Pharmaceutical delivery systems for hydrophobic therapeutic agents and compositions containing it

FIELD: medicine.

SUBSTANCE: there are offered an oral pharmaceutical composition containing a) a testosterone ester and a fatty acid ester of a medium chain size; and b) two or more lipid ingredients, at least first of which contains a hydrophilic surfactant and at least second of which contains a lipophilic surfactant; said lipid ingredients together provide solubilisation of said testosterone ester in amount 10-20 % of weight of a pharmaceutical composition; a method for prevention or release of testosterone deficiency symptoms in mammal subjects and a method for maintenance of prolonged oral testosterone release.

EFFECT: invention provides medium-size testosterone and fatty acid ester delivery of intensified and prolonged adsorption, desired testosterone levels which are detected in people who do not suffer testosterone deficiency.

30 cl, 15 dwg, 4 tbl

Proposal for establishment of priority

This application sets the priority of provisional applications U.S. patent No. 60/671,454, registered on April 15, 2005 and No. 60/721,971, registered on 30 September 2005, both of discoveries is incorporated herein by reference in its entirety.

The technical field to which the invention relates.

The present invention, in General relates to a pharmaceutical delivery system for hydrophobic drugs and compositions containing them. In particular, the present invention relates to pharmaceutical compositions that include testosterone and its esters, with enhanced and extended absorption and pharmacokinetics.

Prior art

Many pharmaceutically active compounds intended for oral administration, poorly soluble in water, creating a challenge for the development of these medicines in the form of a system of drug delivery, manifesting the desired pharmacokinetic profiles in vivo. Poor oral bioavailability may lead to ineffective therapy, the need for higher doses and/or unwanted side effects. Moreover, pharmaceutical drugs with relatively short half-life and require frequent dosing, causing anxiety to the patient and increasing the cost of treatment.

Sex hormones (for example, testoster is n and its esters) are very poorly soluble in water, and attempts were made to increase their bioavailability, particularly when administered orally. However, the use of testosterone in itself creates additional problems. Indeed, although the testosterone flowing oral, almost completely enters the portal circulation, due to extensive metabolism at the first passage through the liver serum concentrations of testosterone after this method of application is low, despite the fact that used very large doses. To overcome this problem, attempts were made to alkilirovanii testosterone in position C-17 (for example, methyl group to form methyltestosterone), to reduce metabolism in the liver. Unfortunately, however, a simple alkylation of testosterone did not lead to the desired bioavailability and has been associated with potentially severe hepatotoxicity.

Have been made other attempts to increase short-term bioavailability of testosterone and its derivatives, lipophilic solvents and surfactants. Despite this, even in cases where bioavailability was improved delivery systems were unable to maintain the desired serum concentration over a long period of time.

Accordingly there is a need in the delivery system of the medicinal product offers enhanced bi is the availability of hydrophobic drugs in vivo. In addition, with regard to therapy with testosterone, there is a need for oral delivery system medicines, providing enhanced bioavailability of testosterone and/or its ester in vivo for a long period of time.

Brief description of the invention

In one embodiment of the present invention provides a pharmaceutical composition comprising testosterone palmitate (TP), or testosterone ester, and two or more lipid component, at least the first of which contains a hydrophilic surfactant, and at least the second of which contains a lipophilic surfactant that provides controlled release systems; these lipid components together provide the solubilization of the TA. The pharmaceutical composition may also include at least three lipid component, at least the first of which comprises a lipophilic surfactant, at least the second of which comprises a lipophilic surfactant that provides controlled release of the TA, and at least a third of which comprises a lipophilic surfactant that provides the solubilization of the TA. In addition, the pharmaceutical composition may also include a second fat-soluble therapeutic agent such as a synthetic progestin. Dosage form containing it, may be a preference for the equipment in the form of orally-active male contraceptive.

The first lipid component may have products HLB of 10 to 45, preferably from 10 to 30, and more preferably from 10 to 20. The second lipid component may be products HLB less than 10, preferably less than about 7, and more preferably less than about 5. Next, the second lipid component may have a melting point in the range from about 25°to about 80°C., preferably from about 35°to about 65°C., and more preferably from about 40°to about 60°C. the Second lipid component may be selected from the group including stearic acid, palmitic acid, glycerin and PEG-esters, Precirol ATO 5 and Gelucires.

In some embodiments lipophilic surfactant also includes a surfactant "long" or "controlled" release, which can be selected from the group consisting of stearic acid, palmitic acid, glycerin and PEG-esters, Precirol ATO 5, Imwitor 191, Myverol 18-06, Imwitor 370, Caprol ET, Cithrol 2MS, Marosol 183, and combinations thereof. The hydrophilic surfactant can be polyoxylene derivative of castor oil. Commercially available products of this class are supplied under the trade names Cremophor and Etocas and include Cremophor EL and RH40 and Etocas 35 and 40. Preferred Cremophor RH40 or Etocas 40.

