FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "TOPICAL EMULSION-GEL COMPOSITION COMPRISING CYCLOBENZAPRINE AND DICLOFENAC AND PROCESS FOR PREPARING THEREOF"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions comprising a combination of Cyclobenzaprine or its pharmaceutical acceptable salts and Diclofenac or its pharmaceutical acceptable salts as active ingredients and also contains absorption and blood flow enhancers for topical application. This invention also relates to process for the preparation of such compositions thereof.
The compositions represent emulsion-gel with unique properties such as high skin penetration, high stability, complete dissolution of the actives and high pain relief.
BACKGROUND OF THE INVENTION
Cyclobenzaprine, also named 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine is a known tricyclic muscle relaxant marketed by Merck & Co., Inc. under the trademark FlexerilTM as oral tablet dosage form. Cyclobenzaprine significantly improves the signs and symptoms of skeletal . muscle spasm. The clinical response includes improvement in local pain and tenderness and increased range of motion. With topical administration, complications associated with oral administration of Cyclobenzaprine such as extensive first pass metabolism and side effects like drowsiness, dry mouth and dizziness can be avoided. Cyclobenzaprine when used topically is highly effective, allowing for effective dosing with minimal systemic absorption.
Diclofenac is the most widely used non-steroidal anti-inflammatory drug ("NSAID") known chemically as 2-[(2,6-dichlorophenyl)amino]phenylacetic acid. The drug was developed in the 1960s by scientists at Ciba-Geigy and is sold around the world by Novartis under various trade names, including CataflamTM and VoltarenTM. Currently most successful topical formulation is Voltaren® emulsion-gel comprising 1.16% Diclofenac diethylamine salt (corresponding to

1% Diclofenac sodium). Development of topical formulation of Diclofenac had been proved to be better alternative in circumventing the serious adverse effects associated with oral administration of Diclofenac such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances.
The usual approach in relieving muscle pain relies on trying to decrease muscle tone and breaking the pain-spasm-pain cycle. The basic pathologies of musculoskeletal pain involve muscle spasm followed by pain and muscle relaxants are one of the drugs of choice in relieving it. Since pain of muscle spasm is one of the chief symptoms and is caused due to release of inflammatory mediators and sensitization of peripheral nociceptors, most guidelines recommend use of NSAIDs. However both classes of drugs have limitations in the treatment of musculoskeletal pain which can be decreased by combining them together which provides additional pain relief through other mechanisms so that a patients' mobility, independence and quality of life can improve. In case of NSAIDs, they are devoid of any direct effect on skeletal muscle contraction while on the other hand the mechanism of analgesia for skeletal muscle relaxants is not fully known. Combining a NSAID with muscle relaxant takes care of the limitation of both groups in relieving muscle pain. The combination would much more effectively break the pain-spam-pain cycle and allow faster mobilization and better relief.
Topical formulations are attractive options because they avoid the hepatic first-pass metabolism, reduce the side effects associated with oral administration, are associated with higher patient compliance and, in some cases, enhance therapeutic efficacy of the drug. Also, they allow for continued long term use as needed and will target the specific site of pain.
U.S. Patent No. 4722938 A and U.S. Patent No. 5260337 A discloses certain combinations of muscle relaxants and NSAIDs mainly for oral administration.

