DESC:DESCRIPTION

FIELD OF THE INVENTION

The present invention provides a transdermal drug delivery system which comprises a therapeutically effective amountof COX-2 inhibitors having anti-inflammatory activity. More particularly, the invention relates to a suitable transdermalpharmaceutical dosage form comprising a composition of COX-2 inhibitors or a pharmaceutically acceptable salt thereof and one or more natural oils and pharmaceutically acceptable excipients with desired physical and chemical parameters. The application also provides various formulations and methods of preparing the same.

BACKGROUND OF THE INVENTION

Now-a-days pain is universal disorder affecting almost all the age groups and covering all fields of occupants. For dealing with pain is a great challenge for health care providers and pharmaceutical companies. Patient has to undergo physical as well as mental trauma due to pain. Pain is classified into acute as well as chronic. Acute pain encountered due to any injury of tissues, inflammation or disease. While, chronic pain has longer period existence and has resistance to medical treatments. There are more than 100 types of arthritis. Pain is of joints throughout the body. Examples of degenerative arthritic diseases are rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and others.

Arthritis causes impairment of normal function of a joint and results in tenderness, aching, pain, and lengthy recovery times, as well as loss of joint mobility or reduced range of motion, tonicity, or elasticity of the joint/articular structures, such as for example, muscle, tendon, capsule, bone, or ligament. Reduced joint mobility may also involve permanently altered or shortened joint or tissue architecture. Altered or abnormal joint mobility or joint architecture may also be associated with or caused by a variety of injuries and conditions such as, for example, metabolic disorders, ischemia, injury to joint, capsule, bone, cartilage, tendon, ligament or muscle, fractures, subluxation, dislocation, crush injuries, prolonged immobilization (e.g., immobilization of a joint in a cast or splint), and paralysis. When non-pharmacological measures are not sufficient to control the symptoms of osteoarthritis, current evidence-based guidelines support pharmacological treatment with acetaminophen or oral nonsteroidal anti-inflammatory drugs (“NSAID”s). Acetaminophen has been linked with an increased risk of hepatic, hypertensive and cardiovascular adverse effects. Diclofenacis used, most commonly, as the sodium or potassium salt for relief from pain and inflammation such as musculoskeletal and joint disorders including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

Cyclooxygenase (COX) enzyme is involved in various normal physiological and inflammatory responses. COX is constituted of two structurally similar isoenzymes i.e. COX-1 and COX-2 but differs in substrate-binding pocket size. COX-1 is expressed in many tissues and involved in various functions with majorly involved in prostaglandin (PG) synthesis. While, COX-2 involvement in inflammatory responses, Non-steroidal anti-inflammatory drugs (NSAIDs) which act non-selectively on COX-1 as well as COX-2 isozymes are generally associated with side effects due to inhibition of COX-1 isozyme.

Pharmacological uses of Diclofenac Sodium is well documented and benefit of these drugs lies in its safety profile of topical dosage form with 1-5% w/w of gel is safe and well tolerated. Diclofenac sodium (Diclofenac diethylamine 1.16% equivalent to 1% Diclofenac Sodium) and Ginger oil both are active constituents. All pharmacokinetic parameters of diclofenac sodium are referred to and standardized individually.Despite, diclofenac sodium has potential side effects of gastric irritation which continues to formulate these drugs in dosage form which is highly safer and effective. Its low aqueous solubility, poor dissolution, delayed percutaneous absorption rate and onset of action limits its application for transdermal delivery.

Inhibitors of cyclooxygenase-2 are a sub-class of the class of drugs known as non- steroidal anti-inflammatory drugs (NSAIDs). The NSAIDs are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process but is also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production of prostaglandin by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway including the enzyme cyclooxygenase (COX). The recent discovery that there are two isoforms of the COX enzyme, the first, COX-1, being involved with physiological functions and the second, COX-2, being induced in inflamed tissue, has given rise to a new approach. While conventional NSAIDs block both the COX-1 and COX-2 enzymes, the identification of the inducible COX-2 enzyme and its association with inflammation has provided a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. A number of selective COX-2 inhibitors have been identified, including rofecoxib, etoricoxib, celecoxib and valdecoxib, and much research continues in this area. COX inhibitors are administered in acute pain conditions i.e. pain associated with dental surgery, primary dysmenorrhea, surgeries associated with orthopedics and patients suffering from osteoarthritis, rheumatoid arthritis, psoriatic Arthritis, Ankylosing Spondylitis, gout as reported in literature.

