WO2001097775A2

WO2001097775A2 - Controlled release anti-inflammatory formulation

Info

Publication number: WO2001097775A2
Application number: PCT/IN2001/000117
Authority: WO
Inventors: Milind Kesharlal Biyani; Shripad Rhushikesh Jathar; Manutosh Manohar Acharya
Original assignee: Ajanta Pharma Ltd
Current assignee: Ajanta Pharma Ltd
Priority date: 2000-06-20
Filing date: 2001-06-18
Publication date: 2001-12-27
Anticipated expiration: 2002-12-20
Also published as: AU2001284382A1; EP1406635A2; US20020012702A1; IN190963B; BR0111879A; WO2001097775A3

Abstract

A controlled release anti-inflammatory nimesulide oral formulation. The formulation comprises 45-65 % by weight of nimesulide and 10-30 % by weight of hydrophilic polymer as retardant pharmaceutically acceptable auxiliary agents and/or excipients. The nimesulide is partially or fully dispersed in the hydrophilic polymer. The process for the preparation of the formulation comprises mixing the nimesulide with the hydrophilic polymer and pharmaceutically acceptable auxiliary agents and/or excipients.

Description

TITLE OF THE INVENTION A controlled release anti-inflammatory formulation and a process for the preparation thereof.

FIELD OF THE INVENTION

This invention relates to a controlled release anti-inflammatory nimesulide oral formulation and a process for the preparation thereof.

PRIOR ART

Nimesulide (4-Nitro-2-phenoxymethane sulfonanilide) is known to be a potent non-steroidal anti-inflammatory drug (NSAID) useful in the treatment of painful inflammatory conditions. It is also reported to have analgesic and antipyretic activity. .

Pharmacologically, it is a selective cyclo-oxygenase-2 en2yme inhibitor (cox-2). Hence it is less likely to cause gastrointestinal tract side effects. Its metabolites also exhibit anti-inflammatory and analgesic action. Nimesulide has a favourable therapeutic index, minimal acute gastrointestinal toxicity and exhibits good general tolerability. Its pharmacokinetic profile makes it safe even in-patients with moderate renal failure. Nimesulide is a hydrophobic drug and is insoluble in water (aqueous solubility is 10 μg/ ml at room temperature). Since it is a weak acidic drug, its aqueous solubility in acidic medium, for example in the pH of gastric juice particularly, is poor. Hence, orally administered nimesulide is likely to be absorbed only in the lower part of the gastrointestinal tract. Nimesulide has a short half-life of 3-4 hours and therefore requires twice a day administration. Nimesulide is a time-tested drug for the past ,„„„„ 01/97775

two decades and has proven safety and efficacy. It is rated to be one of the best amongst the available NSAIDS.

US Patent No. 5744165 discloses inclusion complexes of nimesulide alkali and alkaline earth salts with cyclodextrin and compositions comprising the same. Injectable nimesulide compositions with parenteral absorption enhancing base such as dimethyl acetamide, benzyl benzoate or ethyl oleate for intramuscular administration are known (US Patent No. 5688829). US Patent No. 5756546 describes water-soluble salt of nimesulide with L-lysine, L-arginine and/ or cyclodextrin Nimesulide for external use dispersed in base component such as cream base like carboxyvinyl polymer, oily substance like diisopropyl myristate and a non-ionic surface active agent is known (US Patent No. 58377735). Nimesulide composition with a percutaneous absorption enhancing vehicle/ base, thickening agent and surfactant in water for topical/ transdermal use is known (US Patent No. 5716609). PCT publication no. WO 98/47501 describes nimesulide preparations for local use and application to the oral and rhinopharyngeal cavity for the treatment of inflammation of oral and rhinopharyngeal mucosa. US Patent No.6027747 describes a process for the production of a solid dispersion comprising at least one therapeutic agent in a hydrophilic carrier, by dissolving at least one therapeutic agent in a volatile organic solvent containing a hydrophilic polymer and evaporating the solvent to dryness to form a coprecipitate of the therapeutic agent and the hydrophilic polymer. US Patent No. 6048541 discloses compositions useful for making tablets, which disintegrate rapidly in mouth with optional chewing. PCT publication no. WO 01/22791 A2 describes controlled release compositions comprising Nimesulide.

