Title of Invention

A NOVEL PHARMACEUTICAL COMPOSITION OF STATIN WITH DMARDS

Abstract The present invention discloses improved synergistic fixed dose pharmaceutical compositions comprising a combination of statins with disease modifying antirheumatic agent as claimed in our main application, used in daily therapy for rheumatology. More particularly the invention relates to pharmaceutical compositions comprising statins such as atorvastatin, pravastatin, lovastatin, rosuvastatin, fluvastatin and hydroxychloroquine as the disease modifying antirheumatic agent. The invention is intended to provide a complete therapy for rheumatoid arthritis and lupus patients as well as to provide an alternative option in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A novel pharmaceutical compositions of Statins with DMARDS"
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Related application: This application is a patent of addition and claiming priority from our earlier application No: 154/MUM/2003 dated 5th Feb 2003, titled "A novel pharmaceutical compositions of Statins with DMARDS"
Technical Field
The present invention relates to improved synergistic pharmaceutical compositions for fixed dose combination of statins with disease modifying antirheumatic agent as claimed in our main application, used in daily therapy for rheumatology. More particularly the invention relates to pharmaceutical compositions comprising statins such as atorvastatin, pravastatin, lovastatin, rosuvastatin, fluvastatin and hydroxychloroquine as the disease modifying antirheumatic agent.
Background and Prior Art
Cardiovascular disease (CVD) has a tendency to remain silent in the rheumatoid patients. Rheumatoid patients have higher rates of coronary disease. Traditional cardiovascular risk factors do not seem to be wholly responsible for the increased cardiovascular risk. Novel cardiovascular risk factors, including inflammatory markers, are responsible for accelerating coronary heart disease in patients with rheumatoid arthritis (RA). Also in general, Indian patients show high incidence of atherosclerosis.
Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported in patients with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APLS), or rheumatoid arthritis (RA). Studies found relative risks of 5 for myocardial infarction, 6 to 10 for stroke in SLE patients, and 3.6 for cardiovascular deaths in RA patients. The main risk factors for atherosclerosis included not only the classic factors identified in epidemiological studies such as the Framingham study (advanced age, high cholesterol levels, hypertension, diabetes mellitus, and obesity), but also prolonged glucocorticoid therapy, long duration of SLE, postmenopausal status, and heart failure. SLE per se is an independent risk factor. The current pathogenic hypothesis for
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atherosclerosis involves an inflammatory response (erythrocyte sedimentation rate, C-reactive protein, and fibrin), autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), cytokine-producing activated T cells, and bacterial or viral infections responsible for an immune response against heat shock proteins (endogenous HSP60 and its equivalent, bacterial HSP65).
Cardiovascular death is considered the leading cause of mortality in patients with RA; it is responsible for approximately half the deaths observed in RA cohorts. RA patients have an ultrasonic marker of early atherosclerosis consistent with an increased risk for atherosclerosis.
A striking feature of the cardiac involvement in individual with systemic lupus erythematosus (SLE) and rheumatoid arthritis is aggressive and accelerated atherosclerosis; women with SLE in the 35- to 44- year-old age group are more than 50 times more likely to suffer myocardial infarction than are matched controls.
It is fairly frequent to encounter hyperlipemia on a rheumatic unit. Firstly the symptoms of certain idiopathic hyperlipemias sometimes include rheumatic changes. The latter include firstly, arthritis and tendinitis, above all observed in Type II hyperlipoproteinemia but also mentioned in Type IV, and secondly, exceptional bony lesions (generally of xanthoma type) which seems to occur exclusively in severe hyperglyceridemia. A few bone and joint diseases, such as gout or aseptic necrosis, frequently coexist with dyslipemia. Furthermore, various diseases may be simultaneously responsible for secondary hyperlipemia and involvement of the locomotor apparatus.
Statins are lipid lowering agents which competitively inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co A) reductase. These agents have been used in the treatment of dyslipidemia. Recent advances in the knowledge of the pharmacology of statins have indicated that these drugs rather than to be simple cholesterol lowering molecules display pleiotropic effects on several mechanisms involved in the atherosclerotic plaque
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formation. Their anti-inflammatory activity and particularly their ability to downregulate endothelial cell activation induced by different stimuli strongly suggest their possible use in conditions in which the systemic inflammation and the endothelial activation/damage are thought to represent key pathogenic mechanisms.
It has been observed that patients affected by a chronic inflammatory disease, such as RA, might show acceleration of atherosclerosis despite treatment with anti-inflammatory drugs. Patients with plaques had significantly higher levels of lipids (cholesterol, LDL, LDL/HDL ratio) than patients without plaques, while patient with cusp sclerosis had significantly higher cholesterol and TG levels. The results suggested an accelerated atherosclerosis in patients with RA that is related mainly to lipid levels. Patients with untreated active RA have altered lipoprotein and apolipoprotein patterns that may possibly expose them to higher risk of atherosclerosis. The inflammatory conditions of RA may affect the metabolism of HDL-cholesterol and apo Al.
