FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"CHRONOTHERAPEUTIC DOSAGE FORMS FOR ORAL ADMINISTRATION" "2. APPLICANT(S):
(a) NAME: FDC Limited
(b) NATIONALITY: Indian company incorporated under the Companies
Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is fo be performed.

Technical field:
The present invention relates to oral controlled release pharmaceutical composition and the process for preparation thereof; wherein the said composition releases the medication based on chronotherapy.
Background and prior art:
"Chronotherapeutic" refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. It is based on the observation that there is an interdependent relationship between peak - to - trough rhythmic activity in disease symptoms and risk factors, pharmacologic sensitivity and pharmacokinetics of many drugs. The specific time that patients take their medication is very important as it has significant impact on treatment success. Optimal clinical outcome cannot be achieved if drug plasma concentration is constant. If symptoms of a disease display circadian variation, drug release should be modified over the period of time in accordance with circadian variation. Drug pharmacokinetics can also be time-dependent; therefore, variations both in a disease state and in drug plasma concentration needs to be taken into consideration in developing drug delivery systems intended for the treatment of disease with adequate dose at appropriate time.
Further, the potential benefits of chronotherapeutics have been demonstrated in the management of a number of rhythmic diseases such as allergic rhinitis, rheumatoid arthritis and related disorders, asthma, cancer, cardiovascular diseases and peptic ulcer disease.
Pain management remains an empirical mode of therapeutic strategy in clinics. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed for acute and chronic pain. The major treatment aspect of arthritis and spondylitis is the use of NSAIDs for relieving pain. Even though few NSAIDs are administered twice daily the desired plasma drug concentration at peak incidence time is insufficient to control the symptoms. However, once a day delivery of the said molecules along with anthraquinone as a therapeutic agent offers the solution to the above problem with additional benefits.

Controlled release administration of poorly acid soluble drugs viz., NSAIDs and anthraquinones remains challenging one owing to the poor absorption of drug from stomach, short residential time of drug and/or dosage form in absorption window, especially small intestine, high viscosity of small intestine contents, less possibility of achieving controlled release and low bioavailability.
Various technologies such as time-controlled, pulsed, triggered and programmed drug delivery devices have been developed and extensively studied in recent year for chronopharmaceutical drug delivery.
WO 2009/022821 discloses chronotherapeutically combined pharmaceutical formulation for preventing and treating cardiovascular diseases comprising HMG-CoA reductase inhibitor such as simvastatin and aspirin, wherein the HMG-CoA reductase inhibitor component and the aspirin components are released at different absorption locations or are sequentially released at the same absorption location.
WO 02/072034 discloses a chronotherapeutic pharmaceutical formulation comprising a core containing an active agent and a delayed release compression coating comprising a natural or synthetic gum applied onto the surface of the core.
US2008/0241240 relates to a chronotherapeutic pharmaceutical formulation, comprising a dihydropyridine and a statin as active ingredients, which is designed to control the release of each ingredient of the combined drug in a predetermined rate based on the principle of the so-called chronotherapy and xenobiotics, where drugs are administered to exhibit pharmacological activities at predetermined time intervals.
WO 2008/006216 relates to a chronotherapy tablet comprising a substantially round core having a first end and a second end, the core being comprised of at least two superposed layers of different compositions with an interface between each layer; wherein at least one of said layers comprises a pharmacologically active anti-inflammatory composition and at least one of said layers comprises a pharmacologically active cytoprotective composition.

WO 2007/132293 discloses a delayed onset chronotherapeutic formulations of central nervous system (CNS) drugs wherein the formulation comprises of at least one CNS drug or pharmaceutically acceptable salt and is coated with at least one polymer chosen from water-soluble polymers, water-insoluble polymers and combinations thereof.
WO 2008/044862 relates to a functional combination preparation for the treatment of cardiovascular disease, which comprises (1) an immediate-release granule comprising an ARB (angiotensin-2 receptor blocker) as active ingredients; (2) a delayed-immediate-release granule or coated tablet comprising a dihydropyridine-based calcium channel blocker as active ingredients and a release- controlling material selected from the group consisting of water-soluble polymer, water-insoluble polymer, enteric polymer and a mixture thereof.
WO 2009/153635 discloses a pharmaceutical dosage form for the phase-controlled and chronotherapeutic delivery of one or several pharmaceutical active ingredients. The dosage form has a carrier platform which is a polymer having known biodegradable characteristics. The platform may include a pharmaceutically active ingredient which is released over a predetermined period of time as the platform polymer degrades.
US 6610750 discloses a method of treating osteoarthritis by administering an effective amount of rhein or a rhein derivative, preferably diacerein, either alone or in combination with at least one member selected from the group consisting of analgesics, antipyretics, corticosteroids, anti-inflammatory agents, cyclooxygenase-2 inhibitors and inflammatory cytokine inhibitors to a subject in need of such treatment.
WO 2003/000246 claims a combination of rhein and derivatives thereof with at least one other agent selected from a non-steroidal anti-inflammatory drug, a narcotic analgesic, a local anaesthetic, an NMDA antagonist, a neuroleptic, an anticonvulsant, an antispasmodic, an antidepressant and a muscle relaxant for use in pain therapy, wherein the pain is associated with a disease involving tissue remodelling. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. The time delay material employed is for example glyceryl monostearate or glyceryl distearate.

