DESC:FIELD OF THE INVENTION

The present invention relates to sublingual films of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients with a diffusion flux of 10-110µg/cm2/min through biological mucosal membranes equivalent to human oral mucosa.

BACKGROUND OF THE INVENTION

Ketorolac is a non-steroidal anti-inflammatory agent with potent analgesic properties. Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the chemical structure is:

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of Ketorolac tromethamine is 376.41. Its molecular formula is C19H24N2O6.

The drug is currently administered as the racemic mixture, either orally or by injection, and is commercially available in forms, suited for such modes of delivery. In adults, following administration of single oral or intra-muscular (IM) or intra-venous (IV) doses of Ketorolac tromethamine in the recommended dosage range, the clearance of the racemate does not change implying that the pharmacokinetics of Ketorolac tromethamine in adults, following single or multiple IM, IV doses or recommended oral doses are linear.

Ketorolac oral tablet at a dosage of 10mg is known to result in peak plasma concentration (Cmax) of around 0.7-1.1?g/mL with a Tmax of 40 minutes if well absorbed from the gastro-intestinal tract. Through intra-muscular (IM) injection at a dosage of 30mg, Ketorolac is known to result in Cmax of around 1.7-3.1?g/mL with a Tmax between 15-70 min. Ketorolac at a dosage of 15mg through intra-venous infusion is known to deliver Cmax of around 2.0-3.0?g/mL.

Ketorolac is 85-100% absorbed after oral administration. However, the oral administration of Ketorolac can be quite irritating to the gastrointestinal tract. Thus, for oral use, the FDA has approved only low-dosage tablets containing only 10 mg of Ketorolac tromethamine salt.

During the course of conversion from IM route to oral medication, Ketorolac oral tablets are used as a follow-on therapy to parenteral Ketorolac. The Ketorolac IM should be replaced by an oral analgesic as soon as feasible. Hence, amongst the drug delivery options, despite its challenges, oral administration being the most desirable and common route continues to be pursued for improvement with regard to its disadvantages.

Research efforts in the oral drug delivery segment have led to the recent development of oral fast dissolving film/strips. This form of oral mucosal drug delivery is an alternative method of drug delivery that offers several advantages over injectable, inhalable and enteral methods. Because the oral mucosa is highly vascularized, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, by- passing the gastrointestinal tract and first-pass metabolism in the liver.

The oral film/strips offer the advantages of convenience of dosing, portability and wider acceptability by paediatric as well as geriatric population. The advantages of oral films include larger surface area that leads to rapid disintegration and dissolution along with its ease of swallowing property. The oral films aid in quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa.

In sublingual administration route, the drug placed under the tongue reaches directly into the blood stream through ventral surface of the tongue and floor of the mouth. Through the reticulated vein which lies underneath the oral mucosa, the drug is rapidly absorbed and transported through the facial, internal jugular and brachiocephalic veins to be drained in to systemic circulation.

The sublingual route usually produces a faster onset of action than orally ingested forms, as the drug is absorbed through the sublingual blood vessels bypassing the hepatic first-pass metabolic processes. The main mechanism for the absorption of the drug in to oral mucosa is via passive diffusion into the lipoidal membrane. For sublingual formulations, the small volume of saliva is usually sufficient for disintegration in the oral cavity. The absorption of the drug through the sublingual route is 3 to 10 times greater than oral route. Peak blood levels of most products administered sublingually are achieved within 10 to 15 minutes, which is generally much faster than when those same drugs are ingested orally. Sublingual absorption is efficient. The percent of each dose absorbed is generally higher than that achieved by means of oral ingestion.

Sublingual drug delivery through the sublingual mucosal membranes covers the ventral side of the tongue and the soft palate. Out of the total surface area of the oral cavity, non-keratinised epithelia involved in the sublingual delivery amounts to 37.32 cm2. In terms of permeability, the sublingual area of the oral cavity is more permeable than the buccal (cheek) area, which in turn is more permeable than the palatal (roof of the mouth) area.

