HUT74167A - A novel pharmaceutical for oral administration comprising progesterone and a polyethylene glycol - Google Patents

Description

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AV u ·. The pharmaceutical composition comprises a PEG molecule and an enhancer selected from the group consisting of starch, cellulose _f pectin and tragacanth.

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. ______ S.B.G. & K International Patent Office H-1062 Budapest. Andrássy út 113. Phone: 34-24-950, Fax: 34-24-323 ··· ········· ······ ··· · · · · · · • · · · · · · · · · · · · · · · · · 4 62 066 / HF

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APPLICATION- NEW PHARMACEUTICAL

PREPARATION

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition in unit dosage form for oral administration of progesterone or progesterone and estradiol.

BACKGROUND OF THE INVENTION

Progesterone is a steroid hormone secreted by the mammalian ovary. Its major biological functions include fertilization and implantation of the fertilized egg, preparation of the endometrium and promotion of pregnancy. If conception is delayed, progesterone plays an important role in the maturation of the endometrium, which prevents the epithelial layer from peeling off during menstrual bleeding.

The amount of progesterone secreted by women each day changes during the menstrual cycle. Thus, 1-2 mg daily of progesterone is secreted during the follicular phase, resulting in serum levels of about 0.1 to 1.5 ng / ml. During the luteal phase, approximately 10 to 20 mg of progesterone is secreted daily resulting in serum progesterone levels of approximately 5.7 to 28.1 ng / ml. During the advanced stages of pregnancy, progesterone secretion increases to hundreds of mg / day.

In women, progesterone deficiency may lead, inter alia, to defective uterine bleeding, amenorrhea (loss of blood count), endometrial hyperplasia and carcinoma, premenstrual tension and endometriosis.

The most obvious way to solve the problems associated with progesterone deficiency is to immediately add progesterone to eliminate the deficiency. However, when progesterone is administered orally, non-micronized progesterone generally appears to be of limited bioavailability. This, together with the fact that progesterone's first-pass liver metabolism is very high, has made oral administration of progesterone problematic. Suppositories through the rectum and vagina provide modest levels of progesterone, but are aesthetically pleasing to many women. Progesterone can also be given by intramuscular injection. However, in addition to being painful, this mode of application is uncomfortable as it is inadequate for patients to self-monitor.

Many synthetic progesterones are used as substitutes for progesterone in hormone replacement therapies for the treatment of conditions due to progesterone deficiency and in oral contraceptives.

Such synthetic materials may be prepared with appropriate properties for their absorption and excretion.

Although some of these substances have very similar biological effects to progesterone, they are not identical and adverse reactions are well known. Thus, certain synthetic progesterone-like substances have an androgenic effect on the long-term risk of virilization (masculinity) and the risk of fetal masculinization during treatment during pregnancy. Other derivatives have long-term estrogenic effects. In contrast to progesterone, some of the synthetic progesterone-like substances have no anti-estrogenic effect, anti-aldosterone effect or antiovulatory effect.

U.S. Patent Nos. 5,116,619 and 5,084,277 (Greco et al.) Disclose a vaginal progesterone tablet and a method for preparing the same tablet, respectively. One of the stated objects of the present invention is to provide a vaginal tablet with extended bioavailability. It is noted that optimization of the breakdown time for vaginal tablets is quite different from the more conventional theoretical and practical approaches used for oral dosage forms. The important point, this has been stated, is the choice of breakdown.

The different amounts of moisture present in the mouth and vagina are primarily responsible for the different approaches required for the two areas. When large amounts of super disintegrants, also suitable for tablets when used orally, are used as vaginal tablets, they can form a sponge-like mass after introduction into the vagina. Smaller amounts of super disintegrants may form gelatin-like sheaths around the tablet. In both cases, bioavailability is reduced. Such problems with vaginal tablets can be overcome by using a starch disintegrant. According to Greco et al patents, the optimum composition for a vaginal tablet contains about 7% corn starch. The patent does not describe whether starch has a favorable effect on the bioavailability of progesterone when administered orally.

U.S. Patent 4,196,188 (Besins) describes an oral form of progesterone which is used in a soft gelatin capsule containing an oily carrier.