KR200900226I2 discloses a sustained-release aceclofenac composition to maintain effective blood concentration of the aceclofenac composition for 24 hours and simplify a production process without a floating layer coating machine. A sustained-release aceclofenac composition comprises a sustained-release mixture of aceclofenac, polyvinyl acetate and polyvinylpyrrolidone, binder and lubricant. The sustained-release mixture of polyvinylacetate and polyvinylpyrrolidone additionally includes a surfactant, the binder indicated is polyvinylpyrrolidone.
International Journal of Medicine and Medical Sciences Vol.1 (9) pp.375-382, Sep 2009 discusses the development of matrix tablets for oral controlled release of aceclofenac using various viscosities of hydrophilic polymer HPMC in two different proportions, hydrophobic polymer ethyl cellulose and Guar gum prepared by wet granulation method.
Article in Pharmaceutical Development and Technology, Vol. 15 (2), pp 139-153, March-April 2010, describes lornoxicam sustained release matrix tablets that provide complete drug release that starts in the stomach to rapidly alleviate the painful symptoms and continues in the intestine to maintain protracted analgesic effect as well as meets the reported sustained release specifications. The said composition is prepared by direct compression of hydroxyl propyl methylcellulose matrix tablets to sustain lornoxicam release. Basic pH-modifiers, either sodium bicarbonate or magnesium oxide, were incorporated into these matrix tablets to create basic micro environmental pH inside the tablets favorable to drug release in acidic conditions.
None of the above mentioned prior art discloses chronotherapeutic system comprising of the active ingredient(s), acid insoluble polymer in combination with a pH independent polymer and other pharmaceutical^ acceptable excipients in order to achieve a better chronotherapeutic profile of poorly acid soluble drugs.
The drug release profile of the dosage form in the present invention is modulated in such a way that the dosage form releases 10-30% of the drug in 1 hr. This offers low drug release in stomach which prevents the super saturation and re-crystallization of drug in stomach. The present invention describes hydrophilic matrix comprising of acid insoluble

polymer in combination with a pH independent polymer, wherein solubilization of the acid insoluble polymer at intestinal pH offers faster dissolution of the drug present in the matrix, however retards the dissolved drug release from the matrix to provide better controlled release profile and predictable pharmacokinetics. In the present invention, due to pH independent polymer the high molecular weight hydrophilic polymers erode rather than swelling in distal part of intestine because of low volume of fluid available for swelling. Erosion of polymer granules generates high surface area for solubilization and hence increases the rate of drug dissolution. However, viscosity of intestinal content acts as a rate-controlling factor for drug absorption even with high rate of drug release from matrix. Controlled rate of absorption of drug in distal part of GIT due to high viscosity of intestinal content provides sustained plasma drug concentration.
The present invention offers chronotherapeutic advantages by slow drug release at the initial hours that leads to suboptimal plasma drug concentration at the time when the body doesn't require drug for clinical benefits. Whereas the drug out put from the formulation is optimal thus provides plasma drug concentration with in the therapeutic window, when body requires the drug. The drug release in intestine is controlled by the addition of acid insoluble polymer, which protects the drug from crystallization in stomach and moreover, increase the surface area of drug by its high solubility in intestinal pH.
Object of the invention:
The main object of the present invention is to design a chronotherapeutic system for oral controlled release wherein the active ingredient(s) is embedded in a hydrophilic matrix consisting of acid insoluble polymer(s) in combination with pH independent polymer(s) and other pharmaceutically acceptable excipients.
Another object of the present invention is to deliver poorly acid soluble drugs from the therapeutic categories including non-steroidal anti-inflammatory agents (NSAID), anthraquinone derivatives, cardiovascular drugs, neurotherapeutic agents, chemotherapeutic agents and drugs acting on endocrine system either alone or in combination.