Most of the above formulations of nimesulide are of the immediate release type and are recommended in doses of 100- 200 mg twice daily. Multiple dosing leads to peaks and troughs in nimesulide blood levels. The peak levels of nimesulide may result in undesirable effects or toxicity, while trough levels of nimesulide may be subtherapeutic and may not be very effective. It is reported that when the drug is administered in the presence of food, nimesulide plasma concentration were 2 to 4 fold higher than under fasting conditions suggesting that the drug is better absorbed after meals ["The Pharmacokinetic profile in healthy volunteers", Drugs 46(Suppl 1), 1993, p 66, A Bernareggi, Publsh. Adis International]. Therefore if a tablet of the immediate release type is administered after meal at bedtime by an arthritic patient, it results in peak effect in the night itself with practically no effect the next morning. Further it would necessitate use of another tablet next morning to reduce morning stiffness. Thus conventional dosage pattern has poor patient compliance due to such multiple dosage therapy. Moreover one of the afore mentioned prior art WO 01/22791A2 describing controlled release compositions of nimesulide for arthritis has a drawback that it does not address the problem of morning stiffness i.e. immobilization of joints, faced by arthritic patients. Therefore such controlled release composition does not prove to be useful in reducing early morning stiffness in arthritic patients, like the present invention formulation which is specifically designed to do so, by giving peak plasma levels in the morning and hence it is advantageous over the prior art. OBJECTS OF THE INVENTION

It is an object of the present invention to provide a controlled release anti-inflammatory nimesulide oral formulation, which is a once-a-day formulation having better patient compliance.

Another object of the invention is to provide a controlled release anti-inflammatory nimesulide oral formulation, which provides for relatively constant and desired nimesulide plasma levels to be therapeutically effective and minimizes systemic related side effects.

Another object of the invention is to provide a controlled release anti-inflammatory nimesulide oral formulation, which provides for relatively constant nimesulide plasma levels for a long period of time.

Another object of the invention is to provide a controlled release anti-inflammatory nimesulide oral formulation, which is effective in arthritic conditions, specially in minimizing morning stiffness.

Another object of the invention is to provide a process for the preparation of a controlled release anti-inflammatory nimesulide oral formulation which is a once-a-day formulation having better patient compliance.

Another object of the invention is to provide a process for the preparation of a controlled release anu^inflammatory nimesulide oral formulation which provides for relatively constant and desired nimesulide plasma levels to be therapeutically effective and minimizes systemic related side effects.

Another object of the invention is to provide a process for the preparation of a controlled release anti-inflammatory nimesulide oral formulation, which provides for relatively constant nimesulide plasma levels for a long period of time.

Another object of the invention is to provide a process for the preparation of a controlled release anti-inflammatory nimesulide oral formulation, which is effective in arthritic conditions, specially in rriinirnising early morning stiffness.

DISCLOSURE OF THE INVENTION

According to the invention there is provided a controlled release anti-inflammatory nimesulide oral formulation comprising 45 - 65 % by weight of nimesulide and 10 - 30 % by weight of hydrophilic polymer as retardant with pharmaceutically acceptable auxiliary agents and / or excipients; wherein the nimesulide is partially or fully dispersed in the hydrophilic polymer.

According to the invention there is also provided a process for preparation of a controlled release anti-inflammatory nimesulide oral formulation comprising mixing 45 - 65 % by weight of nimesulide with 10 - 30 % by weight of hydrophilic polymer as retardant and pharmaceutically acceptable auxiliary agents and / or excipients; wherein the nimesulide is partially or fully dispersed in the hydrophilic polymer. Preferably nimesulide is in 50 - 55 % by weight in the controlled release formulation of the invention.

According to the invention the nimesulide is dispersed partially or

5 fully in the hydrophilic polymer to form a matrix. In physiological fluid the matrix swells and the nimesulide is released therefrom by diffusion. The hydrophilic polymer used as retardant controls the release of the nimesulide from the polymer matrix. When partially dispersed, that portion of nimesulide dispersed in the hydrophilic o polymer matrix is released in a controlled manner whereas the remaining portion of nimesulide not dispersed in the matrix is immediately released in the physiological fluid following administration of the formulation. These formulations are of the partially controlled release type (partially immediate release type.)

5 In such partially controlled release formulation as per invention,

25 - 65 % by weight of the total nimesulide content in the formulation of the invention is used for dispersion in the hydrophilic polymer. When the entire nimesulide is dispersed in the hydrophilic polymer matrix, then a fully controlled release o formulation is obtained.

The hydrophilic polymer may be hydroxy propyl methylcellulose (HPMC), ethyl cellulose, cetostearyl alcohol or the like or mixtures thereof. Preferably hydroxy propyl methylcellulose or ethyl 5 cellulose is used. Preferably the hydrophilic polymer is in 15-20 % by weight.