C-reactive protein (CRP), a pattern recognition molecule linked to the innate immune system, is a sensitive marker of low-grade vascular inflammation, which may also have direct proinflammatory actions. The serum level of CRP is a strong predictor of future coronary events. CRP levels can be slightly increased in arthritis.
Recent studies have shown that statin therapy may lower CRP levels independent of lipid-lowering effects. It stabilizes plaque due to its anti-inflammatory effect and effect on CRP.
Rheumatoid arthritis is often complicated by generalized osteopenia due to increased bone resorption by osteoclasts. Patients with rheumatoid arthritis frequently posses a number of risk factors for osteoporosis. Additionally, oral steroids are often used to control active rheumatoid disease and may further potentiate bone loss. Although the true incidence of glucocorticoid-induced osteoporosis is unknown, data suggest that overall estimates of fractures during long term steroid range from 30% to 50%.
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The first report of HMG-CoA reductase inhibitors as potential bone anabolic agents came in December 1999 amid a screening technique developed by Mundy et al to isolate compounds that activated the promotor of the bone morphogenetic protein-2 (BMP-2) gene. Mundy et al tested lovastatin, simvastatin and mevastatin and found that each drug specifically activated the BMP-2 promoter.
Statin stimulate BMP-2 expressions causing increased osteoblast proliferation and differentiation, and subsequently enhanced bone formation. It may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. Statins also lowered the risk of hip fracture. It was associated with a 71% risk reduction in hip fracture. It also increased bone mineral density.
If statin is used along with DMARDs, there will be beneficial effect on atherosclerosis. In addition, anti-inflammatory effect will also reduce joint damage.
Premature atherosclerosis is a recognized complication of systemic lupus erythematosus. Atherosclerosis begins in the pediatric age group, and interventions directed toward prevention should begin in childhood as well. A possible cause of premature atherosclerosis is dyslipoproteinemia from the underlying chronic inflammatory disease or from corticosteroid therapy. A relationship between dyslipoproteinemia and anticardiolipin antibodies has been demonstrated. Dietary therapy is helpful, but many patients continue to have significant dyslipoproteinemia after both dietary modification and fish oil supplementation. Lipid-lowering drugs may be indicated in this subgroup.
Dyslipoproteinemia is a common feature in adult SLE premenopausal patients, which is characterized by an increase in TC, triglycerides and apo B, and an abnormal distribution of HDL subclasses.
Within 3 years of diagnosis, 75.4% of patients with SLE had elevated TC, which was sustained in 40.3% of all patients. Older age at onset as well as increased cumulative dose of steroids and no antimalarial therapy are significant predictors of this group. It is this group
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that experiences the majority of CAD related events. Aggressive lipid lowering therapy should be targeted at such patients.
Lipid-lowering drugs have been shown to have profound actions beyond modulation of lipid profiles. Statins have been shown to reduce the levels of pro-inflammatory cytokines and markers of acute phase response including C-reactive protein and serum amyloid A. Fibrates have also shown to reduce interleukin-6 levels. Both groups of drugs seem to act through a peroxisomal proliferating activating receptor alpha mechanism to achieve these actions. In lupus, there is profound activation of cytokine production and the acute phase response and a markedly increased risk for the development of atherosclerosis.
Statins besides being simple cholesterol lowering molecules display pleiotropic effects on several mechanisms involved in the atherosclerotic plaque formation. Their antiinflammatory activity and particularly their ability to downregulate endothelial cell activation induced by different stimuli strongly suggest their possible use in conditions in which the systemic inflammation and the endothelial activation/damage are thought to represent key pathogenic mechanisms. Also rheumatoid arthritis is often complicated by generalized osteopenia due to increased bone resorption by osteoclasts. Patients with rheumatoid arthritis frequently possess a number of risk factors for osteoporosis. Additionally, oral steroids are often used to control active rheumatoid disease and may further potentiate bone loss. Statins stimulate BMP-2 expressions causing increased osteoblast proliferation and differentiation, and subsequently enhanced bone formation. It may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. Statins may lower the risk of hip fracture.
Disease modifying antirheumatic drugs, have been used in rheumatology to arrest the disease process. Antimalarials have been used to treat rheumatic diseases for more than a century. They include chloroquine and hydroxychloroquine. Chloroquine appears to be more retinotoxic and this probably accounts for the increasingly frequent use of hydroxychloroquine.
