DE19847252A1 - Controlled administration of testosterone, e.g. for hormone replacement therapy, using buccal bioadhesive system containing testosterone ester(s) to give targeted release profile - 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 using only Testosterone esters) in a buccal, bioadhesive accessory riding, so that the effect by fine-tuned dosage substances and selection of esters time-controlled different desired testosterone plasma levels in patients indi vidual, e.g. B. to restore a circadian body's own rhythm can be established or produced nen.

Testosterone is the significant quantitative and qualitative androgen that is synthesized in the body. It will mainly in the testes, in small quantities in the ne adrenal cortex and formed in women in the ovaries. In men, testosterone is responsible for development male expression during fetal, neo natal and pubescent maturation and finally for the Preservation of the male phenotype and androgen dependent functions (e.g. spermatogenesis). testosterone has a protein-anabolic effect (on muscles, bones, Hematopoiesis, kidney, liver) [E. Mutschler, pharmaceuticals effects, 6th edition, pp. 334-337, Scientific Verlagsgesellschaft mbH Stuttgart 1991].

With oral or parenteral administration of testosterone takes place rapid absorption in the gastrointestinal tract including transport through the portal vein into the liver subsequent high metabolism, which is a short one Plasma half-life of testosterone of approx. 10 min dingt [Auterhoff, H., Knabe, J., Höltje, H.-D., textbook der Pharmaceutical Chemistry, 12th ed., 570-573, Wissen  society publishing house mbH Stuttgart 1991]. To the Building up physiological serum levels is oral administration 400 mg (!) testosterone required [p. G. Johnson, E. P. Bennet, V. G. Jensen: Therapeutic effectiveness of oral testosterone. Lancet, 2, 1974, 1473-1475].

To prolong testosterone activity, one injects testosterone ester (testosterone propionate, Testosterone enanthate, testosterone undecanoate) various Chain length intramuscularly as an oily solution or suspensi on. It is known that in contact with body fluids th esters of tissue slowly under the influence of Hydrolyze esterases and the pharmacologically effective Release testosterone. The influence of the ester type on the Growth of the capon crest after i. m. Injection is be already described [Meier R. and Tschopp E .: Arch. Exptl. Pathol. Pharmacol. 226, 532 (1955)].

In addition, testosterone undecanoate (as a soft gel capsule in oleic acid) orally via the lymphatic route applied [preparation Andriol®]. About the oleic acid the drug comes from the gastrointestinal tracts through the thoracic duct into the lymphatic system and such into the systemic circulation. However, it does result variable serum levels and gastrointestinal side effects These effects can be a long-term therapy for Substi make it difficult [A. M. Matsumoto: Hormonal therapy of male hypogonadism. Endocrinol. Metab. Clin. North Am. 23, 1994, 857-875].

Other application routes (transdermal, nasal, sublingu al. buccal. subcutaneous) have been developed by various researchers groups examined [e.g. B .: 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 one too short, rapidly draining testosterone levels (at oral administration) or 2. - in the case of intramuscular injection tion of testosterone esters - the unchangeability con Constantly set testosterone levels over a long period rooms (days to weeks) that do not have an individual time Control of the testosterone effect in an application enable form. In addition, it can be down here regulation of basal testosterone secretion.

Due to the high first-pass effect in the liver Due to low bioavailability, buccal or sublingual application can be avoided. Various Studies prove this [e.g. E.g .: Pitha, J., Analssie, J., Ue kama, K .: g-cyclodextrin: testosterone complex suitable for sublingual administration. J. Pharmaceutical Scien ces, 76 (10) 1987, 788-790].

The buccal application of drugs is in the state known in the art.

EP-0371466 A relates to a quick-dissolving tablet for rapid buccal application u. a. of steroids (e.g. Estrogens, progestins). As the main auxiliary ingredient a water-soluble polyalcohol is used, in the first Sorbitol line. The advantage is the rapid initial increase the drug concentration.

