WO2023128898A1

WO2023128898A1 - Pharmaceutical compositions comprising macitentan as active ingredient and other relevant excipients

Info

Publication number: WO2023128898A1
Application number: PCT/TR2021/051618
Authority: WO
Inventors: Abdulhaluk SANCAK; Ayse Figen ONUK GOREN; Hakan GURPINAR; Asiye Sezgin; Azmatullah ANSARI; Gizem ALKAN; Koray YILMAZ
Original assignee: Humanis Saglik Anonim Sirketi; Adalvo Limited
Priority date: 2021-12-30
Filing date: 2021-12-30
Publication date: 2023-07-06

Abstract

The present invention relates to the preparation of pharmaceutical compositions comprising macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH), having a specific weight ratio of binder to disintegrant in formulation.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING MACITENTAN AS ACTIVE INGREDIENT AND OTHER RELEVANT EXCIPIENTS

Field of invention

The present invention relates to the preparation of pharmaceutical compositions comprising macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH), having a specific ratio of binder to disintegrant in formulation.

Background of the invention

Macitentan has a chemical name as 5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2- yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine and its chemical structure is shown in the Figure I. Macitentan has molecular weight of 588,3 g/mol, white or off-white Solid, crystalline powder.

Figure 1

Macitentan has been used as an orphan drug in the EU with the name of Opsumit and also in United States, is indicated for patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a condition where there is high blood pressure in the arteries that supply the lungs. Pulmonary arterial hypertension (PAH) is also associated with a number of other medical diseases such as cirrhosis and connective tissue diseases like scleroderma.

EP1928409B relates to a pharmaceutical composition comprising macitentan and specific formulation excipients with lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, sodium starch glycolate, a surfactant (polysorbate) and a lubricant.

One of the oral administration way used commonly is tablet form. Tablet form has many advantages like cost-effective, lighter and compact, easiest and cheapest to package, can be masked by coating technique and greatest chemical and microbial stability over all oral dosage forms. A pharmaceutical composition may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients examples can be filler, disintegrant, binder, surfactant, lubricant, solvent, antiadherent, flavor, glidant, preservative, sweetener, suspending/viscosity agent, diluent, colorant and the mixtures thereof.

Ideal pharmaceutical excipient profile should have suitable physical and chemical properties with active ingredient and also other raw materials. These properties can be stable and reproducible, no unwanted interaction with active ingredient, inert property, desired functionality and cost effective.

One of the critical excipient for oral formulation such as tablet is binder in a pharmaceutical composition. Binders can be used for tablets that can provide the required mechanical strength, and also volume for low active dose tablets.

Another critical excipient for oral formulation such as tablet is disintegrant in a pharmaceutical composition. It is also known as disintegrating agents or disintegrators. Disintegrating agents are the substances which are added to an oral solid dosage to promote its rapid disintegration or break down into small particles after administration for facilitating rapid dissolution. Disintegrating agents are added to an oral solid dosage form to get quick drug release. Disintegrants are used to control the disintegration time for oral solid dosage forms such as tablets, capsules and the others as per pharmacopoeia.

Disintegrants can be classified into two groups, traditional and Super Disintegrants. Examples for traditional disintegrants: starch, sodium alginate etc. Examples for Super Disintegrants: crospovidone, croscarmellose sodium, sodium starch glycolate etc.

Summary of the invention

The present invention relates to the preparation of pharmaceutical compositions comprising macitentan, and one or more pharmaceutically acceptable excipients comprising a binder and a disintegrant with a specific ratio.

In this invention, a pharmaceutical composition comprising macitentan or pharmaceutically acceptable salts thereof, a disintegrant, a binder and optionally one or more pharmaceutically acceptable excipients, wherein the weight ratio of the binder to the disintegrant is from 0,55 to 0,72.

Detailed description of the invention

The present invention relates to preperation of pharmaceutical compositions comprising macitentan in the treatment of pulmonary arterial hypertension.

The present invention provides a pharmaceutical composition comprising macitentan for the treatment of pulmonary arterial hypertension, wherein process including wet granulation method. The present invention relates to the preparation of pharmaceutical compositions comprising macitentan or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients.

The present invention relates to the preparation of pharmaceutical compositions comprising macitentan, and one or more pharmaceutically acceptable carriers or excipients, comprising a binder and a disintegrant with a specific weight ratio.

