4. Description

The present invention relates to an improved pharmaceutical compositions of diclofenac or pharmaceutically acceptable salt compirising dispersing agent and pharmaceutically acceptable excipients. The invention relates to pharmaceutical composition of diclofenac or pharmaceutically acceptable salt and lower amount of dispersing agents. By administering such composition  rapid and uniform gastrointestinal absorption of diclofenac can be achieved. The invention also includes process of preparing such composition.

Within the pharmaceutical art  the formulation of pharmaceutically active compounds into usable dosage forms  in which the absorption of the active ingredient is optimized and the extent of controllable side effects is minimized  is challenging to pharmaceutical formulation scientists and  frequently  unpredictable. Representatives of these compounds include  for example  pharmaceutical agents well known in the art as non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Diclofenac.

Diclofenac is one of the routinely prescribed anti-inflammatory agents available for the management of pain and inflammation. It is marketed as injection  oral immediate release tablets  sustained release tablets  liquid filled capsules and conventional topical formulations. The drug is almost completely absorbed after oral administration.

A major portion of commercial diclofenac is available in the form of oral medications. It is widely known that the drug causes serious adverse effects in the gastrointestinal tract. Gastrointestinal bleeding and ulcerations are quite common due to oral diclofenac.

U.S. Patent No. 4 880 835 discloses oral liquid compositions of calcium sulindac with a pharmaceutical vehicle using glycol  a polyol  and alcohol.

K. Chan  et al.  Pharma Research  7:1027 (1990) discloses that diclofenac sodium in form of aqueous solution posses less bioavailability in coparison to its enteric coated tablet.

U.S. Patent No. 4 704 405 discloes that NSAIDs  such a sulindac has absorption problem from the gastrointestinal tract when administered orally.

U.S. Patent No. 5 183 829 discloses oral liquid NSAID formulation containing dispersing agents. The formulation was found to be unsuitable for filling in soft gelatin capsules  as it become tacky due to the inside composition  and adhere to adjacent soft capsules.

U.S. Patent No. 6 365 180 descloses liquid and semi-solid compositions of NSAIDs containing dispersing agents.

On administering the oral solution of diclofenac  it mixes with stomach acid  can form agglomerates  which sediments in a brief period of time over gastrointestinal pasage  making diclofenac less biologically available  and thus exhibit poor gastrointestinal absorption. Prior art references indicates using dispersing agents in the composition in order to inhibit agglomertion. Several methods and compositions of diclofenac have been taught in the art using dispersing agents. Despite this  these compositions either unsuitable to present in particular product form  or may provide uncertain control over the rate of absorption of the active ingrdient or on the side effects.

Hence  there exists an enduring need for alternate  improved and stable pharmaceutical composition of diclofenac or its salts  which can exhbit rapid and uniform gastrointestinal absorption of diclofenac and simultaneously  without compromising on the product stability. Further  the composition ought to minimize the controllable side effects of diclofenac.

The present invention provides a solution to the aforesaid shortcomings. Particularly  the invention provides a pharmaceutical formulations of diclofenac or salt thereof by employing relatively less amount of dispersing agent.

The inventors of the present invention have surprisingly found that it is possible to deivse diclofenac compositions with improved oral bioavailability using relatively less amount of dispersing agent. The inventors of the present invention further empirically found that when dispersing agent are used in relatively less amount  the resulting composition can exhbit rapid and uniform gastrointestinal absorption of diclofenac and simultaneously  that to without compromising on the product stability. Further  the composition advatntageously may minimize the controllable side effects of diclofenac.

The present invention relates to a novel pharmaceutical composition of diclofenac or salt thereof for oral administration  and methods of using such compositions for enhancing the rate and degree of absorption of diclofenac or salt thereof from such compositions  and for minimizing gastric irritation induced or caused by ingestion of diclofenac or salt thereof.

The marketed formulations of diclofenac posses limited flexibity of formulationg in the form different dosage form. For instance  the liquid composition of diclofenac in marketed product  Zipsor® (marketed in USA by Depomed Inc.) is unsuitable to fill in hard gelatin capsules. Other formulations suggested in the prior art unsuitable for filling in soft gelatin capsules  as it become tacky due to the inside composition  and adhere to adjacent soft capsules.

The compositions of diclofenac or salt thereof in accordance with the present invention also posses excellent storage stability and flexibility of presenting in the form of a wide range of products  such as in the form of soft gelatin capsule or hard gelatin capsule. Moreover  the inventors of the present invention have devised a diclofenac composition which is bioequivalent to its marketed formulation Zipsor®.

