1
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
TREATMENT FOR APLASTIC ANEMIA (AA)
APPLICANT(S):
a) NAME ZYDUS LIFESCIENCES LIMITED
b) NATIONALITY INDIAN
c) ADDRESS ZYDUS CORPORATE PARK, SCHEME NO. 63,
SURVEY NO. 536, KHORAJ (GANDHINAGAR),
NR. VAISHNODEVI CIRCLE, AHMEDABAD,
GANDHINAGAR, GUJARAT, INDIA, 382481
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it has to be performed.
2
Field of the invention
The present invention describes a combination of a suitable prolyl hydroxylase inhibitors
with a suitable thrombopoietin (TPO) receptor agonist for the treatment of Aplastic anemia
(AA). The invention also describes the preparation of such combination and its compositions.
Background of the invention
Aplastic anemia (AA) is a rare disorder characterized by suppression of bone marrow
function resulting in progressive pancytopenia.1 The most common cause of AA is immune
system attacking the stem cells in bone marrow. Radiation and chemotherapy treatments are
the other factors that can injure bone marrow and affect blood cell production.2 It is diagnosed
with values have to lower than 10 g/dl for hemoglobin, 1.5 × 109/L for neutrophils and 50 ×
109/L for platelets.3 Megakaryocytes pattern may be useful in distinguishing myelodysplasia
(MDS) from AA since they are often reduced/absent in AA whereas small or aberrant
megakaryocytes are more typical of MDS.4 The clinical consequences are anemia, usually
with a requirement for frequent red blood cell transfusions, life-threatening bleeding from
thrombocytopenia, and infection as a result of neutropenia. Bacterial and fungal infections
are significant cause of morbidity and mortality.5
The standard definitive therapy for treating aplastic anemia is hematopoietic stem cell
transplantation for young and medically fit patients with suitable donors and
immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine.
Thrombopoietin mimetic (TPO agonist), has recently emerged as an encouraging and
promising agents for patients with AA. This class has been demonstrated to be efficacious in
restoring trilineage hematopoiesis. thrombopoietin (TPO) receptor agonist is the main
regulator for platelet production and its receptor (c-Mpl) is present on megakaryocytes and
hematopoietic stem cells.6 thrombopoietin (TPO) receptor agonist are intravenous peptibody
Romiplostim, oral small molecules Eltrombopag, Avatrombopag and lusutrombopag.7
3
Eltrombopag bisethanolamine, chemical name 3'-(2-(l-(3,4-dimethylphenyl)-3-methyl-5-
oxo- 1 ,5-dihydro-4H-pyrazol-4-ylidene)hydrazineyl)-2'-hydroxy-[1,1'-biphenyl]-3-
carboxylic acid 2-hydroxy-N,N,N-trimethylethan-l-aminium (1:1).
Eltrombopag is a small-molecule, non-peptide thrombopoietin (TPO) receptor agonist that
has been shown to stimulate the proliferation and differentiation of megakaryocytes, the bone
marrow cells that give rise to blood platelets in pre-clinical research and clinical trials.
Eltrombopag bisethanolamine is the active ingredient of the marketed drug Promacta® (US)
or Revolade® (EU) indicated in the treatment of chronic immune thrombocytopenia (CIT)
in patients who have had an insufficient response to corticosteroids, immunoglobulins, or
splenectomy. It is also indicated for thrombocytopenia in patients with chronic hepatitis C
and in severe aplastic anaemia. Eltrombopag is disclosed in US Patent No. 7,160,870.
Eltrombopag bisethanolamine salt is disclosed in US Patent No. 7,547,719. Eltrombopag
tromethamine salt is disclosed in International Patent Publication No. W020170042839.
Crystalline forms of Eltrombopag choline are disclosed in International Patent Publication
No. W020190071111 and US Patent No. 11,072,586.
Romiplostim is an active ingredient of the marketed drug Nplate. It is a thrombopoietin
receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic
immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids,
immunoglobulins, or splenectomy. Romiplostim disclosed in US Patent No. 9,145,450 and
WO2000/24770.
The small molecule hypoxia-inducible factor stabilizer compound Desidustat (compound of
formula (Ia)), inhibits the prolyl hydroxylase and has demonstrated hematinic potential by
combined effects on endogenous erythropoietin release and efficient iron utilization. It also
enhances erythroid maturation by suppressing hepcidin-ferroportin axis.8
Several other prolyl hydroxylase inhibitors have been disclosed in EP661269,
WO2007070359, WO2008076425, WO2011007856, WO2012106472, and
4
WO2013043621. Specifically WO2004108681 and WO2008002576 covers the prolyl
hydroxylase inhibitors named Roxadustat and Vadadustat respectively.
WO2014102818 discloses compounds of the following general formula
These compounds are reported to be useful for the treatment of anemia. It has surprisingly
now been found that compound of formula (Ia) as given below:
and its pharmaceutically acceptable salts are effective in the treatment of aplastic anemia
when combine with a suitable TPO receptor agonist improve two lineage of hematopoietic
precursor cells for the benefit of patients. Also, such combination with cyclosporine will be
useful.
Embodiments of the invention
The present invention describes a combination of a suitable prolyl hydroxylase inhibitor or
its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist.
The present invention describes a combination of the compound of formula (Ia) or its
pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist.
5
In an embodiment, the present invention provides a combination of the compound of formula
(Ia) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor
agonist for the treatment of Aplastic anemia (AA).
In a further embodiment is provided a pharmaceutical composition comprising, the
compound of formula (Ia) or its pharmaceutically acceptable salts and a suitable
thrombopoietin (TPO) receptor agonist along with at least one a suitable pharmaceutically
acceptable carrier, diluents, vehicle or excipient for the treatment of Aplastic anemia (AA).
In another embodiment, present invention provides use of combination of the compound of
formula (Ia) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO)
receptor agonist for the treatment of Aplastic anemia (AA).
In an embodiment, the present invention provides a method of treating Aplastic anemia (AA)
using the compound of formula (Ia) or its pharmaceutically acceptable salts.
In an embodiment the present invention provides a combination of the compound of formula
(Ia) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor
agonist optionally with cyclosporine.
Brief description of drawings
Figure 1. The effect of formula (Ia), Romiplostim and their combination on white blood cells
(A) and Platelets (B) in busulphan-induced aplastic anemia in Balb/c mice.
Figure 2. The effect of formula (Ia) and their combination with Romiplostim on white blood
cells (A) and Platelets (B) in cyclophosphamide-induced aplastic anemia in C57 mice.
Summary of the invention
The present invention describes a combination of a suitable prolyl hydroxylase inhibitors
with a suitable thrombopoietin (TPO) receptor agonist for the treatment of Aplastic anemia
(AA). The invention also describes the preparation of such combination and its compositions.
6
Description of the Invention
Definition:
The terms ‘treatment’ or ‘treat’ refer to slowing, stopping, or delaying the progression of the
disease or clinical symptoms in a patient, as evidenced by a decrease or elimination of a
clinical or diagnostic symptom of the disease, disorder or condition. The term ‘subject’ refer
to a human and animal. The term ‘effective amount’ in the context of the administration of
the amount of the drug substance sufficient to have the desired effect. The term
‘pharmaceutically acceptable’ use embraces both human and veterinary use. The compound
of formula (Ia) is Desidustat.
Combination of a suitable prolyl hydroxylase inhibitors with a suitable thrombopoietin
(TPO) receptor agonist
In an embodiment, the present invention describes a combination of a suitable prolyl
hydroxylase inhibitors and suitable thrombopoietin (TPO) receptor agonist.
A suitable prolyl hydroxylase inhibitor is selected from Roxadustat, Vadadustat,
Daprodustat, Molidustat, Enardustat and the compound of formula (Ia) or its
pharmaceutically acceptable salts.
A suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically
acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
Combination of compound of formula (Ia) or its pharmaceutically acceptable salts with
a suitable thrombopoietin (TPO) receptor agonist
In an embodiment, present invention provides a combination of compound of formula (Ia) or
its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist,
wherein formula (Ia) is represented by:
7
.
The pharmaceutical acceptable salts of the compound of formula (Ia) may be selected from
suitable inorganic metal salts or organic amines salts.
The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium,
silver, zinc, ammonium and the like.
Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl
amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-
butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-
trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
