WO2023002338A1

WO2023002338A1 - Compositions, methods of making and using same for the delivery of ulcerogenic drugs thereof

Info

Publication number: WO2023002338A1
Application number: PCT/IB2022/056581
Authority: WO
Inventors: Mahesh Kandula
Original assignee: Avaca Pharma Private Limited
Priority date: 2021-07-23
Filing date: 2022-07-18
Publication date: 2023-01-26

Abstract

The invention relates to a modified release formulation or dosage forms of pharmaceutical compositions using a rate controlling agents selected from compounds of formula I. The composition may further include one or more other pharmaceutical excipients. The release of active agent from the composition is dependent on the pH. The composition is suitable for the safe delivery of active agents which are known to cause mucosal damages and gastrointestinal ulcers. The formulation compositions are effective in reducing the gastrointestinal side effects of NSAIDs or COX-2 inhibitors by retarding the release in acidic conditions.

Description

COMPOSITIONS, METHODS OF MAKING AND USING SAME FOR THE DELIVERY OF ULCEROGENIC DRUGS THEREOF

FIELD OF THE INVENTION

[0001] The present invention relates to pharmaceutical compositions to deliver therapeutic drugs known to cause mucosal or gastrointestinal damage in humans. More particularly, it relates to a release modifying formulations of pharmaceutical compositions which can minimize or reduce gastric ulcerogenicity of non-steroidal anti-inflammatory drugs (NSAIDs) and COX- 2 inhibitors.

BACKGROUND OF THE INVENTION

[0002] Oral ulceration is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers in oral cavity and induce traumatic, infective, aphthous, ulceration related to dermatoses, drug-induced ulceration as a manifestation of systemic disease, and ulceration due to malignancy, and not only oral ulcers but also gastrointestinal ulcers as well.

[0003] Several studies have evaluated the use of drugs that induce the formation of ulcers, including medications such as anti-neoplastic agents (e.g. cytotoxic drugs), anticholinergic bronchodilators, hypoglycemic agents, anti- septic’s, platelet aggregation inhibitors, corticosteroids, vasodilators, b-blockers , antibiotics, anti-rheumatic drugs (e.g. NSAIDs), cardiovascular drugs (e.g. ACE2i and ARB2), tranquilizers , sedatives, gastrointestinal drugs, anti-psychotic agents (e.g. tricyclic antidepressants, SSRIs), anti-retroviral (e.g. Interferons), and immunosuppressants.

[0004] Aspirin is the most widely used NSAID drug in medicine for a variety of indications. The percentage of usage of aspirin is more in elderly population. Aspirin, often used as an analgesic, anti-pyretic and non-steroidal anti-inflammatory drug (NSAID), is able to have an anti-platelet effect by inhibiting the COX activity in the platelet to prevent the production of thromboxane A2 which acts to bind platelets together during coagulation as well as cause vasoconstriction and bronchoconstriction. Aspirin is used as anti-inflammatory agent, it is observed to increase bleeding time, and as an antithrombotic agent. Low-dose aspirin regimens (> 30 mg/day) is reported to effectively suppress platelet aggregation without affecting important endothelial cell functions. While, for inhibition of inflammatory cell function higher, more frequent dosing of aspirin is required. The use of a low-dose aspirin regimen as an antithrombotic measure has become increasingly common for primary and secondary cardiovascular disease (CVD) prevention. Patients with high risk of vascular disease, antiplatelet therapy has been shown to reduce vascular events. Elderly patients are at relatively high risk for the development of vascular disease and might also be expected to derive substantial benefit from regular aspirin administration. Evidence suggests that aspirin may reduce overall cancer incidence and mortality in colorectal, esophageal, and prostate, breast, and lung cancer.

[0005] The common drawback of continuous use of aspirin is the risk of major gastrointestinal ulcers and bleeding, and more rarely, reported side effect is intracranial bleeding, that can occur at any dose. The mortality rates from gastrointestinal complications have continued to rise in aspirin users. Other reported dose-related side effects include tinnitus, hypersensitivity, hypertension, gastrointestinal or renal toxicity and others. ASA being a weakly acidic drug when administered remains unionized in the stomach and some of the drug enter the gastric mucosal cell by passive diffusion and where it is ionized and trapped, resulting in gastro- toxicity. Further, it is reported that inhibition of COX-1 by ASA in stomach inhibits the gastro- protective effects of PGE2 and PGI2. This predisposes the drug users to gastrointestinal complication such as ulceration and bleeding. Thus, it is important to develop a composition which minimize its gastro-toxicity while simultaneously increasing its bioavailability. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

[0006] The degradation of aspirin in presence of water leads to formation of free salicylic acid (FSA). The solid formulations of aspirin when administered orally is absorbed in the gastric mucosa and liver, to be rapidly hydrolyzed in the acidic environment of the stomach. The hydrolyzed products FSA are the cause of common side effects associated with use of aspirin. Enteric coating of aspirin tablets is undertaken in the art to prevent such side effects. Although some enteric-coated formulations of aspirin are advertised as being "gentle to the stomach". Enteric coating is designed to ensure the dosage form only fully dissolves upon reaching the small intestine, potentially reducing stomach irritation. However, there is also some evidence that the coating reduces absorption in some people and enteric coating did not seem to reduce GI risk. Combination of aspirin with other NSAIDs has also been shown to further increase such side effects. Buffering is the other method used to try to mitigate the problem of gastrointestinal bleeding. Buffering agents in the buffered aspirin, are intended to work by preventing the aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed.

[0007] The commercially available sustained release formulation consists of micro- encapsulated drug which may be presented as capsules or tablets. The art broadly discloses the concept of coating granules with a solution of sustained release material and subsequently compressing the coated granules into tablets. These sustained release formulations also do not solve the problem.

[0008] Oral ulcers are frequent lesions of the oral mucosa. Generally, they are circumscribed round or elliptical lesions surrounded by an erythematous halo and covered with an inflammatory exudate in their central portion and are accompanied by painful symptoms. Oral ulcers affect approximately 20% of the population, especially adolescents and young adults. Where, peptic ulcers a loss of tissues lining the lower esophagus, stomach, or duodenum and ulcerative colitis where it affects the innermost lining large intestine (colon) and rectum.

[0009] The clinical manifestations of adverse reactions to drugs depend on the dose and type of medication, as well as on individual differences related to the patient. These reactions might be rapid or persist for a number of days after the use of the drug. According to the literature and to clinical practice, in most drug-induced reactions improvement of clinical symptoms occurs after dose reduction or interruption of the medication. However, severe reactions require rapid withdrawal of the drug or its replacement.

[0010] NSAIDs with cyclooxygenase inhibitory effect exhibits considerable selectivity with their anti-inflammatory/analgesic action and their GI toxicity. Though, from a therapeutic contemplation, there are still several unanswered and unclear issues with these drugs such as: the pharmacologic classification of the COX-2 selectivity; therapeutic value as antirheumatic/analgesic drugs; potential toxicity in patients at risk for the development of ulcer- related complications or patients with inflammatory bowel disease and potential renal toxicity. [0011] The present invention provides a pharmaceutical composition comprising compound of the invention in combination with one or more pharmaceutically active agents administered to patient in need that enable efficient treatment to even patients susceptible to ulcers induced by use of certain medications and the associated side effects.

SUMMARY OF THE INVENTION

[0012] Use of NSAIDs or selective COX-2 inhibitors frequently damages the mucosal lining of the gastrointestinal tract leading to various kind of mucosal dysfunctions resulting in ulceration, bleeding, microbial infections, inflammation of the mucosal lining and associated tissues. This results in many patients withdrawing from the treatment regime by discontinuing the medications and resulting in flaring up of the medical condition for which the patient is being treated.

[0013] The present invention discloses formula I and the compounds of formula I, which can be used as excipients or rate controlling agent in pharmaceutical formulations. Particularly to modify the release profile of the pharmaceutically active agents for achieving a desired therapeutic objective or better patient compliance.

[0014] In certain embodiments, the present invention relates to the compounds of formula I thereof:

FORMULA I wherein,

Ri, R2, R3 independently represents

, capric acid (00:0), lauric acid (02:0), monoglycerides [MG], monocaprin (MG 00:0), glycerol monolaurate (MG 02:0), oleic acid (08:1), elaidic acid (trans-C18:l), linoleic acid (08:2), linolenic acid (08:3), monocaprylate, monooleate, myristoleic acid, glycerol monocaprylate, C8:0, 00:0, 02:0, 04:0, 06:0, 08:0, 08:1, trans-C18:l, 08:2, 08:3, C6:0, C8:0, 00:0, 02:0, 04:0, 06:0, 08:0, 04:1, 06:1, 08:1, trans-C18:l, 08:2, trans-C18:2, 08:3, C20:4, [MGs] 00:0, 02:0, 01:0, 02:0, 03:0, [MGs] 01:0, 02:0, 03:0, C20:4, C8:0, 00:0, 02:0, 04:0, 06:1, 08:1, [MGs]

C8:0, 00:0, 02:0, 04:0, 06:1, or 08:1; within the proviso,

C x:y is defined such that x is the number of carbons in the primary alkyl chain and y is the number of degrees of unsaturation; within the proviso, n = 0 to 80.

[0015] In certain embodiment, the compounds of formula I are dilauryl glyceryl fumarate (DGLF), dilauryl glyceryl succinate (DGLS), dicapryl glyceryl fumarate (DGCF), dicapryl glyceryl succinate (DGCS), dilauryl glyceryl caprylate (DGLC) and others.

[0016] In some embodiments, pharmaceutically active agents is selected from a group of drugs which are commonly known to induce ulcers and other mucosal disorders, GI irritation, GI bleeding, toxicity and others as defined in this application in the patients using them.

[0017] In an embodiment, pharmaceutical composition of present invention is a modified release dosage form/composition. In certain embodiments, the pharmaceutical composition of the present invention is a delayed release composition or an extended-release composition or a controlled release composition.

[0018] In an embodiment, pharmaceutical composition of present invention provides suitable release profile in the gastrointestinal tract without deterioration of bioavailability. [0019] In some embodiments, the release of the active agent from the modified release composition is pH dependent. In another embodiment, pharmaceutical composition of present invention retards drug release from the dosage form to less than 30% in acidic pH such as stomach. In certain embodiments, pharmaceutical composition of present invention retards drug release to less than 20% in acidic pH.

[0020] In another embodiment, pharmaceutical composition of present invention retards drug release to less than 30% in acidic pH such as stomach. In certain embodiments, pharmaceutical composition of present invention retards drug release to less than 20% in acidic pH of 1.0 to

2.0.

[0021] In another embodiment, the pharmaceutical composition of present invention allows NLT 80% release of the drug or active ingredient at a pH 6.0 to 7.2.

[0022] In another embodiment, the pharmaceutical composition of present invention allows NLT 80% release of the drug or active ingredient at a pH 6.0 to 7.4.

