DESC:DESCRIPTION
Technical Field of the invention

The present invention relates to the field of pharmaceutical compound derivatives, more specifically to a technology of liquid-filled hard gelatin capsule of mitotane, using a pharmaceutically acceptable excipient.

Background of the invention

Mitotane is an oral adrenal cytotoxic agent. The chemical name is (±)-1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane. The chemical structure of mitotane is:

Mitotane is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odour. It is soluble in ethanol and has a molecular weight of 320.05.
Mitotane tablet is available under the brand name of LYSODREN” by HRA PHARMA RARE DISEASES. The inactive ingredients in LYSODREN” tablet include microcrystalline cellulose, polyethylene glycol 3350, silicon dioxide, and starch.
Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself.
Despite severe safety issues, Mitotane is the only approved drug for advanced Adrenocortical Carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentration and clinical response.
Mitotane has poor water solubility (0.1 mg mL at 25 oC), being more soluble in organic solvents such as ethanol (20 mg mL), dimethyl sulfoxide (30 mg mL), and dimethyl formamide
Data regarding intestinal absorption, gut transport, bio-disposition of intravenous administration, and hepatic extraction of mitotane are limited. In addition, high variability in plasma con-centration was observed with different doses among patients. Although the compound (single dose of 2 g) reached a maximal plasma concentration of 0.0016 mg mL(data from 9 ACC patients) 10 hours after administration, the time to reach therapeutic plasma concentration (14–20 mg L) was much longer around 116 days with a cumulative dose of approximately 626 g(data from 53 ACC patients).Thus, patients require high daily doses (2–10 g day) to reach steady state in about 3 months after treatment initiation. The bioavailability of the drug is demonstrably low when administered orally, probably due to poor absorption and extensive metabolism.
The present invention relates to a better drug release tablet composition with good physical properties, as the current available medications have poor drug release profile which is unacceptable.
Therefore, to solve the problem described above, and to improve the drug release of Mitotane. Accordingly, inventors of the present invention have developed stable liquid-filled hard gelatin capsule composition of Mitotane using lipid based formulation.
Lipid based formulations have been evaluated to enhance the solubility and bioavailability of poorly soluble drugs for a number of years. A critical early step is to establish the solubility range of the drug in various lipids. Once formed, the drug/lipid mixture can sustain drug concentrations in targeted environments. Lipid formulations produce complex structures comprising micelles, micro- or nano-structures, which are directly responsible for delivering the drug. Lipid formulations can be complex because of the number of additives required to meet performance objectives. The majority of the lipid-based formulations are filled into soft or hard gelatin capsules. Lipid based formulations are generally liquids, but may also be solid or semi solid at room temperature when high melting lipids are used or when lipids are adsorbed on to a carrier.
TPGS / Vitamin E polyethylene glycol succinate is an esterified vitamin E (tocopherol) derivative primarily used as a solubilizer or emulsifying agent because of its surfactant properties. Structurally, it is amphipathic and hydrophilic, unlike the tocopherols, and therefore it is a water-soluble derivative that can be used in pharmaceutical formulations such as capsules, tablets, hot-melt extrusion, microemulsions, topical products, and parenterals. One of the most important applications is its use as a vehicle for lipid-based drug delivery formulations. It can also be used as a source of vitamin E.
Vitamin E polyethylene glycol succinate is a synthetic product. It is available as a white to light-brown, waxy solid and is practically tasteless. Chemically, it is a mixture composed principally of monoesterified polyethylene glycol 1000, the diesterified polyethylene glycol 1000, free polyethylene glycol 1000, and free tocopherol.
A few patents related to our present invention have been discussed below:
The patent “Methods for administering certain VMAT2 inhibitors” (JP7199359B2) relates to a composition for treating a patient with a neurological or psychiatric disease or disorder, comprising: the patient has been treated with a potent cytochrome P450 3A4 (CYP3A4) inducer; The composition comprises (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from 2H-pyrido[2,1- a ]isoquinolin-2-yl esters, and pharmaceutically acceptable salts thereof; Our product is different from the above mentioned patent as our present invention is a liquid-filled hard gelatin capsule formulation of mitotane which is different from the granular or tablet formulation presented in the patent.
The patent “Tyrosine kinase inhibitors” (CN113149983B) relates to compounds that are tyrosine kinase inhibitors, particularly Bruton's (Bruton) tyrosine kinase ("BTK") inhibitors, and are therefore useful in the treatment of diseases treatable by inhibition of BTK, such as cancer, autoimmune diseases, inflammatory diseases, and thromboembolic diseases. Our present invention is a particular formulation designed for better drug release profile and bio-availability than current formulations of mitotane.
Thus, there are many related patents and formulations with Mitotane, still, there exists a need for a formulation that provides better bio-availability and improved drug release profile. Our present invention addresses this need by providing the formulation for a liquid-filled hard gelatin capsule formulation of Mitotane.
OBJECTIVE OF THE INVENTION

