Field of the Invention
The present invention is directed towards modified release formulations of HMG Co-A
reductase inhibitors, which cause reduced incidence of rhabdomyolysis, renal toxicity
and other side effects due to increased hepatic bioavailability and decreased systemic
availability.
More particularly the present invention relates to modified release rosuvastatin
formulation which cause reduced incidence of rhabdomyolysis and renal toxicity
Background of the Invention
Atherosclerosis and its various clinical presentations as coronary artery disease,
cerebrovascular disease, peripheral vascular disease and other conditions, is a major
cause of death in western countries. Hypercholesterolemia is a primary risk factor for
death from these conditions.
HMG CoA reductase inhibitors or Statins are a class of compound that competitively
inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyse
the conversion of HMG CoA to mevalonate, an early rate limiting step in cholesterol
biosynthesis. Inhibitors of HMG-CoA reductase have proved to be most effective in
reducing the plasma levels of cholesterol in patients with both hypercholesterolemia and
normocholesterolemia. These drugs lower cholesterol by slowing down the production of
cholesterol and by increasing the liver's ability to remove the LDL-cholesterol already in
the blood. The large reductions in total and LDL- cholesterol produced by these drugs
resulted in large reductions in heart attacks and heart disease deaths. HMG CoA
reductase inhibitors also produce a modest increase in HDL- cholesterol and reduce
elevated triglyceride levels. For example, simvastatin in clinical trials reduced cholesterol
and LDL cholesterol by 25% and 35% respectively. Simvastatin was reported in trials to
reduce the risk of a major coronary event by 34%. Statins have become the drugs most
often prescribed when a person with heart disease needs a cholesterol- lowering
medicine.
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Rosuvastatin 40mg daily has been shown in clinical trials to provide the greatest LDL-C
reduction (up to 63%) compared to other statins.
The HMG CoA reductase inhibitors available in market are Atorvastatin (Lipitor),
Fluvastatin (Lescol and Lescol XL), Lovastatin (Altoprev) Pravastatin (Pravachol) , ,
Rosuvastatin (Crestor), Simvastatin (Zocor) and Pitvastatin.
However the treatment of patients with inhibitors of HMG-CoA reductase, such as the
statins, is accompanied by adverse side effects, which cause discomfort and may
necessitate discontinuation of medication. As HMG-CoA reductase inhibitors are often
used as a long term means for prevention of heart disease in patients who may be
otherwise healthy, there is a need for a method of treatment of hypercholesterolemia
without the associated adverse effects of HMG-CoA reductase inhibitors.
Adverse effects known to be associated with the use of HMG-CoA reductase inhibitors
include muscle cramps, myalgia, increased risk of myopathy, transient elevation of
creatine phosphokinase levels from skeletal muscle, and even rhabdomyolysis.
Rhabdomyolysis is the breakdown of muscle fibers resulting in the release of muscle
fiber contents into the circulation. Some of these are toxic to the kidney and frequently
result in kidney damage. Crestor, Liptior, Zocor, Mevacor, Pravachol, and Lescol are
believed to increase the risk of rhabdomyolysis. The risk is significantly increased by
concomitant use of drugs that inhibit metabolism of HMG CoA reductase inhibitor. As a
result systemic levels of HMG CoA Reductase Inhibitor are increased resulting in greater
toxicity. The risk of these side effects is further increased when some other lipid lowering
drugs, for example, gemfibrizol, are co-prescribed. Occasionally, HMG CoA reductase
inhibitors use causes an increase in liver enzymes. Because liver problems may develop
without symptoms, people who take HMG CoA reductase inhibitors should have their
liver function tested periodically.
HMG CoA reductase inhibitors may cause muscle pain and tenderness (statin
myopathy). In severe cases, muscle cells can break down (rhabdomyolysis) and release
a protein called myoglobin into the bloodstream. Myoglobin can impair kidney function
and lead to kidney failure. Certain drugs when taken with HMG CoA reductase inhibitors
can increase the risk of rhabdomyolysis. These include gemfibrozil, erythromycin
(Erythrocin), anti fungal medications, nefazodone (Serzone), cyclosporine and niacin.
3

The most common side effects include: nausea, diarrhea, constipation, muscle aching.