Various types of sublingual dosage forms like tablets, sprays and films were developed to overcome the difficulty in swallowing conventional tablet, among paediatric, geriatric and psychiatric patients with dysphagia.

In US Patent 20090246273, Al-Ghananeem reported the development of Ketorolac in a transmucosal spray dosage form i.e., the formulation is sprayed directly onto the tissue under the patient's tongue to obtain relief within 1-5 minutes, with a peak plasma concentration of 1.4?g in 10 minutes.

In US Patent 7,879,901, the preparation of tablets for sublingual administration of Ketorolac or one of its salts along with a ternary mixture of lactose/sorbitol/cellulose is disclosed.

Mettu & Veera Reddy reported on the formulation and pharmacokinetics of Ketorolac tromethamine fast dissolving tablets [Drug Res (Stuttg) 63(11): 586-90 (2013)]. The optimized formulation showed a Cmax of 1.25?g/mL at 1h Tmax, compared to 0.99?g /mL at 2 h Tmax, in the case of conventional tablets.

Problem associated with the sublingual tablet formulation is that there is always a risk that the patient will swallow part of the dose before the active substance has been released and absorbed locally into systemic circulation. This could result in an unwanted prolongation of the pharmacological effect. Even the oral spray drug delivery systems have many disadvantages like inaccuracy of dosing, patient incompliance, cost of the preparation and frequency of administration.

Therefore, Ketorolac drug in preferred low dosage can be delivered in a quick disintegrating sublingual dosage form and, as the disintegration and dissolution of the dosage form occurs rapidly there is rapid onset of action without any lag. The patient can ingest the dosage from anywhere and at anytime without the aid of water which would be helpful especially in cases of unavailability of water, motion sickness, sudden episodes of allergic attacks or deglutition problems.

The present invention addresses the disadvantages of state of the art as the disclosed sublingual films lead to rapid disintegration and dissolution along with its ease of swallowing property. The sublingual films aid in quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa.

OBJECTS OF THE INVENTION

The main object of the invention relates to formulation of sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about10-110?g/cm2/min.

Yet another object of the invention relates to pharmaceutical sublingual films of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and water soluble polymeric components.

Yet another object of the invention relates to pharmaceutical sublingual film of Ketorolac tromethamine with reduced drug load to deliver optimum diffusion flux leading to higher Cmax achievable with IM and IV delivery forms.

Yet another object of the invention relates to pharmaceutical sublingual films of Ketorolac delivering target flux amounts with dosage as low as 2mg/unit via sublingual delivery.

Yet another object of the invention relates to pharmaceutical sublingual films of Ketorolac for quick relief.

Yet another object of the invention relates to pharmaceutical sublingual films of Ketorolac as an alternative to the Ketorolac IM and IV delivery.

Still another object of the invention relates to a process for preparation of pharmaceutical sublingual films of Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient, and water soluble polymeric components.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides formulation and method of preparation of pharmaceutical sublingual films of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients with a diffusion flux of about 10-110?g/cm2/min.

In one embodiment of the invention, the present invention provides a pharmaceutical sublingual film of Ketorolac comprising 10mg of Ketorolac tromethamine and pharmaceutically acceptable excipients with a diffusion flux of about 75-110µg/cm2/min.

In an another embodiment of the invention, the present invention provides a pharmaceutical sublingual film of Ketorolac comprising 5mg of Ketorolac tromethamine and pharmaceutically acceptable excipients with a diffusion flux of about 30-65µg/cm2/min.

In further embodiments of the invention, the present invention provides a pharmaceutical sublingual film of Ketorolac comprising 2mg of Ketorolac tromethamine and pharmaceutically acceptable excipients with a diffusion flux of about 10-30µg/cm2/min.

In another aspect, the present invention provides a pharmaceutical sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient, and water soluble polymeric components.