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Apart from its immunosuppressant effect, hydroxychloroquine shows significant overall improvement in the lipid profile. Hydroxychloroquine may also be cardioprotective by reducing platelet aggregation. It has also shown beneficial effects on glucose metabolism as well as has weak anticoagulant activity. Hence combination of statins with hydroxychloroquine will be beneficial in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
Apart from its immunosuppressant effect, hydroxychloroquine shows significant overall improvement in the lipid profile. Hydroxychloroquine treated patients had low serum levels of cholesterol, triglycerides, and LDL. (Am J Med 1990 Sep;89(3):322-6)
Another study showed that hydroxychloroquine led to a rise in both HDL and %HDL. These trials show that changes in lipids with hydroxychloroquine may lead to a significant reduction in IHD risk.
In addition to its lipid lowering effect, hydroxychloroquine may be cardioprotective by reducing platelet aggregation (Am J Med J 988 Oct 14;85(4A):57-61).
Antimalarials have beneficial effects on glucose metabolism as well as have weak anticoagulant activity. (Lupus, 2001;10(3):148-51)
US Patent Application 20020156122 describes, methods of treatment for various disease conditions using Statins in simultaneous therapy along with variety of other drugs for different diseases.
There has been no report of any formulation of a combination of statins with hydroxychloroquine. No such formulation containing both these drugs in single dosage form has been reported for use in rheumatoid arthritis or atherosclerosis. Any of the above options
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of making available the two drugs together will help patients of rheumatoid arthritis and SLE.
Accordingly, the present inventor had studied the synergistic effect of the simvastatin and hydroxychloroquine A fixed dose combination of statin and hydroxychloroquine is therefore considered to be more effective in rheumatology and hence developed for patient compliance and convenience.
Objectives of the invention:
It is an object of the present invention to provide improved synergistic pharmaceutical compositions comprising a statin with disease modifying antirheumatic agent such as hydroxychloroquine for better or superior therapy for rheumatoid arthritis and SLE patients with or without hypercholesterolaemia.
It is another objective of the present invention to provide a complete therapy for rheumatoid arthritis and lupus patients as well as to provide an alternative option in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
It is further object of the invention to reduce the cost of therapy by providing the synergistic combination.
Summary of Invention
The present invention discloses improved synergistic fixed dose pharmaceutical combination of therapeutically effective amount of statin with therapeutically effective amount of disease modifying antirheumatic agent. The statin is selected from atorvastatin, pravastatin, lovastatin, rosuvastatin, and fluvastatin and hydroxychloroquine is the disease modifying antirheumatic agent. The compositions of the present invention is also useful in treating diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
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Statins usually differ with respect to efficacy, pharmacokinetic profiles, drug interaction profile and tolerability.
According to the present invention, a fixed dose combination of atorvastatin, pravastatin, lovastatin, rosuvastatin or fluvastatin and hydroxychloroquine will therefore help in individualizing the drug according to the patients' requirements. It will be helpful not only in patients with rheumatoid arthritis and lupus but also in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are required. Hydroxychloroquine with its beneficial effect on lipid and glucose metabolism and with its effect on reduction in platelet aggregation will add to the efficacy of statins in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are required.
Brief description of drawings:
Fig 1 shows the Mean & SD of % Inhibition of rat paw edema with different treatment
groups.
Fig 2 shows Mean % Inhibition of inflammation by different treatments.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention discloses improved synergistic pharmaceutical compositions for fixed dose combination of statins with disease modifying antirheumatic agent useful in the field of rheumatology. The Statin used in the invention can be selected from atorvastatin, pravastatin, lovastatin, rosuvastatin, and fluvastatin. The disease modifying antirheumatic agent is
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hydroxychloroquine. The compositions of the present invention are also useful in treating the diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
Thus the pharmaceutical compositions of the present invention provides a complete therapy for rheumatoid arthritis and lupus patients as well as to provide an alternative option in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
The use of stains is well established in coronary heart disease (CHD) and diabetes. Diabetes is considered to be CHD risk equivalent. Basis for using statins in rheumatoid arthritis is the risk of high incidence of atherosclerosis in rheumatoid arthritis (RA) and SLE patients. New cardiovascular risk factors, including inflammatory markers may be responsible for accelerating coronary heart disease in patients with RA. Statins display pleiotropic effects on several mechanisms involved in the atherosclerotic plaque formation. Their antiinflammatory activity and particularly their ability to down regulate endothelial cell activation induced by different stimuli strongly suggest their possible use in conditions in which the systemic inflammation and the endothelial activation/damage are thought to represent key pathogenic mechanisms
