EA013262B1 - Oral sold dosage forms containing a low dose of estradiol - Google Patents

Abstract

The present invention relates to oral solid dosage forms containing a very low dose of estradiol. The dosage forms are formulated in a manner so as to avoid degradation of the estradiol and to minimise the content of polyvinylpyrrolidone, while still achieving similar fast dissolution of the estradiol. The dosage forms are useful in preventing or treating a physical condition in a woman caused by insufficient endogenous levels of estradiol.

Description

Field of Invention

The present invention relates to pharmaceutical compositions, in particular to oral solid dosage forms containing a low dose of estradiol. Dosage forms of the present invention allow to obtain good chemical stability of estradiol during storage, while still achieving a high dissolution rate of estradiol in water.

BACKGROUND OF THE INVENTION

Pharmaceutical dosage forms containing steroid hormones of natural or synthetic origin often contain a low dose of these active ingredients. In the present invention, the dose of estradiol is significantly lower than that which has so far been used orally in the treatment of physical conditions associated with insufficient endogenous levels of estrogen in women.

In accordance with I8 5891868 (Sishshshdk s1 a1.), The risk of bone fractures in postmenopausal women was reduced by applying transdermally approximately 20 μg of estradiol or even less than approximately 20 μg of estradiol per day. Transdermal administration results in effective serum levels in the range of 5 to 20 pg / ml, which remain in this range for an extended period of time. Sishshshdk s1 a1. they also suggested using exogenous estrogen by other suitable methods, for example, by oral or parenteral administration, however, the authors further stated that estrogen should be used parenterally or transdermally rather than orally. These first routes of administration are better than oral administration, because oral administration of estrogen can lead to increased levels of sex hormones that bind globulin. Globulin-binding sex hormones can reduce the positive effects of estrogen in postmenopausal patients, especially in patients showing signs of osteoporosis or loss of bone mineral density. Thus, the oral administration of low doses of estrogen, such as estradiol, is considered problematic for the reason indicated Sishshdsd and C1 A1.

Moreover, it is generally considered problematic to use an oral low dose of the active agent in order to ensure constant and low serum levels in an individual over an extended period of time up to 18-24 hours and to achieve this in a reproducible way among a large female population. Especially considered problematic when the use of estrogen, estradiol, which, despite the fact that it is provided in micronized form, shows an extremely low bioavailability. Thus, the bioavailability of micronized estradiol is only approximately 3-5% after daily oral administration of 1-3 mg of estradiol. This low bioavailability is mainly attributed to extensive metabolism in the digestive tract and in the liver. For this reason, it should be expected that oral administration of a lower dose of estradiol leads to even greater loss of estradiol during this extensive metabolism, since the ratio of metabolic enzymes to estradiol is much higher. Therefore, a qualified person will not expect that an appropriate low dose of estradiol, providing constant serum levels in the range of 5-30 pg / ml, could be successfully determined by linear extrapolation of known serum levels obtained from daily oral administration of 1-3 mg of estradiol.

When formulating a solid oral dosage form intended for immediate release of a low dose of a highly hydrophobic active ingredient such as estradiol, a pharmaceutical expert will consider ί) increasing the disintegration of the oral dosage form into smaller fragments; ίί) increasing the release of the active ingredient in the gastric fluid; and ίίί) increasing the dissolution rate of the active ingredient in the gastric fluid so as to prevent the active ingredient from entering the lower gastrointestinal tract before it is absorbed in the upper gastrointestinal tract, which is the site of primary absorption of large molecules.

In order to do this, a specialist qualified in the pharmaceutical field should have chosen as a first option the formulation of a solid dosage form using the micronized material of the active ingredient to provide a large surface area. A large surface area will then allow rapid dissolution.

As his second option, the scientist should choose a solid dosage form using excipients that promote disintegration, in combination with excipients that promote the hydration / dissolution of the active ingredient in water or in gastric fluid. As a rule, a scientist should choose polyvinylpyrrolidone (RUR), which is a filler that shows a solubilizing effect (improves wettability), as well as a binding ability, making this filler the first choice, especially when prescribing oral solid dosage forms of highly hydrophobic drugs. The solubilizing effect of polyvinylpyrrolidone is well described in the literature. For example, it has been shown that polyvinylpyrrolidone improves the solubility and dissolution rate of atenolone (Moped S1 a1. Ιηΐ. I. Ryats., 175, 1998; 177-183) and significantly increases the dissolution of prednisolone, nitrofurantoin and nitrofural from gels,

- 1 013262 containing 1-10% wt./wt., Polyvinylpyrrolidone (Uof1 s1 a1. Ryagta / 1C 35; 1980: 311-312).

XVO 01/52857 describes the production of oral dosage forms containing 1-3 mg of estradiol with polyvinylpyrrolidone 25000.

However, the inventors of the present invention have found that when lower doses of estradiol are used in a tablet composition similar to that described in Example 1 νθ 01/52857, a significant loss of estradiol during storage, i.e. estradiol is no longer chemically stable.

Therefore, it is an object of the present invention to provide stable, oral solid dosage forms containing a low dose of estradiol without the risk of rapidly releasing and dissolving estradiol in the gastric fluid in such a way as to achieve reliable and sufficiently low serum levels of estradiol over an extended period of time of approximately at least at least 18-24 hours after a single use by a woman of the specified dosage form.

In other words, an object of the present invention is to provide oral solid dosage forms that include low dose estradiol and at the same time meet the following requirements:

Immediate release of estradiol in the gastric fluid after oral administration so that estradiol is absorbed in a highly bioavailable manner;

chemically and physically stable, especially with respect to estradiol;

reliable and sufficient absorption of estradiol in such a way as to achieve serum levels of estradiol, which constantly remain in the range from about 5 to 20 pg / ml;

high homogeneity of content;

preferably, the dose of estradiol is lower than previously used in the treatment of postmenopausal women.

The following describes documents of the prior art describing pharmaceutical compositions without polyvinylpyrrolidone containing estrogen in low doses.

νθ 02/47692 describes a vaginal tablet composition containing 10-30 μg of estradiol. The vaginal tablets disclosed in νθ 02/47692 are not suitable for oral use, and one skilled in the art will immediately recognize that estradiol will be slowly released from such vaginal tablet compositions.

νθ 97/12600 (equivalent to I8 6060077) refers to vaginal capsules containing 2.5-15 μg of 17B-estradiol. Again, such vaginal compositions are not suitable for oral use.

I8 6326366 broadly describes oral dosage forms containing a mixture of 0.2 to 5 mg of estrogen such as estradiol and isoflavone. However, in working examples, 0.625 mg of estrogen is used. The oral solid dosage forms of the present invention are preferably free of isoflavone.

ϋδ 3318925 describes pharmaceutical compositions containing 7a-methyl estrone and 7a-methyl estrone 3-methyl ether in an amount of 50 μg.

SUMMARY OF THE INVENTION

The present invention relates to the problems described above. Thus, in a first aspect, the present invention relates to an oral solid dosage form comprising estradiol or a hydrate thereof, a salt or a pharmaceutically acceptable derivative thereof, in an amount therapeutically equivalent to estradiol hemihydrate, in an amount of from 0.01 to 0.5 mg; and at least one pharmaceutically acceptable excipient, provided that when polyvinylpyrrolidone is present, the weight ratio between polyvinylpyrrolidone and estradiol is less than 10: 1.

