PHARMACEUTICAL FORMULATIONS
FIELD OF THE INVENTION
This invention relates to pharmaceutical formulations comprising 1-(2-thien-2'-yl-2-oxoethyl)-
3-(methanesulfonyl hydrazine carbonyl) pyridinium, its pharmaceutically acceptable
salts, salt-cocrystals and co-crystals, particularly 1-(2-thien-2'-yl-2-oxo-ethyl)-3-
(methanesulfonyl hydrazine carbonyl) pyridinium chloride. The formulations are suitable for
oral administration and also comprise a permeability enhancer or a suitable base or a
mixture thereof. The formulations of this invention are for treating diseases associated with
advanced glycation end products selected from diabetic and aging-related macrovascular
and microvascular complications including, heart failure, nephrological disorder, neuropathy,
atherosclerosis and retinal disorder; dermatological disorder, endothelial or other organ
dysfunction and growth impairment.
BACKGROUND
Maillard in 19 12 found that reducing sugars, such as glucose and ribose react with proteins
to form brown pigments. Further studies have shown that this is an irreversible nonenzymatic
reaction, which occurs in several natural systems including stored foodstuff. The
Maillard reaction occurs in two stages, early and advanced. Initially, proteins react with
glucose to form stable Amadori products, which subsequently cross-links to form advanced
glycation end products (AGE). In most cases, the formation of AGE also accompanies
browning of the proteins and increase in the fluorescence.
In diabetes, where blood glucose level is significantly higher than normal, the reaction of
glucose with several proteins such as haemoglobin and collagen, gives rise to the formation
of AGE, which in turn, is responsible for the complications associated with diabetes, such as
nephropathy, microangiopathy, endothelial dysfunction and other organ dysfunctions. In
addition, the activity of several growth factors, such as basic fibroblast growth factor, is also
impaired. AGE products, unlike normal proteins in tissue, have a slower rate of turnover and
replenishment. It has been reported that AGE products may in fact elicit a complex
immunological reaction involving RAGE (Receptor for Advanced Glycation End Products)
and activation of several incompletely defined immunological processes. (Stehouwer et al;
Cardiovascular Research 1997; 34:55-68 and Smit et al.; Current Medicinal Chemistry
2004; 11:2767-84).
Due to the clinical significance of AGE formation, several successful therapeutic approaches
have been tried based upon intervening in the accumulation of AGEs in vivo. One of the
approaches is to inhibit the formation of AGEs from its precursors, by the administration of
therapeutic agents. In another approach for controlling levels of AGEs in tissues, therapeutic
agent is administered which can reverse or break AGE cross-links, especially in those
tissues in which AGE cross-links have already accumulated to levels which are responsible
for subclinical or clinical pathology.
1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium and its
pharmaceutically acceptable salts is one of a class of compounds which have been shown
to have AGE breaking activity (EP1 2221 7 1; EP1 243581 ) .
1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium chloride has
been shown to improve cardiomyopathy and nephropathy in animal models of Type I I
diabetes (Joshi et al.; J. Cardiovasc. Pharmacol.; 2009, 54(1): 72-81). Clinical studies have
shown this compound to be safe and well tolerated when administered orally (Chandra et
al.; Clin. Drug. Invest; 2009, 29(9): 559-575).
However, it was noted that bioavailability of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl
hydrazine carbonyl) pyridinium compounds, for example, 1-(2-thien-2'-yl-2-oxo-ethyl)-3-
(methanesulfonyl hydrazine carbonyl) pyridinium bromide was very low, when administered
orally to rats. (Data on file)
Further, phase I clinical studies have also revealed that the oral bioavailability of 1-(2-thien-
2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium chloride is very low
(Chandra et al.; Clin. Drug. Invest; 2009, 29(9): 559-575); and high doses (more than 1000
mg bid) are therefore required in order to achieve therapeutically effective response in
humans.
It is an aim of certain embodiments of this invention to provide a pharmaceutical formulation
of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium, its
pharmaceutically acceptable salts, salt-cocrystals and co-crystals. It is an aim of certain
embodiments to provide formulations which deliver a therapeutically effective amount of 1-
(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium its
pharmaceutically acceptable salts, salt-cocrystals and co-crystals orally. It is an aim of
certain embodiments to provide formulations which exhibit an increased oral bioavailability
of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium compound
relative to prior art formulations. Certain embodiments of the invention achieve some or all
of the above aims.
SUMMARY OF THE INVENTION
In a first aspect of the present invention is provided an oral pharmaceutical formulation
comprising:
a compound of formula (I):
or its co-crystal; wherein X is a pharmaceutically acceptable anion or X is absent;
a permeability enhancing agent or a base or a mixture thereof;
and optionally other pharmaceutically acceptable excipients.
The inventors have recognised that compounds of formula (I) are mainly absorbed through
upper Gl tract. It was observed that though oral bioavailability of compound of formula (I) is
very less, it increases substantially in presence of a permeation enhancer or a base. The
inventors have further found that adding a base or a buffer in combination with a
permeability enhancing agent further boosts the oral bioavailability of the compounds of
formula (I).
