WO2008154240A1 - Pharmaceutical composition of a new system for vaginal release of steroids - Google Patents

Abstract

Pharmaceutical compositions appropriate for the vaginal administration of steroids are described, to be used in a hormone replacement therapy, during menopause and to support the luteal phase of in vitro fertilization cycles. Compositions are characterized by the incorporation of polymers and disintegrators combinations, that allow an adequate mucous adherence and bio-availability of steroid hormones in the endometrium. This administration method reduces the systemic levels of steroids, allows a longer term in between doses, thus reducing side effects, and it prevents residues gathering inside the vaginal cavity.

Description

PHARMACEUTICAL COMPOSITION OF A NEW SYSTEM FOR VAGINAL

RELEASE OF STEROIDS

Descriptive Monograph:

The current invention includes a solid pharmaceutical form, containing only progesterone, or progesterone combined with estradiol, to be administered vaginally. It is a proven fact nowadays that the effector reproductive organs (hypophysis-ovary and uterus) receive impulses rather of permissive than controlling type from the hormones addressed to them (de Ziegler, 1995). On the other hand, another even more unexpected phenomenon has been recently disclosed regarding hormones and their effect when vaginally administered. A high efficiency at the endometrium tissue level has become evident, as well as a low progesterone plasmatic concentration achieved with this administration means (Miles et al, 1994; Fanchin et al, 1997).

A growing clinical interest in the search for alternative means to administer drugs has been noted since the nineties. The reason for this interest is mainly the need of avoiding the hepatic first step, with the resulting premature metabolization of orally administered drugs. Orally reached circulating progesterone concentrations are extremely low, as compared to the high concentrations of their alpha-reduced metabolites, which are known as a source of neuropsychological side effects (Nahoul et al, 1987; Arafat et al, 1988). This minimum plasmatic concentration hormone profile explains the reason why oral progesterone has been ruled out as an inducer of predecidual changes in the endometrium (Bourgain et al, 1990; Gibbons et al, 1998), and as a support in the luteal phase of in vitro fertilization cycles (Devroey et al, 1989).

On the other hand, injectable means in prolonged therapies is uncomfortable and not free of side effects, such as pain and complications, like a cold abscess. Vaginal means have been considered one of the alternatives since ancient times. Recently we have witnessed a revival of this drug administration means, since the development of new release systems has resulted into excellent pharmacokinetic profiles, with minimum side effects.

Many of the problems associated to steroids release in the treatment of hormone replacement, and other conditions requiring them for a long term may be overcome with their intra-vaginal administration. It is known that, in general, and including estrogens, they are efficiently and fast absorbed through the epithelium of the vaginal mucous. (Chien, 1992), (Rigg, LA, et al., 1978).

The term 'first uterine step' has been used in the literature to describe a phenomenon by which a drug reaches higher concentration levels in the pelvic organs than in peripheral circulation (Bulletti et al;1997), (Einer-Jensen et al, 2001 ). For this purpose, the local venous-arterial transfer of solutes is required by means of the so-called vascular counter-flow mechanism, the existence of which has been widely proven in the literature (Cicinelly et al, 1998; Alexander et al, 2004) The vagina has a self-cleaning system, which added to the gravity law opposes to the retention of a drug inside the vaginal means. Consequently, muco-adherence is a fundamental feature for a drug release system at a vaginal level. Polymers allow the drugs to stay inside the vagina and being released at a constant speed towards the vaginal means, determining a 'concentration gradient' between vaginal lumen and the wide network of underlying veins and venous capillaries (Bernkop et al, 2004), (Gavini E. et al, 2002). The last concept is fundamental for molecules capable of achieving trans-membrane passive diffusion (Vermani and Garg, 2000). Such diffusion in the vaginal means is favored in lipophilic molecules of low molecular weight (about 300 Daltons), (Niswender,2002). Natural progesterone and estradiol possess such requirements, and their main clinical uses are related to the support of the luteal phase in assisted fertilization cycles, where analogues of the gonadotropin (GnRH) releasing hormone have been used.

