[0090] Suspending agents may be natural or synthetic gums or gum
derivatives or compounds which swell in the presence of aqueous
media.
[0091] Stabilizing agents may include, but are not limited to,
sodium metabisulphite, sodium bisulphite, ethylene diamine
tetraacetic acid (EDTA) or salts thereof, ascorbic acid and the
like or combinations thereof.
[0092] The pH of an oral liquid formulation is a key point in many
regards. Control of the formulation pH, could prevent large changes
during storage. Therefore, most formulations utilize a buffer to
control potential changes in the solution pH. The amount of buffer
capacity needed is generally between 0.01 and 0.1 M, and a
concentration between 0.05 and 0.5 M is usually sufficient. The
selection of a suitable buffer should be based on (i) Whether the
acid-base forms are listed for use in oral liquids, (ii) The
stability of the drug and excipients in the buffer, and (iii) The
compatibility between the buffer and container. A combination of
buffers can also be used to gain a wider range of pH compared to
the individual buffer alone. However, not all buffers are suitable
for use in oral liquids. For example, a boric acid buffer may be
used for optical and IV delivery but not in oral liquids because of
its toxicity. The stabilizing effect of buffers that have multiple
charged species in solution could also determine the potential
reaction between excipients and API. For example, buffers that use
carbonates, citrate, tartrate, and various phosphate salts may
precipitate with calcium ions by forming sparingly soluble salts.
However, this precipitation is dependent upon the solution pH. The
activity of phosphate ions may be lowered due to interactions with
other solution components.
[0093] There are a number of factors that may also affect the
solution pH such as temperature, ionic strength, dilution, and the
amount and type of co-solvents present. For example, the pH of
acetate buffers is known to increase with temperature, whereas the
pH of boric acid buffers decreases with temperature. Finally, the
drug in solution may itself act as a buffer. If the drug is a weak
electrolyte, such as salicylic acid or ephedrine, the addition of
base or acid, respectively, will create a system in which the drug
can act as a buffer.
[0094] One of the most crucial factors involved in formulating a
pharmaceutical suspension is the selection of an appropriate
suspending agent. Suspending agents impart viscosity, and thus
retard particle sedimentation. Other factors considered in the
selection of the appropriate agent include desired rheological
property, suspending ability in the system, chemical compatibility
with other excipients, pH stability, length of time to hydrate,
batch-to-batch reproducibility, and cost. Non-limiting examples of
pH adjusting agents/modifiers and buffers are Acetic acid, Adipic
acid, Ammonium carbonate, Ammonium hydroxide, Ammonium phosphate.
Boric acid, Citric acid, Diethanolamine, Fumaric acid. Hydrochloric
acid, Malic acid. Nitric acid. Propionic acid. Potassium acetate.
Potassium bicarbonate. Potassium chloride, Potassium citrate,
Potassium metaphosphate. Potassium phosphate, Sodium acetate.
Sodium bicarbonate. Sodium borate, Sodium carbonate. Sodium
chloride. Sodium citrate, Sodium glycolate, Sodium hydroxide,
Sodium lactate, Sodium phosphate, Sodium proprionate, Succinic
acid, Sulfuric acid. Tartaric acid. Triethylamine, Triethanolamine,
Tromethamine. Trolamine and the like or any combinations
thereof.
[0095] In some of the aspects of the present invention, the term
"buffering agent" or "buffering agents" may also interchangeably be
used with the terms "pH adjusting agent or pH adjusting agents" or
"pH modifying agent or pH modifying agents" and vice versa and
represents the same meaning.
[0096] Suspending agents can be classified into cellulose
derivatives, clays, natural gums, and synthetic gums. In many
cases, these excipients are used in combination. There are many
water soluble hydrocolloids that can act as suspending agents in
the formulation of pharmaceutical suspensions. They can be of
natural, semi-synthetic or synthetic origin. Non-limiting examples
of suspending agents are Acacia. Agar, Alginic acid. Carbomer.
Carmellose sodium. Dextrin, Gelatin. Veegum or Gel white. Gellan
gum, Sodium alginate. Methylcellulose, Hydroxyethyl cellulose,
Hydroxypropyl cellulose. Hydroxypropylmethyl cellulose,
Hydroxypropyl starch, Hypromellose. Maltodextrin. Methylcellulose,
Modified starch. Pectin, Poloxamer, Polycarbophil, Polyethylene
glycol. Polyvinyl acetate, Poly (vinyl alcohol), Potassium
alginate. Polyvinyl pyrrolidone. Pregelatinized starch. Propylene
glycol alginate. Sodium alginate. Carboxymethyl cellulose or an
alkali metal salt thereof, Microcrysalline cellulose, gum Arabic,
Karaya gum, Sterculia gum. Tragacanth, Xanthangumn, Bentonite,
Carageenan. Guar gum. Colloidal silicon dioxide and the like or any
combinations thereof.
[0097] In some of the non-limiting aspects of the present
invention, the suspending agent is present in the liquid dosage
forms of the present invention at a concentration which helps to
achieve desired dissolution profile of the suspension dosage forms
of the present invention.
[0098] Microbiological contamination presents a significant health
hazard in oral liquids. Therefore, the use of preservatives become
inevitable to prevent the growth of microorganisms during the
product's manufacture and shelf life, although it may be most
desirable to develop a "preservative-free" formulation to address
the increasing concerns about the biological activity of these
compounds. Most formulations require some kind of preservative to
ensure no microbial growth.
[0099] The majority of preservatives are bacteriostatic rather than
bacteriocidal, and consists of both acid and nonacid types. Among
the acidic types are phenol, chlorocresol, 9-phenyl phenol, alkyl
esters of para-hydroxybenzoic acid, benzoic acid, boric acid, and
sorbic acid, and their respective salts. Therefore, the pH of
solution, and the pKa of the preservative need to be carefully
evaluated prior to selecting a preservative for a formulation.
Neutral preservatives include chlorobutanol, benzyl alcohol, and
beta-phenylethyl alcohol. Under alkaline conditions, it is
generally regarded that microbial growth is insignificant and at
these pH values, the need for a preservative is not generally
recommended.
[0100] Many preservatives listed in the FDA inactive ingredient
guide for liquid dosage forms. Unfortunately, many of them are not
recommended for use in oral liquids and hence the choice of an
acceptable preservative for an oral liquid formulation is limited.
In addition, the solubility of many preservatives in aqueous system
may not be high enough for effective antimicrobial activity.
Additionally, it is essential to understand that bacteriostatic
agents like para hydroxyl hbenzoic acids can partition between
organic and aqueous phases in a heterogenous liquid formulations in
such a way that their activity is significantly reduced.