Yet another object of the present invention is to improve the mechanism for drug release in accordance with chronophysiological requirements.
Further object of the present invention is to develop chronotherapeutic dosage form for the treatment of pain associated chronic diseases.
Summary of the invention:
In accordance with the above objectives, the present invention provides a novel chronotherapeutic dosage form which consists of controlled release oral pharmaceutical composition comprising poorly acid soluble drug(s) and hydrophilic matrix system, wherein hydrophilic matrix system comprises acid insoluble polymer(s) in combination with pH independent polymer(s) and other pharmaceutically acceptable excipients. The poorly acid soluble drugs and its pharmaceutically acceptable salts are selected from therapeutic categories like non-steroidal anti-inflammatory drugs (NSAIDs), anthraquinone derivatives, cardiovascular drugs, neurotherapeutic agents, chemotherapeutic agents and drugs acting on endocrine system either alone or in combination. The present invention further describes a process of manufacturing the said chronotherapeutic dosage form.
Detailed description of the invention:
The present invention relates to chronotherapeutic system which consists of oral controlled release pharmaceutical formulation comprising poorly acid soluble drug(s) and acid insoluble polymer(s) in combination with pH independent poIymer(s) in a hydrophilic matrix system and other pharmaceutically acceptable excipients.
In a preferred embodiment, chronotherapeutic composition of the present invention comprises of:
(a) Active pharmaceutical ingredient (s)
(b) Acid insoluble polymer (s)
(c) pH independent polymer (s)
(d) other pharmaceutically acceptable excipients

for effective release of the drug from the matrix at constant rate and at the desired time.
In an embodiment, the active ingredient in the formulation of the present invention is selected from therapeutic categories like non-steroidal anti-inflammatory drugs (NSAIDs), anthraquinone derivatives, cardiovascular drugs, neurotherapeutic agents, chemotherapeutic agents and drugs acting on endocrine system either alone or in combination. The therapeutically effective dosage amount of this drug ranges from 5-80% wAv of dosage form.
In another preferred embodiment, the active drug substances suitable for use in compositions according to the present invention include poorly acid soluble substances such as NSAID either alone or in combination with anthraquinone such as Diacerein.
NSAID are selected from the group consists of salicylic acid derivatives such as aspirin, sodium salicylate and diflunisal, acetic acid derivatives such a s ketorolac, indomethacin, tolmetin, nabumetone, sulindac and etodolac, phenyl acetic acid derivatives such as aceclofenac, diclofenac and lumiracoxib, propionic acid derivatives such as flurbiprofen, ketoprofen, naproxen and ibuprofen, fenamic acid derivatives such as meclofenamates, diarylheterocylics such as celecoxib, valdecoxib abd etoricoxib, enloic acid derivatives such as piroxicam, meloxicam and Iornoxicam other categories such as acetaminophen and naproxen.
In the preferred embodiment, the following NSAID's are employed such as aspirin, ketoralac, indomethacin, sulindac, etodolac, diclofenac, aceclofenac, flurbiprofen, ketoprofen, naproxen, ibuprofen, meclofenamate, celecoxib, etoricoxib, piroxicam, Iornoxicam and acetaminophen.
The polymer system of the present invention comprises an acid insoluble polymer and pH independent polymer in a hydrophilic matrix system. Acid insoluble polymers are used to increase the matrix integrity by forming gel network. Moreover, it prevents the sudden drug release and dose dumping. Acid insoluble polymers are also used to increase the lag time of the formulation and hence delay the Cmax (maximum plasma drug concentration)