Micronized progesterone crystallized and ground in a very specific way is used in the capsule formulation. It has been found that such micronized progesterone is not suitable for processing in compressed dosage forms such as tablets, since the particle size distribution is adversely affected by the tableting process.

British Patent Application 2,091,552 (Carnrick) describes a unit dose of progesterone in combination with a suitable pharmaceutical carrier which may be cholesterol pivalate. No further information is available on the preparation.

It is an object of the present invention to provide a pharmaceutical composition in dosage unit form for oral administration of progesterone which has a favorable bioavailability.

Another object of the present invention is to provide a pharmaceutical composition in unit dosage form for oral use which can be used to treat progesterone deficient conditions.

It is a further object of the present invention to provide a pharmaceutical unit dosage form for oral administration comprising progesterone and estradiol.

Yet another object of the present invention is to provide a pharmaceutical composition in unit dosage form for oral administration wherein the weight of the progesterone components represents a high percentage of the total weight of the tablet.

It is another object of the present invention to provide a process for the preparation of a pharmaceutical formulation of progesterone for oral use having improved bioavailability of progesterone, optionally containing estradiol.

Summary of the Invention

It has surprisingly been found that polyethylene glycol, together with an adjuvant selected from the group consisting of starch, a starch component, a modified starch, a cellulose, a modified cellulose, pectin and tragacanth, has a beneficial effect on the bioavailability of progesterone in oral dosage unit form. availability.

Accordingly, in the broadest sense, the present invention relates to a pharmaceutical composition in dosage unit form for oral administration comprising progesterone and a polyethylene glycol molecule starch, a starch component, a modified starch, a cellulose, a modified cellulose, pectin and tragacanth. with a booster selected from the group consisting of.

In a preferred embodiment of the invention, the dosage unit progesterone is in a micronized state.

In another preferred embodiment of the invention, the composition further comprises estradiol.

In yet another preferred embodiment of the invention, the amount of progesterone in each dosage unit ranges from about 10 mg to about 500 mg, preferably from about 20 mg to about 300 mg, most preferably from about 50 mg to about 225 mg.

In another preferred embodiment of the invention, the amount of estradiol per unit dose is in the range of about 0.1 mg to about 5.0 mg, more preferably about 0.4 mg to about 2.0 mg.

In yet another preferred embodiment of the invention, the composition further comprises a polyethylene glycol molecule having an average molecular weight of about 1000 to about 10,000.

In another preferred embodiment of the invention, the composition comprises a polyethylene glycol molecule having an average molecular weight of about 6,000.

In another preferred embodiment of the invention, the composition comprises starch in the form of starch.

In another preferred embodiment of the invention, the composition comprises starch in the form of potato starch.

In another preferred embodiment of the invention, it comprises starch in the form of a composition.

In another preferred embodiment of the invention, the composition comprises starch.

In another preferred embodiment of the invention, the composition comprises starch in the form of tapioca starch.

In yet another preferred embodiment of the invention, the composition comprises a modified starch.

In another preferred embodiment of the invention, the composition comprises a starch component in the form of amylose.

In yet another preferred embodiment of the invention, the composition comprises a starch component in the form of amylopectin.

In another preferred embodiment of the invention, the amount of starch per unit dose is from about 5% to about 75% by weight of the unit dose, more preferably from about 15% to about 50%, most preferably from about 21% to about 30%. means.

In another preferred embodiment of the invention, the progesterone in unit dosage form represents at least about 25%, more preferably at least 33%, of the total weight of the unit dose.

In another preferred embodiment of the invention, the composition is provided in unit dosage form, comprising an amount of progesterone or progesterone and estradiol that can meet all or part of the subject's daily requirement, e.g. one-third. Most preferably, the unit dosage form comprises the total daily requirement.

Detailed Description of the Invention

Progesterone can exist in two crystalline modifications having the same physiological activity, which are readily convertible. As used herein, the term progesterone refers to both forms. Many references refer to progesterone as a natural progesterone. In the present invention, the term progesterone refers to progesterone of any origin, whether isolated from biological material, synthetic or semisynthetic. Progesterone can also be labeled as pregn-4-ene-3,20-dione.