In addition to the side effects listed above there are serious side effects such as
rhabdomyolysis (which may be fatal) and renal impairment associated with HMG CoA
reductase inhibitors medications.
Further, the use of HMG-CoA reductase inhibitors has also been reported to aggravate
cardiac function and uncommonly, to worsen cardiac failure. These adverse effects in
both skeletal muscle and the heart, are not common, but appear to have a common
pathway related to inhibition of the synthesis of ubiquinone.
Depletion of Coenzyme Q10 in skeletal and cardiac muscle has been linked to the
development of both skeletal myopathy and cardiac myopathy, to the development of
fatigue, and has been proposed as the mechanism of action of statin-induced muscle
disease. Since fatigue is a widely reported symptom in patients with cardiovascular
disease, many of whom are taking HMG-CoA reductase inhibitors for the treatment of
hypercholesterolemia, it is likely that a contribution to the cause of fatigue by these drugs
has not been appreciated and is therefore under-diagnosed.
One way of avoiding/ reducing the side effects associated with immediate release statins
is the use of modified release formulation. The present invention provides administering
statins in a manner that is selective for the liver, and that will reduce
hypercholesterolemia without systemic depression of Coenzyme Q10. Following
ingestion, statins are absorbed through the intestine into the hepatic portal vein and
distributed into the liver, which is the primary site of action and the primary site of
cholesterol synthesis. The formulation slowly releases the HMG CoA reductase inhibitor
such that clinically effective blood levels of the HMG-CoA reductase inhibitor will be
achieved in blood reaching the liver through the portal but the systemic blood levels will
be low and thus will have reduced side effects.
Thus, there exists a need in the art, for new formulations that allow for more optimal
absorption of the statins in the intestine and in the liver. Such modified-release
formulations would help maximize statin absorption in the intestine and liver, and thus
limit systemic exposure and the associated side effects.
4

Rosuvastatin is metabolized slowly in the liver, where metabolism by cytochrome P450
isoenzymes is limited. Although one major N-desmethyl metabolite (formed primarily by
CYP2C9 and CYP2C19) has been identified, it is seven-fold less active than the parent
compound in inhibiting HMG-CoA reductase. Furthermore, it is believed that 90% of the
inhibitory activity of rosuvastatin is due to the parent compound. Rosuvastatin is
selectively taken up into hepatocytes based on a carrier-mediated mechanism, with up
to 90% of the absorbed dose extracted by the liver. Although the presence of food
decreases the rate of absorption, the overall extent of absorption remains constant.
Peak plasma concentrations (Cmax), as well as the AUC, show a relatively linear
relationship with respect to doses ranging from 5 to 80 mg, with a tmax that ranges from
3 to 5 hours. Furthermore, rosuvastatin has a long elimination half-life (t1/2) of 20 hours.
Clearance of rosuvastatin occurs mainly through biliary excretion (90%), while 10% is
excreted in the urine.
Unlike pravastatin (but like atorvastatin), rosuvastatin is stable in acidic environments
like that found in the stomach. Once rosuvastatin passes out of the stomach, it is
believed to enter the circulation via a carrier-mediated transport mechanism in the small
intestine. Following absorption, rosuvastatin enters hepatocytes through a carrier-
mediated transport mechanism. The organic anion transport polypeptide-C, which is
expressed at high levels in hepatocytes, is thought to play a key role in selectively
delivering rosuvastatin to the HMG-CoA reductase target enzyme in the liver.
Accordingly, the amount of rosuvastatin that is ultimately absorbed by the liver and
available for binding to HMG-CoA reductase depends on the rates of uptake in the
intestine and liver. In case of rosuvastatin the development of severe myopathy or
rhabdomyolysis requiring hospitalization for IV hydration occurred at an incidence only at
the 80mg dose.
Researchers estimate that between 1% and 5% of statin users will experience muscle
pain and weakness as a side effect.
The incidence of myopathy, in clinical trials, of rosuvastatin 5 to 40mg were between 0.1
to 0.2% which are similar to rates seen with other currently approved statins. The risk of
muscle and renal toxicity appear dose related and are clearly evident at 80 mg dose.
