The method of making a bioadhesive tablet for controlling testosterone blood level, especially in elderly men suffering from partial androgen deficiency, includes spray-drying an alcoholic solution or suspension of testosterone and at least one testosterone ester, preferably in a ratio of 1:10 to 1:1.5, separately or together, with an organic polymer and optionally one or more auxiliary ingredient to form an active ingredient premix. Then various other auxiliary ingredients are mixed, as needed, with the active ingredient premix to form the bioadhesive tablet with an active ingredient layer and an adhesive layer. The active ingredient layer contains an effective amount of the active ingredient premix. The adhesive layer includes auxiliary ingredients including the bioadhesive polymer. The bioadhesive tablet may be buccally administered to provide a predetermined timed release profile of testosterone, advantageously varying according to a circadian rhythm.

SUMMARY OF THE INVENTION

The object of the present invention is to make use of the advantages of buccal administration of steroids with high first-pass effect and low bioavailability, especially of testosterone and the esters thereof, by exploiting the different pharmacokinetics of the various testosterone esters (depending on chain length), so as to be able, by careful selection of appropriate dosages and esters, to attain a desired drug profile.

This objective is reached by use of testosterone esters with 1 to 20 carbon atoms in the carboxylic acid radical or of a mixture of two or more testosterone esters with different carboxylic acid radicals and/or testosterone, for the preparation of buccally administered bioadhesive systems with time-controlled release of the active ingredient, for treating diseases associated with a modified testosterone level.

Preferably used are testosterone esters wherein the carbon structure of the carboxylic acid radical is linear, branched, alicyclic, saturated and/or unsaturated and contains up to five double and/or triple bonds.

Also preferred is a ratio of testosterone to testosterone ester from 1:100 to 1:1 and particularly from 1:10 to 1:1.5.

It is particularly preferred that the buccally administered bioadhesive systems be prepared by first embedding into an organic polymer the active ingredients, separately or together, in an amorphous state as obtained by use of a spray-drying process.

It is especially preferred to mix the amorphous, spray-dried testosterone products with other auxiliary agents, binders, fillers, lubricants, bioadhesive polymers, surfactants or disintegration accelerators and to compress the mixture into single-layer or multilayer tablets.

The use for a tailored adjustment of therapeutic and/or circadian rhythms of the testosterone levels is preferred.

Surprisingly, we have now found that the chain length of the testosterone ester not only determines the solubility, but, as was shown experimentally, evidently also the kinetics of ester cleavage in the blood or tissue fluids by the corresponding hydrolases. Note in particular, when testosterone esters are employed, the use of the embedding technique of spray-drying in organic polymers (polyvinylpyrrolidone, hydroxypropylmethylcellulose, solid polyethylene glycols) to achieve improved solubility in the oral cavity. This is particularly important in view of the small saliva volumes (about 1-1.5 mL) which here, on the average, are available for the dissolution of sparingly soluble esters. In the publication by Jody Voorspoels [Vorspoels, J., Remon, J. P., Eechaute, W. E. and 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), the testosterone esters (testosterone acetate, testosterone propionate, testosterone enantate, testosterone decanoate) studied in six castrated beagle dogs did not show a higher bioavailability than testosterone in spite of their higher lipophilicity. Because the esters were directly compressed only after dry mixing, without using a special premixing technology (amorphization by spray-drying), these poorer results presumably are due to the low, and in some cases extremely low, solubility of the esters in the crystalline state.

We were able to show that by the use of buccal administration of testosterone in combination with testosterone esters of different chain length, it is possible to attain different blood level patterns or rhythms (such as a circadian rhythm). In selecting the testosterone ester, the choice can be made specifically from three groups: 1. esters of shorter chain length (for example, testosterone acetate or propionate), 2. esters of medium chain length (for example testosterone enantate, cipionate or cyclohexanecarboxylate) and 3. esters of higher chain length (for example testosterone undecanoate, or bucyclate).

According to the invention, this objective is reached by dissolving testosterone or the particular testosterone ester together with the polymer (for example polyvinylpyrrolidone or hydroxypropyl-methylcellulose) in ethanol and processing the mixtures further in a spray-drying unit to form an amorphous, embedded, spray-dried formulation. It is possible in this case 1) to embed said active ingredients separately from each other or 2) to embed them together in a single processing step, to obtain an amorphous mixture.

The fine-particle embedded spray-dried material is then subjected to dry mixing with other auxiliary agents for making bioadhesive buccal tablets [binders: polyvinylpyrrolidone, cellulose ethers; fillers: Cellactose®, mannitol, sorbitol, lactose; lubricants: magnesium stearate, hydrogenated vegetable fats; bioadhesive polymers: polyacrylates (Carbopols®, sodium carboxymethylcellulose) and optionally other auxiliary agents, such as surfactants or disintegration accelerators]. The mixture is then compressed into buccal tablets which can have a layered structure (active ingredient layer, bioadhesive layer; unidirectional or multidirectional release).