There is clear difference between the statins in potency as well as in the interval between initiation of treatment and the onset of clinical benefit. There is also difference in the tolerability of various statins and in its interactions with other drugs. Physicians use different statins for different patients, depending on the type of dyslipidemia, severity of dyslipidemia, concomitant drugs used in the patients and tolerability of the drug.
The use of hydroxychloroquine is well established in rheumatoid arthritis and has been used in rheumatoid arthritis for decades. Apart from its immunosuppressant effect, hydroxychloroquine shows significant overall improvement in the lipid profile.
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Hydroxychloroquine may also be cardio-protective by reducing platelet aggregation. It has also shown beneficial effects on glucose metabolism as well as has weak anticoagulant activity.
Therefore, the present inventor had established the fact that hydroxychloroquine in combination with simvastatin works synergistically and particularly useful in patients with rheumatoid arthritis and lupus as described and claimed in our main application. The inventor had further carried out a study to evaluate the synergy of the combination of other statins with hydroxychloroquine.
Accordingly, in a preferred embodiment, the invention provides a synergistic fixed dose combination of Atorvastatin with hydroxychloroquine, which is useful in the treatment of rheumatoid arthritis and lupus, in treating the diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed. The synergistic combination of the present invention is useful in treating rheumatoid arthritis in patients with or without dyslipidemia. The composition is prepared in the form of film coated tablets or capsules.
In another preferred embodiment, the invention provides a synergistic combination of pravastatin with hydroxychloroquine as fixed dose combination with similar indications mentioned for atorvastatin and hydroxychloroquine combination.
In another preferred embodiment, there is provided a synergistic fixed dose combination of lovastatin with hydroxychloroquine with similar indications mentioned for atorvastatin and hydroxychloroquine combination.
In yet another preferred embodiment, the invention provides a synergistic fixed dose combination of rosuvastatin with hydroxychloroquine with similar indications mentioned for atorvastatin and hydroxychloroquine combination.
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In another preferred embodiment, a synergistic fixed dose combination fluvastatin with hydroxychloroquine is provided with similar indications mentioned for atorvastatin and hydroxychloroquine combination.
The above fixed dose combinations are formulated using pharmaceutically acceptable excipients. Thus the present invention will also satisfy the following requirements such as; improved patient's compliance; reduced cost of therapy; dyslipidemia and bone fracture associated with rheumatology will be taken care of and formulation can be individualized according to the needs of the patient.
The fixed dose pharmaceutical compositions of the present invention is prepared as solid oral dosage forms, preferably in the form of a film coated tablet or capsule, in combination with carriers or excipients such as fillers, binders, disintegrants, anti-oxidants, lubricants, glidants and optionally coloring and flavoring agents.
Pharmaceutically acceptable fillers or binding agents are selected from those known in the art including, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, di basic calcium phosphate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, or xylitol.
In combination with the filler components, the present formulations also comprise disintegrant agents but not limited to, starch, pregelatinized starch and sodium starch glycolate or croscarmellose sodium.
The pharmaceutical formulations also contain preservatives known in the art for example like ascorbic acid and butylated hydroxy 1 toluene.
A lubricant is selected from those known in the art like magnesium stearate or other metallic stearates such as calcium stearate and zinc stearate.
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A glidant is selected from those known in the art, including from the group of colloidal silicon dioxide, talc, metallic stearates.
Film coating composition contains hydroxypropyl methyl cellulose as a coating agent along with titanium dioxide polyethylene glycol-400, polysorbate-80, talc along with additional ingredients such as colors, sugars and flavors to impart certain characteristics to the film coat.
The formulations of the present invention can be conveniently prepared by conventional methods to those skilled in the art such as direct compression, dry granulation, wet granulation or fluidized bed granulation.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLES Example 1
Tablets of Atorvastatin and hydroxychloroquine for oral administration contain 5mg/10mg/20mg/40mg of Atorvastatin, and 200mg/400mg of hydroxychlroquine along with the inactive ingredients selected from dibasic calcium phosphate, Cellulose, Hydroxypropylmethyl Cellulose, Lactose, Magnesium Stearate, sodium starch glycolate, Starch, Talc, Iron Oxide, Titanium Dioxide and other conventional inactive ingredients. Butylated hydroxy toluene and ascorbic acid are added as preservatives. The fixed dose combination of l0mg Atorvastatin and 200mg hydroxychloroquine is shown in table 1.
Table 1