The use of a continued or sequential therapy regarding progestagen is a controverted matter in the 'post WHI era' (Women^'s Health Initiative) and its association to breast cancer is also doubtful. Nevertheless, a recent study of two random clinical essays in Sweden showed that, after experiencing breast cancer, the recurrence does not show an increase trend with the cyclic use of a progestagen for 10 days every three months, while the essay that used a continuous combined therapy was interrupted when a significant increase of breast cancer became evident (von Schultz et al, 2005).

Recent findings of cardiovascular risks with the hormone replacement therapy have risen fears in post-menopause women, who have chosen not to use it for the alleviation of climacteric symptoms. Within this context, measures have been implemented not to harm, which have led to propose hormone therapy through alternative means. Among such regimes, vaginal progesterone (45-100 mg) has been administered ten days a month, or bi-weekly. Recently, a study by the Health National Institute of France (INSERM) indicated that micronized progesterone does not increase the risk of breast cancer, as compared to what occurs with progestagens (Fournie et al, 2005). Vaginal administration of progesterone could then mean achieving a significant effect of the steroid on the effector organs (myometrium and endometrium), with little consequences at a systemic circulation level, avoiding distance effects (Norman and Mac Lennan; 2005). Both the luteal phase support, as well as the hormone replacement therapy, require a prolonged use of progesterone.

For these reasons, it has been established that administration by vaginal means if the most adequate for progesterone.

The vaginal release system of drug

The vaginal means has been traditionally used in the release of drugs that act locally, as anti-microbe and anti-parasite agents. Nevertheless, conventional systems such as creams, foams, pessaries and jellies remain for relatively short terms at their destination site due to the self-cleaning system of the vaginal tract. Consequently, effective therapeutic levels of a drug are limited to a short term, thus requiring a repeated administration through time. A good drug release system must provide controlled and sustained levels of the administered drug.

Many drug release systems are based on mucous adhesive polymers (Lee et al, 2000). The mucous adhesive systems of drug release have been developed both for local and systemic administration through different mucous: oral (Giunchedi et al, 2002), nasal (Lim et al, 2000) and vaginal (Valenta et al, 2001 ), (Lee et al, 1996).

Agents promoting absorbance, known as 'permeation enhancers' in literature, have been thoroughly studied in the last years. Among them, polymers with high and low molecular weight. Chitosane is one of them (Luessen et al, 1997), which in general shows some advantages over low molecular weight polymers, such as the increase of mucous adhesive features, thus allowing high concentrations of them to remain at the absorbance site (Uchiyama et al, 1999). Chitosane is a polysaccharide obtained from partial chitin de-acetylation (Muzzarelli et al, 1988). Due to its great bio-compatibility and bio-degrading, it is widely used as pharmaceutical excipient. Chitosane also shows anti-microbe and cicatrizing properties (Conti et al, 2000), (Kan et al, 2000). The use of chitosane as a mucous adhesive polymer in humans via oral means has already been studied (Giunchedi et al, 2002). Nevertheless, vaginal means for this purpose has not been explored. In general, polymers can be divided into anionic and cationic, being chitosane one of the most used cationic polymers. The permeating effect of this polymer can be shown through several studies on mono-layer Caco-2 cells and in vivo models in rats (Artursson et al, 1994), (Takeuchi et al, 1996), ( Tozaki et al, 1997). The underlying mechanism for the opening of tight junctions by chitosane, has been deemed as caused by the interaction of amino groups positively charged with sialic groups of glycoproteins tied to the cell membrane, negatively charged (Artursson et al, 1994). Also, anionic polymers such as polycarbophil, used in progesterone gel, has also shown permeation promoting features (Clausen et al, 2001 ), (Lehr et al, 1992), (Luessen et al, 1997). As compared to the direct interaction with the membrane showing chitosane, polycarbophil shows a high affinity with calcium, which depletion of the extra-cell means increases the permeability of the cell side domain.