The inventors have shown that compounds of formula (I) associate well with permeability
enhancing agents (e.g. sodium caprate) at high pH but not at low pH, specifically at pH
below 2.0. It is therefore suggested (without wishing to be bound by theory) that the
presence of a base or buffer in the formulation allows the formation in the upper Gl tract of a
suitable microenvironment in the vicinity of the compound of formula (I) and the permeability
enhancing agent. In that microenvironment, the pH is maintained at a sufficiently high level,
preferably more than 2, to allow the permeability enhancing agent to aid the absorption of
the compound of formula (I), thus boosting of bioavailability is observed in comparison to the
formulation when either of permeability enhancer or base is used.
X may be a halide ion. X may be selected from chloride and bromide. Preferably, X is CI .
X may be a carboxylate anion, e.g. a C2-C20 carboxylate anion. X may thus be caprate.
Where X is a carboxylate anion (e.g. caprate), it may be that X is the permeability
enhancing agent. In this embodiment, there may be no other permeability enhancing agent.
In other words, the counter ion may act as the permeability enhancing agent and no other
permeability enhancing agent is required. Though an additional one may be provided
separately if desired and this additional permeability enhancing agent may or may not
comprise the same anion as X .
The compounds of formula (I) in the formulation may have different counter ions. In other
words the active ingredient may be presented with a mixture of two or more counter ions.
Thus it may be that a portion of the compounds of formula (I) have one counter ion and the
remaining compounds of formula (I) have a different counter ion. Thus it may be that in a
portion of the compounds of formula (I) in the formulation X is chloride and in the remaining
compounds of formula (I) X is caprate.
When X absent, compound of formula (I) may exist in ylide form.
In certain preferred embodiments, the formulation comprises:
a compound of formula (I):
or its co-crystal; wherein X is a pharmaceutically acceptable anion or X is absent;
a permeability enhancing agent and a base;
and optionally other pharmaceutically acceptable excipients.
The compound of formula (I) or its co-crystal may be present in an amount from about 0.1%
to about 80% w/w of total formulation, preferably in an amount from about 0.25% to about 70%
w/w of total formulation, and most preferably in an amount from about 5% to about 50% w/w of
total formulation.
A "permeability enhancing agent" or "permeability enhancer" is a compound which increases
the rate of transportation of drugs across biomembranes. Permeability enhancing agent
according to present invention is pharmaceutically acceptable.
Permeability enhancing agent according to present invention may be selected from:
1) Surfactants. Examples include poly oxyethylene ethers, poly oxyethylene esters,
poly oxyethylene sorbitan esters, dodecylmaltoside and the like;
2) Fatty Acids. Examples include cholic acid (CA), hexanoic acid (HA) and heptanoic
acid (HPA), lipoic acid, caprylic acid, palmitic acid, linoleic acid, tetradecanoic acid
(myristic acid) and the like;
3) Salts of Fatty acids. Examples include sodium caprylate, sodium caprate, sodium
laurate and sodium oleate (SOA) and the like;
4) N-Acylated a-Amino Acids and N-Acylated Non-a-Amino Acids. Examples include
N- cyclohexanoylleucine, N-(phenylsulphonyl) leucine and the like;
5) Saponins. Example include glycyrrhizinate;
6) Bile Salts. Examples include chenodeoxycholate, ursodeoxycholate;
7) Medium Chain Triglycerides. Examples include caprylic/capric triglyceride,
glyceryl tricaprylate/caprate and the like;
8) Polymers. Examples include polyoxylene alkyl ethers, polycarbophil (acrylic acid
polymer), chitosan, carbopol, pyrrolidine and the like;
9) Acylcarnitines and Alkanoylcholins. Examples include palmitoyl-DL-carnitine
chloride (PCC);
10) Secretory Transport Inhibitors. Examples include Polysorbate 80,
polyoxyethylene alkyl ethers (e.g. Cremophor EL™), poloxamers (e.g. Pluronic™,
Lutrol™) and the like;
11) Thiolated polymers-thiomers: Examples include polycarbophyl polymer with
covalent attachment of cysteine (PCP-Cys), sodium carboxymethylcellulose-cystine,
chitosan-cysteine, chitosan -4- thio-butylamidine and the like;
12) Complexation agents: Examples include ethylene diamine tetra acetate,
hydroxypropyl betadex, cyclodextrin and the like,
or combinations thereof.
It may be that each permeability enhancing agent is selected from those permeability
enhancing agents which are a salt comprising a metal cation and an organic anion.
It may be that permeability enhancing agent is a C2-C20 carboxylic acid or metal salt or an
ammonium salt or an ester of a C2-C2ocarboxylic acid. It may be a C -C 2 carboxylic acid or
metal salt or an ammonium salt or an ester of a C -C 2 carboxylic acid. It may be a C 0
carboxylic acid or metal salt or an ammonium salt or ester of a C 0 carboxylic acid. The
carboxylic acid may be saturated or the carboxylic acid may be unsaturated. Preferably, the
permeability enhancing agent is a metal salt of capric acid. The metal salt of a carboxylic
acid may be an alkali metal salt, an alkaline earth metal salt or combinations thereof. The
metal salt may be an alkali metal salt, e.g. a potassium salt or a sodium salt. Preferably, it is
a sodium salt.
