Claims:1. A quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition disintegrates in less than about 30 seconds when placed in the oral cavity.
2. The composition of claim 1, wherein said composition exhibits at least one of the following in-vitro release profile:
i. releases at least about 80% of ketorolac within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus;
ii. releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus; or
iii. releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
3. The composition of claim 1, wherein said composition comprises ketorolac in an amount of about 5 mg to about 10 mg.
4. The composition of claim 1, wherein said water insoluble polymer and sugar alcohol are present in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0.
5. The composition of claim 1, wherein said ketorolac and sugar alcohol are present in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0.
6. The composition of claim 1, wherein said water insoluble polymer is present in an amount of from about 30% to about 60% by weight of the composition.
7. The composition of claim 1, wherein said water insoluble polymer is selected from the group comprising microcrystalline cellulose, ethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked dextran or mixtures thereof.
8. The composition of claim 1, wherein said sugar alcohol is present in an amount of from about 20% to about 50% by weight of the composition.
9. The composition of claim 1, wherein said sugar alcohol is selected from the group comprising mannitol, sorbitol, maltitol, sorbitol, xylitol, lactitol, erythritol, isomalt, threitol or mixtures thereof.
10. The composition of claim 1, wherein said composition further comprises a stabilizer selected from water-insoluble antioxidants, pH modifiers or mixtures thereof.
11. The composition of claim 10, wherein said water-insoluble antioxidants are selected from the group comprising butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or mixtures thereof.
12. The composition of claim 10, wherein said pH modifiers are selected from the group comprising citric acid, tartaric acid, maleic acid, fumaric acid, succinic acid, maleic acid, meglumine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, buffering agents such as phosphate buffer, acetate buffer, borate buffer or mixtures thereof.
13. The composition of claim 1, wherein said composition is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 0.5% of total impurities.
14. The composition of claim 1, wherein said composition is stable for at least about 6 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 1.0% of total impurities.
15. The composition of claim 1, wherein said composition is in the form of tablets, lozenges, caplets, pills, wafers, films, powders, granules or sachets.
, Description:The following specification particularly describes the invention and the manner in which it is to be performed

PHARMACEUTICAL COMPOSITIONS OF KETOROLAC

TECHNICAL FIELD
[001] The present application relates to a method of treating pain by providing a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration provides pain relieving concentration in less than about 10 minutes.

BACKGROUND
[002] Ketorolac is a nonsteroidal agent with potent analgesic and moderate anti-inflammatory activity. Chemically it is 5-benzoyl-2, 3-dihydro- l H-pyrrolizine- 1 - carboxylic acid, the formula of which is:

[003] Ketorolac is an inhibitor of prostaglandin synthesis, and has been known for several years by its anti-inflammatory, analgesic and antipyretic action as described in U.S. Pat. No. 4,089,969, in which both the racemic form and each of the dextro and levo isomers of this compound are known. Many pharmaceutically acceptable salts including the most commonly used tromethamine (2-amino-2-hydroxymethyl- l, 3-propanediol) salt, are also known. Ketorolac was known to be administered in several routes of administration. For example, U.S. Pat. No. 4,089,969 suggests the oral, parenteral or topical administration, in several pharmaceutical forms, like tablets, suppository, pills, capsules, powder, solutions, suspensions, emulsions, creams, lotions and unguents. Currently, Ketorolac in the form of tromethanol salt is used for oral administration as tablets containing 10 mg strength or oral drops containing 2% solution, by injection provided in flasks containing 10 or 30 mg strengths, and by rectal administration in suppositories form containing 30 mg strength.
[004] Ketorolac tromethamine is susceptible to significant degradation in aqueous compositions. The drug is known to undergo chemical degradation via oxidation, hydroxylation and other unknown routes. The oxidative degradation product reported is 1-keto analogue, and the hydroxylation degradation product reported is 1-hydroxy analogue. Aqueous and ethanolic solutions of ketorolac or salts thereof are susceptible to degradation when subjected to long term storage under room temperature (PCT application no’s. WO 2009/087658 and WO 2012/127497). Apart from this, ketorolac tromethamine is bitter in taste, and adequate degree of palatability is needed especially for a formulation meant for administration through oral cavity.
[005] Tablets are most commonly preferred oral dosage forms because of its convenience in terms of self-administration and accurate dosing. However, problem of this dosage form is poor patient compliance particularly by the geriatric and pediatric patients who experience difficulty in swallowing. Rapidly disintegrating dosage form, particularly one that disintegrates and dissolves/disperses in saliva and can be administered without need of water, is convenient and appreciated.
[006] Orally disintegrating tablets (ODT) or sublingual technologies have drawn attention in the industry as a promising approach to deliver drugs for a wide range of the patient population. ODT tablets can be prepared by various processes, including, but not limited to Freeze drying (Lyophilization), tablet molding, spray drying, sublimation, direct compression, cotton candy process and mass extrusion. The direct compression represents the simplest and most cost effective tablet manufacturing technique. This technique employs superdisintegrants like croscarmellose sodium, directly compressible diluents, sweeteners and flavoring agents. However, not all drugs can be processed as direct compressible formulation either because of their poor flow characteristics or due to their poor compressibility. As a result, granulation processes need to be applied to gain compressible blends. Hence, the selection of the excipients plays a crucial role for the success of the final product. The other important factors to be considered in the preparation of an ODT include effective taste-masking and to provide acceptable taste upon oral disintegration.
[007] The stability of the ODT dosage forms can be challenging depending upon drugs and excipients used in the formulations. It is hard to achieve stable ODTs, as most of ingredients used in preparing ODTs dissolve in with minimum quantity of water. Therefore, a careful identification and selection of excipients is critical for the development and long-term stability of the tablets.
[008] Conventional oral ketorolac tablets which are available in market are not suitable for acute inflammatory conditions where quick onset of action is required. Particularly due to its use as analgesic, a quick onset of action of ketorolac assumes a significant importance. Multiple attempts were made to provide quick onset of action of ketorolac by formulating it in different possible forms. However, the stability and taste-masking of these formulations appear to be challenging factors, as ketorolac is susceptible to oxidative and hydrolytic degradation, and is bitter in taste leading to poor compliance.
[009] Sublingual formulations of Ketorolac are disclosed in US patent no. 7,879,901 wherein a ternary mixture of lactose/sorbitol/cellulose was found to be the essential component of the composition, and the composition is administered sublingually for rapid absorption.
[0010] PCT application no. WO 2004/108110 discloses a pharmaceutical formulation of a non-steroidal anti-inflammatory agent administered by sublingual route to promote the fast disintegration in the oral cavity, and capable of being absorbed through oral mucosa. Similar to this, US patent no. 7,282,217 and PCT application no. WO 2000/015195 discloses rapidly disintegrating tablet or quick release pharmaceutical compositions.
[0011] There remains a clear unmet clinical need to develop in the art of dosage forms for ketorolac meant for faster pain relief. More specifically there is a need in the art to develop a formulation comprising ketorolac which can be administered orally, that can disintegrate rapidly in the oral cavity, and have improved pharmacokinetic parameters for faster pain relief. It is also desired to have an oral dosage forms with improved taste, and at the same time remains stable thought its shelf life by minimizing hydrolytic and oxidative degradation of the drug.
[0012] In order to achieve an effective pain treatment with quick onset of action, a high rate of absorption of ketorolac in the initial time points is as important as total absorption. It is also important that the initial time point absorption should be as high as possible to achieve minimum effective concentration (MEC) or pain-relieving plasma concentration of the drug. Mandema et al, Clin Pharmacol Ther, 1996; 60 (6): 619-35, discloses EC50 of ketorolac tromethamine of 370 ng/mL. It is crucial to achieve a high partial AUC at such minimum effective plasma concentration of the drug. Also, none of the available arts have disclosed a pharmacokinetic profile with high partial AUC at such minimum effective plasma concentration of the drug in less than 10 minutes.
[0013] Accordingly, the present application relates to a method of treating pain by administering a quick disintegrating composition of ketorolac, wherein said composition upon oral administration provides pain relieving concentration in less than about 10 minutes. In order to provide faster pain relief, it is desired to have a composition of ketorolac that disintegrates or disperses in the oral cavity in less than about 30 seconds. Further it is desired to have oral dosage form that eases the swallowing of the dosage forms.
SUMMARY OF THE APPLICATION

