FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10 and rule 13)
" CHRONOTHERAPEUTIC PHARMACEUTICAL COMPOSITION COMPRISING NON-STEROIDAL ANTI¬INFLAMMATORY DRUGS"


PIRAMAL HEALTHCARE LTD.
an Indian company incorporated under the Companies Act, 1913,having registered office
at
Piramal Healthcare Ltd
Piramal Tower, Ganpatraokadam Marg,
Lower Parel, Mumbai-400013
Maharashtra, India
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION

FIELD OF INVENTION
The present invention relates to chronotherapeutic pharmaceutical composition comprising of atleast one therapeutically effective amount of active ingredient to treat conditions related to arthritis. The present invention further relates to methods of preparing such pharmaceutical compositions. The present invention still further relates to pharmaceutical composition where the active ingredient is made available as per requirement of chronobiology such as to take care of arthritis symptoms like early morning stiffness. The present invention preferably is in tablet dosage form comprising at least one active ingredient of class non-steroidal anti-inflammatory drug (NSAIDs).
BACKGROUND OF THE INVENTION
Oral controlled release has been the most popular drug delivery system for obvious advantages of oral route of drug administration. It ensures sustained action of drug release over a prolonged period of time maintaining plasma concentations in the therapeutic window.
Certain disease conditions demand release of drug after a lag time.The drug should not be released for the first 2 to 6 hours. After this lag time the drug should be released either in pulses or in an extended release manner so as to achieve the desired therapeutic action.
The conditions , which demand such release pattern include :
a)Physiological functions that follow circadian rhythm and cause a rise and fall in
hormones like renin,aldosterone and Cortisol etc.
b)Diseases that display chronopharmaco logical dependence like rheumatoid
arthritis,gastrosophageal reflux disease,bronchial asthma,myocardiaI infarction,angina
pectoris, hypertension etc.
These types of drug delivery systems,which release bioactive agents at a rhythm that ideally matches the biological requirement of a given disease therapy are called

chronotherapeutic drug delivery systems,they include time-controlled and site-specific drug delivery systems.
Researchers have now found that the timing for the taking of a medicine can affect the way the human body responds to the medicine. The science of treating the human body taking into account the natural circadian variation is Chronotherapeutics. Chronotherapeutics relies on the practice of delivering the correct amount of medication to the correct site of action at the most appropriate time period for the particular disease or condition.
The major objective of chronotherapy for indications such as rheumatoid arthritis, gastric acid secretion, asthma and cardiovascular diseases is to deliver the drug in the desired concentrations during the time of greatest need and in lesser concentrations when the need is less. Our circadian rhythm is based on sleep-activity cycle and is influenced by our genetic makeup and thereby affects our bodies' function throughout day and night (24-hour period).
Arthritis is a group of conditions involving damage to the joints of the body. Arthritis is the leading cause of disability in people older than fifty-five years.There are different forms of arthritis; each has a different cause. The most common form of arthritis is osteoarthritis (degenerative joint disease) is a result of trauma to the joint, infection of the joint, or age. Emerging evidence suggests that abnormal anatomy might contribute to the early development of osteoarthritis. Other arthritis forms are rheumatoid arthritis and psoriatic arthritis. Septic arthritis is caused by joint infection.Gouty arthritis is caused by deposition of uric acid crystals in the joint, causing inflammation.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder that most commonly causes inflammation and tissue damage in joints (arthritis) and tendon sheaths, together with anemia. It can also produce diffuse inflammation in the lungs, pericardium, pleura, and the sclera of the eye, and also nodular lesions, most common in subcutaneous tissue under the skin. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility.lt is diagnosed chiefly on symptoms and

