DE102004059880A1 - Stable, hormone-containing (intermediate) product - Google Patents

Abstract

The The invention relates to a pharmaceutical composition which a nonionic surfactant, preferably a polyoxyethylene fatty acid glyceride, and contains a steroid, in particular ethinylestradiol and / or desogestrel. The composition is drawing through an increased storage stability of the steroid contained therein.

Description

The The present invention relates to pharmaceutical compositions, which contain at least one steroid whose storage stability is increased. The compositions preferably contain ethinyl estradiol and / or Desogestrel.

It It is known that steroids, especially certain steroid hormones often are unstable and already chemically decompose after a short time. The most important degradation reactions are oxidation and hydrolysis. To counteract the lack of chemical stability of steroids, is therefore in corresponding pharmaceutical compositions for suppression the hydrolysis of the water content is adjusted to an optimum. Further the active substance is sheathed for protection or by the addition of Stabilized antioxidants.

The most important representatives of steroid hormones include desogestrel and ethinyl estradiol. While desogestrel belongs to the group of progestins, ethinyl estradiol is a representative of estrogens. These two steroids have the following structure:

It is known in the art that desogestrel can be stabilized by embedding agents such as stearic acid and antioxidants such as dl-α-tocopherol. Also for ethinylestradiol stabilizing the use of stearic acid and antioxidants is known. In this context, for example US 5,395,627 and US 5,527,543 to get expelled. In the compositions of the prior art, a combination of several auxiliaries is always used in order to achieve a sufficient storage stability. In particular, the combination of dl-α-tocopherol with stearic acid is widely described. , Pharmaceutical compositions containing ethinylestradiol, desogestrel, stearic acid and dl-α-tocopherol, marketed for example under the name Marvelon ^{®, ®} Mercilon and Lovelle ^®.

The Extent of stability of steroid hormones in the pharmaceutical compositions of the state However, the technique is not optimal. Especially if larger quantities of the compositions - like they are needed in particular during drug production - stored temporarily can be, storage stability the steroids it contains are not always adequately ensured become.

Also is the use of several adjuvants to increase the storage stability of steroid hormones, e.g. the combination of stearic acid with dl-α-tocopherol, laborious and it would be desirable, such a combination of several excipients by a single Substitute replace, without significant loss of the storage stability having to accept.

The Use of stearic acid also has the disadvantage that it is due to its carboxyl group the pH composition so that in such compositions acid-sensitive substances can only be included when the pH is neutralized with a suitable buffer.

It There is therefore a need for pharmaceutical compositions, which steroid hormones, in particular desogestrel and / or ethinyl estradiol contain and advantages over have the compositions of the prior art. The storage stability of steroids in the pharmaceutical compositions should be at least comparable be with the storage stability the compositions of the prior art, preferably should the storage stability be higher. If possible should the storage stability be guaranteed by a single excipient, but not only by a combination of several excipients. With regard The pH should be within the pharmaceutical compositions preferably neutral behavior, so that acidic or base-sensitive substances are added to the compositions can be without the need for the use of buffers.

It has surprisingly been found that steroids which in the 17-position an optionally acylated hydroxyl carry group and an ethynyl, can be stored by nonionic surfactants, so that an embedding in fatty acids (such as stearic acid) and the addition of antioxidants (for example, dl-α-tocopherol), partially or completely can be dispensed with.

As a result, For example, the present invention relates to a pharmaceutical composition or dosage form comprising a nonionic surfactant and a Steroid, which in 17-position an optionally acylated hydroxyl group and carries an ethynyl radical. Furthermore, the invention relates to the use of such a composition for the preparation of a dosage form, preferably a contraceptive, a method for stabilizing such steroids and the use nonionic surfactants for stabilizing such steroids.

worin
R₁ -H oder -C₁-C₆-Alkyl ist;
R₂ -H oder -CO-C₁-C₆-Alkyl ist; und
R₃, R₄, R₅ und R₆ unabhängig voneinander -H, -C₁-C₆-Alkyl, -C₂-C₆-Alkenyl, -C₂-C₆-Alkinyl, -C₅-C₁₀-Aryl, -C₁-C₆-Alkylen-C₅-C₁₀-Aryl, -C₁-C₁₀-Heteroaryl, -C₁-C₆-Alkylen-C₁-C₁₀-Heteroaryl, -C₁-C₆-Alkylen-O-C₁-C₆-Alkyl, -CN, -CO₂H, -CO₂-C₁-C₆-Alkyl, -CONH₂, -CONH-C₁-C₆-Alkyl, -CON(C₁-C₆-Alkyl)₂, -OH, -O-C₁-C₆-Alkyl, -OCO-C₁-C₆-Alkyl, -NH₂, -NH-C₁-C₆-Alkyl, -N(C₁-C₆-Alkyl)₂ oder -NHCO-C₁-C₆-Alkyl sind, oder R₃ zusammen mit R₄, oder R₅ zusammen mit R₆ einen Rest =CH₂ bilden, oder R₃ und R₅ zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen Cyclopropylring bilden.The pharmaceutical composition according to the invention comprises at least one nonionic surfactant and at least one steroid which contains a structural element of the general formula (I)

wherein
R _{1 is} -H or -C ₁ -C ₆ -alkyl;
R _{2 is} -H or -CO-C ₁ -C ₆ -alkyl; and
R ₃ , R ₄ , R ₅ and R ₆ independently of one another are -H, -C ₁ -C ₆ -alkyl, -C ₂ -C ₆ -alkenyl, -C ₂ -C ₆ -alkynyl, -C ₅ -C ₁₀ - Aryl, -C ₁ -C ₆ -alkylene-C ₅ -C ₁₀ -aryl, -C ₁ -C ₁₀ -heteroaryl, -C ₁ -C ₆ -alkylene-C ₁ -C ₁₀ -heteroaryl, -C ₁ -C ₆ -alkylene-OC ₁ -C ₆ -alkyl, -CN, -CO ₂ H, -CO ₂ -C ₁ -C ₆ -alkyl, -CONH ₂ , -CONH-C ₁ -C ₆ -alkyl, -CON ( C ₁ -C ₆ -alkyl) ₂ , -OH, -OC ₁ -C ₆ -alkyl, -OCO-C ₁ -C ₆ -alkyl, -NH ₂ , -NH-C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) ₂ or -NHCO-C ₁ -C ₆ -alkyl, or R ₃ together with R ₄ , or R ₅ together with R _{6 form} a radical = CH ₂ , or R ₃ and R ₅ together with the carbon atoms to which they are attached form a cyclopropyl ring.

