DE19847252B4 - Buccally applicable bioadhesive systems with time-controlled release of active ingredient containing testosterone esters and optionally additional testosterone - Google Patents

Abstract

The use of testosterone esters with 1-20C carboxylic acids (or their mixtures with other such esters and/or testosterone) is claimed in the preparation of buccally applied bioadhesive systems for time-controlled active agent release in the treatment of diseases associated with variations of testosterone levels.

Description

The invention relates to the combination of testosterone with testosterone esters (or use alone of testosterone esters) in a buccal, bioadhesive preparation, so that by finely tuned dosage of active ingredients and selection of esters time-controlled various desired Individual testosterone plasma levels, e.g. to restore of a circadian body Rhythm can be established or established.

Testosterone is quantitative and qualitative the most important androgen that is synthesized in the body. It will mainly in the testes, in small amounts in the adrenal cortex and in Women formed in the ovaries. Testosterone is responsible in men for the Development of the male shaping during the fetal, neonatal and adolescent Maturation and finally for the Receipt of the male phenotype, as well as androgen addicts Functions (e.g. spermatogenesis). Testosterone is protein-anabolic Effect (on muscles, bones, hematopoiesis, kidney, liver) [E. Mutschler, Medicinal Effects, 6th Edition, pp. 334 - 337, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart 1991].

With oral or parenteral administration of testosterone finds rapid absorption in the gastrointestinal tract, subsequently Transport via the portal vein into the liver with subsequent high metabolism which has a short plasma half-life of testosterone of approx. 10 min conditional [Auterhoff, H., Knabe, J., Höltje, H.-D., Textbook of Pharmaceutical Chemistry, 12th ed., 570 - 573, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart 1991]. To build Physiological serum levels require oral administration of 400 mg (!) testosterone [S.G. Johnson, E.P. Bennet, V.G. Jensen: Therapeutic effectiveness of oral testosterone. Lancet, 2, 1974, 1473-1475].

To prolong the testosterone effect testosterone esters (testosterone propionate, Testosterone enanthate, testosterone undecanoate) of various chain lengths intramuscularly as an oily solution or Suspension. It is known that in Contact with body fluids of the tissue slowly hydrolyze these esters under the influence of esterases and release the pharmacologically active testosterone. The influence of the type of ester on the growth of the capon crest after i.m. Injection is already described [Meier R. and Tschopp E .: Arch. Exptl. Pathol. Pharmacol. 226,532 (1955)].

In addition, testosterone undecanoate (as a soft gelatin capsule in oleic acid) orally via the lymphatic path applied. about the oleic acid embedding the drug comes from the gastrointestinal tract through the Thoracic duct in the lymphatic system and thus in the systemic Circulation. However, there are variable serum levels and gastrointestinal Side effects. These effects can complicate long-term therapy for substitution [A.M. Matsumoto: Hormonal therapy of male hypogonadism. Endocrinol. Metab. Clin. North At the. 23, 1994, 857-875].

Other application routes (transdermal, nasal, sublingual, buccal. subcutaneous) have been developed by various research groups examined [e.g .: N.A. Mazer, W.E. Heiber, J.F. Moellmer, A.W. Meikle, J.D. Stringham, S.W. Sanders, K.G. Tolman, W.D. Odell: Enhanced transdermal delivery of testosterone: a new physiological approach for androgen replacement in hypogonadal men. J. Controll. Rel. 19: 347-362 (1992)].

Disadvantages of the aforementioned therapies are 1. either a too short, rapidly draining testosterone level (with oral administration) or 2. - in Case of intramuscular Injection of testosterone esters - the unchangeability of constantly set Testosterone levels above longer periods (Days to weeks) that do not have individual timing of the Enable testosterone effect in one application form. In addition, it can here come down regulation of basal testosterone secretion.

The high first pass effect Low bioavailability in the liver can be caused by buccal or sublingual application can be avoided. Different studies prove this [e.g .: Pitha, J., Anaissie, J., Uekama, K .: g-cyclodextrin: testosterone complex suitable for sublingual administration. J. Pharmaceutical Sciences, 76 (10) 1987, 788-790].

