Field of invention:
The present invention relates to pharmaceutical compositions comprising an effective amount of Diclofenac. Typically, the present invention relates to solid oral pharmaceutical compositions comprising Diclofenac and one or more pharmaceutically acceptable excipients and process for preparation thereof.
Background of invention:
Diclofenacor 2-[(2, 6-dichlorophenyl) amino] benzene acetic belongs to a class of nonsteroidal anti-inflammatory drug (NSAID), known as a therapeutic agent in treatinginflammatory conditions, reducing pain (analgesic) and as antipyretic. The name "diclofenac" derives from its chemical name: 2-(2, 6-dichloranilino) phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pflster and introduced as Voltaren by Ciba-Geigy (now Novartis) in 1973. NSAIDs are usually indicated for the treatment of acute or chronic pain and inflammatory conditions. Due to diclofenac analgesic and anti-inflammatory activities, it is one of the most commonly dispensed drugs. Thus, it is generally indicated for rheumatoid arthritis, osteoarthritis, dysmenorrhea (menstrual pain), headache and migraine, postoperative pain and also for mild to moderate pain after tissue injury.
The primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.
Diclofenac can be administered by different routes including oral, topical as well as by parenteral route. Oral doses of Diclofenac range from 12.5-200 mg/day while parenteral doses range from 75 to 150 mg/day.
Since Diclofenac is among the BCS class II drugs; its bioavailability is limited by its salvation rate and with short biological half-life 1 - 2 hours. Hence attempts are made to enhance the bioavailability by increasing the rate of disintegration and dissolution. It is known that the rate of dissolution of a particulate drug will increase with increasing surface area. One of the several approaches currently used to formulate poorly soluble active agents includes subjecting an active agent to physical conditions that change the agent's physical and or chemical properties to improve its solubility. These r include p^^(Ks^tBc^glogi§s^$l|ett^l^$idr6niialIibn,, mcfdificatioriloTcrystaT'dr polymorphic structure,

development of oil based solutions, use of co-solvents, surface stabilizers or complexing agents, micro-emulsions, supercritical fluid and production of solid dispersions or solutions.
Diclofenac acid is currently approved in the United States for the treatment of mild to moderate acute pain and Osteoarthritis pain in adults. It is commercially marketed by Iroko Pharms LLC in the form of capsules of 18 mg and 35 mg strengths under the trade name ZORVOLEX®.
Following are the several approaches disclosed for enhancing solubility:
In U.S. Pat. No. 8,679,544, 9,017,721, 9,173,854, and 9,180,096 discloses use of diclofenac nano particles in preparing low dose pharmaceutical compositions i.e., I8mg or 35mg administered orally three times daily in treating Osteoarthritis pain with Tmax of l.Ohr fasted and 3.32 hr in fed condition.
U.S. patent no. 8,097,651, 7,759,394, 8,927,604 and U.S. application no. 2015/0064258 covers a method of treating migraine associated with phonophobia or photophobia with liquid or solid formulation of Diclofenac designed to a Cmax of 1500 - 2500ng/ml in maximum time of 10 to 25min. A process of manufacture of 50mg of Diclofenac potassium dosage forms is described in the specification.
U.S. patent no. 8,735,450 discloses a novel formulation of Diclofenac where median particle size of Diclofenac on a particle volume basis is less than 300nm while 90% of Diclofenac on particle volume basis is less than 1700nm. The said composition would achieve the Tmax less than the Tmax of a conventional, non-nanop articulate form of Diclofenac administered to a human subject when the composition is administered at 20% lower dosage as the conventional, non-nanoparticulate form whereas Cmax would be atleast 10% higher.
PCT application no. WO 2016193900 discloses compositions exhibiting comparable dissolution profiles with that of the marketed composition of diclofenac acid (Zorvolex®). The invention particularly relates to solid oral pharmaceutical compositions comprising wet milled diclofenac acid with median particle size of less than 1000 nm.
Thus, although, prior arts disclose the use of several technologies for enhancing dissolution of Diclofenac formulations, these techniques for preparing such pharmaceutical compositions tend to be complex and expensive. Hence, there is a need for simple, stable and economically viable

pharmaceutical compositions comprising effective amount of Diclofenac to treatingacute or chronic pain and inflammatory conditions.
Summary of the invention:
An object of the present invention is to provide solid oral pharmaceutical compositions containing Diclofenac or pharmaceutically acceptable salts or derivatives thereof in a relatively low dose, so as to have the highest possible safety profile and allow self-medication by the patient, if desired.
Another object of the present invention is to provide solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles.
Yet another object of the present invention is to provide solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles, such that when the composition tested in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 50 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8 exhibit diclofenac acid release rate of at least 80% by weight within 10 minutes.
Another object of the present invention is to provide solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles, such that Maximum Plasma Concentration (Cmax) and Area Under Curve (AUC) values of the compositions are within the limit of 80 % to 125 % of Cmax and AUC of the marketed composition of diclofenac acid capsule (Zorvolex®) respectively.
Another object of the invention is a process of preparing a solid oral pharmaceutical composition comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles.