Rosuvastatin levels more than 50ng/ml in plasma developed muscle and or renal
5

toxicity. Only a few patients treated with 40mg rosuvastatin (2%) had drug levels within
this range and greater proportion of patients treated with 80mg (33%) achieved drug
levels greater than 50ng/ml. Further in certain clinical situations which may increase
drug level require careful consideration as patients in these settings may be exposed to
drug levels beyond what is typical for the 20 and 40mg doses.
Several studies were carried out to study the effect of statins on myopathic events. One
such study shows that out of 32,225 patients identified in study to estimate the
prevalence of myopathic events, particularly myalgia, myositis, and rhabdomyolysis were
diabetics (n = 10,247) and nondiabetics (n = 21, 978). A greater proportion of statin
initiators in both the diabetes (7.9% vs 5.5%; P < 0.001) and nondiabetes cohorts (9.0%
vs 3.7%; P < 0.001) experienced myopathic events. The prevalence of severe myositis
was 0.4 per 1000 person-years (95% Cl, 0.2-0.7) and 0.8 per 1000 person-years (95%
Cl, 0.6-1.1) among statin initiators with or without diabetes, respectively. Another study
quantified the risk of myositis associated with statin and fibrate drug. Myositis was
significantly associated with statin monotherapy (RR 2.8 [95% confidence interval,
Cl=1.3-5.9]), statin-fibrate combination therapy (9.1 [95% CI=3.5-23]), comorbid liver
disease (4.3 [95% CN1.5-13], and/or renal disease (2.5 [95% Cl=1.3-5.0]).
Yet another study was undertaken to identify and characterize risk factors for
rhabdomyolysis in patients prescribed statin monotherapy or statin plus fibrate therapy.
Statin users 65 years of age and older have four times the risk of hospitalization for
rhabdomyolysis than those under age 65 (odds ratio (OR) = 4.36, 95% confidence
interval (Cl): 1.5,14.1).
In one another study, of 866 total reported cases, 482 (56%) were associated with
monotherapy and 384 (44%) related to combination therapy with fibric acid. More than
80% of reported cases for each drug resulted in hospitalization for renal failure and
dialysis. 80 patients expired from events related directly to rhabdomyolysis. Reporting
rates for all statins, except for cerivastatin, were similar and much lower than 1 per
100,000 prescriptions.
Further some delayed release statin formulation are described in US 2005/0119331,
applicant Butler et al, relates to method of increasing bioavailability of acid stable, carrier
6

mediated statins. The formulation results in, delayed release of substantial amount of
statin until the composition has passed out of the stomach and than releases the statin
at a rate that avoids saturating the intestinal and hepatocyctic mechanisms.
US 2002/0160044, applicant Howard J Smith and associates, relates to methods of drug
treatment where liver or portal venous circulation is the primary therapeutic target and in
particular to methods of treatment or prevention of diseases that are selective for the
liver and there by minimize side effects. The method involves use of a slow release
formulation of a low dose of HMG CO A reductase inhibitor that is itself metabolized by
the liver.
US 2005/0239884, applicant Novartis, relates to pharmaceutical compositions for
sustained release comprising active ingredient an HMG CoA reductase inhibitor or
pharmaceutically acceptable salt, said composition comprising an inner phase and an
outer phase wherein atleat the outerphase comprises atleast one matrix former.
US 2005/0203186, applicant Ratio harm, relates to medicament containing at least one
active ingredient, which lowers the cholesterol in the blood, characterized in that it has
means for providing release characteristics for the active ingredient with which the active
ingredient is released with at least two different release rates.
While a few patent applications described above discloses the extended release
formulation of statin but none of these explain the need for maintaining the systemic
plasma concentration of statin to less than 50ng/ml for rosuvastatin. The present
invention relates to new modified release statin formulation producing novel blood
plasma levels after ingestion over 24 hours that is not disclosed in nor rendered obvious
by, the prior art.
Thus the present invention finds a novel way of maintaining the plasma levels of statin
with increase in hepatic bioavailability so as to have reduces incidence of statin
myopathy and rhabdomyolysis
7

Objects of the Invention
An object of the present invention is to provide new modified release formulation
comprising HMG CoA reductase and pharmaceutically acceptable carrier having
reduced incidence of adverse effects.