Such combinations of muscle relaxants and NSAIDs are marketed successfully, in the form of the tablets. Aspirin is individually available with three different muscle relaxants, Carisoprodol, Orphenadrine and Meprobamate. Diclofenac and Aceclofenac are available with muscle relaxant Chlorzoxazone. Neodolpasse is a ready to use infusion product approved for marketing in several countries in Europe which contains Diclofenac sodium and Orphenadrine.
U.S. Patent Application No. 20150359740 A1 discloses a compounded transdermal cream which may include Diclofenac, Cyclobenzaprine, Gabapentin, or a combination thereof. A method of compounding the transdermal cream may comprise adding the fine powder medication to a starting transdermal cream or base. A fine powder of above medications may be obtained by crushing the commercial tablets of the medication.
None of the above cited prior art discloses a stable topical formulation comprising a combination of Cyclobenzaprine and Diclofenac in a single topical formulation.
Therefore, there exists a need to develop a preparation containing combination of Diclofenac and Cyclobenzaprine in a single topical formulation, having improved skin permeability, bioavailability and enhanced therapeutic activity.
However, this combination is highly unstable as Diclofenac reacts with Cyclobenzaprine and reduces its assay on stability and phase separation takes place.
Klaus Florey (Analytical Profiles of Drugs Substances, Volume 17, Page 60, 1988) had reported incompatibility of Cyclobenzaprine hydrochloride with acidic drugs. Cyclobenzaprine hydrochloride undergoes acid-catalyzed oxidation and most NSAIDs are weak organic acids. Cyclobenzaprine hydrochloride degrades through oxidation of either a) the endocyclic double bond, b) the exocyclic

double bond to form an epoxide, or c) the oxidation of the nitrogen group to form the corresponding N-oxide. These inherently unstable, initial oxidation products undergo further transformation to more polar compounds and subsequent cleavage of the aliphatic side chain to form dibenzocycloheptatrienone and anthraquinone as major oxidation products. This results into reduction of Cyclobenzaprine assay on stability.
Since, Diclofenac is acidic in nature, a similar reaction likely occurs and causes the degradation of Cyclobenzaprine, when the two are in contact with each other. Therefore, the vehiculation of Cyclobenzaprine and Diclofenac in pharmaceutical products necessitates avoiding contact between these two agents so as to prevent chemical interaction. Thus, maintaining the stability of Diclofenac and Cyclobenzaprine in a single formulation is a challenging task.
The present inventors have surprisingly achieved this goal by isolation of two drugs having diverse physicochemical properties via formulation of microemulsion or emulsion-gel technology.
The present inventors have surprisingly developed a stable pharmaceutical composition comprising a combination of two active ingredients, Cyclobenzaprine or its pharmaceutically acceptable salts and Diclofenac or its pharmaceutically acceptable salts which may additionally contain absorption and blood flow enhancers in a single emulsion-gel topical formulation. A stable formulation of these two incompatible agents was achieved by incorporating aliphatic acid in the formulation.

SUMMARY OF THE INVENTION
The present invention relates to an emulsion-gel for topical application comprising a combination of a local skeletal muscle relaxant Cyclobenzaprine or its pharmaceutical acceptable salts; non-steroidal anti-inflammatory drug (NSAID) Diclofenac or its pharmaceutical acceptable salts, as active ingredients and also contains absorption and blood flow enhancers such as linseed oil, methyl salicylate and menthol.
The composition may also include an emulsifying agent, a neutralizing agent, a chelating agent, preservative, odour masking agent and a coloring agent.
The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those described, set forth, or referenced in this summary. The inventions described and claimed herein are not limited to or by the features of embodiments identified in this summary. The summary is included solely for purposes of illustration and not restriction.
In one embodiment of the invention the NSAID comprises Diclofenac, alone, or in combination with, one or more additional NSAIDs.
The Diclofenac that can be used in this method includes, but is not limited to; a free acid of Diclofenac, an alkali metal salts such as the sodium or potassium salt, or an organic salt, especially an amine salt, such as, for example, diethylamine. The salt with diethylamine is particularly preferred.
In yet another embodiment of the invention the composition further comprises Cyclobenzaprine hydrochloride as smooth muscle relaxant.