Sr.No Ingredients Qty. per tablet
1 Atorvavastatin 010.00mg
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2 Hydroxychloroquine sulphate 200.00mg
3 Dibasic calcium phosphate 030.00mg
4. Starch 070.00mg
5. Talc 003.00mg
6. Magnesium stearate 002.00mg
7. Butylated hydroxyl toluene(BHT) 000.l0mg
8. Ascorbic acid 000.0lmg
9. Sodium starch glycolate 005.00mg
Film coating formula contains hydroxyl propyl methyl cellulose, titanium dioxide, polyethylene glycol-400, polysorbate-80, talc along with additional ingredients such as colors, sugars and flavors to impart certain characteristics to the film coat. The composition of the film coating for the above said composition is shown table 2.
Table 2

Sr.No Ingredients Qty. per tablet
1. Hydroxyl propyl methyl cellulose 15cps 00l.00mg
2. Titanium dioxide 006.50mg
3. Polyethylene glycol-400 000.20mg
4. Polysorbate-80 000.l0mg
5. Talc 003.50mg
6 Isopropyl alcohol 000.05ml
7. Methylene chloride 000.10ml
8. Colour 000.20mg
Example 2
Capsules of Atorvastatin and hydroxychloroquine for oral administration contain 5mg/10mg / 20mg/40mg of atorvastatin, and 200mg/400mg of hydroxychloroquine, along with the other
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following inactive ingredients such as dibasic calcium phosphate, starch, talc, magnesium stearate, sodium starch glycolate and colloidal silicon dioxide. Ascorbic acid and butylated hydroxyl toluene are added as preservatives. The fixed dose combination of l0mg Atorvastatin and 200mg hydroxychloroquine is shown in table 3.
Table 3

