LT4043B - A novel pharmaceutical for oral administration comprising progesterone and a polyethylene glycol together with an excipient - 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

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

Progesterone is a steroid hormone produced in the ovaries of mammals. Its primary biological function is to prepare the lining of the uterus for fertilization and implantation of the fertilized egg and to support pregnancy. In the absence of pregnancy, progesterone plays an important role in uterine maturation and promotes permeability of its epithelial layer during menstrual bleeding.

The daily amount of progesterone produced in a woman varies with the menstrual cycle. During the follicular maturation phase, progesterone is released at a rate of approximately 1-2 mg / day, which is approximately 0.1-1.5 ng / ml in serum. In the middle of the cycle, progesterone is excreted at approximately 10-20 mg / day, which is approximately 5.7-28.1 ng / ml in serum. In mid-pregnancy, progesterone release increases to several hundred mg per day.

In the absence of progesterone, uterine bleeding disorders, amenorrhea, endometrial hyperplasia and carcinoma, premenstrual pressure and endometriosis may occur in the woman.

Thus, it is obvious that in order to prevent disorders due to progesterone deficiency, it should be used prophylactically in preparation for its expected deficiency.

However, progesterone has been shown to have little biological activity when it is taken orally without a good amount of oral administration. This statement, combined with the fact that the metabolism of progesterone, which is predominantly metabolised by the liver, is very high, casts doubt on the oral administration of progesterone. Rectal or vaginal suppositories may slightly increase the amount of progesterone in the body, but aesthetically this is not acceptable for many women. Progesterone can also be given intramuscularly. However, this path is painful and also frustrating if the patient is performing the procedures herself.

Synthetic progestagens have been used as progesterone substitutes in hormone therapy aimed at influencing conditions caused by progesterone deficiency and in oral contraceptives. Such synthetic agents may be obtained with appropriate properties such as absorption and excretion. Although the biological effects of some synthetic agents are very similar to those of progesterone, there are well-known and harmful side effects. Yes, certain progesterones exhibit an androgenic effect, posing a long-term risk of germ virilization and masculinization if treated during pregnancy. Other derivatives have long-lasting estrogenic effects. In contrast to progesterone, some synthetic progesterones do not produce anti-estrogenic, anti-aldosterone or anti-ovulatory effects.

U.S. Pat. U.S. Patent Nos. 5,166,619 and 5,084,277 [Greco et al.] Disclose, respectively, vaginal progesterone tablets and the method of preparing such tablets. One object of the aforementioned inventions is to provide a vaginal tablet having a sustained biological action. The description of the invention indicates that the choice of optimum disintegration times for tablets by vaginal route is significantly different from many of the theoretical and practical routes used to determine the dosage of oral drugs. It is noted that disintegrant selection is important. Namely, different humidity in the mouth and vagina, in particular, and different conditions in these areas, which must be taken into account. If vaginal tablets are used with super-disintegrators suitable for oral tablets, they can form a sponge-like mass when inserted into the vagina. Smaller amounts of such superdisintegrators may form a gelatinous coating on the tablet. In both cases, the biological activity is reduced. These problems, which occur with vaginal tablets, are solved with the help of starch disintegrators. According to Greco et al. According to patents, the optimal formulation of vaginal tablets contains about 7% cereal starch. The patents do not state whether starch has a favorable effect on the biological activity of progesterone when administered orally.

U.S. Pat. 4.196.188 [Besins] describes an oral progesterone which, together with an oily solvent, is contained in a soft gelatin capsule. Crystallized and truncated progesterone used in capsule formulations is pulverized in a very specific manner. It is claimed that the progesterone thus crushed cannot be used in the manufacture of compressed unit dosage forms, such as tablets, since they do not properly modify the particle size composition.

GB patent application no. 2,091,552 [Carnrick] mentions a unit dose of progesterone in combination with a suitable pharmaceutical carrier that could contain cholesterol pivoliate. A detailed description of the composition is not provided.

One object of the present invention is to provide a pharmaceutical composition for oral administration of a unit dose of progesterone, the composition of which contains beneficial effects on biological activity.

Another object of the present invention is a pharmaceutical composition for oral administration of a unit dose of progesterone for use in the treatment of disorders caused by progesterone deficiency.

Another object of the present invention is to provide a pharmaceutical unit dosage form of oral progesterone, which contains progesterone and estradiol in a unit dose.

Yet another object of the present invention is a pharmaceutical unit dosage form of oral progesterone, which comprises a significant proportion of the total weight of the tablet.