Compositions of the present invention may include, based on the weight, 10-70% lipophilic surfactant; 1-40% of a surfactant to trilineage release; and 5-60% of a hydrophilic surfactant; and preferably 30-50% lipophilic surfactant; 5-25% of the surfactant of supervised release; and 30-40% of a hydrophilic surfactant. The composition additionally includes from about 5 to about 50 percent, by weight, testosterone palmitate, preferably, from about 20 to about 40 percent, by weight, testosterone palmitate. The inventive pharmaceutical compositions may also include one or more co-solvents and/or to be filled into hard or soft gelatin capsule.

In another aspect the present invention provides a method of preventing or alleviating the symptoms of testosterone deficiency in mammalian subjects, including the use in mammals of the subjects an effective amount of testosterone palmitate (TP), solubilizing in two or more lipid components, so that the application specified solubilizing TA increased stationary serum testosterone levels in mammalian subjects within the level typical for mammalian subjects who do not have testosterone deficiency, and provide at least some help with these symptoms. Men preferably use one or two times a day to pick up stationary serum testosterone levels to the range of from about 300 ng/the l to about 1100 ng/DL. Women preferred a similar calendar dosing (with a lower daily dose TA) to achieve serum testosterone levels from about 10 to 100 ng/DL. In some embodiments, the method may raise a stationary serum testosterone levels in mammals, 150%, 200%, 300% or 400%. The method may further include applying a number of synthetic progestin, sufficient to inhibit the release of gonadotropin from the named mammalian subjects and cause severe oligospermia or azoospermia.

In another aspect the present invention provides a method of creating a stationary serum levels of testosterone, effective to provide at least some relief of the symptoms of testosterone deficiency, including solubilization of testosterone palmitate (TP) two or more lipid components at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant that provides controlled release of the TA, and the effective number solubilizing TA from a person suffering from symptoms of testosterone deficiency. The method may also include the solubilization TA in at least three lipid components at least the first of which includes gerofi the capacity of the surfactant, at least the second of which comprises a lipophilic surfactant that provides controlled release of the TA, and at least a third of which contains a lipophilic surfactant, optionally providing solubilization TA.

In another aspect the present invention provides a method extended release of testosterone in vivo, the method comprises the solubilization of testosterone palmitate (TP) in the lipid mixture composed of two or more lipid component, at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant having a melting point above about 35°C.

In another embodiment of the present invention provides a pharmaceutical composition comprising testosterone palmitate (TP) and two or more lipid component, at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant, in which at least a first hydrophilic component or at least a second lipophilic component provides controlled release of the TA, and these lipid components work together to provide the solubilization of the TA. In one embodiment, at least a first hydrophilic component provides controlled release of the TA.

In the same respect, before explaining at least one embodiment of the present invention should be understood that the invention is not limited in its application to details of the devices and arrangement of the components placed forth in the following description or illustrated in the drawings. The invention allows embodiments in addition to those which are described and practiced in a variety of ways. In addition, it should be understood that the phraseology and terminology used here, as well as the CVS are descriptive purpose, and should not be considered limiting.

Essentially, one who is versed in the art will understand that the concept, which is based on this discovery, can easily be used as a basis for designing other structures, methods and systems for achieving the specific objectives of the present invention. For example, in some embodiments of the present invention TA can be combined with other active drugs, including hormonal, oral delivery system, which, in particular, prevents, or alleviates the symptoms associated with testosterone deficiency. It is important, therefore, that the statements were regarded as including such equivalent constructions such an extent that they are not separated from the essence and scope of the present invention.

Cu is rigid description of the drawings

Figure 1 depicts a stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms of the TA, increasing up to a maximum daily change, while taking advantage of early T_maxpreferably combined with taking a daily dose of early morning.

Figure 2 depicts the stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms of the TA, increasing up to a maximum daily changes, thus contributing to the late T_maxpreferably combined with taking a daily dose at night.

Figure 3 depicts the stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms TA, causing physiological diurnal changes and early T_maxpreferably combined with taking a daily dose of early morning.

Figure 4 depicts the stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms TA, causing physiological diurnal changes and later T_maxpreferably combined with taking a daily dose of early morning.

Figure 5 depicts the stationary pharmacokinetic profile in serum concentrations of testosterone during the merger Lakers the governmental form TA calling a short half-life and early T_maxpreferably combined with the maximum activity of the patient soon after awakening and dose twice a day.

6 depicts a stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms TA, causing a relatively short half-life and later T_maxwith a maximum activity around the time of awakening. Preferred receiving one or two doses daily at bedtime.

Fig.7 depicts the stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms TA, causing the average half-life and T_maxpreferably combined with the maximum activity of the patient soon after waking up, thus reducing the degree of fluctuations to a physiological level when the dose twice a day.

Fig depicts stationary pharmacokinetic profile in serum concentrations of testosterone during absorption dosage forms TA, causing prolonged half-life and later T_maxpreferably combined with maximum activity around the time of awakening, followed by the reception at night. This dosage form reduces the degree of physiological fluctuations is about the level of testosterone in the dose twice a day.