8
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
A suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically
acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
Modes of Administration
Combination as described above can be administered as oral, rectal, topical, nasal,
pulmonary, ocular, intestinals or parenteral.
An effective amount, e.g., dose, of combination compound or drug can readily be determined
by routine experimentation, as can an effective and convenient route of administration and
an appropriate formulation. Various formulations and drug delivery systems are available in
the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences,; and Hardman,
Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)
A suitable routes of administration may, for example, include oral, rectal, topical, nasal,
pulmonary, ocular, intestinal, and parenteral administration. Primary routes for parenteral
administration include intravenous, intramuscular, and subcutaneous administration.
Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular,
intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal,
intrauterine, and intraventricular administration. The indication to be treated, along with the
physical, chemical, and biological properties of the drug, dictate the type of formulation and
the route of administration to be used, as well as whether local or systemic delivery would
be preferred.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the
range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to
9
350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range
of 1 mg to 25 mg to the subject. In certain embodiments, the compound of formula (Ia) or a
pharmaceutically acceptable salts for oral administration to a subject to provide the
compound of formula (Ia) or a pharmaceutically acceptable salts at a dose of 1 mg to 150
mg. In further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg
to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50
mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or
75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100
mg.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 1 mg to about 500 mg. In a further embodiment, Avatrombopag is administered orally
to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Lusutrombopag
is administered orally to a subject in an amount of about 1 mg to 100 mg.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg. In a further embodiment, Avatrombopag
is administered orally to a subject in an amount of about 20 mg. In a further embodiment,
Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for parenteral administration to a subject at a dose in the range of 1 mg to 50 mg. In a
further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salts,
for parenteral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg
to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg
10
or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
parenteral administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5
mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg
and 10 mg to the subject.
In a further embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg,
about 150 μg to about 350 μg, about 200 μg to about 300 μg.
In a certain embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 125 μg, 250 μg and 500 μg. In a further embodiment.
In certain embodiments, combination of compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist can be further
characterized according to the dose of compound administered to a subject, where subject is
animal or human.
In some embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
and the a suitable thrombopoietin (TPO) receptor agonist are administered as one
composition. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered
separately. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered
consecutively. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered
simultaneously.
11
Method of treating Aplastic anemia (AA) in combination of compound of formula (Ia)
or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor
agonist
In an embodiment, the present invention provides a method of treating Aplastic anemia (AA)
in a subject, comprising administering a combination of compound of formula (Ia) or its
pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist.
The pharmaceutical acceptable salts of the compound of formula (Ia) may be selected from
a suitable inorganic metal salts or organic amines salts.
The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium,
silver, zinc, ammonium and the like.
Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl
amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-
butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-
trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
12
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
A suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically
acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
Combination as described above can be administered as oral, rectal, topical, nasal,
pulmonary, ocular, intestinal or parenteral.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the
range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to
350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range
of 1 mg to 25 mg to the subject. In certain embodiments, the compound of formula (Ia) or a
pharmaceutically acceptable salts for oral administration to a subject to provide the
compound of formula (Ia) or a pharmaceutically acceptable salts at a dose of 1 mg to 150
mg. In further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg
to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50
mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or
75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100
mg.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 1 mg to about 500 mg. In a further embodiment, Avatrombopag is administered orally
13
to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Lusutrombopag
is administered orally to a subject in an amount of about 1 mg to 100 mg.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg. In a further embodiment, Avatrombopag
is administered orally to a subject in an amount of about 20 mg. In a further embodiment,
Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for parenteral administration to a subject at a dose in the range of 1 mg to 50 mg. In a
further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salts,
for parenteral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg
to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg
or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
parenteral administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5
mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg
and 10 mg to the subject.
In a further embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg,
about 150 μg to about 350 μg, about 200 μg to about 300 μg.
In a certain embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 125 μg, 250 μg and 500 μg. In a further embodiment.
In certain embodiments, combination of compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist can be further
14
characterized according to the dose of compound administered to a subject, where subject is
animal or human.
In some embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
and the a suitable thrombopoietin (TPO) receptor agonist are administered as one
composition. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered
separately. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered
consecutively. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered
simultaneously.
Pharmaceutical composition of compound of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist for use in
treating Aplastic anemia (AA)
In an embodiment, present invention provides a pharmaceutical composition comprising
compound of formula (Ia) or its pharmaceutically acceptable salts and a suitable
thrombopoietin (TPO) receptor agonist optionally with one or more pharmaceutically
acceptable excipients for use in treating Aplastic anemia (AA).
The pharmaceutical acceptable salts of the compound of formula (Ia) may be selected from
suitable inorganic metal salts or organic amines salts.
The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium,
silver, zinc, ammonium and the like.
Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl
amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-
butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-
15
trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
A suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically
acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
The pharmaceutical composition as mentioned in above embodiment may be in form of oral,
rectal, topical, nasal, pulmonary, ocular, intestinal, or parenteral.
Oral formulation:
The pharmaceutical composition is in the oral form.
The pharmaceutically oral composition as described above or anywhere in the specification
may be in the form of tablet, capsule and oral liquids.
16
The pharmaceutically acceptable excipients are selected at least one from diluent, binders,
