WO2019004985A2

WO2019004985A2 - Dividable tablet forms of deferasirox

Info

Publication number: WO2019004985A2
Application number: PCT/TR2018/050241
Authority: WO
Inventors: Umit Cifter; Urun Kandemirer; Gulnur YAZICI
Original assignee: Biofarma Ilac Sanayi Ve Ticaret A. S.
Priority date: 2017-05-29
Filing date: 2018-05-17
Publication date: 2019-01-03
Also published as: TR201707764A2; WO2019004985A3

Abstract

The present invention is related to dividable tablet forms of deferasirox or a pharmaceutically acceptable salt thereof for being used in treatment of situations occurred in consequence of excessive iron accumulation in body.

Description

DIVIDABLE TABLET FORMS OF DEFERASIROX

Technical Field

The present invention is related to dividable scored tablet forms of deferasirox or a pharmaceutically acceptable salt of deferasirox.

Prior Art

Deferasirox, is the first of a new group iron chelatagents in the form of tridentate, which is used by oral route in treatment of chronic iron overload and which is named with 4-[3,5- Bis(2-hydroxyphenyl)-lH-l,2,4-triazole-l-yl]benzoic acid chemical formula; and characterized by the formula- 1 indicated below.

Formula-1

Deferasirox is disclosed firstly in the patent application having the number of US6465504.

Deferasirox is the first medicine approved for iron overload treatment which is an approved molecule in 2005 by FDA (Food and Drug Administration).

While iron is an important factor for formation of new red blood cells, excessive of iron causes accumulation of iron in several tissues and causes several health problems. There is a lot of reason which can result in iron overload in body. We can exemplify these like genetic reasons, iron overload, inflammations in body. We can exemplify one of the reasons of excessive iron accumulation also as hereditary hemochromatosis. It is known that this disease results from a mutation in gene which regulates iron absorption amount of the body. If there is hereditary anemia disease in patient, high iron problem may occur due to the treatment. When anemia occurs in case of the body cannot produce enough amount of blood cell, body starts to absorb high amount of iron and the problem of iron overload occurs. Once again, the cases like sideroblastic anaemia, thalassaemia major and absence of pyruvate kinase, also stand in the several diseases that can cause iron load. Excessive iron absorbance occurs when the body absorbs iron more than its requirement while it works to compensate the deficiency of red blood cells. Consuming iron pills that are sold in pharmacies unconsciously also causes iron accumulation and therefore may lead to iron excess.

Furthermore, iron overload is a serious complication that frequent blood transfusion causes in patients having an anemia who are dependent to blood transfusion, like beta thalassemia, sickle cell disease, other rarely seen anemias and myeloproliferative diseases. Intaking of blood via blood transfusion may also cause accumulation of iron in body. Even though, blood transfusion is lifesaving via providing erythrocyte to whom it requires, it is very rich by means of iron. In persons who frequently have blood transfusion, the body has difficulties to absorb excess of iron received and this may result in excessive accumulation of iron.

Because of these situations, deferasirox is indicated in treatment of chronical iron loading ( transfusional hemosiderosis) due to blood transfusion in children aged 2 and above and in grown-ups, also is indicated in treatment of chronical iron loading in patients aged 10 and above who have thalassaemia symptoms not dependent on transfusion.

Deferasirox, is a molecule which is known as an alternative of deferoxamine which is a standard treatment option that is used via parenteral route in treatment of iron overload. It is found out that, chelation treatment is effective for removing iron quickly, reducing iron stores to a low level, inhibiting heart and other organ damage that results from iron overload and effective for prolonging survival in patients who have chronical iron poisoning. Deferasirox has been prepared in tablet form which is taken once a day. It is considered that it is a molecule which is more suitable for long term use and thereby enhances to manage chronical iron poisoning. In addition to this, it may enhance significantly the life quality of patients who have to get iron chelation treatment during all their lifetimes. In the European Patent numbered EP0914118B1, deferasirox is being described wherein the usage of it is disclosed for treatment of diseases that causes iron overload. In this document, a tablet comprising 200 mg of active agent, a coated tablet comprising 400 mg of active agent, hard gelatin capsules comprising 500 mg of active agent, oral suspension powder comprising 300 mg of active agent is disclosed. However, a dividable scored tablet form of deferasirox is not disclosed in said document.