Fig.9 shows dissolution curves TA of the three dosage forms (9, 23 and 24, which are listed in Table 2) in a phosphate buffer medium of dissolution, including Triton X-100 as surfactant, in accordance with the present invention.

Figure 10 shows the dissolution curves TA of the four dosage forms (47, 50, 51 and 54, which are listed in Table 2) in a phosphate buffer medium of dissolution, including Triton X-100 as surfactant, in accordance with the present invention.

11 shows the average inpatient treatment in three modes within seven days.

Fig shows the average equilibrium serum levels of T and DHT after 7 days of application pharmaceutical form 54 twice a day.

Fig shows the conditional average of the stationary profile of the dosage form 50 with respect to the observed profile of the dosage form 54 (both applied twice a day for 7 days).

Fig shows a sample of dissolution profiles in vitro of various dosage forms TA in phosphate buffer (FBI).

Fig shows a sample of dissolution profiles in vitro of various dosage forms TP-stimulated food intake putting fluid (SPIG).

Detailed description of the invention

The present invention provides a pharmaceutical delivery system, preferred the preliminary oral, for hydrophobic drugs. Accordingly, while the present invention is characterized, to some extent, referring to oral delivery systems, the invention can be used for local and intramuscular injection. Next, a hydrophobic drug, as defined here, include both those medicines which are essentially hydrophobic (i.e. having a logP of at least 2), and other hydrophilic drugs, which are converted to hydrophobic with appropriate modifications (e.g., by conjugation with fatty acids and/or lipids). (LogP is the logarithm of the distribution coefficient in the system octanol-water or buffer solution, and can be determined using various methods, those who are versed in this area. The higher the value of logP, the more lipophilic and thus solubility in lipids of the chemical object).

In one embodiment of the present invention testosterone and/or esters of testosterone molecule at position C-17 alone or in combination with other active ingredients can be delivered orally with the use of the inventive delivery system. While many of the embodiments of the present invention describes and provides examples with ether palmitic acid testosterone (also referred to as "those who, tosterone palmitate" or "TP"), scope of the present invention should not be construed and limited only by the delivery of TA or testosterone as such. Virtually any ordinary skilled in the art from the explanation here can be easily understood that the inventive system drug delivery and their compositions can be used for oral delivery of other testosterone esters such as esters of fatty acids with short chain (C2-C6), medium chain (C7-C13) and long chain (C14-C24), preferably esters of fatty acids with long chain and testosterone, and many hydrophobic drugs. Such appropriate medicines which can be produced in accordance with the present invention, include without limitation the following.

Analgesics and anti-inflammatory agents: aloxiprin, auranofin, azapropazone, benorilate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, Ketoprofen, meclofenamic acid, marennikova acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac.

Anthelmintic agents: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, nitazoxanide, complementary, oxibendazole, oxantel embonate, praziquantel, Pyrantel embonate, thiabendazol.

Antiarrhythmic AG the options: amiodarone hydrochloride, disopyramide, flecainide acetate, quinidine sulfate.

Antibacterial agents: benethamine penicillin, cinoxacin, ciprofloxacin hydrochloride, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ciprofloxacin, imipenem, nalidixic acid, nitrofurantoin, rifampin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapiridin, tetracycline, trimethoprim.

Anticoagulants: difenacoum dipyridamole, nicoumalone, phenindione.

Antidepressants: amoxapine, maprotiline hydrochloride, mianserin hydrochloride, nortriptyline hydrochloride, trazodone hydrochloride, trimipramine maleate.

Antidiabetic agents: acetohexamide, hlorpropamid, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.

Antiepileptic agents: reclamed, carbamazepine, clonazepam, ethotoin, Meton, methsuximide, methylphenobarbital, oxcarbazepine, paramethadione, peacetime, phenobarbital, phenytoin, phensuximide, primidone, Altium, valproic acid.

Antifungal agents: amphotericin, butoconazole nitrate, clortrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, Itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine hydrochloride, terconazole, tioconazole,undecenoate acid.

Protivopodagricakih agents: allopurinol, probenecid, Alfin-person.

Antihypertensive agents: amlodipine, benidipine, durodie, dilitiazem hydrochloride, diazoxide, felodipine, guanabenz acetate, isradipine, Minoxidil, nicardipine hydrochloride, nifedipine, nimodipine, phenoxybenzamine hydrochloride, prazosin hydrochloride, reserpine, terazosin hydrochloride.

Antimalarial agents: amodiaquin, chloroquin, chlorproguanil hydrochloride, halofantrine hydrochloride, mefloquine.html, proguanil hydrochloride, pyrimethamine, quinine sulfate.

Caused agents: digidroergotamina mesilate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate.

Protivopanikovye agents: atropine, benzhexol hydrochloride, biperiden, ethopropazine hydrochloride, giostsiamin, mepenzolate bromide, oxyphencyclimine hydrochloride, Tropicamide.

Antineoplastic agents and immunosuppressants: aminoglutethimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustin, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine hydrochloride, tamoxifen citrate, testolactone.

Antibacterial agents: benznidazol, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furano icon, metronidazole, nimorazole, nitrofurazone, Ornidazole, tinidazole.