[0014] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration provides a pain relieving concentration in less than about 10 minutes.
[0015] In an aspect of the above embodiment, the composition of the present application upon oral administration provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0016] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0017] In an aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg to about 10 mg.
[0018] In another aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg.
[0019] In another aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 10 mg.
[0020] In another aspect of the above embodiments, the composition of the present application comprises at least one water insoluble polymer.
[0021] In another aspect of the above embodiments, the composition of the present application comprises at least one sugar alcohol.
[0022] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol.
[0023] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration provides a pain relieving concentration in less than about 10 minutes.
[0024] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0025] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits a Tlag of less than about 5 minutes.
[0026] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes.
[0027] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes and provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0028] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits at least one of the following pharmacokinetic parameters:
(a) AUC0-5min from about 2.64 ng.hr/ml to about 3.96 ng.hr/ml;
(b) AUC0-10min from about 23.35 ng.hr/ml to about 35.03 ng.hr/ml;
(c) AUC0-20min from about 128.20 ng.hr/ml to about 192.30 ng.hr/ml; or
(d) AUC0-30min from about 297.99 ng.hr/ml to about 446.99 ng.hr/ml.
[0029] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits higher partial AUCs compared to the commercially available ketorolac composition.
[0030] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits AUC0-5min of about 4.5 fold higher compared to commercially available ketorolac composition.
[0031] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits AUC0-10min of about 2.6 fold higher compared to commercially available ketorolac composition.
[0032] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits AUC0-20min of about 1.5 fold higher compared to commercially available ketorolac composition.
[0033] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits AUC0-30min of about 1.3 fold higher compared to commercially available ketorolac composition.
[0034] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits bioequivalence to a commercially available ketorolac composition when administered to the human subjects in fasting condition, wherein said bioequivalence is established by: (a) a 90% Confidence Interval for mean Cmax, which is between 80% and 125%, (b) a 90% Confidence Interval for mean AUC(0-t), which is between 80% and 125% and (c) a 90% Confidence Interval for mean AUC(0-8), which is between 80% and 125%.
[0035] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol.
[0036] In an aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg to about 10 mg.
[0037] In an embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition comprises ketorolac in an amount of about 5 mg to about 10 mg.
[0038] In an aspect of the above embodiments, the composition of the present application disintegrates in less than about 30 seconds when placed in the oral cavity.
[0039] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition disintegrates in less than about 30 seconds when placed in the oral cavity.
[0040] In an aspect of the above embodiments, the composition of the present application exhibits at least one of the following in-vitro release profile:
i. releases at least about 80% of ketorolac within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus;
ii. releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus; or
iii. releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
[0041] In one embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition exhibits at least one of the following in-vitro release profile:
i. releases at least about 80% of ketorolac 0within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus;
ii. releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus; or
iii. releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
[0042] In an aspect of the above embodiments, the composition of the present application comprises water insoluble polymer and sugar alcohol in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0.
[0043] In another aspect of the above embodiments, the composition of the present application comprises ketorolac and sugar alcohol in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0.
[0044] In an embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition comprises water insoluble polymer and sugar alcohol in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0.
[0045] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition comprises ketorolac and sugar alcohol in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0.
[0046] In an aspect of the above embodiments, the composition of the present application comprises water insoluble polymer in an amount of from about 30% to about 60% by weight of the composition.
[0047] In another aspect of the above embodiments, the composition of the present application comprises said sugar alcohol is present in an amount of from about 20% to about 50% by weight of the composition.
[0048] In yet another aspect of the above embodiments, the composition of the present application further comprises a stabilizer selected from water-insoluble antioxidants, pH modifiers or mixtures thereof.
[0049] In another aspect of the above embodiments, the composition of the present application is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 0.5% of total impurities.
[0050] In another aspect of the above embodiments, the composition of the present application is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 0.5% of total impurities.
[0051] In another aspect of the above embodiments, the composition of the present application is stable for at least about 6 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 1.0% of total impurities.
[0052] In another aspect of the above embodiments, the composition of the present application is stable for at least about 6 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 1.0% of total impurities.
[0053] In yet another aspect of the above embodiments, the composition of the present application is formulated in form of tablets, lozenges, caplets, pills, wafers, films, powders, granules or sachets.