The present invention relates to the preperation of pharmaceutical compositions comprising macitentan, and one or more pharmaceutically acceptable carriers or excipients, including a binder with a specific interval by tablet weight.

The present invention relates to the preperation of pharmaceutical compositions comprising macitentan, and one or more pharmaceutically acceptable carriers or excipients, including a disintegrant with a specific interval by tablet weight.

In this invention, it is obtained pharmaceutical compositions comprising macitentan and a disintegrant selected from a list consisting of: crospovidone, sodium starch glycolate and croscarmellose sodium or mixture thereof.

In this invention, it is obtained pharmaceutical compositions comprising macitentan and a disintegrant at a concentration of from 2% to 4% (w/w).

In this invention, it is obtained pharmaceutical compositions comprising macitentan and a binder having a concentration of from 1% to 3% (w/w).

According to a preferred embodiment of this invention, the pharmaceutical composition can be in the form of a tablet.

In this invention, target properties of tablet dosage forms is below:

■ Tablet should have elegant product without any cracks, discoloration or contamination.

■ Mechanical stregnth should be sufficient for production packaging, shipping and dispensing.

■ Physical properties shoul maintain the chemical and physical stability.

■ Tablet form should have predictable and reproducible manner for releasing the active ingredients. In preformulation studies for developing tablet dosage form, physicomechanical properties are determined such as particle size, tap density, crystalline form, compressibility, photomicrographs, melting point, taste, color, appearance, and viscosity. These properties has an important role in powder flow and compaction in tablet manufacturing process.

Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing.

Generally, excipients that is used in tablet dosage form are diluent, binder, disintegrants, lubricant, glidant, colouring agent, flavoring agent, sweetening agent and solvent except active ingredient.

In this invention, the ratio of disintegrants used to tablet weight is between 2%-4%. The composition comprises a disintegrant at the concentration of 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8 and 4.0% (w/w). The most preferred amount in this range is 3.0%.

In this invention, the ratio of binder used to the total weight is between 1% - 3%. The composition comprises binder at the concentration of 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8 and 3.0% (w/w). The most preferred amount in this range is 2.0%.

In this invention, manufacturing process generally consisting of four stages: a) Sieving and mixing, b) Wet Granulation, c) Mixing granule with external excipients, d) Tablet compression and Film Coating.

According to this invention, the amount of coating material by weight will be from 2 to 6%, preferably from 3 to 5% and more preferably from 3.5 to 4.5% of the weight of the tablet before its coating.

In this invention, disintegrant and binder are very critical. Disintegrant and binder should be selected with given ratio and properties.

There is a comparison table about test product and the others. Comparison table for our test product, which is the subject of the invention, with the formulation rates specified in the EP 1928409 patent and the opsumit components described in Table 1.

Table 1: Comparison table for relevant excipients of Macitentan lOmg Tablet (Test product), excipients on EP 1928409 examples and excipients of Opsumit product in Russia market.

In this invention, the main point is that the weight ratio of the binder to disintegrant in tablet composition comprising macitentan. When other relevant publications and open sources are evaluated, the originality and novelty of the subject can be seen. Above table supports this situation.

The stability of the pharmaceutical composition may be tested in conventional manner, e.g. by measurement of macitentan and its degradation products, dissolution, friability, disintegration time, appearance and/or microscopy, e.g. after storage at 25 °C and 60% relative humidity, and/or storage at 40°C and 75% relative humidity for defined periods of time.

In this invention, the formulations preferably contain active ingredient, filler, disintegrant, binder, surfactant, lubricant and solvent.

In this invention, tablets may also be produced. The tablets may vary in shape and be, for example, round, oval, oblong, cylindrical, clover-shaped or any other suitable shape.

The term “w/w%” as used herein, and as conventionally used in the pharmaceutical industry, refers to a percentage by weight compared to the total weight of the composition considered.

A pharmaceutical composition according to the invention is considered "stable", if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of macitentan, is maintained over said period of time.

The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.

In this invention, the term "pulmonary hypertension" will be understood to include “a condition where there is high blood pressure in the arteries that supply the lungs”, including Subdivisions of Pulmonary Arterial Hypertension and World Health Organization classifications for Pulmonary Hypertension (PH).

Wet granulation is the most widely used process of granulation in the pharmaceutical industry. Wet granulation process can be very simple or very complex depending on the characteristics of the powders and the available equipments. Basicly, wet granulation method involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction. Then, drying process starts and then sized to obtained granules with desired mesh. The granulate may then be tabletted /compressed, or other excipients may be added prior to tableting with suitable excipients.