Means for treatment of the thyroid gland: carbimazole, propylthiouracil.

Anxiolytics, sedatives, hypnotics and neuroleptics: alprazolam, amylobarbitone, barbiton, bentazepam, bromazepam, bromperidol, brotizolam, butobarbital, carbromal, chlordiazepoxide, hlormetiazola, chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, fluanisone, flunitrazepam, fluororesin, flupentixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepama, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbital, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone.

Beta-blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol.

Heart inotrope agents: amrinone, digitoxin, digoxin, enoximone, lanatoside With, methoxy.

Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, desoximetasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortisone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic sour is a, frusemid, metolazone, spironolactone, triamterene.

Treatment of parkinsonism: bromocriptine mesilate, e.g. maleate.

Gastrointestinal agents: Bisacodyl, cimetidine, cisapride, Diphenoxylate hydrochloride, domperidone, famotidine, loperamide, mesalazin, nizatidine, omeprazole, andosterone hydrochloride, ranitidine hydrochloride, sulfasalazin.

Antagonists of H1-histamine receptors: acrivastine, astemizole, Cinnarizine, cyclizine, ciprogeptadina hydrochloride, dimenhydrinate, flunarizine hydrochloride, loratadine, meclizine hydrochloride, oxatomide, terfenadine.

Means regulating lipid metabolism: bezafibrat, clofibrate, fenofibrate, gemfibrozil, probucol.

Nitrates and other antianginal agents: amyl-nitrate, glyceryl trinitrate, the isosorbide dinitrate treatment, isosorbide Mononitrate, pentaerythritol TETRANITRATE.

Nutritional agents: beta-carotene, vitamin a, vitamin B2, vitamin D, vitamin E, vitamin K.

Opioid analgesics: codeine, dextropropoxyphene, diamorphine, Dihydrocodeine, meptazinol, methadone, morphine, nalbufin, pentazocine.

Sex hormones: clomiphene citrate, danazol, ethinyloestradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated estrogens, progesterone, synthetic progestins (also referred to as the progestogen is), stanozolol stilboestrol, tibolone, testosterone; esters of testosterone, including esters of oleic acid, linoleic acid, stearic acid, myristic acid, lauric acid, palmitic acid, capric (or decanoas) acid, octane (or Caprylic) acid, pelargoniums acid, undecanoic acid, tridecanoic acid, pentadecanoic acid, and analogues of these acids with branched chain and cyclic; analogues of testosterone such as methyl-nortestosterone, and combinations thereof. Synthetic progestins include, for example, levonorgestrel, levonorgestrel of butanoate, drospirenone, norethisterone, desogestrel, etonogestrel, medroxy-progesterone.

Antagonists releasing hormone gonadotropin, which is active when administered orally.

Stimulants: amphetamine, dexamfetamine, dexfenfluramine, fenfluramine, mazindol.

A mixture of hydrophobic drugs can be used, of course, if they are therapeutically effective. For example, in some embodiments it may be preferable combination of testosterone palmitate with orally active inhibitor of 5α-reductase I or type II, or a combination of testosterone palmitate with a synthetic progestin.

System drug delivery of the present invention and compositions containing them, include hydrophobic Lakers the governmental tool or tools, dissolved in the lipophilic surfactant and hydrophilic surfactant. Lipophilic surfactant, as defined here, has more products HLB 10 (products HLB is an empirical expression of the ratio of hydrophilic and lipophilic groups of the surface-active amphiphilic molecules such as surfactant. It is used for indexing surfactants, and its magnitude varies from about 1 to about 45. The higher products HLB, the more water-soluble surfactant is).

In accordance with one aspect of the present invention each of the components of the delivery system (i.e. lipophilic and hydrophilic surfactants) individually has the characteristics of the solvent and contributes, in particular, in the solubilization of the active ingredient. The lipophilic surfactants, which are the main contributors to the dissolution of the medicinal product, are defined here as primary solvents. Primary solvents can also provide the characteristics of a "slow release" or "controlled release" in the system of drug delivery. Secondary solvents are hydrophilic surfactants, which are also solubilizing drug, although to a lesser extent than the primary solvent. In addition to dissolving drugs, secondary solvents facilitate display the Finance delivery system in the aquatic environment or putting liquid, and the subsequent release of the drug. In cases where the secondary solvent is a surfactant with a high melting point, it can also provide slow release of drugs, acting Energetichesky with a lipophilic surfactant.

In order to achieve the desired allocation of the medicinal product from the interior of the dosage form, it may be necessary hydrophilic surfactant. Thus, the hydrophilic surfactant may be required in order to release the drug from the interior of the lipid matrix of the carrier or primary solvent. In this regard, a surfactant with a high products HLB, such as Cremophor RH40. The inventors have observed that in some dosage forms, including high levels of solubilizing TA, in the absence of a surfactant with a high products HLB can largely be missing the release of drugs from mixtures containing only lipophilic surfactants. The level of surfactant with a high products HLB can be installed in such a way as to provide optimal release of the medicinal product without breaking the solubilization of the active ingredient.