High molecular weight polymers are not absorbed through the mucous barrier (Bar et al, 1995), (Takehisa et al, 1997). Consequently, systemic effects may be ruled out. On the other hand, chitosane is not hydro soluble with a pH over 6.5. As a result, its permeating effect does not work in environments with such a pH level. The vaginal pH of healthy women of reproductive age is acid (4 to 5). Such value is maintained by the lactobacillus that converts the glycogen of exfoliated epithelium cells into lactic acid. The pH changes with age, the menstrual cycle, infections and sexual activity. Menstruation, cervix and uterus secretion and semen act as alkalinizing agents, increasing the pH (Richardson and Ilium, 1992).

On the other hand, Carbomer is a polymer of the acrylic acid that shows a crossed reaction with poly alkenyl glycol or divinyl glycol ethers. They are produced from polymer primary particles of about 0.2 to 6 microns average diameter. Floculated agglomerates cannot be divided in the last particles when synthesized. Each particle may be seen as a structural network of the polymer interconnected with others.

Carbomer, which was discovered and patented in 1957, is also known as Carbomer, Carboxipolymethylene and its commercial name, Carbopol®. Since then a wide range of formulations in oral tablets has been patented. Carbomer has a great affinity with water, under which contact it swallows and hydrates. Besides its hydrophilic nature, its inter-crossed structure is essentially insoluble in water. Consequently, it is a potential candidate for its use in drug controlled release systems.

The carboxile groups, provided with acrylic acid, are responsible for many benefits of the product. Carbomer polymers have a weight equivalent to 76 per carboxile group, and are manufactured with an inter-crossing process. Depending from the intercrossing degree and the manufacturing conditions, there are several carbomer degrees available. Each degree has a different meaning, depending on its use for pharmaceutical preparations.

Carbomer 974 is inter-crossed with erythritol penta allyl and polymerized in ethyl acetate. All polymers manufactured this way are neutralized by a 1 % and a 3% potassium hydroxide. The tri-dimensional nature of this polymer provides it with some unique features, such as being biologically inert. Carbomer is a hydrophylic substance not soluble in water: instead of dissolving in the presence of water, carbomer swallows, forming a mucilaginous colloid. Carbomer polymers have a remarkable water absorbance feature, they swallow in the presence of water until reaching over 1 ,000 times their original volume, and 10 times their diameter until forming a gel, when exposed to a pH between 4 and 6.

The polymer chains start to turn and the turning radius becomes longer and longer. Macroscopically, this phenomenon is perceived as swallowing. It has been reported (Maggi et al, 2000; Fazeli et al, 2006; Prabhu et al, 2008) that the polymer carbomer 974 disintegrates more slowly than other polymers, and consequently it has a high degree of disintegration/dissolution. This represents an important disadvantage of this polymer, as compared to other, such as Sodium Carboxymethylcellulose (SCMC), polycarbophil and Hydroxipropylmethylcellulose-W (HPMC-W). Due to the addition of two disintegrators, the current invention decreases such index, both in-vitro as well as in-vivo, preventing the accumulation of residues in the vaginal cavity. On the other hand, the appropriate weighing weight- weight ratio of polymers and of the rest of the excipients allows a higher spacing in- between the doses to be administered. These two features of the current invention represent an innovating advantage over the known vaginal preparations that are a part of the previous art.

In the veterinarian area, one with the highest application of drugs controlled release is that of disease prevention and control, with the release of anthelmintic, antibiotics, anti-parasite agents, growth promoting and nutrition agents. Consequently, the development of mucous adhesive systems of vaginal release is an important target in veterinarian medicine.