Numerous compounds have been reported having therapeutically and/or prophylactically useful selective cyclooxygenase-2 (COX-2) inhibitory effect, and have been disclosed as having utility in treatment or prevention of specific COX-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,760,068 to Talley et al., including for example the compound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as celecoxib (I), and the compound 4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as deracoxib (II).

Other compounds reported to have therapeutically and/or prophylactically useful selective COX-2 inhibitory effect are substituted isoxazolylbenzenesulfonamides as reported in U.S. Pat. No. 5,633,272 to Talley et al., including the compound 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, also referred to herein as valdecoxib (III).

Still other compounds reported to have therapeutically and/or prophylactically useful selective COX-2 inhibitory effect are substituted (methylsulfonyl)phenyl furanones as reported in U.S. Pat. No. 5,474,995 to Ducharme et al., including the compound 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one, also referred to herein as rofecoxib (IV).

U.S. Patent No. 5,981,576 to Belley et al. discloses a further series of (methylsulfonyl)phenyl furanones said to be useful as selective COX-2 inhibitory drugs, including 3-(1-cyclopropylethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one and 3-(1cyclopropylethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.

U.S. Patent No. 5,861,419 to Dube et al. discloses substituted pyridines said to be useful as selective COX-2 inhibitory drugs, including for example the compound 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine (V).

European Patent Application No. 0 863 134 discloses the compound 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopoenten-1-one said to be useful as a selective COX-2 inhibitory drug.

U.S. Patent No. 6,034,256 discloses a series of benzopyrans said to be useful as selective COX-2 inhibitory drugs, including the compound (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (VI).

Many selective COX-2 inhibitory drugs, including celecoxib, deracoxib, valdecoxib and rofecoxib, are hydrophobic and have low solubility in water. This has presented practical difficulties in formulating such drugs for oral administration, particularly where early onset of therapeutic effect is desired or required.

Illustratively, the formulation of celecoxib for effective oral administration to a subject has hitherto been complicated by the unique physical and chemical properties of celecoxib, particularly its low solubility and factors associated with its crystal structure, including cohesiveness, low bulk density and low compressibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract when administered orally, for example in capsule form.

In addition, unformulated celecoxib, which has a crystal morphology that tends to form long cohesive needles, typically fuses into a monolithic mass upon compression in a tableting die. Even when blended with other substances, the celecoxib crystals tend to separate from the other substances and agglomerate together during mixing of the composition resulting in a non-uniformly blended composition containing undesirably large aggregates of celecoxib. Therefore, it is difficult to prepare a pharmaceutical composition containing celecoxib that has the desired blend uniformity. Further, handling problems arising for example from the low bulk density of celecoxib are encountered during preparation of celecoxib compositions.

Accordingly, a need exists for solutions to numerous problems associated with preparation of compositions and dosage forms comprising COX-2 inhibitors particularly celecoxib, particularly transdermal dose units for fast relief and ease in patient compliance.

Although numerous formulations of NSAIDs are being developed to improve its solubility and bioavailability like ethosomes, nanoparticles, microemulsions, complexation with phospholipids and cyclodextrins, solid dispersions inspite formulation challenges imposed by NSAIDs. But disadvantage with methods like microemulsions employ large quantity of surfactants, co-surfactants and other exogenous compounds which are responsible for causing irritation to patients.

Therefore, there is a need to provide a synergistic composition comprising COX-2 inhibitors in combination with various bio-enhancers for improved percutaneous bioavailability of COX-2 inhibitors and its use in management of anti-inflammatory diseases such as arthritic pain.

In order to resolve the problems associated with the prior arts, the inventors of the present invention doan attempt to formulate transdermal dosage form of COX-2 inhibitors with a view to improve percutaneous absorption by using combination of natural oils.

Local transdermal delivery of drugs, while desirable, is limited by current technologies. Thus, improvements in the transdermal delivery of compositions, locally or systemically, are essentially needed.

OBJECTIVE OF THE INVENTION

An object of the present invention is to provide compositions/formulations comprising COX-2 inhibitors in synergistic combination with other pharmaceutically acceptable excipients.