Lipophilic surfactant component, in some embodiments, may also include surfacta the t "controlled release". In other words, in addition to the fact that he is a solvent for drugs, lipophilic surfactant can also provide semi-solid matrix and the matrix sustained-release (SV). Many semi-solid/SV fillers acceptable for any ordinary well-versed in the art, but the present invention is desirable those extras are good solvents for drugs. Thus, the preferred semi-solid lipid fillers that have a high potential to solubilize the drug. In one aspect, the lipophilic surfactants "controlled release" have a melting point from about 25°to about 80°C., preferably from about 35°to about 65°C., and most preferably from about 40°to about 60°C.

No doubt, however, that the surfactants "controlled release" are not limited to lipophilic surfactants. Indeed, some hydrophilic surfactants in the compositions of the present invention can also provide characteristics of supervised release in connection with a lipophilic surfactant.

Lipophilic surfactants suitable for drug delivery of the present invention include:

fatty acids (C_{6 -C24preferably10-C24most preferably C14-C24), for example, octanoic acid, dekanovu acid, undecanoyl acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid. Preferred are stearic and palmitic acid.}

Mono and/or diglycerides of fatty acids, such as Imwitor 988 (glyceryl-mono-/di-kaprilat), Imwitor 742 (glyceryl-mono-dicaprylate/capret), Imwitor 308 (glyceryl-monocaprylin), Imwitor 191 (glyceryl-monostearate), Softigen 701 (glyceryl mono-/di-ricinoleate), Capmul MSM (glyceryl-kaprilat/capret), Capmul MCM(L) (liquid form Capmul MCM), Capmul GMO (glycerol-monooleate), Capmul GDL (glyceryl-dilaurate), Maisine (glyceryl-monolinoleate), Peceol (glyceryl-monooleate), Myverol 18-92 (distilled monoglycerides from sunflower oil) and Myverol 18-06 (distilled monoglycerides from hydrogenerating soybean oil), Precirol ATO (glyceryl-palmitostearate) and Gelucire 39/01 (semi-synthetic glycerides, for example, C_12-18mono-, di - and triglycerides). Preferred members of this class of lipophilic surfactants are partial glycerides of oleic, palmitic and stearic acids and mixtures thereof.

Esters of acetic, succinic, lactic, citric and/or tartaric acids and mono - and/or diglycerides of fatty acids, n is the sample Myvacet 9-45 (distilled acetylated monoglycerides), Migliol 829 (Caprylic/Kasprowy diglyceryl-succinate), Myverol SMG (mono/diskriminirovaniya monoglycerides), Imwitor 370 (glyceryl-stearate citrate), Imwitor 375 (glyceryl-monostearate/citrate/lactate) and Crodatem T22 (diacetyl-tartaric esters of monoglycerides).

Propylene glycol mono - and/or di-esters of fatty acids, such as Lauroglycol (propylene glycol-monolaurate), Mirpyl (propylene glycol-manneristic), Captex 200 (propylene glycol-dicaprylate/dicaprate), Miglyol 840 (propylene glycol-dicaprylate/dicaprate) and Neobee M-20 propylene glycol-dicaprylate/dicaprate).

Polyglyceryl esters of fatty acids, such as Plurol oleique (polyglyceryl-oleate), Caprol ET (polyglyceryl-mixtures of fatty acids) and Drewpol 10.10.10 (polyglyceryl-oleate). The ethoxylates of castor oil with low content of ethoxylate (products HLB<10), such as Etocas 5 (5 mol ethylene oxide reacted with 1 mol of castor oil) and Sandoxylate 5 (5 mol ethylene oxide reacted with 1 mol of castor oil).

Acid and ester ethoxylates, formed by the reaction of ethylene oxide with fatty acids or glycerol esters of fatty acids (products HLB<10), such as Crodet 04 (polyoxyethylene-(4)-lauric acid), Cithrol 2MS ((polyoxyethylene-(2)-stearic acid), Marlosol 183 (polyoxyethylene-(3)-stearic acid) and Marlowet G12DO (glyceryl-12 SW-dioleate). Esters of sorbitol and fatty acids, such as Span 20 (sorbitan-monolaurate), Crill 1 (sorbitan-monolaurate) and Crll 4 (sorbitan-monooleate).

The products of TRANS-esterification of triglycerides of natural or hydrogenating vegetable oils and polyalkylene-polyol (products HLB<10), such as Labrafil M1944CS (polyoxyethylene apricot kernel oil), Labrafil M2125CS (polyoxyethylene corn oil) and Gelucire 37/06 (polyoxyethylene hydrogenomonas oil coconut). It is preferable Labrafil M1944CS.

Ethoxylate alcohols (products HLB<10), for example Volpo N3 (polyoxyethylene (3)-alerby ether), Brij 93 (polyoxyethylene (2)-alerby ether), Marlowet LA4 (polyoxyethylene (4)-lauric ether), and

Pluronic, for example, copolymers and block copolymers polyoxyethylene-polyoxypropylene (products HLB<10), such as Synperonic PE L42 (products HLB=8) and Synperonic PE L61 (products HLB=3).