Buccal application of drugs is known in the art.

EP 0 371 466 A1 relates to a quick-dissolving tablet for rapid buccal application of steroids (eg estrogens, progestins). A water-soluble polyalcohol, primarily sorbitol, is used as the main auxiliary ingredient. The advantage is the rapid initial increase in the drug concentration.

EP 0 286 581 A1 includes the transmucosal buccal application of estrogens (17β-estradiol and ethinylestradiol): The estrogen is used in the context of hormone replacement therapy in postmenopausal women for the treatment of PMS (postmenopausal syndrome) and osteopo-rosotherapy in a dosage of 50 - 100 μg / day (17β-estradiol for PMS therapy) or 200 - 400 μg / day (17β-estradiol for osteoporosis therapy). The buccal application allows therapeutic plasma levels to be achieved bypassing the first-pass effect.

WO 87/04 342 A1 describes a special formulation, which is particularly useful for buccal application of estrogens (e.g. estradiol and esters of estradiol), progestins, androgens and anabolic steroids should be suitable: The formulation contains a) approx. 1 - 20% of a soluble, adhesive polymer (carbomers, partially hydrolyzed PVA, polyethylene oxide, polyacrylate, hydroxypropylmethyl cellulose, b) a soluble, directly tablettable excipient and c) the active ingredient. The adhesive polymer fixes the formulation or pharmaceutical form at the application site.

US 43 96 615 A. describes the treatment of androgen-related diseases by administering the testosterone 5α-reductase inhibitor 6-methylene progesterone using topical formulations. These contain the inhibitor and an inert topical carrier (including silicones, methyl cellulose, hydroxymethyl cellulose).

CA 2105887 A discloses a bio-erodable System for buccal and vaginal application etc. of hormones (Estradiol). The system is water soluble and mucoadherent. It consists of a solid, soluble, lyophilized foam and the active ingredient. The dissolution time is at least 8 h. The system adheres to the mucosal membrane where it is releases the drug. Polymers used are primarily gelatin, sodium carboxy methyl cellulose, Methyl cellulose etc. The advantage of the system is especially the long one Detention period.

In DE 35 03 679 C2 discloses a method for embedding a progesterone derivative in swellable, water-insoluble polymers in order to achieve better solubility and faster release of the active ingredient.

Font WO 91/06 289 A1 sets carrier system for different therapeutic agents (including steroids) that adhere to the mucosa (buccal, vaginal or rectal) controls its active ingredients releases. The carrier itself is a hydratable amorphous silica.

Document WO 96/10 395 A1 describes a preparation with controlled drug release that consists of microparticles calcium or aluminum salts with active ingredients adsorbed thereon consists. The preparation is produced by spray drying, as in the present invention. In Examples 2 and 3, a preparation with slow or moderate release.

WO 96/10 397 A1 describes a microcapsule which discloses a pharmaceutical agent and a biodegradable Contains polymer. The composition according to the invention promotes the absorption of slightly water-soluble substances in the digestive tract.

In conventional drugs the rate of drug release is controlled via galenics, however, according to the invention by using a mixture of different prodrugs in the form of Testosterone esters with variable chain length and structure that pass through endogenous Esterases are hydrolyzed at different speeds. This will allows also complicated, e.g. B. adjust circadian drug profiles.

For release control with conventional Depot drugs predominantly passively dissolving, Diffusion, swelling and erosion processes used [Gröning, R., Drug forms with electronically controlled release, in pharmaceutical Technology: Modern drug forms, p. 441. Ed., Müller, R.H., Hildebrand, G.E. (Ed.), Scientific Publishing Company mbH Stuttgart 1998).

The timed release of Medicaments are also known from the prior art.

JP 07 118 143 A relates to time-controlled capsules which a) are water-insoluble or partially water-soluble, b) from water-swellable substances (powders, granules or pills, e.g. calcium carboxymethyl cellulose, polyvinylpyrrolidone), c) elements (tablets) with an active ingredient in the center of the capsules.