Another object of the present invention is to provide modified release formulation of
rosuvastatin comprising rosuvastatin or its pharmaceutically acceptable salt or prodrug
or metabolite there of and pharmaceutically acceptable carrier which modifies the, said
formulation providing an in vivo plasma profile less than 50ng/ml.
Another object of the present invention is to provide modified release formulations of
HMG CoA reductase inhibitor or its pharmaceutically acceptable salt or prodrug or
metabolite thereof with increased hepatic bioavailability and decreased systemic
bioavailability.
Another object of the present invention is to provide modified release formulation of
HMG CoA reductase inhibitor comprising therapeutically effective amount of HMG CoA
reductase inhibitor or its pharmaceutically acceptable salt or prodrug or metabolite there
of wherein Cmax of statin, most preferably rosuvastatin, in plasma are statistically
significantly lower than the IR formulation.
Another object of the present invention is to provide modified release formulation of
HMG CoA reductase inhibitor comprising therapeutically effective amount of HMG CoA
reductase inhibitor or its pharmaceutically acceptable salt or prodrug or metabolite there
of and a bioadhesive polymer, wherein Cmax of statin, most preferably rosuvastatin, in
plasma are statistically significantly lower than the IR formulation.
Detailed Description of Invention
HMG CoA reductase inhibitors are the most commonly prescribed drugs for lowering
cholesterol levels for long-term use. The adverse effects of HMG CoA reductase
8

inhibitors are headaches, nausea and fever and the major effects are muscle pain and
muscle disease and serious liver problems.
The present invention relates to new modified release HMG CoA reductase inhibitors
formulation producing novel blood plasma levels after ingestion over 24 hours
comprising therapeutically effective amount of statin or pharmaceutically acceptable
salts or prodrugs or metabolites there of and modified release excipients.
For the present invention HMG COA reductase inhibitor and statin are used
interchangeably. Further statin also includes its pharmaceutically acceptable salts or
prodrugs or metabolites there of.
Modified release formulation describes a formulation that does not release active drug
substance immediately after oral dosing and that allows a reduction in dosage
frequency. A modified release formulation includes but is not limited to extended release,
delayed release, sustained release formulations or controlled release or timed release.
Further gastroretentive or bioadhesive formulation will also be included within the scope
of present invention. A controlled release formulation may be administered once a day.
Rate controlling polymer according to present invention includes agents, which controls
the release of drug from the formulation.
"Therapeutically effective amount" means that the amount of active agent, which halts
or reduces the progress of the condition being treated or which otherwise completely or
partly cures or acts palliatively on the condition. A person skilled in the art can easily
determine such an amount by routine experimentation and with an undue burden.
"Optional" or "optionally" means that the subsequently described circumstance may or
may not occur, so that the description includes instances where the circumstance occurs
and instances where it does not.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
Cmax" as used herein, means maximum plasma concentration of the statin produced by
the ingestion of the composition of the invention or the marketed Crestor® formulation.
"Cmin " as used herein, means minimum plasma concentration of the statin, produced
9

by the ingestion of the composition of the invention or the marketed Crestor®
formulation.
"Cavg " as used herein, means the average concentration within the 24-hour interval.
"Tmax " as used herein, means time to the maximum observed plasma concentration.
"AUC" as used herein, means area under the plasma concentration-time curve over the
complete 24-hour interval for all the formulations.
"Adverse effects" as used herein, means those physiological effects to various systems
in the body, which cause pain, and discomfort to the individual subject.
Degree of Fluctuation (DFL)" as used herein, is expressed as: DFL=(Cmax -Cmin)/CaVg
Modified release formulation may be the form of matrix tablet or coated tablets or
compression coated or layered tablet or capsule or bioadhesive formulation or gastro
retentive or any other formulation, which is within the scope of invention.
"Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an
extended period of time. Bioadhesion is one solution to the problem of inadequate
residence time resulting from stomach emptying and intestinal peristalsis, and from
displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate
contact must exist between the bioadhesive and the receptor tissue, the bioadhesive
must penetrate into the crevice of the tissue surface and/or mucus, and mechanical,
electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are
affected by both the nature of the polymer and by the nature of the surrounding media.