Non-limiting examples of preservatives are Alcohol, Ethanol,
Chlorobutanol, Phenoxyethanol, Potassium benzoate, Benzyl alcohol.
Benzoic acid, Potassium sorbate. Sorbic acid, Benzalkonium
chloride, Benzethonium chloride, Cetrimonium bromide,
Cetylpyridinium chloride. Bronopol, Chlorbutol, Chlorocresol,
Cresol Butylparaben, Methylparaben. Propylparaben. Ethylparaben.
Phenol, Thymol. Phenylethanol. Sodium benzoate, Antimicrobial
solvents like Propylene glycol. Glycerin. Chloroform and the like
or any combinations thereof. In addition, some formulation
ingredients like nonionic surfactants, quaternary ammonium
compounds, gelatin, ferric salts, calcium salts and salts of heavy
metals, including silver, lead, and mercury prevent microbial
growth.
[0101] In some of the non-limiting aspects, the liquid dosage forms
of the present invention comprise one or more than one
preservatives. In some of the further non-limiting aspects, the
liquid dosage forms of the present invention comprise combination
of two preservatives. In some of the further non-limiting aspects
of the present invention, the preservatives are present in the
liquid dosage forms of the present invention at a concentration
which helps to prevent microbial growth in the liquid dosage forms
when stored for prolonged time under storage conditions.
[0102] Antioxidants can be compounds that can reduce a drug that
has been oxidized, or compounds that are more readily oxidized than
the agents they are to protect (oxygen scavengers). Many of the
lipid-soluble antioxidants act as scavengers. Antioxidants can also
act as chain terminators, reacting with free radicals in solution
to stop the free-radical propagation cycle. Mixtures of chelating
agents and antioxidants are often used because there appears to be
a synergistic effect. This occurs because many of the agents act at
differing steps in the oxidative process.
[0103] Some substances prone to oxidation include unsaturated
oils/fats, compounds with aldehyde or phenolic groups, colors,
flavors, sweeteners, plastics and rubbers, the latter being used in
containers for products. Oxidation may manifest as products with an
unpleasant odour, taste, appearance, precipitation, discoloration
or even a slight loss of activity. The term rancidity refers to
many typical off-flavors that result from autoxidation of
unsaturated fatty acids that are present in oils and fats, and it
affects many oils and fats. The distinct rancid odour may result
from short-chain, volatile monomers resulting from the cleavage of
the longer chain, less volatile oils and fats. Non-limiting
examples of anti-oxidants are .alpha.-Tocopherol acetate. Ascorbic
acid. Erythorbic acid. Butylated hydroxytoluene (BHT),
d-.alpha.-Tocopherol natural. Monothioglycerol, Sodium bisulfite,
Sodium sulfite. Sodium metabisulfite. Potassium metabisulfite,
Acetone sodium bisulfite. Ascorbyl palmitate, Cysteine,
d-.alpha.-tocopherol synthetic. Nordihydroguaiaretic acid, Sodium
formaldehyde sulfoxylate, Sodium thiosulfate. Acetylcysteine,
Ascorbyl palmitate, Butylated hydroxyanisole (BHA), Cysteine
hydrochloride, Dithiothreitol, Propyl gallate, Thiourea and the
like or any combinations thereof.
[0104] In some instances, there are insufficient drug particles in
a unit dose of suspension to make a pharmaceutically elegant
suspension. This is particularly true for the more highly active
drugs, where the unit dose is small. Under such circumstances, the
formulator will need to add more particles to improve the
appearance of the final product, and also to help stabilize the
suspension. To serve this purpose, bulking agents, also known as
auxiliary suspending agents are used. Non-limiting examples of
bulking agents are Calcium carbonate. Calcium hydroxide. Cellulose,
Crospovidone, Dibasic calcium phosphate, Magnesium carbonate.
Magnesium hydroxide, Microcrystalline cellulose, Silica (silicon
dioxide), Titanium dioxide and the like or any combinations
thereof.
[0105] Many different materials are capable of adsorbing onto the
suspended particles, e.g. natural gums, cellulosics and non-ionic
surfactants. However, not all of them are able to act as protective
colloids and provide steric hindrance to caking at a sufficiently
low concentration. High levels of surfactants, for example, can
increase gastro-intestinal motility. Higher molecular weight gums
and cellulosics may also cause an unacceptable increase in the
viscosity of the system. There are, however, certain polymers, or
grades of polymers, that are capable of acting as protective
colloids at concentrations that do not markedly increase the
viscosity of the system, or increase gut motility, etc. Such
materials include poloxamers, lower molecular weight grades of
povidone, and low molecular weight grades of some other hydrophilic
colloids.
[0106] Surfactant is a general name for materials that possess
surface activity; in solution they tend to orient at the surface of
the liquid. There are several general classes of surfactants:
anionic, cationic, amphoteric and non-ionic. Surfactants are
amphiphilic molecules, i.e. part of the molecule is hydrophilic,
and part is lipophilic. This combination of the two opposite
affinities in the same molecule causes them to orient to the
interface and thereby reduce the interfacial tension between the
continuous and disperse phases, such as in emulsions and
suspensions. Ionic surfactants work primarily through electrostatic
forces, whereas non-ionic surfactants work primarily through steric
forces. Non-limiting examples of surfactants are Sodium lauryl
sulfate. Docusate sodium, Cocamidopropyl amino betaine.
Polyoxyethylene sorbitan fatty acid esters (Polysorbate,
Tween.RTM.), Polyoxyethylene 15 hydroxystearate (Macrogol 15
hydroxystearate, Solutol HS15@). Polyoxyethylene castor oil
derivatives (Cremophor.RTM. EL, ELP, RH 40), Polyoxyethylene
stearates (Myrj.RTM.). Sorbitan fatty acid esters (Span.RTM.),
Polyoxyethylene alkyl ethers (Brij.RTM.), Polyoxyethylene
nonylphenol ether (Nonoxynol.RTM.) and the like or any combinations
thereof.
[0107] Anti-foaming agents may be used in the preparation of the
liquid pharmaceutical compositions of the present invention to
lower the surface tension and cohesive binding of liquid phase.
Non-limiting examples of anti-foaming agents are simnethicone,
organic phosphates, alcohols, paraffin oils, stearates, glycols and
the like or any combinations thereof.
[0108] Chelating agents, also known as sequestrants, are molecules
that have the ability to form stable complexes with metal ions,
particularly di-valent and tri-valent metal ions including trace
metals and heavy metals. These metal ions are often implicated in
API degradation by acting as catalysts, e.g. Mg.sup.2+ will
catalyze both ester hydrolysis and the Maillard interaction between
primary or secondary amines and reducing sugars. Oxidative
degradation is also often catalyzed by heavy metals. In addition,
certain trace metals are required for microbial growth, and
chelation (sequestration) to form complexes can help prevent
microbial growth and spoilage, and thus allow lower levels of
microbiocidal agents to be used. Non-limiting examples of chelating
agents are Calcium disodium edetate, Disodium edetate, Edetic acid
(also known as ethylenediaminetetraacetic acid/EDTA), Citric acid
and the like or any combinations thereof.
