SK19396A3 - Pharmaceutical composition for oral administration comprising micronized progesterone and a polyethyelene glycol together with an excipient and producing method of this composition - Google Patents

Abstract

A pharmaceutical composition for oral administration of progesterone may, conveniently, contain a PEG, and a further excipient selected from the group comprising a starch, a cellulose, pecting, and tragacanth.

Description

Technical field

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

BACKGROUND OF THE INVENTION

Progesterone is a steroid hormone secreted by mammalian ovaries. Its main biological function is to prepare the endometrium of the uterus for fertilization and implantation of the fertilized egg and to support pregnancy. Although fertilization does not occur, progesterone plays an important role in maturation of the endometrium of the uterus, preventing the epithelial layer from detaching during menstrual bleeding.

The amount of menstrual excretion is about progesterone secreted per day by a woman changes over the cycle. During the follicular phase, 1 to 2 mg per day, resulting in a serum level of about 0.1 to 1.5 ng / ml. During the luteal phase about 10 to 20 mg / day is excreted, resulting in a serum level of about 5.7 to 28.1 ng / ml. In the advanced stage of pregnancy, the excretion of progesterone increases to several hundred milligrams per day.

Progesterone deficiency in a woman may cause, inter alia, uterine bleeding dysfunction, endometrial hyperplasia and cancer, ammonorrhea dysfunction, premenstrual pressure, and endometriosis.

The most convenient way to solve the problems associated with progesterone deficiency is to administer progesterone to correct the deficiency. However, when progesterone is administered orally, non-micronized progesterone is generally poorly bioavailable. This, together with the fact that the first passage of progesterone by hepatic metabolism is very intense, makes oral administration of progesterone problematic. Rectal or vaginal laces cause good levels of progesterone, but are aesthetically unacceptable for many women. Progesterone may also be administered by intramuscular injection. Because this method is painful, this method of administration is unacceptable due to the unsuitability of the administration itself.

Many synthetic progesterones in hormone replacement therapy have been used as a replacement for progesterone to treat conditions resulting from progesterone deficiency and oral contraceptives. Such synthetic agents may be formulated to have desirable properties in terms of absorption and excretion. Although the biological effects of some of these agents are very similar to those of progesterone, they are not the same and the adverse reactions are well distinguishable. Some synthetic progesterone agents exhibit an androgenic effect with a long-term risk of virilization and a risk of fetal masculinization when treated during pregnancy. Other derivatives have a long-term estrogenic effect. In contrast to progesterone, some synthetic progesterone agents have no antiestrogenic effect, anti-aldosteronic effect or anti-ovulatory effect.

U.S. Pat. Nos. 5,116,619 and 5,084,277 (Greco et al.) Disclose a vaginal progesterone tablet and a process for its manufacture. One object of the present invention is to provide a vaginal tablet with extended bioavailability. The description states that the optimization of disintegration periods for vaginal tablets is quite different from several traditional theoretical and practical concepts used for oral dosage forms. An important point, as mentioned, is the choice of disintegrant. Different moisture in the mouth and vagina is primarily responsible for the different understandings required in these two areas. If large amounts of super disintegrants are suitable in oral tablets used in vaginal tablets, they may form a sponge-like mass upon insertion into the vagina. Minor amounts of super disintegrants may cause the formation of a gelatinous layer around the tablet. In both cases, bioavailability is reduced. These problems with vaginal tablets are overcome by the use of a starch disintegrant. According to the patents of Grec et al. the optimal vaginal tablet contains about 7% corn starch. The patents contain no indication of the beneficial effect of starch on the bioavailability of progesterone after oral administration.

U.S. Pat. No. 4,196,188 (Besins) discloses an orally administrable form of progesterone that is in a soft gelatin capsule containing an oil vehicle. Micronized progesterone, crystallized and milled in a very specific manner, is used to prepare capsules. Such micronized progesterone is said to be unsuitable for the production of compressed dosage forms such as tablets because the tableting process affects the particle size distribution in an undesirable manner.

English patent application no. No. 2091552 (Carnrick) describes a unit dose of progesterone in association with a suitable pharmaceutical carrier, which may be cholesterol pivalate. There are no further details about the composition.

One object of the present invention is to provide a pharmaceutical composition in the form of a dosage unit for oral administration of progesterone having excellent bioavailability.