In one embodiment of the invention the pharmaceutical sublingual film further optionally comprises of other pharmaceutically acceptable excipients selected from muco-adhesive agents, plasticizers, surfactants/non ionic solubilizers, flavours, sweeteners and colour additives.

In another embodiment of the invention, the “water soluble polymeric components” ranges about 5% to 75% w/w of the total weight of pharmaceutical sublingual film of Ketorolac, preferably about 35% to 75% w/w of the total weight of pharmaceutical sublingual film of Ketorolac and more preferably about 40% to 70% w/w of the total weight of pharmaceutical sublingual film.

In preferred embodiments, the water soluble polymeric components comprises polyethylene oxide, hydrophilic cellulosic polymer (HPMC) and maltodextrin.

In another embodiment, polyethylene oxide present in the sublingual film ranges about 0% to 20% by weight of the water soluble polymeric components, preferably about 1% to 15% by weight of the water soluble polymeric components and more preferably about 10% to 15% by weight of the water soluble polymeric components.

In a further embodiment, hydroxypropylmethyl cellulose present in the sublingual film ranges about 30% to 90% by weight of the water soluble polymeric components, preferably about 40% to 90% by weight of polymeric components, and more preferably about 70% to 85% by weight of the water soluble polymeric components.

In another embodiment, maltodextrin present in the sublingual film ranges about 0% to 60% by weight of water soluble polymeric components, preferably about 1% to 30% by weight of water soluble polymeric components and more preferably about 5% to 15% by weight of the water soluble polymeric components.

In a further aspect, the present invention provides a pharmaceutical sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Ketorolac dosage with a diffusion flux about 50-600?g/cm2 within five minutes through the biological mucosal membranes equivalent to human oral mucosa.

In a further aspect, the present invention provides a pharmaceutical sublingual film of Ketorolac delivering target flux amounts for quick relief to the patients with dosage amount as low as 2mg/unit.

In a further aspect, the present invention provides a process for preparation of pharmaceutical sublingual film of Ketorolac comprising the steps of:
A. Preparing a pharmaceutical sublingual film of Ketorolac comprising Ketorolac tromethamine and water soluble polymeric component to form a slurry;
B. Layering the slurry of step A on polyethylene sheet and
C. Drying the layered composition of step B at 80ºC-100ºC for 10-20 minutes to obtain the sublingual film.

BRIEF DESCRIPTION OF THE DRAWINGS

A complete understanding of the system and method of the present invention may be obtained by reference to the following drawings:

Fig.1 Elucidates the diffusion of ketorolac sublingual film through porcine membrane from compositions given in examples 4, 5 and 6 and the orally dissolving tablet composition disclosed in example-7.

Fig.2 Elucidates the in-vitro dissolution of Ketorolac tromethamine sublingual film composition mentioned in example 11 as per the process described in example 14.

Fig.3 Elucidates the diffusion of ketorolac sublingual film through porcine membrane from compositions given in examples 11, 12 and 13 as disclosed in Example-15.

Fig.4 Elucidates comparative diffusion of ketorolac sublingual film and orally dissolving tablet through porcine membrane using compositions given in example-11 and example-15, respectively.

DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the presently preferred embodiments of the invention, which, together with the following examples, serve to explain the principles of the invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that various structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention.

As used herein the “water soluble polymeric components” refers to polymeric components at least partially soluble in water or fully or predominantly soluble in water or swellable in water.

The present invention provides the formulation of pharmaceutical sublingual films of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 10-110µg/cm2/min. In embodiments of the present invention, the diffusion flux of the Ketorolac sublingual films also ranged between 25 and 100µg/cm2/min.

The recommended dosage unit of the inventive composition is composed of about 2-10mg of Ketorolac, preferably Ketorolac tromethamine. The pharmaceutical sublingual films of the present invention, with the administration of a dose of about 2-10mg upon administration can provide rapid analgesic or anti-inflammatory action.