signs, but also with blood tests (especially a test called rheumatoid factor) and X-rays. Diagnosis and long-term management are typically performed by a rheumatologist, an expert in the diseases of joints and connective tissues. It is the clinical experience of rheumatologists that RA patients particularly experience joint painjoint swelling,morning stiffness and functional disability in the early morning hours,with respect to arthritis,chronobiological patterns have been observed with artiritis pain.People with osteoarthritis tend to have less pain in the morning and more at night, whereas for people with rheumatoid arthritis the pain usually peaks in the morning and decreases as the days wears on. Past animal studies have shown that joint inflammation in rats fluctuates over a 24 hour period, this observation is supported by patients and physician. Potential drug candidates for treatment of arthritis include NSAIDs and corticosteroids. Preferably the dosages should be timed to ensure that the highest blood levels of the drug coincide with peak pain.For osteoarthritis the optimal time for an NSAID would be around noon or mid afternoon.For rheumatic arthritis the optimal time for an NSAID to be taken is after the evening meal.
It is now considered desirable by those skilled in the art to provide the oral controlled release compositions that is adaptable to deliver the drug(s) of class NSAIDs such that the release rates and drug plasma profiles can be matched to physiological and chronotherapeutic requirements.
US20050276853 assigned to Penwest pharmaceuticals is directed to a chronotherapeutic pharmaceutical formulation comprising a core of active ingredient and a delayed release compression coating comprising a natural or synthetic gum applied onto the surface of core.
US6346268 assigned to Duramed pharmaceuticals is directed to a depot drug formulation including active ingredient and three-component release rate controlling matrix composition. The three components of matrix composition used in the invention are pH dependent gelling polymer as alginate component, an enteric polymer component and a pH independent gelling polymer

US20060099260 assigned to Biokey Inc. is directed to a pharmaceutical composition comprising a core comprising bupropion and, a coating comprising a pharmaceutically acceptable pH independent polymer and a surfactant
Inspite of existing prior arts mentioned above there is still need for an invention that is better in controlling symptoms of arthritis and convenient to manufacture ,is economical in process and which meets the need for chronotherapeutic drug delivery system.
Although the chronotherapeutic drug delivery technology can be used for any of drugs from non-steroidal antiinflammatory class(NSAIDs),for the present invention Naproxen was selected for illustration purpose.
Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs.The chemical names for Naproxen and Naproxen sodium are "(S)-6-methoxy-a-methyl-2-naphthaleneacetic acid" and "(S)-6-methoxy-a-methyl-2-naphthaleneacetic acid, sodium salt", respectively. Naproxen and Naproxen sodium have the following structures, respectively represented by formula I:


Naproxen is a non-steroidal anti-inflammatory drug (NSAID) commonly used for the reduction of moderate to severe pain, fever, inflammation and stiffness caused by conditions such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing

spondylitis, menstrual cramps, tendinitis, bursitis , and the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes.Naproxen has a pH dependent solubility i.e. slightly soluble in cidic pH and freely soluble in alkaline pH.It is BCS(Biopharmaceutic classification system) class II drug(low solubility and high permeability).
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, chronotherapeutic pharmaceutical composition is provided for oral administration, said pharmaceutical composition comprising of coating of active ingredient with a pH independent polymer, the polymer coated particles then blended with swellable and rapidly gelling polymers and compressed into tablets.
In accordance with second embodiment of the present invention, chronotherapeutic pharmaceutical composition is provided for oral administration, said pharmaceutical composition comprising of coating of active ingredient with a pH independent polymer, the polymer coated particles then blended with swellable and rapidly gelling polymers and compressed into tablets and further enterically coated.
In accordance with third embodiment of the present invention, chronotherapeutic pharmaceutical composition is provided for oral administration, said pharmaceutical composition comprising of coating of active ingredient of class non-steroidal anti¬inflammatory preferably Naproxen with a pH independent polymer, the polymer coated particles then blended with swellable and rapidly gelling polymers and compressed into tablets and further enterically coated.
In accordance with fourth embodiment of the present invention, chronotherapeutic pharmaceutical composition is provided for oral administration, said pharmaceutical composition is matrix tablet coated by enteric polymer, such enteric coated matrix tablet can give initial lag time upto 4-6 hours and thereafter controlled drug release of drug upto 24hours.