In yet another embodiment of the invention, the composition further comprises an agent which can increase the blood flow to the site of administration, such as methyl salicylate, menthol and linseed oil.
According to a preferred embodiment of the present invention, the topical pharmaceutical composition further comprises aliphatic carboxylic acid such as stearic acid and diethanolamine to avoid phase separation upon storage.
In another embodiment of the invention, the composition is adjusted to a pH in the range 6.5 to 7.5.
In another embodiment of the invention the preservative is benzyl alcohol,
In one preferred embodiment of the invention the chelating agent comprises ethylene diaminetetraacetic acid.
According to a preferred embodiment of the present invention. the topical pharmaceutical composition is in the form of gel; preferably in the form of emulsion-gel.
According to another preferred embodiment of the present invention, the topical pharmaceutical composition is used in the treatment of pain and inflammatory symptoms associated with muscular-skeletal system.
Further advantages and embodiments of the present invention will become apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION
Gels are relatively newer class of dosage form created by entrapment of large amounts of aqueous or hydroalcoholic liquid in a three dimensional swollen network of colloidal solid particles, which may consist of inorganic or organic polymers of natural or synthetic origin. As gels have a higher aqueous component, they simply permit the entrapment of hydrophilic drugs. However major limitation associated with such hydrogels is entrapment and delivery of hydrophobic drugs. Diclofenac is hydrophobic in nature, and difficulty has been raised to researcher for the delivery of such drug in any form of dosage, because of their limited solubility. There has been always a challenging task for the formulation of drug with limited solubility and that needs to deliver topically. When we consider delivering these drugs in conventional dosage form as cream, ointment, lotions, emulsion the problem of stability and bioavailability rises due to their hydrophobic nature. In gel also it is almost negative result to deliver hydrophobic drugs. So the new concept of formulation emulsion in gel has shown better delivery as here the drug are incorporated in oil phase of emulsion and emulsion is better stabilize in the gel and the combination of both of the phase provide the controlled release effect, that improves the bioavailability of that drugs. Such advantages of emulgel provide the big scope for the delivery of hydrophobic drug topically with more efficacy and less production cost. Oils with medicinal value provide the synergistic effect to emulgel.
Emulsion-gel has emerged as a promising drug delivery system for the delivery of hydrophobic drugs as it is engulfed in oil droplets of emulsion. When gels and emulsions are used in combined form the dosage forms are referred as emulsion-gel. The present invention relates to a formulation of emulsion-gel, ideally suited for topical application, comprising a combination of Cyclobenzaprine or its pharmaceutical acceptable salts and Diclofenac or its pharmaceutical acceptable salts.

Diclofenac has four different salts which show significant variability in the degree of permeation in solutions using different solvents. Minghetti et al., performed the permeation studies of sodium, potassium, diethylamine and epolamine salts of Diclofenac across human stratum corneum and epidermis (SCE) as a model membrane. It was concluded that Diclofenac salt with an organic base is best for topical applications. Flux (J mg/cm2/h) of diethylamine salt through skin is observed to be around 2 folds higher than sodium salt of Diclofenac.
Diclofenac diethylamine, has water solubility < 1 mg/ml therefore it is dissolved in oil phase which is made up of linseed oil and stearic acid 50. Here, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) is acting as an emulsifier added in aqueous phase. It has HLB value in a range of 14-16 therefore it tends to form w/o emulsion. Stearic acid is an anionic amphiphile (HLB 15) which can act as an emulsifier and contributes to stabilize the formulation via increasing the viscosity of the oil phase. Thus, possibility of phase separation of w/o emulsion containing Diclofenac is avoided when using stearic acid and Cremophor RH 40 as emulsifying agents.
Cyclobenzaprine hydrochloride is a white crystalline tricyclic amine salt that is freely soluble in water or alcohol. Klaus Florey had reported Cyclobenzaprine hydrochloride undergoes acid-catalyzed oxidation.
Diclofenac is acidic and Cyclobenzaprine is basic in nature. Therefore, Diclofenac tends to react with Cyclobenzaprine and reduces its assay on stability and phase separation takes place. Formulating emulsion-gel system contributes to solve solubility and stability issues of these two drugs via proper vehiculation which eliminates contact between these two agents so as to prevent chemical interaction.