In another aspect, the present invention relates to an oral solid dosage form in accordance with the invention for use as a medicine.

When an oral solid dosage form according to the invention is administered by a woman orally, the resulting serum levels remain consistently low for an extended period of time and with sufficiently effective levels to prevent bone fragility in women whose endogenous estrogen levels are reduced. Accordingly, in yet another aspect, the present invention relates to the use of an oral solid dosage form according to the invention for the manufacture of a medicament for preventing loss of bone mineral density in postmenopausal women.

In a similar aspect, the present invention relates to the use of an oral solid dosage form in accordance with the invention for the manufacture of a medicament for the treatment of symptoms of insufficient endogenous levels of estradiol in a woman, especially a postmenopausal woman.

In an additional aspect, the present invention relates to a method for the production of an oral solid dosage form of estradiol or its hydrate, salt or pharmaceutically acceptable

- 2 013262 of the hedge in a dose of from 0.01 mg to 0.25 mg, which includes the stages:

a) providing a powdered mixture of estradiol or its hydrate, salt or pharmaceutically acceptable derivative and at least one pharmaceutically acceptable excipient;

b) granulating said powder mixture into granulate by adding a binder, provided that when polyvinylpyrrolidone is used, the weight ratio between polyvinylpyrrolidone and estradiol is less than 10: 1; and optional

c) mixing the obtained granulate with additional pharmaceutically acceptable excipients; and

ά) the conversion of the resulting mixture into a solid dosage unit form.

Other aspects of the present invention will become apparent from the disclosure shown below and from the appended claims.

Brief Description of the Drawings

The drawing shows the average serum levels of estradiol (pg / ml) over a period of time up to 48 hours. The ordinate axis shows the serum concentration of estradiol (in pg / ml), and the abscissa axis shows the time (in hours) after applying a single dose of estradiol. The solid and dashed lines show the serum profile after oral administration of a single dose of 190 and 100 μg estradiol hemihydrate, respectively. The average serum level of endogenous estradiol (baseline) is 3-3.5 pg / ml.

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, a qualified specialist as his first option would offer polyvinylpyrrolidone as a binding agent in the preparation of a solid dosage form, since this filler also increases the wettability of the hydrophobic active ingredient. As is clear from Example 1 of this description, the surface of micronized estradiol chemihydrate is highly hydrophobic because it is practically insoluble in water, which would be expected due to an increase in surface area. Example 1 further shows a significant effect on dissolution by adding polyvinylpyrrolidone to micronized estradiol; micronized estradiol dissolves rapidly, despite the mass ratio between estradiol and polyvinylpyrrolidone.

Quite unexpectedly, the inventors of the present invention found that when using polyvinylpyrrolidone in the manufacture of solid dosage forms containing a low dose of estradiol, unacceptable stability problems occur (see Example 3 in this description). Such solid dosage forms containing higher doses of estradiol, such as 1, 2 or 3 mg, were stable as expected by a qualified professional (see example 4 in this description).

Therefore, a qualified person could, only from the aspect of stability, decide to replace the content of polyvinylpyrrolidone with other suitable pharmaceutically acceptable ingredients. However, acceptable alternatives to polyvinylpyrrolidone do not exist in the pharmaceutical field, i.e., pharmaceutically acceptable excipients with binders as well as solubilizing effects, with the exception of RUR, do not exist. Therefore, taking into account the destructive effect of the RUR, the binding agent can be selected among those classified as so-called binding agents of the second choice. However, a qualified person would refuse to use these less effective binding agents, given that they do not have the same excellent wettability as polyvinylpyrrolidone.

Although a qualified person would expect, the inventors of the present invention have now provided a solid dosage form for quick release containing a low dose of estradiol in which estradiol is chemically stable and shows rapid dissolution in water, without the use of solubilizers and even without the use of superdisintegrants (see examples 2 and 5 in this description).

Moreover, as shown in example 6 in this description, one simple oral administration by a woman of the tablet of the present invention, which contains either 100 or 190 μg of estradiol hemihydrate, results in serum levels of estradiol in the desired range of 5 to 20 pg / ml for a long period of time. The data also show that even a very low dose of estradiol hemihydrate (100 μg) leads to the desired levels, despite the fact that this low dose is expected to be metabolized significantly more extensively than a higher dose of 190 μg.

The present invention is directed to oral solid dosage forms containing, as a therapeutically active ingredient, estradiol or its hydrate, salt or pharmaceutically acceptable derivative, in a very low dose. The dosage form shows the following characteristics: rapid disintegration; quick dissolution as regards the active ingredient; acceptable oral bioavailability; serum values of the active ingredient constantly in the range of 2-30 pg / ml; such as, for example, 5-20 pg / ml: high chemical stability with regard to the active ingredient, and high content of homogeneous material.

- 3 013262

In the present context, the term oral solid dosage forms generally refers to tablets (both swallowing and chewing forms), capsules, granules, granules enclosed in sachets, and pills. Therefore, the solid dosage form of the present invention may be in the form of a tablet, capsule, gelatin capsule, granule, sachet or pill. In a preferred embodiment of the invention, the oral solid dosage form is in the form of a tablet or capsule, in particular in the form of a tablet.

In a contemplated embodiment of the invention, the active ingredient is a pharmaceutically acceptable estradiol derivative. The terms its pharmaceutically acceptable derivative and pharmaceutically acceptable derivative of estradiol refer to esters, such as sulfate esters, estradiol; estradiol salts and estradiol esters such as sodium salts, for example sodium sulfate ester salts; as well as other derivatives known in the art. As a rule, estradiol ester is in the 3rd or 7th position of estradiol. Specific examples of typical estradiol esters include estradiol valerate, estradiol acetate, estradiol propionate, estradiol enanthate, estradiol undecylate, estradiol benzoate, estradiol cypionate, estradiol sulfate, estradiol sulfamate, as well as its salt.

The term estradiol is intended to mean that estradiol may be in the form of 17-a-estradiol or 17-b-estradiol. Preferably, estradiol is in the form of 17-in-estradiol. The term estradiol also includes hydrated forms of estradiol, in particular estradiol hemihydrate.

Estradiol or its hydrate, salt or pharmaceutically acceptable derivative is preferably used in a form that facilitates the homogeneous distribution of estradiol in the composition, for example in a form having an increased surface area. Thus, estradiol is preferably in micronized form or can be dissolved in a solvent such as ethanol and then sprayed onto the surface of the particles of an inert carrier. When estradiol or its hydrate, salt or pharmaceutically acceptable derivative is provided in micronized form, it has the following particle size distribution as determined by laser diffraction: 90% of the particles have a diameter of <20 μm and 50% of the particles have a diameter of <10 μm, preferably < 5 microns. It should be understood that the term micronized also means that the particle size distribution, as determined by laser diffraction, is such that 90% of the particles have a diameter greater than 0.1 μm, preferably 0.2 μm. Particle size determination using laser diffraction can be performed using Butra1ec »NEOO8 (dispersion), driven by a pressure of 1-4 bar.