In the patent numbered EP1556013B1, a dispersible tablet comprising deferasirox or pharmaceutically acceptable salt thereof is disclosed. In said document, it is described that, the tablet comprises deferasirox or pharmaceutically acceptable salt thereof in an amount of from 5 to 40% in weight by weight of the total tablet. Also, it is described that the tablet comprises at least one disintegrant in a changing amount from 10% to 35% in weight based on the total weight of the tablet. In the document, dispersible tablet forms of 125 mg, 250 mg and 500 mg are disclosed. However, a dividable scored tablet form of deferasirox is not disclosed in the document.

The European patent application numbered EP1734924 is pertains to a formulation comprising deferasirox or pharmaceutically acceptable salt thereof in an amount of from 42% to 65% in weight by weight of the total tablet. It is mentioned that 125 mg and 1000 mg deferasirox dispersible tablet in the document.

The European patent application numbered EPl 940360 is pertains to a dispersible tablet form wherein deferasirox or a pharmaceutically acceptable salt thereof in an amount of from 42% to 65% in weight by weight of the total tablet. In this document a dispersible tablet, having a total weight of 2000 mg ± 5%, comprising deferasirox in an amount of 1000 mg ± 5%, is disclosed. Moreover, a dispersible tablet comprising 800 mg deferasirox, is disclosed. The European patent application numbered EP2964202 is related to an orally administerable pharmaceutical form which does not comprise sodium lauryl phosphate and lactose wherein it comprises the following: deferasirox or a pharmaceutically acceptable salt thereof, present in an amount of from 45% to 60% by weight based on the total weight of the tablet, said medicine having a reduced release under gastric conditions and fast release at near neutral pH or at neutral pH and comprises deferasirox and at least one pharmaceutically acceptable excipient wherein deferasirox is present in an amount of from 45% to 60% by weight based on the total weight of the tablet. In the document a medicine comprising deferasirox in a free acid form with an amount of 50 mg to 600 mg is described.

The European patent application numbered EP3124018A1 is a divisional application of the cited patent above, wherein deferasirox is present in an amount of from 45% to 60% by weight based on the total weight of the tablet; tablets comprise 90 mg, 180 mg or 360 mg deferasirox and excipients in various ratios.

The dose of the deferasirox to be administered to the patient is dependent on several factors like patient's age, weight, the level of iron accumulation , interaction with the other used drugs if any. The doses to be administered (as mg/kg) are calculated via checking the clinical monitoring indications and applied by adapting them to the closest tablet dose. Recommended initial dose in treatment is 20 mg/kg; it is 30 mg/kg in the grownups who gets erytrocyte transfusion and whose iron load is aimed to be reduced, and 10 mg/kg in the grownups who gets erytrocyte suspension and whose iron load is aimed to be continued at the same level. It is required to watch the levels of serum ferritine monthly and according to the results of this follow up, drug dosage must be adjusted in every 3-6 months if needed. Under these situations if the patient is required to get a higher or lower dose of drug than same level dose which he uses continuously, when he wants to get a different dose, he must buy the tablet comprising a different dose. The applicable suitable dose of deferasirox is from 90 to 360 mg, in particular 90 mg, 180 mg, 360 mg in unit dosage for film coated tablets, and it is from 100 to 400 mg, in particular 100 mg, 200 mg, 400 mg in unit dosage for granule formulation. Presently in the market, there is dispersible tablet formulations known as the trade name Exjade, comprising deferasirox active agent, in 3 different doses as 125 mg, 250 mg and 500 mg, for meeting the requirement of flexible dose, wherein it is known that, each of these are commercialized in separate commercial dose forms in America, Europe and other several countries. In the market, such drug, together with the present doses of it and other drugs comprising deferasirox present in the prior art are substantially expensive. Besides that, when the present drug dose alternatives checked, there is no option in the market for using the individual's required dose in a single package. For example, if a 500 mg drug is prescripted by the doctor, according to the healing condition of the patient, the dose of the drug may desired to reduce by the doctor. Similarly, the doctor may not know the side effects of the pharmaceutical product on the patient. Therefore, he may prescribe the drug having the lowest dose initially. In addition, after a specific treatment period, the doctor may desire to increase this dose. This also causes difficulties in writing prescriptions. In the state of the art, there is no pharmaceutical product comprising deferasirox, having different amount of doses in a single tablet which an individual may use a suitable dose in a single package. Moreover, when a patient takes the recommended dose of the doctor and starts treatment, in the case of a need of dose adjustment, he has to reach the doctor again and make the prescription in another dose form drug written. On the reason that, this situation is tiring for the patient, he may not want to go to the doctor again. And this also causes, failure of treatment and decrease of patient comport. Therefore, for this product comprising deferasirox active agent, the need of improving a pharmaceutical product occurred in a single tablet at least one dose, preferably three doses.