Further prior art relates to sustained-release preparations using polymer, such as, for example EP 0 068 446 A2 for the use of methyl cellulose or carboxymethyl cellulose in mixtures for retardation.

The object of the invention is that Advantages of buccal application of steroids with a high first-pass effect and low bioavailability, specifically from testosterone and its esters, with the use of the different pharmacokinetics of the different testosterone esters (depending on chain length) to be used in such a way that careful Selection of suitable dosages and esters the desired drug profile can be adjusted.

The task is through use of testosterone esters with 1 to 20 carbon atoms in the carboxylic acid residue or mixtures of two or more testosterone esters with different Carboxylic acid residues or Mixtures of testosterone esters with testosterone for manufacture of buccally applicable bioadhesive systems with timed drug release for the treatment of Diseases associated with an altered testosterone level go along, solved.

It is preferred that testosterone esters are used in which the carbon skeletons of the carboxylic acid residues straight chain, branched, alicyclic, saturated and / or unsaturated with up to five Double and / or triple bonds are.

It is further preferred that in mixtures of testosterone esters and testosterone the ratio of Testosterone to testosterone ester is 1: 100 to 1: 1, particularly preferably 1:10 to 1: 1.5.

It is particularly preferred that the buccal to be applied bioadhesive Systems available by first separating the active ingredients or together in a spray drying process amorphously embedded in organic polymers.

It is very particularly preferred that he the amorphous testosterone spray products together with other auxiliaries, binders, fillers, Lubricants, bioadhesive Polymers, surfactants, accelerators and mixes into single or Multi-layer tablets pressed.

The use according to the invention is preferred for the targeted setting of therapeutic or circadian rhythms the testosterone level.

Surprisingly it was found that the chain length of the testosterone ester not only determines the solubility, but as could be shown experimentally, the ester cleavage kinetics in the Blood or tissue fluids through appropriate hydrolases. Particularly noteworthy is the Use of testosterone esters using spray embedding techniques in organic polymers (polyvinylpyrrolidone, hydroxypropylmethyl cellulose, solid polyethylene glycols) to provide a correspondingly improved solubility in the oral cavity to achieve. This is particularly important against the background of less Saliva volumes (approx. 1 - 1.5 ml), which are there on average to solve the poorly soluble Esters available stand. In the publication by Jody Voorspoels [Vorspoels, J., Remon, J.-P., Eechaute, W.E., De Sy, W., Buccal Absorption of Testosterone and Its Esters Using a Bioadhesive Tablet in Dogs, Pharmaceutical Research, Vol. 13, No. 8, 1996, 1228-1223) showed the castrated on 6 Beagle dogs examined testosterone esters (testosterone acetate, Testosterone propionate, testosterone enanthate, testosterone decanoate) despite the higher Lipophilia no higher bioavailability as testosterone. Because the esters can only be mixed directly by dry pressed were without a special pre-formulation technology (Amorphization by spray embedding) was used, these worse results are probably due on the sometimes extremely low solubility of the esters in crystalline Status.

It could be shown that by the buccal application of testosterone in combination with testosterone esters different chain length Different blood level patterns or rhythms (in the sense of a circadian Rhythm) can be set. When choosing the testosterone ester, the selection can be targeted three groups can be carried out: 1. esters of shorter chain length (e.g. Testosterone acetate or propionate), 2. medium chain ester (e.g. Testosterone enanthate, cipionate, cyclohexane carboxylate) and 3rd ester of higher chain length (e.g. Tetosterone undecanoate, bucyclate).

According to the invention the task is thereby solved, that testosterone and the respective testosterone ester in ethanol together with the polymer (e.g. polyvinylpyrrolidone or hydroxypropylmethyl cellulose) dissolved and closed an amorphous spray embedding in a spray drying system is processed further. It is possible that 1. the active ingredients mentioned separately from each other or 2. together in one work step be embedded amorphously.