In embodiments of the present invention, the recommended dosage unit of the inventive composition is composed of 2, 3, 5 & 10mg of Ketorolac tromethamine mixed with the pharmaceutically acceptable excipients.

In embodiments of the present invention the diffusion flux of 2mg Ketorolac tromethamine sublingual film ranges about 10-30µg/cm2/min, 5mg Ketorolac tromethamine sublingual film ranges about 30-65µg/cm2/min and 10mg Ketorolac tromethamine sublingual film ranges about 75-110µg/cm2/min.

The present invention further provides a pharmaceutical sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Ketorolac dosage with a diffusion flux about 50-600?g/cm2 within five minutes through the biological mucosal membranes equivalent to human oral mucosa.

The present invention also provides a pharmaceutical sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Ketorolac dosage with a diffusion flux about 150-1100?g/cm2 within ten minutes through the biological mucosal membranes equivalent to human oral mucosa.

In another embodiment of the present invention, the formulation of pharmaceutical sublingual films of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients deliver a diffusion flux ranging between 260 and 1000µg/cm2/min within ten minutes through the biological mucosal membranes equivalent to human oral mucosa.

The present invention further provides a pharmaceutical sublingual film of ketorolac comprising ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and water soluble polymeric components.

The “water soluble polymer” may be partially water soluble polymer or predominantly water soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer. The polymers may include cellulose or cellulose derivatives. Suitable examples of water soluble polymer includes but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water-swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof. In the embodiments of the invention the most preferred water soluble polymers are cellulosic polymers, maltodextrin and polyethylene oxide or combinations thereof. The cellulosic polymers used in combination with polyethylene oxide and maltodextrin are selected from but are not limited to hydroxy propyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC). The polyethylene oxide polymer in combination with a hydrophilic cellulosic polymer and maltodextrin achieves muco-adhesive, flexible, strong films. In accordance with the present invention “water soluble polymeric components” desirably ranges about 5% to 75%w/w of the total weight of pharmaceutical sublingual film of Ketorolac, preferably about 35% to 75%w/w of the total weight of pharmaceutical sublingual film of Ketorolac and more preferably about 40% to 70% w/w of the total weight of pharmaceutical sublingual film.

In a further embodiment, hydroxypropylmethyl cellulose present in the sublingual film ranges about 30% to 90% by weight of the water soluble polymeric components, preferably about 40% to 90% by weight of polymeric components, and more preferably about 70% to 85% by weight of the water soluble polymeric components.

In another embodiment, maltodextrin present in the sublingual film ranges about 0% to 60% by weight of water soluble polymeric components, preferably about 1% to 30% by weight of water soluble polymeric components and more preferably about 5% to 15% by weight of the water soluble polymeric components.

In another embodiment, polyethylene oxide present in the sublingual film ranges about 0% to 20% by weight of the water soluble polymeric components, preferably about 1% to 15% by weight of the water soluble polymeric components and more preferably about 10% to 15% by weight of the water soluble polymeric components.

A particular embodiment of the invention incorporates a plasticizer to impart flexibility, enhance elasticity and decrease brittleness. Preferred plasticizers include triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof. In accordance with the present invention plasticizer desirably ranges about 0% to 20% w/w of the total sublingual film, preferably about 2% to 15% w/w of the total sublingual film and more preferably about 3% to 12% w/w of the total sublingual film.

Another embodiment of the invention incorporates muco-adhesive polymer for adhesion to mucosal membranes in-vivo/in-vitro, wherein the muco-adhesive polymer is chitosan, hyaluronate, alginate, gelatin, collagen, poly(acrylic acid), poly(methacrylic acid), poly(L-lysine), poly(ethylene imine), poly(ethylene oxide), poly, (2-hydroxyethyl methacrylate) and salts, derivatives or copolymers thereof.

