DESCRIPTION

Technical Field

The present invention is related to an oral tablet formulation comprising Ulipristal Acetate for being used in an emergency contraception after sexual intercourse.

Prior Art

There are several methods for protecting from pregnancy. Nowadays, hormonal protection methods have been denoted as the most reliable and the most preferred protection method. Oral contraceptives are mostly used as a hormonal protection method. Oral contraceptives, shows effect by means of stopping ovulation period temporarily at first, due to the hormones they include. As it is not preferred unnecessary high hormone loading in women not having sexual intercourse regularly, oral contraceptives not having been preferred much for these individuals. On the other hand, methods which have been applied by oral route like oral contraceptives, do not provide protection against sexually transmitted infections. However, the methods applied by oral route like oral contraceptives are preferred because of providing a more effective protection in comparison with the preservatives and other barrier methods. Oral contraceptives are being used daily. The biggest disadvantage of this method is forgetting the intake of the tablets. There may be cases that oral contraceptives may lose the its protective effect in this situation. Besides the use of oral contraceptives that is the most preferred method of protection; there are other pregnancy protection methods like the use of preservatives (condom, sheath), the use of vaginal blocks (diaphragm, spermicide cream, foam, suppository), the use of intrauterine devices (IUD) (spirals), tubal ligation, applying the method of vasectomy (tying of the vas deferens in the men).

In order to prevent unwanted pregnancies, the requirement of emergency protection methods (emergency contraception) have been occured after sexual intercourse, in the situations like; forgetting to take the oral contraceptives, not using any kind of protection method (wrong calculation of the calendar method or being unsuccessful in withdrawal method), breaking of the condom, the wrong usage of women condom, falling off the intrauterine devices partially or totally, wrong placement or early removal or breaking (tearing) of diaphragm or cervical cap, forgetting to take tablets only including progestin, late injection of injectable contraceptives, sexual assault cases. Emergency contraception, is a contraceptive method which is applied to prevent unwanted pregnancies after unprotected sex or even in protected situations due to the reasons cited above. Undesired pregnancies are an important reproductive health problem in terms of individually and socially. For emergency contraception, there are different approaches and the major ones of these are: medicaments like mifepristone, ulipristal acetate and levonorgestrel or intrauterine devices. Nowadays the most widely used contraceptive method is; oral hormonal medicines because of the ease of use. From these, levonorgestrel (LNG) is the most preferred agent. It has been known that progestative agents like levonorgestrel is being used as postcoital emergency contraception after unprotected sex. On the other hand, intrauterine devices have been started to be applied as an emergency contraceptive method on 1976. The most efficient method is the intrauterine devices which comprise copper.

Besides, in recent years ulipristal acetate (UPA) has been found a usage area as a new oral hormonal agent in emergency contraception. Ulipristal acetate is a synthetic selective progesterone receptor modulator (SPRM) and has both an agonistic and antagonistic effect on progesterone receptor. Mechanism of action of it generally is a molecule based on delay or inhibition of ovulation. It is a contraceptive used to prevent pregnancy after a sexual intercourse; after unprotected sex or in the cases in which there is doubts about the applied contraception method. There are other usage areas of Ulipristal Acetate like treatment of several hormonal disorders and uterus fibroids with low doses of it (5-10 mg/day, PO). Further it is known that Ulipristal Acetate is used to reduce the size of a fibroid and used before a planned surgical operation to control the bleeding. Preclinic studies and the first clinical research done with Ulipristal Acetate by HRA Pharma for developing emergency contraception, has proved that it is preventive pregnancy, safe and efficacy when a treatment of Ulipristal Acetate in a single dose of 50 mg applied in 72 hours after sexual intercourse on women who looks for an emergency contraception after an unprotected sex.

Ulipristal Acetate, is a selective progesterone receptor modulator, which is named with the chemical formula of 17a- acetoxy - 11β-[4-Ν, N- dimethylamino-phenyl )-19-norpregna - 4, 9-dien-3, 20-dione and characterised with the formula-1 indicated below:

Formula-1

Ulipristal Acetate has been firstly mentioned in the patents having the numbers US5073548, US4954490 and US5929262.