EP-0286581 A contains the transmucosal buccal appli cation of estrogens (17β-estradiol and ethinylestra diol); The estrogen is used as part of the hormone Replacement therapy for postmenopausal women PMS (postmenopausal syndrome) and osteo  Porose therapy in a dosage of 50-100 µg / day (17β-estradiol for PMS therapy) or 200-400 µg / day (17β-estradiol for osteoporosis therapy). By The buccal application can have therapeutic plasma levels bypassing the first pass effect.

WO-704342 describes a special formulation which u. a. especially for the buccal application of estrogens (e.g. estradiol and esters of estradiol), progestins, Androgens and anabolic steroids are said to be suitable: The formulation contains a) approx. 1-20% of a soluble, adhesive polymers (carbomers, partially hydrolyzed PVA, polyethylene oxide, polyacrylate, hydroxypropylme thylcellulose, b) a soluble, directly tablettable Excipient and c) the active ingredient. The adhesive polymer fi fixes the formulation or pharmaceutical form on the application Job.

US-4396615 A describes the treatment of androgen-related Diseases caused by administration of testosterone 5α-reductase In hibitors 6-methylene progesterone using topical formulation lations. These contain the inhibitor and an inner topical carriers (including silicones, methyl cellulose, Hydroxymethyl cellulose).

CA-2105887 A discloses a bio-erodable system for buccal and vaginal application u. a. of hormones (Estradiol). The system is water soluble and mucoadhesive rent. It consists of a solid, soluble, lyophili based foam and the active ingredient. The dissolution time be wears at least 8 h. The system adheres to the mucosal Membrane where it releases the drug. Poly used mers are primarily gelatin, sodium carboxymethylcel lulose, methyl cellulose etc. The advantage of the system is ins especially the long term.  

Regarding a targeted timing of drugs it should be noted that it is in our currently available Arz drug release is not possible to be variable and an adjustment of the release to the patient's individual drug requirements increase.

For the release control at conventional depot drugs predominantly passively dissolving, Diffusion, swelling and erosion processes are used [Groening, R., drug forms with electronically controlled Release, in Pharmaceutical Technology: Modern Medic neiform, p. 441. Ed., Müller, R.H., Hildebrand, G.E. (Ed.), Wissenschaftliche Verlagsgesellschaft mbH Stutt gart 1998).

The timed release of drugs is also known from the prior art.

JP-07118143 relates to time-controlled capsules which a) are water-insoluble or partially water-soluble, b) from substances swellable in water (powder, granules or Pills z. B. from calcium carboxymethyl cellulose, polyvinyl pyrrolidone), c) elements (tablets) with active ingredient in Center of the capsules included.

Further prior art relates to sustained release preparations using polymer, such as EP-068446 for Use of methyl cellulose or carboxymethyl cellulo se in mixtures for retardation.

The object of the invention is to take advantage of the buccal Application of steroids with a high first-pass effect and low bioavailability, especially of testosterone and its esters, with the use of different Pharmacokinetics of the different testosterone esters (each  according to chain length) so that by careful Selection of suitable dosages and esters desired drug profile can be set.

The task is accomplished through the use of Testostero nests with 1 to 20 carbon atoms in the carboxylic acid residue or Mi from two or more testosterone esters with un various carboxylic acid residues and / or testosterone for the production of buccally applicable bioadhesives Systems with time-controlled drug release for the treatment of diseases that change with a lower testosterone levels are resolved.

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

It is further preferred that the ratio of Testo steron to testosterone ester 1: 100 to 1: 1, especially is preferably 1:10 to 1: 1.5.

It is particularly preferred for the buccal to be applied bioadhesive systems are available by using the active ingredients first separately or together in one Spray drying process amorphous in organic polymers embedded.