Preferably, the permeability enhancing agent is sodium caprate.
It may be that the compound of formula (I) and the permeability enhancing agent (e.g.
sodium caprate) are in the form of a conjugate. It is equally within the scope of this
invention that they are not in the form of a conjugate or associated in any way other than
both being present in the formulation.
The permeability enhancing agent when present, it may be in an amount from about 0.02% to
about 75% w/w of total formulation, preferably in an amount from about 2.5% to about 60%
w/w of total formulation, and most preferably in an amount from about 5% to about 30% w/w of
total formulation.
Base or buffer according to present invention are interchangeable and may be any agent
which increases the pH of any aqueous medium above 2, to which it is added. According to
present invention, base or buffer is pharmaceutically acceptable.
Base may be an organic base. An organic base is generally an organic compound
comprising at least one nitrogen atom having a free lone pair. Common basic functional
groups include amines (including primary amines, secondary amines and tertiary amines),
guanidines, pyridines, imidazoles etc. Organic bases suitable for use in oral pharmaceutical
formulations are often basic amino acids and carbohydrates. Examples of basic amino
acids include arginine, lysine and histidine. Examples of basic carbohydrates include
meglumine and glucosamine.
Base may be a salt of a carboxylic acid, e.g. a metal salt or an ammonium salt of a
carboxylic acid. The carboxylic acid may comprise a single carboxylate group or two
carboxylate groups. The carboxylic acid (whether it has one or two carboxylate groups) may
comprise less than 5 carbons atoms. Examples of ammonium salts include ammonium
acetate and ammonium formate. The base may be a metal acetate. The metal may be an
alkali metal or an alkaline earth metal. The metal may be selected from sodium, calcium,
magnesium and potassium. Examples of metal salts of carboxylic acids include sodium
acetate and potassium propanoate. Where the carboxylic acid comprises two carboxylate
groups it may be that both carboxylate groups are in the form of a metal salt or it may be
that one carboxylate group is in the form of a metal salt and the other is in the form of a
carboxylic acid.
Where the base is a salt of a carboxylic acid, the carboxylic acid may also be present in the
formulation.
Alternatively, the base may be an inorganic base. Suitable inorganic bases include
ammonium of metal hydroxides, carbonates and bicarbonates. Examples of ammonium
salts include ammonium hydroxide. The metal may be an alkali metal or an alkaline earth
metal. Thus the base may be an alkali metal or alkaline earth metal carbonate or
bicarbonate. The metal may be selected from sodium, calcium, magnesium and potassium.
The base may be an alkaline earth metal carbonate or bicarbonate. It may be an alkaline
earth metal carbonate. Examples of inorganic bases include sodium carbonate, sodium
bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium
carbonate, magnesium bicarbonate. In certain preferred embodiments, the base is
magnesium carbonate.
The base may be a phosphate buffer.
The base when present, it may be in an amount from about 0.002% to about 60% w/w of
total formulation, and preferably in an amount from about 0.2% to about 25% w/w of total
formulation, more preferably from about 0.5% to about 15.0% w/w of total formulation, and
most preferably from about 0.5% to about 5.0% w/w of total formulation.
In certain preferred embodiments, the formulation comprises:
Compound of formula la or la':
or its co-crystal
an alkali metal salt of a C -C 2 carboxyllic acid (e.g. sodium caprate), or
a base or a mixture thereof; and
optionally other pharmaceutically acceptable excipients.
Dosage levels, dose frequency, and treatment durations with formulation of the invention are
expected to differ depending on the formulation and clinical indication, age, and co-morbid
medical conditions of the patient. Preferably, however, the formulation is for administration
once daily or twice daily, preferably twice daily. Each formulation or formulations according
to present invention may comprise from 100 mg to 2000 mg of the compound of formula (I)
(e.g. compound la or la' or its co-crystal). Each formulation may comprise from 150 mg to
1500 mg of the compound of formula (I) (e.g. compounds la or la' or its co-crystal).
Preferably, the each formulation comprises from 250 mg to 750 mg of the compound of
formula (I) (e.g. compounds la or la' or its co-crystal).
The formulation may be for use in treating, preventing or managing a disease selected from:
diabetes and aging related macrovascular and microvascular complications including heart
failure, nephrological disorder, neuropathy, atherosclerosis and retinal disorder;
dermatological disorder, endothelial or other organ dysfunction and growth impairment.
The invention also provides a method of treating, managing or preventing a complication
associated with aging and diabetes; the method comprising administering to a subject in
need thereof an oral pharmaceutical formulation comprising compound of Formula (I), la or
la' or its co-crystals as described above, in a therapeutically effective amount.
The invention also provides a method of treating, managing or preventing a disease
selected from: diabetes and aging related macrovascular and microvascular complications
including, heart failure, nephrological disorder, atherosclerosis and retinal disorder;
dermatological disorder, endothelial or other organ dysfunction and growth impairment; the
method comprising administering to a subject in need thereof an oral pharmaceutical
formulation comprising compound of Formula (I), la or la' or its co-crystals as described
above, in a therapeutically effective amount.