Sr.No Ingredients Qty. per capsule
1. Atorvastatin 010.00mg
2. Hydroxychloroquine sulphate 200.00mg
3. Dibasic calcium phosphate 080.00mg
4. Starch 150.00mg
5. Talc 003.00mg
6. Magnesium stearate 002.00mg
7. Butylated hydroxy toluene 000.l0mg
8. Ascorbic acid 000.0lmg
9. Sodium starch glycolate 005.00mg
10. Colloidal silicon dioxide 00l.00mg
Example 3
Similarly tablets and capsules of Pravastatin and hydroxychloroquine for oral administration contain 10mg/20mg of Pravastatin, and 200mg/400mg of hydroxychlroquine along with the inactive ingredients selected from Cellulose, Hydroxypropylmethyl Cellulose, Iron Oxide, Lactose, Magnesium Stearate, Starch, Talc, Titanium Dioxide and other conventional inactive ingredients. Butylated hydroxy toluene and ascorbic acid are added as preservatives.
Example 4
Tablets and capsules of Lovastatin and hydroxychloroquine for oral administration contain 10mg/20mg of Lovastatin, and 200mg/400mg of hydroxychlroquine along with the inactive ingredients selected from Cellulose, Hydroxypropylmethyl Cellulose, Iron Oxide, Lactose,
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Magnesium Stearate, Starch, Talc, Titanium Dioxide and other conventional inactive ingredients. Butylated hydroxy toluene and ascorbic acid are added as preservatives.
Example 5
Tablets and capsules of Rosuvastatin and hydroxychloroquine for oral administration contain 5mg/10mg/20mg/40mg of Rosuvastatin, and 200mg/400mg of hydroxychloroquine along with the following inactive ingredients; Cellulose, Hydroxypropylmethyl Cellulose, Iron Oxide, Lactose, Magnesium Stearate, Starch, Talc, Titanium Dioxide and other ingredients. Butylated hydroxy toluene and ascorbic acid are added as preservatives.
Example 6
Tablets and capsules of Fluvastatin and hydroxychloroquine for oral administration contain 20mg/40mg/80mg of Fluvastatin, and 200mg/400mg of hydroxychloroquine along with the following inactive ingredients; Cellulose, Hydroxypropylmethyl Cellulose, Iron Oxide, Lactose, Magnesium Stearate, Starch, Talc, Titanium Dioxide and other ingredients. Butylated hydroxy toluene and ascorbic acid are added as preservatives.
Example 7
Manufacturing Process:
The tablets of the present compositions are manufactured by conventional manufacturing
techniques for example direct compression method, wet granulation method, dry granulation
or fluid bed granulation techniques. Alternatively, the granules may be filled into capsules.
A typical manufacturing process:
All ingredients as per examples are mixed with active drug(s) in geometric proportion to ensure uniform mixing. The final blend is prepared by adding magnesium stearate to the mixer and mixing. The resultant blend is compressed into tablets of required thickness, hardness on a suitable tablet press using appropriate size tooling.
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Coating is performed in conventional coating pans using hydroxyl propyl methyl cellulose solution prepared with non-aqueous solvents and applying the coating suspension to achieve a suitable film coat. Coating solution contains additional ingredients such as colors, flavours and sugars to impart certain characteristics to the film coat.
Example 8
Anti-inflammatory activity of the atorvastatin and hydroxychloroquine combination
The anti-inflammatory effect of the drugs atorvastatin and hydroxychloroquine were studied
individually and in combination in healthy albino rats (Winster strain) weighing between 150
to 200g obtained from animal house I.P.E.R, Wardha.
Animals were divided in five groups of 6 animals each. The rats were housed in
polypropylene cages, fed a standard diet and water ad-libitum and maintained at 24 to 28°C
temperature and 12hrs day and night cycle. Animals were deprived of food for 12 hrs before
dosing.
Groups of animals
Group 1 :control(0.2 ml water;p.o)
Group 2: AT(0.2ml of 7.14mg/ml of Atorvastatin:p.o)
Group 3: HCQ(0.2ml of 142.85mg/ml of hydroxychloroquine:p.o)
Group 4:AT+HCQ(0.1ml each of above concentration:p.o)
Group 5:AT+HCQ(0.2 ml each of above concentration:p.o)
Dose mentioned above was for rat of 150g. Actual amount was decided on the body weight
basis.
Procedure:
One hour prior to carrageenin administration baseline paw volume (Vo) of each rat of the 5
groups was measured and drugs were administered as per the respective groups. After
administration of inflammatory agent (0.1ml of l%caragenin in 09% NaCl) rat paw volumes
(Vt) were measured at 1,2,4,6 and 9hrs. Data obtained were used to calculate % inflammation
observed at different time points. Also % inhibition of inflammation calculated for each time
point for different treatment. Results were statistically treated for determining significant
level.
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Statistical analysis:
The data is expressed as mean ± SD. The statistical analyses were performed by one way
analysis of variance (ANOVA) followed by Dunnnett's t-test. The/? value less than 0.05 was
considered as statistically significant.
Results:
% inflammation=[(Vt-Vo) of test/Avg.(Vt-Vo) of control x 100]
Whereas Vt is paw volume in a treatment and Vo is baseline paw volume.
Mean and SD of % inflammation by different treatments are shown in table 3 and Mean &
SD of % Inhibition of rat paw edema are shown in table 4.
Table 3: Mean and SD of % Inflammation by different treatments