disintegrating agents, lubricating agents, glidant agent, sweetener, pH modifier, suspending
agent or viscosity modifying agent, flavouring agent and optionally coating redimix.
Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline
cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-
cyclodextrin, sodium chloride, spray dried lactose, and preferably sulfobutyl ether b-
cyclodextrin combinations thereof and other such materials known to those of ordinary skill
in the art.
Binders include, but are not limited to hypromellose 3 Cps, carbomers selected from
carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from
Eudragit, xanthan, lactose and Zein combinations thereof and other such materials known to
those of ordinary skill in the art.
Disintegrating agents include, but are not limited to, croscarmellose Sodium, bicarbonate
salt, chitin, gellan gum, polacrillin potassium and docusate Sodium combinations thereof and
other such materials known to those of ordinary skill in the art.
Glidant agents include, but are not limited to, colloidal silica, calcium silicate, magnesium
silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials
known to those of ordinary skill in the art.
Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate,
mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil, sodium
stearyl fumarate and myristic Acid suitable combinations thereof and other such materials
known to those of ordinary skill in the art.
A suitable pH modifying agents which maintain the pH of the formulation according to the
present invention include, but are not limited to Citric acid and other similar excipients and
their suitable combinations and other materials known to those of ordinary skill in the art.
17
Suspending agents or viscosity agent according to the present invention include, but are not
limited to microcrystalline cellulose and carboxymethylcellulose sodium (Avicel CL 611)
and other similar excipients and their suitable combinations and other materials known to
those of ordinary skill in the art.
Sweetener is selected from Sucrose and all such materials known to those of ordinary skill
in the art.
Flavouring agent is selected from cherry flavour, orange flavour, mango flavour and all such
fruit flavour known to those of ordinary skill in the art.
Coating redimix is selected from Opadry Pink all such materials known to those of ordinary
skill in the art.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the
range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to
350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range
of 1 mg to 25 mg to the subject. In certain embodiments, the compound of formula (Ia) or a
pharmaceutically acceptable salts for oral administration to a subject to provide the
compound of formula (Ia) or a pharmaceutically acceptable salts at a dose of 1 mg to 150
mg. In further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg
to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50
mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or
75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100
mg.
18
Table 1: Stable oral pharmaceutical composition of formula (Ia)
Strength –
5 mg/ml
Strength –
20 mg/ml
Ingredients mg/5ml mg/5ml
Compounds of formula (Ia) 25.00 100.00
Sucrose 3085.66 3010.66
Citric Acid, Anhydrous USP 10.00 10.00
Microcrystalline Cellulose
and Carboxymethylcellulose Sodium (Avicel CL 611)
164.85 164.85
Xanthan Gum NF (Xantural 75) 6.49 6.49
Cherry Flavour 8.00 8.00
A suitable thrombopoietin (TPO) receptor agonist Eltrombopag or its pharmaceutically
acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag
or its pharmaceutically acceptable salts.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 1 mg to about 500 mg. In a further embodiment, Avatrombopag is administered orally
to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Lusutrombopag
is administered orally to a subject in an amount of about 1 mg to 100 mg.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg. In a further embodiment, Avatrombopag
is administered orally to a subject in an amount of about 20 mg. In a further embodiment,
Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
can be further characterized according to the dose of compound administered to a subject,
where subject is animal or human.
In some embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
and a suitable thrombopoietin (TPO) receptor agonist are administered as one composition.
19
In some embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some
embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts and a
suitable thrombopoietin (TPO) receptor agonist are administered consecutively. In some
embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts and the a
suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.
Parenteral:
The pharmaceutical composition of combination of compound of formula (Ia) or its
pharmaceutically acceptable salts and Romiplostim is in parenteral form.
The pharmaceutical composition of combination of compound of formula (Ia) or its
pharmaceutically acceptable salts and Romiplostim can be administered via parenteral rout.
In an embodiment, the parenteral formulation of compound of formula (Ia) or its
pharmaceutically acceptable salts can be prepared as method known in art.
The parenteral formulation of compound of formula (Ia) or its pharmaceutically acceptable
salts comprising one or more pharmaceutically acceptable excipients for use in treating
Aplastic anemia (AA).
The pharmaceutically acceptable excipients are selected at least one from dextrose in water,
captisol in water, microemulsion and cosolvent or emulsifying agent with pH adjustment for
use in treating Aplastic anemia (AA).
Cosolvent or emulsifying agent is selected from Captex™ 300, Solutol™ H15, Propylene
glycol, Phospholipon™ 90G, Solutol™ HS15, dimethylacetamide with ethanol, PEG400 and
N-methylpyrrolidone.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for parenteral administration to a subject at a dose in the range of 1 mg to 50 mg. In a
further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salts,
20
for parenteral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg
to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg
or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
parenteral administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5
mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg
and 10 mg to the subject.
The pharmaceutical composition of a suitable thrombopoietin (TPO) receptor agonist
comprising one or more pharmaceutically acceptable excipients for use in treating Aplastic
anemia (AA).
The pharmaceutical composition as described above is in parenteral form.
A suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically
acceptable salts.
The pharmaceutically acceptable excipients are selected at least one from a buffer, a bulking
agent, a stabilizing agent and a surfactant for the treatment of Aplastic Anemia (AA).
Buffer is selected from glycine, histidine, glutamate, succinate, phosphate, acetate and
aspartate.
Bulking agent is selected from mannitol, glycine, sucrose, dextran, polyvinylpyrolidone,
carboxymethylcellulose, lactose, sorbitol, trehalose or xylitol.
The stabilizing agent is selected from sucrose, trehalose, mannose, maltose, lactose, glucose,
raffinose, cellobiose, gentiobiose, isomaltose, arabinose, glucosamine, fructose, mannitol,
sorbitol, glycine, arginine HCL, poly-hydroxy compounds, including polysaccharides such
21
as dextran, starch, hydroxyethyl starch, cyclodextrins, N-methylpyrollidene, cellulose and
hyaluronic acid, sodium chloride.
The surfactant is selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, dioctyl
sodium sulfonate, chenodeoxycholic acid, N-lauroylsarcosine sodium salt, lithium dodecyl
sulfate, 1-octanesulfonic acid sodium salt, sodium cholate hydrate, sodium deoxycholate,
glycodeoxycholic acid sodium salt, benzalkonium chloride or benzethonium chloride,
cetylpyridinium chloride monohydrate, hexadecyltrimethylammonium bromide, CHAPS,
CHAPSO, SB3-10, SB3-12, digitonin, Triton X-100, Triton X-114, lauromacrogol 400,
polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 40, 50 and 60, glycerol
monostearate, polysorbate 20, 40, 60, 65 and 80, soy lecithin, DOPC, DMPG, DMPC, and
DOPG; sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose.
In a further embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg,
about 150 μg to about 350 μg, about 200 μg to about 300 μg.
In a certain embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 125 μg, 250 μg and 500 μg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
can be further characterized according to the dose of compound administered to a subject,
where subject is animal or human.
In some embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
and Romiplostim are administered as one composition. In some embodiments, compounds
of formula (Ia) or its pharmaceutically acceptable salts and Romiplostim are administered
separately. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and Romiplostim are administered consecutively. In some embodiments,