The progesterone used in the compositions of the present invention is micronized. It is preferred that at least 90% of the particles have a diameter less than gm, about 50% of the particles have a diameter of less than 10 μπι, and that about 10% of the particles have a diameter of less than 5 µm.

As used in the description of the present invention, the term estradiol refers to 17-beta-estradiol, which can also be killed by cis-estradiol or estra-1,3,5 (10) -triene-3,17-beta-diol.

Polyethylene glycol molecules (PEGs) are liquid or solid polymers of the compound of formula H (OCH 2 CH 2) _{n 0} H wherein n is greater than or equal to 4. Generally, each PRG molecule is designated by a number indicating its average molecular weight.

In the case of tablets, starch is a commonly used adjuvant. It usually functions as a binder or disintegrant. The present inventors believe that solving the problem of bioavailability of an oral drug by including starch in the pharmaceutical composition is novel and surprising.

Corn starch, potato starch, rice starch and tapioca starch are examples of starches that can be used in the present invention.

Most starches contain two different types of D-glucopyranose polymers, amylose and amylopectin. Amylose is essentially a linear polymer of 1-4 linked alpha-D-glucopyranosyl units. It is a highly branched polymer of alpha-D-glucopyranosyl units containing 1-4 linkages of amylopectin and has 1-6 linkages at the branching points. Where starch is generally referred to in the present invention, it is preferred to include amylose and amylopectin in this specification.

Some starches used in pharmaceutical formulations are pregelatinised or otherwise modified, such as by acid treatment, oxidation, or hydroxyalkylation. It is preferred that such modified starches are also to be referred to as "starch" when the term is commonly used.

Cellulose, also in various forms, is often used in tablets.

It usually functions as a disintegrant or diluent.

cellulose in its natural form as a powder or in the form of fibers isolated from fruits or vegetables, or may be chemically modified, for example by alkylation, hydroxyalkylation or carboxymethylation. Examples of chemically modified celluloses are methylcellulose (carmellose), ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. The chemical modification may also include crosslinks. An example of this is cross-carmelose. Where cellulose is generally referred to in the present invention, it is preferred that all modified cellulose be included in the description.

An enhancer selected from the group consisting of progesterone, PEG, a starch, a starch component, a modified starch, a cellulose, a modified cellulose, pectin, and tragacanth, and optionally an estradiol in accordance with the present invention. and may include one or more of the commonly used adjuvants in the art, such as diluents, binders, disintegrants, lubricants, puffs, and preservatives. Examples of such enhancers are lactose, triglycerides, polyvinylpyrrolidones, gelatin, stearic acid, magnesium stearate, silica, and talcum powder.

One of the prerequisites that must be met in order to achieve the prescribed dose for self-monitoring by patients is that the medicine be conveniently taken. thus, if possible, the tablets should be taken once daily. Preferably, they should have a comfortable size and should not have an unpleasant smell or taste.

Of course, the absolute minimum size of a tablet should be determined by the amount of active compound that the tablet should contain. In practice, a certain amount of adjuvant is also needed. If a tablet is very small it is not easy to handle. However, very small amounts of the active compound can be used in a tablet of a suitable size if a suitable amount of an inert diluent is included in the tablet formulation.

It is not convenient to swallow a very large tablet and, for example, to take a monthly dose in a handbag. Most conveniently, the total weight of a tablet is about 50 mg to about 500 mg, more preferably about 100 mg to about 300 mg.

The type and amount of enhancer to be included in a pharmaceutical composition will depend on the physicochemical properties of the active compound to be used and the desired absorption profile. As mentioned above, inhalants may be added to increase tablet size. Other adjuvants may be added as lubricants, binders, disintegrants, preservatives, to influence the rate of absorption, or for other reasons. If a large amount of active compound is to be used in a tablet and a large amount of a potency enhancer is desired to achieve the desired pharmaceutical properties, this may be a problem in keeping the tablet small in size convenient for use. 4 of the present invention.