Yet another object of the invention is to provide a method of treating pain comprising administering the solid oral pharmaceutical composition comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles.
Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.
Detailed description:
An object of the present invention is to provide solid oral pharmaceutical compositions containing Diclofenac or pharmaceutically acceptable salts or derivatives thereof in a relatively low dose, so as to have the highest possible safety profile and allow self-medication by the patient, if desired.
As used herein, the term "Diclofenac" includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof selected from the Diclofenac diethylamine, Diclofenac epolamine, Diclofenac potassium, Diclofenac sodium, preferably Diclofenac potassium. The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. In the United Kingdom, United States, India, and Brazil diclofenac may be supplied as either the sodium or potassium salt; in China, it is most often supplied as the sodium salt, while in some other countries it is only available as the potassium salt. It is available as a generic drug in a number of formulations, including Diclofenac diethylamine, which is applied topically.
The term "effective amount" refers to a range of minimum to maximum amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, which have proven to be remarkably effective against osteoarthritis pain and other forms of acute pain.
According to one of the embodiments,the present invention provides immediate release oral dosage forms containing Diclofenac or pharmaceutically acceptable salts or derivatives thereof in a relatively low dose, so as to have the highest possible safety profile and allow self-medication by the patient, if desired.

Accordingly, the preferred pharmaceutical composition of the present invention contains various quantities ranging from about 10 mg to about 45 mg of Diclofenac or a pharmaceutically acceptable salt thereof. Thus, for example, the preferred formulation can contain about 15, 20, 25, 30, 35, 37.5 or 40 mg of Diclofenac. Preferably, pharmaceutical compositions of the present invention comprise 35 mg of diclofenac or 18 mg of diclofenac.
The term "oral dosage forms" includes allconventional oral solid dosage formslikea capsule, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Diclofenac and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.
The main embodiment of the present invention is to provide solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles; and a process for preparation of the same.
In another embodiment, the solid oral pharmaceutical composition is in the form of tablet comprisingDiclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles.
The term "nanoparticle" as used herein encompasses particles having median particle size of less than lOOOnm.
The term "median particle size" means the median particle diameter as determined on an equivalent spherical particle volume basis. Where the term median particle size is used, it indicates that about 50% of all measurable particles measured have a particle size less than the defined median particle size value, and that about 50% of all measurable particles measured have a particle size greater than the defined median particle size value. The median particle size is often written as D50, D(0.50) or D[0.5] or similar. As used herein D50, D(0.50) or D[0.5] or similar shall be taken to mean "median particle size". The "median particle size" also refers to the median particle diameter based on mass which means the particle diameter where one half of the mass of particles is contributed by particles with a lesser diameter and one half of the mass of particles is contributed by particles with a greater diameter. The particle size can be measured using various commonly available methods such as "measurement using" light^ (for example light-scatte'ring^ methods- tJr* turbidimetric methods),

sedimentation methods (for example pipette analysis using an Andreassen pipette, sedimentation scales, photo-sedimentometers or sedimentation in a centrifugal force), pulse methods (for example Coulter counter), or sorting by means of gravitational or centrifugal force.
In a preferred embodiment, the median particle size of the active product ingredient is more than !0u.m. In another preferred embodiment, the median particle size of the active product ingredient is more than 50um.
The term "pharmaceutical^ acceptable excipients" used herein, refers to organic or inorganic ingredients, natural or synthetic, with which an active ingredient is combined to facilitate administration of a composition. Examples of suitable excipients may include, but not limited to, as follows:
Diluents are used in formulations as a diluting agent or filler or thinner. Diluents are added to ease the restricted movement. In the current invention microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to theequipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, theexcipients include at least one diluent selected from microcrystalline cellulose and lactosemo no hydrate can be used.
Binders: Starch paste, pregelatinized starch, alginic acid, cellulose, hydroxy! propyl methyl cellulose, poly vinyl pyrrolidone, poly ethylene glycol,povidone, acacia, carboxymethyl cellulose sodium,methyl cellulose, ethyl cellulose, liquid glucose, sodium alginate, candelilla wax, carnauba wax, corn starch, copolyvidon, poly ethylene oxide, sodium starch.
Permeability enhancers are also added to enhance the permeability through cells. They are not limited to following examples SLS, Tween 80, Fatty acid esters (sodium taurocholate, sodium deoxycholate)
Disintegrants: Alginic acid, citric acid, crosscarmellose sodium, colloidal silicone dioxide, cellulose, carboxy methyl cellulose calcium, micro crystalline cellulose, methyl cellulose, povidone, sodium starch glycolate,sodium carmellose, starch, sodium alginate.
Lubricants: stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated
' E/e£elabl8oilfhydfogenatedHcas^^ macrdgols- or- mixtures thereof. It is

preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate.
Glidants: Fumed silica, magnesium carbonate, talc, colloidal silicone dioxide,tri calcium phosphate.
The pharmaceutical dosage form of the invention can optionally have one or more coatings such as moisture -barrier film coating, sugar coating and other coatings known in the art.
One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden. The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.
According to one of the embodiments of the present invention, the formulation is a conventional oral solid dosage form, preferably a capsule, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet; and more preferably a tablet, comprising Diclofenac as an active ingredient mixed with pharmaceutical carriers like diluents, disintegrant, permeability enhancer and amine derivative along with binder, glidant, lubricant which are commonly used.
In an embodiment of the present invention,the solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles, such that when the composition tested in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 50 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8 exhibit diclofenac acid release rate of at least 80% by weight within 10 minutes.
In another embodiment, the solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles, such that when the composition tested in-vitro by USP Apparatus I (Basket) method of U.S. Pharmacopoeia at 100 rpm, at 37 °C in 900 ml of 0.05% sodium lauryl sulfate in citric acid solution buffered to pH 5.5 exhibit diclofenac release rate of at least 85% by weight within 30 minutes.

Another object of the present invention is to provide solid oral pharmaceutical compositions comprising an effective amount of Diclofenac or pharmaceutical ly acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles, such that Maximum Plasma Concentration (Cmax) and Area Under Curve (AUC) values of the compositions are within the limit of 80 % to 125 % of Cmax and AUC of the marketed composition of diclofenac acid capsule (Zorvolex®) respectively.
Another object of the invention is a process of preparing a solid oral pharmaceutical composition comprising an effective amount of Diclofenac or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles, such that Maximum Plasma Concentration (Cmax) and Area Under Curve (AUC) values of the compositions are within the limit of 80 % to 125 % of Cmax and AUC of the marketed composition of diclofenac acid capsule (Zorvolex®) respectively.
An object of the present invent is to develop a method that is simple and avoids the use of expensive raw materials or complicated technologies or equipments.
Accordingly, a typical embodiment of the present invention is free of nanoparticles, and do not require the application of any such technologies, like nanomilling, micronization, etc.
In further embodiments of the present invention, the pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of Diclofenac, the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the Diclofenac.
The composition of the present invention can be produced by compressing a mixture of the drug substance with excipients. For example, one method for the production includes mixing the diclofenac with the materials for the preparation by a suitable mixer, and directly compressing the mixture to tablets. Other methods include a dry granulating step to produce granules for tablets using

dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders.
One of the preferred methods of preparation is wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a binding solvents or solutions to clump the powders into granules. The granulate is sized suitably either through screening or milling or both, dried and then screened and/or milled to the desired particle size. The granulate may then be tab letted/com pressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.
Likewise the composition of the invention can also be prepared by dry granulation. The drugs and excipients are blended, compacted into a slug or a sheet and then comminuted into compacted ■granules of suitable size. The compacted granules may subsequently be, compressed into a tablet.
The composition can also be prepared by direct compression by compressed directly into a compacted dosage form.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.
In one embodiment, a pharmaceutical composition comprising effective amount of diclofenac potassium of the invention has a comparable bioavailability to the commercial form of diclofenac or salts. In one preferred embodiment, the pharmaceutical composition comprising diclofenac potassium is bioequivalent to commercial form of diclofenac or salts.
Yet another object of the invention is to provide a method of treating pain comprising administering the solid oral pharmaceutical composition comprising an effective amount of Diclofenac or pharmaceutical^ acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients, wherein the active product ingredient is substantially free of nanoparticles.
Examples:
The following experimental details are set forth to aid in an understanding of the invention, and are
not intended, and should not be construed, to limit in any way the invention set forth in the claims
that follow thereafter. A person skilled in the art will readily recognize the various modifications and : ISJ.T OF FT C F P.HF N-N AT 1 n / n a / o n 1 -?■ i c , o

variations that may be performed withoutaltering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.
Example l:Tablet comprising Diclofenac potassium
Ingredients %WAV
Intragranular
Diclofenac potassium 20.5
Lactose monohydrate 21.14
Microcrystalline cellulose 19.42
Croscarmellose sodium 4.85
Binder solution
Povidone k-29/32 4.25
Sodium lauryl sulphate(SLS) '-'0
Purified water q-s.
Extragranular
Croscarmellose sodium 5.25
Microcrystalline cellulose 19.5
Mg Stearate 0.4
Colloidal silicon dioxide 0.69
Optional
Opadry 2$
Water CLS.
Preparation:
1. Required quantity of Diclofenac potassium, lactose monohydrate, microcrystalline Cellulose andcroscarmellose sodium were weighed and passed through sieve # 40.
2. The ingredients of step-1 were loaded onto Rapid Mixer Granulator (RMG) and mixed for 10 minutes with impeller 150 rpm and chopper off.
3. The materials of step-2 were granulated in Rapid Mixer Granulator (RMG) along with the binder solution.
4. The wet mass of step-4 was dried in Rapid drier at 55°C ± 5°C to achieve desired LoD.
5. The dried granules were passed through sieve # 20