BRIEF DESCRIPTION OF THE DRAWING
[0054] FIG. 1 shows plasma ketorolac concentration (ng/mL) vs. time (hr) for an exemplary composition of the present application, as set forth in Example 1 containing 10mg of ketorolac, vis-à-vis KETOROL® 10mg oral tablets administered to healthy human subjects in fasting condition.

DETAILED DESCRIPTION OF THE APPLICATION

[0055] The details of one or more embodiments of the present application are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.
[0056] Definitions: The terms as used herein have the following meanings:
[0057] The term "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. These terms are not in the exclusive sense of "consisting only of." All ranges recited herein include the endpoints, including those that recite a range "between" two values.
[0058] The terms "a" and "the" as used herein are understood to encompass the plural as well as the singular or otherwise clearly mentioned wherever needed. For example, reference to “an excipient” includes reference to one or more of such excipients, and reference to "the carrier" includes reference to one or more of such carriers.
[0059] The terms such as “about”, “up to”, “generally” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value. The term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. As used herein, the term "about" means a slight variation of the value specified, within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum.
[0060] As used herein, the term “at least” refers to presence of recited substance in the composition in recited least amount.
[0061] As used herein, the terms "pharmaceutical composition", “composition” and “formulation” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. Also the terms “composition” and “formulation” may be used to refer to a mixture of one or more active agents with excipients or other carriers, and include solid pharmaceutical products such as tablets, capsules, sachets, pills, or granules, containing a mixture of two or more compounds, elements or molecules.
[0062] The term "quick disintegrating composition” can include one or more composition(s) or formulation(s) provided in an acceptable form for oral administration, wherein said composition which upon administration or when placed inside the oral cavity of the subject or patient, disintegrates or disperses or dissolves within about 60 seconds or less, or within about 30 seconds or less, or within about 15 seconds or less and eases the dosage administration. It also refers to composition that disintegrates or disperses rapidly when contacted with a fluid, particularly an aqueous fluid (e.g., water, bodily fluids (e.g., saliva), and the like), which can be easily swallowed. The quick disintegrating composition of the present application can be present in the form of tablets, lozenges, caplets, pills, wafers, films, powders, granules or sachets.
[0063] The term “disintegrate” is well-understood in the art, and while a composition can be completely disintegrated, the term disintegrate does not necessarily refer to a complete dissolution of the composition, although a dissolved composition (e.g., tablet, lozenge, etc.) would typically be completely disintegrated.
[0064] The term “therapeutically effective amount” or “effective amount” of a drug as used herein, refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is known to be effective. In this instance, an effective amount is an amount of ketorolac that is approximately from about 5 mg to about 10 mg, which is sufficient to provide patients some measure of analgesia or helps in the management of acute, severe or moderate pain or its associated conditions, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The effective amount of said ketorolac or a pharmaceutically acceptable salt will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors within the knowledge and expertise of the attending physician.
[0065] The term "excipients", "pharmaceutically acceptable excipients" or “carriers” as used herein, refers to any pharmaceutically acceptable materials or components of a pharmaceutical product suitable for the present pharmaceutical preparation and as disclosed herein, that is not having any pharmacological effect, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic, do not interact with other components of a composition in a deleterious manner, and are acceptable for veterinary or human use. An "excipient" or a “pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipients.
[0066] The term “ketorolac” as used herein refers to its free base, pharmaceutically acceptable salts, acid addition salts, all polymorphic forms (amorphous or crystalline), hydrates, anhydrous forms, enantiomers, prodrugs of ketorolac and/or mixtures thereof. In an aspect, the term “ketorolac” refers to ketorolac tromethamine.
[0067] The term "pharmaceutically acceptable salt” includes derivatives of the disclosed compounds which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art. The salt can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by the reaction of the pharmaceutically active substance, having a freebase function, with a suitable organic acid or inorganic acid. Further refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salt.
[0068] The term “stability” or “stable” as used herein, includes both chemical stability and physical/polymorphic stability of the present pharmaceutical composition including ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition or said ketorolac remain within the established specifications to maintain its identity, strength, quality and purity throughout the storage, retest or expiry period and do not change or decompose due to internal reaction, or due to the effects of oxygen, heat, light, moisture or pressure; and wherein the drug is present in an amount of at least about 95% to about 100% of the originally specified amount and total impurity of not more than about 1.0% for at least about 3 months upon storage at 25°C / 60% relative humidity (RH) or at 40°C / 75% relative humidity (RH).
[0069] The term “pain” as used herein, refers to pain as recited herein acute pain, migraine pain, cluster headache, neuropathic pain, post-operative pain, chronic lower back pain, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, angina pain, and genitourinary tract-related pain including cystitis, arthritis pain, inflammation, osteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis and primary dysmenorrhea.
[0070] The term “treating pain” as used herein, refers to the short-term (= 5 days) management of moderately severe acute pain that requires analgesia effect, usually in a postoperative patient.
[0071] The term “pain relieving concentration” as used herein, refers to the particular plasma concentration (EC50) of ketorolac that would produce analgesia effect; and wherein said ketorolac concentration is at least about 370 ng/ml or greater.
[0072] The term “Cp” as used herein denotes plasma concentrations.
[0073] The term “partial AUC” refers to the area under the plasma concentration versus time profile over a specified time period, which represents the drug exposure for any time interval of interest, and is calculated by the log-linear trapezoidal rule over the partial dosing interval.
[0074] The term “AUC” refers to the area under the plasma concentration versus time profile, as calculated by the log-linear trapezoidal rule over the complete dosing interval.
[0075] The term “Cmax” refers to the highest plasma concentration of the drug attained within the dosing interval.
[0076] The term “Tmax” refers to the time period which elapses after administration of a single dosage form at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval.
[0077] The term “Tlag” as used herein refers to time delay between administration of the composition and first observed drug concentration in plasma, which is within a limit of quantification.
[0078] The term “commercially available ketorolac composition” as used herein, refers to KETOROL® oral tablets containing 10mg ketrorolac tromethamine or its pharmaceutical equivalents or its therapeutic equivalents or later approved drugs. For example, in some embodiments, KETOROL® includes compressed tablet of ketrorolac tromethamine equivalent to 5 mg or 10 mg of ketorolac base along with excipients. In some embodiments KETOROL® includes its approved therapeutic or pharmaceutical equivalents. KETOROL® is marketed by Dr. Reddy’s Laboratories, Ltd., Russia.
[0079] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration provides a pain relieving concentration in less than about 10 minutes.