Cyclobenzaprine being freely soluble in water, is incorporated in aqueous phase of the w/o emulsion. Oil phase of this emulsion is made up of menthol and methyl salicylate. Diclofenac diethylamine and linseed oil is separately incorporated in oil phase of the w/o emulsion. These emulsions are further mixed into hydrophilic gel base made up of carbomer. Ultimately, w/o emulsions are incorporated in hydrophilic gel matrix to form a multiple emulsion-gel.
Drugs incorporated in micro-sized globules effectively enhance the permeation of these drugs across the skin. Thus, in the present invention, w/o emulsion is formulated to integrate advantages of two drugs in a single formulation. Additional advantage of formulating emulsion gel is to achieve a separation between two drugs.
The excipients mentioned herein are described in A. Kibbe, Handbook of Pharmaceutical Excipients, 3rd Edition, 2000.
Carbomers, in the context of the present invention, are defined as homo or copolymers of acrylic acid that are cross-linked, e.g. with an ally] ether of pentaerythritol (allyl pentaerythritol) or an allyl ether of sucrose (allyl sucrose). In this present invention, carbomer 934 P USP-NF is used as a thickening agent to make a gel in an amount of 0.5-2.0 % in topical preparation.
Carbomers require a neutralizer or a pH adjusting agent to form a gel. The preferred pH range is 6.5 -7.5 to achieve a maximum viscosity. Some of the neutralizing agents which may be used are sodium hydroxide, potassium hydroxide, and triethanolamine. It was observed that if inorganic bases (sodium hydroxide, potassium hydroxide) are used to neutralize the solution, stable water soluble gel is formed. If triethanolamine is used, the gel can tolerate high alcohol concentrations. Therefore this is an advantageous aspect with respect to further inclusion of preservatives and other excipients in the gel.

According to another aspect of the invention, it contains absorption and blood flow enhancers, which are known to increase the blood flow to the site of application. It is well-known that local anesthetic, counter irritant, rubefacients and other pharmacologically stimulated mechanisms of bringing more flow to the site of application, increases the absorption of drug across skin, since the transport of drug is based on a flux mechanism that is often concentration gradient dependent.
Following are examples of preferred embodiments of the composition, without limitation of the choice of ingredients as claimed below.
The absorption and blood flow enhancers may be selected but not limited to linseed oil; methyl salicylate and menthol or combination thereof. In one aspect of the invention, a method is provided for enhancing the flux of the drug through the skin, comprising topically administering the drug in combination with a permeation enhancing amount of a vegetable oil composition. Accordingly, preferred vegetable oils within the aforementioned group include linseed oil, coconut oil, corn oil, cotton seed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil and soybean oil but preferably linseed oil.
In still yet another embodiment of the invention, the composition further comprises methyl salicylate as counter irritant agent which can increase the blood flow to the site of administration.
A further object of the present invention is to obtain a formulation with local anesthetic effect, with the menthol used in said combination stimulating the receptors by which the cold sensation is perceived. Menthol chemically belongs to terpenes and is also reported as topical permeation enhancer.
This gel formulation may optionally include at least one antioxidant and/or one chelating agent (0.1 -0.2%).

Preferred antioxidants for use in the present invention may be selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanis'ole (BHA), ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate, carotenoids, kojic acid, thioglycolic acid, tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18, tocophereth-80, and mixtures thereof.
Preferred chelating agents may be selected from the group consisting of ethylenediamine tetraacetic acid (EDTA), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA, HEDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium phosphate, diammonium citrate, galactaric acid, galacturonic acid, gluconic acid, glucuronic acid, humic acid, cyclodextrin, potassium citrate, potassium EDTMP, sodium citrate, sodium EDTMP, and mixtures thereof.
After a lot of experimentation including many failures the inventors succeeded in obtaining a stable emulsion-gel fulfilling all of the requirements. Therefore the invention relates to a topical pharmaceutical composition, which is in the form of an emulsion-gel and comprises the combination of 1.16% (w/w) of Diclofenac diefhylammonium salt and 2.0 % (w/w) Cyclobenzaprine hydrochloride.
The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the present invention. The example should not be read as limiting the scope of the present invention.