[0109] Palatability of oral medicines is an important factor in
compliance. There are several components to palatability including
flavor, mouth-feel and sweetness. Most patients prefer medicines
that are not too bitter but may be slightly "tart" (acidic). Most
APIs are bitter. However, for bitterness to develop, the drug must
be sufficiently soluble to interact with taste receptors on the
tongue. For insoluble APIs in the form of suspensions, components
of the suspension are also bitter, e.g. preservatives, or very
salty, e.g. buffer systems. However, a slight saltiness and a
slight bitterness are desirable for palatability.
[0110] Traditionally, oral medicines were sweetened using Syrup
(concentrated sucrose solution) or honey (contains fructose).
However, these materials are inadequate for the formulation of many
products because they simply are not able to adequately mask the
very bitter taste of many pharmaceutical materials, including APIs
and excipients. Several alternative sweetening agents have been
developed over the years to better mask unpleasant tastes in both
processed foods and pharmaceuticals.
[0111] Several of the materials classified as sweetening agents are
sugar alcohols (also known as polyhydric alcohols, polyols and
hydrogenated sugars). Several of the commonly used sweetening
agents are ionic and have the potential to interact with other
components of the suspension. Some sweetening agents are more
stable than others in aqueous solution. These will be important
factors in the final selection of the sweetening agent.
Non-limiting examples of sweetening agents are Glucose, Sucralose,
Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose,
Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol,
Xylitol, Saccharine or the corresponding sodium, potassium or
calcium salt, Cyclamate or the corresponding sodium or calcium
salt. Aspartame, or Acesulfame or the potassium salt thereof.
Dulcin or Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt,
Ncohespcridin dihydrochalcone. Thaumatin and the like or any
combinations thereof.
[0112] Flavors are used to improve the palatability of oral
medicines. One problem that can arise with oral suspensions is that
the suspension may produce a "cloying" sensation in the mouth.
While this is not the same as a bitter taste, it can nevertheless
cause problems for the patient and affect compliance. This can be a
particular problem with high levels of inorganic components.
Flavors can help reduce this "cloying" taste and thereby improve
palatability, and ultimately patient compliance.
[0113] There are many different flavors, and most flavors are
complex mixtures of many components. Today most flavors are
developed by specialist flavor houses, and typically the flavor is
formulated for each individual application. Since flavor will be
part of the suspension continuous phase, it has the maximum
potential for interaction, and some flavor components may cause
stability issues (physical or chemical) for the suspension. Flavor
development and compounding is a specialist discipline. When
deciding on which particular flavor is appropriate, the flavor
specialist would benefit from knowledge of the other likely
components in the suspension, just as the formulation scientist
would benefit from knowledge of the components of the flavor.
[0114] Flavors can adsorb onto finely divided solids, thus reducing
their effectiveness. They can also be absorbed by packaging. Flavor
preferences vary with age, but the citrus flavors appear generally
acceptable to most age groups. Non-limiting examples of flavoring
agents are synthetic flavor oils and flavoring aromatics and/or
natural oils, extracts from plants leaves, flowers, fruits, and so
forth and the like or any combinations thereof. These may include
cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay
oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of
nutmeg, oil of sage, oil of bitter almonds, and cassia oil and the
like or any combinations thereof. Also useful as flavors are
vanilla, citrus oil, including lemon, orange, grape, lime and
grapefruit, and fruit essences, including apple, banana, pear,
peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and
so forth and the like or any combinations thereof. Solid forms,
such as spray dried forms of flavoring agents, may also be useful
in the liquid dosage forms disclosed herein.
[0115] Coloring agents may also be used in the preparation of the
liquid compositions of the present invention. Pharmaceutical colors
come in two types; soluble dyes and insoluble pigments. For
pharmaceutical suspensions intended for oral use, soluble dyes are
often used; however, pigments may also be used and would be part of
the disperse phase. Soluble dyes have the potential to interact
with other components of the formulation.
[0116] In some of the aspects, the liquid dosage forms of the
present invention are non-caking liquid dosage forms. The term
"non-caking" as used herein means that the liquid dosage form has a
smooth consistency and doesn't contain any caking or clumping
particles, by visual inspection. Also, the liquid dosage form in
accordance with the present invention does not cake or clump during
manufacture, i.e., when mixed with excipients. Nor does it cake or
clump upon storage, even under relatively humid conditions, e.g., a
relative humidity of about 75% or greater and when stored for
relatively long periods such as about 6 months or longer and even
at elevated temperatures of about 40.degree. C. or greater, or at
any combination of such humidity, time and temperature parameters.
Thus, the liquid dosage forms in accordance with the present
invention will remain non-caking during typical storage and use
conditions. "Imatinib" as used herein, unless the context requires
otherwise, includes Imatinib, its pharmaceutically acceptable salts
and chemical derivatives thereof such as polymorphs, solvates,
hydrates, anhydrous forms, amorphous forms, prodrugs, chelates, and
complexes. "Imatinib" as used herein also includes racemic or
substantially pure forms.
[0117] In one of the further aspects. Imatinib or pharmaceutically
acceptable salt thereof used for the preparation of the liquid
dosage forms of the present invention comprise particles of
Imatinib or pharmaceutically acceptable salt thereof, wherein the
d.sub.90 of the particles of Imatinib or pharmaceutically
acceptable salt thereof is less than about 1000 .mu.m, or less than
about 950 .mu.m, or less than about 900 .mu.m, or less than about
850 .mu.m, or less than about 800 .mu.m, or less than about 750
.mu.m, or less than about 700 .mu.m, or less than about 650 .mu.m,
or less than about 600 .mu.m, or less than about 550 .mu.m, or less
than about 500 .mu.m, or less than about 450 .mu.m, or less than
about 400 .mu.m, or less than about 350 .mu.m, or less than about
300 .mu.m, or less than about 250 .mu.m, or less than about 200
.mu.m, or less than about 150 .mu.m, or less than about 100 .mu.m,
or less than about 90 .mu.m, or less than about 80 .mu.m, or less
than about 70 .mu.m, or less than about 60 .mu.m, or less than
about 50 .mu.m, or less than about 40 .mu.m, or less than about 30
.mu.m, or less than about 20 .mu.m, or less than about 10 .mu.m, or
less than about 5 .mu.m, or less than about 2 .mu.m, or less than
about 1 .mu.m, or less than about 0.5 .mu.m.