[0023] In another embodiment, the pharmaceutical composition of present invention allows NLT 80% release or above of the drug or active ingredient at a pH 6.0 to 7.2.

[0024] In another embodiment, the pharmaceutical composition of present invention allows NLT 80% release of the drug or active ingredient at a pH 6.0 to 7.4.

[0025] In certain embodiments, pharmaceutically active agents known to cause mucosal or gastrointestinal damage is non-steroidal anti-inflammatory drugs (NSAIDs) or selective COX- 2 inhibitors. These medicines are widely used to relieve pain, reduce inflammation, and as antipyretics. Whereas, aspirin is widely used for the management of cardiovascular disease risk and stroke risk patients as a blood thinning agent.

[0026] In another embodiment, non-limiting examples of NSAIDs and selective COX-2 inhibitors includes such as acetylsalicylic acids (aspirin), diclofenac, difhmisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, celecoxib, ketorolac, mefenamic acid, meloxicam, celecoxib, S -methyl N,N-diethylthiolcarbamate sulfoxide, COX- 2 inhibitors, nabumetone, naproxen, oxaprozin, sulindac sulfide, piroxicam, sulindac, and tolmetin. [0027] The compounds of formula I is used for preparing the pharmaceutical composition of drugs to minimize the release at pH range of 1.0 to 3.0 as well as to slow the degradation of drugs/actives when administered orally.

[0028] The compound of formula I reduces or slows the dissolution or disintegration of the dosage form in the pH 1.0 to 3.0 and may protect gastric mucosa from the irritating effects of the active ingredient/active agent/drug release such as NSAIDs or COX-2 inhibitors.

[0029] In some embodiments, the present invention discloses a modified release pharmaceutical composition using compound of formula I and one or more pharmaceutically active agent NSAID or COX-2 inhibitor known to cause mucosal or gastrointestinal damage along with one or more other pharmaceutically acceptable excipients.

[0030] In some embodiments, the present invention discloses a modified release pharmaceutical composition formulated with the compound of formula I for reducing or minimizing GI irritation, ulceration and mucosal damages and associated complications which are induced by NSAIDs and COX-2 inhibitors classes of medications as described in the instant invention.

[0031] In other embodiment, compound of formula I is used in the preparation of non-enteric coated oral tablet having limited drug release in acid environment (stomach).

[0032] In an embodiment, the compound of formula I is a glycol conjugated di-fatty acid mono- fumarate or glycol conjugated di-fatty acid mono -succinate.

[0033] In an embodiment, the amount of compound of formula I sufficient to reduce the etiological effect of the NSAIDs can range from about 5 mg to 800 mg or preferably about 5 mg to 400 mg or more preferably about 20 mg to 800 mg.

[0034] In an embodiment, the pharmaceutical composition may include other pharmaceutically acceptable agents such as glyceryl behenate, lecithin or lipoid or a combination in an amount range from 10 mg to 100 mg per unit dosage form.

[0035] In an embodiment, the pharmaceutical composition may include one or more excipients selected from an rate controlling agent, a compound of formula I, a binder, a disintegrant, a lubricant, a solubilizer, a stabilizing agent, a diluent and a granulating solvent or a combination thereof. [0036] In an embodiment, the modified release dosage form is orally ingestible.

[0037] In an embodiment, the modified release dosage form is in the form of a tablet, capsule, pellets, mini-tablets, liquid filled, granules or mixtures thereof.

[0038] In an embodiment the modified release dosage form can be an immediate release, controlled release, sustained release, delayed release, extended release, pulsatile release, pH mediated and targeted release formulations thereof.

[0039] In an embodiment, the modified release dosage containing a compound of formula I can be formulated to an immediate release, controlled release, sustained release, delayed release, extended release, pulsatile release, pH mediated and targeted release formulations thereof. In an embodiment, the modified release dosage containing two or more compounds of formula I can be formulated to an immediate release, controlled release, sustained release, delayed release, extended release, pulsatile release, pH mediated and targeted release formulations thereof.

[0040] The present invention relates to compounds of formula I used as modified release agent for formulation of for drugs commonly known to induce ulcers and other mucosal disorders. The compounds of the present invention can be safely used in oral delivery of nutrients and/or pharmaceuticals, with improved ulcer activity index (U.I), and more particularly for protecting the mucosal tissue from damages caused by use of certain class of medications. For repair and regeneration of damaged or dysfunctional mucosal tissue in the oral cavity and gastrointestinal tract. Particularly, for reducing or minimizing medication induced oral reactions such as ulcers, aphthous stomatitis, burning mouth syndrome (glossitis, nonspecific ulceration and mucositis), vesico-bullous lesions, xerostomia, swelling, oral thrush, stomatitis, halitosis, sialoeehoea and hemorrhage and also GI ulcers such as stomach ulcers, duodenal ulcers and ulcerative colitis and the restoration of the physiological structure and function to the mucosal tissue.

[0041] In another aspect, the compounds of formula I can be used as multifunctional excipient in formulating various dosages forms which can be administered to the patient by convenient route such as oral, nasal, local, dermal, vaginal, rectal, patches (mucosal, buccal, dermal), injections, self-injectable or parenteral administration and others known in the art. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0042] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0043] It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” or “an therapeutic agent” refers not only to a single active agent but also to a combination of two or more different active agents, “a dosage form” refers to a combination of dosage forms as well as to a single dosage form, and the like.

[0044] The term “pharmaceutically acceptable” means the material incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. “Pharmacologically active” (or simply “active”) as in a “pharmacologically active” derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. The term “pharmaceutically acceptable salts” include acid addition salts, mixtures, which are formed with inorganic and organic acids. The excipient allows the pharmaceutically active ingredient or medicament to be manufactured into a pharmaceutical formulation or a galenic formulation which provides the necessary bioavailability of the medicament to the patient upon the administration of the pharmaceutical composition. The bioavailability of a given dosage form is dependent on process variables and the interrelationship between the various excipients and the active ingredient. [0045] The term “pharmaceutically active agent” or “therapeutic agent” or “pharmaceutically active ingredient”, “medicament”, “medications”, “drug” encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, solvated, hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound. Pharmaceutically active agent are mainly those agents which are known to cause mucosal or gastrointestinal damage.

[0046] The term “combinatorial therapy" or "combined treatment" or "in combination" as used herein denotes any form of concurrent or concomitantly or co-administration of at least two distinct therapeutic agents for treating medical conditions defined in this disclosure.

[0047] The terms “treating” and “treatment” as used herein refer to reduction in severity and or frequency of symptoms, elimination of symptoms and or underlying cause, and improvement or remediation of damage.

[0048] In certain aspects, the terms “treating” and “treatment” as used herein refer to the prevention or reducing or minimizing of the occurrence of symptoms and or their underlying cause. Thus, “treating” a patient as described herein encompasses treating or preventing medication induced oral reactions such as inflammation, pain, fever, cancers, ulcers, aphthous stomatitis, burning mouth syndrome (glossitis, nonspecific ulceration and mucositis), vesico- bullous lesions, xerostomia, swelling, oral thrush, stomatitis, halitosis, sialoeehoea and hemorrhage; also includes gastrointestinal (GI) ulcers such as stomach ulcers, duodenal ulcers and ulcerative colitis collectively referred herein as “ulcers and mucosal damages or disorders”. [0049] The terms “gastric fluid” is used herein to refer to the colorless, watery, acidic digestive fluid that is secreted by various glands in the mucous membrane of the stomach and consists chiefly of hydrochloric acid, pepsin, rennin, and mucin.

[0050] The pharmaceutically active agent/drug/ingredient is the agent intended for use in the diagnosis, mitigation, treatment, cure or prevention of disease in humans or in other animals pharmaceutically active agent are seldom administered alone, but rather as part of a formulation in combination with one or more non-active agents with specialized pharmaceutical function, which are termed as pharmaceutically acceptable excipients or carriers. The pharmaceutical acceptable excipients have various functions depending of the type of formulation or dosage forms.

[0051] The term “dosage form” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration either as a modified releases dosage form.

[0052] The term modified release include immediate release, controlled release, sustained release, delayed release, long-acting, timed release, pulsatile-release, targeted release, extended-release formulations thereof and other forms known in the art.

[0053] The term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate release. The term “controlled release” as used herein includes sustained release, non-immediate release and delayed release formulations or other similar modified release forms known in the art.

[0054] The term “sustained release” (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time or other similar modified release forms known in the art.

[0055] Therapeutic agents are used as medication in certain types of treatment and also can damage the mucosal lining of the oral and gastrointestinal tract as a side-effect of the class of the drugs leading to various kind of mucosal dysfunctions resulting in ulceration, bleeding, microbial infections, inflammation of the mucosal lining and associated tissues. This results in many patients withdrawing from the treatment regime by discontinuing the medications and resulting in flaring up of the medical condition for which the patient is being treated.

[0056] In an embodiment, present invention discloses formula I and the compound of formula I, the glycol fumarate lipid conjugate or glycol succinate lipid conjugate or glycol caprylate lipid conjugate which are used as rate controlling excipients in pharmaceutical formulations in the instant invention. Particularly, to target or modify the release profile or control the release, either by pH dependent or pH independent mechanism of the pharmaceutically active agents for achieving a desired therapeutic objective or better patient compliance, better safety profile with minimal side effects and drug targeting. The term “rate controlling agents” or “rate limiting agents” or “modifying agents” or “release modifying agent” or “rate retarding agent” or the like refers to agents that can affect the rate of release of the active ingredient in the composition. Examples of the other rate controlling agents or polymers other than formula I which can be used in combination with compound of formula I, includes eudragit, ethyl cellulose sodium alginate, carbopol, cellulose acetate sodium alginate-chitosan, polyacrylic acid-chitosan, chitosan-carrageenan (CAP), phospholipids, natural oils, saturated and unsaturated oils, PVP, methyl cellulose, polyethyl cellulose, cellulose acetate butyrate, N, N-diethylaminoethyl methacrylate, 2-hydroxypropyl methacrylate (DEA-HPMA), N, N-diethylaminoethyl methacrylate, 2-hydroxypropyl methacrylate (DEA-HPMA), glyceryl behenate, lecithin, lipoid, and like. The release of the active agent may be activated through pH dependent mechanism, dissolution mechanism, swelling and expanding mechanism, diffusion controlled, mechanism, ion-exchange mechanism or a combination thereof.

[0057] In another embodiment, pharmaceutically active agents are selected from a group of drugs which are commonly known to induce GI disorders, such as ulcers, bleeding and other mucosal disorder as defined in this application in the patients using them.

[0058] In some embodiment, the present invention discloses a modified release pharmaceutical composition using compounds of formula I, rate controlling agent with one or more pharmaceutically active agents. This composition may further include one or more other pharmaceutical acceptable excipients/additives.