Bioadhesive and mucoadhesive can be used interchangeably.
For purposes of this invention, residence time is the time required for a pharmaceutical
dosage form to transit through the stomach to the rectum i.e. the pharmaceutical dosage
forms of the invention may have an increased retention time in the stomach and/or small
and/or large intestine, or in the area of the gastrointestinal tract that absorbs the drug
contained in the pharmaceutical dosage form. For example, pharmaceutical dosage
forms of the invention can be retained in the small intestine (or one or two portions
thereof, selected from the duodenum, the jejunum and the ileum). These pharmaceutical
10

dosage forms as a whole, may include a bioadhesive polymeric coating that is applied to
at least one surface of the dosage form.
The HMG CoA reductase inhibitors or statin, which may be used in the present
invention, includes Lovastatin, pravastatin, atorvastatin, rosuvastatin, cerivastatin,
pitvastatin and others. The most preferred statin is rosuvastatin.
Oral rate controlling polymers that are used in the present formulation may include
hydrophilic polymer, hydrophobic polymer or a combination of hydrophilic and
hydrophilic polymer. Examples of suitable hydrophilic polymers include hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate copolymers,
polysaccharides as alginates, xanthan gum, Chitosan, carrageenan, dextran and the
like, polyalkylene oxides as polyethylene oxide and the likes, methaacrylic acid
copolymers, maleic anhydride/methyl vinyl ether copolymers and the like. Hydrophobic
polymers include acrylates, cellulose derivatives as ethylcellulose, cellulose acetate and
the likes, methaacrylates, high molecular weight polyvinyl alcohols, waxes and the likes.
The polymers used can also be eroding or non-eroding or combination of both.
The polymers, which may be used for bioadhesion, are described below.
Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such
as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen,
chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind
seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid,
polyhyaluronic acid, alginic acid, sodium alginate.
When the bioadhesive polymer is a synthetic polymer, the synthetic polymer is typically
selected from but are not limited to polyamides, polycarbonates, polyalkylenes,
polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl
alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone,
polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and
methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-
glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and
blends and copolymers or mixtures thereof.
11

Other polymers suitable for use in the invention include, but are not limited to, methyl
cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate
butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate,
cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate),
poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate),
poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),
poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl
acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly
(ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl
pyrrolidone, and polyvinylphenol. Polylactides, polyglycolides and copolymers thereof,
poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-
caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)),
polyorthoesters, blends and copolymers thereof.
Another group of polymers suitable for use as bioadhesive polymers but not necessarily
limited to polymers having a hydrophobic backbone with at least one hydrophobic group
pendant from the backbone. Suitable hydrophobic groups are groups that are generally
non-polar. Examples of such hydrophobic groups include alkyl, alkenyl and alkynyl
groups. Preferably, the hydrophobic groups are selected to not interfere and instead to
enhance the bioadhesiveness of the polymers.
A further group of polymers suitable for use as bioadhesive polymers but not necessarily
limited to polymers having a hydrophobic backbone with at least one hydrophilic group
pendant from the backbone. Suitable hydrophilic groups include groups that are capable
of hydrogen bonding or electrostatically bonding to another functional group. Example of
such hydrophilic groups include negatively charged groups such as carboxylic acids,
sulfonic acids and phosponic acids, positively charged groups such as (protonated)
amines and neutral, polar groups such as amides and imines.
Preferably, the hydrophilic groups are selected to not to interfere and instead to enhance
the bioadhesiveness of the polymers. In embodiments of the present invention, a
12

pharmaceutical composition comprises an active agent and atleast one swellable
polymer.
Swellable polymers include, but are not limited to, a crosslinked poly(acrylic acid), a
poly(alkylene oxide), a polyvinyl alcohol), a polyvinyl pyrrolidone); a polyurethane
hydrogel, a maleic anhydride polymer, such as a maleic anhydride copolymer, a
cellulose polymer, a polysaccharide, starch, and starch based polymers.
Polymers can be modified by increasing the number of carboxylic groups accessible
during biodegradation, or on the polymer surface. The polymers can also be modified by
binding amino groups to the polymer. The polymers can be modified using any of a
number of different coupling chemistries available in the art to covalently attach ligand
molecules with bioadhesive properties to the surface-exposed molecules of the
polymeric microspheres.