compounds of formula (Ia) or its pharmaceutically acceptable salts and Romiplostim are
administered simultaneously.
22
Parenteral formulation can be administered by Subcutaneous, Intramuscular, Intravenous and
Intrathecal.
Use of compound of formula (Ia) or its pharmaceutically acceptable salts in
combination with a suitable thrombopoietin (TPO) receptor agonist for use in treating
Aplastic anemia (AA)
In an embodiment, present invention provides use of combination of compound of formula
(Ia) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor
agonist for treating Aplastic anemia (AA).
The pharmaceutical acceptable salts of the compound of formula (Ia) may be selected from
a suitable inorganic metal salts or organic amines salts.
The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium,
silver, zinc, ammonium and the like.
Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl
amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-
butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-
trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
23
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
A suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically
acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
Combination as described above can be administered as oral, rectal, topical, nasal,
pulmonary, ocular, intestinal, or parenteral.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the
range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to
350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range
of 1 mg to 25 mg to the subject. In certain embodiments, the compound of formula (Ia) or a
pharmaceutically acceptable salts for oral administration to a subject to provide the
compound of formula (Ia) or a pharmaceutically acceptable salts at a dose of 1 mg to 150
mg. In further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg
to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50
mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or
75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100
mg.
24
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 1 mg to about 500 mg. In a further embodiment, Avatrombopag is administered orally
to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Lusutrombopag
is administered orally to a subject in an amount of about 1 mg to 100 mg.
In a further embodiment, Eltrombopag is administered orally to a subject in an amount of
about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg. In a further embodiment, Avatrombopag
is administered orally to a subject in an amount of about 20 mg. In a further embodiment,
Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for parenteral administration to a subject at a dose in the range of 1 mg to 50 mg. In a
further embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salts,
for parenteral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg
to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or
15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg
to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg
or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain
embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salts for
parenteral administration to a subject to provide the compound of formula (Ia) or a
pharmaceutically acceptable salts at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5
mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg
and 10 mg to the subject.
In a further embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg,
about 150 μg to about 350 μg, about 200 μg to about 300 μg.
In a certain embodiment, Romiplostim is administered parenterally to a subject in an amount
of about 125 μg, 250 μg and 500 μg. In a further embodiment.
25
In certain embodiments, combination of compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist can be further
characterized according to the dose of compound administered to a subject, where subject is
animal or human.
In some embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
and the a suitable thrombopoietin (TPO) receptor agonist are administered as one
composition. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered
separately. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered
consecutively. In some embodiments, compounds of formula (Ia) or its pharmaceutically
acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered
simultaneously.
Method of treating Aplastic anemia (AA) by compound of formula (Ia)
In an embodiment the present invention provides a method of treating Aplastic anemia (AA)
in a subject, comprising administering an effective amount of compound of formula (Ia) or
its pharmaceutically acceptable salts.
The pharmaceutical acceptable salts of the compound of formula (Ia) may be selected from
a suitable inorganic metal salts or organic amines salts.
The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium,
silver, zinc, ammonium and the like.
Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl
amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-
butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-
trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
26
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
In certain embodiments, the compound of formula (Ia) or its pharmaceutically acceptable
salts, for administration to a subject at a dose in the range of 1 mg to 500 mg or in the range
of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to 350
mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range of
1 mg to 25 mg to the subject. In certain embodiments, the compound of formula (Ia) or a
pharmaceutically acceptable salts for administration to a subject to provide the compound of
formula (Ia) or a pharmaceutically acceptable salts at a dose of 1 mg to 150 mg. In further
embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salts, for
administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5
mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5
mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30
mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or
27
55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg
or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.
In certain embodiments, compounds of formula (Ia) or its pharmaceutically acceptable salts
can be further characterized according to the dose of compound administered to a subject,
where subject is animal or human.
The composition of formula (Ia) or its pharmaceutically acceptable salts can be prepared as
anywhere disclosed in the specification.
Combination of compound of formula (Ia) or its pharmaceutically acceptable salts and
a suitable thrombopoietin (TPO) receptor agonist optionally with cyclosporine
A suitable thrombopoietin (TPO) receptor agonist is Eltrombopag or its pharmaceutically
acceptable salts, Romiplostim or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
The pharmaceutical acceptable salts of the compound of formula (Ia) may be selected from
a suitable inorganic metal salt or organic amines salts.
The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium,
strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium,
silver, zinc, ammonium and the like.
Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl
amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-
butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-
trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
28
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
In an embodiment, present invention provides a pharmaceutical composition comprising
compound of formula (Ia) or its pharmaceutically acceptable salts and a suitable
thrombopoietin (TPO) receptor agonist optionally with cyclosporine.
The pharmaceutical composition, dosage form and rout of administration as described above
or anywhere in the specification.
The compound of formula (Ia) may be prepared by any of the methods known in the art
including those processes disclosed in the prior art such as those mentioned elsewhere in the
specification. Romiplostim may be prepared by any of the methods known in the art including
those processes disclosed in the prior art such as those mentioned elsewhere in the
specification.
Examples
The effect of combination of compounds of formula (Ia) and a suitable thrombopoietin (TPO)
receptor agonist in animal models for Aplastic Anemia (AA) is shown herein below.
Animal models of Aplastic Anemia (AA)
29
Example 1: Effect of formula (Ia), Romiplostim and its combination on busulphan-
induced aplastic anemia in Balb/c mice
Aplastic anemia (AA) was induced in BALB/c mice by administration of busulphan (BU).
BU was dissolved in acetone at concentrations of 5–10 mg/mL. Immediately before
administration, deionized water was added to the BU-acetone solution and the solution was
given by intraperitoneal (ip) injection at dose of 9 mg/kg. Control mice were given vehicle
at the same dose volume.9 Compound of formula (Ia) (15 mg/kg, PO, daily) and Romiplostim
(50 μg/kg, SC, once a week) combination were administered.
Mice were be dosed with vehicle or BU on 10 occasions over a period of 21 days (days 1, 3,
6, 8, 10, 13, 15, 17, 19 and 21). Between 1 to 127 days after the final BU dose, mice from