In a second aspect is provided a conjugate of a compound of formula (I) and a permeability
enhancing agent. Where appropriate (i.e. where they pertain to the identity of the
permeability enhancing agent and the compound of formula (I)), the embodiments described
above for the formulations of the first aspect apply equally to the conjugates of the second
aspect. Thus, the conjugate may be a conjugate of compound la or la' and sodium caprate.
Preferably, formulations comprising conjugate of a compound of formula (I), la or la' and a
permeability enhancing agent may further comprises a permeability enhancer or a base or a
mixture thereof and optionally other pharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
In their simplest form, the formulations of the invention comprise only the compound of
formula (I), la or la' or in association of permeability enhancer or base or a mixture thereof.
However, the formulations of the invention will generally also comprise at least one other
pharmaceutically acceptable excipient (e.g. at least one other adjuvant, diluent or carrier).
Conventional procedures for the selection and preparation of suitable pharmaceutical
formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form
Designs", M. E. Aulton, Churchill Livingstone, 1988 or Handbook of pharmaceutical
excipients (sixth edition, 2009).
The oral pharmaceutical formulation as described herein may be obtained in any suitable
form without limitation such as tablet, capsule, powder, granules, pellets, beads, liquid such
as solution, suspension and the like. Powder, granules, pellets or beads may be filled in
suitable container including sachet or hard gelatine capsules. Preferably, formulation is in
the form of granules which can be either filled in a sachet or compressed to form a tablet.
Most preferably, formulation is in the form of granules filled in sachet. Average particle size
of said granules, as measured through sieve method, is preferably 75 to 850 microns, more
preferably average particle size is 150 to 425 microns. Preferably, size of granules is no
more than 1000 microns to facilitate dissolution/ dispersion of granules from the formulation.
Size of the granules also has significant impact on flowability of material during its
formulation.
The formulation of the invention, when prepared as granules, can be administered to a
mammal, after mixing it in a carrier such as water, soft food, curd, apple sauce and the like,
preferably it is administered with sufficient quantity of water. Such granules may additionally
comprise suspending agent, preferably povidone.
Pharmaceutical formulation according to present invention can be in the form of immediate
release or controlled release formulations. Controlled release formulations may include
delayed release, extended release formulation or mucoadhesive formulation. Alternatively,
formulations can have mixture of immediate release or controlled release formulation.
Pharmaceutical formulation according to present invention can be prepared by any method
known in the art such as by mixing the compound of formula (I) , la or la' with
pharmaceutically acceptable excipients. Alternatively wet granulation or dry granulation
techniques may be employed for the preparation of formulation according to present
invention. Selection of process of preparation of formulation according to present invention
has impact on stability of compound of formula (I), la or la'. Preferably, a stable formulation
is prepared by dry granulation, compaction or direct compression process, wherein water or
aqueous medium is not used. Alternatively, formulation of present invention can be prepared
as matrix based formulation in which compound of formula (I), la or la' is dispersed within a
matrix. Alternatively, compound of formula (I) , la or la' containing particles may be coated by
suitable pharmaceutically acceptable carriers. Types of particles include granules, pellets,
minitablets, microparticles, beads or tablets.
The formulations of the invention may also comprises adjuvant or a carrier or excipient, for
example, diluent such as powdered cellulose, microcrystalline cellulose, silicified
microcrystalline cellulose, starch, pre-gelatinized starch, dibasic calcium phosphate, dibasic
sodium phosphate, tribasic sodium phosphate, calcium silicate, precipitated calcium
carbonate; sugars such as dextrose, lactose or sucrose; sugar alcohols such as mannitol,
sorbitol, xylitol, isomalt or erythritol and the like or mixture thereof; a binder such as polyvinyl
alcohol, polyvinyl pyrrolidone, starch, pregelatinised starch; cellulose derivatives such as
cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose,
methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, zein,
polymethacrylates, sodium alginate, gums, synthetic resins or mixture thereof; disintegrant
such as calcium carboxymethyl cellulose and its salt including sodium or calcium salt,
cross-linked carboxymethyl cellulose sodium (Croscarmellose sodium), cross-linked
carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone, sodium starch glycolate,
pregelatinized starch, low substituted hydroxypropyl cellulose and the like or mixture thereof
and/or a lubricant, for example, magnesium stearate, calcium stearate, magnesium
aluminium silicate (Neusilin®), polyethylene glycol, a wax, paraffin and the like or mixture
thereof. Diluent if present, is in amount of 20-90% w/w of the total formulation; disintegrant if
present, is in amount of 0.1 -20% w/w of total formulation; lubricant if present is in amount of
0.1-20% w/w of total formulation; binder if present, is in amount of 0.1-20% w/w of total
formulation. Said formulation can optionally be coated with suitable functional or non
functional coating.
The formulation of the invention according to any of embodiment, wherein 90% of the
particles of compound of formula (I), la or la' or its co-crystal are in the range from 50
microns to 1000 microns, preferably 50 microns to 700 microns, most preferably 350
microns to 600 microns, when measured through Laser diffraction method, such as Malvern
Mastersizer®. Coarser particles of compound of formula (I), la or la' or its co-crystal help in
improving flow property and increases its content uniformity with excipients.
