Processing

Please wait...

Settings

Settings

Goto Application

1. WO2021112795 - ORAL DOSAGE FORMS CONTAINING INDOMETHACIN

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

ORAL DOSAGE FORMS CONTAINING INDOMETHACIN

Technical Field

The invention relates to an oral dosage form containing indomethacin which provides effective treatment of pain, fever or inflammation while minimizing side effects.

The invention relates in particular to an oral dosage form containing indomethacin, polyvinyl alcohol (PVA) and enteric coating, and in presence thereof an oral dosage form comprising a copolymer and manufacturing methods thereof.

Prior Art

Indomethacin, which is also known by its chemical name as 1 - (p - chlorobenzoyl) - 5 - methoxy - 2 - methyl - indol - 3 - acetic acid) is a non-steroid analgesic / anti inflammatory drug (NSAID), and possesses similar action mechanism compared to other drugs in this group. Indomethacin is the inhibitor of non-selective cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) composed of enzymes involving in the synthesis of prostaglandin from arachidonic acid. Prostaglandins are hormone - like molecules that are normally present in the body and having a variety of actions some of which cause pain, fever and inflammation. Indomethacin reduces pain, fever and inflammation by inhibiting the synthesis of prostaglandins. Indomethacin almost does not dissolve in water. Therefore, it is classified as Class II drug having poor solubility and high permeability. Following oral administration, it is almost absorbed from the Gl system and it reaches its maximum peak concentration (Cmax) in plasma within 2 hours. Its half - life in the plasma is about 2.5 hours. In addition to the fact that it is not a simple analgesic, it is being used in the treatment of serious cases such as acute gout, bursitis, tendinitis and traumatic synovitis, and severe rheumatoid diseases such as ankylosing spondylitis, osteoarthritis, rheumatoid arthritis. Indomethacin is a drug about 20 times more active than Aspirin. It is known to be much more effective than aspirin when tolerated.

Indomethacin shows anti-inflammatory effect by stopping the synthesis of prostaglandins (PG) via inhibiting both cyclooxygenase - 1 (COX-1) and also cyclooxygenase - 2 (COX-2) enzymes. Reduction of PG (in particular, PGE2) synthesis leads to gastric mucosa being unprotected, and as a result of this, to Gl pathway damage. Gastric acid starts forming damages on mucosal membranes as a result of reducing PG; it causes mucosal bleeding (hemorrhagia), ulcer formations and even serious side effects resulting in even puncture of stomach mucosa. It has been reported that these serious side effects have been experienced in particular between from 30 % to 50 % in those patients who have used Indomethacin in therapeutic doses.

The low solubility of Indomethacin in water enables it to be absorbed in non -ionized state. Due to it having a short half - life requires frequent drug administration in order to achieve steady state in plasma by providing the therapeutic effect. As a result of frequent drug administration, in addition to several side effects (cardiovascular, renal, etc.) particularly Gl system damages form. In particular, it causes serious gastric ulcer in a certain percentage of patients who use it frequently. The usage of Indomethacin which is a rather active anti -inflammatory drug is restricted because of the side effects it forms especially in the Gl system.

In the current world market of drugs, presently capsule and suspension formulations are available aimed at oral usage containing Indomethacin. Oral suspension form is in the form of 25 mg / 5 ml_. As capsules, 25 mg and 50 mg hard gelatin capsules and extended release capsules containing 75 mg Indomethacin are available. These drugs are within capsules that dissolve in the stomach, and their design in a manner to prevent side effects that they will form in the stomach has not been done. It has been reported that serious side effects have been observed in the stomachs of patients in the treatment with the existing drugs.

In the European Patent application number EP3247327 B1 , drug delivery system containing Indomethacin is disclosed.

In the American Patent application number US4525345 A, a constant release tablet containing Indomethacin is disclosed. Said tablet comprises 5.0 % by weight a tablet disintegrant and from 40 % to 80 % by weight a pharmaceutically acceptable filling agent.

Indomethacin, which is one of the most powerful non - steroid anti - inflammatory drugs (NSAID), is effectively being used in oral treatment. However, its use is generally limited to irritation of Gl mucosa and its ulceration. Due to its short half -life in the plasma, it is required to be administered frequently. Because of these problems, studies aimed at developing an effective pharmaceutical design for the use of Indomethacin are required. Said side effect problems have been minimized with the present application.

Consequently, due to the above mentioned discrepancies and because of the inadequacy of existing solutions on the issue have made it necessary to develop an improvement in the related technical field.

Brief Description of the Invention

The present invention relates to oral dosage forms comprising Indomethacin which meet the above mentioned requirements as much as possible, which reduce and / or eliminate all disadvantages and which provide some additional advantages.