A recent veterinarian study, addressed the acriflavine release using an in-vitro model (Gavini et al, 2002). Acriflavine was chosen as a model because of being highly soluble in water, because of having a bacteriostatic activity against Gram positive germs, and due to its effectiveness against bovine trichomoniasis. This study compared the combination of different promoting agents of mucous adhesion, such as: methylcellulose, sodium carboxymethylcellulose, sodium alginate, chitosane and carbopol, and it showed that the use of tablets containing two of them, associated to carbopol 974, greatly swelled in the dissolution means and did not disintegrate in more than 24 hours. Besides, among the different excipients studied, carbopol showed the best results in terms of active principle release and showed excellent mucous adhesive properties in the in vitro mucous adherence essays. Preliminary studies carried out by us showed that this polymers combination, used under the same conditions, can be used in the women's vagina, without any significant collateral effect. In these studies the vaginal release of gonadotropins (LH and FSH) was tried, with in vitro fertilization purposes. Such peptide hormones have an extraordinarily high molecular weight as compared to progesterone (≥30.000 vs. 300 Daltons). The results showed a modest vaginal absorbance of gonadotropins, not compatible with its clinical use.

One of the greatest inconveniences shown by this type of polymers is in achieving an industrial formulation that may be conveniently compressed, that is, that the granulate formed mainly by the gelifying agents has an adequate flow, and that the tablet formed does not adhere to the compressor punchers; that it has an adequate size, allowing its vaginal administration; that it has a local action, and that it does not leave residues in the application zone.

Surprisingly, we have found that progesterone administration through this new release system, made of a polymers mixture with well defined ratios, formulated with a disintegrating agent which is formed, in turn, by the combination of at least two of the following agents: Sodium glycolate starch, microcrystalline cellulose, crospovidone or sodium croscarmellose, a diluent and a mixture of lubricants, where at least one of them has a weight between 0.05% and 3.5%, leads to good results, decreasing the disintegration /dissolution index, preventing the residues accumulation in the vaginal cavity.

Progesterone was associated to this new vaginal release system of drugs in replacement of synthetic progestagens, as a hormone replacement therapy during post menopause.

The introduction of this new luteal phase support scheme for in vitro fertilization cycles consists in the administration of a vaginal tablet, containing this new system with natural progesterone as active principles.

The new release system contains chitosane, a polymer extremely abundant in the nature, which is part of the shell of several crustaceans. Chitosane is incorporated to pharmaceutical forms as a powder that, in contact with water, becomes a gel which molecular array that offers the features of a framework. In this invention the term chitosane is not limited only to the product obtained by chitin de-acetylation, but it also includes any chitosane dehvate that has been modified with the purpose of improving its biocompatibility, biodegrading or solubility, as several dehvates known in the state of the technique, such as: partially hydrolyzed chitosane, partially re- acetyled chitosane, etc.

On the other hand, the vaginal tablet also contains a carbomer, a synthetic polymer with a high mucous adhesive power, also known as carboxypolymethylene. The active principles of this pharmaceutical form are two: progesterone and estradiol, both micronized, between 1.0 microns and 30 microns.

The gallenic techniques to manufacture these vaginal tablets are known in the state of the art. For example, the gel of this invention (vaginal tablets) may be prepared with granulation and compression, and dried with 'spray-drying' or liophylization, among others.

Mucous adhesive properties are developed when the tablet is hydrated by the vaginal physiological fluids.

Pharmacokinetic parameters were determined for progesterone, such as maximum concentration, maximum time, elimination mean life, so as to ensure a local, non systemic action. For this purpose a frequent blood sampling was necessary during the first 24 hours after the administration, and then daily until the fourth day.

The composition, according to the invention, is characterized by the fact of containing Progesterone, or Progesterone/Estradiol and excipients pharmaceutically acceptable, such as: polymers, a diluter, a disintegrating agent, a glydant and a mixture of lubricants.

One of the most relevant aspects of the composition described is the fact of possessing mucous adhesive type excipients, which allows the active principle to remain in the vaginal mucous for a longer time. In the state of the art we found that the American patent application US 2004/0132690 refers to a pharmaceutical composition for vaginosis treatment, of vaginal administration, which includes a gel based on chitosane and lactic acid. The American patent US 7,018,992, in turn, describes a pharmaceutical composition containing estradiol for the treatment of vaginal atrophy. This composition includes a matrix with a hydrophilic cellulose film coat, which adheres to the vaginal mucous and hydrates slowly to provide a controlled release of estradiol.