The pharmaceutical sublingual film incorporates at least one flavour, chosen from natural and synthetic flavouring liquids. An illustrative list of such agents includes volatile oils, synthetic flavour oils, flavouring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavours.

The pharmaceutical sublingual film incorporates at least one sweetener, chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.

The pharmaceutical sublingual film incorporates at least one diluent which is selected from but not limited to mannitol, microcrystalline cellulose (MCC), lactose, and combinations thereof. In one particular embodiment mannitol was used.

The pharmaceutical sublingual film incorporates at least one surfactant/non ionic solubilizer chosen from the following but not limited to poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearates, fatty acid glyceryl polyglyceryl esters, polyglyceryl esters, and combinations thereof.

The pharmaceutical sublingual film incorporates at least one colouring agent, which may be provided in a dosage form of the present invention, including pharmaceutically acceptable natural or artificially synthesized dyes. A great variety of such pharmaceutically acceptable dyes have been known to be suitable for use in pharmaceutical compositions, for example natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin/CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, titanium dioxide, turmeric, natural colors, aronia/redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, brilliant blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow and tartrazine.

The present invention provides a process for preparation of pharmaceutical sublingual film of Ketorolac comprising the steps of:
A. Preparing a pharmaceutical sublingual film of Ketorolac comprising Ketorolac tromethamine and water soluble polymeric components to form a slurry;
B. Layering the slurry of step A on polyethylene sheet and
C. Drying the layered composition of step B at 80ºC-100ºC for 10-20 minutes to obtain the sublingual film.

The process for the preparation of the sublingual film uses a solvent, which may be selected from C2-C4 alcohols selected from ethyl alcohol, isopropyl alcohol, purified water and combinations thereof. In a particular embodiment, purified water was used.

The present invention also provides the pharmaceutical sublingual film of Ketorolac tromethamine which has the thickness about 0.07mm (70µm) to about 0.2mm (200µm), resulting in weight in the range of about 25mg to 100mg, and useful as rapid analgesic for treatment of acute pain or for anti-inflammatory action.

The pharmaceutical sublingual film according to the present invention may have any shape but not limited to circular, square, rectangular or triangular.

The following examples illustrate few methods of preparing pharmaceutical sublingual films in accordance with certain non-limiting aspects of the invention. All percentages in the examples are by weight unless otherwise indicated.

Examples-1, 2 & 3:-
Sublingual films of Ketorolac tromethamine-10mg, 5mg & 3mg
Composition:-
Ingredients Percentage range Per Unit
Eg.,1 Eg.,2 Eg.,3
10mg 5mg 3mg
Ketorolac tromethamine 20.8% 20.8% 12.5%
Maltodextrin 8-10% 8-10% 8-10%
Polyethylene Oxide 5-10% 5-10% 5-10%
Sucralose 5-10% 5-10% 5-10%
Mannitol 4-7% 4-7% 4-7%
Hydroxypropylmethyl cellulose 35-50% 35-50% 35-50%
Polyethylene Glycol 7-15% 7-15% -
Glycerol - - 6-13%
Pepper Mint Supreme 1-3% 1-3% 0.8-2.5%
Purified water q.s q.s q.s

Examples- 4, 5 & 6:-
Sublingual films of Ketorolac tromethamine-10mg, 5mg & 3mg
Composition:-
Ingredients mg/Sublingual film
Eg.,4 Eg.,5 Eg.,6
10mg 5mg 3mg
Ketorolac tromethamine 10 5 3
Maltodextrin 4 4 4
Polyethylene Oxide 3 3 3
Sucralose 3 3 3
Mannitol 2 7 9
Hydroxypropylmethyl cellulose 20 20 20
Polyethylene Glycol 5 5 5
Pepper Mint Supreme 1 1 1
Purified water q.s q.s q.s
Total Weight 48mg 48mg 48mg