It is very particularly preferred that the amor phen testosterone spray products along with others Auxiliaries, binders, fillers, lubricants, bioadhesive polymers, surfactants, decay accelerators mixes and compressed into single or multilayer tablets.  

The use according to the invention is preferred for targeted use Setting 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, open also the ester cleavage kinetics in the blood or tissue liquids through appropriate hydrolases. Especially is to be emphasized when using the testosterone ester Use of spray embedding techniques in organic Polymers (polyvinyl pyrrolidone, hydroxypropyl methyl cell loose, solid polyethylene glycols) to a corresponding to achieve improved solubility in the oral cavity. This is particularly important against the background of less Volumes of saliva (approx. 1-1.5 ml), which are there in the through cut to dissolve the sparingly soluble esters 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, 1228-1232) showed the castrated on 6 ten beagle dogs examined testosterone esters (Testosterone acetate, testosterone propionate, testosterones antat, testosterone decanoate) despite the higher lipophilicity no higher bioavailability than testosterone. Since the Esters were pressed directly only by dry mixing, without any special pre-formulation technology (Amorphization by spray embedding) was used, these worse results are probably due to the sometimes extremely low solubility of the esters in kri stalline condition.

It could be shown that the buccal application tion of testosterone in combination with testosterone esters different chain length different blood levels  or rhythms (in the sense of a circadian rhythm) can be adjusted. When choosing the Testo steronic esters can select from three groups be carried out: 1. esters of shorter chain length (e.g. Testosterone acetate or propionate), 2nd ester medium Chain length (e.g. testosterone enanthate, cipionate, cyclo hexane carboxylate) and 3rd esters of higher chain length (e.g. Tetosterone undecanoate, bucyclate).

According to the invention the object is achieved in that Testosterone or the respective testosterone ester in Etha nol together with the polymer (e.g. polyvinylpyrrolidone or hydroxypropylmethyl cellulose) dissolved and to a amorphous spray embedding in a spray drying system is processed further. It is possible that 1. the active ingredients mentioned separately or 2. together men amorphously embedded in one step be tested.

The fine-grained spray embedding is then shared with others Auxiliaries for the production of bioadhesive buccal tablets (Binder: polyvinyl pyrrolidone, cellulose ether; filler medium: Cellactose®, mannitol, sorbitol, lactose, lubricant medium: magnesium stearate, hydrogenated vegetable fats, bioad adhesive polymers: polyacrylates [Carbopole®, sodium car boxymethyl cellulose] and possibly other auxiliaries, such as Surfactants, disintegration accelerators) dry mixed and too Buccal tablets pressed, which are also built up in layers can be (active ingredient layer, bioadhesive adhesive layer; unidirectional or multidirectional release).

Based on blood level tests with the Monosub can punch by choosing the two parameters

- Dosage of the active ingredient

- Choice of ester or chain length on C-17 Appropriate release patterns can be set.  

The combination has proven advantageous, for example of the short-acting testosterone together with the testo steronundecanoate (C-11 chain) with longer half-life result (see exemplary embodiments).

A ratio of the active ingredients to is preferred each other, taking the ratio testosterone: Σ Testostero nests: 1: 100 to 1: 1, particularly preferably 1:10 to Is 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. ... Figures 1 and 3): blood level values <100 ng / are in application example (equimolar combination) extended in the female dog of about 2 h to about 4 h ml; moreover, a pronounced (smaller) 2nd pulse with a maximum after approx. 3 h can be recognized. After 8 hours, the testosterone values of almost 50 ng / ml are still twice as high compared to the administration of the mono substance.

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 lipophilicity and hence solubility, on the other hand in pronounced Way the ester cleavage or hydrolysis rate (Interactions of the ester side chain with the active one Center of the hydrolases). So esters of higher ket split length more slowly than those with medium length  or shorter length. In this sense, it floods through it released testosterone slower than when given a testosterone; the peak appears later. About the Chain length thus there is the possibility of one more or less targeted time control of the medical Effect;
• - The dosage of testosterone or testosterone ester about the direct proportionality of the AUC in relation to the applied dose

This could have an impact on hormone replacement (Hormone Replacement Therapy) in older men with have partial androgen deficiency (so-called PADAM patients), by lacking plasma levels accordingly therapeutic Getting corrected.