which is correlated with chronopharmacological benefits. pH independent hydrophilic polymers are employed to control the drug release in distal part of GIT such as small intestine and colon. The higher extent of solubilization of acid insoluble polymer in distal part of GIT may fail to control the drug release and hence pH independent polymers are incorporated to build the diffusion layer thickness and hence retard the drug release in the small intestine.
Accordingly, in an embodiment, the acid insoluble polymer of the present invention is selected from but not limited to a group comprising methacrylic acid polymers, acrylic acid polymers, hydroxylpropylmethylcellulose acetate, hydroxypropylmethylcellulose phthalate, hydroxypropylethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, cellulose acetate propionate, alginates or mixtures thereof ranging from 5-70% of dosage form.
Primarily, pH independent polymers are incorporated in the formulation to provide pH independent release of drug from the formulation of water soluble drugs. In addition, pH independent polymers provide controlled release of drug in stomach, whereas the controlled mode of drug release will be achieved in distal part of gastrointestinal tract due to high viscosity of diffusion layer of pH independent matrix system, erosion of pH dependent polymer and high solubility of such drugs in alkaline pH.
pH independent gelling polymers are selected from the group consisting of but not limited
to cellulose derivatives, chitosan derivatives, natural gums and polymethacrylates.
Cellulose derivatives are selected from the group consisting of hydroxypropyl Cellulose,
hydroxypropylethylcellulose, hydroxyethylcellulose, hypromellose,
hydroxymethylcellulose. The pH independent polymer in the formulation ranges from 4 % to 90 % w/w.
The other pharmaceutical excipients in the present invention may include but not limited to diluent (s), lubricant(s), glidant (s), opacifying agents, antioxidants, stabilizers and colorant.

The diluent is selected from the group consisting of but not limited to cellulose derivatives, sugars, inorganic phosphates preferably microcrystalline cellulose, lactose, mannitol and dibasic calcium phosphate.
The lubricant is selected from the group consisting of but not limited to magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitosteartae, stearic acid, talc, zinc stearate, magnesium lauryl sulfate and colloidal silicon dioxide.
Glidants are added to improve the flow properties of the formulation and improve the accuracy of dosing. Glidant is selected from the group consisting of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
In yet another embodiment, the oral controlled release delivery system for poorly acid soluble drugs and their pharmaceutically acceptable salts thereof are prepared by direct compression or granulation method in a hydrophilic matrix.
The controlled release composition of the present invention may be formulated as oral dosage forms such as tablets, capsules and the like.
The present invention is exemplified by the following examples, which are provided for illustration only and should not be construed to limit the scope of the invention. Example 1

Sr. No Ingredient mg/tablet
1 Aceclofenac 200
2 HPMC K4M 50
3 Microcrystalline cellulose 100
4 EudragitL100-55 50
5 Magnesium stearate 3
6 Aerosil 2
7 Isopropyl alcohol q.s.
8 Water q.s.

The manufacturing process comprises the following steps:
Weighing and sieving ingredients (1-4) through 30 mesh;
Blending the ingredients of step I in octagonal blender for 30 min;
Granulating the blended material of step 2 with isopropyl alcohol: Water in the ratio of
(70:30);
Drying granules of step 3 and reducing the size of the granules by passing the same
through 30 mesh;
Blending the granules of step 4 with aerosil and magnesium stearate and
Punching the lubricated granules using 10 mm standard concave punches or encapsulated
into the capsule.
Example 2

Sr. No Ingredient mg/ tablet
1 Diacerein 100
2 HPMCK15M 40
3 Lactose 60
4 Cellulose acetate phthalate 30
5 Magnesium stearate 3
6 Aerosil 2
The manufacturing process comprises the following steps:
Weighing and sieving ingredients (1-4) through 30 mesh;
Blending the ingredients of step 1 in octagonal blender for 30 min;
Blend with aerosil and magnesium stearate and
Punching the lubricated granules using 9 mm standard concave punches.
Example 3

Sr. No Ingredient mg/ tablet
1 Lornoxicam 16

2 HPMC K4M 24
3 MicrocrystaJline cellulose 100
4 Hydroxypropy 1 methy Ice llu lose phthalate 30
5 Calcium stearate 3
6 Aerosil 2
7 Isopropyl alcohol q.s.
8 Water q.s. '
The manufacturing process comprises the following steps:
Weighing and sieving ingredients (1-4) through 30 mesh;
Blending the ingredients of step 1 in octagonal blender for 30 min;
Granulating the blended material of step 2 with isopropyl alcohol: Water in the ratio of
(70:30);
Drying granules of step 3 and reducing the size of the granules by passing the same
through 30 mesh;
Blending the granules of step 4 with aerosil and calcium stearate and
Punching the lubricated granules using 8 mm standard concave punches.
Example 4

Sr.
No Ingredient mg/ tablet
1 Aceclofenac 200
2 Diacerein 100
3 HPMCK100M 50
4 Polyvinyl acetate phthalate 100
5 Lactose 90
6 Magnesium stearate 7
7 Aerosil 3
8 Isopropyl alcohol q.s.
9 Water q.s.