The pharmaceutically acceptable auxiliary agents may be diluent, binder, disintegrant and / or mixtures thereof. Diluent may be microcrystalline cellulose (MCC), mannitol, lactose or the like, which provide channelising effect and solubilise the polymer matrix and may be in 2 - 25 %, preferably 5 - 20 % by weight. Preferably diluent used is niicrocrystelline cellulose and/ or mannitol.

Binder may be polyvinyl pyrrolidone (PVP), starch, ethyl cellulose, hydroxy propyl methylcellulose or the like, preferably polyvinyl pyrrolidone and / or starch. Binder may be present in 1 - 10 % by weight, preferably 2 - 5% by weight.

Disintegrant may be sodium starch glycolate (SSG), cross carmellose sodium, cross povidone, starch or the like, preferably starch and/ or sodium starch glycolate. The disintegrant may be in 1-5 %, preferably 2-3 % by weight.

Excipients may be compounds such as dicalcium phosphate dihydrate, sodium citrate, sodium bicarbonate, sodium carboxy methylcellulose, methylcellulose or the like or mixtures thereof which cause swelling of the formulations such as tablets resulting in buoyancy of the tablets. These excipients are useful in the preparation of floating tablets, which maintain the tablet/drug for longer time at the site of absorption, thereby giving an extended release profile. Excipients may also be lubricants such as talc, colloidal silicone dioxide, magnesium stearate or the like or mixtures thereof in 0.25 - 4%, preferably 0.5 - 2 % by weight.

The controlled release formulations of the invention may be in the form of tablets, floating tablets or bilayered tablets, which may be coated. The controlled release formulation of the invention may comprise 50 to 800 mg of nimesulide, preferably 100-600 mg of nimesulide.

According to the invention the release of nimesulide is controlled by the hydrophilic polymeric retardant because of which relatively constant and therapeutically effective or desired nimesulide plasma levels are achieved for extended period of time. Therefore multiple dosage as recommended with conventional dosage is eliminated and the formulation of the invention can be conveniently used as a one-a-day formulation with better patient compliance. The chances of peak and trough nimesulide plasma levels are reduced thereby minimising side effects observed with conventional dosing. Since the drug is made available in the blood for long period of time, the controlled release formulation of the invention has been found to be suitable specially to treat arthritic conditions. The controlled release product of the invention is recommended for use after meal at bedtime. This dosage results in peak levels in the morning, which reduce early morning stiffness usually observed in arthritic patients. The controlled action with the effective of nimesulide has been observed for ~ 16 hours.

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

Example 1

A mix of nimesulide (200 mg), microcrystalline cellulose (60 mg), sodium starch glycolate (20 mg) and mannitol (20 mg) sifted through 30 mesh US screen was granulated using poly vinyl pyrrolidone (20 mg) dissolved in isopropyl alcohol (50 ml) to get a coherent mass. The wet mix was sifted through 6 mesh US screen and air dried to remove isopropyl alcohol and further dried at 45° C for 1 hour. The dried granules were sifted through 20 mesh US screen, hydroxy propyl methylcellulose (K-4M, 40 mg) and 5 hydroxy propyl methylcellulose (K - 15 M, 24 mg) sifted through

40 mesh US screen was blended with the dried granules and the blend was lubricated with talc (8 mg) magnesium stearate (4 mg) and colloidal silicone dioxide (4 mg) and compressed to tablets.

o Example 2

Controlled release tablets comprising 300 mg of nimesulide were prepared as per the procedure of Example 1, but using 1.5 times w/w of each of the ingredients mentioned in Example 1.

5 Example 3

Controlled release tablets comprising 400 mg of nimesulide were prepared as per the procedure of Example 1, but using 2 times w/w of each of the ingredients mentioned in Example 1.

o Example 4

Controlled release tablets comprising 500 mg of nimesulide were prepared as per the procedure of Example 1, but using 2.5 times w/w of each of the ingredients mentioned in Example 1.

5 Example 5

Controlled release tablets comprising 600 mg of nimesulide were prepared as per the procedure of Example 1, but using 3 times w/w of each of the ingredients mentioned in Example 1. Example 6

Controlled release tablets comprising 100 mg of nimesulide were prepared as per the procedure of Example 1, but using 0.5 times w/w of each of the ingredients mentioned in Example 1.