The following exemplary embodiments explain the invention in a non-limiting manner:  

example 1

Bioadhesive tablet with testosterone

Recipe

Manufacturing Preparation of the pre-formulation

The testosterone pre-formulation (20%) is by spray drying made. The active ingredient is combined with the polymer (polyvinylpyrrolidone, hydroxypropylme ethyl cellulose e.g. B.) and possibly another auxiliary (Carrier or antistatic auxiliary) in one suitable solvent dissolved or suspended. The suspension homogenized by constant stirring is in a spray drying system to a fine-grained powder spray dried.  

Production of the active substance layer

This pre-formulation is shared with the others Excipients of the active substance layer (mannitol, cellactose 80) in a suitable mixer (type: Kubusmischer, Tur Bulgarian, tumble mixer etc.) approx. 20 min and then un addition of the outer phase (Carmellose sodium, Magne sium stearate, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc become intimate in a ball mill rubbed. Then you mix in about 20 min suitable mixer (type: cube mixer, turbula mixer, Tumbler etc.) mannitol and cellactose 80, gives the Color rubbing as well as Carmellose sodium and Magnesiumste arat as the outer phase and mix again for 5 min.

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

Fig. 1 shows the blood level profile of a formulation according to Example 1.

Example 2

Bioadhesive tablet with testosterone undecanoate

Recipe

Manufacturing Preparation of the pre-formulation

The testosterone undecanoate pre-formulation (20%) will made by spray drying. The effect fabric together with the polymer (polyvinylpyrrolidone, Hydroxypropylmethylcellulose e.g. B.) and possibly a wide one ren auxiliary (carrier or antistatic auxiliary substance) dissolved in a suitable solvent or sus oscillates. The Sus. Homogenized by constant stirring pension becomes one in a spray drying plant spray-dried fine-grained powder.  

Production of the active substance layer

This pre-formulation is shared with the others Excipients of the active substance layer (mannitol, cellactose 80) in a suitable mixer (type: Kubusmischer, Tur Bulgarian, tumble mixer etc.) approx. 20 min and then un addition of the outer phase (Carmellose sodium, Magne sium stearate, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc become intimate in a ball mill rubbed. Then you mix in about 20 min suitable mixer (type: cube mixer, turbulami mixer, Tumbler etc.) mannitol and cellactose 80, gives the Color rubbing as well as Carmellose sodium and Magnesiumste arat as the outer phase and mix again for 5 min.

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

Fig. 2 shows the blood level profile of a formulation according to Example 2.

Example 3

Bioadhesive tablet with testosterone and testosterone and canoat

Recipe

Manufacturing Preparation of the pre-formulation

The testosterone / testosterone undecanoate pre-formulation (20%) is made by spray drying. In doing so both active ingredients together with the polymer (polyvinyl pyrrolidone, hydroxypropylmethyl cellulose e.g. B.) and possibly another auxiliary (carrier or antistatic we suitable additive) in a suitable solvent dissolves or suspended. The homogeneous by constant stirring  The suspension can be spray-dried can be spray dried to a fine-grained powder.

Production of the active substance layer

This pre-formulation is shared with the others Excipients of the active substance layer (mannitol, cellactose 80) in a suitable mixer (type: Kubusmischer, Tur Bulgarian, tumble mixer etc.) approx. 20 min and then un addition of the outer phase (Carmellose sodium, Magne sium stearate, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc become intimate in a ball mill rubbed. Then you mix in about 20 min suitable mixer (type: cube mixer, turbula mixer, Tumbler etc.) mannitol and cellactose 80, gives the Color rubbing as well as Carmellose sodium and Magnesiumste arat as the outer phase and mix again for 5 min.