As shown above, the dosage form of the present invention includes a low dose of estradiol. The term low dose refers to a dose of estradiol in solid dosage form and defines a dose that is lower than the daily dose, which, as far as is known, is effective in the treatment of hot flashes in postmenopausal women, i.e. the dose is lower than 1- 3 mg estradiol. Therefore, in one embodiment of the invention, the term “low dose” refers to an oral solid dosage form that includes estradiol or its hydrate, salt or pharmaceutically acceptable derivative in an amount therapeutically equivalent to estradiol hemihydrate, from 0.01 to 0.5 mg. Preferably, the oral solid dosage form includes estradiol or its hydrate, salt or pharmaceutically acceptable derivative in an amount therapeutically equivalent to estradiol hemihydrate, from 0.05 mg to 0.4 mg, for example in an amount from 0.05 to 0.3 mg, for example amount from 0.05 to 0.25 mg. More preferably, the oral solid dosage form includes estradiol or its hydrate, salt or pharmaceutically acceptable derivative in an amount therapeutically equivalent to estradiol hemihydrate, from 0.1 to 0.2 mg, for example in an amount from 0.15 to 0.2 mg. In particularly preferred embodiments of the invention, the oral solid dosage form comprises estradiol or a hydrate thereof, a salt or a pharmaceutically acceptable derivative thereof in an amount therapeutically equivalent to estradiol hemihydrate, about 0.1 mg, about 0.11 mg, about 0.12 mg, about 0, 13 mg, approximately 0.14 mg, approximately 0.15 mg, approximately 0.16 mg, approximately 0.17 mg, approximately 0.18 mg, approximately 0.19 mg, or approximately 0.20 mg, preferably approximately 0.1 mg approx total 0.15 mg, approximately 0.19 mg and approximately 0.2 mg. The above doses preferably correspond to the daily dose. In a preferred embodiment of the invention, the active ingredient is estradiol chemihydrate. However, in the case of anhydrous estradiol, an estradiol salt or a pharmaceutically acceptable derivative thereof is used; for those skilled in the art, it is common practice to determine pharmacologically / therapeutically equivalent doses of such other forms when an effective dose of estradiol hemihydrate is known. For example, the study of Ttiteg and Seijk provides guidance on how equivalent doses can be determined (see Vuez. -It sits in Eigoreai 1oit1 οί Ogid Me1aOnkt aib Ryattasoktebsk, 24 (1): 47-53, 1999).

- 4 013262

As indicated above, the oral dosage form of the present invention shows an immediate release of the active ingredient. The expressions immediate release, rapid release and quick release are interchangeable terms that refer to the fact that the disintegration time is short, which can further provide a quick dissolution of the active ingredient. The disintegration time should be less than 10 minutes, preferably less than 5 minutes, as determined in accordance with the United States Pharmacopeia (III 81a (C5 Ryagshasoroe1a) (I8P 27; chapter <701>) without using a disc. Preferably, the disintegration time should be less than less than 4 minutes, even more preferably less than 3 or 2 minutes.

Moreover, the oral dosage form shows the rapid dissolution of estradiol or its hydrate, salt or pharmaceutically acceptable derivative in water. The term rapid dissolution is intended to mean that more than 70% of estradiol or its hydrate, salt or pharmaceutically acceptable derivative is dissolved from the dosage form within 30 minutes after the start of the dissolution study. The dissolution study is carried out in accordance with the standard method of the United States Pharmacopoeia (ИРР 27; chapter <711>), using 900 ml of water brought to a temperature of 37 ° C as a dissolution medium, 50 rpm as a rotation speed and a dissolution apparatus equipped with blades. Preferably, more than 80%, for example more than 90%, of estradiol or its hydrate, salt or pharmaceutically acceptable derivative is dissolved from the dosage form within 30 minutes after the start of the dissolution study. Estradiol can be dissolved even faster, provided that more than 70%, more than 80%, more than 85% or more than 90% of estradiol or its hydrate, salt or pharmaceutically acceptable derivative is dissolved within 15 minutes in the assay described above.

When used in this area, the term high chemical stability is believed to mean that at least 95 wt.% Of the original amount of the active ingredient, such as estradiol hemihydrate, is present in the dosage form after storage at 40 ° C. and 75% relative humidity in the dark for 3 months. In a particularly preferred embodiment of the present invention, at least 85 wt.%, Preferably at least 90 wt.%, Most preferably at least 95 wt.% Of the original amount of the active ingredient, such as estradiol hemihydrate, is present in the dosage form after storage at 40 ° C and 75% relative humidity in the dark for 6 months. In a more preferred embodiment of the present invention, at least 85 wt.%, Preferably at least 90 wt.%, Most preferably at least 95 wt.% Of the original amount of the active ingredient, such as estradiol hemihydrate, is present in the dosage form after storage at 40 ° C and 75% relative humidity in the dark for 9 months. In an even more preferred embodiment of the present invention, at least 85 wt.%, Preferably at least 90 wt.%, Most preferably at least 95 wt.% Of the original amount of the active ingredient, such as estradiol hemihydrate, is present in the dosage form after storage at 40 ° C and 75% relative humidity in the dark for 12 months.

The term high homogeneity of the content means that the relative standard deviation, with regard to the content of estradiol or its hydrate, salt or pharmaceutically acceptable derivative in the dosage form of the present invention is less than 6%, preferably less than 3%, for example less than 2%, for example less than one%.

The term bioavailability is understood to mean the amount of estradiol or its hydrate, salt or pharmaceutically acceptable derivative that is absorbed into the circulating blood after oral administration and is often determined relative to the amount present in the circulating blood after intravenous (ί.ν.) use of a similar amount of the same active ingredient. Bioavailability can be defined as the ratio of AIS (oral use) / AIS (ί.ν. use) or the corresponding ratio of T _max , Stax or mean treatment time (MKT).

The present invention has found that oral solid dosage forms that contain a low dose of estradiol or its hydrate, salt or pharmaceutically acceptable derivative require appropriate adjustment and selection of excipients so that they are chemically stable. First, it has been shown that the amount of fillers that have degradability, for example oxidation, is greater than that of polyvinylpyrrolidone or similar to polyvinylpyrrolidone, should be eliminated or minimized in quantities. Accordingly, contemplated embodiments of the present invention include compositions / oral solid dosage forms in which polyvinylpyrrolidone is absent or is present substantially in low amounts. For example, the content of polyvinylpyrrolidone is limited to the extent that the weight ratio between polyvinylpyrrolidone and estradiol or its hydrate, salt or pharmaceutically acceptable derivative is 10: 1 or less. Preferably the weight ratio between polyvinylpyrrolidone and estradiol or its hydrate, salt or pharmaceutically acceptable derivative is less than 7: 1, for example less than 5: 1, for example less than 2: 1. In a particularly preferred embodiment, the dosage form in accordance with the invention does not contain polyvinylpyrrolidone. Formulated differently, the amount of estradiol or its hydrate, salt or pharmaceutical

- 5 013262 a highly acceptable derivative is at least 10% by weight of the amount of polyvinylpyrrolidone, preferably at least 15%, for example at least 25%, for example at least 50%, more preferably at least 75%, for example at least at least 100%, for example at least 200 wt.% the amount of polyvinylpyrrolidone.

