The present disclosure relates generally to transdermal drug delivery systems for Fenoprofen. More specifically, the disclosure is directed to a topical cream formulation comprising liposomal Fenoprofen. The disclosure further provides a process of preparing the formulation.
BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. [0003] Non-Steroidal Anti-Inflammatory Drugs' (NSAIDs) oral administration is often restricted due to the threat of serious gastrointestinal side effects such as irritation, ulceration, and gastric bleeding. Since majority of NSAIDs have a short elimination half-life, regular doses are required to generate a continuous anti-inflammatory/analgesic effect, resulting in significant gastrointestinal side effects over long periods of time. As a result, topical NSAID administration may be assumed to be helpful in preventing side effects of oral administration, as well as in targeting the drug to inflamed skin and the site of action, thus increasing patient compliance and reducing systemic absorption.
[0004] Fenoprofen Calcium is an NSAID which is used to treat pain, osteoarthritis and rheumatoid arthritis-related discomfort, inflammation, and stiffness. Much like other NSAIDs, its oral administration is limited due to risk of gastrointestinal side effects. A transdermal drug delivery formulation for Fenoprofen Calcium must be designed to overcome the need for frequent dosing caused by short elimination half-life and to decrease the side-effects. Transdermal drug delivery has the ability to deliver drugs directly to the site of action, decreasing systemic absorption and therefore systemic side effects.

[0005] The inventors of the present disclosure provide a transdermal drug delivery system for Fenoprofen Calcium that prevents severe side-effects of other forms of administration and maximizes the therapeutic effect.
OBJECTS OF THE INVENTION
[0006] An object of the present disclosure is to provide a topical cream formulation
comprising liposomal Fenoprofen Calcium.
[0007] Another object of the present disclosure is to provide a topical cream
formulation that has thermodynamic stability and high drug permeability for
Fenoprofen Calcium.
[0008] Yet another object of the present disclosure is to provide a process of
preparing the topical cream formulation.
SUMMARY OF THE INVENTION
[0009] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0010] Aspects of the present disclosure provide a transdermal drug delivery system (TDDS) for Fenoprofen Calcium that overcomes the drawbacks of oral administration of the drug. The transdermal drug delivery system has the ability to deliver the active compound directly to the site of action, decreasing systemic absorption and therefore systemic side effects.
[0011] In an aspect, the present disclosure provides a topical cream formulation comprising liposomes of Fenoprofen Calcium, wherein the liposomes comprise phosphatidylcholine, cholesterol, dipalmitoylphosphatidylcholine, and Fenoprofen Calcium.

[0012] In an embodiment, the formulation comprises phosphatidylcholine in a weight
percentage range of about 50% to about 70% v/v of the formulation.
[0013] In an embodiment, the formulation comprises cholesterol in a weight
percentage range of about 10% to about 30% v/v of the formulation.
[0014] In an embodiment, the formulation comprises dipalmitoylphosphatidylcholine
in a weight percentage range of about 4% to about 6% v/v of the formulation.
[0015] In an embodiment, the formulation comprises Fenoprofen Calcium in a weight
percentage range of about 10% to about 20% w/v of the formulation.
[0016] In an embodiment, the formulation further comprises additives. In an
embodiment, the additive may be selected from surfactant, emulsifier, thickener,
emollient, preservative, solvent, moisturizer, pH adjuster, stabilizing agent, coloring
agent, fragrance, or combinations thereof.
[0017] In an embodiment, the additives may be present in a weight percentage range
of about 1%> to about 3% w/v of the formulation.
[0018] In another aspect, the present disclosure provides a process of producing a
topical cream formulation, wherein the process comprises the steps of: (a) dissolving
Fenoprofen Calcium, cholesterol, phosphatidylcholine, and
dipalmitoylphosphatidylcholine in a solvent mixture of dichloromethane and
methanol; (b) evaporating the solvent to give a thin-film; (c) hydrating the thin-film
with a phosphate buffer at room temperature; (d) homogenizing to give the
liposomes; (e) preparing an aqueous phase by dissolving and heating aqueous
additives in distilled water; (f) preparing an organic phase with organic additives in
paraffin and beeswax; (g) transferring the aqueous phase to the organic phase for
emulsification and then cooling to room temperature; and (h) adding the liposomes of
step (d) and stirring to give the topical cream formulation.
[0019] Other aspects of the invention will be set forth in the description which
follows, and in part will be apparent from the description, or may be learnt by the
practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
Figure 1 provides the cumulative drug permeation profile from a non-liposomal Fenoprofen Calcium cream (blue) and a Fenoprofen Calcium liposome cream formulation (black) as per an embodiment of the present disclosure. Figure 2 provides the in-vitro drug release kinetic models: (a) zero-order, (b) first-order, (c) Korsmeyer-Peppas, and (d) Higuchi of Fenoprofen Calcium from the cream formulation as per an embodiment of the present disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0022] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0023] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various

places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. [0024] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0025] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0026] As used in the description herein and throughout the claims that follow, the meaning of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. [0027] Unless the context requires otherwise, throughout the specification which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense that is as "including, but not limited to."