When formulated as controlled release, present formulations can comprise excipient suitable
for controlling the release of compound of formula (I) , la or la'. Such controlled release
excipient may be present either in matrix form of can be coated over particles, granules,
pellets, beads, tablets or capsules.
The formulations may also contain pharmaceutically acceptable additives such as glidant,
crystal growth inhibitor, film forming polymer, plasticizer, stabilizers, solubilizers,
antioxidants, cosolvents, complexing agents, colouring agent, flavouring agent, sweetening
agent, mucoadhesive agents and tonicity modifiers. Suitable examples and its amount are
known to a person skilled in the art or as given in Handbook of pharmaceutical excipients
(sixth edition, 2009). Preferably, formulation comprises sweetening agent such as sucralose
and flavouring agent such as lemon flavour, Peppermint flavour, Mango Flavour or any other
bitterness modifier, to mask bitter taste of the compound of formula (I) .
The formulation according to present invention may be administered in combination with one
or more additional therapeutic agent selected from a) antihypertensive agent; b) hypolipemic
agent; c) antidiabetic agent; d) antiplatelet agent; e) anti-thrombotic agent; f) antiobesity
agent; g) agent for treatment of heart failure; and h) drug for diabetic vascular complications;
i) agents for cardiovascular risk reduction ; or a pharmaceutically acceptable salts thereof, for
treating, preventing or managing a disease selected from : diabetes and aging related
macrovascular and microvascular complications including heart failure, nephrological
disorder, neuropathy, atherosclerosis and retinal disorder; dermatological disorder,
endothelial or other organ dysfunction and growth impairment.
Alternatively, pharmaceutical formulation according to present invention may comprise one
or more additional therapeutic agent selected from a) antihypertensive agent; b) hypolipemic
agent; c) antidiabetic agent; d) antiplatelet agent; e) anti-thrombotic agent; f) antiobesity
agent; g) agent for treatment of heart failure; and h) drug for diabetic vascular complications;
i) agents for cardiovascular risk reduction ; or a pharmaceutically acceptable salts thereof.
The antihypertensive agent, as mentioned herein, includes but not limited to an angiotensin
converting enzyme (ACE) inhibitor, a renin inhibitor, a beta adrenergic receptor blocker, an
alpha adrenergic receptor blocker, a calcium channel blocker, a potassium channel
activator, an aldosterone synthase inhibitor, a neutral endopeptidase (NEP) inhibitor, a dual
angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an endothelin
receptor antagonist, a dual angiotensin and endothelin receptor antagonist (DARA), a
diuretic or a pharmaceutically acceptable salt thereof; the hypolipidemic agent or lipidlowering
agent as mentioned herein, includes but not limited to a MTP inhibitor, a HMG CoA
reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an ACAT
inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na+/bile acid
co-transporter inhibitor, an upregulator of LDL receptor activity, a cholesteryl ester transfer
protein(CETP) inhibitor, a bile acid sequestrant, and/or nicotinic acid and derivatives or a
pharmaceutically acceptable salt thereof; the antidiabetic agent, as mentioned herein,
includes but not limited to a PPARv agonist, a biguanide, a protein tyrosine phosphatase- 1B
(PTP-1 B) inhibitor, a sulfonylurea, a meglitinide, an alpha glucoside hydrolase inhibitor, a
PPARa agonist, a PPAR5 agonist or antagonist, an alpha-amylase inhibitor, a fatty acid
oxidation inhibitor, an A2 antagonist, a dipeptidyl peptidase IV (DP4) inhibitor, an aP2
inhibitor, a SGLT2 inhibitor, a glycogen phosphorylase inhibitor, a glucagon-like peptide-1
(GLP-1 ) , an insulin or insulin mimetic, a PPAR.alpha./gamma dual agonist, an ΐ -HSD 1
( 1 1-hydroxy-steroid dehydrogenase 1) inhibitor, other insulin sensitizing drug, a
glucokinase activator, a VPAC2 receptor agonist or a pharmaceutically acceptable salt
thereof; the antiplatelet agent as mentioned herein, includes but not limited to
cyclooxygenase inhibitors, Adenosine diphosphate (ADP) receptor inhibitors,
Phosphodiesterase inhibitors, Protease-activated receptor-1 (PAR-1 ) antagonists,
Glycoprotein IIB/IIIA inhibitors, Adenosine reuptake inhibitors, Thromboxane inhibitors ; the
anti-thrombotic agent as mentioned herein, includes but not limited to melagatran and
ximelagatran, warfarin and Factor Xa inhibitors such as rivaroxaban, apixaban, Edoxaban,
razaxaban or in each case, a pharmaceutically acceptable salt thereof; an agent useful for
diabetic vascular complications in present invention includes without limitation aldose
reductase inhibitor, AGE inhibitor or AGE breaker. Aldose reductase inhibitor, among those
suitable for the treatment of diabetic complications, represent those which decrease
intracellular sorbitols by inhibiting aldose reductases, and said sorbitols accumulate
excessively by enhancement of a course of polyol metabolism which is induced by
continuous hyperglycemia shown in tissues developing diabetic complication; the antiobesity
agent, as mentioned herein, include but not limited to a 5HT (serotonin) transporter inhibitor,