Based on blood level studies with the individual drug components alone, it is possible to attain the appropriate release patterns by changing the following two parameters

• dosage of the active ingredient
• selection of the ester or of the chain length at C-17.

An advantageous combination is, for example, that of the short-acting testosterone with testosterone undecanoate (eleven-carbon chain) which has a longer half-life (see practical examples).

To this end, an advantageous ratio of the active ingredients, namely of testosterone to Σ testosterone esters, is from 1:100 to 1:1 and particularly from 1:10 to 1:1.5.

By skillful combination of testosterone with testosterone esters, it is possible to attain blood level patterns which are capable of recreating or simulating the body's own rhythmicity of endogenous testosterone levels. For example, the duration of action of a bioadhesive buccal tablet with testosterone can be prolonged by combining testosterone with testosterone undecanoate (cf. FIG. 1 and FIG. 3). In the practical example (equimolar combination), the duration of blood levels of >100 ng/mL is increased in female dogs from 2 to 4 hours. Moreover, a marked (slower) pulse is reached with a maximum appearing after about 3 hours. After 8 h, the testosterone values of nearly 50 ng/mL are still double as high as those attained with testosterone alone.

In essence, the set blood level pattern of testosterone is controlled through two parameters:

The chain length and steric structure of the ester chain at C-17. This structure determines, on the one hand, the lipophilicity and thus the solubility and, on the other, in a pronounced manner, the rate of ester cleavage and hydrolysis (interactions of the ester side chain with the active center of hydrolases). For example, esters with a longer chain length are cleaved more slowly than those with an intermediate or shorter chain length. In this sense, the released testosterone becomes available more slowly than after administration of pure testosterone, i.e. the peak appears later. Through the chain length, it is thus possible to attain a more or less tailored time control of therapeutic action.

The dosage of testosterone or of the testosterone esters on the basis of direct proportionality between the area under the curve [AUC] and the dose given.

This could be important for hormone replacement therapy in elderly men with partial androgen deficiency (PADAM patients) in that a deficient plasma level could be appropriately corrected.

The following practical examples illustrate the invention without limiting its scope.

Preparation:
Preparation of the Premix

The testosterone premix (20%) was prepared by spray-drying. To this end, the active ingredient together with the polymer (for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose) and optionally another auxiliary agent (carrier or antistatic agent) were dissolved or suspended in an appropriate solvent. The homogenized suspension obtained by steady stirring was spray-dried in a spray-drying unit to obtain a fine powder.

Preparation of the Active Ingredient Layer

This premix was mixed with the other auxiliary agents for the active ingredient layer (mannitol, Cellactose 80) in an appropriate mixer (type: Kubu mixer, Turbula mixer, tumble mixer etc) for about 20 minutes. The outer phase (Carmellose sodium, magnesium stearate, talc) was then added, and mixing was continued for 5 minutes.

Preparation of the Adhesive Layer

Red iron oxide and talc were intimately ground in a ball mill. In an appropriate mixer (type: Kubu mixer, Turbula mixer, tumble mixer etc), mannitol and Cellalactose 80 were mixed for about 20 min. The ground colored mixture, Carmellose sodium and magnesium stearate were then added as the outer phase, and mixing was continued for an additional 5 minutes.

The mixtures for the active ingredient layer and adhesive layer, in the weight ratio given, were then compressed in an appropriate tabletting press to form two-layer tablets.

Preparation:
Preparation of the Premix

The testosterone undecanoate premix (20%) was prepared by spray-drying. To this end, the active ingredient together with the polymer (for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose) and optionally another auxiliary agent (carrier or antistatic agent) were dissolved or suspended in an appropriate solvent. The homogenized suspension obtained by steady stirring was spray-dried in a spray-drying unit to obtain a fine powder.

Preparation of the Active Ingredient Layer

This premix was mixed with other auxiliary agents for the active ingredient layer (mannitol, Cellactose 80) in an appropriate mixer (type: Kubu mixer, Turbula mixer, tumble mixer etc) for about 20 minutes. The outer phase (Carmellose sodium, magnesium stearate, talc) was then added, and mixing was continued for 5 minutes.

Preparation of the Adhesive Layer

Red iron oxide and talc were intimately ground in a ball mill. In an appropriate mixer (type: Kubu mixer, Turbula mixer, tumble mixer etc), mannitol and Cellalactose 80 were mixed for about 20 min. The ground colored mixture, Carmellose sodium and magnesium stearate were then added as the outer phase, and mixing was continued for an additional 5 minutes.

The mixtures for the active ingredient layer and adhesive layer, in the weight ratio given, were then compressed in an appropriate tabletting press to obtain two-layer tablets.
 

Claim 1 of 15 Claims

1. A method of manufacturing a bioadhesive tablet for controlling testosterone blood level in a person for therapeutic purposes, said method comprising embedding testosterone undecanoate alone or a mixture of testosterone undecanoate and testosterone in an organic polymer, hydroxypropymethyl cellulose optionally together with at least one auxiliary agent, by a spray-drying process, so as to form an amorphous active ingredient premix.

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