Accordingly, the principal objective of the present invention is to provide compositions/formulations comprising COX-2 inhibitors in synergistic combination with natural oils such as Orange oil, Ginger oil, Eucalyptus oil and pharmaceutically acceptable excipients.

The combination of the present invention is able to provide a safe composition with enhanced and/or synergistic effects for treatment of diseases associated with inflammation.

The objective of the present invention is to develop a transdermal formulation of COX-2 inhibitors with desired physical and chemical parameters.

Another objective of the present invention is to develop a COX-2 inhibitors pharmaceutical composition with therapeutically effective dosing.

Another objective of the present invention is to develop a COX-2 inhibitors inhibiting pharmaceutical composition with increased patient compliance.

Another objective of the present invention is to develop pharmaceutical composition of COX-2 inhibitorswith desired stability.

Yet another objective of the present invention is to developa transdermal formulation of COX-2 inhibitors along with bio-enhancers with anti-inflammatory properties of natural origin in their respective amounts for improved percutaneous absorption, thereby enhancing bioavailability and bio-efficacy of COX inhibitors.

Another objective of the present invention is to provide synergistic pharmaceutical composition of COX inhibitors along with various penetration enhancers, wherein the comparison counteracts the inflammation caused by complete freund’s adjuvant (CFA) induced inflammation which has symptoms like arthritis.
In an embodiment, the present invention generally relates to the transdermal delivery ofcompositions, locally or systemically, and in some embodiments, to the transdermaldelivery of compositions by a hostile biophysical environment. The subject matter of the present inventioninvolves, in some cases, interrelated products, alternative solutions to a problem, and/or a plurality of different uses of one or more systems and/or articles.

In another embodiment, the present invention, in another aspect, is directed to a method of making one ormore of the embodiments described herein. In yet another aspect, the present inventionis directed to a method of using one or more of the embodiments described herein.

Instill another aspect, the present invention is directed to a method of promoting one ormore of the embodiments described herein.

Accordingly, another objective of the present invention is to develop a formulation which is bioavailable, synergistic, safe from any adverse effects with reduced frequency of drug administration. The formulation will be cost-effective for the people of developed and developing countries suffering from various inflammatory related pain like arthritis.

In addition to providing improved percutaneous absorption efficiency, the composition of the invention may also provide lower irritancy than some other more occlusive delivery systems such as transdermal patches, because the composition is non-occlusive to the skin.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limiting embodiments ofthe invention. In cases where the present specification and a document incorporated byreference include conflicting and/or inconsistent disclosure, the present specificationshall control. If two or more documents incorporated by reference include conflictingand/or inconsistent disclosure with respect to each other, then the document having thelater effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1: Illustrates comparative percentage cumulative release
Fig 2: Illustrates averages percentage retention

DESCRIPTION OF THE INVENTION

The present invention generally relates to the transdermal delivery of variouscompositions. In some aspects, transdermal delivery may be facilitated by the use of ahostile biophysical environment.

One aspect of the invention provides compositions for the transdermal delivery ofsubstances such as pharmaceutical agents (e.g., drugs, biological compounds, etc.). Thepharmaceutical agents may be applied to the skin of a subject, e.g. a human, to aid intreatment of medical conditions or diseases, and/or the symptoms associated thereof. In some embodiments, the invention provides for the treatment of medical conditions ordiseases and/or ailments using pharmaceutical agents (for example, to treat a subjectdiagnosed with a medical condition or disease, as described herein), and in some cases,the invention provides for the delivery of a minimum amount of pharmaceutical agents toprovide effective levels of medication to an effected area topically while limiting sideeffects. In some cases, the effective dosage of the pharmaceutical agent may be lowerthan the effective dosage of the pharmaceutical agent when taken orally.

In another embodiment, the compositions/formulations of the present invention comprises COX-2 inhibitors, wherein the amount of COX-2 inhibitors ranges from 0.01% to 5%.
In another embodiment, the COX-2 inhibitors are selected from celecoxib, rofecoxib, etoricoxib, and valdecoxib or a combination thereof.

In a preferred embodiment, the COX-2 inhibitor is celecoxib.

In the preferable embodiment, the compositions of the present invention further comprise at least one natural oilsselected from orange oil, ginger oil, eucalyptus oilor the like. The amount of oil in the present invention ranges from 0.1% to2.5% by wt. of the composition.