Process for Preparation:-
1. Dispersion of Ketorolac tromethamine in purified water.
2. Addition of Maltodextrin to step 1 and stirring for 3-5 minutes.
3. Addition of Polyethylene oxide to step 2 and stirring for 3-5 minutes.
4. Addition of Sucralose to step 3 and stirring for 3-5 minutes.
5. Addition of Mannitol to step 4 and stirring for 3-5 minutes.
6. Addition of Hydroxypropylmethyl cellulose, polyethylene glycol/glycerol and peppermint supreme to step 5 and stirring for 5-10 minutes to form slurry.
7. The slurry of step 6 was layered on polyethylene sheet and dried for 10-20 minutes at 90°C to obtain the sublingual films.

Example 7: Ex-vivo/In-Vitro Permeation studies on Ketorolac sublingual films prepared from composition mentioned in examples 4, 5 & 6.

Method:- Fresh porcine oral mucosa or synthetic (cellulose acetate) membranes were used to perform the ex-vivo/in-vitro permeability studies. The membrane was inserted between the donor and receptor compartment of Franz diffusion cell (fabricated with a surface permeation area of 1.76 cm2 and total permeation area of 26.15cm2). The receptor compartment was filled with phosphate buffer (pH 7.3) and maintained at 37°C ± 0.2°C and the hydrodynamics were maintained by stirring with a magnetic bead at about 50 rpm. One previously weighed sublingual film was placed in intimate contact with the surface of the membrane that was previously moistened with a few drops of simulated saliva. The donor compartment was filled with 1 mL of simulated saliva of pH 6.8. Test samples were withdrawn at suitable intervals, replacing the same amount with the fresh medium. The percentage of drug permeated was determined by measuring the absorbance at 322nm using UV-Spectrophotometry. The ex-vivo permeation experiments were conducted in triplicate and the mean values are reported.

The ex-vivo permeation results of Ketorolac sublingual films as prepared from compositions in examples 4, 5 & 6 is provided below.

Ketorolac permeation through porcine membrane
Composition Cumulative Flux (µg/cm2)
at diffusion period of 10 min
Ketorolac Sublingual film- 2mg 264
Ketorolac Sublingual film- 5mg 610
Ketorolac Sublingual film- 10mg 1011
Ketorolac Orally Dissolving Tablet-10mg 474

Examples-8, 9 & 10:
Sublingual films of Ketorolac tromethamine-10mg, 5mg & 2mg
Composition:-
Ingredients Percentage range Per Unit
Eg.,8 Eg.,9 Eg.,10
10mg 5mg 2mg
Ketorolac tromethamine 23.3% 11.6% 5%
Maltodextrin 2-8% 2-7% 1-6%
Polyethylene Oxide 5-10% 4-8% 4-9%
Sucralose 4-10% 5-9% 4-8%
Mannitol 2-7% 3-8% -
Polyhydroxylated castor oil - 6-12% 6-13%
Hydroxypropylmethyl cellulose 30-55% 38-55% 45-55%
Polyethylene Glycol 7-15% 7-15% -
Glycerol - - 10-18%
Pepper Mint Supreme 1-4% 1-3% -
Vanilla flavour 6-13%
FD&C Yellow 0.1-0.4% - 0.2-0.4%
Purified water q.s q.s q.s

Examples- 11, 12& 13:
Sublingual film of Ketorolac tromethamine-10mg, 5mg & 2mg
Composition:-
S.No Ingredients mg/Sublingual film
Eg.,11 Eg.,12 Eg.,13
10mg 5mg 2mg
1. Ketorolac tromethamine 10 5 2
2. Maltodextrin 3 3 4
3. Polyethylene Oxide 4 3 4
4. Sucralose 5 3 4
5. Polyhydroxylated castor oil 3 5 5
6. Hydroxypropylmethyl cellulose 13.9 18.9 16.1
7. Glycerol 3 4 4
8. Pepper Mint Supreme 1 1 0.8
9. FD&C Yellow 0.1 0.1 0.1
10. Purified water q.s q.s q.s
Total Weight 43 43 40