Finally, another object of the present invention is to provide a pharmaceutical composition for oral administration of progesterone and, where appropriate, estradiol, which has an enhanced biological activity of progesterone.

Unexpectedly, polyethylene glycol, together with an additive selected from the group consisting of starch, starch component, modified starch, cellulose, modified cellulose, pectin and tragacanth, has a favorable effect on the oral activity of progesterone for oral administration in single doses.

Similarly, in a broader sense, the present invention relates to a pharmaceutical unit dosage form for oral administration of progesterone, comprising progesterone and polyethylene glycol and an additive selected from the group consisting of starch, starch component, modified starch, cellulose, modified cellulose, and pectin. a tragacanth.

In one embodiment of the invention, the progesterone used in unit doses is pulverized.

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

In yet another embodiment, the amount of progesterone per unit dose is from about 10 mg to about 500 mg, preferably from about 20 mg to about 300 mg, and more preferably from about 50 mg to about 225 mg.

In yet another embodiment of the invention, the unit dose of estradiol is from about 0.1 mg to about 5.0 mg, preferably from about 0.4 mg to about 2.0 mg.

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

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

In yet another embodiment of the invention, the composition comprises starch which is derived from corn.

In yet another embodiment of the invention, the composition comprises starch which is obtained from potatoes.

In yet another embodiment of the invention, the composition comprises starch obtained from rice.

In yet another embodiment of the invention, the composition comprises starch obtained from wheat.

In yet another embodiment of the invention, the composition comprises starch which is derived from tapioca.

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

In yet another embodiment of the invention, the composition comprises a starch component, i.e. amylose.

In yet another embodiment of the invention, the composition comprises a starch component, i.e. of amylopectin.

In yet another embodiment, the starch is contained in a unit dose of from about 5% to about 75%, preferably from about 15% to about 50%, and more preferably from about 21% to about 30% by weight of the unit dose.

In yet another embodiment, the amount of progesterone per unit dose is at least about 25%, preferably at least 33%, of the total weight of the unit dose.

In yet another embodiment of the invention, the composition is formulated in a unit dosage form containing a daily amount of progesterone or progesterone and estradiol, or a third or half of the daily requirement. The most acceptable daily dose is a unit dose.

Progesterone can be in the form of two physiologically active crystalline forms which are easily converted into one another. The present invention contemplates progesterone in both forms. In most literary sources, progesterone is described as a natural progesterone. In our description, progesterone will be considered to be progesterone of any origin whether it is derived from biological, synthetic or semi-synthetic material. Progesterone can also be labeled pregn-4-en-3, 20-dione.

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

In the description of the present invention, oestradiol is considered to be 17? -Estradiol, also designated as cis-estradiol or estra-1,3,5 (10) -trien-3,17? -Diol.

Polyethylene glycols (PEGs) are liquid or solid polymers of the general formula H (OCH 2 CH 2) _n OH wherein n is equal to or greater than 4. In general, each PEG is defined by a number that represents its molecular weight.

In tablets, starch is commonly used as an additive. It usually acts as a binder or disintegrant. The present inventors believe that the solution to the problem of enhancing the biological activity of oral drugs by incorporating starch into the pharmaceutical composition is novel and unexpected.

Maize, potato, rice, wheat and tapioca starch are examples of starch which may be used in the invention.

Most starches contain two types of D-glucopyranose polymers, amylose and amylopectin. Amylose is essentially a linear polymer consisting of linked (1 → 4) α-D-glucopyranosyl monomers. Amylopectin is a highly branched polymer consisting of α-D-glucopyranosyl monomers having 1-> 4 bonds at 1-6 bonds at the branching points. When the generic name of the starch is used in the present invention, it is understood that it includes both amylose and amylopectin.

Some starches are converted into gelatin or otherwise modified prior to use in pharmaceutical compositions, e.g., by acid treatment, oxidation or hydroxyalkylation. Modified starches are understood to include the generic name of starch.

Cellulose of various forms is also commonly used as an additive in tablets. It is usually in the form of a binder, disintegrant or solvent. Cellulose may be obtained from natural raw materials in the form of powders or fibers, for example, from fruits or vegetables or by chemical processing, such as alkylation, hydroxyalkylation or carboxymethylation. Examples of chemically processed celluloses include methylcellulose (carmellose), ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. The chemical treatment may result in a cross-linked polymer. An example of this is croscarmellosis. When the common name of cellulose is used in the present invention, it is understood that it includes chemically treated cellulose.