The term polyvinylpyrrolidone is understood to mean a synthetic polymer having the empirical formula (ΟΗ-ίΝΘ) ,! and a molecular weight in the range of from 2500 to 3000000 and which mainly consists of linear 1-vinyl-2-pyrrolidone groups. Obviously, other excipients having the same oxidizing power as polyvinylpyrrolidone with respect to estradiol or its hydrate, salt or pharmaceutically acceptable derivative should be excluded or used in limited quantities in the dosage forms of this invention. An example of such another excipient may be crospovidone. When used in an oral solid dosage form, polyvinylpyrrolidone has a number of functions, such as acting as a disintegrant, as an auxiliary to dissolving the agent (solubilizing agent, improving wettability), as a suspending agent and as a tablet binding agent. Polyvinylpyrrolidone is especially used in connection with highly hydrophobic drugs in order to overcome the critical stage of dissolution of the active drug in the gastric fluid before actual dissolution can occur.

It has been found by the present invention that solubilizers, such as polyvinylpyrrolidone, should be replaced by other excipients that do not have the ability to decompose, for example, oxidize, more than polyvinylpyrrolidone, but which at the same time maintain a high dissolution rate of estradiol.

Therefore, in the considered embodiments of the present invention, polyvinylpyrrolidone is replaced with so-called second-choice binding agents.

The term bonding agent, as used herein, is mainly used to describe an agent that can impart binding properties (s) to the powder material (s), thereby binding the primary particles of the powder materials to secondary aggregates. In the manufacture of tablets using a method that involves directly compressing a powdered mixture of the active ingredient into tablets, a binding agent is added to the powder mixture in order to increase cohesion in the tablet during the pressing steps. Accordingly, it was decided to include a bonding agent in the external phase. On the contrary, in the manufacture of dosage forms in which the active ingredient is mixed with excipients into granules, i.e. in which the production process includes a granulation step, a binding agent can be added to the granulation mixture in order to stabilize the obtained granules. Then it was decided that the binding agent should be present in the internal phase. A binding agent can also be added after the completion of the granulation step, which relates to a binding agent in the external phase. Thus, it should be understood that the term internal phase refers to a composition inside the granules and the term external phase refers to a composition outside the granules. In some contemplated embodiments of the present invention, the binding agent is preferably in the internal phase. If you want to have a binder in the external phase, a person skilled in the art knows that the binder can optionally be added as a dry powder to a mixture of powder materials. Another option is to dissolve or suspend the binder in water or any other suitable solvent or mixture of solvents, including aqueous solutions, which are then used as the granulation liquid. Another other option is to add the binder, partly in the form of a dry powder, to the powder mixture and partly in dissolved or suspended form as a granulation liquid.

The term binding agent of the first choice includes a binding agent that acts as a binding agent (in dry as well as in wetted, swollen and dissolved form) and which also has solubilizing properties. Polyvinylpyrrolidone is the only example of such a binding agent.

The term binding agent of the second choice includes binding agents that act as a binding agent, in a dry, moistened, swollen and dissolved form, in the preparation of an oral dosage form. They are characterized by the absence or presence of limited wettability properties. In other words, by contacting an estrogen, such as micronized estradiol, with a medium (such as an aqueous solution) including a second choice binding agent, the contact angle between the medium and estrogen is not effectively reduced or not completely reduced. Moreover, such a binding agent does not increase the dissolution rate of micronized estradiol. Commonly used binders include gum arabic; alginic acid; alkali metal alginate; carbomer; dextrin; calcium hydrogen phosphate; gelatin; glucose guar gum; hydrogenated vegetable oil; magnesium aluminum silicate; spray cured mannitol; Zein; starch such as maize starch, potato starch, rice starch, cassava starch or wheat starch; partially or fully modified or peptides

- 6 013262 cured starch; starch derivatives such as maltodextrin; partially or fully modified or peptized starch; cellulose, such as microcrystalline cellulose; cellulose derivatives such as carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose and methyl cellulose; and mixtures thereof.

The term starch is generally understood to mean a substance having the empirical formula (C ₆ H ₁₀ O ₅ ) _n , where η is 300-1000 and the molecular weight is 50000-160000, and consisting of amylose and amylopectin, both of which are polysaccharides on based on α-glucose units. Starch is obtained from plant materials and is usually in the form of tiny microscopic granules (5-25 microns in diameter), consisting of stratified layers of starch molecules located around the stratification center of starch grain. The starch granule can be round, oval or angular in shape and consists of a radially oriented crystalline aggregate of two anhydrous Ό-glucose polymers: amylose and amylopectin. The first is a polymer with a linear chain of several hundred glucose units connected via α-Ι-4-glycosidic bonds. Amylopectin is a polymer with a branched chain of several thousand glucose units with α-1-b-glycosidic bonds at the branching sites and α-1-4 bonds in linear regions. Individual branches may have from 20 to 30 glucose residues.

In specific embodiments of the invention, starch is selected from starches that have an amylose content in the range of 10 to 40% by weight. Typical examples are maize starch, potato starch, rice starch, cassava starch, and wheat starch.

In one embodiment of the present invention, starch is used as a binding agent in a concentration of 1-5 wt.% Of the tablet core, preferably in the range of 2 to 3 wt.%, For example about 2.5% (w / w). Starch can be used in swollen, suspended or dissolved form in a granulation liquid or in the form of a dry powder. Starch can be used in its unmodified, modified, as well as partially modified form. When used in this description for the purpose of granulating a powdered mixture of estradiol and at least one pharmaceutically acceptable excipient, the starch is preferably in unmodified form. As will be clear from the examples presented in this description, the total amount of starch can, however, be significantly higher than shown above, for example in the range from 5 to 25 wt.% Of the tablet core.

The terms modified starch and peptized starch are interchangeable terms and are understood as starch that has been chemically and / or mechanically processed to crush all or part of the granules in the presence of water and subsequently dried. Some types of peptized starch can be modified to give them improved compressibility and flow characteristics. Typically, peptized starch contains 5% free amylose, 15% free amylopectin and 80% unmodified starch. Peptized starch may be maize starch, which is processed by the chemical and / or mechanical method described above. Other types of starch than maize starch, such as rice or potato starch, can be peptized.

The terms partially modified starch and peptized starch are interchangeable terms and are understood as peptized starch, which is less modified than peptized starch. Pharmaceutical varieties of fully peptized starch do not use additives and are obtained by spraying an aqueous suspension of non-peptized starch onto hot rollers where gelatinization and subsequent drying takes place. Exposure of moistened starch to mechanical pressure results in partially peptized starch.

The term unmodified starch is understood as raw starch, as defined for the term starch above.