[0028] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0029] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0030] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0031] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0032] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.

[0033] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments. [0034] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed. [0035] As described herein, the term 'effective amount' refers to the amount of the formulation required to bring about a change or improvement in a subject without side effects or overdosing.
[0036] The term, "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein refers to warm¬blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young, the term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0037] The terms 'topical cream formulation', 'topical formulation' and 'transdermal formulation' have been used interchangeably throughout the specification. [0038] Aspects of the present disclosure provide a TDDS for anti-inflammatory and analgesic drug Fenoprofen Calcium.
[0039] In an embodiment, the present disclosure provides a topical cream formulation comprising liposomes of Fenoprofen Calcium, wherein the liposomes comprise phosphatidylcholine, cholesterol, dipalmitoylphosphatidylcholine, and Fenoprofen Calcium.
[0040] In an embodiment, the formulation comprises phosphatidylcholine in a weight percentage range of about 50% to about 70% v/v of the formulation.

[0041] In an embodiment, the formulation comprises cholesterol in a weight
percentage range of about 10% to about 30% v/v of the formulation.
[0042] In an embodiment, the formulation comprises dipalmitoylphosphatidylcholine
in a weight percentage range of about 4% to about 6% v/v of the formulation.
[0043] In an embodiment, the formulation comprises Fenoprofen Calcium in a weight
percentage range of about 10% to about 20% w/v of the formulation.
[0044] In an embodiment, the formulation further comprises additives. In an
embodiment, the additive may be selected from surfactant, emulsifier, thickener,
emollient, preservative, solvent, moisturizer, pH adjuster, stabilizing agent, coloring
agent, fragrance, or combinations thereof.
[0045] In an embodiment, the additives may be present in a weight percentage range
of about 1%> to about 3% of the formulation.
[0046] In an embodiment, the surfactant may be selected from sorbitan monostearate,
sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene
sorbitan monooleate, poloxamer 118, D-a-tocopheryl polyethylene glycol succinate,
or combinations thereof. However, a person skilled in the art would appreciate that
any other surfactant(s) can be utilized to serve the intended purpose without departing
from the scope and spirit of the invention.
[0047] In an embodiment, the emulsifier may be selected from beeswax, emulsifying
wax, lecitin, lanolin, cetyl alcohol, stearyl alcohol, sodium dioctyl sulfosuccinate,
glycerol monostearate, glycerol distearate, sodium lauryl sulphate, sodium
monopalmitate, sodium oleate, or combinations thereof. However, a person skilled in
the art would appreciate that any other emulsifier(s) can be utilized to serve the
intended purpose without departing from the scope and spirit of the invention.
[0048] In an embodiment, the thickener may be selected from hydroxyethyl cellulose,
guar gum, cetyl alcohol, stearyl alcohol, acacia, tragacanth, methyl cellulose, sodium
carboxymethyl cellulose, or combinations thereof. However, a person skilled in the
art would appreciate that any other thickener(s) can be utilized to serve the intended
purpose without departing from the scope and spirit of the invention.