each group were autopsied for blood.9
The changes in the white blood cell (WBC) and platelet count were measured after 44 days
of treatment. Data are mean ± SEM (n =6 for each group).
Table 2. The effect of formula (Ia) alone, Romiplostim alone and its combination on white
blood cell (WBC) and platelets in busulphan-induced aplastic anemia in Balb/c mice.
Treatment Dose WBC
(10^3/uL)
% Change
against vehicle
control
Platelets
(10^3/uL)
% Change
against vehicle
control
Normal
control NA 5.5 ± 0.7 134.7 ± 29.1 1261.7 ± 100.3 143.6 ± 19.4
Vehicle
control 10 ml/kg 2.4 ± 0.3 0.0 ± 13.4 517.8 ± 70.5 0.0 ± 13.6
Formula (Ia) (15
mg/kg) 2.6 ± 0.2 10.9 ± 10.4 676.2 ± 80.1 30.6 ± 15.5
Romiplostim (50
μg/kg) 4.2 ± 0.5 79.3 ± 23.2 1257.0 ± 57.0 142.7 ± 11.0
Formula (Ia)
+
Romiplostim
(15
mg/kg) +
(50
μg/kg)
5.0 ± 0.4 113.4 ± 16.0 1330.0 ± 89.7 156.8 ± 17.3
30
#P<0.05 against normal control and *P<0.05 against vehicle control was considered
significant.
Conclusion: Combination of Formula (Ia) and Romiplostim significantly increased two
lineages of hematopoiesis in busulphan- induced aplastic anemia in Balb/c mice.
Example 2: Effect of formula (Ia) and its combination with Romiplostim on
cyclophosphamide-induced aplastic anemia in C57 mice
Aplastic anemia (AA) was induced in C57 mice by administration of cyclophosphamide.
Cyclophosphamide was dissolved in deionized water at concentrations of 20 mg/mL.
Immediately before administration, deionized water was added to the stock solution and the
solution was given by intraperitoneal (ip) injection at dose of 100 mg/kg. Mice were dosed
with vehicle or cyclophosphamide for 4 days. Control mice were given vehicle at the same
dose volume.10 Compound of formula (Ia) (15 mg/kg, PO, daily) and Romiplostim (30 μg/kg,
SC, once a week) combination were administered.
Blood was collected from each group after 11 days of treatment. The changes in the white
blood cell (WBC) and platelet count were measured. Data are mean ± SEM (n =6 for each
group).
Table 3. The effect of formula (Ia) and its combination with Romiplostim on white blood
cell (WBC) and platelets in cyclophosphamide-induced aplastic anemia in C57 mice.
Treatment Dose WBC
(10^3/uL)
% Change
against
vehicle
control
Platelets
(10^3/uL)
% Change
against vehicle
control
Normal
control NA 9.2 ± 0.6 44.7 ± 9.3 1143.2 ± 28.8 103.5 ± 5.1
Vehicle
control
(10
ml/kg) 6.4 ± 0.5 0.0 ± 8.1 561.8 ± 83.2 0.0 ± 14.8
Formula (Ia) (15
mg/kg) 7.0 ± 1.0 10.1 ± 15.6 742.3 ± 31.0 32.1 ± 5.5
31
Formula (Ia)
+
Romiplostim
(15
mg/kg)
+ (30
μg/kg)
8.7 ± 0.5 37.2 ± 8.4 1334.2 ± 113.1 137.5 ± 20.1
#P<0.05 against normal control and *P<0.05 against vehicle control was considered
significant.
Conclusion: Combination of Formula (Ia) and Romiplostim significantly increased two
lineages hematopoiesis in cyclophosphamide- induced aplastic anemia in C57 mice.
References:
1. Dezern AE, Brodsky RA. Clinical management of aplastic anemia. Expert Rev
Hematol. 2011 Apr;4(2):221-30. doi: 10.1586/ehm.11.11. PMID: 21495931;
PMCID: PMC3138728.
2. Young NS. Aplastic Anemia. N Engl J Med. 2018 Oct 25;379(17):1643-1656. doi:
10.1056/NEJMra1413485. PMID: 30354958; PMCID: PMC6467577.
3. Peslak SA, Olson T, Babushok DV. Diagnosis and Treatment of Aplastic Anemia.
Curr Treat Options Oncol. 2017 Nov 16;18(12):70. doi: 10.1007/s11864-017-0511-
z. PMID: 29143887; PMCID: PMC5804354.
4. Olcay L, Yetgin S, Aoshima H. Disorders mimicking myelodysplastic syndrome and
difficulties in its diagnosis. IntechOpen; 2016 Sep 7.
5. Desmond R, Townsley DM, Dunbar C, Young NS. Eltrombopag in aplastic anemia.
Semin Hematol. 2015 Jan;52(1):31-7. doi: 10.1053/j.seminhematol.2014.10.002.
Epub 2014 Oct 31. PMID: 25578417; PMCID: PMC4293077.
6. Lum SH, Grainger JD. Eltrombopag for the treatment of aplastic anemia: current
perspectives. Drug Des Devel Ther. 2016 Sep 13;10:2833-2843. doi:
10.2147/DDDT.S95715. PMID: 27695288; PMCID: PMC5028092.
7. Al-Samkari H, Kuter DJ. Optimal use of thrombopoietin receptor agonists in immune
thrombocytopenia. Ther Adv Hematol. 2019 Apr 11;10:2040620719841735. doi:
10.1177/2040620719841735. PMID: 31007886; PMCID: PMC6460888.
32
8. Joharapurkar AA, Patel VJ, Kshirsagar SG, Patel MS, Savsani HH, Kajavadara C,
Valani D, Jain MR. Prolyl hydroxylase inhibitor desidustat improves anemia in
erythropoietin hyporesponsive state. Curr Res Pharmacol Drug Discov. 2022 Apr
30;3:100102. doi: 10.1016/j.crphar.2022.100102. PMID: 35570856; PMCID:
PMC9096675.
9. Turton JA, Sones WR, Andrews CM, Pilling AM, Williams TC, Molyneux G,
Rizzo S, Gordon‐Smith EC, Gibson FM. Further development of a model of chronic
bone marrow aplasia in the busulphan‐treated mouse. International journal of
experimental pathology. 2006 Feb;87(1):49-63.
10. Lu W, Jia D, An S, Mu M, Qiao X, Liu Y, Li X, Wang D. Calf Spleen Extractive
Injection protects mice against cyclophosphamide-induced hematopoietic injury
through G-CSF-mediated JAK2/STAT3 signaling. Sci Rep. 2017 Aug 21;7(1):8402.
doi: 10.1038/s41598-017-08970-3. PMID: 28827748; PMCID: PMC5566473.
33
We claim:
1. A combination of compound of formula (Ia) or its pharmaceutically acceptable salts with
a suitable thrombopoietin (TPO) receptor agonist, wherein formula (Ia) is represented by:
.
2. A combination as claimed in claim 1, wherein the pharmaceutical acceptable salts of the
compound of formula (Ia) is selected from a suitable inorganic metal salts or organic amines
salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium,
barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum,
cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine,
dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl
amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane
diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline),
tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl)
guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-
(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-
methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine,
piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine,
proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine,
cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine,
diphenylamine, α-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-
naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-
4-chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
34
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
3. A combination as claimed in claim 1, wherein a suitable thrombopoietin (TPO) receptor
agonist is selected from Eltrombopag or its pharmaceutically acceptable salts, Romiplostim
or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable
salts and Lusutrombopag or its pharmaceutically acceptable salts.
4. A combination as claimed in claim 1 can be administered orally or parenterally.
5. A combination as claimed in claim 1, wherein the compound of formula (Ia) or its
pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to
500 mg or 50 mg to 450 mg or 100 mg to 400 mg or 150 mg to 350 mg or 200 mg to 300 mg
or 1 mg to 50 mg or 1 mg to 25 mg to the subject.
6. A combination as claimed in claim 1, wherein the compound of formula (Ia) or its
pharmaceutically acceptable salts is administered orally to a subject at a dose of 1 mg to 2.5
mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg
to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg
or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50
mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to
75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg
to 100 mg.
7. A combination as claimed in claim 1, wherein Eltrombopag is administered orally to a
subject in an amount of 1 mg to 500 mg, Avatrombopag is administered orally to a subject
in an amount of 1 mg to 100 mg and Lusutrombopag is administered orally to a subject in an
amount of 1 mg to 100 mg.
8. A combination as claimed in claim 1, wherein Eltrombopag is administered orally to a
subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, Avatrombopag is
administered orally to a subject in an amount of 20 mg and Lusutrombopag is administered
orally to a subject in an amount of 3 mg.
35
9. A combination as claimed in claim 1, wherein the compound of formula (Ia) or its
pharmaceutically acceptable salts is administered parenterally to a subject in amount of 1 mg
to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or
12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg
to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg
or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5
mg to 50 mg.
10. A combination as claimed in claim 1, wherein the compound of formula (Ia) or its
pharmaceutically acceptable salts is administered parenterally to a subject in amount of 0.5
mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg,
7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.
11. A combination as claimed in claim 1, wherein thrombopoietin (TPO) receptor agonist
which is Romiplostim, administered parenterally to a subject in an amount of 1 μg to 500 μg,
50 μg to 450 μg, 100 μg to 400 μg, 150 μg to 350 μg, 200 μg to 300 μg.
12. A combination as claimed in claim 1, wherein thrombopoietin (TPO) receptor agonist