The term cellulose derivatives is intended to include cellulose in which part or all of the free hydroxy groups have been replaced by ester and / or ester groups. Thus, the cellulose derivative is cellulose esters and / or cellulose esters. The ester or ester groups can have different carbon chain lengths, for example chains with up to 10 carbon atoms, preferably up to 8, 6, 5 or 4 carbon atoms. Typical examples of cellulose derivatives are sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose. Consider binders are low substituted cellulose derivatives, especially hydroxypropyl methylcellulose and hydroxypropyl cellulose. The term low substituted indicates that not less than 5% and not more than 16% of the hydroxyl groups are replaced by ester and / or ester groups. Derivatives of cellulose can be selected in accordance with their obtained viscosity in a 2% aqueous solution. Typically, cellulose derivatives suitable as binding agents show the range of viscosity obtained in a 2% aqueous solution of 1-20 mPa-s, preferably 2-12 mPa-s, most preferably about 3-6 mPa-s. Cellulose derivative is usually

- 7 013262 used in a concentration of 0.5-5 wt.% The core tablets.

In a contemplated embodiment of the present invention, hydroxypropyl cellulose, such as low substituted hydroxypropyl cellulose, is used in a concentration of 0.5-5 wt.% Of the tablet core, preferably in the range of 1 to 3 wt.%, For example, about 2% (w / w).

In a preferred embodiment of the invention, a binding agent is present in the so-called internal phase of the granular mixture together with the active ingredient and optionally one or more additional pharmaceutically acceptable excipients. Thus, the binding agent can be suspended or dissolved in a suitable granulation liquid, which is then sprayed onto a powder mixture of the active ingredient. When a bonding agent is used to produce a granular substance, the bonding agent is preferably selected from unmodified starch, maltodextrin, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

Thus, it should be understood that the binding agent in some embodiments of the present invention is present only in the internal phase, i.e. internally and / or on the surface of a granular form of the active ingredient. In other embodiments of the invention, the binding agent is present in the external phase, i.e. just outside the granules. In other embodiments of the present invention, the binding agent is present in the internal phase, as well as in the external phase.

Oral solid dosage forms of the present invention are prepared without the addition of superdisintegrants. Not wanting to be limited to a specific theory, the addition of superdisintegrants is not necessary due to the acceptable characteristics of the disintegration of dosage forms in accordance with the invention. Specific examples of super disintegrants include sodium starch glycolate, croscarmellose, and cross-linked polyvinylpyrrolidone. Accordingly, in a preferred embodiment, the dosage form of the present invention does not contain super disintegrants.

The term “disintegrant” is meant to mean an agent providing a disintegration process in which the dosage form breaks up into fragments and particles, exposing a large surface area of the active ingredient of the gastric fluid, and thereby leading to dissolution proceeding more quickly. Typical examples of normal disintegrants are agar-agar; alginic acid; alginates; bentonite; Vitum; cellulose derivatives such as sodium carboxymethyl cellulose; gelatin; pectins; derivatives of polymethacrylic acid starch; unmodified, modified, as well as partially modified starch; polymeric sugar derivatives such as soy polysaccharides; polymer cyclodextrin; and xylan. The disintegrant may be present in the internal or external phase. In the present embodiment of the invention, the disintegrant is starch, such as a mixture of unmodified starch and modified starch.

Provided that the solid dosage form is in tablet form, an additional critical parameter that must be considered in order to ensure rapid disintegration is the tablet hardness. A compressed tablet may show sufficient hardness to withstand physical stress during packaging, transportation and use. On the other hand, hardness should allow the passage of rapid disintegration of the tablet. Thus, in one embodiment of the present invention, a curing agent is added.

In the present context, the term “curing agent” means a filler that is incorporated into a compressed tablet composition to give it increased hardness. Examples of curing agents include calcium carbonate; calcium phosphate and calcium hydrogen phosphate; calcium sulfate; microcrystalline cellulose; powdered cellulose; dextrates; dextrin; sugars such as dextrose, fructose, lactose, mannitol, sorbitol and sucrose; glyceryl palmitostearate; kaolin; magnesium carbonate; magnesium oxide; maltodextrin; potassium chloride, sodium chloride; starch; peptized starch; talcum powder and hydrogenated vegetable oil. In a preferred embodiment, the curing agent is a modified starch.

The tablet hardness is measured as the force in newtons (N) needed to break the tablet. In the present embodiment, a tablet of the present invention has a hardness in the range of 25 to 120 N, preferably in the range of 35 to 90 N, most preferably in the range of 40 to 80 N, which refers to the round core of the tablet of about 80 mg by weight. Those skilled in the art are well aware that determining acceptable hardness ranges depends on the size and shape of the tablets.

Dosage forms of the present invention may contain, in addition, additional active ingredients and / or excipients. Accordingly, in some embodiments, the dosage form further includes one or more hormones, such as progestin. Progestin can be selected from drospirenone, levonorgestrel, norgestrel, gestodene, dienogest, cyproterone acetate, norethisterone, norethisterone acetate, desorgestrel, or 3-ketodesorgestrel. Preferably, such progestins are in micronized form. Preferably, the dosage form of the present invention does not contain isoflavone.

- 8 013262

Examples of additional excipients include fillers (sugars such as lactose, sucrose, dextrose and dextrates; sugar alcohols such as mannitol, sorbitol and xylitol; alkaline earth metal carbonates and phosphates such as calcium carbonate and calcium phosphate; cellulose such as powdered cellulose and microcrystalline cellulose; colloidal silica; titanium dioxide; kaolin; talc) and lubricants (such as magnesium stearate).

The tablet core may be provided with a film coating to facilitate swallowing of the tablet. The film coating may contain film coating agents such as hydroxypropylmethyl cellulose, macrogol (tasgodo1), talc and coloring agents such as titanium dioxide, yellow iron oxide pigment.

As indicated above, the inventors of the present invention have been successful in preparing acceptable oral solid dosage forms without the use of solubilizers. However, the dosage form of the present invention may contain one or more solubilizers, such as naturally occurring phosphatides, for example lecithin or soya lecithin; condensation products of ethylene oxide, for example with a fatty acid, a long chain fatty alcohol, or a partial ester derived from fatty acids and hexite or hexitol anhydride, for example polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, etc .; or salts of long chain aliphatic phosphates, such as sodium lauryl sulfate. However, in a preferred embodiment, the dosage form of the present invention does not contain a solubilizer.

As will be understood, the various embodiments presented herein may be combined. Thus, in a preferred embodiment, the oral solid dosage form of the present invention includes:

ί) estradiol or its hydrate, salt or pharmaceutically acceptable derivative in an amount therapeutically equivalent to estradiol hemihydrate, in an amount of from 0.01 to 0.25 mg;

ίί) a filler in an amount of 50-90 wt.%, for example 55-85 wt.%. The filler may be sugar (usually such as lactose, glucose or sucrose), sugar alcohol (usually such as mannitol), starch (usually such as maize or potato starch), or mixtures thereof;

ίίί) peptized (modified) starch in an amount of 6-18 wt.% and ίν) a binding agent in an amount of 1-5 wt.%, a binding agent, as a rule, is starch, starch derivatives, partially or fully peptized starch, cellulose, cellulose derivatives.