In an embodiment  the pharmaceutical composition of diclofenac or pharmaceutically in accordance with the present invention exhibits no significant difference in one or both of the rate and extent of absorption of diclofenac or salts thereof as compared to formulation of diclofenac marketed under the trade name Zipsor®.

The composition can be devised in the form of liquid and semi-solid compositions  which can be administered in liquid form or can be used for preparing capsules containing such pharmaceutical compositions. The compositions of diclofenac in the form of liquid in accordance with the present invention may demonstrate good reproducible distribution in gastric juice and  thereby  better absorption.

In one general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w.

In another general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprisng one or more dispersing agents  one or more solubilizing agents  one or more surfactants  and one or more plasticizing agents; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w.

In another general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprisng one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w  and characterized in that the composition exhibits a significant difference in one or both of the rate and extent of absorption of diclofenac or salts thereof as compared to formulation of diclofenac marketed under the trade name Zipsor®.

In another general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprisng one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w  and characterized in that said composition retains at least 90% w/w of total potency of diclofenac or salt thereof after storage at 40°C and 75% relative humidity for at least 3 months.

In another general aspect  there is provided a dosage form selected from liquid  soft gelatin capsule  or hard gelatin capsule comprising diclofenac or pharmaceutically acceptable salt thereof  one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w.

In another general aspect  there is provided a method of improving the rate of absorption of diclofenac or pharmaceutically acceptable salt thereof in the patient  comprising administering to the patient in need of the treatment with diclofenac a composition comprising diclofenac or pharmaceutically acceptable salt thereof  one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w.

In another general aspect  there is provided a method of accelerating the onset of the therapeutic benefit provided by diclofenac or pharmaceutically acceptable salt thereof in the patient  comprising administering to the patient in need of the treatment with diclofenac a composition comprising diclofenac or pharmaceutically acceptable salt thereof  one or more dispersing agents  and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w.

In another general aspect  there is provided use of a pharmaceutical composition for the preparation of medicaments useful for providing relief from mild to moderate acute pain  the composition comprising diclofenac or pharmaceutically acceptable salt thereof  one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w.

The pharmaceutical composition of the present invention comprises diclofenac or salt thereof  one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.98 w/w. In an embodiment  the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.01 to about 3:0.8 w/w. In a further embodiment  the ratio of diclofenac or salt thereof to dispersing agent in the composition is from about 3:0.05 to about 3:0.5 w/w.

Preferred sals of diclofenac suitable for use in the present invention includes  but not limited to sodium and potassium salt  and potassium salt being more preferred.

The compositions of the present invention comprises a pharmaceutically non-toxic and therapeutically effective amount of at least one pharmaceutically acceptable  non-toxic dispersing agent. As used herein  the term "pharmaceutically acceptable " when referring to any or all components of the present compositions  means that such component(s) are compatible with other components therein  and not deleterious to the recipient thereof. Such dispersing agents are well known in the art and include  for example  the polymeric dispersing agents which include  for example  polyvinylpyrrolidone (PVP; commercially known as Plasdone®)  acrylate polymers (Eudragit®)  and the carbohydrate dispersing agents such as  for example  hydroxypropylmethylcellulose (HPMC)  hydroxypropylcellulose (HPC)  and the cyclodextrins. Preferred dispersing agents include acrylate derivatives  PVP  dextrins  starch  derivatized starch and dextrans  while of the dextrins  derivatized cyclodextrins are especially preferred. Of such cyclodextrins  hydroxypropyl ß-cyclodextrin and ?-cyclodexrin are especially preferred.

The ratio of diclofenac or salt thereof to a polymeric and/or carbohydrate dispersing agent is from about 3:0.01 to about 3:0.98 w/w.

For the present compositions  one or more dispersing agents can be used to obtain the ratios of diclofenac or salt thereof to dispersing agent as set forth above.

In a further embodiment  the composition in accordance with present invention is useful as oral  liquid medicaments which can also be used to fill soft or hard gelatin capsules or solidified  as taught herein  to be used in hard capsules  particularly soft gelatin capsules and hard gelatin capsules  respectively.

The compositions of the present invention comprises a pharmaceutically non-toxic and therapeutically effective amount of diclofenac or salt thereof. Accordingly  any suitable non-toxic and therapeutically effective amount of diclofenac known in the art can be used.

In an embodiment  the amount of diclofenac or salt thereof in the composition of the present invention may range from about 0.1 % to about 95% w/w of the composition.

In another embodiment  the amount of diclofenac or salt thereof in the composition of the present invention may range from about about 1 % to about 30% w/w of the composition.