Another object of the present invention is to provide a pharmaceutical composition in the form of a dosage unit for oral administration, which is suitable for the treatment of progesterone deficiency conditions.

It is another object of the present invention to provide a pharmaceutical composition in the form of a dosage unit for oral administration, wherein the dosage unit comprises progesterone and estradiol.

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

Yet another object of the present invention is to provide a process for the manufacture of a pharmaceutical composition of progesterone, optionally also containing estradiol, for oral administration with improved bioavailability of progesterone.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that polyethylene glycol together with a carrier selected from the group consisting of starch, starch component, modified starch, cellulose, modified cellulose, pectin, and tragacanth has an excellent effect on the bioavailability of progesterone in oral dosage forms.

Accordingly, in its broadest scope, the present invention relates to a pharmaceutical composition in the form of a dosage unit for oral administration, wherein the composition comprises progesterone and polyethylene glycol together with a carrier selected from the group consisting of starch, starch component, modified starch, cellulose, modified cellulose, pectin and tragacanth.

According to one preferred embodiment of the invention, the progesterone contained in the dosage unit is micronized.

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

According to another preferred embodiment of the invention, the amount of progesterone contained in each dosage unit is in the range of 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.

According to another preferred embodiment of the invention, the amount of progesterone contained in the dosage unit is at least 25%, more preferably at least 33% of the total weight of the dosage unit.

According to another preferred embodiment of the invention, the composition is in the form of a dosage unit comprising an amount of progesterone or progesterone and estradiol which is suitable to cover either the full daily requirement of the person being treated or a simple fraction thereof, such as half or a third of the full daily requirement. Most preferred is a dosage unit containing a full daily need.

Progesterone can exist in two crystalline modifications with the same physiological activity that are readily interconvertible. In the present invention, the designation progesterone includes both forms. In several references, progesterone is referred to as natural progesterone. In the present specification, progesterone includes progesterone of any origin, both isolated from biological material and synthetic or semi-synthetic. Progesterone can also be referred to as pregn-4-en-3,20-dione.

The progesterone used in the compositions of the present invention is micronized. Preferably, at least 90% of the particles have a diameter of less than 15 m, about 50% of the particles have a diameter of less than 10 m, and about 10% of the particles have a diameter of less than 5 m.

The term estradiol in this specification means 17S-estradiol, also referred to as cis-estradiol or estra-1,3,5 (10) -trien-3,17-diol.

Polyethylene glycols (PEG) are liquid or solid polymers of the general formula H (OCH ₂ CH ₂ ) _n OH, in which n is greater than or equal to 4. Generally, each polyethylene glycol is indicated by a number which represents its average molecular weight.

Starch is commonly used as an ingredient in tablets. usually

S acts as a binder or as a disintegrant. The present inventors believe that the solution to the problem of improving the bioavailability of an orally administered drug compound by including starch in a pharmaceutical composition containing it is novel and surprising.

Corn starch, potato starch, wheat starch and tapioca starch are examples of starches that may find application in the present invention.

Most starches contain D-glucopyranose polymers, amylose; a substantially linear polymer of linked units (1 → 4). Amylopectin is -D-glucopyranosyl units, 1-> 6 linkages at branching points, termed starch generically, includes amylose and amylopectin.

two different types and amylopectin. Amylose is a -D-glucopyranosyl highly branched polymer containing 1 -> 4 bonds with

If, in the present description, it is preferred that this designation

Some starches for use in pharmaceutical compositions are pregelatinized or otherwise modified, for example by treatment with acid, oxidation or hydroxyalkylation. It is preferred that such modified starches also fall within the designation of starches when a generic process is used.

Cellulose in various forms is also commonly used as a tablet additive. It usually acts as a binder, as a disintegrant or as a diluent. The cellulose may be used in natural form as a powder or in the form of fibers, for example isolated from fruit or vegetables, or it 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 crosslinking. An example of this is cross-linked carmellose (croscarmellose). When the cellulose is labeled in a generic manner in the present invention, it is preferred that all of the modified celluloses are also included in the label.

In addition to progesterone (PEG), an ingredient selected from the group consisting of starch, starch ingredient, modified starch, modified cellulose, pectin and tragacanth and optionally estradiol, the pharmaceutical compositions of the present invention may further comprise one or more ingredients commonly used in the art such as are diluents, binders, disintegrants, lubricants, buffers, and preservatives. Examples of such additives are lactose, triglycerides, polyvinylpyrrolidones, gelatin, stearic acid, magnesium stearate, silica and talc powder.