Process for Preparation:-
1. Dispersion of Ketorolac tromethamine in purified water.
2. Addition of Maltodextrin to step 1 and stirring for 3-5 minutes.
3. Addition of Sucralose to step 2 and stirring for 3-5 minutes.
4. Addition of Polyethylene oxide to step 3 and stirring for 3-5 minutes.
5. Addition of Hydroxypropylmethyl cellulose, glycerol and peppermint supreme to step 4 and stirring for 5-10 minutes.
6. Addition of Polyhydroxylated castor oil to step 5 and stirring for 3-5 minutes.
7. Addition of FD&C Yellow to step 6 and stirring for 3-5 minutes to form slurry.
8. The slurry of step 7 was layered on polyethylene sheet and dried for 10-20 minutes at 90°C to obtain the sublingual films.

Physical Properties of the Sublingual films of Example-11, 12, & 13

Parameter Eg.,11 Eg.,12 Eg.,13
Film Weight 45mg ± 5mg 45mg ± 5mg 40mg ± 5mg
Film Thickness 103µ ± 5µ 103µ ± 5µ 103µ ± 5µ
Film Folding Endurance >250 folds >250 folds >250 folds

Example-14:- In-Vitro Dissolution Study of Ketorolac sublingual films prepared by examples 11, 12 and 13 in comparison to Ketorolac ODT Tablet.

Method: in-vitro dissolution studies were carried out using water or simulated salivary fluid (pH 6.8) as a dissolution medium. Temperature of the dissolution medium was maintained at 37±0.5°C. Samples were withdrawn at required interval, filtered (through 0.45µ) and replaced with equivalent amount of fresh dissolution medium. The samples were suitably diluted and estimated UV-Spectrophotometrically at 322nm. The dissolution experiments were conducted in triplicate and the mean values are reported.

Ketorolac --In-Vitro Dissolution% in Salivary Fluid (simulated)

Dissolution
Period Ketorolac SF
(2mg) Ketorolac SF
(5mg) Ketorolac SF
(10mg) Ketorolac ODT
(10mg)
2 min 98.7 97.1 95.6 52.3
5 min 100 98.3 97.3 68.8

Ketorolac SF—In-Vitro Dissolution% in Water

Dissolution
Period Ketorolac SF
(2mg) Ketorolac SF
(5mg) Ketorolac SF
(10mg) Ketorolac ODT
(10mg)
2 min 95.6 94.1 97.3 49.2
5 min 98.4 95.9 98.0 68.2

As elucidated in Fig.2, in-vitro dissolution of Ketorolac composition (Sublingual film) provided complete drug disintegration within 75 seconds and drug release up to 95% within 2 minutes. The in-vitro dissolution of Ketorolac orally dissolving tablet indicated drug release up to 52% in 2 minutes and 69% in 5 minutes.

Example-15:- Ex-Vivo Permeation of Ketorolac Sublingual films prepared by Examples 11, 12 and 13 in comparison to Ketorolac ODT Tablet.

Method: Fresh porcine oral mucosa or synthetic (cellulose acetate) membranes were used to perform the ex-vivo/in-vitro permeability studies. The membrane was inserted between the donor and receptor compartment of Franz diffusion cell (fabricated with a surface permeation area of 1.76 cm2 and total permeation area of 26.15cm2). The receptor compartment was filled with phosphate buffer (pH 7.3) and maintained at 37°C ± 0.2°C and the hydrodynamics were maintained by stirring with a magnetic bead at about 50 rpm. One previously weighed sublingual film was placed in intimate contact with the surface of the membrane that was previously moistened with a few drops of simulated saliva. The donor compartment was filled with 1 mL of simulated saliva of pH 6.8. Test samples were withdrawn at suitable intervals, replacing the same amount with the fresh medium. The percentage of drug permeated was determined by measuring the absorbance at 322nm using UV-Spectrophotometry. The ex-vivo permeation experiments were conducted in triplicate and the mean values are reported.