[0080] In an aspect of the above embodiment, the composition of the present application upon oral administration provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0081] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0082] In an aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg to about 10 mg.
[0083] In another aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg.
[0084] In another aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 10 mg.
[0085] In some embodiments, the present composition of the present application upon oral administration to a human subject under fasting conditions provides Tlag of less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes, or less than about 1 minute.
[0086] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes.
[0087] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes and provides a pain relieving concentration in less than about 10 minutes.
[0088] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes and provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0089] In another aspect of the above embodiments, the composition of the present application comprises at least one water insoluble polymer.
[0090] In another aspect of the above embodiments, the composition of the present application comprises at least one sugar alcohol.
[0091] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol.
[0092] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration provides a pain relieving concentration in less than about 10 minutes.
[0093] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0094] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes.
[0095] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes and provides a pain relieving concentration in less than about 10 minutes.
[0096] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration exhibits a Tlag of less than about 5 minutes and provides a pain relieving concentration of at least about 370 ng/ml in less than about 10 minutes.
[0097] The quick disintegrating composition of ketorolac discloses herein can have variety of improved pharmacokinetic parameters. In some embodiments, the composition of the present application can have an improved pharmacokinetic parameter in comparison to a commercially available ketorolac oral composition, such as AUC0-5min, AUC0-10min, AUC0-20min, AUC0-30min or Tlag etc.
[0098] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits at least one of the following pharmacokinetic parameters:
(a) AUC0-5min from about 2.64 ng.hr/ml to about 3.96 ng.hr/ml;
(b) AUC0-10min from about 23.35 ng.hr/ml to about 35.03 ng.hr/ml;
(c) AUC0-20min from about 128.20 ng.hr/ml to about 192.30 ng.hr/ml; or
(d) AUC0-30min from about 297.99 ng.hr/ml to about 446.99 ng.hr/ml.
[0099] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-5min from about 2.64 ng.hr/ml to about 3.96 ng.hr/ml.
[00100] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-5min of about 4.5 fold higher compared to commercially available ketorolac composition.
[00101] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-10min from about 23.35 ng.hr/ml to about 35.03 ng.hr/ml.
[00102] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-10min of about 2.6 fold higher compared to commercially available ketorolac composition.
[00103] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-20min from about 128.20 ng.hr/ml to about 192.30 ng.hr/ml.
[00104] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-20min of about 1.5 fold higher compared to commercially available ketorolac composition.
[00105] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-30min from about 297.99 ng.hr/ml to about 446.99 ng.hr/ml.
[00106] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition upon oral administration exhibits AUC0-30min of about 1.3 fold higher compared to commercially available ketorolac composition.
[00107] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition upon oral administration exhibits at least one of the following pharmacokinetic parameters:
(a) AUC0-5min from about 2.64 ng.hr/ml to about 3.96 ng.hr/ml;
(b) AUC0-10min from about 23.35 ng.hr/ml to about 35.03 ng.hr/ml;
(c) AUC0-20min from about 128.20 ng.hr/ml to about 192.30 ng.hr/ml; or
(d) AUC0-30min from about 297.99 ng.hr/ml to about 446.99 ng.hr/ml.
[00108] In an aspect of the above embodiments, the composition of the present application upon oral administration exhibits bioequivalence to a commercially available ketorolac composition when administered to the human subjects in fasting condition.
[00109] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition when administered to said patient under fasting condition exhibits bioequivalence to a commercially available ketorolac composition.
[00110] In an aspect of the above embodiment, the composition of the present application upon oral administration exhibits bioequivalence to a commercially available ketorolac composition when administered to the human subjects in fasting condition, wherein said bioequivalence is established by: (a) a 90% Confidence Interval for mean Cmax, which is between 80% and 125%, (b) a 90% Confidence Interval for mean AUC(0-t), which is between 80% and 125% and (c) a 90% Confidence Interval for mean AUC(0-8), which is between 80% and 125%.
[00111] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition exhibits bioequivalence to a commercially available ketorolac composition when administered to the human subjects in fasting condition.
[00112] In another embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition exhibits bioequivalence to a commercially available ketorolac composition when administered to the human subjects in fasting condition and said bioequivalence is established by: (a) a 90% Confidence Interval for mean Cmax, which is between 80% and 125%, (b) a 90% Confidence Interval for mean AUC(0-t), which is between 80% and 125% and (c) a 90% Confidence Interval for mean AUC(0-8), which is between 80% and 125%.
[00113] In an aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg to about 10 mg.
[00114] In another aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 5 mg.
[00115] In another aspect of the above embodiments, the composition of the present application comprises ketorolac in an amount of about 10 mg.
[00116] In an aspect of the above embodiments, the present method of treating pain in a patient in need thereof comprises administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition disintegrates in less than about 30 seconds when placed in the oral cavity.
[00117] In an aspect of the above embodiments, the present method of treating pain in a patient in need thereof comprises administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition disintegrates in less than about 15 seconds, about 20 seconds, about 25 seconds or about 30 seconds when placed in the oral cavity.
[00118] In an embodiment, the present application relates to a method of treating pain in a patient in need thereof comprising administering to the patient a quick disintegrating composition of ketorolac comprising:
(a) therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof,
(b) at least one water insoluble polymer, and
(c) at least one sugar alcohol,
wherein said composition disintegrates in less than about 30 seconds when placed in the oral cavity.
[00119] In an aspect of the above embodiments, the present method of treating pain in a patient in need thereof comprises administering to the patient a quick disintegrating composition of ketorolac or a pharmaceutically acceptable salt thereof, wherein said composition is in the form of tablets, lozenges, caplets, pills, wafers, films, powders, granules or sachets.
[00120] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol.
[00121] In yet another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients.
[00122] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition comprises ketorolac in an amount of about 5 mg to about 10 mg.
[00123] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition comprises ketorolac in an amount of about 5 mg.
[00124] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition comprises ketorolac in an amount of about 10 mg.
[00125] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition disintegrates in less than about 30 seconds when placed in the oral cavity.
[00126] In an aspect of the above embodiments, the composition of the present application comprises water insoluble polymer and sugar alcohol in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0.
[00127] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said water insoluble polymer and said sugar alcohol are present in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0.