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

Fig. 3 shows the blood level profile of a formulation according to Example 3.

Example 4

Bioadhesive tablet with testosterone, testosterone anthat)

Recipe

Manufacturing Preparation of the preformulation:

The testosterone / testosterone enanthate pre-formulation (20%) is made by spray drying. Both will Active ingredients together with the polymer (polyvinylpyrrolidone, Hydroxypropylmethylcellulose e.g. B.) and possibly a wide one ren auxiliary (carrier or antistatic auxiliary substance) dissolved in a suitable solvent or sus oscillates. The Sus. Homogenized by constant stirring  pension becomes one in a spray drying plant spray-dried fine-grained powder.

Production of the active substance layer

This pre-formulation is shared with the others Excipients of the active substance layer (Mannitol, Emcompress) in a suitable mixer (type: cube mixer, turbula mixer, tumble mixer etc.) approx. 20 min and then under Add the outer phase (Carbopol® 974, Magnesiumstea rat, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc are, for example, in one Ball mill rubbed intimately. Then mix approx. 20 min in a suitable mixer (type: cube mixer, Turbulamischer, tumble mixer etc.) Mannitol and Emcom press, gives the trituration as well as Carbopol® 974 and Add magnesium stearate as the outer phase and still mix 5 min.

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

Example 5

Bioadhesive tablet with testosterone propionate and testosterone decanoate

Recipe

Manufacturing Preparation of the pre-formulation

The testosterone propionate / testosterone decanoate Preformulation (20%) is made by spray drying. Both active ingredients are used together with the Polymer (polyvinyl pyrrolidone, hydroxypropyl methyl cellulose e.g. B.) and possibly another auxiliary (carrier or antistatic auxiliary) in a suitable Solvent dissolved or suspended. The through constant Stirring homogenized suspension is sprayed  Spray the drying system into a fine-grained powder dries.

Production of the active substance layer

This pre-formulation is shared with the others Excipients of the active substance layer (Mannitol, Emcompress) in a suitable mixer (type: cube mixer, turbula mixer, tumble mixer etc.) approx. 20 min and then under Add the outer phase (Carbopol® 974, Magnesiumstea rat, talc) mixed again for 5 min.

Production of the adhesive layer

Iron oxide red and talc become intimate in a ball mill rubbed. Then you mix in about 20 min suitable mixer (type: cube mixer, turbulami mixer, Tumble mixer etc.) Mannitol and Emcompress, gives the Color grinding as well as Carbopol® 974 and magnesium stearate as an outer phase and mix again for 5 min.

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

Claims (6)

1. Use of testosterone esters with 1 to 20 C- Atoms in the carboxylic acid residue or mixtures of two or several testosterone esters with different Carboxylic acid residues and / or testosterone for manufacture development of buccally applicable bioadhesive systems with timed release of active ingredient for loading act of diseases associated with a change testosterone levels. 2. Use according to claim 1, characterized in that the carbon skeletons of the carboxylic acid residues grad chain, branched, alicyclic, saturated and / or unsaturated with up to five doubles and / or three subject ties are. 3. Use according to claim 1 or 2, characterized records that the ratio of testosterone to Testosterone ester 1: 100 to 1: 1, preferably 1:10 to 1: 1.5. 4. Use according to any one of claims 1 to 3, characterized characterized in that the buccal to be applied bioadhesive systems are available by using the Active ingredients separately or together in one Spray drying process amorphous in organic polymers re embedded.   5. Use according to claim 4, characterized in that that the amorphous testosterone spray products together with other auxiliaries, binders, fillers agents, lubricants, bioadhesive polymers, surfactants, Accelerators mix and mix to one or more layered tablets pressed. 6. Use according to one of the preceding claims for the targeted setting of therapeutic or approx dian rhythms of testosterone levels.