[0059] In some embodiment the present invention discloses a modified release pharmaceutical composition formulated with the compounds of formula I for reducing or minimizing ulceration and mucosal damages and associated complications which are induced by medications. In some embodiment the present invention discloses a modified release pharmaceutical composition formulated with the compound of formula I which reduced or slows dissolution or disintegration or swelling of the dosage form in pH 1.0 to 3.0. The pharmaceutical composition of the present invention: protects the drug/active ingredient/active agent from the acidity of the stomach, protects the mucosal lining of the gastro intestinal tract from the detrimental effect of the drug and prevents the release of the drug in the stomach wherein the pH is acidic. Further, the composition is useful for drugs/active ingredients that are unstable in acidic pH of the stomach. [0060] In an embodiment the modified releases dosage form can be immediate release, controlled release, sustained release, delayed release, extended release, pH modulated and targeted release formulations thereof.

[0061] In another embodiment, pharmaceutical composition of present invention retards drug release to less than 30% in acidic pH such as stomach. In certain embodiments, pharmaceutical composition of present invention retards drug release to less than 20% in acidic pH.

[0062] In another embodiment, the pharmaceutical composition of present invention allows more than 80% release of the drug at a pH 6.0 to 7.4.

[0063] Certain pharmaceutically active agents or medications used in treating cancer, arthritic pains, antibiotics etc. have the potential to cause damage to the mucosal lining results in ulcer and other compilations. In certain embodiment non-limiting examples of pharmaceutically active agents known to cause gastrointestinal damage can be selected from non-steroidal anti inflammatory drugs (NSAIDs) or COX-2 inhibitors classes of drugs in the art.

[0064] In another embodiment non-limiting examples of pharmaceutically active agents known to cause gastrointestinal damage include NSAIDs and selective COX-2 inhibitors such as acetylsalicylic acids (aspirin), diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, S -methyl N,N- diethylthiolcarbamate sulfoxide, COX-2 inhibitors, nabumetone, naproxen, oxaprozin, sulindac sulfide, celecoxib, piroxicam, sulindac, and tolmetin.

[0065] In an embodiment the present invention relates to compounds of formula I used as modified release agent for formulation of pharmaceutical compositions which can be safely used in oral delivery of nutrients and/or pharmaceuticals, with improved ulcer activity index (U.I), and more particularly for protecting the mucosal tissue from damages caused by use of medications especially for reducing the sides effects of medication induced ulcers, aphthous stomatitis, burning mouth syndrome (glossitis, nonspecific ulceration and mucositis), vesico- bullous lesions, xerostomia, swelling, oral thrush, stomatitis, halitosis, sialoeehoea and hemorrhage and also GI ulcers such as stomach ulcers, duodenal ulcers and ulcerative colitis and the restoration of the physiological structure and function to the mucosal tissue. [0066] The compound of formula I may be used in the composition with any pharmaceutical active agent in a pharmaceutical formulation to reduce the gastrointestinal ulceration.

[0067] In another aspect, the compound of formula I can be used as multifunctional excipient or carrier or an agent in formulating various drug dosages forms which can be administered to the patient by convenient route such as oral, nasal, local, dermal, vaginal, rectal, patches (mucosal, buccal, dermal), injections, self-injectable or parenteral administration and others known in the art.

[0068] In an embodiment, the dosage form is orally ingestible. In some embodiment, the dosage form is in the form of a tablet, capsule, pellets, mini-tablets, liquid filled, granules or mixtures thereof.

[0069] In certain embodiment, the pharmaceutical composition of the present invention can protect the physiological structure and function to the mucosal tissues.

[0070] In certain embodiment, the pharmaceutical composition of the present invention is used for protecting the mucosal tissue from damages caused by medications.

[0071] In certain embodiment, the pharmaceutical composition of the present invention may be used for promoting repair and regeneration of damaged or dysfunctional mucosal tissue in the oral cavity and GI tract.

[0072] In an embodiment, the compound of formula I is a glycol conjugated di-fatty acid mono- fumarate or glycol conjugated di-fatty acid mono -succinate.

[0073] In certain embodiment, the compounds of formula I is used to modify the release profile of the active agents/rate controlling agent in the pharmaceutical composition. The non-limiting examples of Formula I includes DGLF [dilauryl glyceryl fumarate], DGLS [dilauryl glyceryl succinate], DGCF [dicapryl glyceryl fumarate], DGCS [dicapryl glyceryl succinate] and others. The function of the compounds of formula I is used to modify the release of drugs from the pharmaceutical composition. The compounds of formula I may be in amphiphilic in nature comprising glycol conjugate having lipophilic fatty acid and hydrophilic carboxylic acid. The lipophilic fatty acid in the compound of formula I, reduces water wetting of the active agent and slows the dissolution of the active agent thus retarding the release of active ingredient. [0074] In certain embodiment, the compounds of formula I is used as carriers to modify the release profile of the active agents/rate controlling agent in the pharmaceutical composition. The non-limiting examples of Formula I includes DGLF [dilauryl glyceryl fumarate], DGLS [dilauryl glyceryl succinate], DGCF [dicapryl glyceryl fumarate], DGCS [dicapryl glyceryl succinate] and others. The function of the compounds of formula I is used to modify the release of drugs from the pharmaceutical composition [0075] Non-limiting Examples of compounds of Formula I: dilaurylglyceryl fumarate (DGLF):

dilaurylglyceryl succinate (DGLS):

dilauryl glyceryl caprylate (DGLC):

[0076] In certain embodiments, the compound of formula I sustains or reduce or slow or retard the release of the active agent(s) in acid environment or pH condition less than 3.0. The compound of formula I is useful for, modifying the release of the therapeutic agents and preventing the damage to mucosal linings. The compound of formula I reduces or slows the dissolution or disintegration in the drug in the pH is 1.0 to 3.0. The compound of formula I reduces or slows the dissolution or disintegration in the dosage form in the pH is 1.0 to 2.0. The compound of formula I may protect gastric mucosa from the irritating effects of the active ingredient/active agents/drugs such as NSAIDs with the limited exposure to the gastric lining of the actives. Drugs such as NS A TPs and COX-2 inhibitors have irritating effects on the mucosal lining of the stomach. In order to protect the stomach and avoid GI ulceration, the present invention provides a non-enteric coated oral composition that will retard the release in acidic pH. In the art different formulations and drug delivery system have been developed to minimise release of drugs in acidic pH, which have certain drawbacks such as incomplete release of drug, variability in pharmacokinetic profile, inter patient bioavailability variability, frequent dosing and others. Compound of formula I used in the current pharmaceutical composition may obviate such issues.

[0077] In certain embodiments, the pharmaceutically active agents known to cause mucosal damages and gastrointestinal ulcers are formulated using compounds of formula I to modify the release profile. Non-limiting examples of compounds of formula I include DGLF, DGLS, DGCF, DGCS thereof.

[0078] In an embodiment, the amount of compound of formula I, sufficient to reduce the gastrointestinal side effects of the NSAIDs or selective COX-2 inhibitors would range from about 5 mg to 800 mg or 5 mg to 400 mg or 5 mg to 600 mg or preferably 10 to 400 mg or 5 mg to 100 mg.

[0079] In an embodiment, the pharmaceutical composition may include other pharmaceutically acceptable agents such as glyceryl behenate, lecithin or lipoid or a combination in an amount range from 5 mg to 100 mg.

[0080] In an embodiment, the pharmaceutical composition may include one or more excipients selected from an rate controlling agent compound of formula I, a binder, a disintegrant, a lubricant, a solubilizer, a stabilizing agent, a diluent and a granulating solvent or a combination thereof.

[0081] In an embodiment the modified release dosage form can be an immediate release, controlled release, sustained release, delayed release, extended release, pulsatile release, pH mediated and targeted release formulations thereof. [0082] In an embodiment the modified release dosage containing a compound of formula I can be formulated to an immediate release, controlled release, sustained release, delayed release, extended release, pulsatile release, pH mediated and targeted release formulations thereof. In an embodiment the modified release dosage containing two or more compounds of formula I can be formulated to an immediate release, controlled release, sustained release, delayed release, extended release, pulsatile release, pH mediated and targeted release formulations thereof.

[0083] In specific embodiment, the anti-rheumatic agents known to cause mucosal damages and gastrointestinal ulcers are formulated into a modified release composition using the DGLF or DGCF or DGLS or DGCS or DGLC along with one or more pharmaceutically acceptable excipients.

[0084] The anti-rheumatic agents such as NS A IDs (e.g. acetylsalicylic acids, diclofenac) should be used with caution in patients who are more prone to adverse events. The elderly may be more susceptible to the toxic effects of salicylates. Continuous prolonged use of aspirin should be avoided in the elderly because of the risk of gastrointestinal bleeding and perforation which may be fatal. Where prolonged therapy is required, patients should be reviewed regularly. Aspirin is to be used with caution in cases of hypertension and patients with a stomach ulcer or a history of stomach ulcers or duodenal ulcer or hemorrhagic episodes or undergoing therapy with anticoagulants. If gastrointestinal bleeding or ulceration occurs the treatment is withdrawn. [0085] Present invention provides modified release pharmaceutical composition comprising active agents known to cause mucosal damages and gastrointestinal ulcers. The compounds of formula I is used to modify or target the release criteria of active agents known to cause mucosal damages and gastrointestinal ulcers to sustain the release of the drug in the stomach to prevent ulceration.

[0086] In an embodiment, the pharmaceutical composition may include one or more excipients selected from a rate controlling agent, a binder, a disintegrants, a lubricant, a solubilizer, a stabilizing agent, a diluent and a granulating solvent or a combination thereof.

[0087] In an embodiment, the modified release pharmaceutical composition comprises of aspirin, glyceryl behenate, Dilaurylglyceryl fumarate, microcrystalline cellulose, hypromellose E5, citric acid anhydrous, crospovidone, isopropyl alcohol, Dilaurylglyceryl fumarate, colloidal silicon dioxide and stearic acid.

[0088] In an embodiment, the modified release pharmaceutical composition comprises of diclofenac sodium, DGLF, microcrystalline cellulose, sodium starch glycolate, HPMC E15, colloidal silicon dioxide, and magnesium stearate.

[0089] In another embodiment, the modified release pharmaceutical composition comprises of sulindac, DGLF, sodium lauryl sulfate, microcrystalline cellulose, HPMC E50 and magnesium stearate.

[0090] In an embodiment, the modified release pharmaceutical composition comprises of celecoxib, DGLF, MCC, hypromellose, sodium lauryl sulfate, magnesium stearate.

[0091] In an embodiment, the modified release pharmaceutical composition comprises of naproxen, DGLF, croscarmellose sodium, microcrystalline cellulose, hypromellose K4M, hypromellose K100, croscarmellose sodium, and magnesium stearate.