Mixtures of suitable lipophilic surfactants, such as the above, can be used optionally, and in some cases have the advantage. For example, glycerin ester palmitate and glycerol-stearate individually and in mixtures are the preferred lipophilic surfactants and matrix controlled release.

Of lipophilic surfactants listed above, those that are suitable as components of "controlled release", include without limitation, stearic acid, palmitic acid and glycerol and PEG-esters, Precirol AT, Imwitor 191, Myverol 18-06, Imwitor 370, Imwitor 375 Caprol ET, Cithrol 2MS, Marosol 183, Gelucire 39/01, and combinations thereof.

Any pharmaceutically acceptable hydrophilic surfactants (for example, with products HLB value above 10) can be used in the present invention. Some examples, without limitation, include:

derivatives of polyoxyethylene-sorbitol and fatty acids, for example, Tween 20 (polyoxyethylene-(20)-monolaurate), Tween 80 (polyoxyethylene-(20)-monooleate), Crillet 4 (polyoxyethylene-(20)-monooleate) and Montanox 40 (polyoxyethylene-(20)-monopalmitate). It is preferable Tween 80 (Polysorbat 80).

Castor oil ethoxylates hydrogenerating castor oil (products HLB>10), such as Cremophor EL (polyoxyethylene-(35)-castor oil), Cremophor RH40 (polyoxyethylene-(40)-hydrogenomonas castor oil), Etocas 40 (polyoxyethylene-(40)- castor oil), Niccol HCO-60 (polyoxyethylene-(60)-hydrogenomonas castor oil), Solutol HS 15 (polyethylene glycol 660-hydroxystearate), Labrasol (capillary macrogol-8 glycerides), alpha-tocopherol polyethylene glycol-1000-succinate (TPGS), ascorbyl-6-palmitate. It is preferable Cremophor RH40.

Gelucire, preferably Gelucire 50/13 (PEG-mono - and diesters of palmitic and stearic acids). (As for Glycerol, the first digit (for example, 50) corresponds to the melting temperature of the material, and the second (e.g., 13) - value products HLB).

The ethoxylates of fatty acids (products HLB>10), such as Myrj 45 (polyoxyethylene-(8)-with Ararat), Tagat L (polyoxyethylene-(30)-monolaurate), Marlosol 1820 (polyoxyethylene-(20)-stearate) and Marlosol OL15 (polyoxyethylene-(15)-oleate). It is preferable Myrj 45.

Ethoxylates alcohols (products HLB>10), such as Brij 96 (polyoxyethylene-(10)-alerby ether), Volpo 015 (polyoxyethylene-(15)-alerby ether), Marlowet OA30 (polyoxyethylene-(30)-alerby ether) and Marlowet LMA20 (polyoxyethylene-(20)-C₁₂-C₁₄fatty ether).

Copolymers of polyoxyethylene-polyoxypropylene and copolymers (products HLB>10), which are commercially available under the trademark Pluronic or Poloxamer, such as Poloxamer 188 and 407, also known as Syperonic PE L44 (products HLB=16) and Syperonic F127 (products HLB=22), respectively.

Anionic surfactants, such as lauryl-sulfate sodium, sodium oleate, dioctyl-sulfosuccinate sodium.

Alkylphenol surfactants (products HLB>10), such as Triton N-101 (polyoxyethylene-(9-10)-Nonylphenol) and Syperonic NP9 polyoxyethylene-(9)-Nonylphenol.

From hydrophilic surfactants listed above, those which are suitable as surfactants "controlled release", include, without limitation, Gelucire with high value products HLB, such as Gelucire 50/13.

As mentioned, in one aspect of the present invention, each of the components of the delivery system (i.e. lipophilic and hydrophilic surfactants) individually has the characteristics of the solvent and contributes, in particular, in the solubilization of the active ingredi the NTA. Thus, not communicating or being limited by theory, the present invention does not require additional solvents, such as additional digestible oil and/or co-solvents, but they can be optionally included in the systems and dosage forms of the invention.

Digestible oil is defined as oil that can be deesterification or hydrolysis in the presence of pancreatic lipase in vivo under normal physiological conditions, namely digestible oils can be full glycerin treeframe fatty acids with medium chain (C₇-C₁₃) or long chain (C₁₄-C₂₂with low molecular weight (up To₆) mono-, di - or polyhedrally alcohols. Some examples of digestible oils for use in the present invention respectively include: vegetable oils (e.g. soybean oil, safflower oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil; almond oil, borage oil, peppermint oil and apricot kernel oil) and animal fats (such as fish oil, shark oil, mink oil).

In addition to the CSO, additional co-solvents suitable for the present invention are, for example, water, mono-, di - and polyetilene alcohols, short-chain, such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene-carbonate, polyethylene glycol with an average molecular weight from about 200 to about 10,000, diethylene glycol-monotropy ether (e.g., Transcutol HP), and combinations thereof.

Other optional ingredients that may be included in compositions of the present invention are those that are typically used in systems of drug delivery based on oils, for example, antioxidants, such as tocopherol, tocopherol acetate, ascorbic acid, butyl-hydroxytoluene, butyl-hydroxyanisole and propyl-gallate; pH stabilizers such as citric acid, tartaric acid, fumaric acid, acetic acid, glycine, arginine, lysine and potassium phosphate; thickeners/suspendresume agents, such as hydrogenomonas vegetable fat, beeswax, colloidal silicon dioxide, mannitol, gums, cellulose, silicates, bentonite; flavorings such as cherry, lemon and anise; sweeteners, such as aspartame, acesulfam K, Sucralose, saccharin and cyclamate etc.

The relative proportions of lipophilic surfactant and hydrophilic surfactant in the preferred system media hydrof the service of drugs of the present invention are, in General, is not particularly critical, except that the concentration of lipophilic and hydrophilic surfactants should be sufficient to solubilisate hydrophobic drug, thus freeing him both in vitro and in vivo. It should be noted that in some embodiments of the present invention one hydrophobic drug can serve as a lipid solvent for the other. More specifically, for example, the ester of testosterone may serve as a carrier for testosterone. More specifically, the TA can serve as a lipid solvent for testosterone. In addition, the TA may serve, in some embodiments, as its own solvent "controlled release", which can eliminate the need for additional lipids "controlled release"mentioned above.

In General, preferred are the following relative concentration by weight (percentage based on a total content of hydrophilic surfactant and a lipophilic surfactant(s)):

hydrophilic surfactant: 5-60%, more preferably 15-45%, and most preferably 30-40%.

Lipophilic surfactant: 10-90%, preferably 20-80%, and most preferably 30-60%.

Lipophilic surfactant "controlled release": 1-40%, more preferably 2.5 to 30%, and most preferably 5-25%.

Konz is trace drugs in finished pharmaceutical form should be such that which is required in order to provide the desired therapeutic effect desired drug, but in General should be in the range from 0.1% to 50% by weight, preferably from about 10% to 30% by weight, and most preferably from about 10% to 20% by weight, based on the weight of the final composition. However, in many cases, because the proposed composition may have greater bioavailability than known compositions need drugs, the drug concentration can be reduced compared with conventional drugs without loss of therapeutic effect. In specific regard to the treatment of testosterone authors of the present invention know that in particular, preferably the use of ether palmitate, and So Really, when absorption is long and fully saturated chain fatty acids from T slow down the rate of hydrolysis of its ester linkages, thus extending the circulation system and accordingly So for Example, dosage forms of the present invention (for example, the dosage form No. 50 and 54 (below)include TA, with the half-life T of about 8-9 hours. In comparison, the half-life for T is about 30 minutes for T-undecanoate about 1.5 hours.

In other embodiments the dosage form of the present invention can be self-emulsifiers properties, forming encodes rnie emulsion when diluted in water or putting fluid in vivo. In other words, the dosage form can have a high content of surfactants and lipids, selected for adequate dispersion when mixed in the aquatic environment. A qualitative description of the self-emulsifying properties of the inventive dosage forms can be visually observed at the time of their dissolution in vitro. On the other hand, can be carried out quantitative measurements of particle size emulsification droplets using laser scattering and/or turbidity in the environment dissolution using a spectrophotometer operating in the ultraviolet and visible region. Any of these methodologies are appropriate and known to those of ordinary skill in the art.

Pharmaceutical compositions in accordance with the present invention can be liquid, semi-solid or solid at ambient temperature, but preferably supplied in a liquid or semi-solid form. Hard drugs are defined as solid, powder medicines, mixed with powdered fillers and directly filled into hard gelatin or cellulose capsules, or compressed into tablets. The present invention, however, preferably includes a solid, powder medicines (e.g., TA), which solubilization in the presence of lipid surfactant aggregates (in the example, any combination of lipophilic and hydrophilic surfactants mentioned above). Accordingly, the melting point of the surfactants used as one factor that may determine whether the obtained composition is liquid or semisolid at ambient temperature. Particularly preferred compositions of the present invention are liquid or semi-solid oral forms a separate dosing, more preferred are filled into hard or soft capsules, for example, gelatin or cellulose capsules. Technology encapsulating pharmaceuticals lipid based well-known to those of ordinary skill in the art. Because the inventive delivery systems and dosage forms described herein are not limited to any particular way of encapsulating the specific technology of encapsulation are not further discussed.

System carriers of drugs and pharmaceuticals in accordance with the present invention can be prepared using available technologies for systems of drug delivery vehicles on a lipid basis. In a typical preparation procedure is the preferred system of the carriers of the present invention lipophilic surfactant is weighed into a suitable vessel made of stainless steel, and then VSUES who live hydrophilic surfactant and added to the container. The mixing of the two components can be carried out using a homogenizing mixer or other device with a large shearing force. If the material is solid at room temperature, apply sufficient heat to achieve melting and liquid state without chemical destruction.