Example 7 a) To a mix of nimesulide (100 mg), Sodium starch glycolate (7 mg) and microcrystalline cellulose (26 mg) sifted through mesh size 20, starch paste was added and the mix was granulated. The granules were sifted through 8-mesh size, dried and further sifted through 20-mesh size. The dried granules were mixed with talc (5 mg), magnesium stearate (1.5 mg) and aerosil (2.5 mg) for lubrication. This provided the immediate release fraction.

b) A mix of nimesulide (100 mg) and microcrystalline (57 mg) sifted through 20 mesh size was granulated using poly vinyl pyrrolidone (K-30, 6 mg) dissolved in isopropyl alcohol (50 ml). The wet mix was sifted through 8-mesh size, dried and further sifted through 20-mesh size. With these granules was blended a mixture of hydroxy propyl methylcellulose (E-10 M, 20 mg) hydroxy propyl methylcellulose (K 4 MCR, 25 mg) and hydroxy propyl methylcellulose (K-100 M, 30 mg). This blend was then lubricated using talc (7 mg), magnesium stearate (2.5 mg) and aerosil (2.5 mg). This provided the controlled release fraction.

c) Granules of steps (a) and (b) were filled in two different hoppers and compressed together using double rotary compression machine to get a bilayered tablets. Example 8

Controlled release bilayered tablets comprising 300 mg of nimesulide were prepared as per the process of Example 5 having 100 mg of nimesulide release fraction and 200 mg as the sustained release fraction. The quantities of the other ingredients in the formulation were as per Example 5.

Example 9

Controlled release bilayered tablets comprising 400 mg of nimesulide were prepared as per the process of Example 5 having 200 mg of nimesulide release fraction and 200 mg as the sustained release fraction. The quantities of the other ingredients in the formulation were as per Example 5.

Example 10

Controlled release bilayered tablets comprising 400 mg of nimesulide were prepared as per the process of Example 5 having 100 mg of nimesulide release fraction and 300 mg as the sustained release fraction. The quantities of the other ingredients in the formulation were as per Example 5.

Example 11

Controlled release bilayered tablets comprising 500 mg of nimesulide were prepared as per the process of Example 5 having 200 mg of nimesulide as the instant release fraction and 300 mg as the sustained release fraction. The quantities of the other ingredients in the formulation were as per Example 5. Example 12

Controlled release bilayered tablets comprising 600 mg of nimesulide were prepared as per the process of Example 5 having 300 mg of nimesulide as the instant release fraction and 300 mg as the sustained release fraction. The quantities of the other ingredients in the formulation were as per Example 5.

Example 13

Controlled release bilayered tablets comprising 600 mg of nimesulide were prepared as per the process of Example 5 having 200 mg of nimesulide as the instant release fraction and 400 mg as the sustained release fraction. The quantities of the other ingredients in the formulation were as per Example 5.

Example 14

Nimesulide (200 mg), mannitol (15 mg) and sodium carboxy methylcellulose (100 mg) were sifted through 20-mesh U.S. screen, and mixed to get a uniform blend. This blend was granulated using poly vinyl pyrrolidone K-30 (10 mg) dissolved in isopropyl alcohol. The granulated mass was sifted through 6 mesh U. S. screen and air-dried. The dried granules were sifted through 30 mesh U.S. screen. Methyl cellulose 4000cPs (50 mg), ethyl cellulose (10 mg), hydroxy propyl methylcellulose K4M (25 mg) and hydroxy propyl methylcellulose K 100 M (10 mg) were sifted through 40 mesh U. S. screen and added to the above granules and mixed. The blend was lubricated using talc (10 mg) and magnesium stearate (5 mg) which were previously sifted through 60 U.S. screen. The blend was compressed using suitable punches. This process gave nimesulide controlled release floating tablets. INVfVO STUDIES :

Pilot bioequivalence studies using 2 x 100 mg dosage of a commercially available nimesulide formulation of the immediate release type and 1 x 200 mg controlled release formulation of Example 1 of the complete specification of the invention were conducted on a single healthy volunteer. The concentrations (c) of nimesulide in plasma at various time intervals were as given in Table I and Table II.