[0049] In an embodiment, the emollient may be selected from propyl paraben, paraffin, cetyl palmitate, isopropyl myristate, propylene glycol, tricapryl citrate, stearyl alcohol, polyethylene glycol 4000, or combinations thereof. However, a person skilled in the art would appreciate that any other emollient(s) can be utilized to serve the intended purpose without departing from the scope and spirit of the invention.
[0050] In an embodiment, the preservative may be selected from propyl paraben, methyl paraben, ethyl paraben, butyl paraben, sodium metabisulfite, or combinations thereof. However, a person skilled in the art would appreciate that any other preservative(s) can be utilized to serve the intended purpose without departing from the scope and spirit of the invention.
[0051] In an embodiment, the solvent may be selected from an aqueous solvent or an organic solvent. In an embodiment, the aqueous solvent may be selected from water, distilled water, de-mineralized water, or combinations thereof. In an embodiment, the organic solvent may be selected from propylene glycol, methanol, acetone, dichloromethane, ethanol, 1-propanol, ethyl acetate, methyl acetate, isobutyl acetate, formic acid, or combinations thereof.
[0052] In an embodiment, the coloring agent may be selected from erythrosine, tartrazine, amaranth carmine, saffron, sunset yellow, brilliant blue, caramel, indigotine, or combinations thereof. However, a person skilled in the art would appreciate that any other coloring agent(s) can be utilized to serve the intended purpose without departing from the scope and spirit of the invention. [0053] In an embodiment, the fragrance may be selected from mangosteen, lemon oil, rose oil, peppermint oil, menthol, or combinations thereof. However, a person skilled in the art would appreciate that any other fragrance(s) can be utilized to serve the intended purpose without departing from the scope and spirit of the invention. [0054] The formulation may be used for treating pain, inflammation, stiffness, osteoarthritis, rheumatoid arthritis, and associated conditions.

[0055] In some embodiments, the liposomes may have an entrapment efficiency of the drug - Fenoprofen Calcium, of up to 85%. In some embodiments, the formulation may release up to 85% of the drug within 24 hours of application. In some embodiments, the formulation has a release kinetics that follows the fickian diffusion phenomenon.
[0056] The amount of the drug permeating through the skin in a cream formulation without liposomes is much lower indicating the surprising synergistic effect of the formulation of the present disclosure comprising liposomes. The formulation of the present disclosure may also provide higher anti-inflammatory and analgesic activity owing to the higher permeation of drug.
[0057] The topical cream formulation overcomes side-effects associated with oral drug delivery systems, such as irritation, ulceration, or gastric bleeding and also does not require frequent dosing. The formulation reduces systemic absorption and helps in targeting the drug directly to inflamed skin or at the site of action. The topical cream formulation has higher patient compliance compared to oral drug delivery systems. Topical formulation penetrates the NSAID deep into the subcutaneous tissues, enhancing drug deposition in the muscle surrounding the application site. [0058] The formulation is moisturizing, non-greasy, and has no grittiness. The formulation has ideal viscosity for high spreadability on the skin and has skin sensitive pH in the range of about 6 to about 7.
[0059] Aspects of the present disclosure provide a process of synthesizing or producing the topical cream formulation, wherein the liposomes are produced by thin-film hydration method.
[0060] In another embodiment, the present disclosure provides a process of producing a topical cream formulation, wherein the process comprises the steps of: (a) dissolving Fenoprofen Calcium, cholesterol, phosphatidylcholine, and dipalmitoylphosphatidylcholine in a solvent mixture of dichloromethane and methanol; (b) evaporating the solvent to give a thin-film; (c) hydrating the thin-film with a phosphate buffer at room temperature; (d) homogenizing to give the

liposomes; (e) preparing an aqueous phase by dissolving and heating aqueous
additives in distilled water; (f) preparing an organic phase with organic additives in
paraffin and beeswax; (g) transferring the aqueous phase to the organic phase for
emulsification and then cooling to room temperature; and (h) adding the liposomes of
step (d) and stirring to give the topical cream formulation.
[0061] In an embodiment, the solvent mixture comprises dichloromethane and
methanol in a ratio of about 2:1.
[0062] In some embodiments, the yield of liposomes obtained from the present
process may be up to 70%.
[0063] In an embodiment, the present disclosure provides a method of treating,
preventing or ameliorating arthritis and associated conditions in a subject by
administering a therapeutically effective amount of the topical cream formulation.
[0064] In another embodiment, the disclosure provides use of the topical cream
formulation for reduction of pain, inflammation, and other symptoms associated with
arthritis.
[0065] While the foregoing describes various embodiments of the disclosure, other
and further embodiments of the disclosure may be devised without departing from the
basic scope thereof. The scope of the invention is determined by the claims that
follow. The invention is not limited to the described embodiments, versions or
examples, which are included to enable a person having ordinary skill in the art to
make and use the invention when combined with information and knowledge
available to the person having ordinary skill in the art.
EXAMPLES
[0066] The disclosure will now be illustrated with working examples, which is
intended to illustrate the working of disclosure and not intended to take restrictively
to imply any limitations on the scope of the present disclosure. Unless defined
otherwise, all technical and scientific terms used herein have the same meaning as
commonly understood to one of ordinary skill in the art to which this disclosure
belongs. Although methods and materials similar or equivalent to those described

herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.
[0067] MATERIALS: The Fenoprofen Calcium used for the purposes of the example was obtained from Suven Pharmaceuticals Ltd, Telangana, India. Cholesterol was procured from Loba Chemicals Private Limited, Mumbai, India. Phosphatidylcholine and dipalmitoylphosphatidylcholine were obtained from Sigma-Aldrich Chemicals Private Limited. [0068] EXAMPLE 1: Manufacture of liposomes
[0069] The liposomes were produced by thin-film hydration method. Fenoprofen Calcium, Phosphatidylcholine (PC), Dipalmitoylphosphatidylcholine (DPPC) and cholesterol were dissolved in 30 mL dichloromethane: methanol mixture (2:1). The mixtures were evaporated in a rotary evaporator (Perfit, India) at 40°C and 50 rpm to remove the solvents leading to film formation. The film was then hydrated with 50 mL phosphate buffer (pH 7.4) for 1 h at room temperature. The dispersion was homogenized using probe sonicator (Ultrasonic probe sonicator, PCI analytics) at 230 V, 50 Hz AC current at 20 seconds interval which lead to formation of drug-loaded liposomes. Total nine Fenoprofen Calcium liposomes (FPC-LS-1 to FPC-LS-9) were manufactured as per the compositions given in Table 1 below. The Fenoprofen Calcium liposomes were then tested for their entrapment efficiency and percent yield. [0070] Entrapment Efficiency - Fenoprofen Calcium liposomes were centrifuged for 30 minutes at 5000 rpm via cooling centrifuge apparatus followed by separation of supernatant and analysis by UV spectrophotometer at 270 nm. The % entrapment efficiency was calculated using Eq. (1):
% Entrapment efficiency, % w/w = Ct°tal'c°ut xlOO Eq. (1)
ctotal
[0071] Where, Cout was free Fenoprofen Calcium concentration detected when liposome suspension was diluted with water and ultra-filtered through a Millipore

filter to remove the liposomes and Ctotai was the total Fenoprofen Calcium concentration detected when liposome suspension was diluted with heated ethanol (70°C) in order to disrupt the liposomes completely and release the encapsulated drugs into the solvent. The ethanol solution was cooled and ultra-filtered through a Millipore filter. The entrapment efficiencies are provided in Table 1. [0072] Percent yield - Percent yield was calculated as weight percentage of phytosomes recovered from each experiment, with respect to initial total weight of lipids and Fenoprofen Calcium using Eq. (2).The percent yields of FPC-LS-1 to FPC-LS-9 are provided in Table 1.
100 Eq. (2)
% Yield, w/w
Total weight of liposomes
Initial weight of lipids and Fenoprofen Calcium

Table 1 : Fenoprofen Calcium Liposomes|
Liposome code Fenoprofen
Calcium
(mg) PC
(mg) DPPC
(mg) Cholesterol (mg) Entrapment efficiency
(%) Yield
(%)
FPC-LS-1 100 200 20 50 65.38 45.79
FPC-LS-2 100 200 20 100 72.44 55.86
FPC-LS-3 100 200 20 150 76.87 59.74
FPC-LS-4 100 300 30 50 68.79 48.46
FPC-LS-5 100 300 30 100 75.62 57.39
FPC-LS-6 100 300 30 150 85.32 69.53
FPC-LS-7 100 400 40 50 67.23 49.12
FPC-LS-8 100 400 40 100 77.14 61.19
FPC-LS-9 100 400 40 150 82.31 65.28
[0073] Fenoprofen Calcium liposomes (FPC-LS-6) comprising of 100 mg Fenoprofen Calcium, 300 mg Phosphatidylcholine, 30 mg Dipalmitoylphosphatidyl choline and 150 mg cholesterol was selected as an optimized