a NE (norepinephrine) transporter inhibitor, a CB-1 (cannabinoind-1 receptor)
antagonist/inverse agonist, a ghrelin antibody, a ghrelin antagonist, a H3 (histamine H3)
antagonist/inverse agonist, a NPY1 (neuropeptide Y Y1) antagonist, a NPY2 (neuropeptide
Y Y2) agonist, a NPY5 (neuropeptide Y Y5) antagonist, leptin or its derivative, an opioid
antagonist, an orexin antagonist, a BRS3 (bombesin receptor subtype 3) agonist, a CCK-A
(cholecystokinin-A) agonist, a CNTF (ciliary neurotrophic factor), a CNTF derivative, a GHS
(growth hormone secretagogue receptor) agonist, 5HT2c (serotonin receptor 2c) agonist, a
Mc3r (melanocortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor) agonist, a
monoamine reuptake inhibitor, a 3 (beta adrenergic receptor 3) agonist, a DGAT1
(diacylglycerol acyltransferase 1) inhibitor, a DGAT2 (diacylglycerol acyltransferase 2)
inhibitor, a FAS (fatty acid synthase) inhibitor, a PDE (phosphodiesterase) inhibitor, a thyroid
hormone agonist, an UCP-1 (uncoupling protein 1) , 2,.or 3 activator, an acyl-estrogen, a
glucocorticoid antagonist, a SCD-1 (stearoyl-CoA desaturase-1 ) inhibitor, a lipase inhibitor, a
fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor; agents for cardiovascular
risk reduction , as mentioned herein, include but not limited to the compounds as disclosed
in WO2007 100295, which is cited herein as reference; or pharmaceutically acceptable salts
thereof.
Preferably, said additional therapeutic agent is selected from metformin, glyburide, glipizide,
gliclazide, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, glimepiride,
rosiglitazone, pioglitazone, dapagliflozin, empagliflozin, canagliflozin, alogliptin, saxagliptin,
linagliptin, sitagliptin, vildagliptin, amlodipine, felodipine, nicardipine, diltiazem,
lercanidipine, captopril, benazepril, quinapril, fosinopril, ramipril, enalapril, lisinopril,
perindopril, aliskiren, carvedilol, metoprolol, bisoprolol, atorvastatin, simvastatin,
rosuvastatin, pravastatin, fluvastatin, cerivastatin, fenofibrate, gemfibrozil, clofibrate,
bezafibrate, ciprofibrate, clinofibrate, probucol, ezetimibe, aliskiren, nicorandil, clopidogrel,
prasugrel, aspirin, ticlopidine, hydrochlorothiazide, rivaroxaban, indapamide,
trichlormethazide, altizide, chlorthalidone, furosemide, digitoxin, digoxin, spironolectone or
pharmaceutically acceptable salts thereof.
Throughout the description and claims of this specification, the words "comprise", "include"
and "contain" and variations of them mean "including but not limited to", and they are not
intended to (and do not) exclude other moieties, additives, components, integers or steps.
Throughout the description and claims of this specification, the singular encompasses the
plural unless the context otherwise requires. In particular, where the indefinite article is
used, the specification is to be understood as contemplating plurality as well as singularity,
unless the context requires otherwise.
The term "conjugate" as used throughout the specification means compound of formula (I) la
or la' is in vicinity of at least one permeation enhancer. Permeation enhancer can form
complex with compound of formula (I) or la or la' or can be present in same crystal lattice to
form co-crystals. Conjugate also include mixture of salt and co-crystal of compound of
formula (I) or la or la' and permeation enhancer. Said conjugates are prepared by mixing
compound of formula (I), la or la' with permeation enhancer, optionally in presence of base,
so that permeation enhancer remains in close vicinity of compound of formula (I), la or la'.
The embodiments pertaining to formulation of compound of formula (I), la or la' and method
of treating using these compounds, equally apply to conjugates prepared according to
present invention.
The term "co-crystals" as used herein above means that the compound of formula (I) or la or
la' and at least one permeability enhancer as co-former are present in the same crystal
lattice.
The phrase "a therapeutically effective amount" means the amount of compound in the
formulation of present invention that, when administered to a patient for treating, preventing
or managing a disease, is sufficient to effect such treatment, prevention or management for
the disease.
Features, integers, characteristics, compounds, chemical moieties or groups described in
conjunction with a particular aspect, embodiment or example of the invention are to be
understood to be applicable to any other aspect, embodiment or example described herein
unless incompatible therewith. All of the features disclosed in this specification (including
any accompanying claims, abstract and drawings), and/or all of the steps of any method or
process so disclosed, may be combined in any combination, except combinations where at
least some of such features and/or steps are mutually exclusive. The invention is not
restricted to the details of any foregoing embodiments. The invention extends to any novel
one, or any novel combination, of the features disclosed in this specification (including any
accompanying claims, abstract and drawings), or to any novel one, or any novel
combination, of the steps of any method or process so disclosed.