In accordance with fifth embodiment of the present invention, chronotherapeutic pharmaceutical composition is provided for oral administration, said pharmaceutical composition is enteric coated matrix tablet, such enteric coated matrix tablet can give initial lag time upto 4-6 hours so that substantial portion of the active ingredient in enteric coated delayed release oral pharmaceutical composition is released between 2-3 a.m or between 3-4 a.m and the active ingredient is absorbed from the gastrointestinal tract and thereafter controlled drug release of drug upto 24hours.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed at once a day chronotherapeutic pharmaceutical composition comprising of atleast one active ingredient and method of making the same. The invention described herein is matrix based tablet dosage form. The technology comprises the coating of active ingredient in the powder or granule form with a pH independent polymer in a fluidized bed processor (FBP), the polymer coated particles were then blended with swellable and rapidly gelling polymers followed by compression into tablets. The compressed tablets were coated by using enteric polymer.
The technology provides two approaches i) Initial delayed release i.e. lag time upto 4-6 hours ii) Followed by controlled drug release upto 24 hours.
The term "delayed release" as used herein means the release of active ingredient is delayed for 4-6 hours (lag time) and where drug release should be less than 10% of label claim.
The term "active ingredient" as used herein is from class Non-steroidal anti-inflammatory drug (NSAID)
The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient for example, fillers, diluents, carriers, alkalinizer, plasticizer, anti adherents, glidants, binders, solvents and the like. The excipients that are

useful in preparing a pharmaceutical composition are safe, non-toxic and are acceptable for pharmaceutical use.
The term "diluent" or "filler" as used herein means inert substances used as fillers to create the desired bulk, flow properties. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, powdered cellulose, precipitated calcium carbonate, starch, lactose, glucose and combinations thereof and other such materials known to those skilled in the art.
The term "binder" as used herein means agents used while making granules of the active ingredient by mixing it with diluent/filler. Such compounds include, by way of example and without limitation, polyvinyl pyrrolidone, hydroxypropyl cellulose (HPC), pregelatinized starch, starch, hydroxyl propyl methyl cellulose (HPMC), crospovidone and hydroxy ethyl cellulose (HEC) and combinations thereof and other such materials known to those skilled in the art.
The term "glidant" as used herein means agents used in formulations to improve flow-properties. Such compounds include, by way of example and without limitation, colloidal silicon dioxide, calcium silicate, magnesium silicate, cornstarch, talc, combinations thereof and other such materials known to those skilled in the art.
The term "pH independent polymer" as used herein means polymers which shows similar change throughout all pH range i.e. it doesn't show any specific change in specific pH range. Such compounds include, by way of example and without limitation, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), methylcellulose, guar gum, xanthan gum, gum arabic. hydroxyethyl cellulose and ethyl acrylate and methyl methacrylate copolymer dispersion (Eudragit NE 30 D), combinations thereof and other such materials known to those of ordinary skill in the art.
The term "swellable polymers" as used herein means polymers, which have pronounced affinity due to their chemical structures for aqueous solutions, in which they swell rather

than dissolve. Such compounds include, by way of example and without limitation, polyethylene oxide, cellulose ethers, guar, guar derivatives, locust bean gum, psyllium, gum arabic, gum ghatti, gum karaya, gum tragacanth, carrageenan, agar, alginates, xanthan, scleroglucan, dextran, pectin, starch, chitin and chitosan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), carboxymethylhydroxyethyl cellulose (CMHEC), hydroxypropylhydroxyethyl cellulose (HPHEC), methyl cellulose (MC), methylhydroxypropyl cellulose (MHPC), methylhydroxyethyl cellulose (MHEC), carboxymethylmethyl cellulose (CMMC), hydrophobically modified carboxymethyl cellulose (HMCMC), combinations thereof and other such materials known to those of ordinary skill in the art.
The term "enteric coating polymers" as used herein means polymers, used to define a "pH dependent" coating which will resist dissolution in the acidic medium of the stomach and will dissolve in the environment of the small intestine. Such compounds include, by way of example and without limitation, shellac, methacrylic acid copolymers, (Eudragit® S or L) cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate and polyvinyl acetate phthalate (Opadry® enteric white OY-P-7171), combinations thereof and other such materials known to those of ordinary skill in the art.
Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
The following example is provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention. The examples should not be read as limiting the scope of the present invention.