Example 4 describes four different tablet formulations for tablets containing 100 mg of progesterone. Two tablet formulations, A and D, have nearly the same bioavailability.

However, Tablet A weighs 800 mg, which is not convenient in practice, whereas Tablet D, weighing 262.72 mg, is convenient in size.

The compositions of the present invention may be prepared by methods known in the art.

Thus, tablets or capsules containing the compositions of the present invention may be provided, for example, as follows:

a component or a modified starch, with the exception of a lubricant other than a lubricant and optionally adding estradiol;

b) granulating the mixture using polyethylene glycol as a binder;

c) optionally mixing a lubricant with the granulate; and

d) compressing the granulate to form tablets or fill into capsules.

• · · · · · · ···········

The tablets of the present invention may be coated or uncoated. The coated tablets may be sugar coated or film coated.

In a preferred embodiment, the present invention relates to a composition for oral administration comprising progesterone and estradiol. Such a composition may be used, inter alia, in the treatment of perimenopausal or other disorders that require so-called reverse hormone replacement therapy.

In yet another preferred embodiment of the invention, a composition comprising progesterone as the sole hormone component is used. Such a composition may be used, inter alia, as an oral contraceptive and in the treatment of disorders caused by progesterone deficiency, such as in certain cases of infertility, premenstrual syndrome, and abnormal bleeding. Further, such compositions may be used in peri and postmenopausal hormone replacement therapies.

The dosage for the patient to be treated with the composition of the present invention should be determined by one of ordinary skill in the art.

The present invention is further illustrated by the following examples, which are not, however, to be construed as limiting the scope of the invention. The features set forth in the following description and the following examples, taken separately and in combination, may serve as embodiments of various embodiments of the invention.

Example 1

Tablets containing 100 mg progesterone and 1 mg estradiol

For a tablet containing 100 mg of progesterone and 1 mg of estradiol, the appropriate formulation (in mg) contains:

Progeszteron100

Ösztradiol1

Maize starch50.5

Laktóz30,5

Polyethylene glycol 600033

Cross-Carmellose Sodium 9.2

Magnesium stearate 1,2

Talkum por4.6

Összesen230,0

Estradiol and lactose are mixed and passed through a 300 mesh sieve. Then, progesterone, corn starch and cross-carmellose sodium are added and stirring is continued for another two minutes. Polyethylene glycol 6000 was added to the powder mixture and the granulation was carried out with high speed mixing. The granules were passed through a 2400 mesh sieve and cooled on a liquid bed. After cooling, the granules are passed through a 1100 mesh sieve. Talc powder and magnesium stearate are added, followed by stirring for three minutes.

The tablets are compressed on a rotary tabletting machine.

tablet weight 230 mg tablet diameter 9 mm

Instead of corn starch, pregelatinised corn starch, potato starch, pregelatinized potato starch, rice starch or wheat starch can be used.

Example 2 mg progesterone and 1 mg

Each tablet of 5 0 mg progesterone contains the following:

progesterone

estradiol

Corn starch Lactose

Polyethylene glycol Cross-carmellose Magnesium stearate Talc powder Total estradiol and 1 mg

6000 tablets containing estradiol (in mg quantities) a

31.98

11.97

17.25 Sodium 4.8

0.6

2j 4

120.0

The granulate was prepared as described in Example 1.

The tablets are compressed on a rotary tabletting machine.

···· ···· tablet weight

0 mg tablets diameter mm

Instead of corn starch, pregelatinised corn starch, potato starch, pregelatinized potato starch, rice starch or wheat starch may be used.

Example 3

Tablets containing 100 mg progesterone and 2 mg estradiol

For a tablet containing 100 mg of progesterone and 2 mg of estradiol, the appropriate formulation (in mg) contains:

Progeszteron100

Ősztradiol2

Maize starch50.0

Laktóz30,0

Polyethylene glycol 600033.05

Cross-Carmelose Sodium 9.2

Magnesium stearate 1.15 Talcum powder 4.6 Altogether 230.0

The granulate was prepared as described in Example 1.

The tablets are compressed on a rotary tabletting machine.

tablet weight 230 mg tablet diameter mm

Instead of corn starch, pregelatinised corn starch, potato starch, pregelatinized potato starch, rice starch or wheat starch can be used.

