FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
(See section 10 and rule 13)
FENOFIBRATE FORMULATION WITH ENHANCED ORAL BIOAVAILABILITY
PANACEA BIOTEC LIMITED


A COMPANY INCORPORATED UNDER THE LAWS OF INDIA HAVING THEIR
OFFICE AT 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA, ANDHERI
(E), MUMBAI 400099, MAHARASHTRA, INDIA
The following specification describes the invention


FIELD OF THE INVENTION:
The present invention relates to a novel formulation of fenofibrate with enhanced oral bioavailability, to a process for its manufacture and to dosage forms comprising the formulation.
BACKGROUND OF THE INVENTION:
Fenofibrate or 2-[4-(4- chlorobenzoyl) phenoxy]-2-methyl-propanoic acid. 1-methylethyl ester belongs to a class of lipid regulating agents known as fibrates, which are useful in reducing elevated serum triglyceride levels in hypertriglyceridemic patients and cholesterol and LDL-C levels in hypercholesterolemia and mixed dyslipidemic patients.
Fenofibrate is a white solid, virtually insoluble in water. On oral administration, it is absorbed and metabolized to the active substance fenofibric acid, which has a plasma elimination half life of about 20 hours. It is well known that poor aqueous solubility limits the dissolution and hence absorption of fenofibrate from the gastrointestinal tract. Despite its poor solubility, it is reported to be well absorbed when dosed in the "fed state" and less so in the "fasted state". Various attempts have been made to improve the solubility and bioavailability of fenofibrate, such as use of surface active agents and surface stabilizers with fenofibrate and by elaborate manufacturing processes such as micronisation and spray-drying to reduce the effective average particle size of fenofibrate. Solubility enhancement has also been attempted by dissolving it in agents such as organic solvents, oily materials and triglycerides. Different hydrophilic and hydrophobic agents have been evaluated for the purpose.
For example, PCT Application No. 2006107411 discloses fibrate compositions with fibrates in intimate association with PEG and Poloxamer 407. United States Patent No 5545628
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claims fenofibrate with polyglycolized glycerides. United States Patent No. 6,814,977 discloses fenofibrate dissolved in a medium chain glycerol ester of fatty acid. United States Patent No. 6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol, or dimethylisosorbide and U.S. Patent No. 5. 827,536 discloses fenofibrate dissolved in diethyleneglycol monoethyl ether.
A United States patent No. 6294192 discloses a capsule dosage form for any hydrophobic therapeutic agent having a carrier system which comprises of at least one hydrophilic surfactant and at least one hydrophobic surfactant having an HLB value of less than about 10. The carrier system contains the surfactants in such amounts that on dilution with water, a clear aqueous dispersion is obtained. For this purpose, the amount of hydrophilic surfactant has to be considerably higher than the hydrophobic surfactant. As mentioned in its specification, the hydrophobic surfactant is less than about 200% by weight of the hydrophilic surfactant, and preferably is about 10 to 60% by weight of the hydrophilic surfactant.
One of the recent products using the lowest effective doses of fenofibrate so far is a tablet composition launched by Lifecycle Pharma in United States under the brand name Fenoglide®. It is available in two doses of 40mg and 120mg. Lifecycle Pharma's United States patent application No. 20070026062 describes a solid dosage form comprising a solid dispersion or solid solution of a fibrate. The composition contains the flbrate in a solid form and is not a soft dosage form containing a liquid medium. It is prepared by techniques such as spray drying, controlled agglomeration, freeze drying, coating on carrier particles and other solvent removal processes, wherein the vehicle is generally a solid which has to be brought in a liquid form by processes such as melting.
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Thus, numerous attempts have been made in the direction of solubility enhancement of fenofibrate, although few have translated in satisfactory products. It would be advantageous to develop a formulation of fenofibrate which improves its solubility, demonstrates superior bioavailability over the commercially available products and at the same time involves the use of least number of excipients and is simple to manufacture. It would also be advantageous to have a formulation of fenofibrate which is similarly effective in both fed and fasted state of the subject and hence which can be administered without regards to meals.
DESCRIPTION OF THE INVENTION:
The inventors of the instant invention have found a formulation which surprisingly, while being extremely simple in manufacture and design, has demonstrated unexpectedly high bioavailability for fenofibrate. It has also shown promising results with regard to reducing or even eliminating the food effects of fenofibrate.
Moreover, the unexpectedly superior bioavailability of the instant formulation may translate into the formulation being effective at a lower dose, thereby also improving on the side effect
profile.
This instant invention provides a formulation comprising fenofibrate dissolved in a lipophilic surfactant. Preferably, it also comprises of another surfactant which is hydrophilic in nature. Optimal results have been obtained when the weight ratio of the lipophilic and hydrophilic surfactants has been from 1:2 to 2:1. Without wishing to be bound by theory, it is believed that the lipophilic surfactant maintains the fenofibrate in a dissolved and easily absorbable state, while the hydrophilic surfactant ensures sufficient availability of fenofibrate at the site
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of absorption. The formulation may further include such other auxiliary excipients as may be required for optimal manufacture and use.
The lipophilic surfactants which have demonstrated unexpectedly good results belong to the class of esters of propylene glycol. The esters are generally of fatty acids such as laurate, caprylate, stearate, ricinoleate, oleate etc. and include both mono- and di- esters. Some non-limiting examples include propylene glycol monolaurate, propylene glycol monocaprylate, propylene glycol dicaprylate/dicaprate, propylene glycol monooleate, propylene glycol ricinoleate, propylene glycol distearate, propylene glycol myri state, propylene glycol monostearate, propylene glycol isostearate etc. They are preferably used in the amounts of 10%w/w to 80% w/w of the formulation. A particularly preferred lipophilic surfactant is propylene glycol monocaprylate, available from Gattefosse under the tradename of Capryol 90®orCapryolPGMC®.
In an embodiment of the invention, the hydrophilic surfactants used belong to a unique class of nonionic surfactants known as polyoxyethylene sorbitan fatty acid esters. This class includes a series of partial fatty acid esters of sorbitol and its anhydrides copolymerized with different moles of ethylene oxide. The generic name for these compounds is 'polysorbates'. Preferred polysorbates for the instant invention are those containing 20 units of oxyethylene, such as the Polysorbate 80. Polysorbate 80, also known as Tween 80, is a viscous, water-soluble ester of polyoxylated sorbitan and oleic acid. Satisfactory results are obtained when the polysorbates are included in the formulation in the range of 80% w/w to 20%w/w.
In an alternative embodiment of the invention, the hydrophilic surfactants used belong to the class of- polymeric surfactants known as polyoxyethylene-polyoxypropylene block
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copolymers. This class includes various agents with hydrophilic and hydrophobic moieties present in well defined ratios and positions, providing compounds with a wide range of hydrophilic - hydrophobic characteristics. The generic name for these compounds is 'poloxamers'. Preferred poloxamers for the instant invention are the hydrophilic poloxamers such as poloxamer 108, 188, 217, 238, 288, 338 and 407. Satisfactory results are obtained when they are included in the formulation in the range of 80% w/w to 20%w/w.
Although not excluded from the scope of the invention, it has been observed that in certain aspects, no other excipients are required in the formulation of the instant invention. Particularly, no stabilizers or further solublizers are required for optimal dissolution and storage stability. The formulation is extremely simple in design, utilizing least number of excipients.
An aspect of the instant invention also relates to the process for manufacture of the above described formulation. The process is extremely simple and involves dissolving fenofibrate in the lipophilic surfactant with the help of slight heat if required, adding the hydrophilic surfactant to it and adequately mixing to get a clear or slight hazy solution. By way of illustration, a formulation may be prepared wherein about 0.1% to 50% w/w of fenofibrate is dissolved in about 10% to 80% w/w of lipophilic surfactant. About 80% to 20%w/w of hydrophilic surfactant is added to the solution and mixed till a clear or slight hazy solution is obtained.
A further aspect of the invention relates to dosage forms comprising the instant formulation. The dosage form could be any of those known in the art and suitable for including the
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formulation of the invention. More preferred are the capsule dosage forms, specially the soft gelatin capsules, which can be filled with the formulation and sealed.
Exemplary formulations are provided as follows:
Example 1:

Sr. No. Ingredient Qty ( mg/capsule)
1 Fenoflbrate 100.0
2 Propylene glycol monocaprylate 337.5
Polysorbate 80 437.5
Fenoflbrate was dissolved in Propylene glycol monocaprylate with the use of slight heat. Polysorbate 80 was added and mixed adequately. The solution was filled into soft gelatin capsules.
Example 2:

Sr. No. Ingredient Qty ( % w/w)
1 Fenoflbrate 11
2 Propylene glycol monocaprylate 78.8
3 Poloxamer 407 10.2
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Fenofibrate was dissolved in Propylene glycol monocaprylate with the use of slight heat. Poloxamer 407 was added and mixed adequately. A hazy solution was obtained. The solution was filled into soft gelatin capsules.
Example 3:
In vivo studies to demonstrate the bioavailability of the instant formulation relative to the bioavailability of the commercially available reference fenofibrate formulation, i.e. Tricor®. were carried out.
Wistar rats (n=6) (fasted) were treated orally with 2 different formulations of fenofibrate. Formulation A was the fenofibrate formulation of the invention as given in Example 1, at the dose of 62 mg/kg body weight of rat. Formulation B was the commercial product Tricor® administered at the dose of 90mg/kg body weight of rat.
Blood samples were collected from the retro-orbital sinus at regular intervals of 0, 0.5. 1, 3,6. 9 and 12 hours, and the plasma was submitted for analysis of fenoflbric acid by LC-MS/MS. Figure 1 represents the resulting data in graphical form.
The results, indicated as mean ± Sem, n=6, are as follows:

Formulation Tmax (hr) Cmax (u-g/ml) AUC 0-t last (u.g-hr/ml)
A 271.81 ±40.02 2473.4 ± 122.5
B T
J 189.08 ±23.87 1648.7 ±85.1
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The fenofibrate formulation demonstrated a relative bioavailability of 150% as compared to Tricor® even at a much reduced dose of 62 mg/kg body weight of rat as compared to the dose of 90 mg/kg body weight of rat for Tricor®. The results thus indicate a superior fenofibrate formulation of the invention with surprisingly enhanced oral bioavailability.
Example 4:
Further in vivo studies were designed to evaluate the effect of food, if any, on the pharmacokinetics of fenofibrate administered through the formulation of the instant invention. Fed and overnight fasted (12 h) rats were treated orally with the formulation A of the invention. Blood samples (400 u-L) were collected from retro-orbital sinus at regular intervals as mentioned above, and the plasma was analyzed for fenoflbric acid by LC-MS/MS. Figure 2 represents the data in graphical form.
The results, indicated as mean ± Sem, n=5-6, are as follows:

Formulation -AUC {o-1 last)
ug-hr/ml Tmax(h) ^--max
u_g/ml-
A(Fed) 1874.9±93.9 3.0 239± 15.5
A (Fasted) 1952.6 ±98.5 3.0 273.4 ± 24.6
The results indicate comparable AUC, Cmax and Tmax values. There is no significant difference in the plasma profiles of fenoflbric acid after administration of fenofibrate under fed and fasted states, indicating an absence of food effect.
The formulation and dosage form of the instant invention has thus demonstrated unexpectedly enhanced bioavailability, simplicity of design and manufacture and absence of food effect.
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Various modifications of the system of the invention may be made without departing from the spirit or scope of the invention. The above description and examples illustrate various aspects of the invention and should not be construed to limit its scope.
Dated this 6 of July 2008
FOR PANACEA BIOTEC LIMITED (Dr. MAHALAXMI ANDHERIA)
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