In a particularly preferred embodiment, the oral solid dosage form of the present invention includes:

ί) estradiol or its hydrate, salt or pharmaceutically acceptable derivative in an amount therapeutically equivalent to estradiol hemihydrate, from 0.1 to 0.2 mg. Most preferably, estradiol is in the form of estradiol hemihydrate;

ίί) a filler, preferably lactose monohydrate, in an amount of 50-90 wt.%, for example 55-85 wt.%;

ίίί) starch, preferably maize starch, in an amount of 10-26 wt.%;

ίν) peptized (modified) starch in an amount of 6-18 wt.% and

ν) a binding agent, preferably hydroxypropyl cellulose, in an amount of 1-5 wt.%.

As shown by way of example above, in the present embodiment, the dosage form of the present invention is in granular form.

The phrase granular form indicates that the obtained physical form, when the powder mixture of the active ingredient and one or more excipients is converted into partially agglomerated particles and / or granules, has a particle size larger than the untreated powder mixture. The conversion can occur using any suitable device known to the skilled person, preferably by contacting the powder mixture with the granulation liquid using suitable granulation equipment, such as fluidized bed granulation.

Thus, in an additional aspect, the present invention relates to a method for producing an oral solid dosage form of estradiol or a hydrate, salt or pharmaceutically acceptable derivative thereof in a dose of from 0.01 to 0.25 mg, which comprises the steps of:

a) providing a powdered mixture of estradiol or its hydrate, salt or pharmaceutically acceptable derivative and at least one pharmaceutically acceptable excipient;

b) granulating said powder mixture into granulate by adding a binder, provided that when polyvinylpyrrolidone is used, the weight ratio between polyvinylpyrrolidone and estradiol is less than 10: 1; and optional

c) mixing the obtained granulate with additional pharmaceutically acceptable excipients; and

b) converting the resulting mixture into a solid dosage unit form.

- 9 013262

The term granulation is understood to mean a mechanical process in which a powder containing an active component and excipients partially agglomerates into particles and / or granules having a larger particle size than the raw powder. In one embodiment, the powdered mixture of estradiol and excipients is brought into contact with a granulation liquid, which may contain a binding agent, swollen, partially dissolved or completely dissolved in the granulation liquid. The granulation liquid may be any suitable solvent, but mainly aqueous solutions or only water are suitable. In one embodiment, the powder mixture is contacted with the granulation liquid using suitable wet granulation equipment, such as fluidized bed equipment. In addition, granulation with high shear can be used instead of granulation in a fluidized bed.

In another suitable embodiment of the invention, the granulation liquid does not contain a binding agent. Next, the binding agent is added in dry form to the powder mixture of estradiol simultaneously with the granulation liquid.

All statements made above regarding preferred embodiments, such as preferred dosage forms, preferred binding agents, etc., including preferred concentrations of such excipients, apply mutatis mutandis to the manufacturing aspect of the present invention.

In yet a further aspect, the invention relates to the use of an oral solid dosage form of the invention for the manufacture of a medicament for the treatment or prophylaxis of a woman's physical condition caused by insufficient endogenous levels of estrogen such as estradiol. These conditions include, but are not limited to, osteoporosis, headaches, nausea, depression, flushing, decreased bone mineral density, and an increased risk or incidence of bone fractures, including spinal and / or hip fractures. Preferably, said woman is a postmenopausal woman. Thus, more preferably, the present invention also relates to the use of an oral solid dosage form of the present invention for the manufacture of a medicament for the prevention of loss of bone mineral density in postmenopausal women. Moreover, the present invention also relates to the use of an oral solid dosage form of the present invention for the manufacture of a medicament for the treatment of symptoms of insufficient endogenous levels of estrogen, such as estradiol, in a woman.

Similarly, the present invention also relates to a method for preventing or treating a woman’s physical condition caused by insufficient endogenous levels of estrogen, such as estradiol, said method comprising oral administration of an oral solid dosage form of the invention to a woman who needs it. These conditions include, but are not limited to, osteoporosis, headaches, nausea, depression, flushing, decreased bone mineral density, and an increased risk or incidence of bone fractures, including spinal and / or hip fractures. Preferably, said woman is a postmenopausal woman. Thus, more preferably, the present invention also relates to a method for preventing loss of bone mineral density in postmenopausal women, which includes oral administration of an oral solid dosage form of the present invention to a woman who needs it. Moreover, the present invention also relates to a method for treating the symptoms of insufficient endogenous levels of estrogen, such as estradiol, in a woman, which comprises oral administration of an oral solid dosage form of the present invention to a woman who needs it.

While the present invention has been described mainly with reference to estradiol or its hydrate, salt or pharmaceutically acceptable derivative, a qualified specialist will understand that the principles described in this description can be easily extended to also include other estrogens, especially estrogens that are sensitive to polyvinylpyrrolidone, i.e. which are chemically unstable in the presence of polyvinylpyrrolidone. Accordingly, in another aspect, the present invention relates to an oral solid dosage form which comprises estrogen in an amount therapeutically equivalent to estradiol hemihydrate, in an amount of from 0.01 to 0.5 mg and at least one pharmaceutically acceptable excipient, provided that, when polyvinylpyrrolidone is present, the weight ratio between polyvinylpyrrolidone and estradiol is less than 10: 1.

The term estrogen is intended to include all compounds (natural or synthetic, steroidal or non-steroidal compounds) showing estrogenic activity. Such compounds include natural and synthetic estradiol and its derivatives; conjugated estrogens; specific estrogen receptor agonists and non-steroidal compounds showing estrogenic activity. The following term is intended to include all isomeric and physical forms of estrogen, including hydrates such as hemihydrate; solvates; salts; and complexes, such as complexes with cyclodextrins. Preferably estrogen is sensitive to polyvinylpyrrole

- 10 013262 donu, i.e. estrogen is chemically unstable in the presence of polyvinylpyrrolidone. Such estrogens can be determined by manufacturing dosage forms in the presence and absence of polyvinylpyrrolidone and controlling the chemical stability of estrogen during storage of the dosage form for a period of approximately 3 months in the dark at a temperature of 40 ° C and a relative humidity of 75%.

The term conjugated estrogen is understood to mean natural conjugated estrogens such as estrone and equiline and others obtained from mare's urine. Conjugated estrogens are also synthetically prepared. Examples of synthetically prepared estrogens include estropipate and ethinyl estradiol. Additionally, the term conjugated estrogens refers to esters of such compounds, such as sulfate esters, salts of such compounds, such as sodium salts, and esters of salts of such compounds, such as sodium salts of sulfate ester, as well as other a derivative known in the art. Some specific examples include 17-α and β-dihydroequiline, equilenine, 17-α and β-dihydroequilenine, estrone and their sodium sulfate esters.

Thus, all the statements made above in connection with aspects including estradiol or its hydrate, salt or pharmaceutically acceptable derivative are applied with corresponding changes to the aspect related to estrogen. Thus, whenever the term estradiol or its hydrate, salt or pharmaceutically acceptable derivative is used in the present context, it should be understood that the term may be replaced by the term estrogen.

The invention is further illustrated by the following non-limiting examples.

Examples

Example 1. Ιη νίίτο dissolution of micronized estradiol.