[0118] In one of the further aspects, the liquid dosage forms of
the present invention comprise particles of Imatinib or
pharmaceutically acceptable salt thereof, wherein the d.sub.90 of
the particles of Imatinib or pharmaceutically acceptable salt
thereof is less than about 1000 .mu.m, or less than about 950
.mu.m, or less than about 900 .mu.m, or less than about 850 .mu.m,
or less than about 800 .mu.m, or less than about 750 .mu.m, or less
than about 700 .mu.m, or less than about 650 .mu.m, or less than
about 600 .mu.m, or less than about 550 .mu.m, or less than about
500 .mu.m, or less than about 450 .mu.m, or less than about 400
.mu.m, or less than about 350 .mu.m, or less than about 300 .mu.m,
or less than about 250 .mu.m, or less than about 200 .mu.m, or less
than about 150 .mu.m, or less than about 100 .mu.m, or less than
about 90 .mu.m, or less than about 80 .mu.m, or less than about 70
.mu.m, or less than about 60 .mu.m, or less than about 50 .mu.m, or
less than about 40 .mu.m, or less than about 30 .mu.m, or less than
about 20 .mu.m, or less than about 10 .mu.m, or less than about 5
.mu.m, or less than about 2 .mu.m, or less than about 1 .mu.m, or
less than about 0.5 .mu.m.
[0119] In one of the aspects, general formula of the liquid dosage
forms according to the present invention may be provided as
follows.
TABLE-US-00001 TABLE 1 General formula of liquid dosage forms of
the present invention Quantity (% w/v) Solution Suspension Sr No
Ingredient dosage form dosage form 1 Irnatinib or pharmaceutically
0.01-25 0.01-25 acceptable salt thereof (active ingredient) 2
Suspending agent(s)/thickening -- 0.01-10 agent(s)/viscosity
modifying agent(s) 3 Preservative(s) 0.01-10 0.01-10 4 Wetting
agent(s) -- 0-90 5 pH adjusting agent(s)/pH modifying Q.S. to Q.S.
to agents adjust the pH adjust the pH 6 Buffering agent(s) Q.S. to
Q.S. to adjust the pH adjust the pH 7 Solvent(s)/co-solvent(s) Q.S.
Q.S. 8 Solubilizer(s) Q.S. Q.S. 9 Anti-foaming agent(s) -- 0.01-10
10 Anti-caking agent(s) -- 0-10 11 Antioxidant -- 0-10 12
Surfactant(s) 0-10 0.01-10 13 Sweetening agent(s) 0.01-15 0.01-50
14 Flavoring agent(s) 0.01-5 0.01-5 15 Coloring agent(s) .sup. 0-2
.sup. 0-2 16 Vehicle(s) Q.S. Q.S. Q.S. = Quantity Sufficient
[0120] Those who are skilled in the art will appreciate that
different types of liquid dosage forms as described herein can be
prepared by using suitable excipients or additives known in the
art. Thus, the name of excipients or additives and proportionate
range thereof provided in the Table-1 is provided herein for the
illustration purpose only and should not be construed as the exact
or the only scope of the present invention.
[0121] The liquid dosage forms of the present invention may be
prepared using suitable excipients or additives in any suitable
amount.
[0122] In one of the further aspects, the present invention
provides process for the preparation of the liquid dosage forms of
Imatinib or pharmaceutically acceptable salt thereof.
[0123] Process-1: Preparation of Solution Dosage Forms [0124] 1.
Add one or more sweetener(s) followed by one or more
preservative(s) in the suitable vehicle; [0125] 2. Add Imatinib or
pharmaceutically acceptable salt thereof; [0126] 3. Add one or more
buffering agent(s) to adjust the desired pH followed by flavoring
agent; and [0127] 4. Adjust the volume to the required quantity
with vehicle.
[0128] Process-2: Preparation of Solution Dosage Forms [0129] 1.
Add one or more solvent(s) followed by one or more sweetener(s) and
one or more preservative(s) in the suitable vehicle; [0130] 2. Add
Imatinib or pharmaceutically acceptable salt thereof; [0131] 3. Add
one or more buffering agent(s) to adjust the desired pH followed by
flavoring agent; and [0132] 4. Adjust the volume to the required
quantity with vehicle.
[0133] Process-3: Preparation of Suspension Dosage Forms [0134] 1.
Add one or more preservative(s) followed by one or more buffering
agent(s) to adjust the desired pH in the suitable vehicle; [0135]
2. Add one or more sweeteners) and flavoring agent followed by one
or more suitable solvent(s)/co-solvent(s) and/or one or more
solubilizer(s); [0136] 3. Add one or more suspending agent(s)
followed by one or more anti-foaming agent(s) and one or more
surfactant(s); [0137] 4. Add Imatinib or pharmaceutically
acceptable salt thereof; and [0138] 5. Adjust the volume to the
required quantity with vehicle.
[0139] Process-4: Preparation of Suspension Dosage Forms [0140] 1.
Add and mix one or more solubilizer(s) in the suitable vehicle;
[0141] 2. Add one or more suspending agent(s); [0142] 3. Add one or
more antioxidant(s) and one or more sweetener(s) dissolved in the
suitable solvent(s) to step (2); [0143] 4. Add Imatinib or
pharmaceutically acceptable salt thereof; and [0144] 5. Add
flavoring agent and adjust the volume to the required quantity with
vehicle.
[0145] Those who are skilled in the art can understand that some
variations in the process described herein can be adopted. A
skilled person may omit use of some pharmaceutical excipients as
described herein above. A skilled person may also alternatively use
some or all pharmaceutical excipients as described herein from the
same excipient classes. Such variations are well within the scope
of the present invention. A skilled person can also change and/or
omit steps of their sequences of the herein described process for
the purposes of suitability and convenience where one or more
pharmaceutically acceptable excipients may or may not be used
without affecting and diminishing the quality and characteristics
of the resulting product. Such
variations/changes/omissions/additions are well within the scope of
the present invention.
[0146] The liquid dosage forms of the present invention may also be
prepared using processes generally known to those skilled in the
art. The processes for the preparation of liquid dosage forms of
the present invention may vary depending upon the final dosage
form. e.g. solution, suspension, etc. The processes for the
preparation of the liquid dosage forms of the present invention may
comprise multiple steps. Such steps may include sequential addition
of suitable excipients/additives. Such steps may also include
physical processes for example mixing, stirring, agitation etc.
[0147] In one of the aspects, the liquid dosage forms of the
present invention are suitable for administration to a subject to
treat or prevent a disease or condition. Preferably, the subject is
a mammal. More preferably, the mammal is a human. Preferably, the
disease or condition is a disease or condition that is treatable by
the administration of Imatinib or pharmaceutically acceptable salt
thereof.