Treatment/ Time point AT HCQ AT+HCQ1/2 AT+HCQ
Mean SD Mean SD Mean SD Mean SD
lh 65.91 ±6.34 58.17 ±6.43 50.97* ±7.78 46.33* ±6.36
2h 46.68 ±8.88 45.14 ±4.93 48.93 ±7.83 44.23 ±4.49
4 1. 39.95 ±7.34 40.47 ±6.32 40.97 ±7.78 36.34 ±6.36
6h 37.16 ±8.18 34.87 ±2.97 33.92 ±6.01 27.44* ±3.46
9h 36.05 ±6.53 30.29 ±4.43 27.58 ±7.35 20.79* ±5.84
The values are expressed as the Mean ±SD (n=6).
♦Significantly different from AT/HCQ at/? Table 4: Mean & SD of % Inhibition of rat paw edema

Treatment/ Time point AT HCQ AT+HCQ1/2 AT+HCQ
Mean SD Mean SD Mean SD Mean SD
lh 34.08 ±6.34 41.82 ±6.43 49.02 ±7.78 53.66 ±6.36
2h 53.3 ±8.88 54.85 ±4.93 51.06 ±7.83 55.77 ±4.49
4h 60.04 ±7.34 59.52 ±6.32 59.02 ±7.78 63.66 ±6.36
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6h 62.83 ±8.18 65.12 ±2.97 66.07 ±6.01 72.55 ±3.46
9h 63.94 ±6.53 69.70 ±4.43 72.41 ±7.35 79.20 ±5.84
Discussion:
Atorvastatin (AT), a potent lipid lowering drugs also possesses anti-inflammatory activity. Hydroxychloroquine (HCQ) is effective anti-inflammatory as used in the treatment of Rheumatoid arthritis and lupus erythematosus. In the present study anti-inflammatory effect of both AT and HCQ was found significant when compared to control. The results suggests that AT and HCQ when used in combination, there is significant anti-inflammatory activity than both drug used alone. In combination treatment at the half the dose of individual drug the activity found significant at 1 hr (p Conclusions:
In combination, AT and HCQ showed profound increase in anti-inflammatory activity as compared to their individual action. It suggests their additive or synergistic effect in combination
"While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims".
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We claim,
1. Novel fixed dose pharmaceutical composition useful in providing a complete therapy for the treatment of rheumatoid arthritis, atherosclerosis, and systemic lupus erythematosus as well as to provide an alternative option in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from aspirin and clopidogrel are required comprising
a statin;
a disease modifying anti-rheumatic drug (DMARD);
as claimed in our main patent application no. 154/MUM/2003, wherein the improvement comprises, the statin is selected from Atorvastatin, pravastatin, lovastatin, rosuvastatin, and fluvastatin and the said DMARD is hydroxychloroquine, wherein said composition is suitably formulated using pharmaceutical excipients selected from the group consisting of:
a) binders such as lactose, microcrystalline cellulose, sucrose, mannitol, calcium
phosphate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol or
starch;
b) lubricants such as magnesium stearate or other metallic stearates such as calcium stearate or zinc stearate;
c) disintegrant agents such as starch, pregelstarch, sodium starch glycolate, or crosscarmellose sodium;
d) preservatives such as ascorbic acid or butylated hydroxy toluene;
e) glidants such as colloidal silicon dioxide, talc, metallic stearates, calcium silicates; and
f) film coating agents such as cellulose polymer or titanium dioxide.
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2. The novel fixed dose pharmaceutical composition as claimed in clam 1, wherein the amount of said statin is in the range of 5mg to 80mg.
3. The novel fixed dose pharmaceutical composition as claimed in clam 1, wherein the amount of said hydroxychloroquine is in the range of 200 mg to 400mg.
4. The novel fixed dose pharmaceutical compositions as claimed in claims 1 to 3 wherein
the cellulose polymer used is hydroxy propyl methyl cellulose.
5. Novel fixed dose pharmaceutical compositions as substantially described herein with
reference to the foregoing examples 1 to 7.