The main objective of our present invention is to provide a formulation of Mitotane which has a better drug release profile and bio-availability than current formulations of mitotane.
Another objective of our present invention is to provide a formulation of mitotane using lipid formulations, so that a stable liquid-filled hard gelatin capsule composition of Mitotane is obtained.
Brief Summary of the invention

The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure, and it does not identify key/critical elements of the invention or delineate the scope of the invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later.

The following summary is provided to facilitate a clear understanding of the new features in the disclosed embodiment and it is not intended to be a full, detailed description. A detailed description of all the aspects of the disclosed invention can be understood by reviewing the full specification, the drawing and the claims and the abstract, as a whole.
The present invention relates to a formulation of liquid-filled hard gelatin capsule of Mitotane, a pharmaceutically acceptable excipient using a lipid based formulation.
The present invention discloses novel composition of mitotane preferably in liquid-filled hard gelatin capsule dosage form with pharmaceutically acceptable excipients and method of preparation thereof. Mitotane is dissolved in the liquid form TPGS (Tocopheryl Polyethylene Glycol Succinate). TPGS improves the dissolution of active pharmaceutical ingredients in-vitro. Liquid-filled hard gelatin capsule formulation of mitotane in such a way exhibits superior performance with respect to dissolution data.

Brief Description of the Drawings

The invention will be further understood from the following detailed description of a preferred embodiment taken in conjunction with an appended drawing, in which:

The manner in which the present invention is formulated is given a more particular description below, briefly summarized above, may be had by reference to the components, some of which is illustrated in the appended drawing It is to be noted; however, that the appended drawing illustrates only typical embodiments of this invention and are therefore should not be considered limiting of its scope, for the system may admit to other equally effective embodiments.
Throughout the drawings, the same drawing reference numerals will be understood to refer to the same elements and features.
The features and advantages of the present invention will become more apparent from the following detailed description a long with the accompanying figures, which forms a part of this application and in which:
Fig 1: Graph Diagram comparing the dissolution profile of existing Mitotane tablet formulation against the embodiments of the liquid-filled hard gelatin capsule of Mitotane, in accordance with our present invention;
Fig 2: Block Diagram showing the method of preparation of the liquid-filled hard gelatin capsule of Mitotane, in accordance with our present invention;
REFERENCE NUMERALS
100 – : To a container TPGS (tocopheryl polyethylene glycol succinate) was added under heating
101 – To the above step, Mitotane was finally added to the liquid form of TPGS under stirring and heating at 50°C.
102 – Filling of Capsule: Above prepared semi solids are filled in hard gelatin capsules (Size ‘’ 00’’) as per target fill weight.
103 – The product temperature was maintained at 50°C.