[0148] In one of the aspects, the present invention is directed to
the method for the treatment of a disease or disorder or medical
condition that can be treated by inhibiting protein-tyrosine kinase
comprising administering to a patient, such as human, an effective
dosage amount of a liquid dosage form comprising Imatinib or
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients or additives as disclosed
and described herein.
[0149] In one of the further aspects, the present invention is
directed to the method for the treatment of a tumor disease or
cancer disease, including without limitation, colon cancer, thyroid
cancer, ovarian cancer, breast cancer, lung cancer (non-small cell
lung cancer), head and neck cancer, uterine cancer, non-hodgkin
lymphoma, blood cancer, skin cancer, prostate cancer, kidney
cancer, rectal cancer, peritoneal cavity cancer, brain cancer,
gastric cancer, metastatic cancer, colorectal cancer, pancreatic
cancer, endometrial cancer, stomach cancer, gastrointestinal
cancer, bladder cancer, and the like comprising administering to a
patient, such as human, an effective dosage amount of a liquid
dosage form comprising Imatinib or pharmaceutically acceptable salt
thereof and one or more pharmaceutically acceptable excipients or
additives as disclosed and described herein.
[0150] In one of the further aspects, the present invention is
directed to the method for the treatment of at least one disease or
condition selected from the group comprising of chronic myeloid
leukemia, acute lymphoblastic leukemia, myelodysplastic diseases,
myeloproliferative diseases, aggressive systemic mastocytosis,
hypereosinophilic syndrome and/or chronic cosinophilic leukemia,
unresectable, recurrent and/or metastatic dermatofibrosarcomna
protuberans, and unresectable and/or metastatic malignant
gastrointestinal stromal tumors comprising administering to a
patient, such as human, an effective dosage amount of a liquid
dosage form comprising Imatinib or pharmaceutically acceptable salt
thereof and one or more pharmaceutically acceptable excipicnts or
additives as disclosed and described herein.
[0151] "Effective dosage amount" as used herein with respect to,
for example Imatinib liquid dosage forms shall mean that dosage
that provides the specific pharmacological response for which
Imatinib administered in a significant number of subjects in need
of such treatment. It is emphasized that "effective dosage amount",
administered to a particular subject in a particular instance will
not always be effective in treating the diseases described herein,
even though such dosage is deemed a "effective dosage amount" by
those skilled in the art.
[0152] In one of the further aspects, the present invention is
directed to use liquid dosage forms of the present invention for
the treatment of a disease or disorder that can be treated by
inhibiting protein-tyrosine kinase. In one of the further aspects,
the present invention is directed to use liquid dosage forms of the
present invention for the treatment of a tumor disease or a cancer
disease, including without limitation, colon cancer, thyroid
cancer, ovarian cancer, breast cancer, lung cancer (non-small cell
lung cancer), head and neck cancer, uterine cancer, non-hodgkin
lymphoma, blood cancer, skin cancer, prostate cancer, kidney
cancer, rectal cancer, peritoneal cavity cancer, brain cancer,
gastric cancer, metastatic cancer, colorectal cancer, pancreatic
cancer, endometrial cancer, stomach cancer, gastrointestinal
cancer, bladder cancer, and the like.
[0153] In one of the further aspects, the present invention is
directed to use liquid dosage forms of the present invention for
the treatment of at least one diseases or condition selected from
the group comprising of chronic myeloid leukemia, acute
lymphoblastic leukemia, myelodysplastic diseases,
myeloproliferative diseases, aggressive systemic mastocytosis,
hypereosinophilic syndrome and/or chronic eosinophilic leukemia,
unresectable, recurrent and/or metastatic dermatofibrosarcoma
protuberans, and unresectable and/or metastatic malignant
gastrointestinal stromal tumors.
[0154] The liquid dosage forms of the present invention are
proposed to have unexpectedly dramatic dissolution profiles. Rapid
dissolution of an administered active agent is preferable, as
faster dissolution generally leads to greater bioavailability and
faster onset of action. To improve the dissolution profile and
bioavailability of Imatinib it would be useful to increase
Imatinib's dissolution so that it could attain a level dose to 100%
dissolution of the drug substance.
[0155] The liquid dosage forms of the present invention comprising
Imatinib or a pharmaceutically acceptable salt thereof, exhibit
improved or comparable pharmacokinetic profiles as compared to
known Imatinib compositions, e.g. Gleevec.RTM.. For example, the
Cmax and/or AUC of the liquid dosage forms of Imatinib of the
present invention can be greater than or substantially equal to the
Cmax and/or AUC for known Imatinib compositions administered at the
same dose. In addition, the Tmax of the liquid dosage forms of
Imatinib of the present invention can be lower than or
substantially equal to that obtained for a known Imatinib
compositions, administered at the same dose. In addition,
combinations of an improved or comparable Cmax, AUC and Tmax
profile can be exhibited by the liquid dosage forms of Imatinib of
the invention, as compared to known Imatinib compositions. In
further aspects, the liquid dosage forms of Imatinib of the present
invention may result in minimal different absorption levels when
administered under fed as compared to fasting conditions.
[0156] In one of the aspects, a liquid dosage form comprising
Imatinib or pharmaceutically acceptable salt thereof exhibits in
comparative pharmacokinetic testing with an Imatinib marketed or
known formulation, administered at the same dose, a Tmax not
greater than about 90%, not greater than about 80%, not greater
than about 70%, not greater than about 60%, not greater than about
50%, not greater than about 30%, not greater than about 25%, not
greater than about 20%, not greater than about 15%, not greater
than about 10%, or not greater than about 5% of the Tmax exhibited
by the marketed or known Imatinib formulation.
[0157] In one of the further aspects, the liquid dosage form
comprising Imatinib or pharmaceutically acceptable salt thereof
exhibits in comparative pharmacokinetic testing with an Imatinib
marketed or known formulation, administered at the same dose, a
Cmax which is at least about 50%, at least about 100%, or at least
about 150%, greater than the Cmax exhibited by the marketed or
known Imatinib formulation. In one of the further aspects, the
liquid dosage form comprising Imatinib or pharmaceutically
acceptable salt thereof exhibits in comparative pharmacokinetic
testing with an Imatinib marketed or known formulation,
administered at the same dose, a Cmax which is in the range between
about 70% and about 150%.