which is Romiplostim , administered parenterally to a subject in an amount of 125 μg, 250
μg and 500 μg.
13. A combination as claimed in claim 1, wherein combination of the compound of formula
(Ia) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor
agonist is administered to a subject, where subject is animal or human.
14. A combination as claimed in claim 1, wherein the compound of formula (Ia) or its
pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is
administered as one composition, separately, consecutively or simultaneously.
15. A pharmaceutical composition comprising compound of formula (Ia) or its
pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist
optionally with one or more pharmaceutically acceptable excipients for use in treating
Aplastic anemia (AA).
16. The pharmaceutical composition for use as claimed in claim 15, wherein the
pharmaceutical acceptable salts of the compound of formula (Ia) is selected from a suitable
36
inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected
from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper,
cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic
amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-
propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine,
t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl
ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl
cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-
methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,
hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl
benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-
aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine,
2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine,
cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, α-
naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-
3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-
chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-
quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-
hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine,
L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine,
metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and
N-ethylmorpholine.
17. The pharmaceutical composition for use as claimed in claim 15, wherein a suitable
thrombopoietin (TPO) receptor agonist is selected from Romiplostim or its pharmaceutically
acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its
pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable
salts.
18. The pharmaceutical composition for use as claimed in claim 15 is in the form of oral or
parenteral.
37
19. The pharmaceutical composition for use as claimed in claim 18 is in oral form.
20. The pharmaceutical composition for use as claimed in claim 19, wherein the
pharmaceutically acceptable excipient is selected from diluent, binders, disintegrating agents,
lubricating agents, glidant agent, sweetener, pH modifier, suspending agent or viscosity
modifying agent, flavouring agent and optionally coating redimix; wherein diluent is selected
from monohydrate, lactose, microcrystalline cellulose, polymethacrylates selected from
Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride, spray dried
lactose, and preferably sulfobutyl ether b-cyclodextrin; binder is selected from hypromellose
3 Cps, carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil,
polymethacrylates selected from Eudragit, xanthan, lactose and Zein; disintegrating agent is
selected from croscarmellose Sodium, bicarbonate salt, chitin, gellan gum, polacrillin
potassium and docusate sodium; lubricant is selected from calcium stearate, magnesium
stearate, mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable
oil, sodium stearyl fumarate and myristic Acid; glidant is selected from colloidal silica,
calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc; suspending agents is
selected from microcrystalline cellulose and carboxymethylcellulose sodium (Avicel CL
611); sweetener is selected from sucrose; flavouring agents is selected from cherry flavour,
orange flavour and mango flavour; coating redimix is selected from Opadry Pink.
21. The pharmaceutical composition for use as claimed in claim 19, wherein the compound
of formula (Ia) or its pharmaceutically acceptable salts is administered orally to a subject in
amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg
to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg to the subject.
22. The pharmaceutical composition for use as claimed in claim 19, wherein the compound
of formula (Ia) or its pharmaceutically acceptable salts is administered orally to a subject at
a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg
to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5
mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg
to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65
38
mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or
90 mg to 95 mg or 95 mg to 100 mg.
23. The pharmaceutical composition for use as claimed in claim 19, wherein Eltrombopag is
administered orally to a subject in an amount of 1 mg to 500 mg, Avatrombopag is
administered orally to a subject in an amount of 1 mg to 100 mg and Lusutrombopag is
administered orally to a subject in an amount of 1 mg to 100 mg.
24. The pharmaceutical composition for use as claimed in claim 19, wherein Eltrombopag is
administered orally to a subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg,
Avatrombopag is administered orally to a subject in an amount of 20 mg and Lusutrombopag
is administered orally to a subject in an amount of 3 mg.
25. The pharmaceutical composition for use as claimed in claim 19, wherein combination of
the compound of formula (Ia) or its pharmaceutically acceptable salts and a suitable
thrombopoietin (TPO) receptor agonist is administered orally to a subject, where subject is
animal or human.
26. The pharmaceutical composition for use as claimed in claim 19, wherein the compound
of formula (Ia) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO)
receptor agonist is administered orally as one composition, separately, consecutively or
simultaneously.
27. The pharmaceutical composition for use as claimed in claim 18 is in parenteral form.
28. The pharmaceutical composition for use as claimed in claim 27, wherein excipient used
with formula (Ia) is selected from dextrose in water, captisol in water, microemulsion and
cosolvent or emulsifying agent with pH adjustment; wherein cosolvent or emulsifying agent
is selected from Captex™ 300, Solutol™ H15, Propylene glycol, Phospholipon™ 90G,
Solutol™ HS15, dimethylacetamide with ethanol, PEG400 and N-methylpyrrolidone.
29. The pharmaceutical composition for use as claimed in claim 27, wherein the compound
of formula (Ia) or its pharmaceutically acceptable salts is administered parenterally to a
subject in amount of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg
or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg
to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35
39
mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or
45 mg to 47.5 mg or 47.5 mg to 50 mg.
30. The pharmaceutical composition for use as claimed in claim 27, wherein the compound
of formula (Ia) or its pharmaceutically acceptable salts is administered parenterally to a
subject in amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg,
5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.
31. The pharmaceutical composition for use as claimed in claim 27, wherein a suitable
thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable
salts.
32. The pharmaceutical composition for use as claimed in claim 27, wherein
pharmaceutically acceptable excipients used with Romiplostim selected from a buffer, a
bulking agent, a stabilizing agent and a surfactant; wherein buffer is selected from glycine,
histidine, glutamate, succinate, phosphate, acetate and aspartate; bulking agent is selected
from mannitol, glycine, sucrose, dextran, polyvinylpyrolidone, carboxymethylcellulose,
lactose, sorbitol, trehalose or xylitol; stabilizing agent is selected from sucrose, trehalose,
mannose, maltose, lactose, glucose, raffinose, cellobiose, gentiobiose, isomaltose, arabinose,
glucosamine, fructose, mannitol, sorbitol, glycine, arginine HCL, poly-hydroxy compounds,
including polysaccharides such as dextran, starch, hydroxyethyl starch, cyclodextrins, N-
methylpyrollidene, cellulose and hyaluronic acid, sodium chloride; surfactant is selected
from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate,
chenodeoxycholic acid, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, 1-
octanesulfonic acid sodium salt, sodium cholate hydrate, sodium deoxycholate,
glycodeoxycholic acid sodium salt, benzalkonium chloride or benzethonium chloride,
cetylpyridinium chloride monohydrate, hexadecyltrimethylammonium bromide, CHAPS,
CHAPSO, SB3-10, SB3-12, digitonin, Triton X-100, Triton X-114, lauromacrogol 400,
polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 40, 50 and 60, glycerol
monostearate, polysorbate 20, 40, 60, 65 and 80, soy lecithin, DOPC, DMPG, DMPC, and
DOPG; sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose.