A pharmaceutical tablet for oral administration is described in the patent documents of EP2365800A2 and EP3103445 that is the divisional of EP2365800A2, which are stated in the prior art. In this document, it is mentioned that the formulation comprises Ulipristal Acetate. In the document, it is mentioned that a diluent, a binding agent, a disintegrant and a lubricant like other excipients are used besides Ulipristal Acetate. The lubricant stated in the document is Magnesium Stearate.

In another document of prior art, having the number EP2365811 (Al); a contraception method which the women can apply throughout 1-2 days for emergency contraception treatment is described. In such document, a progesterone receptor modulator administered preferably with an oral dose is described wherein for emergency contraception, this receptor must be administered in a dose of between 10-150 mg daily. For a low contraception dose, it is mentioned that this receptor is to be administered daily below 10 mg. In the document it is stated that said progesterone receptor modulator is Ulipristal Acetate. In another document of prior art, having the number EP2916871 (Bl), a co-micronisation product which protects from pregnancy is mentioned. Said co-micronisation product comprises an active agent selected from Ulipristal Acetate group, a metabolite thereof or mixtures of same and a pharmaceutically acceptable solid surfactant selected from C8-C20 alkyl sulfate salts and mixtures of same. In the document, it is mentioned that the co- micronisation product comprises pharmaceutically acceptable excipients. It is stated that the excipients are a diluent, a binder, a flow agent, a lubricant, a disintegrant and mixtures thereof. The preferred lubricant of the document is Magnesium Stearate.

Another document of prior art, having the number EP2550288A1 is related administration of ulipristal acetate in treatment of endometriosis and the pain related thereof or of uterus myomas via administration daily with periods of at least 4 months to a vaginal mucosa of a woman who needs it.

All the solid dose pharmaceutical products produced in the state of the art comprises at least one active agent. In order this pharmaceutical product to be easily and comfortably used by patient and to be successful in production, the active agent or agents of the product contains, must be produced with at least one excipient. Excipients in the pharmaceutical products may be, binders, diluents, disintegrants, colouring agents, coaters. A prerequisite of most of the solid dose forms and one of the most important excipients which provides the product functionality is lubricants. The selection of proper lubricant for increasing the patient comfort in the solid dose form of pharmaceutical product is substantially important.

Therefore, Ulipristal Acetate formulation must be improved for increasing activity, clinical benefit, properties and efficiency of the molecule of Ulipristal Acetate which is used for Ulipristal Acetate formulations. For improving Ulipristal Acetate oral tablet formulations, the lubricant is to be used with Ulipristal Acetate must be selected suitably. On the other hand, it is a desired situation that the stability of pharmaceutical products to be high. Pharmaceutical products are exposed to a couple of structural transformations in time when they are exposed to environmental impacts like temperature, moisture, light. To understand these transformations, several stability tests must be done. The aims of the stability tests are; to provide evidence when a change occurs of an active agent or of quality of the product due to several environmental factors like temperature, moist and light in time; to determine active agent retest period or to determine shelf life and to determine recommended storage conditions of the product. The changes in stability may be chemical, physical and microbiological. For the changes of stability to be minimum and for a high quality of the product, it is required to select the excipients to be used in the pharmaceutical product also appropriate.

Brief Description of the Invention The aim of the invention is to carry out a Ulipristal Acetate oral tablet formulation which is known with the chemical formula of "17a- acetoxy- 11β- [4- N , N- dimethylamino- phenyl] -19-norpregna-4,9-dien-3,20-dione", which is easy to use, has a high influence and developed for being used in emergency contraception after sexual intercourse. In the invention, as a result of numerous tries, it is decided that, the lubricants to be used have to be Sodium Stearyl Fumarate and PEG 6000 for increasing influence, clinical benefit, properties and efficiency of the active agent Ulipristal Acetate molecule. Therefore, the flow properties, hardness, disintegration time of the tablet is decreased, and dissolution of the tablet is increased with the said preferred lubricants in the invention. Ulipristal Acetate is a agent which is difficult to dissolve. When it is used with proper and sufficient amount of lubricant, the dissolution in stomach increases. In the invention, in order to increase dissolution of the active agent, Sodium Stearyl Fumarate and PEG 6000 is used together as lubricant. Detailed Description of the Invention:

The pharmaceutical product subject to the invention, comprises Ulipristal Acetate as active agent and at least one excipient for being used in emergency contraception (pregnancy preventive) after sexual intercourse. In the preferred embodiment of the invention, pharmaceutical product comprises 30 mg Ulipristal Acetate in a unit tablet.