[0092] In another embodiment, the compound of formula I can be used in the solid, semi-solid, or liquid formulation as rate controlling agent. Non-limiting examples of formulation where formula I can be used for controlling the release profile include tablet, capsule, caplet, modified release tablet, suspension, solution, emulsion, suppository, granules, pellets, beads, power, lozenges, spray (oral, nasal, topical or dermal), cream, ointment, lotion, patches, pre-filled syringe, pre-filled pen, and gel.

[0093] The compounds of formula I of the present invention is suitable excipient for solid, semi-solid or liquid dosage forms. Non-limiting examples of dosage forms includes tablet, lozenge, capsule, caplet, modified release tablets suspension, solution, emulsion, suppository, granules, pellets, beads, powder, sprays (oral, nasal, dermal), cream, ointment, lotion, patches, pre-filled syringe, pre-filled pen, and gel or the like, preferably in unit dosage form suitable for single administration of a precise dosage.

[0094] Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995). For those compounds that are orally active, oral dosage forms are generally preferred, and include tablets, lozenge, capsules, caplets, solutions, suspensions and syrups, and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated.

[0095] In another embodiment, the pharmaceutical composition comprising any of the combination as disclosed in the preceding embodiments are formulated into discrete dosage units each containing a predetermined, ‘unit dosage’ quantity of an one or more active agents in combination calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients.

[0096] The present composition can be in the form of modified release formulation. In certain aspect it may be controlled release oral dosage forms. Generally, the dosage forms provide for sustained release, i.e., gradual, release of the compound of the present invention alone or in combination from the dosage form to the patient's body over an extended time period, typically providing for a substantially constant blood level of the agent over a time period in the range of about 2 hrs to about 4 hrs or 8 hours or 12 hours, typically in the range of about 4 to about 10 hours.

[0097] The present formulations may be immediate release oral dosage forms. Generally, the dosage forms provide for immediate release, i.e., fast, release of the compound of the present invention alone or in combination from the dosage form to the patient's body immediately after oral administration time period, typically providing for a substantially constant blood level of the agent within 10, seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds or 60 seconds to hours to evaluate the PK profile and other parameters of the formulation composition containing Formula I compound.

[0098] The present formulations may be a combination of immediate and delayed release oral dosage forms. Preferably a retarded release which is controlled by the physiological pH condition of GI tract.

[0099] The present formulations may be an immediate release formulation with the selected composition described in the specification and oral dosage forms with a low hardness, low Kp

2 to 5. [00100] In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet. In one embodiment, the first portion includes the first pharmaceutically active agent, and the second portion includes the second pharmaceutically active agent.

[00101] In another embodiment, other suitable other pharmaceutically acceptable excipients examples include one or more fillers and diluents, binders and adhesives, glidants, stability enhancer, lubricants and anti-adherents, disintegrants, coatings changing the dissolution rates of active species, colors, flavors, sweeteners, preservatives, sorbents and others known in the art of formulation. In certain embodiment, pharmaceutically acceptable excipients include rate controlling agent, binder, disintegrant, glidants, lubricant, solubilizer, stabilizing agent, diluent, granulating solvent, enteric coating agent, vehicle or a combination thereof. [00102] In an embodiment, the suitable excipient can be selected from those which can further alter or manipulate the release profile of the active indigent along with the compound of Formula I for example use of a disintegrants selected based on the swelling property in the presence of fluid (water or gastric fluid) can aid in the dissolution

[00103] In another embodiment, for solid formulation, the non-limiting examples of other pharmaceutically acceptable excipient include plant cellulose, dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate, starches, sugars, cellulose or modified cellulose such as microcrystalline cellulose, Glyceryl behenate hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), lactose, lecithin, or sugar alcohols Isopropyl alcohol like xylitol, sorbitol or maltitol, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, povidone K25/30/90, PG starch, sucrose and polyethylene glycol, cellulose, methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol, colloidal silicon dioxide, talc or silica, fats, vegetable stearin, magnesium stearate or stearic acid, PEG 300,400&600, cross linked polyvinyl pyrrolidone, polyvinyl pyrrolidone K90 sodium starch glycolate, cross linked sodium carboxymethyl cellulose (crosscarmellose), crospovidone and sodium glycolate, cross linked cellulose, crosslinked polymer and a crosslinked starch, cellulose film coating, synthetic polymers, shellac, polysaccharides, Eudragit, soybean oil, oleic acid, lipoid, safflower oil, ethanol, methylene chloride, mint, cherry, peach, liquorice, raspberry, citrus bioflavonoids, neohesperidin or carob powder and vanilla, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, citric acid, medium and long chain fatty acids, polymers, sodium citrate, methyl paraben, propyl paraben. [00104] In certain embodiment, the pharmaceutically acceptable excipient used in the composition include compound of formula I such as DGLF, hypromellose, starch, PG starch, colloidal silicon dioxide(aerosil), croscarmellose sodium, stearic acid, lecithin, citric acid, citric acid anhydrous, microcrystalline cellulose, glyceryl behenate, isopropyl alcohol, crospovidone, Eudragit, soybean oil, oleic acid, lipoid, safflower oil, ethanol, methylene chloride and a combination thereof.

[00105] In certain embodiment, the pharmaceutical composition may comprise a drug- containing layer that contains the active ingredient, between a first water- swellable gel-forming layer and a second water- swellable gel-forming layer. The water- swellable gel-forming layers are formed from a composition that contains at least a water-swellable gel-forming agent such as carboxyvinyl polymer, starches and derivatives thereof, agar, alginic acid, arabinogalactan, galactomannan, cellulose and derivatives thereof, carrageen, dextran, tragacanth, gelatin, pectin, hyaluronic acid, gellan gum, collagen, casein, and xanthan gum; a film-forming agent such as polyvinyl alcohol, polyvinyl pyrrolidone (PVP), hydroxyalkyl cellulose, and alkyl celluloses; and a polyvalent metal compound for cross-linking linking gel forming and film forming agent such as aluminum sulfate, aluminum potassium sulfate, iron chloride alum, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, calcium chloride, iron citrate, magnesium oxide, calcium oxide or zinc salts.

[00106] In an embodiment, the pharmaceutical composition comprising at least one combination as disclosed is dissolved in a suitable excipient that is incorporated into the liquid formulation.

[00107] In an embodiment, non-limiting examples of excipients for preparing liquid formulation such as suspension and solution comprises of vehicles/ solvents (such as water, alcohol, glycerin, Propylene Glycol, Polyethylene Glycol 400 and others); co-solvents (such as glycerol, propylene glycol, ethanol, the low molecular weight PEGs and the likes) surfactants (such as anionic (e.g., sodium dodecyl sulfate), cationic (e.g., trialky lammonium), zwitterionic (e.g., glycine and proteins) and nonionic (e.g., polyethylene glycol); preservatives (such as phenol, benzoic acid, boric acid, chloro-cresol, 9-phenyl phenol, alkyl esters of para- hydroxybenzoic acid, sorbic acid, and their respective salts, chlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol); viscosity modifiers/ suspending agents (such as cellulose derivatives (e.g., methylcellulose, microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose etc), clays (e.g., hectorite, bentonite, aluminum and/or magnesium silicate), natural gums (e.g., acacia, guar gum, tragacanth, xanthan gum, alginates, carrageenan and locust bean gum), synthetic polymers (e.g., carbomers, polyvinyl pyrrolidone, polyvinyl alcohol and poloxamer), and miscellaneous compounds (e.g., colloidal silicon dioxide and silicates). In many cases, these excipients are used in combination).

[00108] Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

[00109] For parenteral administration, fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred. The active ingredient, depending on the form and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the water- soluble active ingredient can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing. Advantageously, adjuvants, carriers, drugs, preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that an active, ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient. [00110] In addition to oral and parenteral administration, the rectal and vaginal routes can be utilized. The combination of active ingredients can be administered by means of a suppository. A vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized. For example, cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.

[00111] Examples of useful other excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe - Publisher: Science and Practice.

[00112] The term "unit dosage form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoonful, tablespoonful, dropperful, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.

[00113] In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

[00114] In certain embodiments, the pharmaceutical compositions of the instant invention are used as a combinatorial therapy for the treating gastrointestinal side effects caused by irritants and for promoting repair and regeneration of damaged or dysfunctional mucosal tissue in the oral cavity and GI tract.

[00115] The ulcer and mucosal damages which are induced by various medication includes ulcers, aphthous stomatitis, burning mouth syndrome (glossitis, nonspecific ulceration and mucositis), vesico-bullous lesions, xerostomia, swelling, oral thrush, stomatitis, halitosis, sialoeehoea and hemorrhage; GI ulcers such as stomach ulcers, duodenal ulcers and ulcerative colitis.

[00116] In certain embodiments, the present invention provides modified release pharmaceutical compositions are formulated using compounds of formula I with ulcerogenic drugs known in the art targeted to reduce the ulceration induced by use of such ulcerogenic medications such as NSAIDs or COX-2 inhibitors as defined in the specification known to damage mucosal lining of oral and gastrointestinal tract.

[00117] The following examples illustrates the invention in further details. Method of synthesis and the formulation examples are generally described and illustrated in the examples herein, are viewed as exemplary of the principles of the present invention and not as restrictive to a particular method or formulation for implementation of those principles. These examples do not intent to limit the scope of the invention but is merely representative of presently preferred embodiments of the invention.

Methods of Synthesis

[00118] General Schema:

The general scheme of synthesis of compounds of Formula I is described and can be used for the synthesis of various compounds of formula I with fatty acids with carbon chains length from 1 to 30 with the reagents, catalysts, solvents and reaction conditions as described.

Example II: Methods of Synthesis

Example III

[00119] General scheme for synthesis of Synthesis of 4-((L3- bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid:

[00120] Synthesis of 2-oxopropane-l,3-diyl dioctanoate (3): To an ice cold solution of l,3-dihydroxypropan-2-one ( p 25.0 g, 0.277 mol) in dichloromethane (500 mL) was added 4- dimethylaminopyridine (10.17 g, 0.083 mol) and pyridine (49.2 mL, 0.610 mol) and stirred for next 5 min. To the above mixture octanoyl chloride (2, 105.4 mL, 0.610 mol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered; the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as white solid. Yield: 70.0 g, 73%.

MS (ESI) m!z 343.19[M+1]⁺; *H NMR (400 MHz, DMSO-d6); d 4.84 (s, 4H), 2.37 (t, J = 12 Hz, 4H), 1.45-1.62 (m, 4H), 1.15-1.35 (m, 16H), 0.78-0.92 (m, 6H).

[00121] Synthesis of 2-hydroxypropane-l,3-diyl dioctanoate (4): To an ice cold solution of 2-oxopropane-l,3-diyl dioctanoate (3, 70.0 g, 0.204 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (15.43 g, 0.245 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 12 to 15% ethyl acetate in hexanes to afford the desired product 4 as yellow liquid. Yield: 50.0 g, 71%.