The American patent US 6,465,626 mentions chitosane as a bio-adhesive material, as part of a formulation for nasal administration of an antiviral.

On the other hand, the American patent US 4,565,694 protects a tablet to be used as a contraceptive, with a vaginal administration means. Such tablet must be placed inside the vagina 10 minutes before intercourse.

Other patent applications, such as US 2005/0008694 and WO 00/28970, describe tablets for the vaginal administration of progesterone, but for a systemic use, as in patent US 5,1 16,619.

In US 6,905,701 a formulation for vaginal administration and its systemic use is also described. In this case, the active principle is a Biphosphonate.

Vaginal tablets containing progesterone have been described in the literature, but they must be administered twice a day (Levy et col, 1999), as well as tablets containing Clotrimazole and a combination of bio-adhesive polymers such as:

Carbomer 934P, sodium carboxymethylcellulose and sodium alginate, to be administered once a day. (Sharma, G. et col, 2006).

We did not find in the previous literature any Progesterone formulation for non systemic action, as the one described in the current patent.

Thus, the current invention provides a tablet for vaginal administration of micronized progesterone for non systemic use which includes the steps of: a) Mixing the micronized progesterone with other pharmaceutically acceptable excipients. b) Forming a tablet by the traditional compressing system with the micronized progesterone, which has been mixed with other pharmaceutically acceptable excipients, such as: mucous adhesive excipients, diluters, a disintegrating agent, a glydant and a mixture of lubricants.

Preferably, micronized progesterone and estradiol must have a particle size between

1.0 and 30.0 microns.

Preferably, micronized progesterone must be in a weight ratio between 1 : 2 to 1 : 6, regarding the mixture of mucous adhesive polymers.

Preferably, mucous adhesive polymers must be chitosane and carbomer 974P, in a weight ratio of 1 : 3 to 1 : 5 in between them.

Preferably, the diluter must be one of the following agents: Lactose, Lactose monohydrate, Lactose Spray dried, calcium di-basic Phosphate, Sucrose, Mannitol or cellulose, with a weight between 0.05% and 50.0% of the tablet total weight.

Preferably, the disintegrating agent must be formed by the mixture of, at least, two of the following: Sodium glycolate starch, microcrystalline cellulose, crospovidone and sodium croscarmellose, with a weight between 0.02% and 30.0% of the tablet total weight for each of the agents.

Preferably, to include in the composition a glydant agent, such as colloidal silicon, with a weight between 0.01 % and 5.0% of the tablet total weight.

Preferably, the lubricants mixture must be talcum and magnesium stearate, and at least one of them with a weight between 0.05% and 3.5% of the tablet total weight.

The compositions indicated in this patent are an example and they do not limit the scope and protection of the invention.

Several determinations of the tablets obtained with the formulations detailed in examples 1 to 6, are based on the methodologies and conditions required by USP27; NF22 of 2004. Among the most significant we can mention: Unit Dose Uniformity (905), page 2396, for the weight variation determination and its relative standard deviation, which was carried out with an analytical scale, table 1 ; Disintegration (701 ), page 2302, disintegration is visualized in the state of any residue of the unit that remains in the mesh of the equipment as a soft mass. Disintegration is a guide for the preparation of the optimal formula and the comparison tests. Drugs disintegration depends on the diluter used, the kind and quantity of agglutinating, and mainly the disintegrating agent, the lubricant quantity, the compacting pressure and the incorporation method. If a tablet disintegrates, it does not mean that the drug dissolves: the disintegration time was established with the pharmacopeia equipment and criteria, using distilled water as a means, table 2; Dissolution ( 71 1 ), page 2303, as the disintegration test does not guarantee that the formulation releases the drug, the dissolution test is carried out, since tablets must dissolve before absorbance or act in the site of action. Frequently the absorbance speed of a drug is determined by the dissolution speed of the tablets; the dissolution kinetics for each of the formulations was carried out considering the equipment and criteria of pharmacopeia, using purified water at 37^aC as a means, 50 rpm and the method II, Table 2 and graphs 1 , 2 and 3.