[00128] In another aspect of the above embodiments, the composition of the present application comprises ketorolac and sugar alcohol in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0.
[00129] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said ketorolac and said sugar alcohol are present in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0.
[00130] In an embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition releases at least about 80% of ketorolac within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus.
[00131] In an embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus.
[00132] In an embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
[00133] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said composition exhibits at least one of the following in-vitro release profile:
i. releases at least about 80% of ketorolac within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus;
ii. releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus; or
iii. releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
[00134] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said water insoluble polymer and said sugar alcohol are present in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0 and said composition exhibits at least one of the following in-vitro release profile:
i. releases at least about 80% of ketorolac within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus;
ii. releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus; or
iii. releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
[00135] In another embodiment, the present application relates to a quick disintegrating oral composition of ketorolac comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer,
(b) an extragranular portion comprising at least one sugar alcohol, and
(c) one or more pharmaceutically acceptable excipients,
wherein said ketorolac and said sugar alcohol are present in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0 and said composition exhibits at least one of the following in-vitro release profile:
i. releases at least about 80% of ketorolac within about 5 minutes when measured in 600ml of pH 1.2 simulated gastric fluid at 50 rpm and at 37°C using USP type II apparatus;
ii. releases at least about 90% of ketorolac within about 5 minutes when measured in 600ml of pH 4.5 acetate buffer at 50 rpm and at 37°C using USP type II apparatus; or
iii. releases at least about 95% of ketorolac within about 5 minutes when measured in 600ml of pH 6.8 phosphate buffer and/or purified water at 50 rpm and at 37°C using USP type II apparatus.
[00136] In some embodiments, the quick disintegrating oral composition of the present application comprises at least one water insoluble polymer in the intra-granular portion.
[00137] The water insoluble polymer may be present in the composition disclosed herein a variety of concentrations. For example, the quick disintegrating oral composition disclosed herein can comprise water insoluble polymer in an amount of at least 30% by weight, at least 35% by weight, at least 40% by weight, at least 45% by weight, at least 50% by weight, at least 55% by weight, at least 60% by weight, or a percentage between any two of the above values, based on the total weight of the composition.
[00138] In some embodiments, the quick disintegrating oral composition of ketorolac of present application comprises of at least one water insoluble polymer in an amount of from about 30% to about 60% by weight, or from about 30% to about 55% by weight, or from about 30% to about 50% by weight, or from about 30% to about 45% by weight, or from about 30% to about 40% by weight, or from about 30% to about 35% by weight, based on the total weight of the composition.
[00139] Suitable examples of water insoluble polymer used in the present application include, but are not limited to, microcrystalline cellulose, ethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked dextran and the like or mixtures thereof.
[00140] In some embodiments, the quick disintegrating oral composition of the present application comprises at least one sugar alcohol in the extra-granular portion. Sugar alcohol present in extra-granular portion helps in avoiding the problem of sticking during the granulation process and also helps to achieve desired disintegration/ dissolution of the formulation in the oral cavity.
[00141] The sugar alcohol may be present in the composition disclosed herein a variety of concentrations. For example, the quick disintegrating oral composition disclosed herein can comprise sugar alcohol at least 20% by weight, at least 25% by weight, at least 30% by weight, at least 35% by weight, at least 40% by weight, at least 45% by weight, at least 50% by weight, or a percentage between any two of the above values, based on the total weight of the composition.
[00142] In some embodiments, the quick disintegrating oral composition of ketorolac of present application comprises of at least one sugar alcohol in an amount of from about 20% to about 50% by weight, or from about 20% to about 45% by weight, or from about 20% to about 40% by weight, or from about 20% to about 35% by weight, or from about 20% to about 30% by weight, or from about 20% to about 25% by weight, based on the total weight of the composition.
[00143] Suitable examples of sugar alcohol used in the present application include, but are not limited to, mannitol, maltitol, sorbitol, xylitol, lactitol, erythritol, isomalt, threitol and the like or mixtures thereof.
[00144] In some embodiments, the quick disintegrating oral composition of ketorolac of present application comprises at least one stabilizer selected from selected from water-insoluble antioxidants, pH modifiers or mixtures thereof.
[00145] The stabilizer may be present in the composition disclosed herein a variety of concentrations. For example, the quick disintegrating oral composition disclosed herein can comprise stabilizer at least 0.05% by weight, at least 0.06% by weight, at least 0.07% by weight, at least 0.08% by weight, at least 0.09% by weight, at least 0.1% by weight, or a percentage between any two of the above values, based on the total weight of the composition. The amount of stabilizer that may be used in the present application ranges from about 0.05% to about 1.0% by weight of the composition.
[00146] Suitable examples of water-insoluble antioxidants used as a stabilizer in the present application include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or mixtures thereof.
[00147] Suitable examples of pH modifiers used as a stabilizer in the present application include, but are not limited to, citric acid, tartaric acid, maleic acid, fumaric acid, succinic acid, maleic acid, meglumine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, buffering agents such as phosphate buffer, acetate buffer, borate buffer or mixtures thereof.
[00148] The pharmaceutical composition of the present application further comprises pharmaceutically-acceptable excipients selected from the group of diluents, lubricants, glidants, sweeteners, solvent such as non-aqueous solvent includes, but not limited to, various organic solvents, for example, lower alcohols such as methanol and ethanol, isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, methylene chloride, and the like.
[00149] Other suitable pharmaceutically-acceptable excipients that may be used to formulate the present the quick disintegrating oral composition, are any excipients known to a person skilled in the art, and are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated herein by reference.
[00150] In an embodiment, the pharmaceutical composition of the present application is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH).
[00151] In an embodiment, the pharmaceutical composition of the present application is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH).
[00152] In another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH).
[00153] In another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH).
[00154] In another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 6 months upon storage at 25°C / 60% relative humidity (RH).
[00155] In another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 6 months upon storage at 40°C / 75% relative humidity (RH).
[00156] In yet another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 0.5% of total impurities.
[00157] In yet another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 0.5% of total impurities.
[00158] In yet another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 6 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 1.0% of total impurities.