The fine-grained spray embedding is then shared with others Auxiliaries for the production of bioadhesive buccal tablets (binder: Polyvinyl pyrrolidone, cellulose ether; Filler: mannitol, sorbitol, Cellulose, lactose, lubricant magnesium stearate, hydrogenated vegetable fats, bioadhesive Polymers: polyacrylates, sodium carboxymethyl cellulose and possibly others Excipients, such as surfactants, disintegration agents) mixed dry and pressed into buccal tablets, which can also be built up in layers (active ingredient layer, bioadhesive adhesive layer; uni- or multidirectional release).

• – Dosierung der Wirkstoffkomponente
• – Wahl des Esters bzw. der Kettenlänge an C-17 entsprechende Freisetzungsmuster eingestellt werden.

Based on blood level tests with the mono substances, you can choose the two parameters

• - Dosage of the active ingredient
• - Selection of the ester or the chain length can be set at C-17 corresponding release patterns.

Has proven advantageous, for example the combination of the short-acting testosterone together with the Testosterone undecanoate (C-11 chain) with a longer half-life (see exemplary embodiments).

A ratio of is preferred Active ingredients to each other, the ratio of testosterone: F testosterone ester: 1: 100 to 1: 1, particularly preferably 1:10 to 1: 1.5.

By cleverly combining testosterone and testosterone esters, it is possible to set blood level profiles that are able to map or simulate the body's own rhythmicity of endogenous testosterone levels: For example, the duration of action of a bioadhesive buccal tablet with testosterone can be extended by combining it with testosterone undecanoate (cf. 1 and 3 ): Blood level values> 100 ng / ml are extended in the application example (equimolar combination) in the female dog from approx. 2 h to over 4 h; in addition, a pronounced (smaller) 2nd pulse with a maximum after approx. 3 h can be recognized. After 8 hours, the testosterone levels of almost 50 ng / ml are still twice as high compared to the administration of the mono substance.

• – die Kettenlänge und räumliche Struktur der Esterkette an C-17: Diese bestimmt einerseits die Lipophilie und damit die Löslichkeit, andererseits in ausgeprägter Weise die Esterspaltungs- bzw. Hydrolysegeschwindigkeit (Wechselwirkungen der Esterseitenkette mit dem aktiven Zentrum der Hydrolasen). So werden Ester höherer Kettenlänge langsamer gespalten als solche mit mittlerer bzw. kürzerer Länge. In diesem Sinne flutet das dadurch freigesetzte Testosteron langsamer an als bei Gabe reinen Testosterons; der Peak erscheint später. Über die Kettenlänge besteht somit die Möglichkeit einer mehr oder minder gezielten Zeitsteuerung der arzneilichen Wirkung;
• – die Dosierung von Testosteron und Testosteronester in der Mischung über die direkte Proportionalität der AUC (Fläche unter der Kurve, Integral des Serumspiegels über die Zeit) in Relation zur applizierten Dosis

Essentially, the set blood test course is controlled by two parameters:

• - The chain length and spatial structure of the ester chain at C-17: This determines the lipophilicity and thus the solubility on the one hand, and the rate of ester cleavage or hydrolysis on the other hand (interactions of the ester side chain with the active center of the hydrolases). For example, esters of higher chain lengths are split more slowly than those with medium or shorter lengths. In this sense, the testosterone released thereby floods more slowly than when pure testosterone is administered; the peak appears later. Over the chain length there is thus the possibility of more or less targeted time control of the medicinal effect;
• - The dosage of testosterone and testosterone ester in the mixture via the direct proportionality of the AUC (area under the curve, integral of the serum level over time) in relation to the dose applied

This could have an impact on hormone replacement (Hormone Replacement Therapy) in older men with partial androgen deficiency (so-called PADAM patients) have a corresponding lack of plasma levels be corrected therapeutically.