It was preferred using water as an in vitro essay means, because it is more demanding for the products to be controlled and compared than physiological conditions.

From the results, Table 2 and graphs 1 , 2 and 3, from examples 4, 5 and 6 it is understood that the addition of a disaggregating agent, formed by two substances allows decreasing the disintegration times, remarkably improving the disintegration/dissolution index.

Graph 2 dissolution kinetics 24 hours — Φ— Example5Progesterone

% Dissolved — ^ — Example2Progesterone

time(h)

Graph 3 dissolution kinetics 24 hours Example6Progesterone

% Dissolved ...^s — Example3Progesterone

Time(h) CITED REFERENCES

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EXAMPLE 1

EXAMPLE 3

Weight (mg) %

Progesterone 200.0 11.7

Chitosane 200.0 11.7

Carbomer 974 P 800.0 46.8

Avicel PH 102 300.0 17.5

Lactose Spray Dried 200.0 11.7

Talcum 9.0 0.5

Magnesium stearate 1.0 0.06

Total 1710.0 100.0

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6

Claims

1. Solid, compressed pharmaceutical composition for vaginal administration, CHARACTERIZED for containing, at least, one steroid hormone, a mucous adhesive excipient, formed by the combination of chitosane and carboxypolymethylene, a disintegrating agent, a diluter and a mixture of lubricants, where at least one of them is present at a ratio between 0.05% and 3.5% p/p.

2. The composition as per claim 1 , CHARACTERIZED by the fact that the steroid hormone is progesterone and it can be associated to estradiol.

3. The composition as per claims 1 and 2, CHARACTERIZED by the fact that the steroid hormone has a weight ratio between 1 : 2 to 1 : 6 as regards the mucous adhesive polymers mixture.

4. The composition as per claims 1 to 3, CHARACTERIZED by the fact that steroid hormones are micronized.

5. The composition as per claims 1 to 4, CHARACTERIZED by the fact that the particle size of the steroid hormones is between 1 .0 microns and 30 microns.

6. The composition as per claims 1 to 5, CHARACTERIZED by the fact the mucous adhesive polymers are chitosane and carboxypolymethylene and they are at a weight ratio between 1 : 3 to 1 : 5 in between them.

7. The composition as per claims 1 to 6, CHARACTERIZED by the fact that mucous adhesive polymers are chitosane and carboxypolymethylene and are preferably at a weight ratio 1 : 4, respectively.

8. The composition as per claims 1 to 7, CHARACTERIZED by the fact that the diluter is: lactose monohydrate, lactose, lactose Spray Dried, calcium dibasic phosphate, sucrose, mannitol or cellulose, with a weight between 0.05% and 50.0% of the tablet total weight.

9. The composition as per claims 1 to 8, CHARACTERIZED by the fact that the disintegrating agent is formed by at least two substances, which may be chosen among: sodium glycolate starch, microcrystalline cellulose, crospovidone and sodium croscarmellose, and each of them with a weight between 0.02% and 30.0% of the tablet total weight.

10. The composition as per claims 1 to 9, CHARACTERIZED by the fact that it also includes a glydant agent, with a weight between 0.01 % and 5.0% of the tablet total weight

11. The composition as per claims 1 to 10, CHARACTERIZED by the fact that: i) Remarkably decreases the disintegration/dissolution index of carboxypolymethylene 974, and ii) It allows a higher posology spacing.

12. The composition as per claims 1 to 1 1 , CHARACTERIZED by the fact that the lubricant is a mixture which components can be chosen between: talcum, magnesium stearate, magnesium oxide, silicon dioxide, colloidal silicon dioxide, fuming silicon dioxide, sodium aluminum silicate, calcium silicate, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium trisilicate and stearic acid. At least one of them with a weight between 0.01 % and 3.5% of the tablet total weight.