The term "oral solid dosage form" as used herein denotes solid preparations (e.g. tablets) for oral administration each containing a single dose of one or more active substances.

Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, filler, disintegrant, binder, surfactant, lubricant, solvent and the mixtures thereof, to facilitate the physical formulation of various dosage forms for oral administration like tablets.

As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties ofthe compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.

Suitable disintegrants according to the present invention include, but are not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose (crosslinked carboxymethylcellulose) sodium, cross-linked polyvinylpyrrolidone, crospovidone (crosslinked povidone, a synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidone), alginic acid, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch. The preferred disintegrant is crospovidone.

Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), HPMC E5, acacia, alginic acid, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch. The preferred binder is Povidon K30.

Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate.

Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, lactose such as example the anhydrous form or the hydrate form such as the monohydrate form, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non- hygroscopic are preferred, with non-hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries. The preferred filler is microcrystalline cellulose.

Suitable surfactants and wetting agents according to the present invention include, but are not limited to, heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate, polyoxyethylen sorbitan monolaurate, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbates, for example polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, sorbitan monopalmitate, sodium salts of fatty alcoholsulfates such as sodium lauryl sulfate, sodium dodecylsulfate, sodium salts of sulfosuccinates such as sodium dioctylsulfosuccinate, partially esters of fatty acids with alcohols such as glycerine monostearate, partially esters of fatty acids with sorbitans such as sorbitan monolaurate, partially esters of fatty acids with polyhydroxyethylene sorbitans such as polyethyleneglycol sorbitan monolaurate, - monostearate or -monooleate, ethers of fatty alcohols with polyhydroxyethylene, esters of fatty acids with polyhydroxyethylene, copolymers of ethylenoxide and propylenoxide (Pluronic®) and ethoxylated triglycerides. The preferred surfactant is polysorbate 80.

Suitable film-forming agents and coating materials according to the present invention include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose, HPMC), methylcellulose, ethylcellulose, cellulose acetate phthalate, shellac, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester.

Solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is purified water.

The present invention is described in the following example in more details. This example is not limiting the scope of the present invention and is to be considered under the light of the foregoing detailed description.

In this invention, dissolution tests has been performed to compare Opsumit 10 mg Film coated tablet (Reference product) and Macitentan 10 mg Film Tablet (Test product). The results have been compared to the reference product Opsumit 10 mg Film coated tablet and Macitentan 10 mg Film Tablet (Test Product). Relevant figures for Reference product / Test product are shown in Figure 1-3. Advantages

It is obtained optimum value for pharmaceutical composition comprising macitentan that is well ratio for tablet dosage form by using binder and disintegrant as excipients.

When the physical and chemical test results of the pharmaceutical composition obtained by using a specific ratio of binder and disintegrant are evaluated, it has been observed that it has positive effect on the manufacturing process.

It effects on many specifications during determining and designing manufacturing process for pharmaceutical products.

The pharmaceutical compositions of the invention are particularly suited for the oral administration.

The pharmaceutical compositions of the invention are particularly shows similar property in the stability and dissolution, it is extremely useful as a pharmaceutical product preparation technique.

The present invention provides pharmaceutical composition comprising macitentan and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation

Tablet dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance.

The advantages of wet granulation method:

• Improving flow property and compression characteristics and increases density of granules

• Better distribution of color and soluble drugs if added in the binding solution.

• Reducing dust hazards

• Preventing segregation of powders

The compositions of the invention are advantageously in the form of unit dose. Preferably, each unit dose according to the invention comprises 1 to 100 mg, e.g. 5 to 50 mg, advantageously 8 to 20 mg, e.g. about 10 mg according to the invention, advantageously in combination with standard excipients and additives well known to one skilled in the field.

In present invention, tablet containing a binder shows similar dissolution property and by the addition of it, the drug dissolution property could be easily controlled.

Dissolution Tests

In this invention, dissolution testing has been performed in pH 1,2 (0,1 HCI + 0.1% cetyltrimethylammonium bromide (CTAB)), acetate buffer pH 4,5 (0,1% CTAB), phosphate buffer pH 6,8 (0,1% CTAB). General properties of relevant batches are shown in Table 2. The results have been compared to the reference product Opsumit 10 mg Film coated tablet and Macitentan 10 mg Film Tablet (Test Product).