Lectins can be covalently attached to polymers to render them target specific to the
mucin and mucosal cell layer. The attachment of any positively charged ligand, such as
polyethyleneimine or polylysine, to a polymer may improve bioadhesion due to the
electrostatic attraction of the cationic groups coating the beads to the net negative
charge of the mucus. The mucopolysaccharides and mucoproteins of the mucin layer,
especially the sialic acid residues, are responsible for the negative charge coating. Any
ligand with a high binding affinity for mucin could also be covalently linked to most
polymers with the appropriate chemistry, such as with carbodiimidazole (CDI), and be
expected to influence the binding to the gut. For example, polyclonal antibodies raised
against components of mucin or else intact mucin, when covalently coupled to a
polymer, would provide for increased bioadhesion. Similarly, antibodies directed against
specific cell surface receptors exposed on the lumenal surface of the intestinal tract
would increase the residence time when coupled to polymers using the appropriate
chemistry. The ligand affinity need not be based only on electrostatic charge, but other
useful physical parameters such as solubility in mucin or specific affinity to carbohydrate
groups.
The covalent attachment of any of the natural components of mucin in either pure or
partially purified form to the polymers generally increases the solubility of the polymer in
13

the mucin layer. The list of useful ligands include but are not limited to the following:
sialic acid, neuraminic acid, n-acetyl-neuraminic acid, n- glycolylneuraminic acid, 4-
acetyl-n-acetylneuraminic acid, diacetyl-n- acetylneuraminic acid, glucuronic acid,
iduronic acid, galactose, glucose, mannose, fucose, any of the partially purified fractions
prepared by chemical treatment of naturally occurring mucin, e.g., mucoproteins,
mucopolysaccharides and mucopolysaccharide-protein complexes, and antibodies
immunoreactive against proteins or sugar structure on the mucosal surface.
The attachment of polyamino acids containing extra pendant carboxylic acid side
groups, such as polyaspartic acid and polyglutamic acid, may also increase
bioadhesiveness. The polyamino chains would increase bioadhesion by means of chain
entanglement in mucin strands as well as by increased carboxylic charge.
Solubilizing agents are the agents that help the drug to solubilize either in formulation or
in the site of absorption or action. Solubilizing agents include but are not limited to
surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination
thereof.
Non-limiting examples of surfactants include water-soluble or water dispersible nonionic,
semi-polar nonionic, anionic, cationic, amphoteric, or zwitterionic surface-active agents;
or any combination thereof.
Other solubilizing agents include but not necessarily limited to vitamin E substance and
its derivatives; monohydric alcohol esters such as trialkyl citrates, lactones and lower
alcohol fatty acid esters; nitrogen-containing solvents; phospholipids; glycerol acetates
such as acetin, diacetin and triacetin; glycerol fatty acid esters such as mono-, di- and
triglycerides and acetylated mono- and diglycerides; propylene glycol esters; ethylene
glycol esters; and combinations thereof.
Pharmaceutically acceptable excipients include but are not limited to binders, diluents,
lubricants, glidants and surface-active agents.
The amount of additive employed will depend upon how much active agent is to be
used. One excipient can perform more than one function.
14

The formulation will, in general comprise of one or more excipients. Examples of
excipients include, but are not limited to, diluents, disintegrants, lubricant, glident,
binders, fillers, surfactant, solubilizers, wetting agents, chelating agents, stabilizers,
alkalizing agents or aminoacids. A combination of excipients may also be used.
Binders include, but are not limited to, starches such as potato starch, wheat starch,
corn starch; microcrystalline cellulose such as products known under the registered
trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose,
sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid
glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl
amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations
there of and other materials known to one of ordinary skill in the art and mixtures thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic ortribasic, calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of
ordinary skill in the art.
The present formulations may optionally contain a surface-active agent. The preferred
agent is poloaxmer. However, other agents may also be employed such as dioctyl
sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS),
polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or
other pharmaceutically acceptable surface-active agents known to one ordinary skilled in
the art.