The prioritized object of the invention is to minimize side effects encountered in oral dosage forms containing Indomethacin and indicated above in detail.

Another object of the invention is to provide an oral dosage form comprising Indomethacin that provides treatment of pain, fever or inflammation effectively while minimizing side effects at the same time.

The invention aims at effectively treating pain, fever or inflammation by means of an oral dosage form which containing Indomethacin, and while doing this, minimizing the side effects that are frequently encountered in prior art.

In order to achieve the above mentioned objects, the invention includes an oral dosage form containing Indomethacin, polyvinyl alcohol and enteric coating; an oral dosage form containing Indomethacin, a carrier co-polymer, polyvinyl alcohol and enteric coating; and the preparation of these forms by nanoprecipitation technique.

Structural and characteristic features all advantages of the invention will be understood more clearly by means of the detailed description given below and therefore it should be appreciated by considering this detailed description.

Detailed Description of the Invention

In this detailed description an oral dosage form comprising Indomethacin of invention is described aimed at only better understanding of the subject and without forming any limiting effect.

The invention describes an oral dosage form containing Indomethacin.

According to an embodiment of the invention, an oral dosage form containing Indomethacin is provided, wherein it comprises polyvinyl alcohol (PVA) and enteric coating.

According to an embodiment of the invention, the oral dosage form is in the form of controlled release. By means of the controlled release, it is achieved for the active substance of Indomethacin to remain in the plasma at a desired level for a certain period of time, which active substance has a short half - life in the plasma and therefore requiring frequent administration.

According to an embodiment of the invention, the controlled release is being provided by the enteric coating. The enteric coating used here comprises one of the group indicated as methacrylic acid - ethyl acrylate copolymer (1 : 1) (Kollicoat ® MAE 100 P), poly(methaclic acid - co - ethyl acrylate) (1 : 1) (Eudragit ® L100 - 55), hydoxypropyl cellulose - acetate succinate, hydroxypropyl cellulose or mixtures thereof.

According to an embodiment of the invention, enteric coating is methacrylic acid -ethyl acrylate copolymer (1 : 1) (Kollicoat ® MAE 100 P).

According to an embodiment of the invention, an oral dosage form containing Indomethacin comprises also at least one drug carrying copolymer.

According to an embodiment of the invention, drug carrying copolymers can be selected from the group of synthetic, natural or semi synthetic polymers. These polymers are being selected as being one of the groups indicated as poly - lactic acid - co - glycolic acid (PLGA), polylactic acid (PLA), polycaprolactone (PCL) or mixtures thereof.

According to an embodiment of the invention, PLGA has been selected as the polymer. PLGA is a synthetic biocompatible polymer. This polymer has been selected because it enables maintaining the action of Indomethacin for a long time.

According to an embodiment of the invention, an oral dosage form comprising Indomethacin is being achieved by the nanoprecipitation technique.

In the nanoprecipitation technique, organic solvents which can be mixed with water can be used. These can be selected from a group of acetone, acetonitrile, ethanol, 1 - propanol, 2 - propanol, 1 ,4 - dioxane, methanol or mixtures thereof. Preferably, in this invention, acetone or acetonitrile has been used.

According to an embodiment of the invention, an oral dosage form comprising Indomethacin includes the following process steps;

- Dissolving Indomethacin in organic solvent,

Addition of this solution into aqueous polyvinyl alcohol solution and stirring it,

Rotavapor application to remove the organic solvent and obtaining nanosuspension,

Sonication of these nanosuspensions

Then, addition of these nanosuspensions into enteric coating solution which has been prepared in absolute ethanol,

Rotavapor application to remove ethanol and obtaining concentrated nanosuspension,

Sonication of these concentrated nanosuspensions,

Then, performing centrifuging process,

Re - suspending precipitated nanosuspension particles by addition of ultra - pure water,

Drying process.

According to an embodiment of the invention, an oral dosage form comprising Indomethacin includes the following process steps;

Dissolving Indomethacin and poly - lactic acid - co - glycolic acid (PLGA) in organic solvent,

- Addition of this solution into aqueous polyvinyl alcohol solution and stirring,

Rotavapor application to remove organic solvent and obtaining nanosuspension,

Sonication of these concentrated nanosuspensions,

Then, addition of these nanosuspensions into enteric coating solution which has been prepared in absolute ethanol,

Rotavapor application to remove ethanol and obtaining concentrated nanosuspension,

Sonication of these concentrated nanosuspensions,

Then, performing centrifuging process,

- Re - suspending precipitated nanosuspension particles by addition of ultra - pure water,

Drying process.

Rotavapor application is a process performed via vacuum and in this manner organic solvents have been removed from the medium.

By means of sonication process, obtaining homogenous mixture has been aimed.