Example 4

Pharmacokinetic results of progesterone absorption studies in women

In healthy postmenopausal women, four different tablet formulations containing 100 mg progesterone and 2 mg estradiol were compared in pharmacokinetic absorption studies. The composition of the tablets used is given in Table 1 and the pharmacokinetic data for the four formulations are summarized in Table 2.

Table 1

Component / A

B C D tablets

Progesz- 10 0 mg 10 0 mg 100 mg 10 0 mg DOCA PEG 6000 43.5 mg 21.7 mg 63.09 mg Kollidon.RTM 1.4 mg 1.4 mg k25 Kollidon.RTM 46.5 mg VA64 Maize 320.0 mg 18.45 mg 18.45 mg 65.66 mg starch stearic 21.7 mg gelatine 0.5 mg 0.5 mg 0.5 mg Lactose 320.0 mg 18.45 mg 18.45 mg 18.45 mg estradiol 2.00 mg 2.00 mg 2.00 mg 2.00 mg Colloidal 2.0 mg 2.0 mg 2.63 mg silicon- dioxide Cross - 9.9 mg 9.9 mg 8.48 mg carmelose sodium Magnesium 4.20 mg 0.98 mg 0.98 mg 1.51 mg stearate Talcum powder 8.00 mg 0.4 mg 0.4 mg 0.4 mg Total weight 8 00 mg 197.6 mg 197.6 mg 262.72 mg

Table 2

Preparation Patients AUC Mean _Cmax Mean _Tmax Mean (nM xh) (nM) (h) ···· ·········· ···· · »···· · ···

THE 16 363.2 249.5 1.7 B 16 159.0 38.9 2.3 C 15 54.6 14.2 2.3 D 8 392.2 269.8 1.6

In Table 2, AUC = area under the curve showing plasma concentration (in nM) versus time (h). ^c max ⁼ maximum serum progesterone concentration (in nM). T _max = time between the administration of progesterone and the time to peak serum concentration (in hours).

Table 2 shows that formulations A and D exhibit very similar pharmacokinetic properties. However, for formulation A, the tablet containing 100 mg of progesterone weighs 800 mg and is thus too large for convenient oral use. For formulation D, the tablet containing 100 mg of progesterone weighs 262.72 mg, which is very convenient.

• ·· ·

PATENT CLAIMS

Claims (9)

A pharmaceutical composition for oral use, comprising a micronized progesterone, a polyethylene glycol molecule and an adjuvant selected from the group consisting of starch, starch component, modified starch, cellulose, modified cellulose, pectin and tragacanth. Pharmaceutical composition according to claim 1, characterized in that the composition further comprises an estradiol. Pharmaceutical composition according to claim 1 or 2, characterized in that the amount of progesterone per unit dose ranges from about 10 mg to about 500 mg. Pharmaceutical composition according to claim 2 or 3, characterized in that the amount of estradiol per unit dose ranges from about 0.1 mg to about 5.0 mg. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises starch selected from the group consisting of corn starch, potato starch, rice starch, wheat starch and tapioca starch. «··· ···· Pharmaceutical composition according to any one of claims 1 to 4, characterized in that it comprises a starch component selected from the group consisting of amylose and amylopectin. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that it contains a modified starch. Pharmaceutical composition according to any one of the preceding claims, characterized in that the amount of starch is a dose unit weight about 5% - 75%, still preferably about 15% - 50%, Most preferably, about 21 % to about 30% It is formed. 9. A process for the preparation of a pharmaceutical preparation of progesterone for oral use, wherein the composition has an improved bioavailability, the process comprising the steps of: a) mixing the micronized progesterone with an adjuvant selected from the group consisting of a starch, a starch component, a modified starch, cellulose, a modified cellulose, pectin and tragacanth, and a further adjuvant and optionally estradiol; b) granulating the mixture using polyethylene glycol as a binder; ···· ···· t c) optionally mixing a lubricant with the granulate; and d) compressing the granulate to form tablets or fill into capsules. H- ¹ ff.Sientpeter Adam