Detailed Description of the invention

The principles of operation, design configurations and evaluation values in these non-limiting examples can be varied and are merely cited to illustrate at least one embodiment of the invention, without limiting the scope thereof.
The embodiments disclosed herein can be expressed in different forms and should not be considered as limited to the listed embodiments in the disclosed invention. The various embodiments outlined in the subsequent sections are constructed such that it provides a complete and a thorough understanding of the disclosed invention, by clearly describing the scope of the invention, for those skilled in the art.
Throughout this specification various indications have been given as to preferred and alternative embodiments of the invention. It should be understood that it is the appended claims, including all equivalents, which are intended to define the spirit and scope of this invention.
The current embodiment of the present invention relates to a formulation of mitotane prepared using lipid formulation, so that mitotane is made available as a liquid-filled hard gelatin capsule of Mitotane.
Excipient used in the formulation of one embodiment of our present invention is TPGS / Vitamin E polyethylene glycol succinate.
Preparation of Liquid-Filled Hard Gelatin Capsule, as per our present invention (fig 2):
Brief Manufacturing Method: To a container TPGS (tocopheryl polyethylene glycol succinate) was added under heating (100). The product temperature was maintained at 50°C (103). To the above step (100), Mitotane was finally added to the liquid form of TPGS under stirring and heating at 50°C (101).
Filling of Capsule (102): Above prepared semi solids are filled in hard gelatin capsules (Size ‘’ 00’’) as per target fill weight.
A few different compositions of our present invention obtained by varying the weight per quantity of the ingredients listed in our formulation so that different dosages of the formulation are given in the tables 1, 2,3 as shown below:
Embodiment: 1 - Mitotane formulation preparation 1
Table: 1
Ingredients Quantity per Tablet (mg)
Mitotane 500.00
Microcrystalline Cellulose 152.40
Pregelatinized Starch 35.00
Colloidal Silicon Dioxide 7.00
Polyethylene Glycol 5.60
Total Weight 700.00

Embodiment: 2 - Mitotane formulation preparation 2
Table: 2
Ingredients Quantity per Capsule (mg)
Mitotane 500.00
TPGS (tocopheryl polyethylene glycol succinate) 1000.00
Total Weight 1500.00

Embodiment: 3 - Mitotane formulation preparation 3
Table: 3
Ingredients Quantity per Capsule (mg)
Mitotane 50.00
TPGS (tocopheryl polyethylene glycol succinate) 1000.00
Total Weight 1050.00 mg

Dissolution Study:
Dissolution profile of the pharmaceutical dosage form of one embodiment of the present invention was carried out using USP apparatus II (paddle) with sinker. In this method, purified water of 900 ml was used as dissolution media at 50 RPM for 60 min of time duration at (37 ± 0.5) oC. Dissolution profile of the pharmaceutical dosage form as per the present invention was compared with the Tablet form available in the market, wherein table 4 shows that Comparative dissolution profile of Mitotane (Tablet Vs Capsule) in purified water.
Table 4
Time
(min) Dissolution (% Drug released)
Media: Purified Water
Tablet 500 mg Capsule 500 mg + 1 ml TPGS (present invention) Capsule 50 mg + 1 ml TPGS (present invention)
10 0 0 0
15 0 0 0
30 1.16 8.59 42.96
45 1.48 11.01 55.03
60 2.0 14.81 74.01

From the figure 1 and table 4, we can see that drug release was improved from 2.0% to 74.01% after the formulation of our present invention.
,CLAIMS:CLAIMS
I/We Claim:
I/We claim:
1. A formulation of liquid-filled hard gelatin capsule of mitotane, wherein the formulation contains Mitotane, along with a pharmaceutically acceptable excipient - TPGS / Tocopheryl Polyethylene Glycol Succinate and prepared as follows:
a. To a container TPGS (tocopheryl polyethylene glycol succinate) was added under heating (100).
b. The product temperature was maintained at 50°C (103).
c. To the above step a, Mitotane was finally added to the liquid form of TPGS under stirring and heating at 50°C (101).
d. Filling of Capsule: Above-prepared semi solids are filled in hard gelatin capsules (Size ‘’ 00’’) as per target fill weight (102).
2. The formulation of liquid-filled hard gelatin capsule of mitotane, as claimed in claim 1, wherein the formulation can include one or more of the following ingredients: Microcrystalline Cellulose, Pregelatinized Starch, Colloidal Silicon Dioxide, Polyethylene Glycol.