15

The pharmaceutical formulation according to the present invention include but is not
limited to tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive
tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified
release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules,
sustained release formulations, capsules, microcapsules, tablets in capsules and
microspheres, matrix formulations, microencapsulation and powder/pellets/granules for
suspension.
The pharmaceutical dosage form of the invention can optionally have one or more
coatings such as film coating, sugar coating, enteric coating, bioadhesive coating and
other coatings known in the art. These coatings help pharmaceutical formulations to
release the drug at the required site of action. In one example, the additional coating
prevents the dosage from contacting the mouth or esophagus. In another example, the
additional coating remains intact until reaching the small intestine (e.g., an enteric
coating). Premature exposure of a bioadhesive layer or dissolution of a pharmaceutical
dosage form in the mouth can be prevented with a layer or coating of hydrophilic
polymers such as HPMC or gelatin. Optionally, Eudragit FS 30D or other suitable
polymer may be incorporated in coating composition to retard the release of the drug to
ensure drug release in the colon.
These coating layers comprises one or more excipients selected from the group
comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents,
colouring agents, antitacking agents and the like.
Coating agents which are useful in the coating process, include, but are not limited to,
polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose,
hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses);
polyvinylpyrrolidone, acacia, corn, sucrose, gelatin,shellac, cellulose acetate pthalate,
lipids, synthetic resins,acrylic polymers,opadry, polyvinyl alcohol (PVA), copolymers of
vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone)
and polymers based on methacrylic acid such as those marketed under the brand name
of Eudragit. These may be applied from aqueous or non-aqueous systems or
combinations of aqueous and non-aqueous systems as appropriate. Additives can be
16

included along with the film formers to obtain satisfactory films. These additives can
include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol(PEG)
and the like, antitacking agents such as talc, stearic acid, magnesium stearate and
colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauryl
sulphate fillers such as talc, precipitated calcium carbonate, Polishing agents such as
Beeswax, carnauba wax, synthetic chlorinated wax and opacifying agents such as
titanium dioxide and the like. All these excipients can be used at levels well known to the
persons skilled in the art.
Pharmaceutical dosage forms of the invention can be coated by a wide variety of
methods. Suitable methods include compression coating, coating in a fluidized bed or a
pan and hot melt (extrusion) coating. Such methods are well known to those skilled in
the art.
Non-permeable coatings of insoluble polymers, e.g., cellulose acetate, ethylcellulose,
can be used as enteric coatings for delayed/modified release (DR/MR) by inclusion of
soluble pore formers in the coating, e.g., PEG, PVA, sugars, salts, detergents, triethyl
citrate, triacetin, etc.
In a preferred embodiment of the present invention the pharmaceutical formulation is
multiplayer tablets comprising a first, a second and/or a third layer, where each layer
includes one or more excipient(s).
Multi-layer or gradient tablets can be assembled in several different ways.
In one embodiment, the tablet comprises at least one solid core and two outer layers,
each comprising one or more pharmaceutical polymers and/or pharmaceutical
excipients. The core comprises active ingredient and rate-controlling polymer. The two
outer layers are bioadhesive.
In another embodiment, the tablet comprises at least one core and two outer layers,
each comprising drug and one or more pharmaceutical polymers and/or pharmaceutical
excipients. Such tablets can also be used to commence release of different drugs at
different times, by inclusion of different drugs in separate layers.
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In another embodiment, the multi-layer tablet consists of a core and two outer layers,
each comprising a drug and one or more pharmaceutical polymers or pharmaceutical
excipients, wherein at least one polymer or excipient is hydrophobic.
In another preferred embodiment the present invention relates to formulation which
consists of multilayer tablet wherein atleast one layer consist of a controlled release
polymer and the active ingredient and at least one layer which consist of bioadhesive
polymer, where each layer includes one or more excipients.
In another embodiment the present invention relates to formulation which consists of
multilayer tablet wherein atleast one layer consist of a controlled release polymer and at
least one layer which consist of bioadhesive polymer, where each layer includes one or
more excipients and drug.