The pharmaceutical composition comprises one or more pharmaceutically acceptable non-toxic solubilizing agents. Such readily available solubilizing agents are well known in the art and is typically represented by the family of compounds known as polyethylene glycols (PEG) having molecular weights from about 200 to about 8 000. For compositions of the present invention when a liquid is desired for the final formulation or a liquid is to be used to fill soft capsules  preferably soft gelatin capsules  preferred molecular weights range from about 200 to about 600 with PEG 400 being especially preferred. For composition of the present invention when a semi-solid is preferred  especially for filling a hard capsule  preferably a hard gelatin capsule  preferred molecular weight is about 3350 while an especially preferred molecular weight is 3350 plus sufficient 400 molecular weight PEG to improve capsule filling characteristics.

Another solubilizing agent which may be utilized in composition of the present invention is water  preferably purified  and more preferably  deioniozed. For such compositions  the concentration of water is from about 0.01 % to about 95 % w/w.

In an embodiment  when the compositions of the present invention is filled into soft gelatin capsules  the amount of water in the composition ranges from about 0.01% to about 5%.

In a further embodiment  when more than one plasticizing agents are used in the compositions of the present invention  the amount of solubilizing agent may range from about 0.01% to about 80%.

In a further embodiment  the preferred concentration of solubilizing agent in the compositions is from about 60 % to about 90 % w/w.

The pharmaceutical composition of the present invention further optionally comprises one or more non-toxic plasticizing agents. The plasticizing agents  which are well known in the pharmaceutical formulation art  include  for example  glycerin  propylene glycol  and sorbitol. Such commercially available plasticizers can be prepared to include more than one plasticizing agent component.

In an embodiment  the compositions of the present invention comprises glycerin as the preferred plasticizing agent.

In a further embodiment  propylene glycol may be used both as a plasticizing agent and as a solubilizing agent when used alone or in combination with another solubilizing agent.

The amount of plasticizing agent suitable for use in the composition of the present invention may range from about 0.1% to about 75 % w/w.

In an embodiment  the amount of plasticizing agent ranges from about 0.1% to about 50 % w/w. In a further embodiment  the amount of plasticizing agent ranges from about 1% to about 30 % w/w.

In a further embodiment  when the compositions of the present invention is filled into soft capsules  the amount of plasticizing agent may range from about 5 % to about 10 % w/w.

The pharmaceutical composition of the present invention further optionally comprises one or more non-toxic surfactants selected one or more from anionic  cationic  non-ionic and zwitterionic surfactant. Non-ionic surfactant is preferred.

Examples of suitable surfactants include macro gel esters (Labrafils)  Tandem 522®  Span 80®  Geluciere® such as  for example  Geluciere 44/14  tocopherol polyethylene glycol 1000 succinate; polysorbate 20; and polysorbate 80. Geluciere® is more preferred.

Surprisingly  it was found that when  along with low amount of dispersing agent  high amount of surfactant is used in the composition of present invention  it may render faster  reproducible  and a more uniform absorption rate of diclofenac.

The amount of surfactant suitable for use in the composition of the present invention may range from about 0.1% to about 90 % w/w.

In an embodiment  the amount of surfactant ranges from about 5% to about 80 % w/w. In a further embodiment  the amount of surfactant ranges from about 20% to about 70 % w/w.

The order of addition of the various components of the present invention will not affect the formation of a solution  when desired  of the present invention. However  when surfactant is used  it may be added after the addition of diclofenac or salt thereof.

In an embodiment  the process of preparing the pharmaceutical composition of the present invention comprises the steps of:
(a) forming a mixture of one or more solubilizers by heating;
(b) adding one or more surfactants to the heated mixture of solubilizers formed in step (a);
(c) adding diclofenac or salt thereof to the mixture formed in step (b) by heating to form a liquid;
(d) adding one or more polymeric dispersing agents to the liquid formed in step (c); and
(d) optionally  filling the liquid formed in step (d) in soft or hard gelating capsules.

It was found that the aforesaid process of preparing the pharmaceutical composition may provide the surprising result of maintaining diclofenac in solution during the process  resulting in a stable pharmaceutical composition of the present invention with its attending benefits as set forth herein.

The capsules filled with pharmaceutical composition of the present invention may be coated with any non-toxic  pharmaceutically acceptable coating. Such coatings include  for example  enteric  taste-masking  color-coating  sustained or delayed release  non-performance flavor coatings  and the like  and are prepared and applied via techniques well known to one of ordinary skill in the art.