Table 2: Summary of Batches used in In Vitro Dissolution Tests

In this invention, the dissolution test has been performed for Opsumit 10 mg FTB and Macitentan 10 mg Tablet (Test Product) pH 1.2 with 0,1 HCL + % 0,1 CT AB. It is shown in Table 3 and Figure 1. Drug release for both the test product and the reference product were found to be satisfactory.

Table 3: Summary of Dissolution Results of Macitentan 10 mg Film tablet (Test Product) in Comparison to Opsumit 10 mg FTB (Reference Product) in pH 1.2 with 0,1 HCL + 0,1% CTAB.

Figure 1: Comparative Dissolution Profiles of Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) pH 1.2 with 0,1 HCL + 0,1% CTAB.

In this invention, the dissolution test has been performed for Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) in acetat buffer pH 4.5 with 0.1% CT AB. It is shown in Table 4 and Figure 2. Drug release for both the test product and the reference product were found to be satisfactory.

Table 4: Summary of Dissolution Results of Macitentan 10 mg Film Tablet (Test Product) in Comparison to Opsumit 10 mg Film Tablet (Reference Product) in acetat buffer pH 4.5 with % 0.1 CTAB.

Figure 2: Comparative Dissolution Profiles of Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) in in acetat buffer pH 4.5 with % 0.1 CTAB.

In this invention, the dissolution test has been performed for Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) in phosphate buffer pH 6.8 with 0,1% CTAB. It is shown in Table 5 and Figure 3. Drug release for both the test product and the reference product were found to be satisfactory.

Table 5: Summary of Dissolution Results of Macitentan 10 mg Film Tablet (Test Product) in Comparison to Opsumit 10 mg Film Tablet (Reference Product) in phosphate buffer pH 6.8 with 0,1% CTAB.

Figure 3: Comparative Dissolution Profiles of Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) in phosphate buffer pH 6.8 with 0,1% CTAB.

Overall conclusion for dissolution results:

In-vitro comparative dissolution data and profiles has been demonstrated above in pH 1.2, pH 4.5, pH 6.8. All the multi media profiles were comparatively similar to that of the selected Reference product Opsumit 10 mg Film Tablet. Example 1: Macitentan lOmg uncoated tablet unit formula

The process for the preparation of Macitentan lOmg uncoated tablet according to the present invention can be carried out according to the following process:

1. Stage 1 Sieving and Mixing Sieving and mixing: macitentan, lactose monohydrate, microcrystalline cellulose and

Povidone K30.

12 2. Stage 2 Wet Granulation

Wet granulation was done with purified water which contains polysorbate 80 into it.

3. Stage 3 Sieving and Mixing

Dried granules were sieved and mixed with crospovidone, magnesium stearate

4. Stage 4 Tablet compression and Film Coating

Tablet compression and Film Coating

Brief description of the figures included in the description:

Figure 1: Comparative Dissolution Profiles of Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) pH 1.2 with 0,1 HCL + 0,1% CT AB

Figure 2: Comparative Dissolution Profiles of Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) in in acetate buffer pH 4.5 with % 0.1 CTAB

Figure 3: Comparative Dissolution Profiles of Opsumit 10 mg Film Tablet and Macitentan 10 mg Film Tablet (Test Product) in phosphate buffer pH 6.8 with 0,1% CTAB

Claims

1. A pharmaceutical composition comprising macitentan or pharmaceutically acceptable salts thereof, a disintegrant, a binder and optionally one or more pharmaceutically acceptable excipient, wherein the weight ratio of the binder to the disintegrant is from 0,55 to 0,72.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the binder to the disintegrant is from 0,58 to 0,70, preferably from 0.60 to 0.65.

3. The pharmaceutical composition according to any proceeding claims, wherein the disintegrant is selected from crospovidone, sodium starch glycolate, croscarmellose sodium or mixtures thereof.

4. The pharmaceutical composition according to any proceeding claims, wherein the binder comprises povidone, hydroxypropyly methylcellulose (HPMC), hydroxypropylcellulose (HPC) or mixtures thereof.

5. The pharmaceutical composition according to any proceeding claims, wherein one or more pharmaceutically acceptable excipient is selected from filler, surfactant and lubricant.

6. The pharmaceutical composition according to any proceeding claims, wherein the composition is an oral solid dosage form, preferably a tablet.

7. The pharmaceutical composition according to claim 6, wherein the composition is a film coated tablet.