From the state of the art well-known wording:

Bioadhesive tablet with testosterone

recipe

production:

Preparation of the preformulation:

The pre-formulation of testosterone (20%) is by spray drying manufactured. The active ingredient is combined with the polymer (polyvinylpyrrolidone, Hydroxypropylmethylcellulose e.g.) and possibly another auxiliary (Carrier or antistatic auxiliary) in a suitable solvent solved or suspended. The through constant stir homogenized suspension becomes a in a spray drying system fine-grained Spray dried powder.

Production of the active substance layer

This pre-formulation is put together with the other additives in the active substance layer (mannitol, cellulose, Lactose) in a suitable mixer (type: cube mixer, turbulami mixer, Tumble mixer etc.) approx. 20 min and then adding the outer phase (Carmellose sodium, magnesium stearate, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc are in a ball mill rubbed intimately. Subsequently mix for approx. 20 min in a suitable mixer (type: cube mixer, Turbulators, tumble mixers etc.) mannitol, cellulose and lactose, gives the trituration as well as carmellose sodium and magnesium stearate as the outer phase add and mix again for 5 min.

Active ingredient and adhesive layer subsequently on a suitable tablet press according to the mass relation compressed into two-layer tablets.

1 shows the blood level curve of a formulation corresponding to the above-mentioned prior art.

Example 1:

Bioadhesive tablet with testosterone undecanoate

recipe

production:

Preparation of the preformulation:

The pre-formulation of testosterone undecanoate (20%) is by spray drying manufactured. The active ingredient is combined with the polymer (polyvinylpyrrolidone, Hydroxypropylmethylcellulose e.g.) and possibly another auxiliary (Carrier or antistatic auxiliary) dissolved in a suitable solvent or sus commutes. The through constant stir homogenized suspension becomes a in a spray drying system fine-grained Spray dried powder.

Production of the active substance layer

This preformulation, together with the other excipients of the active substance layer (mannitol, cellulose and lactose), is carried out in a suitable mixer (type-cube mixer, turbulami mixer, tumble mixer etc.) for about 20 minutes and then with the addition of the outer phase (carmellose sodium, magnesium stearate, Talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc are in a ball mill rubbed intimately. Subsequently mix for approx. 20 min in a suitable mixer (type: cube mixer, Turbulatory, tumble mixer etc.) mannitol, cellulose and lactose, gives the trituration as well as carmellose sodium and magnesium stearate as the outer phase add and mix again for 5 min.

Active ingredient and adhesive layer subsequently on a suitable tablet press according to the mass relation compressed into two-layer tablets.

2 shows the blood level curve of a formulation according to Example 1.

Example 2:

Bioadhesive tablet with testosterone and testosterone undecanoate

recipe

production:

Preparation of the preformulation:

The testosterone / testosterone undecanoate pre-formulation (20%) is by spray drying manufactured. Both active ingredients are used together with the polymer (Polyvinylpyrrolidone, hydroxypropylmethyl cellulose e.g.) and possibly another auxiliary (carrier or antistatic active agent) in a suitable solvent solved or suspended. The through constant stir Homogenized suspension can be combined in a spray drying system fine-grained Spray dried powder become.

Production of the active substance layer

This pre-formulation is put together with the other excipients of the active substance layer (mannitol, cellulose and lactose) in a suitable mixer (type: cube mixer, turbula mixer, Tumble mixer etc.) approx. 20 min and then adding the outer phase (Carmellose sodium, Magnesium stearate, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc are in a ball mill rubbed intimately. Subsequently mix for approx. 20 min in a suitable mixer (type: cube mixer, Turbulatory, tumble mixer etc.) mannitol, lactose and cellulose, gives the trituration as well as carmellose sodium and magnesium stearate as the outer phase add and mix again for 5 min.

Active ingredient and adhesive layer subsequently on a suitable tablet press according to the mass relation compressed into two-layer tablets.

3 shows the blood level curve of a formulation according to Example 2.