[0158] In one of the further aspects, the liquid dosage form
comprising Imatinib or pharmaceutically acceptable salt thereof
exhibits in comparative pharmacokinetic testing with an Imatinib
marketed or known formulation, administered at the same dose, an
AUC which is at least about 25%, at least about 50%, at least about
75%, at least about 100%, at least about 125%, at least about 150%,
at least about 175%, or at least about 200%, greater than the AUC
exhibited by the marketed or known Imatinib formulation. In one of
the further aspects, the liquid dosage form comprising Imatinib or
pharmaceutically acceptable salt thereof exhibits in comparative
pharmacokinetic testing with an Imatinib marketed or known
formulation, administered at the same dose, an AUC which is in the
range between about 80% and about 125%.
[0159] In one of the further aspects, the Tmax of Imatinib or salt
thereof, when assayed in the plasma of the mammalian subject, is
less than about 6 to about 8 hours. In other aspects of the
invention, the Tmax of Imatinib or salt thereof is less than about
6 hours, less than about 5 hours, less than about 4 hours, less
than about 3 hours, less than about 2 hours, less than about 1
hour, or less than about 30 minutes after administration.
[0160] In some aspects, the liquid dosage forms of Imatinib of the
present invention exhibit improved or comparable bioavailability as
compared to known Imatinib compositions, e.g. Gleevec.RTM..
[0161] The present invention is further exemplified by the
following non-limiting examples.
Best Mode of Carrying Out the Invention
Examples
[0162] The liquid dosage forms of the present invention are
explained in more detail with reference to the following examples.
These examples are provided by way of illustration only and should
not be construed as to limit the scope or spirit of the claims in
any manner.
Examples 1-4: Preparation of Solution Dosage Forms of Imatinib
TABLE-US-00002 [0163] TABLE 2 Examples of Irnatinib solution dosage
forms (without glycerine) Example 1 Example 2 Example 3 Ingredients
Quantity (mg/mL) Irnatinib mesylate 95.6 (free 95.6 (free 95.6
(free base = 80.0) base = 80.0) base = 80.0) Liquid maltitol 300.0
300.0 300.0 Methyl paraben 5.0 5.0 5.0 Ethyl paraben 1.0 1.0 1.0
Citric acid Q.S. to Q.S. to Q.S. to desired pH desired pH desired
pH Sodium citrate Q.S. to Q.S. to Q.S. to desired pH desired pH
desired pH Strawberry flavour 0.1 0.1 0.1 Purified Water Q.S. to 1
mL Q.S. to 1 mL Q.S. to 1 mL Q.S. = Quantity sufficient; desired pH
= between about 2.0 to about 7.0
[0164] Method or Preparation: [0165] 1. Take required quantity of
water; [0166] 2. Dissolve required quantity of Methyl paraben and
Ethyl paraben in water. If required mixture may be heated to
dissolve Methyl paraben & Ethyl paraben and cooled down; [0167]
3. Add required quantity of Liquid maltitol and mix till get
homogenously mixed; [0168] 4. Add required quantity of Imatinib
mesylate and mix till completely dissolved; [0169] 5. Add Citric
acid and Sodium citrate till desired pH is attained; [0170] 6. Add
required quantity of Strawberry flavour and mix till completely
dissolved; and [0171] 7. Make up the final desired volume with
water.
TABLE-US-00003 [0171] TABLE 3 Stability data at different stability
conditions of different Irnatinib liquid compositions Single
maximum Freeze-thaw study impurity Total observation (Unknown)
impurities (Freezer -10.degree. C. Stability condition pH NMT 0.2%
NMT 1.0% to -20.degree. C. for 2 days) Example 1 Initial 3.48 0.02
0.57 Do not freeze but dark 3 M 40.degree. C./25% RH 3.47 0.02 0.57
brownish colour 3 M 25.degree. C./40% RH 3.48 0.02 0.57 observed
Example 2 Initial 4.31 0.03 0.66 Product was 3 M 40.degree. C./25%
RH 4.31 0.03 0.69 precipitated out 3 M 25.degree. C./40% RH 4.27
0.03 0.66 Example 3 Initial 5.05 0.02 0.63 Product was 3 M
40.degree. C./25% RH 5.05 0.03 0.65 precipitated out 3 M 25.degree.
C./40% RH 5.03 0.03 0.62 NMT = Not more than
TABLE-US-00004 TABLE 4 Irnatinib solution dosage form (with
glycerine) Example 4 Ingredients Quantity (mg/mL) Irnatinib
Mesylate 95.6 (free base = 80.0) Liquid maltitol 100.0 Glycerine
300.0 Sodium benzoate 0.2 Acesulfame potassium 1.0 Citric acid
monohydrate Q.S. to desired pH Strawberry flavour 0.1 Purified
Water Q.S. to 1 mL Q.S. = Quantity sufficient; desired pH = between
about 2.0 to about 7.0
TABLE-US-00005 TABLE 5 Irnatinib solution dosage form (with
glycerine) Example-4 Ingredients Quantity (mg/mL) Irnatinib
mesylate 1-1000 Liquid maltitol 0-500 Glycerin .sup. 250-800 Sodium
benzoate 0-4.0 Acesulfame potassium 0.01-10 Citric acid monohydrate
Q.S. to desired pH Strawberry flavour 0.01-10 Purified water Q.S.
to 1 mL Q.S. = Quantity sufficient; desired pH = from about 2.0 to
about 7.0
[0172] Method of Preparation: [0173] 1. Take required quantity of
purified water, [0174] 2. Add required quantity of Glycerin and mix
till get homogenously mixed; [0175] 3. Add required quantity of
Liquid maltitol and mix till get homogenously mixed; [0176] 4. Add
required quantity of Sodium benzoate and mix till completely
dissolved; [0177] 5. Add required quantity of Acesulfame potassium
and mix till completely dissolved; [0178] 6. Add required quantity
of Imatinib mesylate and mix till completely dissolved; [0179] 7.
Add Citric acid till desired pH is attained; [0180] 8. Add required
quantity of Strawberry flavour and mix till completely dissolved;
and [0181] 9. Make up the final desired volume with Water.
TABLE-US-00006 [0181] TABLE 6 Stability data of Example 4 Single
maximum impurity Total (Unknown) impurities Stability conditions pH
NMT 0.2% NMT 1.0% Initial 4.44 ND ND 40.degree. C. .+-. 2.degree.
C./ 1 M 4.4 ND ND 25% RH 2 M 4.42 0.08 0.37 3 M 4.64 0.06 (RRT
0.68) 0.63 6 M 4.6 0.07 (RRT 0.68) 0.69 25.degree. C. .+-.