We claim:

1. A combination of a suitable prolyl hydroxylase inhibitors and a suitable thrombopoietin (TPO) receptor agonist.

2. A combination as claimed in claim 1, wherein a suitable prolyl hydroxylase inhibitor is selected from Roxadustat, Vadadustat, Daprodustat, Molidustat, Enardustat and formula (la) or its pharmaceutically acceptable salts.

3. A combination as claimed in claim 1, wherein a suitable thrombopoietin (TPO) receptor agonist is selected from Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.

4. A combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist, wherein formula (la) is represented by:

Formula (la)

5. A combination as claimed in claim 4, wherein the pharmaceutical acceptable salts of the compound of formula (la) is selected from a suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene- methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl

benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-a-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and N-ethylmorpholine.

A combination as claimed in claim 4, wherein a suitable thrombopoietin (TPO) receptor agonist is selected from Eltrombopag or its pharmaceutically acceptable salts, Romiplostim or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.

A combination as claimed in claim 4 can be administered orally or parenterally.

A combination as claimed in claim 4, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg or 50 mg to 450 mg or 100 mg to 400 mg or 150 mg to 350 mg or 200 mg to 300 mg or 1 mg to 50 mg or 1 mg to 25 mg to the subject.

A combination as claimed in claim 4, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject at a dose of 1 mg to

2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or

12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.

10. A combination as claimed in claim 4, wherein Eltrombopag is administered orally to a subject in an amount of 1 mg to 500 mg, Avatrombopag is administered orally to a subject in an amount of 1 mg to 100 mg and Lusutrombopag is administered orally to a subject in an amount of 1 mg to 100 mg.

11. A combination as claimed in claim 4, wherein Eltrombopag is administered orally to a subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, Avatrombopag is administered orally to a subject in an amount of 20 mg and Lusutrombopag is administered orally to a subject in an amount of 3 mg.

12. A combination as claimed in claim 4, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to

47.5 mg or 47.5 mg to 50 mg.

13. A combination as claimed in claim 4, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg,

6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

14. A combination as claimed in claim 4, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 1 pg to 500 pg, 50 pg to 450 pg, 100 pg to 400 pg, 150 pg to 350 pg, 200 pg to 300 pg.

15. A combination as claimed in claim 4, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim , administered parenterally to a subject in an amount of 125 pg, 250 pg and 500 pg.

16. A combination as claimed in claim 4, wherein combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, where subject is animal or human.

17. A combination as claimed in claim 4, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered as one composition, separately, consecutively or simultaneously.

A method of treating Aplastic anemia (AA) in a subject, comprising administering a combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein the pharmaceutical acceptable salts of the compound of formula (la) is selected from suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-a-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and N-ethylmorpholine.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein a suitable thrombopoietin (TPO) receptor agonist is selected from Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.

21. A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein combination can be administered orally or parenterally.

22. A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg to the subject.

23. A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.

24. A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein Eltrombopag is administered orally to a subject in an amount of 1 mg to 500 mg, Avatrombopag is administered orally to a subject in an amount of 1 mg to 100 mg and Lusutrombopag is administered orally to a subject in an amount of 1 mg to 100 mg.

25. A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein Eltrombopag is administered orally to a subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, Avatrombopag is administered orally to a subject in an amount of 20 mg and Lusutrombopag is administered orally to a subject in an amount of 3 mg.

26. A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or

17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to

42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 1 pg to 500 pg, 50 pg to 450 pg, 100 pg to 400 pg, 150 pg to 350 pg, 200 pg to 300 pg.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 125 pg, 250 pg and 500 pg.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, where subject is animal or human.

A method of treating Aplastic anemia (AA) in a subject as claimed in claim 18, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered as one composition, separately, consecutively or simultaneously.

A pharmaceutical composition comprising compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist optionally with one or more pharmaceutically acceptable excipients for use in treating Aplastic anemia (AA).

The pharmaceutical composition for use as claimed in claim 32, wherein the pharmaceutical acceptable salts of the compound of formula (la) is selected from a suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-

methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-a-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and N-ethylmorpholine.

The pharmaceutical composition for use as claimed in claim 32, wherein a suitable thrombopoietin (TPO) receptor agonist is selected from Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.

The pharmaceutical composition for use as claimed in claim 32 is in the form of oral or parenteral.

The pharmaceutical composition for use as claimed in claim 35 is in oral form.