With regard to the structural element of the general formula (I), the following definitions apply:
"C ₁ -C ₆ -alkyl" means a linear or branched alkyl radical such as -CH ₃ , -CH ₂ CH ₃ , -CN ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) CH ₃ , -C (CH ₃ ) ₃ , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , etc .;
"C ₂ -C ₆ alkenyl" means a linear or branched alkenyl radical such as -CH = CH ₂ , -CH ₂ CH = CH ₂ , -CH = CH-CH ₃ , -CH ₂ CH ₂ CH = CH ₂ , -CH = CHCH = CH ₂ , etc .;
"C ₂ -C ₆ alkynyl" means a linear or branched alkynyl radical such as -CCH, -CH ₂ CCH, -CC-CH ₃ , -CH ₂ CH ₂ CCH, etc .;
"C ₅ -C ₁₀ aryl" means a mono- or binuclear aromatic such as phenyl, biphenyl, naphthyl, etc .;
"C ₁ -C ₁₀ heteroaryl" means a mono- or binuclear heteroaromatic containing 1, 2, 3, 4, 5 or 6 heteroatoms independently of one another selected from N, O and S, such as, for example, pyrrolyl, imidazolyl, pyridyl, indolyl, Quinolyl, isoquinolyl, thienyl, furyl, etc .; and
"C ₁ -C ₆ -alkylene" denotes a linear or branched alkylene radical, such as -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH (CH ₃ ) -, -CH ₂ CH ₂ CH ₂ -, -CH (CH ₃ ) CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, etc.

With regard to the stereochemistry in the 17-position of the steroid contained in the pharmaceutical compositions according to the invention, the following substitution pattern is particularly preferred:

"Steroids" in the sense of the description are all chemical substances which are considered derivatives of gonans can be understood. The structural element of the general formula (I) preferably comprises the steroid's D-ring.

For details on the definition, structure and action of steroids, see also S. Gal laway, The Steroid Bible, Belle Intl; 3rd edition, 1997; PE Micevych, RP Hammer, Neurobiological Effects of Sex Steroid Hormones, Cambridge University Press, 1995 and Steroid Hormones: A Practical Approach, IRL Press 1987.

In a preferred embodiment, in the general structure of the formula (I), the radical R _{1 is} -H, -CH ₃ or -CH ₂ CH ₃ , more preferably -CH ₃ or -CH ₂ CH ₃ and the radical R ₂ -H or - COCH ₃ . In a further preferred embodiment, R ₃ , R ₄ , R ₅ and R _{6 are} -H.

In a particularly preferred embodiment, R _{1 is} -CH ₃ or -CH ₂ CH ₃ and R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are -H.

The Pharmaceutical according to the invention Composition may comprise one steroid or more steroids, which contain the structural element of the general formula (I). In a preferred embodiment is just one such steroid included, in another preferred one embodiment two different such steroids are included.

at the steroids, which is a structural element of the general formula (I) and in the pharmaceutical composition according to the invention are contained, it is preferably to substances which Properties of sex hormones. It is preferable They are progestogens and / or estrogens.

Numerous progestins which contain a structural element of the general formula (I) are known in the art. As important representatives of the gestagens, which are substituted in 17-position accordingly, can be called:

As a result, contains the pharmaceutical invention Composition preferred as a steroid selected from a progestogen the group consisting of desogestrel, 3-keto-desogestrel, lynestrenol, Tibolone, delta-4-tibolone, etynodioldiacetate, levonorgestrel, norgestimate, Norethisterone, norethisterone acetate and gestodene. Desogestrel is particularly according to the invention prefers.

In addition to the progestagens mentioned above, some estrogens contain the structural element of the general formula (I). As important representatives can be mentioned:

As a result, contains the pharmaceutical invention Composition preferred as a steroid selected from an estrogen the group consisting of ethinylestradiol and ethinylestradiol-3-methyl ether. ethinylestradiol is particular to the invention prefers.

In a particularly preferred embodiment contains the pharmaceutical invention Composition of either ethinylestradiol or desogestrel, in particular preferably contains the pharmaceutical invention Composition of both ethinyl estradiol and desogestrel.

The Pharmaceutical according to the invention Composition contains the steroid or the combination of steroids in usual pharmaceutically effective amounts, preferably as microdosing, preferably in the range of 0.001 to 5.0 wt .-%, more preferably 0.01 to 1.0 wt.%, more preferably 0.05 to 0.75 wt.%, most preferably 0.1 to 0.4 wt .-% and in particular 0.2 to 0.25 wt .-% based on the total weight of the pharmaceutical composition.

Contains the pharmaceutical according to the invention Composition desogestrel, so is the weight fraction of desogestrel preferably 0.0008 to 4.2% by weight, more preferably 0.008 to 0.8% by weight, more preferably 0.042 to 0.63 wt%, most preferably 0.08 to 0.33 wt .-% and in particular 0.16 to 0.21 wt .-% based on the Total weight of the pharmaceutical composition.

When the pharmaceutical composition of the present invention contains ethinyl estradiol, the weight proportion of ethinyl estradiol is preferably 0.0002 to 0.8% by weight, more preferably 0.002 to 0.2% by weight, still more preferably 0.008 to 0.12% by weight, on most preferably from 0.02 to 0.07% by weight, and more preferably from 0.04 to 0.05 Wt .-% based on the total weight of the pharmaceutical composition.