MS (ESI) m/z 345.29[M+1]⁺;

*H NMR (400 MHz, DMSO-d6): d 5.25 (d, /= 5.2 Hz, 1H), 3.92-4.03 (m, 4H), 3.81-3.90 (m, 1H), 2.29 (t, /= 7.6 Hz, 4H), 1.45-1.59 (m, 4H), 1.12-1.35 (m, 16H), 0.85 (t, / = 6.8 Hz, 6H).

[00122] Synthesis of 4-((l,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6): To a solution of 2-hydroxypropane-l,3-diyl dioctanoate (4, 50.0 g, 0.145 mol) in chloroform (200 mL), dihydrofuran-2,5-dione (5, 17.44 g, 0.174 mol) and triethylamine (30.0 mL, 0.218 mol) were added at room temperature. The reaction mixture was stirred at 120 °C for 3h. After completion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 10 to 15% ethyl acetate in hexanes to affored the desired product 6 as white solid. Yield: 47.0 g, 72%.

MS (ESI) m/z 443.2[M-1]; *H NMR (400 MHz, DMSO-d6): d 12.22 (s, 1H), 5.12-5.22 (m, 1H), 4.18-4.25 (m, 2H), 4.09- 4.17 (m, 2H), 2.42-2.50 (m, 4H), 2.29 (t, / = 7.24 Hz, 4H), 1.44-1.55 (m, 4H), 1.15-1.31 (m, 16H), 0.79-0.90 (m, 6H).

Example IV :

[00123] General scheme for synthesis of Synthesis of 4-((L3- bis(dodecanoyloxy)propan-2-yl -4-oxobutanoic acid:

[00124] Synthesis of 2-oxopropane-l,3-diyl didodecanoate (3A): To an ice cold solution of l,3-dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above mixture dodecanoyl chloride 2A (218.50 g, 1.167 mol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered; the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). Organic layer was separated and dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3A as white solid. Yield: 78 g, 51%.

MS (ESI) m/z 455.37[M+1]⁺;

¾ NMR (400 MHz, DMSO-d6); d 4.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55-1.25 (m, 32H), 0.87 (m, 6H).

[00125] Synthesis of 2-hydroxypropane-l,3-diyl didodecanoate (4A): To an ice cold solution of 2-oxopropane-l,3-diyl didodecanoate 3A (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether to afford the desired product 4A as white solid. Yield: 60.0 g, 80%.

MS (ESI) m/z 457.48[M+1]⁺;

*H NMR (400 MHz, DMSO-d6); d 5.26 (d, /= 5.2 Hz, 1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H), 0.83 (m, 6H).

[00126] Synthesis of 4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (6A): To a solution of 2-hydroxypropane-l,3-diyl didodecanoate 4A (40.0 g, 0.087 mol) in chloroform (200 mL), dihydrofuran-2,5-dione 5 (10.50 g, 0.105 mol) and triethylamine (18.50 mL, 0.131 mol) were added at room temperature. The reaction mixture was stirred at 120°C for 3h. After completion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 25 to 30% ethyl acetate in hexanes to afford the desired product 6A as white solid. Yield: 20.0 g, 41%.

MS (ESI) m/z 555.40[M-1];

*H NMR (400 MHz, DMSO-d6); d 12.30 (s, 1H), 5.17 (m, 1H), 4.18-4.25 (m, 4H), 2.50-2.47 (m, 8H), 1.23-1.25 (m, 36H), 0.83 (m, 6H).

Example V :

[00127] Synthesis of (E)-4-( bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-

enoic acid:

[00128] Synthesis of 2-oxopropane-l,3-diyl didodecanoate (3*): To an ice cold solution of l,3-dihydroxypropan-2-one (1, 30.0 g, 0.33 mol) in dichloromethane (500 mL) was added 4- dimethylaminopyridine (20.30 g, 0.167 mol) and pyridine (107 mL, 0.1.332 mol) and stirred for next 5 min. To the above reaction mixture dodecanoyl chloride 2 (218.50 g, 1.167mol) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered, the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N HC1 solution (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to get crude. The crude was triturated with diethyl ether to afford the desired product 3* as white solid. Yield: 78 g, 51%. MS (ESI) m/z 455.37[M+1]+; 1H NMR (400 MHz, DMSO-d6): d 4.74 (s, 4H), 2.43 (m, 4H), 1.64 (m, 4H), 1.55-1.25 (m, 32H), 0.87 (m, 6H).

[00129] Step-2: Synthesis of 2-hydroxypropane-l,3-diyl didodecanoate (4*): To an ice cold solution of 2-oxopropane-l,3-diyl didodecanoate 3 (75.0 g, 0.165 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium cyanoborohydride (12.41 g, 0.198 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude was triturated with diethyl ether to afford the desired product 4* as white solid. Yield: 60.0 g, 80%. MS (ESI) m/z 457.48[M+1]+; 1H NMR (400 MHz, DMSO-d6): d 5.26 (d, J = 5.2 Hz, 1H), 3.92-3.98 (m, 4H), 2.28 (m, 4H), 1.50 (m, 4H), 1.23 (m, 33H) and 0.83 (m, 6H).

[00130] Step-3: Synthesis of (E)-4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2- enoic acid (6*) [ DGLF, dilaurylgylcerylfumarate ]: To an ice-cold solution of 2- hydroxypropane-l,3-diyl didodecanoate 4 (10.0 g, 21.91 mmol) in THF (170 mL) was added fumaric acid 5 (2.54 g, 21.91 mmol), benzoyl chloride (2.5 mL, 21.91 mmol) and DMAP (0.67 g, 5.477 mmol). The resulting mixture was stirred at RT for 16h. After completion of reaction (TLC monitoring), reaction mixture was concentrated under reduced pressure. The crude was diluted with water (200 mL), adjust pH ~2-3 using 1N-HC1 and extracted with 1,2 dichloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column chromatography eluting with 80% ethyl acetate in hexanes to afford the desired product 6* as white solid. Yield: 400 mg, 3.30% (un-optimized yield). LC-MS: m/z 553.64[M-1]; 97.27% purity. 1H NMR (400 MHz, DMSO-d6): d 13.26 (br s, 1H), 5.17 (d, J = 15.8 Hz, 2H), 5.29 (m, 1H), 4.30-4.33 (m, 2H), 4.19-4.23 (m, 2H), 2.28 (m, 4H), 1.48 (m, 4H), 1.22 (m, 32H) and 0.83 (m, 6H).

[00131] Similarly the other compounds of formula I can be prepared using the above similar method of synthesis as per schema as disclosed in examples 1 to 3 and the process can be optimized for scale-up up to multiple kilograms [Kgs].

[00132] The common drawback of continuous use of NS AID such as aspirin is the risk of gastrointestinal ulcers, bleeding, and rarely intracranial bleeding that can occur at any dose. The mortality rates from gastrointestinal complications have continued to rise in aspirin users. Other reported dose-related side effects include tinnitus, hypersensitivity, hypertension, gastrointestinal or renal toxicity and others.

[00133] Non-limiting numerous pharmaceutical compositions using compound of formula I is illustrated in the below examples. In the exemplified compositions comprises of mostly widely used NSAID is aspirin and other NSAIDs as the active agents along with the compound of formula I and other excipients. The glycol conjugated compound of formula I modifies the release profile of ASA to minimize its GI risk and improving the safely profile.

[00134] In the compositions exemplified below the active agent aspirin can be replaced with any other pharmaceutical active agents as disclosed in the paragraphs above using the analysis and formulation process known in the art of pharmaceutical formulation.

[00135] Examples of oral compositions: aspirin tablet compositions 75mg, 81mg and 325mg

[00136] Batch ACG004C0102001

[00137] Batch with different concentrations of Dilaurylglyceryl fumarate are prepared to evaluate the effect of Dilaurylglyceryl fumarate on aspirin drug release profile of the composition.

Table 1: Oral composition comprising Aspirin

[00138] Manufacturing Process

1. Dispense all the ingredients as per composition.

2. Sift step-1 materials through #30 sieve.

3. Material of step 2 was blended for 5 min.

4. Compression of blend of step 3 was done using 12.8 mm punches. [00139] Analytical data of Batch ACG004C0102001

Table 2: Dissolution data: Phosphate Buffer, pH 6.8; I (Basket); 100 rpm, 1000 mL

[00140] With increase in Dilaurylglyceryl fumarate concentration the drug release was found to be retarded in pH 1.0 to 2.0 within the studied range of 0 to 300mg of Dilaurylglyceryl fumarate.

[00141] Batch ACG004C0102002B

[00142] Batch 2002B with drug: Dilaurylglyceryl fumarate ratio is 1:4 are prepared with lecithin in the composition to study the physico chemical properties of the composition.

Table 3: Oral composition comprising Aspirin

Binder solution

[00143] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix Aspirin, lecithin, DGLF and aerosil for 5 min. iii. Step 2 was sifted through #30 mesh. iv. Dissolve citric acid and HPMC in water. v. Granulate step 3 blend with step 4 binder solution. vi. Dry the wet mass of step 5 at 45°C for 2 hrs. vii. Sift the dried granules through #30 mesh. viii. Blend granules of step 7 with extra granular material. ix. Compress the blend of step 8 with following parameters.

Table 4: Compression parameters:

[00144] Batch ACG004C0102003B

[00145] Batch 2003B with Drug: Dilaurylglyceryl fumarate ratio 1:2 are prepared with lecithin in the composition, to study the physico chemical properties of the composition.

Table 5: Oral composition comprising Aspirin

[00146] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and Mix Aspirin, lecithin, DGLF and aerosil for 5 min. iii. Step 2 was sift through #30 mesh. iv. Dissolve citric acid and HPMC in water. v. Granulate step 3 with step 4 solution. vi. Dry the wet mass of step 5 at 45°C for 2 hrs. vii. Sift the dry granules through #30 mesh. viii. Blended granules of step 7 with extra granular material. ix. The blend of step 8 was compressed according to below parameters.

Table 6: Compression parameters:

[00147] The drug release was found to be satisfactory, in acid stage however incomplete release was observed in buffer stage. [00148] Batch ACG004C0102004

[00149] Batch 2004 with Drug: Dilaurylglyceryl fumarate ratiol:l are prepared with lecithin in the composition, to evaluate the physico chemical properties of the composition.

Table 7: Oral composition comprising Aspirin

[00150] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and Mix Aspirin, lecithin, DGLF and aerosil for 5 min. iii. Step 2 was sifted through #30 mesh. iv. Dissolve citric acid and HPMC in water. v. Granulate step 3 with step 4 solution. vi. Dry the wet mass of step 5 at 45°C for 2 hrs. vii. Sift the dry granules through #30 mesh. viii. Blend granules of step 7 with extra granular material. ix. Blend of step 8 was compressed according to below parameters.