EXAMPLE I:
The ingredients and the mg per unit dose formula of the composition of these examples are set forth in tables below:
Step I: Development of Naproxen granules using fluidized bed processor (FBP)

Ingredients Mg per tablet
Naproxen 500.0
Dibasic calcium phosphate dihydrate 126.5
Colloidal silicon dioxide 3.5
Polyvinyl pyrrolidone K30 70.0
Demineralised (DM) water q.s.
Procedure:
1. Naproxen, Dibasic calcium phosphate dihydrate and Colloidal silicon dioxide were weighed and passed through #40 mesh American society for testing materials standards (ASTM).
2. The above blend was transferred to fluidized bed processor and mixed well for 2 minutes.
3. Required quantity of polyvinyl pyrrolidone K30 was weighed and added to DM water with continuous stirring to prepare final 25% w/v aqueous solution as binding solution.
4. Mixed blend of step 2 was granulated into fluidized bed processor by using binding solution of step 3.
5. Prepared granules were dried in fluidized bed processor to get 2-3% moisture content.

Step II: Coating of Naproxen granules of Step I by 5% w/w polyacrylates dispersion (Eudragit® NE 30D) using FBP.

Ingredients Mg per tablet
Eudragit® NE 30 D 35.0
Talc 17.5
DMWater q.s
Procedure:
1 .Required quantity of Eudragit NE 30 D was weighed.
2. Required quantity of talc was weighed and sifted through #60 mesh (ASTM).
3. Required quantity of DM water was weighed and the talc from step 2 was added to it under stirring (avoiding foam formation).
4. Once uniform dispersion was obtained, Eudragit® NE 30 D was added slowly to the dispersion of step 3 and mixed for 30 minutes. Final dispersion contains 20 % w/v solid contents.
5.The dispersion was used for coating of Naproxen granules.
6.The granules #60 mesh ASTM passed and #80 mesh ASTM retained were used for
coating with Eudragit® NE 30 D (pH independent polymer).
Step III: Compression of Naproxen chronotherapeutic drug release tablets (500mg) and its enteric coating

Ingredients Mg per tablet
5% w/w Eudragit® NE 30 D coated Naproxen granules 752.5
Dibasic calcium phosphate dihydrate 116.5
Polyethylene oxide 110.0
Sodium alginate 110.0

Magnesium stearate 11.0
Uncoated tablet weight 1100.0
Enteric coating solution
Polyvinyl acetate phthalate
(ft)
(Opadry enteric white OY-P-7171) 66.0
Isopropyl alcohol: methylene chloride (60:40) q.s.
Enteric-coated tablet weight 1166,0
Procedure:
I.Required quantity of 5% w/w Eudragit® NE 30D coated Naproxen granules were
weighed.
2. Granules of step 1 were mixed with #40 mesh ASTM passed dibasic calcium
phosphate dihydrate, polyethylene oxide and sodium alginate.
3.The blend of step 2 was lubricated by magnesium stearate and compressed into tablets.
4.Compressed tablets were then enteric coated with polyvinyl acetate phthalate (Opadry
enteric white OY-P-7171).
The chronotherapeutic pharmaceutical composition of Naproxen was then tested for its dissolution profile under dissolution conditions: USP Type-II, 1000 mL, 75 RPM, 0-2 Hrs. 0.1N HCl & 2-24 Hrs. Phosphate buffer pH 6.8.The dissolution profiles are set forth below in Table 1 and a graphical representation is shown in Figure 1.



Table 1: Dissolution Profile

Time (hrs) % Dissolution
1 0.0
2 0.1
4 8.4
6 18.7
8 31.1
10 44.6
12 57.0
16 78.4
20 94.7
24 104.3

1
" CHRONOTHERAPEUTIC PHARMACEUTICAL COMPOSITION FOR
RHEUMATOID ARTHRITIS"
Piramal Healthcare Ltd.
Percentage drug release profile
120 i-

8 12 16
Time in hours

20

24

Figure I: In- vitro release profile of Example I