Contains the pharmaceutical according to the invention Composition of both desogestrel and ethinyl estradiol, see above is the relative weight ratio Desogestrel: Ethinylestradiol preferably in the range of 10: 1 to 1: 2, more preferably 9: 1 to 1: 1, even more preferably 8: 1 to 2: 1, most preferably 7: 1 to 3: 1 and especially 6: 1 to 4: 1.

The Pharmaceutical according to the invention Composition contains at least one nonionic surfactant. Numerous nonionic surfactants are known in the art. Nonionic surfactants are detergent-active Substances that do not contain dissociable functional groups and therefore do not separate into ions in the water. Like every surfactant are also the nonionic surfactants from a nonpolar and a built up polar part. Preferably, nonionic surfactants are defined as organic substances with surface-active properties, consisting of one or more hydrophilic and one or more hydrophobic groups of such type and size exist that they have the ability own, the surface tension of water, monomolecular scattering or adsorption layers at the water / air interface to form emulsions and / or microemulsions and / or micelles to form and attach to water / solid interfaces, without dissociating in water in ions.

In a preferred embodiment is the nonionic surfactant a substance which at 25 ° C solid or waxy. Particularly preferred are nonionic Surfactants, which at 25 ° C are waxy and have a softening point in the range of 25 to 80 ° C, more preferably 27 to 70 ° C, more preferably 30 to 60 ° C, most preferably 33 to 50 ° C and in particular 35 to 40 ° C exhibit.

According to the invention preferred Representatives of the nonionic surfactants are fatty alcohols; sterols; Polyoxyethylene fatty acid ester; Polyoxypropylene fatty acid esters; alkylpolyglycosides; Alkylphenol ethoxylates and propoxylates; polyoxyethylene and polyoxypropylene fatty alcohol ethers; Poloxamers and fatty acid esters polyhydric alcohols, e.g. Sorbitan fatty acid esters, polyoxyethylene and Polyoxypropylene sorbitan Polyoxyethylene and polyoxypropylene fatty acid glycerides, and glyceryl fatty acid esters.

These the nonionic surfactant is a fatty acid ester a polyhydric alcohol, the ester is preferably derived from a polyhydric alcohol having preferably 2 to 8 carbon atoms, in particular 3 to 6 carbon atoms. Preferably, the polyvalent contains Alcohol 2 to 8 hydroxyl groups, in particular 3 to 6 hydroxyl groups. examples for such polyhydric alcohols are glycerol, threitol, erythritol, arabitol, Adonite, xylitol, sorbitol, mannitol and dulcitol. The number of esterified Hydroxyl groups of the polyhydric alcohol may vary, preferably At least one hydroxyl group is not esterified when four or more more hydroxyl groups are present, are preferably at least two, more preferably at least three hydroxyl groups are not esterified.

In a preferred embodiment is the nonionic surfactant selected from the group consisting from fatty alcohols, sterols, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, Polyoxyethylene fatty acid glycerides Polyoxyethylene Fettsäureestern, Polyoxyethylene fatty alcohol ethers, glyceryl fatty acid esters and poloxamers. Representatives of the abovementioned substance classes are those skilled in the art known. In this context, for example, H.P. Fiddler, Lexicon of excipients for Pharmacy, cosmetics and related areas, Editio Cantor Aulendorff, 2002 be referenced.

"Fatty acids" in the sense of the description are linear or branched, monocarboxylic acids having 8 to 32 carbon atoms, preferably 12 to 24 carbon atoms, in particular 14, 16 or 18 carbon atoms. The fatty acids can although monounsaturated or polyunsaturated but preferably they are saturated fatty acids. Further can the carbon atoms with 1, 2 or 3 hydroxyl groups substituted be. The fatty acids are preferred selected from the group consisting of saturated Carboxylic acids, such as. caprylic, Capric acid, Lauric acid, myristic, palmitic acid, stearic acid, arachidonic acid, behenic and lignoceric acid; and saturated hydroxy, such as. hydroxystearic, in particular 12-hydroxy-stearic acid.

"Fatty alcohols" in the sense of the description are derived from the above-defined fatty acids in that the carboxylic acid group was reduced to a hydroxymethyl group.

According to the invention preferred Fatty alcohols and sterols are cetyl alcohol, stearyl alcohol, cetylstearyl alcohol and cholesterol.

According to the invention preferred sorbitan are sorbitan fatty acid monoesters such as. Sorbitan monolaurate, sorbitan monopalmitate and sorbitan monostearate; but also sorbitan fatty acid diester, such as. Sorbitan dilaurate, sorbitan dipalmitate and sorbitan distearate and sorbitan fatty acid triesters, such as.

sorbitan, Sorbitan tripalmitate and sorbitan tristearate. The sorbitanic acid and Triest can also of different fatty acids derive, i. a hydroxyl group may, for example, with stearic acid, a others with palmitic acid be esterified.

According to the invention preferred Polyoxyethylene sorbitan are polyoxyethylene sorbitan monolaurate (polysorbate 20), polyoxyethylene sorbitan monopalmitate (Polysorbate 40), polyoxyethylene sorbitan monostearate (polysorbate 60) and polyoxyethylene sorbitan tristearate (polysorbate 65).

According to the invention preferred Polyoxyethylene fatty acid glycerides are macrogol 1000 glyceryl monofatty acid esters such as. Macrogol 1000 glyceryl monolaurate, macrogol 1000 glyceryl monostearate and macrogol 1000 glyceryl monopalmitate; but also representatives like Macrogol 1500 glyceryl tripalmitate, macrogol 1500 glyceryl tristearate and macrogol glyceryl hydroxystearate (Polyoxyl 40 Hydrogenated Castor Oil).

