DESIGN OF TERBINAFINE HYDROCHLORIDE LOADED LIPOSOME INCLUDED PULLULAN FILM SYSTEM FOR UNGUAL TREATMENT OF

ONYCHOMYCOSIS

Technical Field

The invention is about preparation of terbinafine hydrochloride loaded liposome included pullulan film formulation for ungual treatment of onychomycosis. The invention is about preparation a topical film formulation of Terbinafine hydrochloride that will be an alternative formulation of systemic tablet formulation and could reduce side effects of active substance

The State-of-the-Art (Prior Art)

Onychomycosis is a common chronic nail fungal infection that caused by dermatophytes. Ruggedly methods as mechanical and chemical nail avulsion and abrasions are sometimes used as adjuvant therapies to topical and systemic treatments of onychomycosis. Total or partial nail avulsion by a surgical intervention are adjuvant treatment of onychomycosis resultant in a reduced fungal mass. However, the nail appearance may be affected. Reduction of the nail mass can also be achieved by nail abrasion. An option to the surgical is a chemical nail avulsion. Wheather chemical nail avulsion is painless, the appearance of the nails will alter as with surgical avulsion. Systemic and topical therapies are used for treatment of fungal nail infection.

Terbinafine hydrochloride is an antifungal agent that used for systemic treatment of onychomycosis. By the way emulsion, solution, spray and gel form of terbinafine hydrochloride are used for treatment of skin fungal infections.

For systemic application 250 mg and 500 mg divisible tablets are available. Also, 125 mg tablets are used for children. Concerning to the slow growth of the nail the drugs have to be applied for weeks. Adverse events caused by terbinafine treatment are mostly mild to moderate and reversible after treatment termination. Very frequently adverse events with a frequency above 10% are gastrointestinal disorders like abdominal fullness, loss of appetite, dyspepsia, nausea, slight stomach ache, diarrhoea. Adverse events on the skin, rash and urticarial, and muscle, arthralgia and myalgia, are reported to appear seldom, particularly less than in 0.1% of the cases. 1% of the patients taking the drug complain about headache. Changes of the flovour sense till flavour sense defict can appear in a frequency above 0.1%. however, the disorder of the flavor is reversible after treatment termination. Further adverse events are indicated to occur in less than 0.1% of the cases. Hepatic dysfunction and liver failure are seldom but severe adverse events and require therapy stop. The liver function has to be examined before a therapy can start.

There is no any marketed product of terbinafine hydrochloride for topical treatment of onychomycosis. This product will be first marketed product for ungual treatment of onychomycosis with terbinafine hydrochloride. By the way there are some topical formlations of terbinafine for treatment of skin fungal infection as cream, solution, spray and gel formulation. These systems included 1% of terbinafine hydrochloride. But these products could not get effective therapy because of difference between skin and nail structure. Sometimes they are used to help systemic therapy.

There are some products on the market for topical treatment of onychomycosis which formulated with other active substance. These formulations are nail lacquer or cream. The organic solution of the nail lacquer evaporates and leaves a polymer film containing the drug molecules on the nail surface. Efficient treatment could not achieved with these formulations because of hard structure of nail plate.

There is no formulation of liposome included terbinafine hydrochloride on the drug market. And also there is no any liposome formulation which produces for fungal nail infection. By the way there are some marketed liposome product as Ambisome® (AmfoterisinB), Doxi®/Caelyx® (Doxorubisin), DaunoXome® (Daunorubisin citrate).

It was seen that liposomes are appropriate vehicle for many active substances. There are many studies for different diseases as bacterial and fungal infections, hormonal disease, gene therapy, pulmonary disease.

Films are bioadhesive and elastic systems that included active substances. Transdermal film systems could use easily by patients. There are film products that used for onychomycosis on the market. By the way anyone included terbinafine hydrochloride as active substance. And effective therapy cannot achieve with this products.

Pullulan is an exocellular homopollysaccharide produced by fungus. It is a linear mix of a- D-glucan consisting mainly of maltotriose repeating units interconnected by a-(l-6) linkages. Pullulan is a bioadhesive polymer and frequently using to produce film formulations. Pullulan is using especially in food and pharmaceutic industries. But there is not any Pullulan film formulation with terbinafine hydrochloride. The technical problems that the invention aims to handle

To avoid disadvantage of product on the market, terbinafine hydrochloride loaded liposome included film formulations were prepared in this study. Terbinafine could absorbed easily after oral application. After application 70% of drug was found in portal vein in 2 hours. By the way bioavailability of drug is low. After absorption 50% of drug is burst because of first pass effect. The maximum drug concentration in the blood was found 0.9-1.3 μg/ml after 250 mg oral dose. Therefore; topical (ungual) therapy should use for treatment of onychomycosis. Liposomes are prepared with phospholipid and they have not got any toxic effect. And also to use film formulations is easy, more patient compliance could achieve. Topical terbinafine hydrochloride could reduce side effects of systemic application. The important advantage of these systems is application nail plate and therapy could stop anytime.

The film has bioadhesive effect therefore the formulation could stay on nail plate long time and effectiveness will increase, treatment time will decrease.

Detailed Description of the Invention

Terbinafine hydrochloride loaded liposome included film formulation were prepared with terbinafine hydrochloride, phosholipon 90 G ®, cholesterol, propylene glycol and pullulan. Firstly, terbinafine hydrochloride loaded liposome formulations were prepared to apply nail plate surface. Thin film hydration method was used to prepare liposome formulation. Phospholipon 90 G® is a lecithin produced from soybean and it is safe to use because it is already found in the human skin. So, it has no toxic effect. Cholesterol is another skin lipid that used for liposome. It is affect stability of liposome vesicles. Cholesterol and lecithin were dissolved in chloroform and then chloroform was evaporated by using evaporator. And thin film was formed in the flask. This film was dissolved with phosphate buffer saline and liposme vesicles were performed. Multilamellar vesicles were transform unilamellar by using a probe sonicator. Pullulan were dispersed with Terbinafine hydrochloride loaded liposome suspension. Pullulan is using in food industry very often. It is bioadhesive polymer. Therefore when it applied nail surface formulation could stay on the surface long time and effect of formulation could increase. Propylene glycol also was added to form flexible film formulation. Mixture heated at 30°C and water content evaporated to form film formulation. Prepared film formulation was analysis macroscopically and it was seen formulation is homogeneous, thin and flexible. Weight of film was tested. Bioadhesive properties of formulation was tested by using human cadaver nail plate. Breakable of film was tested by using Texture analyzer. Stability of formulation was performed and it was seen formulation stable during stability period via appearance, active substance amount, weight and thickness. The antifungal activity of formulation was tested via release studies from cadaver nail plate. The amount of active substance (terbinafine hydrochloride) in the nail plate was calculated after release studies. Microbiologically it was shown that formulation stopped proliferation of Trichophyton mentagrophytes ATCC 9533 and Trichophyton rubrum ATCC 28188. And lastly, the effectiveness of formulation was shown via in-vivo studies. Nail of rabbits that have fungal nail infection were used for in-vivo studies. And it was seen infection were treated with film formulation.

As a conclusion, it was aimed to prepare transungual film formulation of terbinafine hydrochloride as an alternative systemic application. Terbinafine hydrochloride loaded liposome formulation was prepared firstly with this study. This is one of the novelties of this project. And an also liposome loaded film formulation was prepared firstly, too. It was thought this film formulation will be a good alternative to systemic therapy. Liposome pullulan film formulation is effective and has easy application to the nail plate.

The applicability of the invention to the industry

Film systems and liposomes have already proven to be applicable in the market for different diseases. Drug industry will be able to produce this new formulation using the already existing infrastructure. Transungual formulation of terbinafine hydrochloride is expected to be an alternative to the current formulations that have various disadvantages.