In addition to progesterone, PEG, an additive selected from the group consisting of starch, starch component, processed starch, cellulose, modified cellulose, pectin and tragacanth, and if necessary estradiol, the pharmaceutical compositions of this invention may contain one or more additives commonly used in the art. such as diluents, binders, disintegrants, lubricants, buffers and preservatives. Examples of such additives are lactose, triglycerides, polyvinylpyrrolidones, gelatin, stearic acid, magnesium stearate, silica and talcum powder.

One of the conditions that must be met if the patient's independence requirement is to be met is that the medication be convenient to use. Yes, tablets should be taken once a day if possible. It is preferable that they are of a reasonable size and do not have an unpleasant odor or taste.

The minimum absolute tablet size is defined by, of course, the amount of active compound required. In practice, a certain amount of additives is required. If the tablet is too small, it is uncomfortable to use. However, a very small amount of the active ingredient may be present in a tablet of appropriate size provided that a suitable amount of an inert solvent is incorporated into the tablet.

Extra large tablets are uncomfortable to swallow or carry, such as a monthly pack in a purse. Conveniently, the total weight of the tablet is from about 50 mg to about 500 mg, more preferably from about 100 mg to about 300 mg.

The type and amount of additives to be incorporated into the pharmaceutical composition will depend strongly on the physicochemical properties of the active compound and the mode of absorption required. As mentioned above, inert additives may be added to enlarge the tablet itself. Other additives are added to act as lubricants, binders, disintegrants, preservatives to influence the rate of absorption, or for other reasons. If a large amount of the active compound and additives are added to the tablet in order to obtain the desired pharmaceutical composition properties, the tablet may be uncomfortable due to its excessive size. Example 4 of our application provides four different formulations of 100 mg progesterone tablets. The two formulations, A and D, exhibit almost the same biological activity. However, Tablet A weighs 800 mg and is very uncomfortable to use, while Tablet D, weighing 262.72 mg, is a really reasonable size.

The compositions of the present invention are prepared by methods known in the art. For example, tablets or capsules comprising the compositions of the invention are obtained as follows:

(a) mixing progesterone with starch, starch component or modified starch, adding additives other than ointment and optionally estradiol;

b) granulating using polyethylene glycol as a binder;

(c) optionally blending into the granulate ointment; and

(d) extruding the granulate. forming tablets or filling them in capsules.

The tablets of the invention may be coated or uncoated. The coated tablets may be sugar-coated or film-coated by techniques well known in the art.

One embodiment of the invention is an oral composition comprising progesterone and estradiol. Such a composition may be used, for example, in the treatment of disorders of the climacteric period, in the prophylaxis or treatment of osteoporosis, and in the treatment of other disorders by means of so-called reverse hormone replacement therapy.

Another aspect of the present invention relates to a composition comprising only one hormonal component, progesterone. Such a composition could be used, for example, as an oral contraceptive and for the treatment of disorders caused by progesterone deficiency, such as certain infertility cases, premenstrual syndrome, bleeding disorders. In addition, such compositions may be used during menopause and postmenopausal hormone replacement therapy.

The procedure for administering the compositions of the invention to the patient is determined by one skilled in the art.

The following are illustrative examples of the invention, which are in no way to be construed as limiting the scope. The features set forth in the descriptions and examples below, when used in isolation or in combination in the practice of the invention, may result in adverse effects.

example

100 mg progesterone and 1 mg estradiol tablets

Tablet containing 100 mg progesterone and 1 mg estradiol (content in mg):

Progesterone 100

Estradiol 1

Maize starch

Lactose 30.5

Polyethylene Glycol-6000 33

Croscarmellose sodium 9.2

Magnesium stearate 1,2

Talcum powder 4.6

Total 230.0

Estradiol and lactose are mixed and passed through sieve-300. Add progesterone, corn starch and carmellose sodium and stir for another two minutes. When added to the powder mixture, polyethylene glycol-6000 is granulated in a high speed mixer. The resulting pellets are passed through a 2400 sieve and cooled in a flush bath. The chilled pellets are passed through a sieve-1100. Add talcum powder and magnesium stearate and mix for 3 minutes.

The tablets are compressed on a rotary tablet machine.