[00159] In yet another embodiment, the quick disintegrating oral composition of the present application is stable for at least about 6 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 1.0% of total impurities.
[00160] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH).
[00161] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH).
[00162] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 0.5% of total impurities.
[00163] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 0.5% of total impurities.
[00164] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is stable for at least about 6 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 1.0% of total impurities.
[00165] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is stable for at least about 6 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 1.0% of total impurities.
[00166] In an aspect of the above embodiments, the quick disintegrating oral composition of the present application can be packaged in any suitable packaging material known in the art that can ensure the stability of said composition and ketorolac or a pharmaceutically-acceptable salt thereof during storage, transit and administration.
[00167] In an aspect of the above embodiments, the quick disintegrating oral composition of the present application can be packaged using suitable packaging materials selected from high-density polyethylene (HDPE) container, aluminum-aluminum (Alu-Alu) blister package, aluminum-desiccant-aluminum (Alu-Des-Alu) blister package or polyvinyl chloride – polyvinylidene chloride (PVC-PVdC) blister package and the like materials.
[00168] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is packaged using aluminum-desiccant-aluminum (Alu-Des-Alu) blister package, and said composition is stable for at least about 3 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 0.5% of total impurities.
[00169] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is packaged using aluminum-desiccant-aluminum (Alu-Des-Alu) blister package, and said composition is stable for at least about 3 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 0.5% of total impurities.
[00170] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(c) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(d) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is packaged using aluminum-desiccant-aluminum (Alu-Des-Alu) blister package, and said composition is stable for at least about 6 months upon storage at 25°C / 60% relative humidity (RH) and produces less than 1.0% of total impurities.
[00171] In some embodiments, the quick disintegrating oral composition of the present application comprising:
(a) an intragranular portion comprising therapeutically effective amount of ketorolac or a pharmaceutically acceptable salt thereof and at least one water insoluble polymer, and
(b) an extragranular portion comprising at least one sugar alcohol,
wherein said composition is packaged using aluminum-desiccant-aluminum (Alu-Des-Alu) blister package, and said composition is stable for at least about 6 months upon storage at 40°C / 75% relative humidity (RH) and produces less than 1.0% of total impurities.
[00172] In an embodiment, the present application relates to a process to prepare a quick disintegrating oral composition comprising ketorolac or a pharmaceutically acceptable salt thereof, which includes any method known to a person skilled in the art such as, but not limited to, spraying a suspension or dispersion of drug in a conventional coating pan or fluidized bed equipment (such as a Wurster or Glatt) to prepare drug containing granules, followed by drying of the granules when desired granule size is achieved. Such prepared drug containing granules can be mixed with extragranular material including sugar alcohol to prepare desired pharmaceutical composition.
[00173] For preparing granules, any method known to a person skilled in the art such as, but not limited to, operations such as mixing, granulation methods employing planetary mixer, a screw mixer and the like; high-speed mixing granulation methods using a Henschel mixer, a Super mixer and the like; extruding granulation methods using a cylindrical granulator, a rotary granulator, a screw extruding granulator, a pellet mill type granulator and the like; wet high-shear granulation methods, fluidized-bed granulation methods, compression granulation methods, crushing granulation methods and spraying granulation methods can be used.
[00174] Once the granulation process is completed, drying operation can be performed using an oven dryer, a fluidized bed dryer and the like; post drying crushing and sieving can be carried out to obtain granules or fine granules for use.
[00175] Suitable equipment for processing pharmaceutical compositions of the present application include, but not limited to, mechanical sifters, blenders, roller compactors, granulators (rapid mixer or fluid bed granulator), fluid bed dryers, compression machines, rotating bowls or coating pans or a combinations of various equipment.
[00176] In an aspect of the above embodiments, the present application relates to a process to prepare quick disintegrating oral composition of ketorolac comprises the steps of:
(a) preparing a mixture of therapeutically effective amount of ketorolac and at least one water insoluble polymer;
(b) granulating the mixture of step (a) with required quantity of stabilizer;
(c) drying the granules of step (b) followed by mixing with extra-granular material comprising at least one sugar alcohol; and
(d) formulating the mixture of step (c) into desired composition.
[00177] In another aspect of the above embodiments, the present application relates to a process to prepare quick disintegrating oral composition of ketorolac comprises the steps of:
(a) preparing a mixture of therapeutically effective amount of ketorolac and at least one water insoluble polymer;
(b) granulating the mixture of step (a) with required quantity of stabilizer;
(c) drying the granules of step (b) followed by mixing with extra-granular material comprising at least one sugar alcohol; and
(d) formulating the mixture of step (c) into desired composition
wherein said water insoluble polymer and sugar alcohol are present in a weight ratio of from about 1.0: 1.0 to about 1.5: 1.0.
[00178] In another aspect of the above embodiments, the present application relates to a process to prepare quick disintegrating oral composition of ketorolac comprises the steps of:
(a) preparing a mixture of therapeutically effective amount of ketorolac and at least one water insoluble polymer;
(b) granulating the mixture of step (a) with required quantity of stabilizer;
(c) drying the granules of step (b) followed by mixing with extra-granular material comprising at least one sugar alcohol; and
(d) formulating the mixture of step (c) into desired composition
wherein said ketorolac and sugar alcohol are present in a weight ratio of from about 0.3: 1.0 to about 1.0: 1.0.
[00179] In an aspect of the above embodiments, the process of preparing quick disintegrating composition of ketorolac comprises applying/ spraying the stabilizer over the granules using at least one non-aqueous solvent.
[00180] In an aspect of the above embodiments, the present quick disintegrating composition of ketorolac can be formulated in form of tablets, lozenges, caplets, pills, wafers, films, powders, granules or sachets.
[00181] In an aspect of the above embodiments, the quick disintegrating oral composition of ketorolac is formulated as taste-masked composition, to mask the bitter taste of ketorolac, and to have an improved taste, palatability and patient compliance.
[00182] In an aspect of the above embodiments, the quick disintegrating oral composition of ketorolac can be administered with or without a sip of water.
[00183] In yet another aspect of the above embodiments, the present quick disintegrating oral composition of ketorolac can also be co-administered (simultaneously or sequentially) with one or more pharmaceutical agents of value in treating pain or related disease conditions.
[00184] The quick disintegrating oral composition of ketorolac can be administered for the treatment of acute pain including short-term (= 5 days), management of moderately to severe acute pain that requires analgesia at the opioid level, or as advised by the qualified physician.
[00185] The present application is further illustrated by the examples which are provided merely to be exemplary of the pharmaceutical composition described above and do not limit the scope of the application. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