Table I

Time Immediate release Controlled release

(hrs) Formulation formulation of

(μg / ml) Example 1 (μg / ml)

1 1.03 0.28

2 3.91 0.21

3 9.65 0.48

4 7.66 0.19

6 5.18 3.5

8 2.62 7.04

10 1.85 6.2

12 1.42 3.1

16 0.54 1.63

20 0.29 0.99

24 0.13 0.53

Table II

Parameter Immediate release Controlled release

Formulation formulation of Example 1 max 9.65 μg/ml 7.04 μg/ml

I max 3.0 hrs 8.0 hrs

AUC 53.22 units 55.29 units From the above data it is clear that the controlled release formulation of the invention provided maximum concentration of nimesulide at about 8 hours (Cmax = 7.04 μg/ ml, Tmax = 8 hours) following administration, as against the maximum concentration achieved as early as within 3 hours with the immediate release formulation. Thus the formulation of the invention provides for sustained effect of the nimesulide. Further the plasma concentration of nimesulide at the end of 12 and 20 hours following administration of the formulation of the invention are much higher then those with the immediate release formulation, further eliciting the sustained effect achieved with the formulation of the invention. The results of AUC (Area Under Curve) of the immediate release formulation and the formulation of invention from Table 2 confirm that the formulation of the invention in addition to providing sustained effect shows adequate bioequivalence of the order of 103.89%.

Claims

Claims :

1) A controlled release anti-inflammatory nimesulide oral formulation comprising 45 - 65 % by weight of nimesulide and 10 - 30 % by weight of hydrophilic polymer as retardant with pharmaceutically acceptable auxiliary agent and / or excipients; wherein the nimesulide is partially or fully dispersed in the hydrophilic polymer.

2) A formulation a claimed in claim 1, wherein the nimesulide is in 50 - 55 % by weight and the retardant is in 15 - 20 % by weight.

3) A formulation as claimed in claim 1 or 2, which is a partially controlled release formulation comprising 25 - 65 % by weight of the nimesulide.

4) A formulation as claimed in claim 1 to 3, wherein the hydrophilic polymer is hydroxy propyl methyl cellulose or ethyl cellulose.

5) A formulation as claimed in any of claim 1 to 4, wherein the pharmaceutically acceptable auxiliary agents are diluent, binder, disintegrant or mixtures thereof.

6) A formulation as claimed in claim 5, wherein the diluent is microcrystalline cellulose and / or mannitol in 5 - 20 % by weight. 7) A formulation as claimed in claim 5 or 6, wherein the binder is polyvinyl pyrrolidone and / or starch in 2 - 5% by weight.

8) A formulation as claimed in any one of claims 5 to 7, 5 wherein the disintegrant is starch and / or sodium starch glycolate in 2 - 3 % by weight.

9) A formulation as claimed in any one of claims 1 to 8, which is in the form of tablets, bilayered tablets or floating

L0 tablets.

10) A formulation as claimed in any one of claims 1 to 9, which comprises 100 - 600 mg of nimesulide.

L5 11) A process for the preparation of a controlled release anti-inflammatory nimesulide oral formulation comprising mixing 45 - 65 % by weight of nimesulide with 10 - 30 % by weight of hydrophilic polymer as retardant and pharmaceutically acceptable auxiliary agents and/ or excipients; wherein the nimesulide is

20 partially or fully dispersed in the hydrophilic polymer.

12) A process as claimed in claim 11, wherein the nimesulide is in 50 - 55 % by weight and the retardant is in 15 - 20 % by weight.

25

13) A process as claimed in claim 11 to 12, wherein the formulation is a partially controlled release formulation comprising 25 - 65 % by weight of the nimesulide. 14) A process as claimed in any one of claims 11 to 13, wherein the hydrophilic polymer is hydroxy propyl methyl cellulose or ethyl cellulose.

15) A process as claimed in any one of claims 11 to 14, wherein the pharmaceutically acceptable auxiliary agents are diluent, binder, disintegrant or mixtures thereof.

16) A process as claimed in claim 15, wherein the diluent is microcrystalline cellulose and/ or mannitol in 5 - 20 % by weight.

17) A process as claimed in claim 15 or 16, wherein the binder is polyvinyl pyrrolidone and / or starch in 2 - 5 % by weight.

18) A process as claimed in any one of claim 15 to 17,

wherein the disintegrant is starch and /or sodium starch glycolate

in 2 - 3 % by weight.

19) A process as claimed in any one of claims 11 to 18, wherein the formulation is in the form of tablets, bilayered tablets or floating tablets.

20) A process as claimed in any one claims 11 to 19, wherein the nimesulide is in 100 - 600 mg. 21) A method of treating a patient in need of treatment for inflammation, analgesic, rheumatoid arthritis, the method comprising of administration to the patient a controlled release nimesulide oral formulation as claimed in claim 1 after dinner to reduce morning stiffness.