In the state of the art, commercial dose forms as three different dosages of 90 mg, 180 mg and 360 mg is present which Novartis commercialized under the name of Jadenu. Similarly again under the brand of Exjade, Novartis has different commercial dose forms for 3 different doses as 125 mg, 250 mg and 500 mg. However, there is no scored pharmaceutical product which provides three different dosages on the same tablet. Whereas, due to the physiologic structure of the patient, the used forms vary. Brief Description of the Invention

For this purpose, the present invention of scored product may be divided at least into two. The number of dose is preferably three for a pharmaceutical product (tablet or dispersible tablet). According to the pharmaceutical form, these doses are 125 mg, 250 mg, 500 mg for dispersible tablet or 90 mg, 180 mg, 360 mg for tablet. Therefore, with the invention, the user is able to supply a pharmaceutical product in which he can get the dose that he wants that of the different one which the doctor recommended without purchasing another commercial dose form of deferasirox. Thereby, with the scored pharmaceutical product of present invention, also patient comfort is going to increase.

Detailed Description of the Invention:

Description of the Figures

Figure 1: Schematic top view of pharmaceutical product subject to the invention.

Figure 2: Schematic side view of pharmaceutical product subject to the invention.

Description of the References in the Figures:

The parts in the figures are numbered individually and the equivalents of these numbers are given below for understanding of the invention.

1- Product

10- Unit Dose

11- Score

The present invention, is related to a dividable scored pharmaceutical product (1), comprising deferasirox or a pharmaceutically acceptable salt of deferasirox which is known as 4-[3,5-Bis(2- hydroxyphenyl )-lH-l,2,4-triazole-l-yl]benzoic acid chemical name for treatment of the situations occurred via excessive accumulation of iron in the body.

The pharmaceutical product (1) subject to the invention comprises, at least one dividable unit dose (10) and at least one score (11) that provides divisibility. In the preferred embodiment of the invention, pharmaceutical product (1) is in the form of Figure- 1 and preferably comprises 4 pieces of unit dose (10) but not limited to this. A unit dose (10) comprises deferasirox or a pharmaceutically acceptable salt of deferasirox. Said score (11) is preferably in the form of "+" but not limited to this and when the patient applies force on the product (1), the product (1) can be broken easily from the score (11). In an embodiment of the invention, the product (1) can be divided into two, from the score (11). In said embodiment, the product (1) which remains in two-unit dose (10) after dividing into two, and when a force again applied to one of this two-unit doses (10), the remained part can also be divided into two and totally it can be divided in four equal unit doses (10). In other words, when a patient applies a force on the product (1), the product (1) can be divided from the score (11) easily. Therefore, different unit doses (10) can be provided from one product (1). Thereby, dose flexibility can be provided with the invention. Said unit dose (10) comprises minimum 90 mg deferasirox or a pharmaceutically acceptable salt thereof. In the present invention of pharmaceutical product (1), active agent is deferasirox or a pharmaceutically acceptable salt thereof.

Every dividable dose (10) has an equivalent dose amount to each other whereby in one embodiment, the amount of deferasirox or a pharmaceutically acceptable salt thereof in every unit dose (10) is minimum 90 mg. Pharmaceutical product (1) may be in a large variety of tablet forms. In the preferred embodiment of the invention, pharmaceutical product (1) is in the form of a dispersible tablet or a tablet form but not limited to these.