According to the invention preferred polyoxyethylene fatty acid ester is polyoxyethylene 40 stearate (Myrj ^® 52), polyoxyethylene 50 stearate (Myrj ^® 53) and polyoxyethylene 100 stearate (Myrj ^® 59). The numbers 40, 50 and 100 indicate the average number of ethylene oxide units.

According to the invention preferred Polyoxyethylene fatty alcohol ethers are macrogollauryl ether, polyoxyethylene (23) lauryl ether and polyoxyl 20 cetostearyl ether. The numbers are 20 and 23 indicates the average number of ethylene oxide units.

According to the invention preferred glyceryl are glyceryl monostearate, glyceryl monopalmitate and glyceryl monolaurate.

According to the invention preferred Poloxamers are poloxamer 188 and poloxamer 407. Poloxamers are ethylene oxide-propylene oxide copolymers.

According to the invention, the nonionic surfactant is more preferably a macrogol glyceryl hydroxystearate. Preferably, the average amount of covalently bonded ethylene oxide units per mole of glycerol is 1 to 100 mol, more preferably 5 to 90 mol, more preferably 10 to 80 mol, most preferably 25 to 75 mol, and most preferably 35 to 65 mol. Macrogol Glycerylhydroxystearate having an average of 40 or 60 Ethylenoxidäquivalenten are commercially available, for example under the name Cremophor ^® RH 40 and Cremophor ^® RH 60 (BASF, Ludwigshafen).

The Pharmaceutical according to the invention Composition contains the nonionic surfactant is preferably in an amount of 0.0001 to 99.9999 wt%, more preferably 1.0 to 99 wt%, more preferably 10 to 95% by weight, most preferably 20 to 90% by weight, and especially 25 to 75 wt .-% based on the total weight of the pharmaceutical Composition.

Prefers is the relative weight ratio nonionic surfactant: steroid 1000: 1 to 1: 2, more preferably 100: 1 to 1: 1, more preferably 10: 1 to 2: 1, most preferably 7: 1 to 3: 1 and especially 6: 1 to 4: 1.

The Pharmaceutical according to the invention Composition contains preferably at least one solid tabletting aid. The solid Tabletting aid preferably has a melting temperature above 25 ° C, preferably above 75 ° C, even more preferably above 100 ° C and in particular above 150 ° C.

The solid tabletting aid preferably has a specific surface area, determined to DIN 66131, of 10 to 1000 m ² / g, more preferably 25 to 750 m ² / g, even more preferably 50 to 500 m ² / g, most preferably 100 to 300 m ² / g and in particular 150 to 250 m ² / g.

The mean size of the primary particles of the solid tabletting aid is preferably in the range of 2 to 25 nm, more preferably 4 to 20 nm and especially 6 to 15 nm.

Preferably, the solid tableting aid is selected from the group consisting of fillers, Binders, tablet disintegrants, lubricants and flow improvers. Such tabletting aids are known to the person skilled in the art. In this regard, reference may be made, for example, to HP Fiedler, Encyclopedia of Excipients in Pharmacy, Cosmetics and Related Fields, Editio Cantor Aulendorff, 2002.

• – hochdisperses Siliziumdioxid (z.B. Aerosil^® der Typenbezeichnungen 150, 200, 300 oder 380° der Fa. Degussa, aber auch andere SiO₂-Produkte, welche z.B. unter den Bezeichnungen Carbosil^®, Insusil^®, Ludox^® und Levasil^® vermarktet werden),
• – mikronisierte Laktose,
• – mikrokristalline Cellulose,
• – Kaolin und
• – Polyvinylpyrrolidon.

Examples of suitable solid tabletting aids are

• - colloidal silicon dioxide (such as Aerosil ^® the reference numbers 150, 200, 300 or 380 ° from Degussa, but other SiO ₂ products, which are marketed under the names Cabosil ^®, Insusil ^®, Ludox ^® and Levasil ^® for example.)
• - micronised lactose,
• - microcrystalline cellulose,
• - kaolin and
• - Polyvinylpyrrolidone.

In a preferred embodiment, the pharmaceutical composition contains a solid tableting aid selected from the group consisting of high-density silica, micronized lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone. In this case, preferred relative weight ratios of the nonionic surfactant (s), the steroid (s) and the solid tableting aid selected from the above group are summarized in the following table:

colloidal anhydrous Silica and polyvinylpyrrolidone are solid tableting excipients particularly preferred, with fumed silica being most preferred is.

Contains the pharmaceutical Composition Polyvinylpyrrolidone, so is its weight fraction preferably in the range of 45 to 90% by weight, more preferably 50 to 85 Wt%, more preferably 55 to 80 wt%, most preferably 60 to 75 wt .-% and in particular 65 to 70 wt .-% based on the Total weight of the pharmaceutical composition.

Contains the pharmaceutical Composition fumed silica, so is its weight fraction preferably in the range of 25 to 65% by weight, more preferably 30 to 60 Wt%, more preferably 35 to 55 wt%, most preferably 40 to 50 wt .-% and in particular 42.5 to 47.5 wt .-% based on the total weight of the pharmaceutical composition.

Prefers the solid tabletting aid serves as a carrier, at least one part its surface coated with the nonionic surfactant is. It is particularly preferred that the steroid in the nonionic Surfactant solved or suspended. Accordingly, the pharmaceutical according to the invention contains Composition prefers particles which form a core of solid Tabletting aid contained, the surface of the Particles completely or at least partially coated with nonionic surfactant is and the steroid is solved or suspended in the coating is made of nonionic surfactant.

Of the Weight fraction of the solid tabletting aid is preferred in the range of 20 to 95% by weight, more preferably 30 to 90% by weight more preferably 40 to 85% by weight, most preferably 45 to 80% by weight, and more preferably 50 to 75% by weight based on the total weight of the pharmaceutical composition.