Table 8: Compression parameters:

[00151] The drug release was found to be satisfactory, in acid stage however incomplete release was observed in pH 7.0.

[00152] Batch ACG004C0102005B

[00153] Batch similar to ACG004C0102004B (1) and intragranular addition of

Microcrystalline cellulose were prepared, to check its impact on dissolution and physico chemical properties of composition.

Table 9: Oral composition comprising Aspirin

[00154] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Step 1 materials was sift through #30 mesh. iii. Mix Aspirin, lecithin, MCC, DGLF and aerosil for 5 min. iv. Dissolve citric acid and HPMC in water. v. Granulate step 3 with step 4 binder solution. vi. Dry the wet mass of step 5 at 45°C for 2 hrs. vii. Sift the dried granules through #30 mesh. viii. Blended granules of step 7 with extra granular material. ix. Blend of step 8 was compressed according to below parameters.

Table 10: Compression parameters:

[00155] The disintegration time was observed to be similar as Batch 2004. Hence, the, tablets were not tested for dissolution.

[00156] Batch ACG004C0102006B

[00157] Batch with addition of glyceryl behenate as release modifier were prepared to check its impact on dissolution and physico chemical properties of the composition.

Table 11: Oral composition comprising Aspirin

[00158] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and mix Aspirin, lecithin, and glyceryl behenate and blend for 5 min. iii. Added MCC, HPMC, aerosil, citric acid, stearic acid to step 2 and blend for 5 min. iv. The blend of step 3 was granulated using IPA. v. The wet mass of step 4 was dried at 45°C for 2hr. vi. Sift the dried granules through #40 mesh. vii. The granules of step 6 were lubricated with stearic acid. viii. Blend of step 7 was compressed according to below parameters.

Table 12: Compression parameters

[00159] The drug release was found to be faster and more than 20% in acid media.

[00160] Batch ACG004C0102007B

[00161] Batch similar to 2006B with reduced quantity of microcrystalline cellulose were prepared to evaluate its impact on drug dissolution and physico chemical properties of the composition.

Table 13: Oral composition comprising Aspirin

[00162] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and mix Aspirin, lecithin, and glyceryl behenate and blend for 5 min. iii. Add MCC, HPMC, aerosil, citric acid, stearic acid and blend for 5 min. iv. The blend of step 2 was mixed with step 3 and blended for 10 min. v. Blend of step 4 was compress according to below parameters.

Table 14: Compression parameters:

[00163] Sticking of tablets was observed during compression, further studies not done.

[00164] Batch ACG004C0102008

[00165] Batch comprising of Dilaurylglyceryl fumarate along with glyceryl behenate in the composition were prepared to evaluate dissolution and physico chemical properties of composition.

Table 15: Oral composition comprising Aspirin

[00166] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and mix Aspirin, DGLF, lecithin, and glyceryl behenate and blend for 5 min. iii. Add MCC, HPMC, aerosil, citric acid, stearic acid and blend for 5 min. iv. Blend by adding HPMC (lOmg/tab) and compress with below parameters.

Table 16: Compression parameters:

[00167] Batch ACG004C0102009

[00168] Batch similar to 2008 (1) with reduced quantity of lecithin and increased aerosil concentration were prepared to check its impact on dissolution and physico chemical properties of composition.

Table 17: Oral composition comprising Aspirin

[00169] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and mix Aspirin, lecithin, DGLF, glyceryl behenate, MCC, HPMC, citric acid, aerosil and blend for 5 min iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dry granules through #30 mesh. vi. Blend was compress as per below parameters.

Table 18: Compression parameters:

Table 19: Dissolution of batch AC G004C0102009

[00170] Sticking was not observed during compression. The drug release increased and was more than 20% in acid stage and in buffer stage the drug release was found to be about 80% after 2 hours

[00171] Batch ACG004C0102010

[00172] Batch similar to 2009 with crospovidone as disintegrant in intragranular portion to improve dissolution was prepared.

Table 20: Oral composition comprising Aspirin

[00173] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dried step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #30 mesh and blended with extragranular material. vi. Blend was compressed according to below parameters.

Table 21: Compression parameters:

[00174] The drug release was found to increase more than 20% in acid stage and in buffer stage the drug release was found to be about 80% after 2 hours.

[00175] Batch ACG004C0102011

[00176] Batch similar to 2010 with increased concentration of Dilaurylglyceryl fumarate and without glyceryl behenate and crospovidone was prepared, to retard the drug release in acid stage.

Table 22: Oral composition comprising Aspirin

Tablet weight

240.00

100.00

[00177] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dry granules through #30 mesh and blend with extragranular material. vi. Compress the blend according to below parameters.

Table 23: Compression parameters:

[00178] The drug release was found to be below 20% in the acid stage. However, the drug release decreased to 69% in the buffer stage.

[00179] Batch ACG004C0102012

[00180] Batch with reduced quantity of Dilaurylglyceryl fumarate and addition of glyceryl behenate as release modifiers was prepared to check its impact of drug product dissolution and physico-chemical properties.

Table 24: Oral composition comprising Aspirin

[00181] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dry granules through #40 mesh. vi. The dried granules were blended with extra granular material. vii. Blend was compressed according to below parameters.

Table 25: Compression parameters:

[00182] The drug release was found to be below 20% in the acid stage. However, the drug release decreased to about 52% in the buffer stage.

[00183] Batch ACG004C0102013B

[00184] Batch with 6mg/tab, PG starch as disintegrant and glyceryl behenate as extragranular addition was prepared to evaluate drug product dissolution and physico-chemical parameters. Table 26: Oral composition comprising Aspirin

[00185] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. The dried granules were sifted through #40 mesh. vi. To the dried granules extra granular material was added and blended for 10 min. vii. The blend was compressed according to below parameters.

Table 27: Compression parameters:

[00186] The drug release was found to be below 23% in the acid stage. However, the drug release decreased to about 79% in the buffer stage.

[00187] Batch ACG004C0102014B

[00188] Batch similar to 2013B with reduced quantity of PG starch to 3mg/tab was check for its effect on drug release in acid stage.

Table 28: Oral composition comprising Aspirin

[00189] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and mix the intragranular material and blend for 5 min. iii. Granulate step 2 with isopropyl alcohol. iv. Dry step 3 wet mass at 40°C for 40 min. v. The dried granules were sifted through #40 mesh. vi. The granules were blended with extra granular material. vii. Blend was compressed according to below parameters.

Table 29: Compression parameters

[00190] There was no change in disintegration pattern it was similar to 2013B. Therefore, dissolution test was not performed.

[00191] Batch ACG004C0102015

[00192] Batch without Dilaurylglyceryl fumarate and glyceryl behenate was prepared to check its impact on dissolution and physico-chemical properties of drug product.

Table 30: Oral composition comprising Aspirin

[00193] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Sift and Mix intragranular material and blend for 5 min. iii. Granulate step 2 with isopropyl alcohol. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. The granules were blended with extra granular material. vii. Blend was compressed with below parameters.

Table 31: Compression parameters:

[00194] The drug release was found to be below 20% in the acid stage. However, the drug release decreased to about 62% in the buffer stage.

[00195] Batch ACG004C0102023

[00196] Batch with liquid fill approach using lipoid S75, oleic acid and Dilaurylglyceryl fumarate and rate controlling polymers to check its impact on drug product

Table 44: Oral composition comprising Aspirin

[00197] Manufacturing Process i. Dispense all the ingredients as per composition ii. Blend of lipoid S75 and oleic acid was heated to 40°C to obtain clear solution iii. Disperse aspirin in step 2 blend and add safflower oil and mixed well iv. The blend of step 3 was filled in capsule with target fill weight.

Table 45: Parameters:

[00198] Batch ACG004C0102024

[00199] Batch similar to 2023 and to submit samples to ARD for development purpose.

Table 47: Oral composition comprising Aspirin

[00200] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Blend of lipoid S75 and oleic acid was heated to 40°C to obtain clear solution iii. Disperse aspirin in step 2 blend and add safflower oil and mixed well iv. The blend of step 3 was filled in capsule with target fill weight.

[00201] Batch ACG004C0102025

[00202] Batch similar to 2023 to check physico-chemical properties and to load for stability.

Table 48: Oral composition comprising Aspirin

[00203] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Blend of lipoid S75 and oleic acid was heated to 40°C to obtain clear solution. iii. Disperse aspirin in step 2 blend and add safflower oil and mixed well iv. The blend of step 3 was filled in capsule with target fill weight. v. The capsules were packed in HDPE bottle and loaded for stability.

Table 49: Parameters:

Table 50:Dissolution data:

[00204] The drug release was found to be satisfactory in sodium bicarbonate buffer

[00205] Batch ACG004C0102026 Table 51: Composition of batch ACG004C0102026

[00206] The composition exemplified in the table above is a modified release pharmaceutical composition comprising NS A TPs such as acetylsalicylic acids using the compounds of formula I to modify the drug release and enhance safety profile. The results of the dissolution table of the of the composition indicated less drug release in the acid stage and complete drug release in the bicarbonate buffer stage. The compounds of formula I used as the release modifiers that controls the release of NSAID in the acidic pH conditions of stomach.

Table 51A: A Dissolution study of ACG004C01020026

Formula I reduces the acetylsalicylic acids (aspirin) release in the acidic pH condition.

[00207] Batch ACG004C0102026B

[00208] Batch similar to #010B with increased quantity of DGLF to modify drug release and to check physico-chemical properties and to load for stability.

Table 52: Oral composition comprising Aspirin

[00209] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulated step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compression of blend according to below parameters.

Table 53: Compression parameters:

[00210] Compressed tablets of step 7 were coated with aqueous coating of Opadry II brown to obtain a weight gain of 3%w/w

Table 54: Analytical data:

Table 55: Dissolution data: 0.1N HC1 followed by bicarbonate buffer without enzymes; paddle; 100 rpm; 1000 mL

[00211] Drug release was found to be below 20% in acid stage and complete drug release in 60 min in 0.05 sodium bicarbonate buffer.

[00212] Batch ACG004C0102027

[00213] Batch for 325mg strength of active with composition similar to 2026 and with increase concentration of DGLF to check physico-chemical properties on drug product.

Table 56: Oral composition comprising Aspirin

[00214] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulated step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compression the blend according to below parameters.

Table 57: Compression parameters:

Table 58: Analytical data:

[00215] The drug release was observed to be below 20% in acid stage.

[00216] Batch ACG004C0102029B

[00217] Batch with composition similar to #26 to check physico-chemical properties and to load for stability.

Table 59: Oral composition comprising Aspirin

[00218] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulated step 2 with IP A iv. Dry step 3 wet mass at 40°C for 40 min

Note: blend process until intragranular stage and kept on hold

[00219] Batch ACG004C0102031

[00220] Batch for 75mg strength of aspirin, to check physico-chemical properties on drug product.

Table 60: Oral composition comprising Aspirin

[00221] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to below parameters.