In one embodiment, when the amount of deferasirox or a pharmaceutically acceptable salt thereof in each unit dose (10) is 90 mg, the total amount of deferasirox or a pharmaceutically acceptable salt thereof in the pharmaceutical product (1) is 360 mg. In another embodiment, when the amount of deferasirox or a pharmaceutically acceptable salt thereof in each unit dose (10) is 125 mg, the total amount of deferasirox or a pharmaceutically acceptable salt thereof in the pharmaceutical product (1) is 500 mg. On the reason that pharmaceutical product (1) has a dividable scored (11) form, the doctor can manage the dose according to the need of patient easily at the initial and continuation of the treatment. In this case, a patient who uses a dose form of 360 mg, can take the dose recommended by the doctor from the same package, without purchasing a commercial dose comprising another dose form. The user, can achieve 90 mg of active agent dose via dividing the pharmaceutical product (1) into four unit dose (10) and 180 mg of active agent dose via dividing it into two. Similarly, when the doctor started the treatment from a high dose, if he requires to decrease the drug load, he can recommend decreasing the dose over the same package. In this case, the user started from a high dose (for example 500 mg) can achieve to a low dose (for example 125 mg) via dividing the pharmaceutical product (1) from its score (11). Therefore, when the doctor desires to change the dose, the economical lost resulted from disposing the pharmaceutical product (1) of which the user didn't take, is minimized. The most important factor that provides divisibility of the product (1) in a unit dose (10) is the score (11). Another physical factor that provides the divisibility of the scored product (1) in a unit dose (10) is hardness. In order to take the desired amount of dose from said pharmaceutical product (1), in order to divide to product (1) into desired unit dose (10), the pharmaceutical product (1) is compressed with the predetermined pressure force (for instance in the hardness of 7-8 kp). Therefore, the product (1) can be divided easily by the user via applying pressure to the score (11).

On the other hand, the amount of active agent of the dose in a unit dose (10), which is obtained by dividing the pharmaceutical product (1) thanks to the score (11), is stable. In other words, if the active agent in every unit dose (10) is 125 mg, active agent obtained in every unit dose (10) is 125 mg when the product (1) is divided. Namely, the active agent taken, compensates the desired, required dose amount. In Table- 1, average weight of 30 tablets for each is indicated, of which are randomly selected for obtaining divisibility test results. Table-1

Furthermore, in Graphic-1, dissolution rate profile of pharmaceutical product (1) and dividable doses thereof, comprising deferasirox having 500 mg dispersible tablet weight, is indicated. As to be understood from Graphic-1, the dissolution rate profiles of the dose in unit doses (10) which are obtained via division of pharmaceutical product (1) with the help of the score (11), are similar.

Gra hic -1

The invention is not limited with the disclosed embodiments above, a skilled person in the art can produce different embodiments of the invention easily. They should be evaluated within the scope of the invention protection demanded with claims.

Claims

1. This invention is related to a dividable pharmaceutical product (1) of deferasirox or any pharmaceutically acceptable salt thereof, characterized in that, it comprises at least one-unit dose (10) and at least one score (11) which provides divisibility.

2. The dividable pharmaceutical product (1) according to claim 1, characterized in that, it can be divided at least into two.

3. The dividable pharmaceutical product (1) according to claim 1, characterized in that, it can be divided into four.

4. The dividable pharmaceutical product (1) according to claim 1, characterized in that, a unit dose (10) comprises minimum 90 mg deferasirox or any pharmaceutically acceptable salt thereof.

5. The dividable pharmaceutical product (1) according to claim 4, characterized in that, it is in form of a dispersible tablet.

6. The dividable pharmaceutical product (1) according to claim 4, characterized in that, it is in form of a tablet.

7. The dividable pharmaceutical product (1) according to claim 5 or 6, characterized in that it comprises 500 mg deferasirox or any pharmaceutically acceptable salt thereof.

8. The dividable pharmaceutical product (1) according to claim 5 or 6, characterized in that it comprises 360 mg deferasirox or any pharmaceutically acceptable salt thereof.

9. The dividable pharmaceutical product (1) according to any of the preceding claims, wherein the score (11) is in a form of "+".