Description

The present invention relates to an improved pharmaceutical compositions of diclofenac or pharmaceutically acceptable salt and pharmaceutically acceptable excipients  wherein the composition is substantially free of solubilizing agents. By judicially using pharmaceutical excipients other than solubilizing agent  pharmaceutical composition of diclofenac or its salts with rapid and uniform gastrointestinal absorption of diclofenac can be achieved. The composition of the invention can also minimize the controllable side effects of diclofenac.

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 comparison 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 solubilizing 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 solubilizing agents.

Thus  several methods and compositions of diclofenac have been taught in the art using solubilizing 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 which is substantially free of any solubilizing agent.

The inventors of the present invention have surprisingly found that it is possible to devise diclofenac compositions with improved oral bioavailability without using any solubilizing agent. The inventors of the present invention further empirically found that when pharmaceutical excipients other than solubilizing agents are judicially used  the resulting composition can exhibit rapid and uniform gastrointestinal absorption of diclofenac and simultaneously  that to without compromising on the product stability. Further  the composition advantageously 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 wide range of products  for instance 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 composition of diclofenac in accordance with the present invention in liquid form 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 comprises one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

In another general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more dispersing agents  one or more surfactants  one or more plasticizing agents; wherein the composition is substantially free of any solubilizing agent.

In another general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent  and characterized in that the composition comprises from about 5% to about 90% w/w of surfactant.

In another general aspect  there is provided a pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent  and characterized in that 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 comprising one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent  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 comprising one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent  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 comprising one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

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 and one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

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 and one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

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 and one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

The pharmaceutical composition of the present invention comprises diclofenac or salt thereof and one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

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.

In particular  the composition of the present invention is substantially free of any solubilizing agents known in the art. For instant  the composition is substantially free of solubilizing agents used in various marketed formulation of diclofenac (e.g. Zipsor®)  such as water  propylene glycol  and polyethylene glycol.

The term "substantially free" used throughout the specification refers to pharmaceutical compositions of diclofenac or salt thereof comprising less than about 10% solubilizing agent by weight of diclofenac or salt thereof.

In an embodiment  the composition in accordance with the 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 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..

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

In a further embodiment  when more than one dispersing agents are used in the compositions of the present invention  the amount of dispersing agent may range from about 0.1% to about 60%.

In a further embodiment  the preferred concentration of one or more dispersing agent may range from about 0.5% to about 50%.

In a further embodiment  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.

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  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.

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 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  without using any solubilizing agent.

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 plasticizers by heating;
(b) adding one or more surfactants to the heated mixture of plasticizers 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 being substantially free 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 without using any 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.

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 Glycerin 48.5
3 PEG-8 caprylic/capric glycerides (Labrasol) 35
4 Cremophore EL (Polyoxyl 35 Castor Oil ) 90
5 Eudragit 7.5
Total weight 206

Process: Glycerin was heated with stirring. Cremophore EL and Labrasol were added to the heated glycerin  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.

We Claim-

1. A pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable excipients; wherein the composition is substantially free of any solubilizing agent.

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

3. The pharmaceutical composition of claim 2  wherein the dispersing agent comprises one or more of polymeric dispersing agents and carbohydrate dispersing agents.

4. The pharmaceutical composition of claim 3  wherein the polymeric dispersing agent comprises polyvinylpyrrolidone  acrylate polymers  or mixtures thereof.

5. The pharmaceutical composition of claim 3  wherein the carbohydrate dispersing agent comprises one or more of hydroxypropylmethylcellulose  hydroxypropylcellulose  and cyclodextrins.

6. The pharmaceutical composition of claim 1  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.

7. The pharmaceutical composition of claim 2  wherein the composition comprises from about 5% to about 90% w/w of surfactant.

8. 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.

9. A pharmaceutical composition of diclofenac or pharmaceutically acceptable salt thereof comprising 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 composition is substantially free of any solubilizing agent.

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