The reader's attention is directed to all papers and documents which are filed concurrently
with or previous to this specification in connection with this application and which are open
to public inspection with this specification, and the contents of all such papers and
documents are incorporated herein by reference.
EXAMPLES
Example 1 : Formulations
Table 1
F1 F2 F3
%w/w %w/w %w/w
39.74
20.52
Microcrystalline 46.5 -- 39.74
cellulose (Avicel 112)
Methanol Q.S
o aTFormulation
1(F1) and 2(F2): 2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine
carbonyl) pyridinium chloride and sodium caprate were mixed in sodium hydroxide solution
and dried. Obtained dried mixture was cosifted with mixture of mannitol (Formulation 1) or
microcrystalline cellulose (Formulation 2) and light magnesium carbonate and mixture was
blended for 5 minutes. Neusilin® was added in obtained mixture followed by co-sifting and
blending for 5 minutes. Obtained mixture was dry granulated (slugging) and prepared slugs
were sized through #20 mesh to obtain granules. Granules were filled in sachet.
Formulation 3(F3) : 2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl)
pyridinium chloride and sodium caprate were dissolved in water and mixed to form
dispersion. To the obtained dispersion, methanol was added. Obtained solution was sprayed
over microcrystalline cellulose using Glatt machine. Obtained granules were compressed to
form tablets.
Example 2 : Assessment of bioavailability
Bioavailability of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl)
pyridinium compound was checked using formulations as given in Table 2.
Table 2
Ingredient F4 F5 F6 F7 F8 F9 F 10
Qty Qty Qty Qty Qty Qty Qty
(mg/ml) [nig/ml) (nig/ml) (mg/ml) / l (mg/ml) (nig/ml)
hen- ~ 4 1 c ™ ~ 4 —
2-oxo-ethyl)-3-
(methanesulfon
yl hydrazine
carbonyl)
pyridinium
chloride
Conjugate of 1- 7.3 7.9 7.9 7.9
(2-thien-2'-yl-2-
oxo-ethyl)-3-
(methanesulfon
yl hydrazine
carbonyl)
pyridinium
chloride and
sodium caprate
Sodium caprate 4.0 4.0
Magnesium 0.05 0.3 0.05
a g t
(MgC0 3)3
* Mg(
OH)2
*3H20
NaHC0 3 4.0
(Sodium
Bicarbonate)
Meglumine 4.4
L-Arginine 0.2
Hydroxy Propyl 50.0 50.0 50.0
cellulose
(klucel-LF)
Purified Water Upto 1 Upto 1 Upto 1 Upto 1 Upto 1 Upto 1 Upto 1
ml ml ml ml ml ml ml
Formulation 4 (F4) was prepared by co-dispensing 1-(2-thien-2'-yl-2-oxo-ethyl)-3-
(methanesulfonyl hydrazine carbonyl) pyridinium chloride with sodium caprate. Purified
water added and sonicated to prepare suspension. Final volume was made up with purified
water. Analogous to formulation 4, formulation 5 (F5) was prepared.
Formulation 6 (F6) was prepared by dissolving light magnesium carbonate in purified water
followed by dispersing 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl)
pyridinium chloride and sonication.
Formulation 7 (F7) was prepared by preparing conjugate of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-
(methanesulfonyl hydrazine carbonyl) pyridinium chloride and sodium caprate by dissolving
1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium chloride and
sodium caprate using solution of sodium hydroxide and drying the solution to prepare
conjugate. Said dried conjugate was added in the aq solution of NaHC0 3 and hydroxypropyl
cellulose. Analogous to formulation 7, formulation 8 to 10 (F8-F1 0) were prepared.
The assessment of oral pharmacokinetics was carried out. Formulations F4 to F10 were
administered orally to jugular vein cannulated Wistar rats (n = 5). The blood samples were
withdrawn at pre-determined time points; pre-dose (0.0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24
hrs post dose. Plasma obtained at each time point was subjected to quantification of 1-(2-
thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium compound.
LC-MS/MS method was used for the quantification of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-
(methanesulfonyl hydrazine carbonyl) pyridinium compound using an internal standard. The
plasma samples were analyzed using solid phase extraction techniques in the calibration
range of 0.500 ng/mL to 1000.000 ng/mL.
Pharmacokinetic (PK) parameters such as Cmax and AUC were calculated from
concentration versus time data of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine
carbonyl) pyridinium compound using non-compartmental PK methods with the PK analysis
software Phoenix WinNonlin software (version 6.3, Pharsight Corporation, USA). Data were
presented with MeaniSD (standard deviation) and compared with 1-(2-thien-2'-yl-2-oxoethyl)-
3-(methanesulfonyl hydrazine carbonyl) pyridinium compound PK data obtained after
oral administration of solution of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine
carbonyl) pyridinium chloride in water under similar conditions.
The data is provided in tables 3 and 4.
Table 3
Thus, use of permeability enhancing agent, in this case sodium caprate, and a base, in
this case MgC0 3, with 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine
carbonyl) pyridinium chloride increase the bioavailability. Additionally, the combination
of a permeability enhancing agent and a base provides a greater boost to bioavailability
of 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium
compound than either the permeability enhancing agent or base on their own.