The product obtained from pharmaceutical formulation subject to the invention; is in a pharmaceutical product form which a user can quite easily use. Pharmaceutical product, is in a tablet form in the preferred embodiment of the invention.

In the formulation subject to the invention, various excipients are used with the Ulipristal Acetate active agent when preparing the tablet. Diluents and/or binders and/or lubricants and/or disintegrants but are not limited to the referred in here may be counted among the excipients which can be used.

For improving Ulipristal Acetate oral tablet formulations, the excipients and especially lubricant shall be selected suitably which will be used with Ulipristal Acetate. The invention comprises at least one lubricant. In the preferred embodiment of the invention, one of the used lubricants is Sodium Stearyl Fumarate. Said lubricant is in an amount of 9 mg by weight in unit formulation. In the preferred embodiment of the invention, another lubricant used is PEG 6000 (Polyethylene Glycol 6000). Said lubricant is in amount of 6 mg by weight in unit formulation. In the invention, when Sodium Stearyl Fumarate and PEG 6000 is used together as the lubricant, tablet compressing is quite simplified in production phase. Also to increase activity, clinical benefit, properties and efficiency of the active agent Ulipristal Acetate molecule, Sodium Stearyl Fumarate and PEG 6000 is used together in the invention. In addition, when both two lubricants are used together, beside the increase in tablet quality properties like increase in solubility and decrease in disintegration time of the tablet, it has been seen that total impurity values are rather low in the tablet. Likewise, the change in physical (the changes in medicine solubility or transformations causing a difference in the appearance of the product) and chemical (breaking/forming of the covalent bonds, decreasing in the effect) stabilities are in small ratios.

Also, when Sodium Stearyl Fumarate and/or PEG 6000 is preferred as lubricants, it is observed that, there is an increase in a produced tablet of the pharmacotechnical properties (tablet quality and stability) and there is an improvement in dissolution profile of the active agent. Moreover, after various trials, it is found out that sticking problem and friction is minimized in tablet compressing process of the production and flow characteristic of the powder material is increased during the production via selection of said lubricants. In the prior art, the most used lubricant is Magnesium Stearate. However, studies have showed that when Sodium Stearyl Fumarate and/or PEG 6000 is used together as lubricant, the robustness of the tablet increases and the force (ejection force) required to eject back the final tablet is decreased. Therefore, sticking of the tablet to compression device decreases. So, this provides increment in production efficiency. Moreover, it has been understood in studies that, Sodium Stearyl Fumarate and/or PEG 6000 shows an efficient lubricant performance at least as much as Magnesium Stearate. Besides that, when Sodium Stearyl Fumarate and/or PEG 6000 are used together instead of Magnesium Stearate; increase in tablet hardness, better tablet solubility, better API (Active Pharmaceutical Ingredient) compatibility and better API stability are provided. The compatibility of Magnesium Stearate with API is weaker than Sodium Stearyl Fumarate.

Other excipients used in formulation may be mentioned as, Lactose Monohydrate as diluent and/or povidone K30 (or povidone) as binder and/or Croscarmellose Sodium as disintegrant.

Furthermore, formulation comprises Lactose Monohydrate as diluent in amount of 225 mg by weight and/or povidone K30 as binder in amount of 15 mg by weight and/or Croscarmellose Sodium as disintegrant in amount of 15 mg, PEG 6000 as a lubricant in amount of 6 mg and/or 9mg Sodium Stearyl Fumarate as another lubricant. These amount ranges of excipients mentioned in here which are used in the invention are for a tablet unit formulation of 30 mg Ulipristal Acetate.

An example table of the applied formulation of the invention is indicated below. The invention is not limited with such example. The amounts by weight and percentages of the excipients indicated in the example table below, are for a tablet unit formulation of 30 mg Ulipristal Acetate. Total weight of the tablet is 300 mg. Example

30 mg Ulipristal Acetate tablet unit formulation

The statement of (a/a) % indicated in the table above shows the ratio of related material amount to total tablet amount. According to this, the percentage amount of Ulipristal Acetate used in the tablet is 10%. Furthermore, the percentage amount of Lactose Monohydrate is 75%; the percentage amount of Povidone K30 is 5%, the percentage amount of Croscarmellose Sodium is 5%, the percentage amount of Sodium Stearyl Fumarate is 3% and the percentage amount of PEG 6000 is 2%.

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.