Example 3:

sBioadhesive tablet with testosterone, testosterone enanthate)

recipe

production:

Preparation of the preformulation:

The pre-formulation of testosterone / testosterone enanthate (20%) is by spray drying manufactured. Both active ingredients are used together with the polymer (Polyvinylpyrrolidone, hydroxypropylmethyl cellulose e.g.) and possibly another auxiliary (carrier or antistatic auxiliary) in a suitable solvent solved or suspended. The through constant stir homogenized suspension becomes a in a spray drying system fine-grained Spray dried powder.

Production of the active substance layer

This pre-formulation is put together with the other additives in the active substance layer (mannitol, calcium phosphate) in a suitable mixer (type: cube mixer, turbula mixer, Tumble mixer etc.) approx. 20 min and then adding the outer phase (Polyacrylic acid, Magnesium stearate, talc) mixed again for 5 min.

Iron oxide red and talc, for example in a ball mill rubbed intimately. Then mixes approx. 20 min in a suitable mixer (type: cube mixer, turbulami mixer, Tumble mixer etc.) Mannitol and calcium phosphate, gives the color rubbing and polyacrylic acid and magnesium stearate as the outer phase and mix 'again 5 min.

Active ingredient and adhesive layer subsequently on a suitable tablet press according to the mass relation compressed into two-layer tablets.

Example 4:

Bioadhesive tablet with testosterone propionate and testosterone decanonate

recipe

production:

Preparation of the preformulation:

The testosterone propionate / testosterone decanoate pre-formulation (20%) is made by spray drying. Both active ingredients are combined with the polymer (polyvinylpyrrolidone, Hydroxypropylmethylcellulose e.g.) and possibly another auxiliary (Carrier or antistatic auxiliary) in a suitable solvent solved or suspended. The through constant stir Homogenized suspension becomes a in a spray drying system fine-grained Spray dried powder.

Production of the active substance layer

This pre-formulation, together with the other excipients of the active ingredient layer (mannitol, calcium phosphate) in a suitable mixer (type: cube mixer, turbula mixer, tumble mixer etc.), is repeated for about 20 minutes and then with the addition of the outer phase (polyacrylic acid, magnesium stearate, talc) 5 min mixed.

Production of the adhesive layer

Iron oxide red and talc are in a ball mill rubbed intimately. Subsequently mix for approx. 20 min in a suitable mixer (type: cube mixer, Turbulatory, tumble mixer etc.) mannitol and calcium phosphate, gives the trituration as well as polyacrylic acid and magnesium stearate as the outer phase add and mix again for 5 min.

Active ingredient and adhesive layer subsequently on a suitable tablet press according to the mass relation compressed into two-layer tablets.

Claims (7)

Buccally applicable bioadhesive systems with time-controlled Active ingredient release of testosterone esters with 1 to 20 C atoms in the carboxylic acid residue or mixtures of two or more testosterone esters with different Carboxylic acid residues or mixtures of the testosterone esters with testosterone, the Active ingredient release through the choice of chain length and the spatial Structure of the carboxylic acid residue of the ester as well as about the dosage of testosterone and testosterone ester is controlled. Buccally applicable bioadhesive Systems according to claim 1, characterized in that the Carbon skeletons the carboxylic acid residue straight chain, branched, alicyclic, saturated and / or unsaturated with up to five Double and / or triple bonds are. Buccally applicable bioadhesive Systems according to one the preceding claims, characterized in that in Mixtures of testosterone esters and testosterone have the ratio of Testosterone to testosterone ester 1: 100 to 1: 1, preferably 1:10 to 1: 1.5. Buccally applicable bioadhesive Systems according to one the preceding claims, characterized in that they available by first separating the active ingredients or together in a spray drying process amorphously embedded in organic polymers. Buccally applicable bioadhesive Systems according to claim 4, characterized in that one the amorphous testosterone spray products mixes with other excipients and to single or multi-layer tablets pressed. Use of the buccally applicable bioadhesive systems according to one of the preceding claims for the treatment of diseases with a changed Testosterone levels go hand in hand Use of the buccally applicable bioadhesive systems according to claim 6 for the targeted setting of therapeutic or circadian rhythms the testosterone level.