6. The extragranular materials such as croscarmellose sodium, microcrystalline cellulose, magnesium stereate and colloidal silicon dioxide were weighed and passed through suitable meshes.
7. The step-5 materials were added to the step 6 material and blended for 5 minutes.
8. The step-7 materials were compressed by desired punches.
9. (Optional) Preparation of coating solution: Opadry blue was added to purified water under continuous stirring for 45 minutes.
10. The step-8 material was coated with step-9 material upto 2.5 % weight build-up.
Example 2:Capsule Tilled granules comprising Diclofenac potassium
Ingredients %WAV
Diclofenac potassium USP 37.5
Lactose monohydrate 4.83
Sodium starch glycolate 8.6
Microcrystalline cellulose 41.77
Maize starch 5.3
Mg Stearate 1.0
Colloidal silicon dioxide 1.0
Preparation:
1. Required quantity of Diclofenac potassium, lactose monohydrate, microcrystalline Cellulose and sodium starch glycolate were weighed and passed through sieve # 40.
2. Diclofenac potassium, lactose monohydrate and microcrystalline'Cellulosewere loaded into Rapid Mixer Granulator (RMG) and mixed for 2 minutes with impeller 150 rpm and chopper off.
3. The step-2 materials were granulated in Rapid Mixer Granulator (RMG) using water as granulating fluid.
4. The wet mass of step-4 was dried in Rapid drier at 55°C ± 5°C to achieve desired LoD.
5. The dried granules were passed through sieve # 20.
6. The lubricating ingredients such as maize starch, colloidal silicon dioxide were weighed and passed through # 40 mesh,while magnesium stearate was passed through # 60 mesh.
7. Step-5 materials were added to the step-6 material and blended for 5 minutes.
E 8V! ^eQMned^rinulfs ftgfNllA -fnfo cages' <#&sir& Size 7 15=53

Claims:
I. A solid oral pharmaceutical composition comprising:
i. 15 - 40mg of Diclofenac or pharmaceutically acceptable salts or derivatives thereof; and
ii. one or more pharmaceutically acceptable excipients; wherein, the composition is substantially free of nanoparticles, and such that Maximum Plasma Concentration (Cmax) and Area Under Curve (AUC) values of the composition are within the limit of 80 % to 125 % of Cmax and AUC of the marketed composition of diclofenac acid capsule (Zorvolex®) respectively.
2. A solid oral pharmaceutical composition comprising:
i. 18mg of Diclofenac or pharmaceutically acceptable salts or derivatives thereof; and
ii. one or more pharmaceutically acceptable excipients; wherein, the composition is substantially free of nanoparticles, and when tested in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 50 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8 exhibit diclofenac acid release rate of at least 80% by weight within 10 minutes.
3. A solid oral pharmaceutical composition comprising:
i. 35mg of Diclofenac or pharmaceutically acceptable salts or derivatives thereof; and
ii. one or more pharmaceutically acceptable excipients; wherein, the composition is substantially free of nanoparticles, and when tested in-vitro by USP Apparatus II (Paddle) method of U.S. Pharmacopoeia at 50 rpm, at 37 °C in 900 ml of phosphate buffer, pH 6.8 exhibit diclofenac acid release rate of at least 80% by weight within 10 minutes.
4. A solid oral pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is in the form of a capsule, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet.
5. A solid oral pharmaceutical composition as claimed in any of the preceding claims, wherein the pharmaceutically acceptable salt of Diclofenac is selected from Diclofenac diethylamine, Diclofenac epolamine, Diclofenac potassium, Diclofenac sodium or mixtures thereof.

6. A solid oral pharmaceutical composition as claimed in any of the preceding claims, wherein the pharmaceutically acceptable salt of Diclofenac is Diclofenac potassium.
7. A solid oral pharmaceutical composition as claimed in any of the preceding claims, wherein the composition comprises one or more pharmaceutically acceptable excipients selected from a group consisiting of binders, diluents, fillers, lubricants, glidants, disintegrants, sweeteners, flavouring agents, preservatives, buffers, wetting agents, effervescent agents and mixtures thereof.