[00186] Examples 1-3:
[00187] The pharmaceutical composition comprising ketorolac or a pharmaceutically acceptable salt thereof may be prepared as given in Table 1.
Table 1
S. No. Ingredients % w/w
Intragranular Example 1 Example 2 Example 3
1 Ketorolac Tromethamine 14.29 16.67 19.80
2 Microcrystalline Cellulose 38.68 - -
3 Mannitol - 59.72 51.42
4 Silicon dioxide 0.71 0.67 -
6 Butylated Hydroxyanisole 0.15 0.10 -
7 Crospovidone - - 3.96
8 Purified water q.s. q.s. q.s.
9 Isopropyl alcohol q.s. q.s. q.s.
Extragranular
10 Microcrystalline Cellulose - 5.79 14.72
11 Mannitol 32.86 - -
12 Crospovidone 7.5 8.89 4.95
13 Sucralose 3 2.67 2.57
14 Spearmint Flavor 1 - -
15 Lemon flavour - - 0.59
16 Lake Of Quinoline Yellow 0.1 - -
17 Silicon dioxide 0.71 0.67 0.99
18 Magnesium stearate 1 1.22 -
19 Sodium stearyl fumarate - - 0.99
Total 100 100 100

[00188] Procedure:
(a) Ketorolac tromethamine and other intragranular materials were mixed and granulated using purified water.
(b) The granules obtained in step (a) were dried.
(c) Butylated hydroxyanisole (BHA) solution was prepared in isopropyl alcohol and sprayed on the dried granules of step (b).
(d) The granules obtained in step (c) were dried, sifted and milled till desired size is obtained.
(e) Extragranular materials were sifted and blended with the granules obtained in step (d) and the blend was compressed into tablets.
[00189] Example 4:
[00190] The pharmacokinetic parameters for quick disintegrating oral composition as prepared in Example 1 containing ketorolac 10mg was studied in comparison with KETOROL® 10 mg oral tablets. A randomized, open-label, single dose, two-treatment, two-period, two-sequence, crossover, comparative bioavailability study was done by administering a single dose oral composition of Example 1 (containing ketorolac 10mg) and KETOROL® 10 mg oral tablets (Dr. Reddy’s Laboratories Ltd, Russia) in 18 healthy, adult, male subjects under fasting conditions. The results of various pharmacokinetic data are shown in Tables 2, 3, 4 and in Figure 1.