Table 61: Compression parameters:

Table 62: Dissolution:

[00222] Drug release was found to be below 20% in acid stage and complete drug release in 60 min.

[00223] Batch ACG004C0102032

[00224] Batch for 325mg strength of aspirin to check physico-chemical properties on drug product.

Table 63: Oral composition comprising Aspirin

[00225] Manufacturing Process i. Dispense all the ingredients as per composition ii. Mix intragranular material and blend for 5 min iii. Granulated step 2 with IP A iv. Dry step 3 wet mass at 40°C for 40 min v. Sift the dried granules through #40 mesh vi. Blend with extra granular material vii. Compress the blend according to below parameters

Table 64: Compression parameters:

Table 65: Dissolution:

[00226] Drug release was found to be more than 20% in acid stage and complete drug release in 60 min. [00227] Batch ACG004C0102033

[00228] Batch for 325mg strength of aspirin with 5mg/tab Dilaurylglyceryl fumarate and to check physico-chemical properties on drug product.

Table 66: Oral composition comprising Aspirin

[00229] Manufacturing Process i. Dispense all the ingredients as per composition ii. Mix intragranular material and blend for 5 min iii. Granulate step 2 with IP A iv. Dry step 3 wet mass at 40°C for 40 min v. Sift the dried granules through #40 mesh vi. Blend with extra granular material vii. Compress the blend according to below parameters Table 67: Compression parameters:

Table 68: Dissolution:

The drug release was found to be more than 20% in acid stage.

[00230] Batch ACG004C0102034

[00231] Batch based on #032 for 325mg strength of aspirin by decreasing DGLF concentration to 5mg/tab to load for stability

Table 69: Oral composition comprising Aspirin

[00232] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to the below parameters.

Table 70: Compression parameters:

Table 71: Dissolution:

[00233] Batch ACG004C0102034A1:

[00234] The compressed tablets of step 7 were coated with aqueous dispersion of Opadry II brown to obtain a weight gain of 3%w/w.

Table 72: Dissolution:

[00235] Batch ACG004C0102035

[00236] Batch for 325mg strength of aspirin without glyceryl behenate, to check drug physico chemical properties.

Table 73: Oral composition comprising Aspirin

[00237] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh vi. Blend with extra granular material vii. Compress the blend according to below parameters

Table 74: Compression parameters:

Table 75: Dissolution:

Time (min)

% Drug release

[00238] The drug release for found to be about 83% in buffer stage.

[00239] Batch ACG004C0102036

[00240] Batch similar to #034 A without Lecithin

Table 76: Oral composition comprising Aspirin

[00241] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to below parameters

Table 77: Compression parameters:

[00242] The drug release of tablet in acid stage was found to be more than 20%.

[00243] Batch ACG004C0102037

[00244] Batch for 75mg strength without glyceryl behenate to evaluate drug product physico chemical properties

Table 78: Oral composition comprising Aspirin

[00245] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulated step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to the below parameters.

Table 79: Compression parameters:

[00246] The drug release was found to be about 28% in the acid stage and complete release in 0.05M sodium bicarbonate buffer within 15 min.

[00247] Batch ACG004C0102038

[00248] Batch based on #032 with 5mg /tab Dilaurylglyceryl fumarate for 325 mg of active to evaluate drying efficiency.

Table 80: Oral composition comprising Aspirin

[00249] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 40°C for 40 min. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to below parameters

[00250] Batch ACG004C0102039

[00251] Batch with intragranular addition of Dilaurylglyceryl fumarate and evaluation of impact of HPMC, lecithin on dissolution

Table 81: Oral composition comprising Aspirin

[00252] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with alcohol. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to below parameters.

Table 82: Compression parameters

[00253] Batch ACG004C0102040

[00254] Batch based on #031 with lecithin, 5mg /tab.

Table 83: Oral composition comprising Aspirin

[00255] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with isopropyl alcohol. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to the below parameters.

Table 84: Compression parameters:

Table 85: Dissolution:

[00256] The drug release was found to be more than 20% in the acid stage.

[00257] Batch ACG004C0102041

[00258] Batch, granulation of aspirin with Dilaurylglyceryl fumarate and HPMC and addition of 5mg/tab starch

Table 86: Oral composition comprising Aspirin

[00259] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with alcohol. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to the below parameters.

Table 87: Compression parameters:

Table 88: Dissolution:

[00260] The drug release was found to be 20% in the acid stage. However, the drug release in buffer stage was found to be incomplete.

[00261] Batch ACG004C0102042 [00262] Batch, granulation of aspirin with Dilaurylglyceryl fumarate and HPMC and addition of 5mg/tab starch

Table 89: Oral composition comprising Aspirin

[00263] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with isopropyl alcohol. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh vi. Blend with extra granular material. vii. Compress the blend according to the below parameters. viii. The tablets were packed in HDPE bottle and loaded for stability study.

Table 90: Compression parameters:

Table 91: Dissolution:

Table 92: Stability data:

Table 93: Stability data:

[00264] Batch ACG004C0102043

[00265] Batch, granulation of aspirin with Dilaurylglyceryl fumarate and HPMC and addition of 5mg/tab starch

Table 94: Oral composition comprising Aspirin

[00266] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with alcohol. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to the below parameters viii. The tablets were packed in HDPE bottle and loaded for stability study

Table 95: Compression parameters:

Table 96: Stability data:

[00267] The drug product was found to be stable up to 3 months at accelerated stability study conditions.

[00268] Batch ACG004C0102044 [00269] Batch, granulation of aspirin with Dilaurylglyceryl fumarate and HPMC and addition of 5mg/tab starch

Table 97: Oral composition comprising Aspirin

[00270] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with alcohol. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to below parameters. viii. The tablets were packed in HDPE bottle and loaded for stability study.

Table 98: Compression parameters:

Table 99: Stability data:

[00271] Batch ACG004C0102045A

[00272] Batch with Granulation of aspirin with HPMC E15 and check for dissolution and load for stability study

Table 100: Oral composition comprising Aspirin

[00273] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Dissolve HPMC in alcohol and dichloro methane solvent mixture. iv. Granulate step 2 with binder solution of step 3. v. Dry step 4 wet mass at 45 °C for 2 hrs. vi. Sift the dried granules through #40 mesh. vii. Blend with extra granular material. viii. Compress the blend according to below parameters.

Table 101: Compression parameters:

[00274] Batch ACG004C0102045A1

[00275] Granulation of aspirin with Hypromellose E15 and extragranular addition of PG starch and check for dissolution.

Table 102: Oral composition comprising Aspirin

[00276] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Dissolve HPMC in alcohol and dichloromethane solvent mixture. iv. Granulate step 2 with binder solution of step 3. v. Dry step 4 wet mass at 45 °C for 2 hrs. vi. Sift the dried granules through #40 mesh. vii. Blend with extra granular material. viii. Compress the blend according to the below parameters.

Table 103: Compression parameters:

Table 104: Stability data:

[00277] Batch ACG004C0102046A

[00278] Granulation of aspirin with Hypromellose E5 and extragranular addition of Dilaurylglyceryl fumarate and check for dissolution.

Table 105: Oral composition comprising Aspirin

[00279] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Dissolve HPMC in alcohol and dichloro methane solvent mixture. iv. Granulate step 2 with binder solution of step 3. v. Dry step 4 wet mass at 45 °C for 2 hrs. vi. Sift the dried granules through #40 mesh. vii. Blend with extra granular material. viii. Compress the blend according to the below parameters.

Table 106: Compression parameters:

Table 107: Stability data:

[00280] Batch ACG004C0102047A

[00281] Batch with Granulation of aspirin with polyvinyl pyrrolidine K90 and extragranular addition of Dilaurylglyceryl fumarate and check for dissolution.

Table 108: Oral composition comprising Aspirin

[00282] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Dissolve PVP k90 in isopropyl alcohol. iv. Granulate step 2 with binder solution of step 3. v. Dry step 4 wet mass at 45 °C for 2 hrs. vi. Sift the dried granules through #40 mesh. vii. Blend with extra granular material. viii. Compress the blend according to below parameters.

[00283] The drug release was found to be very slow

[00284] Batch ACG004C0102048A

[00285] Granulation of aspirin with Isopropyl alcohol and extragranular addition of Dilaurylglyceryl fumarate and check for dissolution.

Table 109: Oral composition comprising Aspirin

[00286] Manufacturing Process i. Dispense all the ingredients as per composition. ii. Mix intragranular material and blend for 5 min. iii. Granulate step 2 with IP A. iv. Dry step 3 wet mass at 45°C for 2 hrs. v. Sift the dried granules through #40 mesh. vi. Blend with extra granular material. vii. Compress the blend according to below parameters. viii. The tablets were packed in HDPE bottle and loaded for stability study.

Table 110: Compression parameters:

Table 111: Stability data:

Table 112: Comparative Drug release profile of Aspirin Modified release tablet 325mg, in acid stage.

[00287] The drug release of test products was observed to be limited to around 20% in 2hrs in acid stage medium i.e. 0.1N HC1.

[00288] Batch ACG004C0102049B

[00289] Reproducible Batch with composition similar to #043 to load for stability and check for dissolution.

Table 113: Oral composition comprising Aspirin

[00290] Manufacturing Process i. Dispense all the ingredients as per composition. ii. The intragranular material of step 1 were sifted through #30 mesh and blend for 5 min. iii. Granulate step 2 with isopropyl alcohol. iv. The wet mass of step 3 was dried at 45°C for 2 hrs. v. The dried granules of step 4 were sifted through #40 mesh. vi. The granules of step 5 were blended with extra granular material for 10 min. vii. Blend of step 6 was lubricated with #60 passed stearic acid for 5 minutes. viii. Lubricated blend of step 7 was compressed with below parameters. ix. The tablets were packed in HDPE bottles and loaded for stability study.

Table 114: Compression parameters:

Table 115: Stability data:

[00291] Batch ACG004C0102050B

[00292] Reproducible Batch with composition similar to #043 to load for stability.

Table 116: Oral composition comprising Aspirin

[00293] Manufacturing Process i. Dispense all the ingredients as per composition. ii. The intragranular material of step 1 were sifted through #30 mesh and blend for 5 min. iii. Granulate step 2 with isopropyl alcohol. iv. The wet mass of step 3 was dried at 45°C for 2 hrs. v. The dried granules of step 4 were sifted through #40 mesh. vi. The granules of step 5 were blended with extra granular material for 10 min. vii. Blend of step 6 was lubricated with #60 passed stearic acid for 5 minutes. viii. Lubricated blend of step 7 was compressed according to below parameters ix. The tablets were packed in HDPE bottles and loaded for stability study. Table 117: Compression parameters:

Table 118: Stability data:

[00294] Comparative drug release profile of Bayer genuine Aspirin325mg and Aspirin Modified release tablet 325mg & 81mg, in Fasted state simulated gastric fluid (FaSSGF; pH 1.6)

Table 119: Dissolution

[00295] The drug release of reference product was found to be complete in 30 minutes. However, the test products were observed to be limited to around 20% in 2hrs in fasted state simulated gastric fluid.