batch of liposome with maximum entrapment efficiency (85.32%),) and yield (69.53%). Therefore, FPC-LS-6 batch was selected for further incorporation into cream formulation.
[0074] EXAMPLE 2: Manufacture of topical cream formulation [0075] Tween 80, Span 60 and propyl paraben were dissolved in distilled water and heated to 75-80°C for complete dissolution to prepare aqueous phase. An oil-phase was prepared by melting the hard paraffin and beeswax at 75°C and afterwards liquid paraffin, cetyl alcohol, stearyl alcohol, cetyl palmitate and isopropyl myristate were added with gentle mixing. The mangosteen and erythrosine were added to aqueous phase as fragrance and coloring agent, respectively. The aqueous phase was slowly transferred to the oil phase for emulsification which was then cooled to room temperature with constant stirring. FPC-LS-6 was incorporated in the pre-prepared cream base with modest stirring for 10 minutes to manufacture topical cream formulation loaded with Fenoprofen Calcium liposomes. Similarly, for comparison cream of pure Fenoprofen Calcium without liposomal Fenoprofen Calcium was also manufactured.
[0076] The physical parameters of the prepared formulation were evaluated: [0077] Organoleptic characteristics: Fenoprofen Calcium liposomal cream was tested by visual observation for physical appearance, color and phase separation. Homogeneity and texture were evaluated on the basis of consistency of cream and presence of coarse particles through pressing little amount of cream between index finger and thumb. The cream was pink colored, transparent, homogeneous with smooth texture and had no phase separation. Immediate skin feel of cream was moisturizing, non-greasy, and absence of grittiness.
[0078] Spreadability and pH Value: Spreadability of the cream formulation was evaluated by spreading diameter of 1 g of cream between two horizontal glass plates of 10 cm x 20 cm dimensions. The standard weight imposed upon upper plate was 25 g for 1 minute. The pH was measured by pH meter (361, Systronics, India) calibrated through standard buffer solutions (pH 4, 7, and 10). Spreadability

(spreading diameter after 1 minute) and pH of the cream were found to be 42 mm and 6.1, respectively. The data ensures that the cream can be applied over skin with lower risk of skin irritation since topical cream formulation should have a pH in the range of 6-7 to prevent skin pH alteration.
[0079] Viscosity measurement: Brookfield rotational digital viscometer model DV-II with LV-spindle #64 at 6 rpm was used to determine viscosity of the cream. Approximately 50g cream was used for measurement which was maintained at a temperature of 25°C during the measurements. All measurements were taken in triplicate and represented as mean ±SD. The viscosity of Fenoprofen Calcium liposomal cream was found to be 29000 centipoises.
[0080] Thermodynamic stability: Thermodynamic stability study was performed by heating-cooling cycle and centrifugation test. Six cycles between refrigerator temperature (4°C) and 45°C with storage at each temperature of 6 hrs were conducted, and examined for physical stability. For centrifugation test, formulations were centrifuged at 3,500 rpm for 30 min, and observed for any phase separation. No phase separation was visible after thermodynamic stability study via heating-cooling cycle and centrifugation test which illustrated stability of the topical liposome-based cream formulation.
[0081] Drug Release and Permeation analysis: Dialysis membrane having 12,000-14,000 Da molecular weights (Himedia, India) was mounted between cell compartments of Franz diffusion cell. The surface area of the release membrane was 2.54 cm2. The acceptor compartment was charged with 20 mL phosphate buffer, pH 6.8 as receptor medium, and agitated at 200 rpm via magnetic bar in the acceptor medium to reduce the stagnated surfaces. Fenoprofen Calcium cream formulation and Fenoprofen Calcium liposome cream formulation were applied over dialysis membrane facing towards the donor compartment. During the experiments, the temperature of Franz diffusion cell chamber the solution in receptor side was maintained at 37±0.5°C. Approximately 0.5 mL samples were removed from the acceptor compartment at 0.5, 1, 2, 4, 6, 8, 12, and 24 h and analyzed at 270 nm using

spectrophotometer. Equivalent amount of medium were transferred to cell through the side tube. Experiments of release analysis were replicated three times. Fenoprofen Calcium liposomal cream formulation revealed a biphasic fickian diffusional release pattern with an initial 'burst release' of approximately 18.73% loosely bound Fenoprofen Calcium on or near the surface of lipid particles during first 0.5 h succeeded by release of 51.22% drug within 4 h. Afterwards, sustained release of drug due to diffusion from the liposomes with maximum drug release of 85.36%) over 24 h was achieved.This sustained drug release from liposomes indicates relatively homogenous dispersal of drug into the lipids. The total quantity (Q) (ug) permeated by the dialysis membrane was determined by multiplying the drug's accumulated concentration (ug/mL) in the receptor chamber and its receptor chamber volume (mL). The amount of drug permeated per unit area (ug/cm2) from the formulation of liposomal cream and non-liposomal cream was plotted versus time (refer Figure 1). It was observed that the quantities of Fenoprofen permeated across membrane from liposomal cream formulation, as per the present disclosure, was considerably higher (*p<0.05) compared to pure drug cream formulation.
[0082] Release kinetics: In-vitro dissolution kinetic models like zero-order, first-order, Higuchi and Korsmeyer-Peppas, were implemented to illustrate the drug release phenomenon from the cream formulation of the present disclosure. In Korsmeyer-Peppas kinetics, the release exponent value < 0.45, 0.46-0.88, 0.89 and > 0.89, respectively, corresponds to fickian diffusion, anomalous diffusion, case II transport and super-case II transport. The correlation coefficients for zero-order, first-order, Higuchi and Korsmeyer-Peppas models were found to be 0.7718, 0.5955, 0.9601 and 0.932, respectively (refer, Figure 2). The release exponent 'n' for Korsmeyer-Peppas model was found to be 0.3799 (n< 0.45) indicating that fickian diffusion conquered the drug release mechanism from the formulation. [0083] From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein merely for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the

invention and should not be construed so as to limit the scope of the invention or the appended claims in any way.
ADVANTAGES OF THE PRESENT INVENTION
[0084] The present disclosure provides a transdermal drug delivery system, i.e., a
topical cream formulation comprising liposomal Fenoprofen Calcium.
[0085] The present disclosure provides a topical cream formulation that has
thermodynamic stability and high drug permeability.
[0086] The present disclosure provides a topical cream formulation that overcomes
the drawbacks of oral delivery systems and increases patient compliance.

We Claim:

1. A topical cream formulation comprising liposomes of Fenoprofen Calcium, wherein the liposomes comprise phosphatidylcholine, cholesterol, dipalmitoylphosphatidylcholine, and Fenoprofen Calcium.
2. The formulation as claimed in claim 1, wherein the formulation comprises phosphatidylcholine in a weight percentage range of 50% to 70% v/v of the formulation.
3. The formulation as claimed in claim 1, wherein the formulation comprises cholesterol in a weight percentage range of 10%> to 30% v/v of the formulation.
4. The formulation as claimed in claim 1, wherein the formulation comprises dipalmitoylphosphatidyl choline in a weight percentage range of 4% to 6% v/v of the formulation.
5. The formulation as claimed in claim 1, wherein the formulation comprises Fenoprofen Calcium in a weight percentage range of 10% to 20% w/v of the formulation.

6. The formulation as claimed in claim 1, wherein the formulation further comprises additives.
7. The formulation as claimed in claim 6, wherein the additive is selected from surfactant, emulsifier, thickener, emollient, preservative, solvent, moisturizer, pH adjuster, stabilizing agent, coloring agent, fragrance, or combinations thereof.
8. The formulation as claimed in claim 7, wherein the surfactant is selected from sorbitan monostearate, sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, poloxamer 118, D-a-tocopheryl polyethylene glycol succinate, or combinations thereof.
9. The formulation as claimed in claim 7, wherein the emulsifier is selected from beeswax, emulsifying wax, lecitin, lanolin, cetyl alcohol, stearyl alcohol, sodium dioctyl sulfosuccinate, glycerol monostearate, glycerol distearate, sodium lauryl sulphate, sodium monopalmitate, sodium oleate, or combinations thereof.

10. The formulation as claimed in claim 7, wherein the thickener is selected from hydroxyethyl cellulose, guar gum, cetyl alcohol, stearyl alcohol, acacia, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.
11. The formulation as claimed in claim 7, wherein the emollient is selected from propyl paraben, paraffin, cetyl palmitate, isopropyl myristate, propylene glycol, tricapryl citrate, stearyl alcohol, polyethylene glycol 4000, or combinations thereof.
12. The formulation as claimed in claim 7, wherein the preservative is selected from propyl paraben, methyl paraben, ethyl paraben, butyl paraben, sodium metabisulfite, or combinations thereof

13. A process of producing a topical cream formulation, wherein the process comprises the steps of: (a) dissolving Fenoprofen Calcium, cholesterol, phosphatidylcholine, and dipalmitoylphosphatidylcholine in a solvent mixture of dichloromethane and methanol; (b) evaporating the solvent to give a thin-film; (c) hydrating the thin-film with a phosphate buffer at room temperature; (d) homogenizing to give the liposomes; (e) preparing an aqueous phase by dissolving and heating aqueous additives in distilled water; (f) preparing an organic phase with organic additives in paraffin and beeswax; (g) transferring the aqueous phase to the organic phase for emulsification and then cooling to room temperature; and (h) adding the liposomes of step (d) and stirring to give the topical cream formulation.
14. The process as claimed in claim 13, wherein the solvent mixture comprises dichloromethane and methanol in a ratio of 2:1.