In an embodiment, the composition of the present invention further comprises a gelling agent selected from carbopol, transketol, PEG-400 in the range of 15 to 25% or the like.

In another embodiment, the compositions according to the present invention can be formulated together with the penetration enhancer incorporated into a dosage form for transdermal application to the skin of animals. Suitable dosage forms include creams, lotions, gels, soft gel, ointments, mousses, sprays, aerosols, or any one of a variety of transdermal devices for use in the continuous administration of systematically active drugs by absorption through the skin, underlying soft tissue or joints.

Orange oil along with eucalyptus oil was proposed as penetration enhancer and perfumery agent. Similarly, ginger oil is proposed as anti-inflammatory natural origin-based oil. Orange oil and eucalyptus oil counteracts the pungent odour of ginger oil. Curcumin is added as acolouring agent to provide aesthetic appeal to formulation.

In some aspects of the invention, a composition of the invention is administeredto a subject using a delivery vehicle such as a cream, gel, liquid, lotion, spray, aerosol, ortransdermal patch. In one set of embodiments, a composition of the invention may beapplied or impregnated in a bandage or a patch applied to the skin of a subject. A"subject," as used herein, means a human or non-human animal. Examples of subjectsinclude, but are not limited to, a mammal such as a dog, a cat, a horse, a donkey, a rabbit,a cow, a pig, a sheep, a goat, a rat, a mouse, a guinea pig, a hamster, a primate (e.g., a monkey, a chimpanzee, a baboon,an ape, a gorilla, etc.), or the like.

Such delivery vehicles may be applied to the skin of asubject, such as a human subject. Examples of delivery vehicles are discussed herein.The delivery vehicle may promote transfer into the skin of an effective concentration ofthe nitric oxide donor and/or the pharmaceutical agent, directly or indirectly. Forinstance, the delivery vehicle may include one or more penetrating agents, as furtherdescribed herein. Those of ordinary skill in the art will know of systems and techniquesfor incorporating a nitric oxide donor and/or a pharmaceutical agent within deliveryvehicles such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch.

Examples

This example illustrates one method of preparing a transdermal formula of theinvention including celecoxib. The final composition is shown in Table 1. Of course,those of ordinary skill in the art will understand that percentages other than the oneslisted below are also possible, according to other embodiments of the invention.

One more embodiment of the present invention provides a process for the preparation of pharmaceutical composition, the said process comprising steps of:
a) mixing the isopropyl alcohol with combination of oils, transketol and drug (COX-2 inhibitors); b) gelling agents as carbopol with suitable grade PEG mixed with propylene glycol; c) mixing of colouring agent by continuous stirring under ambient temperature to form a gel. Penetration enhancer can be added before, during or after the stirring, but prior to forming a smooth composition.

While several embodiments of the present invention have been described andillustrated herein, those of ordinary skill in the art will readily envision a variety of othermeans and/or structures for performing the functions and/or obtaining the results and/orone or more of the advantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention. More generally,those skilled in the art will readily appreciate that all parameters, dimensions, materials,and configurations described herein are meant to be exemplary and that the actualparameters, dimensions, materials, and/or configurations will depend upon the specificapplication or applications for which the teachings of the present invention is/are used.

All definitions, as defined and used herein, should be understood to control overdictionary definitions, definitions in documents incorporated by reference, and/orordinary meanings of the defined terms.

The indefinite articles "a" and "an," as used herein in the specification and in theclaims, unless clearly indicated to the contrary, should be understood to mean "at leastone."The phrase "and/or," as used herein in the specification and in the claims, shouldbe understood to mean "either or both" of the elements so conjoined, i.e., elements thatare conjunctively present in some cases and disjunctively present in other cases.

Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present otherthan the elements specifically identified by the "and/or" clause, whether related orunrelated to those elements specifically identified. Thus, as a non-limiting example, areference to "A and/or B'', when used in conjunction with open-ended language such as"comprising" can refer, in one embodiment, to A only (optionally including elementsother than B); in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionally including otherelements); etc.