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Abstract
The present invention discloses improved synergistic fixed dose pharmaceutical compositions comprising a combination of statins with disease modifying antirheumatic agent as claimed in our main application, used in daily therapy for rheumatology. More particularly the invention relates to pharmaceutical compositions comprising statins such as atorvastatin, pravastatin, lovastatin, rosuvastatin, fluvastatin and hydroxychloroquine as the disease modifying antirheumatic agent. The invention is intended to provide a complete therapy for rheumatoid arthritis and lupus patients as well as to provide an alternative option in diabetic patients, patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from Aspirin and Clopidogrel are needed.
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Documents:

1840-mum-2007-abstract.doc

1840-mum-2007-abstract.pdf

1840-MUM-2007-CLAIMS(AMENDED)-(1-3-2013).pdf

1840-MUM-2007-CLAIMS(AMENDED)-(6-12-2012).pdf

1840-MUM-2007-CLAIMS(MARKED COPY)-(1-3-2013).pdf

1840-MUM-2007-CLAIMS(MARKED COPY)-(6-12-2012).pdf

1840-mum-2007-claims.doc

1840-mum-2007-claims.pdf

1840-MUM-2007-CORRESPONDENCE(26-11-2009).pdf

1840-MUM-2007-CORRESPONDENCE(5-10-2007).pdf

1840-mum-2007-correspondence-received.pdf

1840-mum-2007-description (complete).pdf

1840-mum-2007-drawings.pdf

1840-MUM-2007-FORM 1(5-10-2007).pdf

1840-MUM-2007-FORM 18(26-11-2009).pdf

1840-MUM-2007-FORM 2(TITLE PAGE)-(20-9-2007).pdf

1840-mum-2007-form-1.pdf

1840-mum-2007-form-2.doc

1840-mum-2007-form-2.pdf

1840-mum-2007-form-26.pdf

1840-mum-2007-form-3.pdf

1840-MUM-2007-REPLY TO EXAMINATION REPORT(6-12-2012).pdf

1840-MUM-2007-REPLY TO HEARING(1-3-2013).pdf


Patent Number 256350
Indian Patent Application Number 1840/MUM/2007
PG Journal Number 23/2013
Publication Date 07-Jun-2013
Grant Date 05-Jun-2013
Date of Filing 20-Sep-2007
Name of Patentee IPCA LABORATORIES LIMITED
Applicant Address 48, KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (WEST), MUMBAI.
Inventors:
# Inventor's Name Inventor's Address
1 PAREEK, ANIL FLAT NO. M-6/7 BHANUMATI CO-OPERATIVE, HOUSING SOCIETY LTD., BANGUR NAGAR, NEAR POST OFFICE, GOREGAON (WEST), MUMBAI-400 090.
PCT International Classification Number A61K31/366
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA