FIELD OF THE INVENTION

The present invention relates to topical sprayable compositions of ketorolac tromethamine. The invention also provides the process for preparation of such compositions. Furthermore, the invention relates to the use of said compositions for the treatment of acute pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.

BACKGROUND OF THE INVENTION

Ketorolac is a non-steroidal anti-inflammatory agent. It exhibits analgesic, antiinflammatory and antipyretic activity. It is mainly indicated for short term management of acute pain.

"Ketorolac" refers to the compound having a chemical name (±)-5-benzoyl-2,3-dihydro- lH-pyrrolizine-l-carboxylic acid and the following structural formula (1).

(1)

The term ketorolac encompasses the free acid, its pharmaceutically acceptable salts and esters thereof. Pharmaceutically acceptable salt refers to those salts, which retain the biological effectiveness and properties of the free acid, and which are not biologically or otherwise undesirable. A commercially used pharmaceutically acceptable salt is the "tromethamine" salt of ketorolac, i.e., ketorolac tromethamine (2), available in various dosage forms eg. tablets, injectables, topical gel, intranasal spray and ophthalmic solution.

(2) A commercial product containing ketorolac tromethamine for the treatment of acute pain is available in the form of 2% topical gel. This topical gel product is inconvenient to apply on large areas of the skin and has slower onset of action. A quick onset of action and instant relief is a prerequisite in few conditions, specifically for acute pain due to tissue injury in sports or during exercise. Therefore, a topical composition, which is easy to apply and provides instant relief, is often preferred.

For topical compositions of ketorolac tromethamine, the key challenge is its re- crystallization. Ketorolac tromethamine has a very good solubility in non-aqueous solvents, which rapidly evaporate after the application and leads to its re -crystallization. This affect the performance of the composition as the entire drug does not permeate through skin. Hence, a specific ratio of aqueous and non-aqueous solvents is required.

The other disadvantage due to rapid evaporation of solvents from the topical compositions is the dryness of skin which eventually irritates the skin. There remains, therefore, an unmet need for a topical composition that provides an instant relief, convenience in application, no irritation and no re -crystallization of ketorolac tromethamine on application.

In an attempt to develop novel compositions of ketorolac tromethamine, the present inventors have surprisingly found that a composition comprising one or more solvents, a penetration enhancer and a buffering agent, delivered as a topical spray provides quick onset of action and instant relief, thereby improving the patient convenience and also exhibiting at least comparable efficacy to topical gel compositions currently available in the market. Such compositions are effective in the treatment of pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.

SUMMARY OF THE INVENTION

The present specification relates to a topical sprayable composition of ketorolac tromethamine comprising one or more solvents, a penetration enhancer and a buffering agent. In one aspect, the present specification relates to a topical sprayable composition comprising:

(i) ketorolac tromethamine;

(ii) one or more solvents;

(iii) a penetration enhancer;

(iv) a buffering agent; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect, the present specification relates to a topical sprayable composition comprising:

(i) 1-5% w/w ketorolac tromethamine;

(ii) 10-95% w/w of one or more solvents;

(iii) 1-10% w/w of penetration enhancer;

(iv) 0.1-5% w/w buffering agent; and

(v) 0-20% w/w of one or more pharmaceutically acceptable excipients.

In another aspect, the present specification provides a stable and transparent topical sprayable composition of ketorolac tromethamine.

In yet another aspect, the topical sprayable composition according to the present specification may be used for treating pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.

DESCRIPTION OF THE INVENTION

The present specification relates to a topical sprayable composition of ketorolac tromethamine comprising one or more solvents, a penetration enhancer and a buffering agent.

In one aspect, the present specification relates to a topical sprayable composition comprising:

(i) ketorolac tromethamine;

(ii) one or more solvents; (iii) a penetration enhancer;

(iv) a buffering agent; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect, the present specification relates to a topical sprayable composition comprising:

(i) 1-5% w/w ketorolac tromethamine;

(ii) 10-95% w/w of one or more solvents;

(iii) 1-10% w/w of penetration enhancer;

(iv) 0.1-5% w/w buffering agent; and

(v) 0-20% w/w of one or more pharmaceutically acceptable excipients.

In another aspect, the present specification relates to a topical sprayable composition comprising:

(i) 2% w/w ketorolac tromethamine;

(ii) 40-50% w/w isopropyl alcohol; 10-20% propylene glycol; 20-30% purified water;

(iii) 5-10% w/w dimethyl sulfoxide;

(iv) 0.1-2% w/w sodium acetate trihydrate/ glacial acetic acid buffer; and

(v) 0-20% /w one or more pharmaceutically acceptable excipients.