Other pharmaceutically acceptable  non-toxic pharmaceutical additives may be included in the compositions of the present invention and include  for example  sweetening agents  local anesthetics  antibacterials  a lower alkyl alcohol such as ethanol  and the like.

Accordingly  the novel compositions of the present invention provides beneficial pharmaceutical properties while using relatively less amount of dispersing agtent and utilizing a minimum number of components.

Diclofenac is known to cause gastrointestinal irritation  typically in the form of peptic ulceration  bleeding  and perforation. Because of the improved absorption or bioavailability using dispersing agent  such composition may inhibit side effects of diclofenac  such as gastroirritation induced by chronic use of diclofenac.

As used herein  the term "inhibit" is defined to include its generally accepted meaning and includes  without limitation  a reduction  holding in abeyance  and/or minimizing the side effects (e.g. gastroirritation) induced and/or resulting from the administration of diclofenac compared to such side effects (e.g. gastroirritation) induced and/or resulting from the administration of conventional pharmaceutical formulations of diclofenac.

The present invention further provides a method of improving the rate of absorption of diclofenac or salt thereof in patients  comprising administering the composition of the present invention to a patient in need of the treatment of diclofenac.

The present invention further provides a method of accelerating the onset of the therapeutic benefits of diclofenac or salt thereof in patients  provided by diclofenac or salt thereof comprising administering the composition of the present invention to a patient in need of the treatment with diclofenac.

The composition of the present invention may be formulated to deliver a typical  non-toxic daily dosage level of from about 0.25 mg to about 400 mg per day of diclofenac. Preferred doses diclofenac used in the composition of the present invention will  of course  be determined by the particular circumstances surrounding the case including  for example  an attending physician considering the state of being of the patient and the severity of the pathological condition being treated. Preferred daily doses may range from about 10 mg to about 2 000 mg per day. Typically  the composition of the present invention may be formulated to deliver about 10 mg to 500 mg per teaspoon of a liquid product.

The liquid or semi-solid composition of the present invention can be used to fill capsules  particularly hard gelatin capsules and  especially  soft gelatin capsules wherein the amount of diclofenac in each such capsule may range from about 10 mg to about 250 mg.

The present invention further provides a method of treating paroxysmal headaches  particularly migraine headaches comprising administering to a patient  in need of such treatment  a composition of the present invention comprising diclofenac or salt thereof  preferably in capsule form  and especially in hard gelatin capsule form.

Furthermore  composition of the present invention in which diclofenac or salt thereof  preferably administered in combination with  concurrent to  or subsequent to the administration of a motility agent as taught above  provides more rapid relief from pain  as a general analgesic  and particularly from injury or from surgical procedures such a dental surgery  hysterectomy  and arthroscopy.

In addition to the analgesic effect  such composition also provide more rapid relief from inflammation caused by injury  stress  surgical procedures  and the like. The dosage regime and dosage strength for using such compositions of the present invention for analgesic and anti-inflammation are as set forth above for the treatment of paroxysmal headache.

Accordingly  another aspect of the present invention provides a method of treating pain and for treating inflammation in a patient  comprising administering to the patient in need of treatment a composition of the present invention  preferably in capsule form  and especially in hard gelatin capsule form.

As used herein  the term "treatment"  or a derivative thereof  contemplates partial or complete inhibition of the stated disease state such as  for example  pain  when a composition of the present invention is administered prophylactically or following the onset of the disease state for which such composition of the present invention is administered.

"Bioequivalency" is established by a 90% Confidence Interval (Cl) of between 0.80 and 1.25 for both Cmax and AUC under USFDA regulatory guidelines  or a 90% Cl for AUC of between 0.80 to 1.25 and a 90% Cl for Cmax of between 0.70 to 1.43 under the European regulatory guidelines (EMEA).

The term "confidence interval" as used herein refers to the plain meaning known to one of ordinary skill in the art. The confidence interval refers to a statistical range with a specified probability that a given parameter lies within the range.

The term "covariance" as used herein refers to the plain meaning known to one of ordinary skill in the art. It is a statistical measure of the variance of two random variables that are observed or measured in the same mean time period. This measure is equal to the product of the deviations of corresponding values of the two variables from their respective means.

The bioequivalence studies were carried out between Zipsor® (reference) and compositions of the invention (test) in fed state. The study was monitored in terms of Cmax  AUC  Tmax achieved with the test products and the reference product (Zipsor®).

The compositions of the invention exhibits pharmacokinetic profile characterized by Cmax of about 290.8 to 413.12µg/ml  Tmax of about 1.3 to 2.2h  AUCo-t of about 821.3 to 911.6 µg.h/ml  AUCinf of about 833.4 to 1125.9 µg.h/ml.