As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separatingitems in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusionof at least one, but also including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated to the contrary, suchas "only one of' or "exactly one of," or, when used in the claims, "consisting of," willrefer to the inclusion of exactly one element of a number or list of elements. In general, theterm "or" as used herein shall only be interpreted as indicating exclusive alternatives(i.e. "one or the other but not both") when preceded by terms of exclusivity, such as"either," "one of," "only one of," or "exactly one of." "Consisting essentially of," whenused in the claims, shall have its ordinary meaning as used in the field of patent law.

It should also be understood that, unless clearly indicated to the contrary, in anymethods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of themethod are recited.

In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding,""composed of," and the like are to be understood to be open-ended, i.e., to meanincluding but not limited to. Only the transitional phrases "consisting of' and"consisting essentially of' shall be closed or semi-closed transitional phrases.

The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.

Example 1 – Table 1
S. No. Ingredients %w/w
1 COX-2 inhibitors 0.01 to 5%
2 Natural Oil 0.1 % to 2.5%
3 Gelling Agent 15-25%
4 Coloring Agent q.s
5 Solvents q.s.

Example 2 – Table 2
S. No Ingredients % w/w
1 Celecoxib 0.01 to 5
2 Orange Oil 0.1 to 1
3 Ginger oil 1 to 2.5
4 Eucalyptus oil 0.1 to 0.5
5 Transketol 1 to 3
6 Isopropyl Alcohol 10-15
7 Curcumin 0.01 to 0.05
8 Poly-ethylene glycol
(PEG-200 to 600 molecular weight) 10 to 20
9 Propylene glycol 5 to 15
10 Diethylene glycol monoethyl ether 5 to 15

To get a comparative result ex-vivo release studies have been conducted and result is tabulated in tables below.

Table 3: Result of % Average Cumulative Release
% Average Cumulative release
Time (in min) Normal gel F1 F2
0 0 0 0
10 1.35±0.39 2.04±0.17 1.89±0.16
30 2.40±0.21 4.01±0.12 3.65±0.27
45 3.09±0.15 6.03±0.27 5.14±0.12
60 3.98±0.30 7.49±0.22 7.19±0.20
120 5.49±0.36 15.84±0.18 14.57±0.22
180 12.29±0.25 33.69±3.70 20.68±1.78
300 17.13±2.34 42.88±5.37 32.40±1.72

Table 4: Result for % Retention Studies

Formulation % RT SD
Normal 5.45 1.04
F1 3.68 1.65
F2 4.35 1.27

Conclusion:Formulated F1 formulation has high permeability and low retention due to presence of high concentration of permeation enhancers. Ex-vivo release studies predicted that marketed gel has low permeation, high retention, and low bioavailability of drug. However, the proposed formulations F1 and F2 have high rate of bioavailability and more effective. Similarly, retention data also predicted the same. Marketed gel has high retention in comparison to formulated F1 and F2.

Although the field of the invention has been described herein with limited reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention.
,CLAIMS:We Claim:

1. A pharmaceutical composition comprising:
COX-2 inhibitors; and
One or more natural oils;
wherein thenatural oil selected from orange oil, ginger oil, eucalyptus oil or the like and/or combinations thereof.

2. The pharmaceutical composition as claimed in claim 1, wherein the COX-2 inhibitors are selected from celecoxib, rofecoxib, etoricoxib and valdecoxib or a combination thereof.

3. The pharmaceutical composition as claimed in claim 1, wherein an amount of COX-2 inhibitors ranges from 0.01% to 5% by wt. of the composition.

4. The pharmaceutical composition as claimed in claim 1, wherein an amount of natural oil ranges from 0.1 % to 2.5% by wt. of the composition.

5. The pharmaceutical composition as claimed in any of the preceding claims, further comprising pharmaceutically acceptable excipients.

6. The pharmaceutical composition as claimed in claim 7, wherein the pharmaceutically acceptable excipients are selected from a penetration enhancer, gelling agent and coloring agent and a solvent.

7. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of acreams, lotions, gels, soft gel, ointments, mousses, sprays, aerosols, or any one of a variety of transdermal devices for use in the continuous administration of systematically active drugs by absorption through the skin, underlying soft tissue or joints.

8. A process for preparing a pharmaceutical composition as claimed in claim 1 comprising:
a) mixing the solvent with combination of oils, gelling agent and drug (COX-2 inhibitors);
b) addition of suitable grade PEG mixed with propylene glycol in step (a);
c) mixing of colouring agent by continuous stirring under ambient temperature to obtain the final formulation.