2.degree. C./ 3 M 4.55 0.06 (RRT 0.68) 0.55 40.degree. .+-. 5% RH 6
M 4.55 0.06 (RRT 0.68) 0.57 ND = Not detected; NMT = Not more
than
Example 5: Preparation of Suspension Dosage Form of Imatinib
TABLE-US-00007 [0182] TABLE 7 Example of Irnatinib suspension
dosage form Quantity Ingredients Function (mg/mL) Irnatinib or salt
thereof Active ingredient 10-200 Methyl paraben Preservative
0.1-5.0 Ethyl paraben Preservative 0.1-5.0 Xanthan gum Suspending
agent/viscosity 0.1-10.sup. builder Sorbitol solution Sweetener
0.1-500 Flavor Flavoring agent 0.1-50.sup. Glycerin Solvent or
co-solvent/ 0-900 Wetting agent Disodium hydrogen phosphate
Buffering agent 1-50 dihydrate Sodium dihydrogen phosphate
Buffering agent 1-50 dihydrate Simethicone Anti-foaming agent
0.01-20 Polysorbate 80 Surfactant/wetting agent 0-20 Purified water
Vehicle Q.S. to 1 mL pH = between about 5.0 and about 8.5 Q.S. =
Quantity sufficient
[0183] Method of Preparation: [0184] 1. Take required quantity of
purified water; [0185] 2. Add methyl paraben and ethyl paraben and
mix till get dissolved, heating may be required, if necessary;
[0186] 3. Add disodium, hydrogen phosphate dihydrate and sodium
dihydrogen phosphate dihydrate and mix till get dissolved; [0187]
4. Add sorbitol solution and flavor and mix till get dissolved;
[0188] 5. Add glycerin and mix till get disperse d; [0189] 6. Add
xanthan gum and mix till get dispersed; [0190] 7. Add simethicone
and polysorbate 80 one by one and mix till get dispersed; [0191] 8.
Add Imatinib or salt thereof and mix to form homogenous suspension;
and [0192] 9. Adjust the final quantity with purified water.
Example 6: Preparation of Suspension Dosage Form of Imatinib
TABLE-US-00008 [0193] TABLE 8 Example of Irnatinib suspension
dosage form Ingredients Quantity (mg/mL) Irnatinib or salt thereof
10-200 Ethanol (absolute) .sup. 0.001-0.5 (mL) Butylated hydroxyl
toluene (BHT) 0.01-1.0 Sucralose 0.1-25.sup. Colloidal silicon
dioxide 1-50 Flavor 0.1-25.sup. Caprylocaproyl macrogo 8 glycerides
1-200 Medium chain triglyceride Q.S. to 1 mL
[0194] Method of Preparation: [0195] 1. Add required quantity of
medium chain triglyceride; [0196] 2. Add and mix caprylocaproyl
macrogol 8 glycerides till get uniformly dispersed; [0197] 3. Add
and mix colloidal silicon dioxide till get uniformly dispersed;
[0198] 4. Add butylated hydroxy toluene (BHT) and sucralose
dissolved in ethanol mixture to step (3); [0199] 5. Add Imatinib or
salt thereof; and [0200] 6. Add flavour and make up volume with
medium chain triglycerides.
Example 7: Bio-Equivalency Study of the Liquid Dosage Forms of the
Present Invention Prepared According to Example 4
[0201] The liquid dosage forms prepared according to Example 4 of
the present invention were tested for its bio-equivalence against
the reference product, i.e. Gleevec.RTM. marketed tablets. The
results of the bio-equivalence study shows that the liquid dosage
forms of the present invention have improved and/or comparable
pharmacokinetic profile and/or bioavailability when compared
against the known Imatinib formulations. The results are summarized
in the table below.
TABLE-US-00009 TABLE-9 Bio-equivalence study results Cmax Tmax
AUC.sub.t K.sub.ck T.sub.1/2 AUC.sup..infin. AUC_ratio Mean 2170.34
2.81 34479.46 0.05 14.80 35929.20 96.00 SD 800.16 0.98 13581.91
0.01 3.08 14259.21 0.29 Geometric Geometric Lower Upper Mean Mean
T/R Intra Inter confidence confidence Parameters (Test) (Reference)
Ratio Power % CV % CV interval interval LAUCt 33498.56 32140.21
104.23 100.00 13.74 36.48 98.15 110.68 LCmax 2149.35 2044.66 105.12
100.00 12.65 32.05 99.46 111.10
Example 8; Effect of Co-Solvent on the Liquid Dosage Form of the
Present
TABLE-US-00010 [0202] 9.56% Imatinib mesylate + 10% liquid maltitol
+ 20% glycerin + sodium 9.56% Imatinib mesylate + 9.56% Imatinib
mesylate + benzoate + acesulfame 10% liquid maltitol + 15% 10%
liquid maltitol + 30% potassium + citric acid glycerin + 15%
polyethylene polyethylene glycol + monohydrate + strawberry glycol
+ sodium benzoate + sodium benzoate + flavor + water acesulfame
potassium + acesulfame potassium + (the composition freezed citric
acid monohydrate + citric acid monohydrate + after 1.sup.st cycle)
strawberry flavor + water strawberry flavor + water Freeze
(freezed) (freezed) thaw Freeze Freeze Composition Cycle III thaw
thaw Test 60.degree. C. (clear 60.degree. C. Cycle III 60.degree.
C. Cycle III Parameters Initial 7 days solution) Initial 7 days
(freezed) Initial 7 days (freezed) Related substances RRT-0.48
0.08% 0.09% 0.08% 0.09% 0.09% 0.08% 0.09% 0.08% 0.07% RRT-0.59
0.03% 0.03% 0.03% 0.03% 0.03% 0.03% 0.039% 0.03% -- RRT-0.66 -- --
-- -- -- -- -- -- -- RRT-0.67 -- -- -- -- -- -- -- -- -- RRT-0.68
0.09% 0.07% 0.05% 0.09% 0.07% 0.01% 0.09% 0.08% 0.06% RRT-0.90 --
-- -- -- 0.03% -- -- 0.03% -- RRT-0.95 -- -- -- -- 0.03% -- --
0.03% -- RRT-1.20 0.12% 0.13% 0.12% 0.13% 0.13% 0.13% 0.13% 0.12%
0.11% RRT-1.43 -- -- -- -- -- -- -- -- -- Total 0.34% 0.43% 0.40%
0.44% 0.49% 0.47% 0.40% 0.42% 0.37% impurities RRT = Relative
retention time
[0203] From above data it can be concluded that the liquid dosage
form comprising only glycerin does not freeze after gone through
freeze-thaw cycles whereas the liquid dosage forms comprising (i)
mixture of glycerin and polyethylene glycol and (ii) only
polyethylene glycol gets freezed after gone through freeze-thaw
cycle (for further data see Table-10 below). Thus, glycerin is the
preferred solvent/co-solvent/solubilizer according to the present
invention and at least 25% or more glycerin is required to achieve
optimum results.