A particularly preferred embodiment the composition of the invention contains ethinylestradiol and / or desogestrel, at least one solid tabletting excipient selected from the group consisting of fumed silica, micronised Lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone, preferably fumed silica, and as nonionic Surfactant is a polyoxyethylene fatty acid glyceride, preferably macrogol glyceryl hydroxystearate.

The pharmaceutical composition according to the invention may, in addition to the above-mentioned solid tabletting aid further Tablettierungshilfsstoffe such as are customary for pharmaceutical dosage forms, for example (optionally further) fillers, binders, disintegrants, lubricants, flow improvers, dyes, flavorings, preservatives, etc.

Fillers increase the bulk and volume of a pharmaceutical composition. Suitable fillers include lactose, mannitol, sorbitol, cellulose, xylitol, dextrose, fructose, calcium phosphate, NaCaPO ₄ , sucrose and mixtures thereof. The fillers may account for preferably from 70 to 95% by weight, based on the total weight of the pharmaceutical composition.

binder impart cohesive properties to a pharmaceutical composition and improve, for example, granularity. Suitable binders are e.g. Hydroxypropylcellulose, amylopectin, starch, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose and gelatin. The binders can a weight proportion of preferably 0.5 to 5.0 wt .-% make up based on the total weight of the pharmaceutical composition.

Disintegrants be added to a pharmaceutical composition to the Decay of a tablet prepared from the composition favor. Suitable disintegrating agents are e.g. modified or unmodified Strength (Corn starch, Wheat starch, Potato starch, etc.), clay minerals, cross-linked polyvinylpyrrolidone, modified or unmodified cellulose, gum or algins. The tablet disintegrants can a weight proportion of preferably 5.0 to 50% by weight, more preferably 5.0 to 15 wt .-% based on the total weight of the pharmaceutical Composition.

lubricant are added to a pharmaceutical composition to give it flow behavior at the granulation to improve the adhesion of the composition on the devices to prevent granulation or compression to the friction between the particles decrease and around the leaching out of the To facilitate tablets from the molds. Suitable lubricants are e.g. Talc, long chain fatty acids such as stearic acid and palmitic acid, their salts such as magnesium stearate and calcium stearate, polyethylene glycol and hydrogenated vegetable oils. The lubricants can a weight proportion of preferably 0.25 to 3.0 wt .-% make up based on the total weight of the pharmaceutical composition.

From The lubricants are usually flow improvers distinguished which of the composition after granulation and added before tableting to prevent the clumping of the Prevent granules. A suitable flow improver is e.g. colloidal Silica. The flow improvers can one Weight fraction of preferably 0.1 to 3.0 wt .-% make up on the total weight of the pharmaceutical composition.

solvent can also in the pharmaceutical according to the invention Be contained in the composition, e.g. Water, ethanol or mixtures from water and ethanol. Preferred is the pharmaceutical composition but free from solvents, i.e. it has a (residual) moisture of less than 10 wt .-%, more preferably less than 5.0% by weight, more preferably less than 2.0% by weight, most preferably less as 1.0 wt .-% and in particular less than 0.5 wt .-% based on the total weight of the pharmaceutical composition. The inventive pharmaceutical Composition is preferably in solid form, in particular as a powder.

In a preferred embodiment contains the pharmaceutical composition does not contain long-chain fatty acid (e.g. stearic acid or palmitic acid) and / or no antioxidant (such as dl-α-tocopherol).

In a preferred embodiment is the pharmaceutical according to the invention Composition not for immediate administration to the patient determined, but first requires further processing. This is the case with the pharmaceutical composition according to the invention preferably a storage-stable preparation of the steroid, which optionally after the addition of further excipients to the final pharmaceutical dosage form can be further processed. Accordingly, the pharmaceutical according to the invention is Composition in this embodiment preferably in solid form, in particular as a free-flowing powder, is therefore neither granulated nor compacted (pressed). Such storage stable Preparation of the steroid contains preferably, the steroid (s), the nonionic surfactant (s) and a solid tabletting excipient selected from the group consisting from fumed silica, micronized lactose, microcrystalline Cellulose, kaolin and polyvinylpyrrolidone, but preferably none other ingredients.

The provision of the storage-stable pharmaceutical composition according to the invention, which is optionally converted into a suitable administration form only at a later time, has the advantage that that it is suitable for the production of microdosed dosage forms. Thus, due to their high effectiveness, steroid hormones are administered only in comparatively low dosages. For example, a typical tablet for the administration of ethinyl estradiol and desogestrel has a weight of 80 mg but contains only about 30 μg ethinylestradiol and only about 150 μg desogestrel. The proportion by weight of steroids in such a case is thus only about 0.225% by weight, based on the total weight of the tablet. In the production of tablets with such low drug concentrations, a homogeneous distribution and thus a small inter-individual deviation of the active ingredient content of individual tablets by mere mixing of the pure drug with the tabletting excipients hardly be achieved. In the pharmaceutical composition according to the invention, however, the solid tabletting aid is preferably at least partially coated with the nonionic surfactant in which the steroid or the mixture of different steroids is homogeneously dissolved or suspended. In this way a solid pharmaceutical composition is obtained in which the steroids are distributed homogeneously over the particles of the solid tabletting aid. Since the weight of this composition is already substantially higher than the weight of the pure steroid contained therein, the composition can be much better handled and processed into a dosage form with a homogeneous distribution of active ingredients. Mixing with further tabletting aids then no longer presents any particular difficulties with regard to the homogeneity of the active substance distribution.

is the pharmaceutical invention Composition determined only after the addition of other excipients to be further processed into a suitable dosage form, Thus, the proportion by weight of the steroid is significantly higher than in the final Dosage form, as with the addition of other auxiliaries dilution accompanied. In this case, the weight fraction of the steroid or the steroids preferably in the range of 0.1 to 50% by weight, more preferably 1.0 to 25 wt%, more preferably 2.5 to 20 wt%, most preferably 5.0 to 15 wt .-% and in particular 7.5 to 12.5 wt .-% based on the total weight of the pharmaceutical composition.