The pharmaceutical composition for use as claimed in claim 36, wherein the pharmaceutically acceptable excipient is selected from diluent, binders, disintegrating agents, lubricating agents, glidant agent, sweetener, pH modifier, suspending agent or viscosity modifying agent, flavouring agent and optionally coating redimix; wherein diluent is selected from monohydrate, lactose, microcrystalline cellulose,

polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b- cyclodextrin, sodium chloride, spray dried lactose, and preferably sulfobutyl ether b- cyclodextrin; binder is selected from hypromellose 3 Cps, carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein; disintegrating agent is selected from croscarmellose Sodium, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate sodium; lubricant is selected from calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic Acid; glidant is selected from colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc; suspending agents is selected from microcrystalline cellulose and carboxymethylcellulose sodium (Avicel CL 611); sweetener is selected from sucrose; flavouring agents is selected from cherry flavour, orange flavour and mango flavour; coating redimix is selected from Opadry Pink.

38. The pharmaceutical composition for use as claimed in claim 36, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg to the subject.

39. The pharmaceutical composition for use as claimed in claim 36, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.

40. The pharmaceutical composition for use as claimed in claim 36, wherein Eltrombopag is administered orally to a subject in an amount of 1 mg to 500 mg, Avatrombopag is administered orally to a subject in an amount of 1 mg to 100 mg and Lusutrombopag is administered orally to a subject in an amount of 1 mg to 100 mg.

41. The pharmaceutical composition for use as claimed in claim 36, wherein Eltrombopag is administered orally to a subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, Avatrombopag is administered orally to a subject in an amount of 20 mg and Lusutrombopag is administered orally to a subject in an amount of 3 mg.

42. The pharmaceutical composition for use as claimed in claim 36, wherein combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered orally to a subject, where subject is animal or human.

43. The pharmaceutical composition for use as claimed in claim 36, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered orally as one composition, separately, consecutively or simultaneously.

44. The pharmaceutical composition for use as claimed in claim 35 is in parenteral form.

45. The pharmaceutical composition for use as claimed in claim 44, wherein excipient used with formula (la) is selected from dextrose in water, captisol in water, microemulsion and cosolvent or emulsifying agent with pH adjustment; wherein cosolvent or emulsifying agent is selected from Captex™ 300, Solutol™ Hl 5, Propylene glycol, Phospholipon™ 90G, Solutol™ HS15, dimethylacetamide with ethanol, PEG400 and N- methylpyrrolidone .

46. The pharmaceutical composition for use as claimed in claim 44, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg.

47. The pharmaceutical composition for use as claimed in claim 44, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

The pharmaceutical composition for use as claimed in claim 44, wherein a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts.

The pharmaceutical composition for use as claimed in claim 44, wherein pharmaceutically acceptable excipients used with Romiplostim selected from a buffer, a bulking agent, a stabilizing agent and a surfactant; wherein buffer is selected from glycine, histidine, glutamate, succinate, phosphate, acetate and aspartate; bulking agent is selected from mannitol, glycine, sucrose, dextran, polyvinylpyrolidone, carboxymethylcellulose, lactose, sorbitol, trehalose or xylitol; stabilizing agent is selected from sucrose, trehalose, mannose, maltose, lactose, glucose, raffinose, cellobiose, gentiobiose, isomaltose, arabinose, glucosamine, fructose, mannitol, sorbitol, glycine, arginine HCL, poly-hydroxy compounds, including polysaccharides such as dextran, starch, hydroxyethyl starch, cyclodextrins, N-methylpyrollidene, cellulose and hyaluronic acid, sodium chloride; surfactant is selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, chenodeoxycholic acid, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, 1 -octanesulfonic acid sodium salt, sodium cholate hydrate, sodium deoxycholate, glycodeoxycholic acid sodium salt, benzalkonium chloride or benzethonium chloride, cetylpyridinium chloride monohydrate, hexadecyltrimethylammonium bromide, CHAPS, CHAPSO, SB3-10, SB3-12, digitonin, Triton X-100, Triton X-114, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 40, 50 and 60, glycerol monostearate, polysorbate 20, 40, 60, 65 and 80, soy lecithin, DOPC, DMPG, DMPC, and DOPG; sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose.

The pharmaceutical composition for use as claimed in claim 44, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 1 pg to 500 pg, 50 pg to 450 pg, 100 pg to 400 pg, 150 pg to 350 pg, 200 pg to 300 pg.

The pharmaceutical composition for use as claimed in claim 44, thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 125 pg, 250 pg and 500 pg.

The pharmaceutical composition for use as claimed in claim 44, wherein a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, where subject is animal or human.

The pharmaceutical composition for use as claimed in claim 44, wherein compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered as one composition, separately, consecutively or simultaneously.

Use of combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist for treating Aplastic anemia (AA). Use of combination as claimed in claim 54, wherein the pharmaceutical acceptable salts of the compound of formula (la) is selected from suitable inorganic metal salts or organic amines salts; wherein the inorganic metal is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-a-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-adamantanmethylamine, tritylamine, glucamine, N-methyl

pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and N-ethylmorpholine.

Use of combination as claimed in claim 54, wherein a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.

Use of combination as claimed in claim 54, wherein combination can be administered orally or parenterally.

Use of combination as claimed in claim 54, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg to the subject.

Use of combination as claimed in claim 54, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject at a dose of 1 mg to

2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or

12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.

Use of combination as claimed in claim 54, wherein Eltrombopag is administered orally to a subject in an amount of 1 mg to 500 mg, Avatrombopag is administered orally to a subject in an amount of 1 mg to 100 mg and Lusutrombopag is administered orally to a subject in an amount of 1 mg to 100 mg.

Use of combination as claimed in claim 54, wherein Eltrombopag is administered orally to a subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, Avatrombopag is administered orally to a subject in an amount of 20 mg and Lusutrombopag is administered orally to a subject in an amount of 3 mg.

Use of combination as claimed in claim 54, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to

47.5 mg or 47.5 mg to 50 mg.

63. Use of combination as claimed in claim 54, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered parenterally to a subject in amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg,

6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

64. Use of combination as claimed in claim 54, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 1 pg to 500 pg, 50 pg to 450 pg, 100 pg to 400 pg, 150 pg to 350 pg, 200 pg to 300 pg.

65. Use of combination as claimed in claim 54, wherein thrombopoietin (TPO) receptor agonist which is Romiplostim, administered parenterally to a subject in an amount of 125 pg, 250 pg and 500 pg.

66. Use of combination as claimed in claim 54, wherein combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, where subject is animal or human.

67. Use of combination as claimed in claim 54, wherein compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist is administered as one composition, separately, consecutively or simultaneously.

68. A method of treating Aplastic anemia (AA) in a subject, comprising administering an effective amount of compound of formula (la) or its pharmaceutically acceptable salts.

69. A pharmaceutical composition comprising, a compound of formula (la) or a pharmaceutically acceptable salts thereof and sucrose, citric acid, microcrystalline cellulose and carboxymethyl cellulose sodium (Avicel CL 611) and xanthum for the treatment of Aplastic anemia (AA).

70. A combination of compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist optionally with cyclosporine.