One of the preconditions that must be met in order to comply with the prescribed regimen is that the patient himself must be comfortable with the drug. Preferably, the tablets should be taken only once a day, preferably of an acceptable size, and should not have a repellent odor or taste.

Of course, the absolute smaller tablet size limit is limited by the amount of active compound that the tablet contains. In practice, it will also be necessary to contain a certain amount of ingredients. If the tablet is very small, it is difficult to handle. The tablet may contain a very small amount of the active compound while maintaining its acceptable size and content of an appropriate amount of inert diluent.

Too large a tablet is neither pleasant to use nor well handled, for example if, for daily use, it is in a purse for a month. The total weight of the tablet should be from about 50 mg to about 500 mg, more preferably from about 100 mg to about 300 mg.

The type and amount of ingredients to be contained in the pharmaceutical composition depends on the physiological properties of the active compound administered and the desired absorption profile. As mentioned above, inert ingredients may be added to enlarge the tablet. Other additives such as lubricants, binders, disintegrants, preservatives, absorbency modifiers or others can be added. When a large amount of the active compound is administered in a tablet and a large number of ingredients are reported to achieve the desired pharmaceutical technical properties of the composition, it may be difficult to keep the tablet size small enough to be pleasant. Example 4 of the description describes four different tablet formulations of 100 mg progesterone tablets. Two of these formulations, A and D, have nearly the same bioavailability. However, tablet A weighs 800 mg, making it very unpleasant in practice, while tablet D, which weighs 262.72 mg, is indeed of a suitable size.

The compositions of the present invention are made by methods known in the art. Tablets or capsules containing the composition of the invention may be made, for example

(a) mixing progesterone with starch, a starch component or modified starch and adding other ingredients, with the exception of a lubricant and, where appropriate, estradiol;

b) granulation using polyethylene glycol as a binder,

c) optionally mixing the lubricant into the granulate; and

d) compressing the granulate so obtained into tablets or filling it into casples.

The tablets of the present invention may be coated or uncoated. The coating material of the tablets is sugar or film, as is known in the art.

In a preferred embodiment, the present invention relates to an oral composition comprising both progesterone and estradiol. Such a composition may be used, inter alia, for the treatment of perimenopausal disorders, for the prevention or treatment of osteoporosis, and for the treatment of other disorders requiring so-called "osteoporosis". reverse hormone replacement therapy.

In another preferred embodiment of the present invention, a composition is used which comprises progesterone as the hormone component itself. Such a composition may find utility, inter alia, as oral contraceptives and in the treatment of disorders caused by progesterone deficiency, such as certain cases of infertility, premenstrual syndrome and dysfunctional bleeding. These compositions may further find utility in peri- and postmenopausal hormone replacement therapy.

The regimen for any patient treated with the compositions of the present invention should be determined by one skilled in the art.

The present invention is further illustrated by the following non-limiting examples. The data described in the preceding description and in the following examples, both separately and in any combination thereof, may be a material for carrying out the invention in its individual forms.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Tablets containing 100 mg of progesterone and 1 mg of estradiol

A suitable formulation of a tablet containing 100 mg of progesterone and 1 mg of estradiol is the following formulation (amount in mg):

progesterone estradiol corn starch lactose polyethylene glycol 6000 sodium croscarmellose magnesium stearate talk powder

100

50.5

30.5

9.2

1.2

4.6 total

230.0

Estradiol and lactose are mixed and passed through a 300 mesh screen. Progesterone, corn starch and sodium croscarmellose are added and stirring is continued for another two minutes. Polyethylene glycol 6000 is added to the powder mixture and granulation is performed in a high speed mixer. The granules are passed through a 2400 mesh screen and cooled in a fluid bed. After cooling, the granules are passed through a 1100 mesh screen. Add talcum powder and magnesium stearate and mix for 3 minutes.

The tablets are compressed on a rotary tabletting machine.

tablet mass 230 mg tablet diameter 9 mg Maize starch can be replaced pregelatinized corn starch, potato starch, pregelatinized potato starch or wheat starch starch.

Example 2

Tablets containing 50 mg of progesterone and 1 mg of estradiol

A suitable formulation of a tablet containing 50 mg of progesterone and 1 mg of estradiol is the following formulation (amount in mg):

progesterone 50 estradiol 1 maize starch 31.98 lactose 11.97 polyethylene glycol 6000 17.25 sodium croscarmellose 4.8 magnesium stearate 0.6 talk powder 2.4

pretty

120.0

The granulate was prepared as described in Example 1.