The dissolution characteristics of micronized estradiol and a mixture of micronized estradiol and polyvinylpyrrolidone are respectively investigated in the ίη νίίτο dissolution test system. The test instrument for dissolution is I8P apparatus 2 (paddle system) (see И8Р 27, <711>), using 900 ml of purified water, which is maintained at 37 ° C, as a dissolution medium, and a rotation speed of 50 rpm. Estradiol and mixtures in powder form are placed in flasks for dissolution in an amount corresponding to 100 μg of micronized estradiol hemihydrate.

Table 1

Dissolution Test Results

Powdered composition Amount of estradiol (mcg) dissolved through:

5 minutes 10 minutes 20 minutes 30 min 60 min 100 mcg estradiol <3 * <3 * <3 * <3 * <3 mcg * 100 mcg of estradiol + 100 mcg sixteen 29th 48 56 68 polyvinylpyrrolidone 100 mcg estradiol + 4 mg nineteen 47 65 76 87

polyvinylpyrrolidone ___________________________________________________ * Means that the amount of estradiol is below the limit of quantification (3 μg).

The results show a significant effect of polyvinylpyrrolidone on the dissolution of micronized estradiol.

Example 2. Obtaining oral solid dosage forms with a low dose of estradiol.

Get 80 mg tablet cores having the following composition.

Ingredient Amount (mg)

I estradiol (hemichydrate, micronized) 0.05 0.1 0.19 II lactose monohydrate up to 80 up to 80 up to 80 III maize starch 14.40 14.40 14.40 IV modified starch (maize) 9.60 9.60 9.60 V maize starch 2 2 2 VI magnesium stearate 0.80 0.80 0.80

Maize starch, designated V, may be replaced by another second binding agent, such as 1.6 mg hydroxypropyl cellulose (low substituted)

Oral solid dosage forms are obtained by loading the fluid-bed granulator with ингреди-ΐν ingredients (estradiol, lactose monohydrate, maize starch and modified starch) and activating said fluidized bed. Aqueous solution of ingredient V

- 11 013262 (maize starch) is then sprayed continuously on the fluidized bed, while drying by heating the air flow of the fluidized bed so as to apply 2 mg to the core of the tablet 80 mg. At the end of the process, magnesium stearate is introduced into the granulator and mixed with the granules by maintaining a fluidized bed. Alternatively, magnesium stearate can be added using a blender. The granules obtained are compressed into tablet cores by compression using a tablet press.

Example 3. Stability of dosage forms with a low dose of estradiol.

Three different compositions of tablets A, B and C are examined for the chemical stability of estradiol (hemihydrate form and micronized) for a period of 12 months of storage in the dark at a temperature of 40 ° C and a relative humidity of 75%. During storage, tablets are kept in closed containers.

All tablet compositions (A, B and C) contain nominally 0.05 mg of micronized estradiol chemihydrate at the beginning of the stability study and are provided with a film coating containing hydroxypropyl methylcellulose, macrogol, talc, titanium dioxide and yellow iron oxide pigment. The core of 80 mg tablets have the following composition (+ indicates the presence of this component).

Ingredient Amount (mg) BUT in from I Estradiol (hemihydrate, 0.05 + + + micronized) II lactose monohydrate up to 80 mg + + + III maize starch 14.40 4- 4- + IV modified starch 9.60 4- 4- 4- (maize) V maize starch 2 4- V polyvinylpyrrolidone 4 + V hydroxypropyl cellulose 1,6 4- VI magnesium stearate 0.80 + 4- 4-

The composition of tablet A is identical to the composition shown in example 2 (with 0.05 mg of estradiol and 2 mg of maize starch (V)). The compositions of tablets B and C are identical to those of tablet A, except that 2 mg of maize starch (ingredient V) is replaced with 4 mg of polyvinylpyrrolidone and 1.6 mg of hydroxypropyl cellulose, respectively.

Table 2 The content of intact estradiol after storage at 40 ° C / 75% atmospheric humidity

Months Composition of tablets A Composition of tablets B Composition of tablets C

0 98.5% 101.1% 100.6% one 96.7% 95.1% 96.5% 3 98.1% 92.4% 98.1% b 95.6% 87.7% 97.8% nine 96.3% 86.6% 97.5% 12 95.7% 82.4% 97.7%

The amount of estradiol (%) in the range of 98-102% corresponds to 100%.

The data obtained clearly illustrate that polyvinylpyrrolidone has a destabilizing effect on estradiol.

Example 4. The stability of the tablets with a high content of estradiol and the presence of polyvinylpyrrolidone.

The composition of tablets K is examined for the chemical stability of estradiol (hemihydrate and micronized) for a period of 6 months of storage in the dark at a temperature of 40 ° C and a relative humidity of 75%. During storage, tablets are kept in closed containers.

The composition of tablet K contains nominally 1 mg of micronized estradiol chemihydrate at the beginning of the stability study. The requirement is 0.9-1.050 mg per tablet. The composition of tablet K is identical to the composition of tablet B (4 mg RUR), as described in example 3, except that the composition of tablet K contains 1 mg of micronized estradiol hemihydrate.

It was found that the amount of intact estradiol is 98% after storage for 1, 3 and 6 months, respectively, at 40 ° C and a relative humidity of 75%. These data show that

- 12 013262 estradiol is chemically stable when provided in the composition of the tablet K. It can be assumed that the shelf life of the composition of the tablet K is approximately 4 years.

Example 5. Characteristics of the dissolution of the dosage form with a low dose of estradiol.

The dissolution profile of the composition of tablets A, B, C, and Ό is determined using the ίη νίΐτο dissolution test system using an I8P apparatus 2 (paddle system) (see I8P 27, <711>) using 900 ml of purified water, which is maintained at a temperature of 37 ° C, as a dissolution medium and a rotation speed of 50 rpm

The compositions of tablets A, B and C are as described in example 3, and the composition of tablet Ό is identical to the composition of tablet A with such a modification that the film coating does not contain macrogol.

Table 3

Dissolution Test Results

Tablet Amount of estradiol (mcg) dissolved through:

10 minutes 20 minutes 30 min 45 min 60 min A: maize starch 2 mg 84.1 96.3 99.5 100.5 100.6 B: polyvinylpyrrolidone 4 mg 81.2 97.8 100,2 100,2 99.6 C: hydroxypropyl cellulose 82.1 97.8 100,2 100,2 101.0 1.6 mg A: like A, but without a macrogol in film coating 86.3 98.4 102.5 102.5 102,4

The amount of estradiol (%) in the range of 98-102% corresponds to 100%.

The results in the table. 3 show that all four compositions of tablets A, B, C and Ό show the same dissolution profile in water.

Example 6. Pharmacokinetic endpoints (bioavailability) for tablet compositions with a low dose of estradiol.

A bioavailability study is carried out in order to determine serum levels of estradiol after a single application of a tablet composition identical to that described in Example 2, containing 190 and 100 μg of micronized estradiol chemohydrate, respectively. The research model is an open labeled, 3 periods, 3 treatments, a cross-sectional method with a single application of each treatment and a two-week wash between each period. The population included in the study was 24 healthy postmenopausal women, aged 55-75 years. The condition of abstinence from food is fulfilled.