At 90% confidence interval; area under the concentration time curve (AUC0-t and /or AUCinf) and maximum plasma concentration (Cmax) values of composition of the invention lies between 0.70 and 1.70 as compared to that obtained by a 25 mg diclofenac potassium formulation marketed under the trade name Zipsor®.

The relative bioavailability study of the test composition and the reference formulation as demonstrated in Example 2 & 3 (Table 2 & 3) concludes that the composition explored in present invention provides equivalent rate and/or extent of absorption compared to diclofenac potassium formulation marketed under the trade name Zipsor®.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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 invention.

Example 1:
Table 1
Sr. No. Ingredients Mg/capsule
1 Diclofenac Potassium 25
2 Proplyene Glycol(PG) 21.1
3 Polyethylene Glycol -400 21.6
4 Water 5.8
5 PEG-8 caprylic/capric glycerides (Labrasol) 35
6 Cremophore EL (Polyoxyl 35 Castor Oil ) 90
7 Eudragit 7.5
Total weight 206

Process: The mixture of polyethylene glycol 400  propylene glycol and water was heated with stirring. Cremophore EL and Labrasol were added to the heated mixture  and the heating is continued with stirring until the Cremophore EL and Labrasol were completely dissolved. Diclofenac potassium was added to the heated mixture with stirring until diclofenac potassium was completely dissolved to form drug containing mixture. Eudragit was then added to the drug containing mixture with heating and stirring until the Eudragit was completely dissolved. The mixture was allowed to cool to ambient temperature and then filled into hard gelatin capsules using standard procedures.

Example 2: Bioequivalence data of the composition of the invention against Zipsor® with respect to pharmacokinetic parameters:

Table 2
Sr. No. Pharmacokinetic Paramaters Zipsor® Composition of the Invention
1 Cmax 390.09 350.66
2 Tmax 2.05 1.78
3 AUC0-t (µg.h/ml) 793.49 891.18
4 AUCinf (µg.h/ml) 974.23 945.11

Example 3: Bioequivalence data with respect to Test (Composition of the invention) to reference Zipsor® ratios (T/R ratios) at 90% Confidence Interval (C.I.):

Table 3
Sr. No. Pharmacokinetic Paramaters Ratio 90% C.I. % CV
Lower Upper
1 Cmax (µg/ml) 97.36 59.88 158.29 51.71
2 AUC0-t (µg.h/ml) 116.69 94.99 143.34 20.82
3 AUCinf (µg.h/ml) 104.07 80.15 135.13 26.61

While the invention has been described in terms of its specific embodiments  certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

We Claim-

1. A pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the ratio of the amount of diclofenac or salt thereof to dispersing agent in the composition ranges from about 3:0.01 to about 3:0.98 w/w.

2. The pharmaceutical composition of claim 1  wherein the pharmaceutically acceptable excipients comprises one or more of solubilizing agents  surfactants  and plasticizing agents.

3. The pharmaceutical composition of claim 1  wherein the dispersing agent comprises one or more of polymeric dispersing agents and carbohydrate dispersing agents.

4. The pharmaceutical composition of claim 2  wherein the polymeric dispersing agent comprises polyvinylpyrrolidone  acrylate polymers  or mixtures thereof.

5. The pharmaceutical composition of claim 2  wherein the carbohydrate dispersing agent comprises one or more of hydroxypropylmethylcellulose  hydroxypropylcellulose  and cyclodextrins.

6. The pharmaceutical composition of claim 1  wherein the composition retains at least 90% w/w of total potency of diclofenac or salt thereof after storage at 40°C and 75% relative humidity for at least 3 months.

7. A pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more dispersing agents and one or more pharmaceutically acceptable excipients; wherein the composition exhibits a significant difference in one or both of the rate and extent of absorption of diclofenac or salts thereof as compared to formulation of diclofenac marketed under the trade name Zipsor®  and characterized in that the ratio of the amount of diclofenac or salt thereof to dispersing agent in the composition ranges from about 3:0.001 to about 3:0.95 w/w.

8. A method of providing relief from mild to moderate acute pain in a patient comprises of administering to said patient the pharmaceutical composition of claim 1.

9. A method of treating acute post-bunionectomy or post-osteotomy pain in a patient comprises of administering to said patient the pharmaceutical composition of claim 1.

10. A hard gelatin capsule or soft gelatin capsule filled with the pharmaceutical composition of claim 1.

Dated this 16th day of October 2012 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory