Patent Description:
While only <NUM>% of the new chemical molecules show high solubility and high permeability, approximately <NUM>% of them show difficulty in formulation due to poor water solubility and fail in drug development studies. Limited solubility due to poor water solubility results in the low bioavailability of the drugs. If the water solubility of BCS Class <NUM> drugs is increased according to the Biopharmaceutics Classification System (BCS), which has poor water solubility and good permeability, the in vivo activities and bioavailability of the drugs will also increase. Various techniques are used to increase the solubility and bioavailability of drugs that are poorly soluble in water. These are techniques such as cosolvent use, micronization, chemical drug modification, surfactant use, particle size reduction technology, nanoparticle technology, nanocrystalline technology, nanosuspension, self emulsifying lipid-based systems, and solid dispersion technique.

Lipid-based drug delivery systems are one of the most important strategies used to increase the solubility and bioavailability of drugs with low water solubility and lipophilic structure. Depending on the developing technology and requirements, it is developed as different dosage forms such as oily solutions, emulsions, microemulsions, self emulsifying drug carrier systems (SEDDS, SMEDDS, and SNEDDS), and liposomes.

SNEDDS are known as self emulsifying isotropic mixtures containing oil, surfactant, and co-surfactant. In systems that are self nanoemulsifying when combined with the aqueous phase in the gastrointestinal tract, the droplet size is below <NUM> and is used to improve the dissolution and absorption of BCS Class <NUM> drugs. SNEDDS show a significant increase in dissolution rate, solubility, and permeability, and also they significantly reduce p-gp efflux, first-pass effect through the liver, and intra-individual and inter-individual variability depending on the conditions in the gastrointestinal tract. There are many drugs developed in the form of self emulsifying systems on the market: Neoral®, Vesanoid®, Accutane®, Sandimmune®, Kaletra®, Aptivus®, Norvir®, Fortovase®, Agenerase®, Solufen®, and Lipirex®.

Self emulsifying systems have many advantages; however, the observation of general stability problems in lipid-based systems, leakage from the oily system during packaging and transportation, the possibility of irritation in the gastrointestinal system of the high amount of surfactant used in these systems, the soft gelatin capsule where liquid SEDDS formulations can be filled has disadvantages such as being an expensive technology.

Solid self nanoemulsifying systems (S-SNEDDS) are an alternative approach to overcoming the problems of self emulsifying systems. S-SNEDDS combine the advantages of solid dosage forms, such as low production cost, ease of process control, high stability and reproducibility, better patient compliance, with the increased solubility and bioavailability of SEDDS. In addition, S-SEDDS are generally preferred to liquid SEDDS due to its ease of transportation and stability.

There are methods such as adsorption, spray drying, dry emulsion, solid dispersion, melt extrusion on solid carriers to obtain S-SNEDDS, and the prepared S-SNEDDS can then be converted into pellets, tablets, and capsules.

Solid carriers have the ability to adsorbtion the liquid / semi-solid self emulsifying systems. A freely flowing powder mass is obtained by mixing, which is a simple procedure. Later, this free-flowing powder mass is formulated with appropriate excipients and made ready for tablet compression. Solid dosage forms with better content uniformity are obtained with this technique.

Microporous inorganic materials, colloidal inorganic adsorbents with large surface area, crosslinked polymers or nanoparticles can be used as carrier material for the absorption of the self emulsifying system.

Magnesium aluminometasilicate has a large specific surface area, high porosity, high oil adsorption capacity. Magnesium aluminometasilicate has been accepted worldwide to be used in formulations containing antibiotics, lipophilic active ingredients, slightly soluble active ingredients, herbal mixtures, and vitamins. In pharmaceutical applications, it is widely used as a carrier and filler to improve the quality of tablets, powders, granules, and capsules, as well as carriers for solid dispersions and self emulsifying drug systems. It is useful in increasing the compressibility and fluidity of powders, increasing the hardness of tablets even at low compression forces, increasing the stability of moisture sensitive active substances, and formulating lipophilic oils or active substances with adsorption capacity.

Bosentan monohydrate is a non-peptide endothelin receptor antagonist, specifically administered orally in the treatment of pulmonary arterial hypertension (PAH). Reference and equivalent products used in the treatment of PAH are available in the pharmaceutical market in the form of <NUM> and <NUM> tablets. In order to observe the therapeutic effect of the products in patients, they should be used at a dose of <NUM> twice a day in the first four weeks of treatment and then at a dose of <NUM> twice a day. This treatment requires lifelong drug use. Since it is a very expensive treatment, its economic cost to both patients and society is quite high. Bosentan, a BCS Class <NUM> drug, has a problem of solubility, bioavailability, and dose-dependent side effects. To solve these problems, it is necessary to increase the bioavailability with appropriate formulation strategies and to reduce the side effects and the amount/number of doses.

Various dosage forms were prepared for bosentan monohydrate such as osmotic controlled tablets, solid dispersion, extended-release matrix tablets prepared with synthetic/natural polymers, mucoadhesive microsphere, extended-release pellet, controlled release system with microspheres prepared with biodegradable polymer mixture, transdermal patch, inhaled controlled release polymeric colloid, fast-dissolving nanosuspension, nanocomposite, self microemulsifying, and self nanoemulsifying systems. <NPL>) discloses in vitro characterization studies of liquid and solid self-nanoemulsifying bosentan systems. With these systems, it is aimed to increase the solubility/dissolution rate of the active substance and thus increase the treatment efficiency.

In the present invention, it is aimed to combine the advantages of the solid dosage form and conventional systems with a new self nanoemulsifying system. In addition, it is thought that designing the solid dosage S-SNEDDS form of bosentan monohydrate will be more advantageous than the dosage form in the market, considering the advantage of the use of the patient and the reduction of possible pharmacoeconomic treatment costs.

S-SNEDDS tablets were prepared to increase the in vitro dissolution and bioavailability of bosentan monohydrate, which has a very low water solubility and dissolution rate. In the preparation of SNEDDS, glyceryl monolinoleate (Maisine®) as oil, polyoxyl <NUM> hydrogenated castor (Cremophor®RH <NUM>) oil as surfactant and caprilocaproyl polyoxyl-<NUM> glycerides (Labrasol®) as cosurfactant were used. Magnesium aluminometasilicate (Neusilin® US2) was used for solidification of the liquid SNEDD system. In the preparation of the solid system, the method of adsorbing on a carrier adsorbent was chosen.

After the adsorption process, the characterization studies of the powder mass were carried out by scanning electron microscopy, X-ray diffraction analysis, differential scanning calorimetry, total pore volume and specific surface area analysis.

Croscarmellose sodium and magnesium stearate were used as excipient for tabletting the powder mass by direct compression, and tablet controls were carried out on the obtained tablets. In vitro dissolution studies were carried out by using distilled water environment containing <NUM>% SLS, which is the in vitro dissolution medium recommended by the FDA, and in Fasted State Simulating Intestinal Fluid (FaSSIF) and Fed State Simulating Intestinal Fluid (FeSSIF) biorelevant media. As a result, bosentan monohydrate was successfully loaded into liquid SNEDDS and magnesium aluminomethacilica, the tablets with good powder properties and obtained by direct compression of this powder passed the tablet controls successfully.

The liquid SNEDDS formulation in distilled water containing <NUM>% SLS released more than <NUM>% of the commercial tablet within <NUM> minutes and all of the bosentan monohydrate within <NUM> minutes. S-SNEDDS tablet released <NUM>% at the end of <NUM> minutes. In FaSSIF medium, which mimics biorelevant media, the commercial tablet released approximately <NUM>% of the active substance after <NUM> minutes, while the liquid SNEDDS formulation loaded with bosentan monohydrate released <NUM>% and S-SNEDDS tablet <NUM>%. In the FeSSIF medium, the commercial tablet released approximately <NUM>% of the active substance after <NUM> minutes, while the liquid SNEDDS formulation loaded with bosentan monohydrate released <NUM>% and the S-SNEDDS tablet <NUM>%.

The ratio of components in an exemplary liquid SNEDDS formulation is <NUM>: <NUM>: <NUM> by weight, which is oil: surfactant: cosurfactant. Accordingly, the ratio of glyceryl monolinoleate, polyoxyl <NUM> hydrogenated castor oil and caprylocaproyl polyoxyl-<NUM> glycerides by weight is <NUM>: <NUM>: <NUM> (w/w/w).

In the liquid SNEDDS formulation, the particle size is below <NUM> and the polydispersity index (PDI) is less than <NUM>. Liquid SNEDDS has a droplet particle size of <NUM> and a polydispersity index of <NUM>.

<NUM> gram of the liquid SNEDDS formulation contains <NUM> of bosentan monohydrate.

The ratio of the liquid SNEDDS formulation to magnesium aluminometacilicate can be between <NUM>:<NUM> and <NUM>:<NUM> (w/w) by weight. Liquid SNEDDS: magnesium aluminometasilicate ratio is preferably <NUM>:<NUM> (w/w).

<NUM>% croscarmellose sodium (w/w) and <NUM>% magnesium stearate (w/w) were used as excipients in tablet formulation of liquid SNEDDS: magnesium aluminometasilicate powder mass.

Solubility studies of bosentan monohydrate in different oil groups have been carried out. Considering the hydrophilic-lipophilic balance values (HLB), the highest solubility glyceryl monolinoleate, polyoxyl <NUM> hydrogenated castor oil, caprylocaproyl polyoxyl-<NUM> glycerides were chosen as oil, surfactant, and cosurfactant. One type of mixtures were obtained by scanning the surfactant and cosurfactant ratio between <NUM>: <NUM> to <NUM>: <NUM>. Smix (surfactant: cosurfactant ratio) was determined as <NUM>: <NUM>. The obtained homogeneous mixtures were then mixed with oil in the ratio of <NUM>: <NUM>-<NUM>: <NUM> to create a homogeneous system. These systems were then titrated with water and the boundaries of the ternary phase diagrams containing the nanoemulsion field were determined.

Mixtures of different proportions within the confines of the ternary phase diagrams were diluted with <NUM>:<NUM> distilled water to determine whether nanoemulsion was formed. The determined extreme values were evaluated with the Design Expert® program, and the optimum SNEDDS formulation was created and the strength of the formulation was supported by characterization studies. Based on the SNEDDS formulation supported by studies, liquid SNEDDS formulations loaded with bosentan monohydrate were prepared. Different amounts of active substance were tested and mixed with blank formulations and vortexed until homogeneous preparations were obtained. It was then allowed to dissolve completely in a water bath at <NUM> for <NUM> hours, and the resulting bosentan monohydrate loaded SNEDDS formulations were stored at room temperature until use. In this study, <NUM> of bosentan monohydrate was loaded into <NUM> of liquid SNEDDS formulation.

<NUM> liquid SNEDDS formulation loaded with <NUM> bosentan monohydrate was added to the magnesium aluminometasilicate selected as an adsorbent in a mortar and turned into a solidified (S-SNEDDS) powder form. For this purpose, three different ratios of bosentan monohydrate loaded liquid SNEDDS: magnesium aluminometasilicate as <NUM>: <NUM>, <NUM>: <NUM>, <NUM>: <NUM> were tested. In order to prepare tablets, <NUM>% of the main mass was determined as croscarmellose sodium and <NUM>% magnesium stearate as excipients and mixed in a cubic mixer. After examining the powder flow properties and characterization studies, the ratio of <NUM>: <NUM> was selected and tablets were obtained by direct compression technique.

The in vitro dissolution study test conditions performed with reference product Tracleer® tablet (expiry date <NUM>/<NUM> and batch number IW067A0401), BOS-loaded liquid SNEDDS formulation and BOS-loaded S-SNEDDS tablet are given below. Dissolution studies were carried out according to the specified experimental conditions. <NUM> of the aliquots were withdrawn at predetermined time intervals, (<NUM>, <NUM>, <NUM>, <NUM>, and <NUM>) from the dissolution medium and with an equal volume of fresh medium to maintain the total volume. The withdrawn samples were filtered using a <NUM>.

Biorelevant media was prepared by dissolving <NUM> of SIF powder in one liter of pH <NUM> buffer for FaSSIF and by dissolving <NUM> of SIF powder in one liter of pH <NUM> buffer for FeSSIF.