Ketorolac Sublingual Film:
Ketorolac permeation through porcine membrane at various diffusion periods
Strength Diffusion
Period Permeation %
Cumulative Flux
(?g/cm2) ‘J’
(?g/cm2/min)
Ketorolac Sublingual film
2mg 2 min 3.3 37 18.5
5 min 5.5 62 12.4
10 min 13.8 157 15.7
5mg 2 min 3.6 103 51.5
5 min 10.4 295 59.0
10 min 11.0 311 31.1
10mg 2 min 6.5 366 183
5 min 10.1 570 114
10 min 13.9 789 78.9
Ketorolac ODT Tablet
10mg 2 min 2.4 136 49.0
5 min 3.1 175 23.6
10 min 6.1 345 22.7

As elucidated in Fig.3, Ketorolac cumulative flux (µg/cm2) at various strengths ranging from 2 to 10mg was recorded after 2, 5 and 10 minutes through porcine membrane.

The Ex-vivo permeability studies at various time intervals conducted on the sublingual films employing fresh porcine oro-mucosa demonstrated a Ketorolac cumulative flux (µg/cm2) between 18 and 180 µg/cm2 after 2 minutes of diffusion period for Ketorolac drug dosages ranging from 2mg to 10mg per film. The Ketorolac cumulative flux (µg/cm2) ranged between 60 and 570 µg/cm2 after 5 minutes of diffusion period for Ketorolac drug dosages ranging from 2mg to 10mg per film. When the diffusion period was extended, the Ketorolac cumulative flux (µg/cm2) ranged between 155 and 790 µg/cm2 after 10 minutes of diffusion period for Ketorolac drug dosages ranging from 2mg to 10mg per film.

Fig. 4 elucidates the cumulative flux (µg/cm2) of Ketorolac sublingual film (10mg) and Ketorolac orally dissolving tablet (10mg) at diffusion periods of 2 and 5 minutes through the biological (porcine oral mucosa) membrane. The Ketorolac sublingual films exhibited cumulative flux more than 2 folds when compared to the Ketorolac orally dissolving tablet form.
,CLAIMS:Claims:-

1. The pharmaceutical sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 10-110µg/cm2/min.

2. The pharmaceutical sublingual film according to claim 1, wherein said pharmaceutically acceptable excipients comprise water soluble polymeric components.

3. The pharmaceutical sublingual film according to claim 2, wherein said water soluble polymeric components comprise at least one water soluble polymer selected from maltodextrin, hydroxypropylmethyl cellulose and polyethylene oxide.

4. The pharmaceutical sublingual film according to claim 1, wherein the said active ingredient consists of about 2 to 10mg of ketorolac or pharmaceutically acceptable salts thereof.

5. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 2mg of Ketorolac tromethamine and pharmaceutically acceptable excipients with a diffusion flux about 10-30µg/cm2/min.

6. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 5mg of Ketorolac tromethamine and pharmaceutically acceptable excipients with a diffusion flux about 30-65µg/cm2/min.

7. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 10mg of Ketorolac tromethamine and pharmaceutically acceptable excipients with a diffusion flux about 75-110µg/cm2/min.

8. The pharmaceutical sublingual film of Ketorolac comprising Ketorolac or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Ketorolac dosage with a diffusion flux of about 50-600 ?g/cm2 within five minutes through the biological mucosal membranes equivalent to human oral mucosa.

9. A process for preparation of pharmaceutical sublingual film of Ketorolac comprising the steps of:
a) Preparing a pharmaceutical sublingual film of Ketorolac comprising Ketorolac tromethamine and water soluble polymeric components to form a slurry;
b) layering the slurry as per step (a) on polyethylene sheet
c) drying the layered composition of step b) at 80ºC-100ºC for 10-20 minutes to obtain the sublingual film.