The figure shows the average serum levels of estradiol (pg / ml) over a period of up to 48 hours

The solid line refers to the average serum levels of estradiol, which is achieved by applying a single dose of 190 μg to the population included in the study, and the dashed line refers to the average serum levels of estradiol, which are achieved by applying a single dose of 100 μg to the population included in the study. The average serum level of endogenous estradiol is 3-3.5 pg / ml.

The results show that oral administration of 100 or 190 μg of micronized estradiol chemihydrate results in average serum levels in the desired range of 5-20 pg / ml over an extended period of time.

Claims (37)

CLAIM 1. Oral solid dosage form, including estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, from 0.01 to 0.5 mg and at least one pharmaceutically acceptable excipient, and this dosage form does not contain polyvinylpyrrolidone or crospovidone, in which said estradiol or its hydrate, salt or pharmaceutically acceptable ester is in micronized form or dissolved in a solvent such as ethanol, and then sprayed onto the surfaces of the inert carrier particles, and at least one pharmaceutically acceptable excipient is a binding agent selected from the group comprising gum arabic; alginic acid; alkali metal alginate; carbomer; dextrin; calcium phosphate; gelatin; glucose; guar gum; hydrogenated vegetable oil; magnesium aluminum silicate; spray cured mannitol; zein; starch; partially or fully modified or peptized starch; starch derivatives, cellulose, cellulose derivatives, and mixtures thereof. 2. The dosage form of claim 1, wherein the pharmaceutically acceptable estradiol ester is selected from the group consisting of estradiol valerate, estradiol acetate, estradiol propionate, estradiol enanthate, estradiol undecylate, estradiol benzoate, estradiol cypionate, estradiol sulfate and - 13 013262 estradiol sulfamate or their salt. 3. A dosage form of claim 1, wherein the estradiol hydrate is an estradiol hemihydrate. 4. Dosage form according to any one of the preceding paragraphs, in which more than 70% of estradiol or its hydrate, salt or pharmaceutically acceptable ester is dissolved from the dosage form within 30 minutes, as determined using I8P 27 (paddle system), using 900 ml water at 37 ° C as the dissolution medium and 50 rpm as the rotation speed. 5. A dosage form according to claim 4, in which more than 80% of estradiol or its hydrate, salt or pharmaceutically acceptable ester is dissolved from the dosage form within 30 minutes. 6. The dosage form of claim 5, wherein more than 90% of estradiol or its hydrate, salt, or pharmaceutically acceptable ester is dissolved from the dosage form within 30 minutes. 7. Dosage form according to any one of the preceding paragraphs, in which more than 70% of estradiol or its hydrate, salt or pharmaceutically acceptable ester is dissolved from the dosage form within 15 minutes, as determined using I8P 27 (paddle system), using 900 ml water at 37 ° C as the dissolution medium and 50 rpm as the rotation speed. 8. The dosage form of claim 7, wherein more than 80% of estradiol or its hydrate, salt or pharmaceutically acceptable ester is dissolved from the dosage form within 15 minutes. 9. A dosage form according to any one of the preceding claims, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, from 0.05 to 0.4 mg. 10. A dosage form according to claim 9, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, from 0.05 to 0.3 mg. 11. A dosage form as defined in claim 10, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, from 0.05 to 0.25 mg. 12. A dosage form as defined in claim 11, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, from 0.1 to 0.2 mg. 13. The dosage form of claim 12, wherein the oral solid dosage form comprises estradiol or a hydrate thereof, a salt or a pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, from 0.15 to 0.2 mg. 14. A dosage form as defined in claim 13, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, about 0.2 mg. 15. The dosage form of claim 13, wherein the oral solid dosage form comprises estradiol or a hydrate thereof, a salt or a pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, about 0.19 mg. 16. A dosage form as defined in claim 13, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, about 0.15 mg. 17. A dosage form as defined in claim 12, wherein the oral solid dosage form comprises estradiol or its hydrate, salt or pharmaceutically acceptable ester, in an amount therapeutically equivalent to estradiol hemihydrate, approximately 0.1 mg. 18. Dosage form according to any one of the preceding paragraphs, in which at least 95 wt.% The initial amount of estradiol or its hydrate, salt or pharmaceutically acceptable ester is present in the dosage form after storage at 40 ° C and 75% relative humidity in the dark in for 3 months. 19. Dosage form according to any one of the preceding paragraphs, in which at least 85 wt.% The initial amount of estradiol or its hydrate, salt or pharmaceutically acceptable ester is present in the dosage form after storage at 40 ° C and 75% relative humidity in the dark in for 12 months. 20. A dosage form according to any one of the preceding claims, wherein the binding agent is selected from the group that includes starch, starch derivatives, partially or fully modified or peptized starch, cellulose, cellulose derivatives, and mixtures thereof. 21. A dosage form as defined in claim 20, wherein the starch is selected from the group comprising maize starch, potato starch, rice starch, cassava starch and wheat starch. 22. A dosage form as defined in claim 21, wherein the starch is maize starch. 23. A dosage form as defined in claim 20, wherein the starch derivative is maltodextrin. 24. Dosage form according to claim 20, in which the cellulose is a microcrystalline cellulose. - 14 013262 25. The dosage form of claim 20, wherein the cellulose derivative is selected from the group that includes carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and methylcellulose. 26. A dosage form of claim 25, wherein the cellulose derivative is hydroxypropylcellulose. 27. Dosage form according to any one of the preceding paragraphs, in which the dosage form does not contain isoflavone. 28. Dosage form according to any one of the preceding paragraphs, in which the dosage form does not contain a solubilizer. 29. Dosage form according to any one of the preceding paragraphs, in which the dosage form does not contain superdisintegrant. 30. A dosage form according to any one of the preceding claims, wherein the dosage form is in the form of a tablet, capsule, gelatin capsule, granule, sachet, or pill. 31. The dosage form of claim 30, wherein the dosage form is in tablet form. 32. Dosage form under item 31, in which the tablet is covered with a film. 33. A method for producing an oral solid dosage form as defined in claim 1, which includes the steps of: a) providing a powdered mixture of micronized estradiol or its hydrate, salt or pharmaceutically acceptable ester and at least one pharmaceutically acceptable excipient; b) granulating said powder mixture into granules by adding a binding agent selected from the group comprising gum arabic; alginic acid; alkali metal alginate; carbomer; dextrin; calcium phosphate; gelatin; glucose; guar gum; hydrogenated vegetable oil; magnesium aluminum silicate; spray cured mannitol; zein; starch; partially or fully modified or peptized starch; starch derivatives, cellulose, cellulose derivatives, and mixtures thereof; and optional c) mixing the obtained granulate with additional pharmaceutically acceptable excipients and g) transformation of the resulting mixture into a solid standard dosage form. 34. The method according to p, where the specified binder is the same as defined in any of PP-26. 35. The use of an oral solid dosage form, as defined in any one of claims 1 to 32, for the manufacture of a medicament for treating or preventing a physical condition in a woman caused by insufficient endogenous estrogen levels. 36. The use according to claim 35, wherein the physical condition is osteoporosis, headaches, nausea, depression, flushing, a decrease in bone mineral density, or an increased risk or incidence of bone fractures. 37. The use according to claim 35 or 36, wherein the woman is a postmenopausal woman.