The manufacturing process comprises the following steps:
Weighing and sieving ingredients (1-5) through 30 mesh;
Blending the ingredients of step \ in octagonal blender for 30 min;
Granulating the blended material of step 2 with isopropyl alcohol: Water in the ratio of
(90:10);
Drying granules of step 3 and reducing the size of the granules by passing the same
through 30 mesh;
Blending the granules of step 4 with aerosil and magnesium stearate and
Punching the lubricated granules using 12 mm standard concave punches.
Dissolution data:
Dissolution media: pH 6.8 phosphate buffer

Time (hr) % Aceclofenac dissolved
1 26
2 56
4 72
8 84
12 92
Example 5

Sr.
No Ingredient mg/ tablet
1 Lornoxicam 16
2 Diacerein 100
3 HPMCK15M 50
4 Eudragit 100
5 Microcrystalline cellulose 84
6 Magnesium stearate 7
7 Aerosil 3
8 Water q.s

The manufacturing process comprises the following steps:
Weighing and sieving ingredients (1-5) through 30 mesh;
Blending the ingredients of step 1 in octagonal blender for 30 min;
Granulating the blended material of step 2 with water;
Drying granules of step 3 and reducing the size of the granules by passing the same
through 30 mesh;
Blending the granules of step 4 with aerosil and magnesium stearate and
Punching the lubricated granules using 10 mm standard concave punches.

We claim
1. A chronotherapeutic drug delivery system consists of oral controlled release pharmaceutical formulation comprising poorly acid soluble drug(s) and acid insoluble polymer(s) in combination with pH independent poIymer(s) in a hydrophilic matrix system and other pharmaceutical ly acceptable excipients.
2. The pharmaceutical formulation as claimed in claim 1, wherein the poorly acid soluble drug(s) are selected from the therapeutic categories including nonsteroidal anti-inflammatory agents (NSAID), anthraquinone derivatives, cardiovascular drugs, neurotherapeutic agents, chemotherapeutic agents and drugs acting on endocrine system, present in an amount of 5-80% w/w of dosage form.
3. ,The pharmaceutical formulation as claimed in claim 2, wherein, the poorly acid soluble drug(s) are NSAID either alone or in combination with anthraquinone such as Diacerein.
4. The pharmaceutical formulation as claimed in claim 3, wherein the NSAID are selected from the group consisting of salicylic acid derivatives such as aspirin, sodium salicylate and diflunisal, acetic acid derivatives such as ketorolac, indomethacin, tolmetin, nabumetone, sulindac and etodolac, phenyl acetic acid derivatives such as aceclofenac, diclofenac and lumiracoxib, propionic acid derivatives such as flurbiprofen, ketoprofen, naproxen and ibuprofen, fenamic acid derivatives such as meclofenamates, diarylheterocylics such as celecoxib, valdecoxib and etoricoxib, enloic acid derivatives such as piroxicam, meloxicam and lornoxicam, other categories such as acetaminophen and naproxen.
5. The pharmaceutical composition as claimed in claim 4, wherein the NSAID are selected from the group consisting of aspirin, ketoralac, indomethacin, sulindac, eodolac, diclofenac, aceclofenac, flurbiprofen, ketoprofen, naproxen, ibuprofen, meclofenamate, celecoxib, etoricoxib, piroxicam, lornoxicam and acetaminophen.
6. The pharmaceutical formulation as claimed in claim 1, wherein the acid insoluble polymer is selected from the group consisting of methacrylic acid polymers,

acrylic acid polymers, hydroxylpropylmethylcellulose acetate,
hydroxypropylmethylcellulose phthalate, hydroxypropylethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, cellulose acetate propionate, alginates or mixtures thereof ranging from 5 % to 70 % of dosage form.
7. The pharmaceutical formulation as claimed in claim I, wherein the pH independent gelling polymer(s) are selected from the group comprising of cellulose derivatives, chitosan derivatives, natural gums and polymethacrylates.
8. The pharmaceutical formulation as claimed in claim 7, wherein the cellulose derivatives are selected from the group consisting of hydroxypropyl cellulose, hydroxypropylethylcellulose, hydroxyethylcellulose, hypromellose, hydroxymethyIcellulose ranging from 4 % to 90 % w/w.
9. The pharmaceutical formulation as claimed in claim 1, wherein the pharmaceutical^ acceptable excipients are selected from diluent(s), lubricant(s), glidant(s), opacifying agents, antioxidants, stabilizers and colorant.