Example:
Composition with pH adjusting agent:

Sr.
No. Ingredients %w/w
Gel phase
1. Purified water 49.144
2. Disodium EDTA 0.1
3. Carbomer 934 P 1.32
4. Diethanolamine 0.7
5. ■ Purified water 1.25
Emu sion consisting of Cyclobenzaprine (Phase I)
Aqueous phase-I
6. Cyclobenzaprine hydrochloride 2.4
7. Purified water 5
Oil phase-I
8. Menthol 5.25
9. Methyl salicylate 10.5
10. Cremophor RH 40 1
Emu sion consisting of Diclofenac (Phas eII)
Aqueous phase-II
11. Purified water 8.4
12. Cremophor RH 40 2.5
13. Citric acid monohydrate 0.01
Oil phase-II
14. Linseed oil 3
15. Butylated hydroxytoluene 0.2
16. Diclofenac diethylamine 1.276
17. Stearic acid 50 5
External phase
18. Benzyl alcohol 1
19. Diethanolamine 0.7
20. Purified water 1.25
100

Procedure:
Procedure for preparation of emulsion-gel of combination comprises of 4 steps:
1. Preparation of gel phase.
2. Preparation of w/o primary emulsion consisting of Cyclobenzaprine or its pharmaceutically acceptable salts thereof (Phase-I).
3. Preparation of w/o primary emulsion consisting of Diclofenac or its pharmaceutically acceptable salts thereof (Phase-II).
4. Combination of above two primary emulsions in gel phase (External Phase).
Both emulsion phase-I and emulsion phase-II were separately added to gel phase under continuous stirring to form a multiple emulsion-gel.
Preservatives were added and pH of the formulation was adjusted again at 6.5-7.5 using diefhanolamine solution. Checked the weight of the emulsion-gel and adjusted to required weight with purified water under stirring. The emulsion-gel was allowed to cool at room temperature under stirring.
As mentioned in detailed description combination of cyclobenzaprine and diclofenac is highly unstable as Diclofenac reacts with Cyclobenzaprine and reduces its assay on stability via acid catalyzed oxidation. Therefore long term, intermediate and accelerated stability studies of formulation were carried out. Results obtained reveal that Diclofenac as well as Cyclobenzaprine remain stable in a single formulation due to proper vehiculation of both the drugs in a single formulation.

We Claim:
1. A stable topical pharmaceutical composition comprising a combination of Diclofenac or its pharmaceutically acceptable salts and Cyclobenzaprine or its pharmaceutically acceptable salts in the form of an emulsion-gel.
2. A stable topical pharmaceutical composition as claimed in claim 1 which is in the form of an emulsion-gel, and comprises a combination of Diclofenac or its pharmaceutically acceptable salts thereof is present from about 1 % w/w to about 35 % w/w of composition and Cyclobenzaprine or its pharmaceutically acceptable salts thereof is present from about 1 % w/w to about 35 % w/w of composition.
. 3. A stable topical pharmaceutical composition comprising a combination of Diclofenac or its pharmaceutically acceptable salts and Cyclobenzaprine or its pharmaceutically acceptable salts and one or more absorption and blood flow enhancers in the form of an emulsion-gel.
4. A stable topical pharmaceutical composition as claimed in claim 1 and 3
which is in the form of an emulsion-gel, and comprises 1.16 % (w/w)
Diclofenac diethylammonium salt and 2.0 % (w/w) Cyclobenzaprine
. hydrochloride.
5. A stable topical pharmaceutical composition as claimed in claim 1 and 3
which is in the form of an emulsion-gel comprising a) Diclofenac or its
pharmaceutically acceptable salts b) Cyclobenzaprine or its
pharmaceutically acceptable salts and c) one or more absorption and
blood flow enhancers selected from linseed oil; methyl salicylate and
menthol or combination thereof.