By means of centrifuging process, excess polyvinyl alcohol has been removed from the medium.

Drying process is being performed with the lyophilization or spray drying technique.

Example 1 : Enteric coated PLGA nanoparticle formulation comprising

Indomethacin


In the preparation of the nanoparticles present in the formulation of Example 1 “Nanoprecipitation” method has been used. 25 mg of PLGA and 5 mg of Indomethacin have been dissolved in 2.5 mL of acetonitrile by stirring for 30 minutes at 750 rpm in a multi - point magnetic stirrer. This prepared organic phase has been added dropwise at a constant rate to a 2.5 mL aqueous PVA (0.1 %, w / v) solution which is being stirred in a multi - point magnetic stirrer at a speed of 1000 rpm for 5 minutes by the aid of a 5 cc injector (22G). After dropping process, stirring has been continued for 10 minutes. Then, in order to remove the organic solvent from the medium via vacuum, rotavapor set at 60 rpm speed and 40 °C temperature has been used for 5 minutes. The obtained nanoparticle suspension has been added dropwise over the 2 % (w / v) Kollicoat® MAE 100P solution which has been prepared in 2.5 mL absolute ethanol with a multi - point magnetic stirrer at a speed of 1000 rpm. Dropping process has been achieved for a period of 5 minutes (min) and with the aid of 5 cc injector (22G). Then, in order to remove the organic solvent from the medium, rotavapor set at 60 rpm speed and 40 °C temperature has been used for 5 minutes. The obtained red colored suspension has been held in ultrasonic bath for 2 minutes from the point of view of the coating to be homogenous. Then, for a period of 30 minutes, nanoparticles which had been centrifuged at 10000 rpm (10.304xg) have been precipitated, excess PVA and uncoated Kollicoat® MAE 100P residues have been removed. The precipitated nanoparticles have been suspended by the addition of ultra - pure water. Freezing at - 20 °C and subsequently lyophilization for 24 hours or spray drying technique are performed (they are preferably lyophilization). At the end of the time period, nanoparticle systems as dry powder have been obtained.

Example 2 : Nanosuspension formulation comprising enteric coated

Indomethacin


In the preparation of the nanoparticles present in the formulation of Example 2, “Nanoprecipitation” method has been used. 5 mg of Indomethacin have been dissolved in 2.5 ml_ of acetonitrile by stirring for 30 minutes (min) at 750 rpm in a multi - point magnetic stirrer. This prepared organic phase has been added dropwise at a constant rate to a 2.5 ml_ aqueous PVA (0.1 %, w / v) solution which is being stirred in a multi - point magnetic stirrer at a speed of 1000 rpm for 5 minutes (min) by the aid of a 5 cc injector (22G). After dropping process, stirring has been continued for 10 minutes. Dropping has been then left at more at its own state by mixing for a further 5 minutes. From the point of view of obtained nanosuspensions to be homogenous, they have been held in ultrasonic bath for 2 minutes and then the rotavapor which had been set at a speed of 60 rpm and 40 °C temperature has been used for 2 minutes in order to remove the organic solvent from the medium. The obtained nanosuspensions have been subjected to sonication again for 10 minutes in the ultrasonic bath. Indomethacin nanosuspension has been added dropwise over 0.2 % (w / v) Kollicoat® MAE 100P solution which had been prepared in 2.5 ml_ of absolute ethanol by using multi - point magnetic stirrer at a speed of 1000 rpm. Dropping operation has been achieved for a period of 5 minutes (min) and by the aid of 5 cc injector (22G). The obtained nanosuspension has been held in ultrasonic bath for 1 minute from the point of view of the coating to be homogenous. Organic solvent has been removed from the medium by using the rotavapor set at a speed of 60 rpm and temperature of 40 °C for a period of 2 minutes. The concentrated nanosuspensions have been subjected to sonication again for 5 minutes in the ultrasonic bath. These residual enteric coated nanosuspensions have been centrifuged for 30 minutes at 10000 rpm (10.304xg). Thus, nanosuspensions have been precipitated and the residue PVA has been removed. After the supernatant has been removed, the precipitated nanosuspension particles have been re - suspended by the addition of ultra - pure water, frozen at - 20 °C and subsequently lyophilization for 24 hours or spray drying technique has been applied (they are preferably lyophilization). At the end of the time period, nanoparticle systems as dry powder have been obtained.

For the preparation of the formulation, in order to be obtained in dry powder state, at room conditions (ranging from 18 °C to 25 °C) for 0,5 to 1 hour, a period of 24 hours (ranging from - 50 °C to - 80 °C) proves to be sufficient.

According to an embodiment of the invention, nanoparticles obtained in the state of dry powder systems should be used by suspending in pure water at the time of usage.