Example-9: Free-Thaw Study and Super Accelerated Stability Study of
Different Liquid Dosage Forms Prepared
TABLE-US-00011 [0204] TABLE 10 Freeze-thaw cycle data of different
liquid dosage forms Cycle 1 Cycle 2 Cycle 3 Freezer Freezer Freezer
(-10.degree. C. (-10.degree. C. (-10.degree. C. Composition Batch
No. to -20.degree. C.) to -20.degree. C.) to -20.degree. C.) 9.56%
Irnatinib mesylate + 10% liquid INBL2050 Slightly Clear solution-
Clear solution- maltitol + 20% glycerin + sodium freezed not
freezed not freezed benzoate + acesulfame potassium + citric acid
monohydrate + strawberry flavor + water 9.56% Irnatinib mesylate +
10% liquid INBL2056 Clear solution- Slightly Freezed maltitol + 15%
glycerin + 15% not freezed freezed polyethylene glycol + sodium
benzoate + acesulfame potassium + citric acid monohydrate +
strawberry flavor + water 9.56% Irnatinib mesylate + 10% liquid
INBL2059 Half bottle Half bottle Freezed maltitol + 30%
polyethylene glycol + freezed freezed sodium benzoate + acesulfame
potassium + citric acid monohydrate + strawberry flavor + water
Example 10; Stability Comparison Between Test Formulations and
Reference Formulation
TABLE-US-00012 [0205] TABLE-11 Super-accelerated stability study of
test formulations and reference formulation 9.56% Imatinib mesylate
+ 20% Glycerin + 5% Polyvinyl pyrrolidone + 30% Sucrose + 9.56%
Imatinib mesylate + 9.56% Imatinib mesylate +- sodium citrate
dihydrate + l0% liquid maltitol + 30% 10% liquid maltitol + 20%
citric acid 1 hydrate + glycerin + sodium benzoate + glycerin +
sodium benzoate Disodium edetate + acesulfame potassium + +
acesulfame potassium + sucralose + methyl citric acid monohydrate +
citric acid monohydrate + paraben + propyl paraben + strawberry
flavor + water strawberry flavor + water sodium metabisulfite (Test
formulation-1) (Test formulation-2) (Reference formulation)
Composition 60.degree. C. 60.degree. C. 60.degree. C. Test Initial
7 days Initial 7 days Initial 7 days parameters Clear yellow Clear
yellow Clear yellow Clear yellow Clear yellow Clear yellow
Description solution solution solution solution solution solution
Related substances RRT-0.00 -- -- -- -- -- -- RRT-0.09 -- -- -- --
-- 0.03% RRT-0.10 -- -- -- -- 0.03% -- RRT-0.33 -- -- -- -- 0.09%
0.03% RRT-0.48 0.08% 0.09% 0.08% 0.09% 0.08% 0.09% RRT-0.49 -- --
-- -- -- -- RRT-0.59 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% RRT-0.60
-- -- -- -- -- -- RRT-0.64 -- -- -- -- -- -- RRT-0.66 -- -- -- --
-- -- RRT-0.67 -- 0.06% -- -- -- 0.06% RRT-0.68 0.08% -- 0.09%
0.07% 0.06% -- RRT-0.69 -- -- -- -- -- -- RRT-0.70 -- -- -- --
0.03% -- RRT-0.84 -- -- -- -- -- -- RRT-0.90 -- -- -- -- -- --
RRT-0.95 -- -- -- -- -- -- RRT-1.20 0.12% 0.13% 0.12% 0.13% 0.12%
0.12% RRT-1.43 -- -- -- -- -- -- Total 0.35% 0.41% 0.34% 0.43%
0.46% 0.45% impurities RRT = Relative retention time
[0206] The inventors of the present invention had prepared two
formulations as Test Formulation-1 and Test Formulation-2 according
to the present invention containing 30% glycerin and 20% glycerin
respectively. The inventors have compared these two test
formulations with reference formulation prepared according to WO
2014041551. From above table it can be seen that both the test
formulations have total impurities less than the reference
formulation.
Example 11: Effect of Polyvinyl Pyrrolidone on Liquid Dosage Forms
of the Present Invention
[0207] In order to find out the effect of viscosity regulating
agent preferred in the specification of '551 publication (i.e.
polyvinyl pyrrolidone) on the liquid dosage forms of the present
invention, the inventors of the present invention prepared two
formulations, (i) with polyvinyl pyrrolidone, and (ii) without
polyvinyl pyrrolidone. These two formulations were tested for its
stability after seven days when kept under super-accelerated
conditions, i.e. 60.degree. C. The results are summarized in the
table below.
TABLE-US-00013 9.36% Irnatinib mesylate + 10% 9.36% Irnatinib
mesylate + 10% liquid maltitol + 30% glycerin + 5% liquid maltitol
+ 30% glycerin + polyvinyl pyrrolidone + sodium benzoate +
acesulfame potassium + benzoate + acesulfame potassium + citric
acid monohydrate + citric acid monohydrate + strawberry strawberry
flavor + water flavor + water Composition 60.degree. C. 6.degree.
C. Test parameters Initial 7 days Initial 7 days Description Clear
yellow Clear yellow Clear yellow Dark brownish solution solution
solution solution Related substances RRT-0.48 0.08% 0.09% 0.08%
0.09% RRT-0.59 0.03% 0.03% 0.03% 0.03% RRT-0.67 0.08% 0.06% 0.08%
0.06% RRT-0.90 -- -- 0.09% 0.12% RRT-0.95 -- -- 0.06% 0.09%
RRT-1.20 0.12% 0.13% 0.12% 0.13% RRT-1.43 -- -- -- -- Total
impurities 0.35% 0.41% 0.46% 0.58% RRT = Relative retention
time
[0208] From above data, it can be seen that the appearance of the
liquid dosage form without polyvinyl pyrrolidone does not change
after one week whereas the appearance of the liquid dosage form
with polyvinyl pyrrolidone changes from clear yellow solution to
dark brown solution. Further, it can also be seen that the
percentage amount and numbers of impurities dramatically increases
in the liquid dosage form with polyvinyl pyrrolidone at initial
stage and even after one week. Upon looking at the stability study
data, the liquid dosage form without polyvinyl pyrrolidone found
more stable than liquid dosage form with polyvinyl pyrrolidone.
[0209] From the foregoing examples, it is apparent that the liquid
dosage forms of Imatinib prepared according to the present
invention are suitable for use in the industry.
[0210] It should be understood that various changes and
modifications to the embodiments described herein will be apparent
to those skilled in the art. Such changes and modifications can be
made without departing from the spirit and scope of the subject
matter of the present invention and without diminishing its
intended advantages. It is therefore intended that such changes and
modifications be covered within the scope of the present
invention.
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