The term "ketorolac" as used herein is defined to mean at least one form of ketorolac selected from free acid, base, active metabolites thereof, complexes thereof, pharmaceutically acceptable salts thereof. Example is ketorolac tromethamine. The concentration of ketorolac tromethamine employed in the present specification is from 1-5% w/w, e.g. 2% w/w of the composition.

As used herein the term "topical sprayable compositions" refers to a ketorolac composition, which provides a convenient application in a form of topical spray on external body surface. As used herein the term "solvents" refers to any pharmaceutically acceptable solvent e.g. aqueous or non-aqueous solvents or combinations thereof. The aqueous solvent is purified water. The ratio of aqueous to non-aqueous solvents employed in the present specification is 1 :1 to 1 :10, e.g. 1 :2, 1 :8. The range of one or more solvents employed in the present specification is from 10-95% w/w of the composition.

Suitable "Solvents" may be selected from purified water or non-aqueous solvents. The non-aqueous solvent may be selected from aliphatic alcohol, propylene glycol, polyethylene glycol 400, N-methyl pyrrolidone, acetone, ethyl acetate, ethyl formate, methyl acetate, methyl ethyl ketone or combinations thereof. The aliphatic alcohol may be selected from methanol, ethanol, propanol, isopropyl alcohol, butanol or combinations thereof. The range of purified water that may be employed in the present specification is from 5-40% w/w of the composition. The range of one or more non-aqueous solvent that may be employed in the present specification is from 20-90% w/w, e.g. 40-80% w/w of the composition. The range of isopropyl alcohol that may be employed in the present specification is from 30-70% w/w, e.g. 50% w/w of the composition. The range of propylene glycol that may be employed in the present specification is from 10-30% w/w, e.g. 15% w/w of the composition.

As used herein, the term "penetration enhancer" refers to a substance, which increases the penetration of composition in the skin. The penetration enhancers used herein may be single or a combination of two or more, selected but not limited to lipophilic solvents, surfactants, fatty acid esters and polyhydric alcohols. The penetration enhancers may be selected from dimethyl sulfoxide, diethylene Glycol Mono ethyl ether, glycerin, benzyl alcohol, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol or combinations thereof. The penetration enhancer as described above may be employed in the present specification in concentration ranging from 1-15% w/w, e.g. 5-10% w/w of the composition.

As used herein, the term "buffering agent" refers to a pharmaceutically acceptable agent that provides sufficient buffering capacity at the desired pH range. Examples of buffers useful in the present specification include, but are not limited to, acetate, glutamate, citrate, tartrate, benzoate, lactate, gluconate, phosphate and glycine and conjugate acids thereof. The buffering agent that may be employed in the present specification comprises sodium acetate trihydrate and glacial acetic acid in concentration ranging from 0.1-5% w/w, e.g. 0.1-2% w/w of the composition.

The composition according to the present specification optionally comprises one or more pharmaceutically acceptable excipients used in the cosmetics or pharmaceutical field, such as surfactants, sequestering agents, antioxidants, preservatives, fillers, electrolytes, humectants, colorants, common mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingo lipids, self-tanning compounds such as DHA, and calmants and protective agents for the skin such as allantoin. Needless to say, a person skilled in the art will take care to select this or these optional excipient(s), and/or the amount thereof.

These excipients may be present in the composition in a range from 0 - 20% w/w of the composition.

Examples of fragrances include plant extracts and essential oils like eucalyptus, lemon, orange, cinnamon, mint, tangerine, grapefruit, spearmint, peppermint, clove, or rosemary oil, or synthetic fragrances such as vanilline and calm valley.

Examples of preservatives include benzalkonium chloride, phenoxy-ethanol, benzyl alcohol, diazolidinylurea and parabens, or combinations thereof.

In yet another aspect, the topical sprayable composition of ketorolac tromethamine is packed in a HDPE bottle fitted with spray pump or a kit comprising HDPE bottle and a spray pump assembly, which needs to be assembled with the bottle by removing screw cap before the first application.

In yet another aspect, the topical composition of ketorolac tromethamine may be delivered as a spray on external body surface. In yet another aspect, the present specification provides a process for the preparation of the topical sprayable composition of ketorolac tromethamine. The process for the preparation may be any conventional suitable process comprising the mixing of ketorolac tromethamine with other excipients of composition.

In yet another aspect, the topical sprayable composition according to the present specification may be used for treating pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.

The specification will now be described in greater detail by reference to the following non-limiting examples.

EXAMPLES

Example 1

Process:

1. In the first vessel, a buffer solution was prepared by mixing sodium acetate trihydrate and glacial acetic acid in purified water. Ketorolac was added to this buffer solution to prepare the drug solution.

2. In a separate vessel, a solvent mixture was prepared by mixing DMSO in ethanol followed by the addition of propylene glycol. 3. In the final step, drug solution was added into the solvent mixture followed by the addition of calm valley to form a clear solution and this solution was filled into HDPE bottles.