The person skilled in the art is familiar with other further ingredients with the aid of which the pharmaceutical composition, ie the above-described storage-stable preparation, can be converted into a suitable administration form for administration to the patient. For example, mixtures of suitable tabletting aids are commercially available, which can be mixed with the storage-stable preparation and then compressed into tablets. Such commercially available mixture marketed for example under the name Ludipress ^® from BASF AG, Ludwigshafen. Ludipress ^® contains 93 ± 2 wt .-% lactose monohydrate and respectively 3.5 ± 0.5 wt .-% povidone (Kollidon ^® 30) and cross-povidone (Kollidon ^® CL). Ludipress ^® LCE contains 96 ± 1.8 wt .-% lactose monohydrate and 3.5 ± 0.5 wt .-% povidone (Kollidon ^® 30).

In a particularly preferred embodiment contains the pharmaceutical invention Composition either polyvinylpyrrolidone or highly dispersed Silica, the latter being more preferred. In this case it is particularly preferred that in addition to the steroid or the steroids, the nonionic surfactant and the polyvinylpyrrolidone or the highly dispersed Silica no further adjuvants such as e.g. the above mentioned filler, Binders, disintegrants, lubricants, flow improvers, dyes, Flavorings, Antioxidants, Stabilizers, Preservatives, etc., are included. Preferably, the pharmaceutical composition contains either fumed silica or polyvinylpyrrolidone, however, no combination of these two substances.

The Pharmaceutical according to the invention Composition may contain other active ingredients, especially other steroids contain. Preferably contains however, the pharmaceutical composition desogestrel and / or Ethinyl estradiol and no other active ingredients.

The pharmaceutical according to the invention Compositions are characterized by a good storage stability of it contained steroids and good handling. They behave pH neutral. If the compositions are in powder form, see above These are free-flowing and are characterized by a good bulk density and flowability, low cohesion and low tendency to electrostatic charge. Further they are tasteless and odorless. In particular, the Compositions good for pharmaceutical dosage forms such as Tablets, dragees, multiparticulate dosage forms (such as Granules or pellets), suppositories, in particular vaginal suppositories, Ointments, creams, aerosols, transdermal patches, implants, Injection solutions, etc. be further processed.

The pharmaceutical composition according to the invention comprises at least one steroid which comprises the structural element of the general formula (I) and is storage-stabilized with the aid of at least one nonionic surfactant. This means that decomposition and degradation reactions are reduced compared to otherwise identical pharmaceutical compositions containing the steroid but not a nonionic surfactant.

Prefers is the content of the stabilized according to the invention Steroids over after storage 8 months at 25 ° C still at least in the air with a relative humidity of 50% 90.0% by weight of the original amount contained in the pharmaceutical composition, more preferably at least 92.0% by weight, more preferably at least 94.0% by weight, on most preferably at least 96.0% by weight and in particular at least 98.0% by weight of the original contained amount. The skilled person is aware of how the content of various Steroids are quantified in pharmaceutical compositions can. In this connection, it is possible to refer to the relevant pharmacopoeia (European Pharmacopoeia, US Pharmacopoeia, etc.). For ethinylestradiol For example, the quantitative analysis with the help of HPLC using suitable detectors, e.g. UV detectors.

The The invention also relates to the use of those described above pharmaceutical composition for the preparation of a dosage form for hormone treatment and / or contraception.

• (a) Zusammenbringen des Steroids mit einem nichtionischen Tensid. Bevorzugt umfasst das Verfahren ferner Schritt (b)
• (b) Auflösen des Steroids mit Wasser, einem leichtflüchtigen organischen Lösungsmittel, vorzugsweise Ethanol, oder einem Gemisch aus Wasser und dem leichtflüchtigen organischen Lösungsmittel; und bevorzugt Schritt (c)
• (c) Entfernen des Wassers, leichtflüchtigen organischen Lösungsmittels oder des Gemisches aus Wasser und dem leichtflüchtigen organischen Lösungsmittel.

Furthermore, the invention relates to a method for stabilizing a steroid as defined above, which comprises the step

• (a) contacting the steroid with a nonionic surfactant. Preferably, the method further comprises step (b)
• (b) dissolving the steroid with water, a volatile organic solvent, preferably ethanol, or a mixture of water and the volatile organic solvent; and preferably step (c)
• (c) removing the water, volatile organic solvent or the mixture of water and the volatile organic solvent.

Prefers the removal by distillation, more preferably in a Pressure below atmospheric Pressure, for example by spray drying.

• (d) Zusammenbringen des Steroids mit einem festen Tablettierungshilfsstoff, vorzugsweise ausgewählt aus der Gruppe bestehend aus hochdispersem Siliziumdioxid, mikronisierter Laktose, mikrokristalliner Cellulose, Kaolin und Polyvinylpyrrolidon.

In a particularly preferred embodiment, the method further comprises step (d)

• (d) contacting the steroid with a solid tableting aid, preferably selected from the group consisting of fumed silica, micronized lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone.

The Order of the above-defined steps (a), (b), (c) and (d) may vary, with step (b) inevitably prior to step (c) takes place.

Preferably, the method according to the invention comprises steps (a), (b), (c) and (d) according to one of the following orders:
(A) - (b) - (d) - (c);
(B) - (a) - (d) - (c); or
(B) - (d) - (a) - (c).

"Volatile organic Solvent "in the sense of the description have one at atmospheric pressure Boiling point below 100 ° C on. They are preferably alcohols or ketones with 1 to 6 carbon atoms, in particular methanol, ethanol, isopropanol and acetone. Ethanol is particularly preferred according to the invention.