Tablet weight 230 mg

Tablet diameter 9 mm

Instead of wheat starch, wheat starch gelatin, potato starch, potato starch gelatin, rice starch or wheat starch can be used.

example mg progesterone and 1 mg estradiol tablet

Suitable tablet containing 50 mg progesterone and 1 mg estradiol (content in mg):

Progesterone 50 Estradiol 1 Corn starch 31.98 Lactose 11.97 Polyethylene glycol-6000 17.25 Croscarmellose sodium 4.8 Magnesium stearate 0.6 Talcum powder 2.4

Total 120.0

Granulate as described in Example 1.

The tablets are compressed on a rotary tablet machine.

Tablet weight 120.0 mg

Tablet diameter 8 mm

Instead of wheat starch, wheat starch gelatin, potato starch, potato starch gelatin, rice starch or wheat starch can be used.

example

100 mg progesterone and 2 mg estradiol tablets

Suitable tablet containing 100 mg progesterone and 2 mg estradiol (content in mg):

Progesterone 100 Estradiol 2 Corn starch 50.0 Lactose 30.0 Polyethylene glycol-6000 33.05 Croscarmellose sodium 9.2 Magnesium stearate 1.15 Talcum powder 4.6

Total

230.0

Granulate as described in Example 1.

The tablets are compressed on a rotary tablet machine.

Tablet weight 230 mg

Tablet diameter 9 mm

Instead of wheat starch, wheat starch gelatin, potato starch, gelatin starch gelatin, rice starch or wheat starch can be used.

example

Pharmacodynamic data on progesterone absorption in women

The absorption kinetics of four different types of tablets containing 100 mg progesterone and 2 mg estradiol were studied in healthy postmenopausal women. The composition of the tablets used in these pharmacodynamic studies is presented in Table 1 and the data obtained from the four formulations are presented in Table 2.

table

Composition of tablets components A B C D Progesterone 100 mg 100 mg 100 mg 100 mg PEG-6000 43.5 mg 21.5 mg 63.09 mg Kolidon-k25 1.4 mg 1.4 mg Kolidon-va64 46.5 mg Wheat starch 320.0 mg 18.45 mg 18.45 mg 65.66 mg Stearic acid 21.7 mg Gelatin 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 silicon dioxide 2.0 mg 2.0 mg 2.63 mg Sodium croscarmellosis 9.9 mg 9.9 mg 8.48 mg Magnesium stearate 4.20 mg 0.98 mg 0.98 mg 1.51 mg Talcum powder 8.00 mg 0.4 mg 0.4 mg 0.4 mg Total mass 800 mg 197.6 mg 197.6 mg 262.72 mg

table

Recipe Patients number PPK (nM x or.) C _max Mean (nM) T | rigx Mean (or.) A 16th 363.2 249.5 1.7 B 16th 159.0 38.9 2.3 C 15th 54.6 14.2 2.3 D 8th 392.2 269.8 1.6

Table abbreviations: PPK - area under the curve obtained by plotting the progesterone concentration (nM) in time as a function of time (hr); C _max is the maximum serum progesterone concentration (nM); T _max is the time (in hours) from the start of progesterone administration to the time when peak serum concentrations are reached.

From the data in Table 2, it is clear that the pharmacodynamic properties of the A and D formulations are very similar. However, for Formula A, a 100 mg progesterone tablet weighs 800 mg and is too large to be comfortable to use. For Formula D, a 100 mg tablet weighs only 262.72 mg and is therefore particularly convenient.

Claims (9)

DEFINITION OF INVENTION Claims 1. An oral pharmaceutical composition comprising crushed progesterone, polyethylene glycol and an additive 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 it may contain estradiol. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that the amount of progesterone per unit dose is from 10 to 500 mg. Pharmaceutical composition according to claim 2 or 3, characterized in that the amount of estradiol per unit dose is 0.1 to 5.0 mg. Pharmaceutical composition according to any one of the preceding claims, characterized in that the starch is selected from the group consisting of corn, potato, rice, wheat and tapioca starch. 6. A pharmaceutical composition according to any one of the preceding claims, wherein the starch component is selected from the group consisting of amylose and amylopectin. Pharmaceutical composition according to any one of the preceding claims, 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 per unit dose is from 5 to 75% by weight, preferably from 15 to 55% by weight, and preferably from 21 to 30% by weight. 9. A process for the preparation of a biologically active progesterone composition for oral administration comprising: (a) mixing the crushed progesterone with an additive selected from the group consisting of starch, starch component, modified starch, cellulose, pectin and tragacanth, followed by addition of other additives and optionally estradiol; b) granulating using polyethylene glycol as a binder; (c) optionally blending into the granulate ointment; and (d) compressing the granulate to form tablets or capsules.