Therefore, formulation according to present invention in tern increases therapeutic
efficacy of compound of formula (I).
Table 4
Table 4 shows that improved bioavailability is still observed when the permeability
enhancing agent and 1-(2-thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl)
pyridinium chloride are formulated as the conjugate.
Example 3 :
Formulations
Ingredients F11 F12 F13
%w/w %w/w %w/w
Conjugate of 1-(2-thien- 4 1.67 4 1.67 42.37
2'-yl-2-oxo-ethyl)-3-
(methanesulfonyl
hydrazine carbonyl)
pyridinium chloride and
sodium caprate
Magnesium carbonate 2.08 2.08 2.1 2
light
(MgC0 3)3*Mg(OH) 2*3H 20
Mg Aluminium trisilicate 0.83 0.83 0.85
(Neusilin® UFL2)
Mannitol 38.75 38.75 39.41
Sucralose 6.67 6.67 6.78
Povidone K30 3.33 3.33 3.39
Lemon Flavour 2.08 2.08 2.1 2
Peppermint Flavour 4.17 4.1 7 2.1 2
Mango Maracuja -- 0.42 0.42
Bitterness Modifier from IFF 0.42 -- 0.42
Total 100.00 100.00 100.00
Mannitol, magnesium carbonate light were cosifted through #20 mesh. Conjugate of 1-(2-
thien-2'-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium chloride and
sodium caprate was separately cosifted with Mg Aluminium trisilicate through #20 mesh and
mixed with cosifted mannitol and magnesium carbonate light. Obtained mixture was blended
for 10 minutes in Conta blender and then subjected to roller compaction to prepare granules,
followed by sizing by using quadro mill. Obtained granules were mixed with povidone,
sucralose, lemon flavour, peppermint flavour, Mango Maracuja (In F 12 and F 13) and
Bitterness modifier (In F 1 1, and F 13) in Conta blender and obtained material was filled in the
sachet.
CLAIMS
1. An oral pharmaceutical formulation comprising
a compound of formula (I):
or its co-crystal; wherein X is a pharmaceutically acceptable anion or X is absent;
a permeability enhancing agent or a base or a mixture thereof;
and optionally other pharmaceutically acceptable excipients.
2. The formulation according to claim 1, wherein X is selected from halide or a carboxylate
ion.
3. The formulation according to claim 2, wherein X is chloride.
4. The formulation according to claim 2, wherein X is caprate.
5. The formulation according to claim 1, wherein a permeability enhancing agent is selected
from surfactant, fatty acid, salts of fatty acid, N-acylated a-amino acids, N-acylated non- aamino
acids, saponins, bile salts, medium chain triglycerides, polymers, acylcarnitines and
alkanoylcholins, secretory transport inhibitors, thiolated polymers-thiomers and complexation
agents.
6. The formulation according to claim 5, wherein a permeability enhancing agent is selected
from salts of fatty acid.
7. The formulation according to claim 6, wherein salt of fatty acid is sodium caprate.
8. The formulation according to claim 5 or 6, wherein a permeability enhancing agent is
present in an amount from about 0.02% to about 75% w/w of total formulation; preferably in
an amount from about 2.5% to about 60% w/w of total formulation ; most preferably in an
amount from about 5% to about 30% w/w of total formulation.
9. The formulation according to claim 1, wherein base is selected from organic base,
inorganic base and salt of carboxylic acid.
10. The formulation according to claim 9, wherein base is inorganic base.
11. The formulation according to claim 10, wherein inorganic base is magnesium carbonate.
12. The formulation according to claim 9 or 10, wherein base is present in an amount from
about 0.002% to about 60% w/w of total formulation, preferably in an amount from about 0.2%
to about 25%w/w of total formulation, more preferably in an amou nt from about 0.5% to
about 15.0% w/w of total formulation, most preferably in an amount from about 0.5% to
about 5% w/w of total formulation.
13. The formulation according to claim 1, wherein compound of formula (I) and a
permeability enhancing agent is in the form of conjugate.
14. The formulation according to claim 1, wherein compound of formula (I) or its co-crystal is
present in amount from about 0.1% to about 80% w/w of total formulation, preferably in an
amount from about 0.25% to about 70% w/w of total formulation, most preferably in an amount
of about 5% to about 50% w/w of total formulation.
15. A method of treating disease condition selected from diabetes and aging related
macrovascular and microvascular complications including heart failure, nephrological
disorder, neuropathy, atherosclerosis and retinal disorder; dermatological disorder;
endothelial or other organ dysfunction and growth impairment by administering formulation
according to claim 1, to a mammal in need thereof.
16. Use of formulation according to claim 1 for treating disease condition selected from
diabetes and aging related macrovascular and microvascular complications including heart
failure, nephrological disorder, neuropathy, atherosclerosis and retinal disorder;
dermatological disorder; endothelial or other organ dysfunction and growth impairment.
17. The formulation according to claim 1, wherein formulation comprises from 150 mg to
1500 mg of compound of formula (I) or its co-crystal.
8. The formulation according to claim 17, wherein formulation comprises from 250 mg to
50 mg of compound of formula (I) or its co-crystal.