/ 0

The tablets are compressed on a rotary tabletting machine.

tablet mass

120 mg tablet diameter mg

The corn starch may be replaced by pregelatinized corn starch, potato starch, pregelatinized potato starch or wheat starch.

Example 3

Tablets containing 100 mg of progesterone and 2 mg of estradiol

A suitable formulation of a tablet containing 100 mg of progesterone and 2 mg of estradiol is the following formulation (amount in mg).

progesterone 100 estradiol 2 maize starch 50.0 lactose 30.0 polyethylene glycol 6000 33.05 sodium croscarmellose 9.2 magnesium stearate 1.15 talk powder 4.6

pretty

230.0

The granulate was prepared as described in Example 1.

The tablets are compressed on a rotary tabletting machine.

tablet mass 230 mg tablet diameter 9 mg Maize starch can be replaced pregelatinized corn starch, potato starch, pregelatinized potato starch or wheat starch starch.

Example 4

Pharmacokinetic results of a progesterone absorption study in a woman

Four different tablet formulations containing 100 mg of progesterone and 2 mg of estradiol were compared in pharmacokinetic studies in healthy, postmenopausal women. The tablet composition is shown in Table 1 and the pharmacokinetic data of the four formulations are summarized in Table 2.

Table 1

Ingredients tablets A (mg) B (mg) C (mg) D (mg) progesterone 100 100 100 100 PEG 6000 43.5 21.7 63.09 Kollidon k25 1.4 1.4 Kollidon va64 46.5 maize starch 320 18.45 18.45 65,66 stearic acid 21.7 gelatin 0.5 0.5 0.5 lactose 320 18.45 18.45 18.45 estradiol 2.0 2.0 2.0 2.0 colloidal silicon dioxide 2.0 2.0 2.63 sodium croscarmellose 9.9 9.9 8.48 magnesium stearate 4.20 0.98 0.98 1.51 talc powder 8.00 0.4 0.4 0, 4 total weight 800 197.6 197.6 262.72

/ 2

Table 2

composition Number of patients AUC average (nM x h) ^c max Diameter (nM) ^T max Diameter (h) A 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, the AUC is the area under the curve, representing the plasma concentration (in nM) as a function of time (hours). C _max is the maximum concentration (in nM) of serum progesterone. T _max is the time (hours) from the administration of progesterone to the maximum serum concentration.

As can be seen from Table 2, the pharmacokinetic properties of formulations A and D are very similar. However, in the case of Formulation A, a tablet containing 100 mg of progesterone weighs 800 mg and is too large to be acceptable in normal use. In the case of Formulation D, a tablet containing 100 mg of progesterone weighs 262.72 mg and is very convenient.

Claims (9)

PATENT CLAIMS A pharmaceutical composition for oral administration comprising micronized progesterone, polyethylene glycol and an additive selected from the group consisting of starch, starch component, modified starch, cellulose, modified cellulose, pectin and tragacanth. 2. A pharmaceutical composition according to claim 1 comprising estradiol. The pharmaceutical composition of claim 1 or 2, wherein the amount of progesterone is in the range of about 10 mg to about 500 mg per dosage unit. The pharmaceutical composition of claim 2 or 3, wherein the amount of estradiol is in the range of about 0.1 mg to about 5.0 mg per dosage unit. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises a 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 the preceding claims 1 to 4, characterized in that it contains a starch component selected from the group consisting of amylose and amylopectin. Pharmaceutical composition according to any one of the preceding claims 1 to 4, characterized in that it contains a modified starch. / Y Pharmaceutical composition according to any one of the preceding claims, characterized in that the amount of starch is from about 5% to about 75%, more preferably from about 15% to about 50% by weight, most preferably from about 21% to about 30% by weight. dosage unit. it 9. A process for the manufacture of a pharmaceutical composition of progesterone for oral administration with improved bioavailability, comprising the steps of: (a) mixing progesterone with starch, starch component or modified starch, cellulose, modified cellulose, pectin and tragacanth, adding further additives and optionally estradiol; b) granulation using polyethylene glycol as a binder, c) optionally mixing the lubricant into the granulate; and d) compressing the granulate so obtained into tablets or filling it into capsules.