Table 2: Mean partial AUCs
Parameters
Mean partial AUCs (ng.hr/ml) Example 1 KETOROL®
(10 mg) % T/R ratio
AUC0-5min 3.30 0.73 452.06
AUC0-7.5min 11.634 3.812 305
AUC0-10min 29.19 11.39 256.28
AUC0-20min 160.25 103.43 154.94
AUC0-30min 372.49 291.93 127.60

Table 3: Comparative Tlag values
Composition Total no. of subjects No. of subjects with median Tlag < 5 minutes % Population with Tlag < 5 minutes
Example - 1 18 14 78%
KETOROL® (10 mg) 18 4 22%

Table 4: Pharmacokinetic parameters
Parameters Example-1 KETOROL® (10 mg) %T/R 90%CI Lower 90%CI Upper
Cmax(ng/ml) 1450 1461 99 91 109
AUC0-t (ng.hr/ml) 5826 5672 103 98 108
AUC0-inf (ng.hr/ml) 6098 5940 103 98 108
CI: Confidence Interval

[00191] From Table 2 (mean partial AUCs data), it is evident that exemplary composition of the present application, as set forth in Example 1 containing 10mg of ketorolac has better pharmacokinetic profile compared to KETOROL® 10mg oral tablets.
[00192] From Table 3 (Tlag), it is evident that exemplary composition of the present application, as set forth in Example 1 containing 10mg of ketorolac has Tlag of less than 5 minutes compared to KETOROL® 10mg oral tablets.
[00193] From Table 4 (pharmacokinetic parameters), it is evident that exemplary composition of the present application, as set forth in Example 1 containing 10mg of ketorolac is bioequivalent to commercially available ketorolac composition, i.e. KETOROL® 10mg oral tablets.
[00194] From Fig. 1, it is evident that exemplary composition of the present application, as set forth in Example 1 containing 10mg of ketorolac achieves mean plasma concentration or pain relieving concentration (EC50) of about 370 ng/mL, in about 8.5 minutes (0.14 hr) compared to 12 minutes (0.20 hr) of KETOROL® 10mg oral tablets.

Example- 5:
[00195] The pharmaceutical compositions as prepared in Example 1, 2 and 3 were subjected for disintegration study in comparison with KETOROL® (10 mg). The results are shown in Table 5.
Table 5: Comparative disintegration time
Composition Example-1 Example-2 Example-3 KETOROL® 10 mg
Disintegration time (seconds) 10 45 25 205

[00196] Example 6:
[00197] The pharmaceutical composition as prepared in Example 1 was subjected to dissolution studies in different media like, purified water, pH 1.2 simulated gastric juice, pH 4.5 acetate buffer and pH 6.8 phosphate buffer. The study was conducted using 600ml media, at 50 rpm, at 37°C using USP type II apparatus. The dissolution results in comparison with KETOROL® (10 mg) are shown in Table 7.

Table 7

Time (Min) Purified water pH 1.2 simulated gastric juice pH 4.5 Acetate buffer pH 6.8 Phosphate buffer
KETOROL® Example 1 KETOROL® Example 1 KETOROL® Example 1 KETOROL® Example 1
Average (% drug release)
5 58 103 51 88 66 97 16 105
10 100 105 86 96 98 98 82 106
15 99 105 89 93 100 101 98 109
20 101 105 91 96 101 102 102 108
30 102 105 93 95 102 102 103 108

[00198] Example 7:
[00199] The pharmaceutical composition as prepared in Example 1 was studied for effect of different packaging materials. Composition of Example 1 was packed in using Alu-Alu Blister and Alu-Des-Alu Blister as packaging materials and the packaged compositions were subjected to accelerated stability testing for a period of 6 months under storage conditions at 40°C /75% RH. At the end of 6 months, the compositions were tested for various parameters and the results are shown in Table 8.

Table 8
Storage Condition Pack Time Point Assay (%) 1-Keto analog impurity (%) Any other individual impurity (%) Total Impurity (%)
40°C / 75%RH Alu-Alu Blister 0 99.1 0.01 0.02 0.05
1 99.4 0.13 0.20 0.37
2 100 0.21 0.32 0.62
3 99.2 0.30 0.50 0.86
6 98.5 0.50 0.81 1.45
Alu-Des-Alu Blister 0 99.1 0.01 0.02 0.05
1 99.9 0.07 0.04 0.17
2 102.6 0.09 0.09 0.23
3 97.1 0.10 0.10 0.29
6 99.7 0.16 0.23 0.57
Alu-Alu: Aluminum-Aluminum; Alu-Des-Alu: Aluminum-Desiccant-Aluminum

[00200] Example 8:
[00201] The pharmaceutical compositions as prepared in Example 1 and 2 containing different antioxidant concentration were studied for its effect during stability. The accelerated stability study was done for a period of 3 months under the storage conditions at 40°C /75% RH using Alu-Desiccant Alu Blister. The results are shown in Table 9.

Table 9
Parameters Example 1 Example 2
0M 1M 2M 3M 0M 1M 2M 3M
Ketorolac 1- hydroxy analogue 0 ND ND 0 0 0 ND 0
Ketorolac 1-keto analogue 0 0.1 0.1 0.1 0 0.1 0.1 0.54
Any other individual impurity 0 0 0.1 0.1 0.1 0.1 0.1 0.44
Total Impurities 0.1 0.2 0.2 0.29 0.1 0.2 0.3 1.09
M: Month, ND: Not Detected

[00202] While several particular forms of the application have been illustrated and described, it will be apparent that various modifications and combinations of the application detailed in the text can be made without departing from the spirit and scope of the application.