The liquid SNEDD system carrying <NUM> of bosentan monohydrate obtained consists of <NUM>% glyceryl monolinoleate, <NUM>% polyoxyl <NUM> hydrogenated castor oil, and <NUM>% caprilocaproyl polyoxyl-<NUM> glycerides. The ratio of components is about <NUM>: <NUM>: <NUM> by weight (w/w/w).

The liquid SNEDD system loaded with bosentan monohydrate has a droplet size of <NUM> and a polydispersity index of <NUM>.

The powder properties of the bosentan monohydrate loaded liquid SNEDDS: magnesium aluminometasilicate <NUM>: <NUM> ratio were found suitable (Table <NUM>).

Morphological analyses of bosentan monohydrate, magnesium aluminometasilicate and liquid SNEDDS: magnesium aluminometasilicate (<NUM>:<NUM>) and BOS-loaded liquid SNEDDS: magnesium aluminometasilicate (<NUM>:<NUM>) by SEM were performed. It was observed that the liquid SNEDDS loaded with bosentan monohydrate was successfully adsorbed to the adsorbent and the spherical smooth structure of magnesium aluminometasilicate was not disturbed (<FIG>).

DSC analysis were performed for bosentan monohydrate, tablet excipients, magnesium aluminometasilicate and liquid SNEDDS: magnesium aluminometasilicate (<NUM>:<NUM>) and BOS-loaded liquid SNEDDS: magnesium aluminometasilicate (<NUM>:<NUM>) and bosentan monohydrate is compatible with tablet excipients. It was determined by thermograms that monohydrate loaded liquid SNEDDS was successfully adsorbed to the adsorbent (<FIG>). XRD analysis results were obtained for bosentan monohydrate, magnesium aluminometasilicate, liquid SNEDDS: magnesium aluminometasilicate (<NUM>:<NUM>), and BOS-loaded liquid SNEDDS: magnesium aluminometasilicate (<NUM>:<NUM>). The results shown that BOS-loaded liquid SNEDDS was successfully adsorbed onto adsorban (<FIG>).

Characterization studies performed on the S-SNEDDS tablet were found appropriate (Table <NUM>).

More than <NUM>% of bosentan monohydrate was dissolved after <NUM> minutes from commercial products and formulations in distilled water containing <NUM>% SLS, as shown in <FIG>.

As seen in <FIG> in FaSSIF medium, after <NUM> minutes from commercial products and formulations, bosentan monohydrate dissolved <NUM>% from the commercial product, while <NUM>% from the S-SNEDDS tablet. BOS-loaded S-SNEDDS tablet showed <NUM>-fold more cumulative dissolution than commercial product for bosentan monohydrate.

As seen in <FIG> in FeSSIF medium, after <NUM> minutes of commercial products and formulations, bosentan monohydrate dissolved <NUM>% from the commercial product and <NUM>% from the S-SNEDDS tablet. BOS-loaded S-SNEDDS tablet showed <NUM>-fold more cumulative dissolution than commercial product for bosentan monohydrate.

As a result, the feature of the S-SNEDDS tablet containing Bosentan monohydrate, which is the subject of the invention, is that the liquid SNEDDS containing Bosentan monohydrate as an active substance is adsorbed on magnesium aluminometasilicate. The liquid SNEDD system contains glyceryl monolinoleate as oil, polyoxyl <NUM> hydrogenated castor oil as a surfactant, and caprilocaproyl polyoxyl-<NUM> glycerides as co-surfactant.

The production method of the S-SNEDDS tablet containing Bosentan monohydrate of the present invention includes the following steps:.

Claim 1:
Solid Self Nanoemulsifying System tablet comprising bosentan monohydrate, wherein the Bosentan monohydrate containing liquid self nanoemulsifying system is adsorbed on magnesium aluminometasilicate and the liquid self nanoemulsifying system comprises glyceryl monolinoleate as an oil, polyoxyl <NUM> hydrogenated castor oil as a surfactant and caprylocaproyl polyoxyl-<NUM> glycerides as a co-surfactant.