Example 2

Process:

1. In the first vessel, a buffer solution was prepared by mixing sodium acetate trihydrate and glacial acetic acid in purified water. Ketorolac was added to this buffer solution to prepare the drug solution.

2. In a separate vessel, a solvent mixture was prepared by mixing DMSO in isopropyl alcohol followed by the addition of propylene glycol.

3. In the final step, drug solution was added into the solvent mixture followed by the addition of calm valley to form a clear solution and this solution was filled into HDPE bottles fitted with metered dose spray pump.

Example 3-5

Process:

1. In the first vessel, mix sodium acetate trihydrate and glacial acetic acid in purified water to prepare a buffer solution. Add Ketorolac to this buffer solution to prepare the drug solution.

2. In a separate vessel, mix DMSO in isopropyl alcohol or isopropyl alcohol and ethanol mixture to prepare a solvent mixture, and then add propylene glycol to the solvent mixture.

3. In the final step, add the drug solution into the solvent mixture followed by the addition of calm valley to form a clear solution and fill this solution into HDPE bottles fitted with metered dose spray pump.

Stability study

The stability of the topical spray compositions of present specification were evaluated through accelerated stability studies. The composition was prepared according to the formula and process of example 2, and was subjected to stability study at various temperature and humidity conditions. The composition was found to be stable at accelerated conditions. Table 1 represents the study result data. Table 1 : Stability study

*ND: Not detected

*RH: Relative humidity

Staining property evaluation:

Staining property of the composition of the present specification was evaluated by spraying the composition prepared in accordance with example 2 on a white cotton cloth and was kept for few minutes and observed for staining. The study was conducted on initial sample (room temperature) and stability sample kept on 40°C/75 %RH 1 Month. No stain was observed in both the sample after spraying. The studies indicate that the non-staining property of the composition retained both in room temperature condition and accelerated condition (40°C/75 %RH).

Spray volume measurement:

Spray volume per actuation of the composition of the present specification was evaluated by using an analytical balance. Spray rate was performed by taking initial weights of spray bottles and weight taken each actuation. Quantity of liquid was delivered by difference between initial weight and final weight. The study repeated 10 times for each spray pump and five pumps were taken as different experiments. Table 2 represents the spray volume data. Table 2: Spray volume per actuation

These studies indicate that pumps are able to deliver 180±5% μΐ of drug solution in different actuation, which reflects on dose uniformity of the product.

Comparative bioavailability Study:

Bioavailability of the topical spray composition according to the present specification was compared with a reference gel product, which is a 2% Ketorolac topical gel composition. The reference product was prepared in accordance to composition disclosed in table 3 using conventional methods.

Table 3 : Reference gel product composition

Dimethyl Sulfoxide (DMSO) 15

Propylene Glycol 30

Ethanol 5

Tromethamine 1.5

Purified Water 39

Dreamon Inde 0.3

Sodium Methyl Hydro xybenzoate 0.18

Sodium Propyl Hydroxybenzoate 0.02

Carbomer 974 P (Carbopol 974P) 2

Glycerol 5

The test spray product of the present specification and the reference gel product were subjected to a randomized, open-label, balanced, single -dose, two-treatment, 2-period, 2-sequence crossover bioavailability study in 24 normal healthy, adult, human subjects. Following an overnight fast of at least 10 hours, subjects were administered with either test or reference product in sitting position as per the randomization schedule as described in Table 4.

Table 4: Comparative bioavailability study dosing

Name: Test product (T) Reference product (R)

Ketorolac Tromethamine Spray 2%w/w Ketorol Gel 2%w/w

Dose: 12 actuations dose (6 actuations on each knee) 2 gm dose (1 gm on each knee)

40.32 mg 40 mg

(Each actuation of Ketorol Spray 2%w/w (1 gram of Ketorolac Tromethamine delivers 3.36 mg of Ketorolac Tromethamine) Gel contains 20mg of Ketorolac

Tromethamine)

Dose: For quantification of ketorolac concentrations in plasma samples, a relatively higher dose of test and reference formulation (approx. 40 mg of ketorolac tromethamine - 12 actuations of spray (test) and 2 gm of gel (reference)) compared to clinically recommended dose were administered in the study). Serial blood samples were collected up to 24 h post dose in each period and plasma samples were analysed for ketorolac using validated LC -MS/MS method. The results were shown in Table 5.

Table 5 : Comparative bioavailability study

The bioavailability study results indicates that both test product (Ketorolac Tromethamine Spray 2%w/w) and reference product (Ketorol Gel 2%w/w) are well tolerated in the study and had comparable pharmacokinetic profile with T/R ratio for Cmax and AUCO-t within the acceptable range of 80.00 to 125.00%.