The dosage forms may be coated with one or more coatings, functional or non-
functional. Non-functional coating includes film coating and functional coating may be
enteric or modified release coating. The polymers which may used are shellac, zein,
hydroxypropylmethylcellulose, ethyl cellulose, polymethacrylates, polyvinyl acetate
pthalate, cellulose acetate pthalate, triacetin, dibutyl sebecate, a mixture of polyethylene
glycol, titanium dioxide and the like. The coating may further comprise of other
excipients.
Further the modified release formulation of statin may include an immediate release
layer. Also combination of statin with other lipid lowering agents such as other statins,
fibric acid derivatives, bile acid sequestrants, niacin, HDL increasing agents such as
omega 3 fatty acids, or anti-hypertensive agents or PDE-5 inhibitors such as Sildenafil,
platelet inhibiting agents as aspirin and other agents also fall within the scope of the
invention. These other agents used in combination with statins can be in immediate
release or modified release formulations. For the present invention combination will
include sequential or simultaneous or co-administered or combined administration.
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The formulation of the present invention may be prepared by conventional techniques
well known to those skilled in the art such as wet granulation, melt granulation, direct
compression or dry compaction and/or slugging and the like.
The modified release formulation of the present invention provides in-vivo plasma
concentration of the statins with decreased systemic concentration and increased
hepatic bioavailability. The decrease in systemic concentration and increased hepatic
bioavailability reduces the major side effects of statin. Thus one of the objectives of the
present invention is to keep the Cmax concentration of rosuvastatin below 50ng/ml and
for other statins the Cmax concentration should be less than the concentration, which
starts the incidence of the side effects.
It is known that rosuvastatin was first proposed to market at doses ranging from 10 to 80
mg. However the original application revealed safety concerns for 80mg dose. Data
presented by sponsor showed that the development of severe myopathy or
rhabdomyolysis requiring hospitalization for IV hydration occurred at an incidence only at
the 80mg dose. The incidences of CK elevations > 10xULN and myopathy in clinical
trials of rosuvastatin 5 to 40 mg were between 0.2 to 0.4 % and 0.1 to 0.2% respectively.
Data from the clinical trials in this application show that patients receiving rosuvastatin
had an increased rate of developing proteinuria with and without hematuria. Proteinuria
was most pronounced at the 80mg dose.
At the 40mg dose the incidence of proteinuria ranged from 3.8 to 5% between the
controlled trails and open label extensions while the incidence of combined proteinuria
and hematuria was 1.3 to 1.5% respectively.
The incidence of myopathy, in clinical trials, of rosuvastatin 5 to 40mg, were between 0.1
to 0.2% which are similar to rates seen with other currently approved statins. The risk of
muscle and renal toxicity appear dose related and are clearly evident at 80 mg dose.
Rosuvastatin levels more than 50ng/ml in plasma developed muscle and or renal
toxicity. Only a few patients treated with 40mg rosuvastatin (2%) had drug levels within
this range an d greater proportion of patients treated with 80mg (33%) achieved drug
levels greater than 50ng/ml. Further in certain clinical situations which may increase
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drug level require careful consideration as patients in these settings may be exposed to
drug levels beyond what is typical for the 20 and 40mg doses.
In conclusion elevated serum rosuvastatin levels more than 50ng/ml seen with daily
doses of 40mg or higher were associated with severe adverse events such as
rhabdomyolysis and renal failure. The potential also exists for higher unsafe serum
levels of rosuvastatin at lower daily doses (such as 10-20 mg) as a consequence of drug
interaction or use in patients with severe renal disease or in geriatric patients.
Thus the modified release formulations of the present invention, which comprise a
pharmaceutically acceptable polymer, provide modified release statin, most preferably
rosuvastatin, in vivo when given once daily. Maximum concentrations (Cmax) of statin,
most preferably rosuvastatin, in plasma are statistically significantly lower than the IR
formulation.
The mean DFL for the composition of the invention is statistically lower than the IR in
vivo profile. The lower DFL indicates that the ER formulations of the invention provide
less variable statin concentrations throughout the day than the IR composition. Thus
the formulation of the present invention is less prone to cause the serious side effects of
currently marketed statin formulation. Further administration with other lipid lowering
agents or cardiovascular agents or platelet inhibiting agents can improve the safety,
efficacy and improve tolerability of the combination products.