• 1. Lösen des Steroids bzw. der Steroide in einem leichtflüchtigen organischen Lösungsmittel, vorzugsweise in Ethanol, vorzugsweise bei 25°C,
• 2. Zugeben eines festen Tablettierungshilfsstoffs, vorzugsweise ausgewählt aus der Gruppe bestehend aus hochdispersem Siliziumdioxid, mikronisierter Laktose, mikrokristalliner Cellulose, Kaolin und Polyvinylpyrrolidon, vorzugsweise bei 25°C,
• 3. Einrühren des nichtionischen Tensids und
• 4. Abdampfen des leichtflüchtigen organischen Lösungsmittels; oder:
• 1. Lösen des Steroids bzw. der Steroide in einem leichtflüchtigen organischen Lösungsmittel, vorzugsweise Ethanol, vorzugsweise bei 25°C,
• 2. Einrühren des nichtionischen Tensids,
• 3. Zugeben eines festen Tablettierungshilfsstoffs, vorzugsweise ausgewählt aus der Gruppe bestehend aus hochdispersem Siliziumdioxid, mikronisierter Laktose, mikrokristalliner Cellulose, Kaolin und Polyvinylpyrrolidon, in einem leichtflüchtigen organischen Lösungsmittel, vorzugsweise Ethanol, und
• 4. Abdampfen des leichtflüchtigen organischen Lösungsmittels; oder:
• 1. Lösen des Steroids bzw. der Steroide in geschmolzenem nichtionischen Tensid bei einer Temperatur oberhalb der Erweichungstemperatur des nichtionischen Tensids, vorzugsweise bei ca. 50°C,
• 2. Zugeben von Wasser,
• 3. Einrühren eines festen Tablettierungshilfsstoffs, vorzugsweise ausgewählt aus der Gruppe bestehend aus hochdispersem Siliziumdioxid, mikronisierter Laktose, mikrokristalliner Cellulose, Kaolin und Polyvinylpyrrolidon, und
• 4. Abdampfen des Wassers; oder:
• 1. Lösen des Steroids bzw. der Steroide in geschmolzenem nichtionischen Tensid bei einer Temperatur oberhalb der Erweichungstemperatur des nichtionischen Tensids, vorzugsweise bei ca. 50°C,
• 2. Zugeben eines leichtflüchtigen organischen Lösungsmittels, vorzugsweise Ethanol,
• 3. Zugeben von Wasser,
• 4. Verrühren mit einem festen Tablettierungshilfsstoff, vorzugsweise ausgewählt aus der Gruppe bestehend aus hochdispersem Siliziumdioxid, mikronisierter Laktose, mikrokristalliner Cellulose, Kaolin und Polyvinylpyrrolidon, und
• 5. Abdampfen des Lösungsmittelgemisches.

Particularly preferred process variants comprise the following sequence of steps:

• 1. dissolving the steroid or steroids in a volatile organic solvent, preferably in ethanol, preferably at 25 ° C.,
• 2. adding a solid tabletting aid, preferably selected from the group consisting of fumed silica, micronised lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone, preferably at 25 ° C,
• 3. Stirring in of the nonionic surfactant and
• 4. evaporation of the volatile organic solvent; or:
• 1. dissolving the steroid or steroids in a volatile organic solvent, preferably ethanol, preferably at 25 ° C.,
• 2. stir in the nonionic surfactant,
• 3. Adding a solid tabletting aid, preferably selected from the group consisting of fumed silica, micronized lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone, in a volatile organic solvent, preferably ethanol, and
• 4. evaporation of the volatile organic solvent; or:
• 1. dissolving the steroid or steroids in molten nonionic surfactant at a temperature above the softening temperature of the nonionic surfactant, preferably at about 50 ° C,
• 2. adding water,
• 3. stirring a solid tabletting aid, preferably selected from the group consisting of fumed silica, micronized lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone, and
• 4. evaporation of the water; or:
• 1. dissolving the steroid or steroids in molten nonionic surfactant at a temperature above the softening temperature of the nonionic surfactant, preferably at about 50 ° C,
• 2. adding a volatile organic solvent, preferably ethanol,
• 3. adding water,
• 4. Stirring with a solid tableting aid, preferably selected from the group consisting of fumed silica, micronized lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone, and
• 5. evaporation of the solvent mixture.

The The invention also relates to stabilized compositions which obtainable by any of the methods described above, and the use of a nonionic surfactant described above to increase the storage stability a steroid as defined above.

The The following examples serve to further illustrate the invention, however, are not limiting as to to interpret their scope.

Example 1:

10 ml of ethanol were placed in a 50 ml round bottom flask. Successively, 30 mg of ethinylestradiol and 150 mg of desogestrel were dissolved at 25 ° C. Subsequently, 2.4 g of polyvinylpyrrolidone (PVP) were dissolved at 25 ° C. A clear solution in which 1 g of Cremophor ^® RH 40 stirring it was obtained. The solution became cloudy by the addition of Cremophor ^® RH 40th The ethanol was removed by rotary evaporation at reduced pressure. A solid residue was obtained.

Example 2:

3 ml of ethanol were placed in a 50 ml round bottom flask. Successively, 30 mg of ethinylestradiol and 150 mg of desogestrel were dissolved at 25 ° C. The mixture was stirred 800 mg Cremophor ^® RH 40 and received a clear solution. Subsequently, 800 mg of silica were added to the active ingredient mixture using 10 ml of ethanol. A pulpy mass was obtained, which did not stir well. The ethanol was removed by rotary evaporation at reduced pressure. A solid residue was obtained.

Example 3:

Was dissolved at 50 ° C 30 mg of ethinyl estradiol and desogestrel 150 mg in 800 mg molten Cremophor ^® RH 40 and gave a clear melt. It was then diluted slowly with 25 ml of purified water and stirred in 800 mg of silica. The water was removed from the rotavapor under reduced pressure. A solid residue was obtained.