[00296] Manufacturing Process

Step-1 Dispensing: Dispense all the required raw materials using a calibrated weighing balance.

Step-2 Sifting: Sift aspirin, glyceryl behenate, Dilaurylglyceryl fumarate, Microcrystalline cellulose, Hypromellose, citric acid, Crospovidone and aerosil through ASTM #40 sieve.

Step-3 Binder solution preparation: Isopropyl alcohol alone are used as granulating fluid.

Step 4 Dry mixing: Dry mixed the sifted materials of step 2 for 10 min.

Step 5 Granulation: Granulate the dry mix blend of step 4 with granulation fluid.

Step 6 Drying: Dry the wet mass of step 5, at an inlet temperature of NMT 50°C and product temperature of NMT 45 °C until LOD of NMT 3.0% is obtained.

Step 7 Sizing: The dried material of step 6 was passed through ASTM sieve no.30

Step 8 Blending: The granules of step 7 were blended with extra-granular materials (passed through ASTM 40 sieve) i.e. Dilaurylglyceryl fumarate, and colloidal silicon dioxide for 10 min.

Step 9 Lubrication: Lubricate the blend of step 8 with #60 passed stearic acid for 5 min. Step 10 Compression: Compress the blend of step 9 using 8.0 mm round shape tooling.

Step 11 Packaging: Filled 40 tablets of step 10 in 40cc HDPE bottle along with one 2g silica gel bag and lg absorbent cotton as filler, induction sealed and closed with 33 mm CR closure.

Table 117: Aspirin tablets 325 mg

Table 118: Aspirin tablets 81 mg

[00297] Examples of oral compositions of naproxen, sulindac, celecoxib, diclofenac and ibuprofen.

Table 119: Naproxen ER Tablets 250 mg and 500 mg

Table 120: Naproxen ER Tablets 250 mg and 500 mg

[00298] Manufacturing process:

Step 1: Dispensed all raw materials as per batch composition.

Step 2: Sifted intragranular material through ASTM 30 sieve

Step 3: Binder solution preparation: HPMC was dissolved in water by stirring under laboratory stirrer, uniform solution was observed

Step 4: Transfer the step 2 material into RMG and dry mix for 10 minutes. Step 5: Granulated step 4 material with step 3 binder solution by RMG process for 2 min.

Step 6: wet mass of the step 5 material was dried in FBP at inlet temperature 55°C ± 5°C and dried until LOD reaches NMT 3.0 %.

Step 7: Sift dried granules through ASTM 30 sieve and mill the sieve retains through 1.0 mm screen in cone mill.

Step 8: Sifted dried granules transferred into bin blender and lubricated with magnesium stearate (previously sifted through ASTM 60 sieve) for 5 min at 15 RPM.

Step 9: Compressed the step 8 lubricated blend using suitable tooling.

Table 121: Sulindac ER Tablets 250 mg and 500 mg

Table 122:Sulindac Tablets 200mg

[00299] Manufacturing process:

Stepl: Dispensed all raw materials as per batch composition.

Step 2: Sifted intragranular material through ASTM 30 sieve

Step 4: Transfer the step2 material into RMG and dry mix for 10 minutes.

Step 5: Granulated step4 material with step3 binder solution by RMG process for 2 min.

Step 6: wet mass of the step5 material was dried in FBP at inlet temperature 55°C ± 5°C and dried until LOD reaches NMT 3.0 %.

Step 9: Compressed the step 8 lubricated blend with 12.60 mm round shape punches.

Step 10: Packing: filled the step 9 tablets in 60cc HDPE containers along with 2g of silica gel bag and lg of absorbent cotton, closed and induction sealed with 33 mm CR closures

Table 123: Celecoxib Tablets 200 mg

[00300] Manufacturing process:

Step 1: Dispensed all raw materials as per batch composition.

Step 2: Sifted intragranular material through ASTM 30 sieve

Step 4: Transfer the step 2 material into RMG and dry mix for 10 minutes.

Step 5: Granulated step 4 material with step 3 binder solution by RMG process for 2 min.

Step 9: Compressed the step 8 lubricated blend with 13.5 x 8.5 mm oval shape punches.

Step 10: Packing: filled the step 9 tablets in 60cc HDPE containers along with 2g of silica gel bag and lg of absorbent cotton, closed and induction sealed with 33 mm CR closures.

Table 124: Diclofenac Sodium ER tablets 100 mg

Table 125: Diclofenac Sodium ER tablets 100 mg

[00301] Manufacturing process:

Stepl: Dispensed all raw materials as per batch composition.

Step 2: Sifted intragranular material through ASTM 30 sieve

Step 8: Sifted dried granules transferred into bin blender and prelubricated with extra granular material colloidal silicon dioxide (previously sifted through ASTM 40 sieve) for 15 min at 15 RPM.

Step 9: Step 8 material was lubricated material with magnesium stearate (Previously sifted through ASTM 60 sieve) for 5 min at 15 RPM.

Step 10: Compressed the step 9 lubricated blend with 8.0 mm round shaped punches.

Step 11: Packing: filled the step 10 tablets in 40cc HDPE containers along with 2g of silica gel bag and lg of absorbent cotton, closed and induction sealed with 33 mm CR closures.

Table 126: Ibuprofen Tablets 200 mg

[00302] Manufacturing process:

Stepl: Dispensed all raw materials as per batch composition.

Step 2: Sifted intragranular material through ASTM 30 sieve.

Step 4: Transfer the step 2 material into RMG and dry mix for 10 minutes.

Step 8: Sifted dried granules transferred into bin blender and prelubricated with extragranular material colloidal silicon dioxide (previously sifted through ASTM 40 sieve) for 15 min at 15 RPM.

Step 10: Compressed the step 9 lubricated blend with 12.60 mm round shaped punches

Stepll: Packing: filled the step 10 tablets in 40cc HDPE containers along with 2g of silica gel bag and lg of absorbent cotton, closed and induction sealed with 33 mm CR closures

[00303] Gastrointestinal-Sparing Effects experimental investigations of NSAID or COX-2 compositions in Rats is well known in the art male Sprague-Dawley rats (225-250 g body weight) on regular feed and fasted for 24 h prior to experiments, aspirin administration will done intragastrically by gavage. The stomach is opened along the greater curvature, rinsed with cold isotonic saline and the gastric mucosa evaluated grossly under dissecting microscope.

INCORPORATION BY REFERENCE

[00304] All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims

laim:

1. A pharmaceutical composition comprising of: a. a salt or derivative of non-steroidal anti-inflammatory drug (NSAIDs) or selective COX-2 inhibitors; b. a compound of formula I; and c. at least one pharmaceutically acceptable excipient, wherein said composition is a modified release dosage form.

2. The dosage form as claimed in claim 1, wherein said dosage form is orally ingestible.

3. The dosage form as claimed in claim 1, wherein said dosage form is in the form of a tablet, capsule, pellets, mini-tablets, liquid filled, granules or mixtures thereof.

4. The dosage form as claimed in claim 1, wherein said compound of formula I is dilauryl glyceryl fumarate (DGLF), dilauryl glyceryl succinate (DGLS), dicapryl glyceryl fumarate (DGCF), dicapryl glyceryl succinate (DGCS), dilauryl glyceryl caprylate (DGLC) or a combination thereof, wherein, said compound of formula I is present in an amount sufficient to control the release of the NSAID or COX-2 inhibitor.

5. The dosage form as claimed in claim 4, wherein said amount of compound of formula I, sufficient to modify the release of the NSAIDs or selective COX-2 inhibitors is about lOmg to 800 mg or about lOmg to 400 mg or about 5mg to 100 mg.

6. The dosage form according to claim 1, wherein said NSAIDs and selective COX-2 inhibitors is selected from the group consisting of acetylsalicylic acids, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, S -methyl N,N-diethylthiolcarbamate sulfoxide, COX-2 inhibitors, nabumetone, celecoxib, naproxen, oxaprozin, sulindac sulfide, piroxicam, sulindac, tolmetin or any mixture thereof.

7. The dosage form as claimed in claim 1, wherein said modified release of the NS A TPs or selective COX-2 inhibitors by the rate controlling agents is activated by a pH dependent mechanism.

8. The dosage form as claimed in claim 7, wherein said pH dependent release of NSAIDs or selective COX-2 inhibitor is less than 30% at the pH range of 1.0 to 3.0.

9. The dosage form as claimed in claim 6, wherein said pH dependent release of NSAIDs or selective COX-2 inhibitor is more than 80% at the pH range of 6.0 to 7.4.

10. The dosage form as claimed in claim 1, wherein said pharmaceutically acceptable excipient is selected from a rate controlling agent or a carrier, a release modifier, a diluent, a binder, a glidant, a disintegrant, a lubricant, a stabilizer, a diluent, a granulating agent or a combination thereof.

11. The dosage form as claimed in claim 10, wherein said pharmaceutically acceptable excipients is selected from a group comprising of hypromellose, crospovidone, glyceryl behenate, lecithin, microcrystalline cellulose, colloidal silicon dioxide, steric acid, citric acid, croscarmellose sodium, alcohol: methylene chloride, isopropyl alocol, magnesium stearate, sodium starch glycolate, mannitol, sodium lauryl sulfate eudragrit, soyabean oil, oleic acid, lipoid, alcohol, polyvinyl pyrrolidine, water or a combination thereof.

12. A modified release dosage form comprising: a. acetyl salicylic acid or salt or derivatives thereof; and b. a rate controlling agent selected from compound of formula I.

13. The dosage form as claimed in claim 12, wherein said compound of formula I is DGLF.

14. The dosage form as claimed in claim 12, wherein said dosage form further includes one or more rate controlling agents selected from glyceryl behenate, lecithin or a combination thereof.

15. The dosage form as claimed in claim 12, wherein said dosage form further include a diluent, wherein the diluent is microcrystalline cellulose.

16. The dosage form as claimed in claim 12, wherein said dosage form further include a stabilizer, wherein the stabilizer is critic acid anhydrous.

17. The dosage form as claimed in claim 12, wherein said dosage form further include a disintegrant, wherein the disintegrant is crospovidone, croscarmellose sodium or sodium starch glycolate or a combination thereof.

18. The dosage form as claimed in claim 12, wherein said dosage form further include a glidant, wherein the glidant is colloidal silicon dioxide.

19. The dosage form as claimed in claim 12, wherein said dosage form further include a binder solution, wherein the binder solution consisting of hypromellose, alcohol, methylene chloride, isopropyl alcohol or purified water or a combination thereof .

20. The dosage form as claimed in claim 12, wherein said dosage form further include a lubricant, wherein the lubricant is stearic acid.