Example 4:

Was dissolved at 50 ° C 30 mg of ethinyl estradiol and desogestrel 150 mg in 800 mg Cremophor ^® RH 40 and gave a clear melt. After the melt had cooled slightly, it was diluted with 2 ml of ethanol and 12.5 ml of purified water were added slowly, giving a slightly turbid mixture. 1450 .mu.l were taken up, and the mixture was made up to a volume of 30 ml with water and immediately mixed with 80 mg of silicon dioxide. The ethanol-water mixture was withdrawn on a Rotavapor under reduced pressure. A solid residue was obtained.

Example 5:

Was dissolved at 50 ° C 30 mg of ethinyl estradiol and desogestrel 150 mg in 800 mg Cremophor ^® RH 40 and gave a clear melt. After the melt had cooled slightly, it was diluted with 1 ml of ethanol and slowly added to 5 ml of purified water to give a mixture which became slightly cloudy after about 30 minutes. 600 μl was taken, diluted with purified water to a volume of about 20 ml and stirred with 80 mg of silica. The ethanol-water mixture was withdrawn on a Rotavapor under reduced pressure. A solid residue was obtained.

determination the storage stability

The storage stability desogestin and ethinyl estradiol in the examples 1 to 5 prepared pharmaceutical compositions were examined. The compositions were at 25 ° C and a relative humidity of 50% stored in sealed HPLC vials and the content on desogestrel and ethinylestradiol before storage (= 100%) and after storage determined by HPLC analysis.

The Results are summarized in Tables 1 and 2; the quantities for water and ethanol refer to those in the preparation of the pharmaceutical Composition temporarily existing quantities:

Table 1:

Table 2:

As The examples can prove, by the inventive method a pharmaceutical composition are prepared in the Desogestrel and ethinyl estradiol after 8 months storage at 25 ° C still salary levels of more than 95%. On antioxidant or embedding agent like stearic acid can be dispensed with.

The Storage-stable composition can be pulverized, for example, mortared and further processed for the production of tablets or other dosage forms become.

Claims (18)

A pharmaceutical composition comprising a nonionic surfactant and a steroid containing a structural element of the general formula (I)

wherein R _{1 is} -H or -C ₁ -C ₆ -alkyl; R _{2 is} -H or -CO-C ₁ -C ₆ -alkyl; and R ₃ , R ₄ , R ₅ and R _{6 are} independently -H, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₅ -C ₁₀ -Aryl, -C ₁ -C ₆ -alkylene-C ₅ -C ₁₀ -aryl, -C ₁ -C ₁₀ -heteroaryl, -C ₁ -C ₆ -alkylene-C ₁ -C ₁₀ -heteroaryl, -C ₁ - C ₆ -alkylene-OC ₁ -C ₆ -alkyl, -CN, -CO ₂ H, -CO ₂ -C ₁ -C ₆ -alkyl, -CONH ₂ , -CONH-C ₁ -C ₆ -alkyl, -CON (C ₁ -C ₆ -alkyl) ₂ , -OH, -OC ₁ -C ₆ -alkyl, -OCO-C ₁ -C ₆ -alkyl, -NH ₂ , -NH-C ₁ -C ₆ -alkyl, - N (C ₁ -C ₆ alkyl) ₂ or -NHCO-C ₁ -C ₆ alkyl, or R ₃ together with R ₄ , or R ₅ together with R _{6 form} a group = CH ₂ , or R ₃ and R ₅ together with the carbon atoms to which they are attached form a cyclopropyl ring. A composition according to claim 1, characterized in that R _{1 is} -CH ₃ or -CH ₂ CH ₃ and that R ₂ , R ₃ , R ₄ , R ₅ and R _{6 are} -H. Composition according to Claim 1 or 2, characterized that it comprises two different steroids, both of which are a structural element of the general formula (I). Composition according to one of the preceding claims, characterized characterized in that it contains ethinylestradiol and / or desogestrel. Composition according to one of the preceding claims, characterized characterized in that the nonionic surfactant is selected from the group consisting of fatty alcohols, sterols, sorbitan fatty acid esters, Polyoxyethylene sorbitan, Polyoxyethylene fatty acid glycerides Polyoxyethylene Fettsäureestern, Polyoxyethylene fatty alcohol ethers, glyceryl fatty acid esters and poloxamers. Composition according to one of the preceding claims, characterized characterized in that the nonionic surfactant is a polyoxyethylene fatty acid glyceride is. Composition according to one of the preceding claims, characterized in that the nonionic surfactant is macrogol glyceryl hydroxystearate is. Composition according to one of the preceding claims, characterized characterized in that the composition is a solid tableting excipient contains. Composition according to Claim 8, characterized that the solid tableting aid is selected from the group consisting from fumed silica, micronized lactose, microcrystalline Cellulose, kaolin and polyvinylpyrrolidone. Composition according to one of the preceding claims, characterized characterized in that it is in powder form. Use of a pharmaceutical composition according to one of the claims 1 to 10 for the preparation of a medicament for hormone treatment and / or a contraceptive. A method for stabilizing a steroid defined as in claim 1 or 2 comprising the step (a) Matching of the steroid with a nonionic surfactant. Method according to claim 12, characterized in that that it comprises step (b) (b) contacting the steroid with water, a volatile organic solvents or a mixture of water and volatile organic solvent. Method according to claim 13, characterized in that that it includes the step (c) removing the water, volatile organic solvent or mixtures of water and volatile organic solvents. Method according to one of claims 12 to 14, characterized that it comprises step (d) (d) contacting the steroid with a solid tabletting aid, preferably selected from Group consisting of fumed silica, micronized Lactose, microcrystalline cellulose, kaolin and polyvinylpyrrolidone. Method according to claims 12 to 15, characterized in that steps (a), (b), (c) and (d) follow one of the following orders carried out are: (a) - (b) - (d) - (c); (B) - (a) - (d) - (c); or (b) - (d) - (a) - (c). Pharmaceutical composition available by a method according to claim 16. Use of a nonionic surfactant to increase the storage stability a steroid as defined in claim 1 or 2.