Lipophilic surfactant "controlled release" and then add, if desired, to the other two components in a vessel of stainless steel and mixed with the use of proper equipment. Hydrophobic drug is then weighed and added to a combined lipid mixture, and continue mixing until until cooked homogeneous solution. Dosage form may then be deaerated prior to encapsulation in soft or hard capsules. In some cases, fill the form may be stored at elevated temperature using a suitable receptacle with backshell for processing.

Returning to the delivery of testosterone, in one embodiment of the present invention, the delivery system for the drug of the present invention may be suitable for treatment with testosterone. Testosterone is the main androgen in humans. Leydig cells in the testes produce approximately 7 mg of testosterone daily, providing the serum concentration is from about 300 to about 1100 ng/DL. Women also synthesized testosterone in the ovaries and in the adrenal glands, but its amount is about one-tenth of that observed in Euganean men. The vast majority (about 98%) of circulating testosterone is bound to a globulin that binds sex hormones and biologically active only when the release into free form. The term "free" thus means not connected or is not located within, for example, biomolecules, cells and/or lipid matrices dosage forms of the invention described herein. In General, the "free" medication described here relate to the medications available for metabolic enzymes circulating in the serum.

While the present invention is not limited to delivery of testosterone or any particular esters, TA was found to possess unique physical and chemical characteristics that make it preferable in some embodiments. The authors of the present invention know that the ester of palmitic acid and testosterone, in particular, can exhibit a higher bioactivity than other equivalent esters (for example, testosterone-undecanoate (TU)). Not communicating or being limited by theory, it is believed that the TA is superior, in particular, other esters of testosterone, since it has about obinna high log P compared with similar analogues (log R TA more than 9, compared with the log P for ONE 6.5).

Accordingly, TA, adsorbiruya in the bloodstream, can passively diffuse into red blood cells (KKK)circulating in the blood. In particular, since palmitic acid is also an important component of the membranes of the KKK, and, as shown, is transported through the membrane, TA is better is in equilibrium and is transported through the said membrane. Thus, some portion of the total concentration of free TP at a certain given time may be within the KKK. Next, in doing the KKK, some of the TA thus protected from esterases found in the serum. Since the transformation TA in testosterone is a direct consequence esterase activity, the greater inaccessibility for esterase involves prolonged half-life of TA. For this reason, it is considered that the time TA in the blood more than expected for other saturated esters with shorter length of the carbohydrate chain.

Moreover, the use of TP, in contrast to other oral applied esters of testosterone does not cause a sharp increase in serum dihydrotestosterone ("DHT") in relation to the physiological level (i.e. approximately from 300 to 1100 ng/DL) in Euganean men. Testosterone interacts with the corresponding receptor androgens or C is directly, or after transformation into DHT under the action of 5α-reductase. DHT is a more powerful androgen than testosterone, and elevated, according to some scientists, increases the risk of prostate cancer. Increased levels of DHT is a noticeable problem when using, for example, TU. Thus, the TA provides another unexpected advantage in comparison with other esters of testosterone.

A specific embodiment of the present invention will hereinafter be described in non-limiting examples. Table 1 shows the details of various dosage forms of testosterone (T) or esters of testosterone (T-esters), in accordance with the teachings of the present invention. For calculation purposes, 1 mg testosterone equivalent: 1,39 mg T-antanta, 1,58 mg T-undecanoate, 1,43 mg T-cypionate and 1.83 mg T-palmitate. TA is the preferred ether in some of the dosage forms listed below. Details of the compositions from Table 1 (mg per capsule and the percentage by weight) based on 800 mg by weight on a hard gelatin capsule "00". However, when the amounts of ester testosterone less than about 100 mg per capsule, the shape can be scaled to a smaller overall weight, allowing you to use smaller hard gelatin capsules (e.g., size "0").

In addition, any ordinary skilled in the art will understand that many, e is not all surfactants of this category (for example, lipophilic, hydrophilic, and so on) can be replaced by another surfactant of the same category. Thus, although table 1 lists the dosage forms containing Labrafil M1944CS (products HLB=3) and Precirol ATO (products HLB=5), any ordinary specialist in the art knows that they can come and other lipophilic surfactants (for example, those listed above). Similarly, although table 1 lists the dosage forms containing Cremophor RH40 (products HLB=13) and Labrasol (products HLB=14), any ordinary specialist in the art knows that it is possible to use other hydrophilic surfactants.

Table 2 shows the details of different dosage forms of the TA in accordance with the doctrine of the present invention, and figure 1 shows the dissolution of selected forms in vitro. TA can be synthesized by the esterification of testosterone, which is the chloride in a mixture of acetone/pyridine. Raw testosterone palmitate purified by filtration, crystallized from methanol/methylene chloride, and washed with methanol. If necessary, repeat the recrystallization in heptane, then washed with methanol.

The preferred dosage form TA in accordance with the present invention:

In some embodiments it may be preferable to reduce the absolute concentration of testosterone and/or its ester to provide a relatively rapid release of testosterone and/or air from within the lipid solvent. Thus, it was found, surprisingly, that the decrease in the concentration of TP in some cases can cause accelerated kinetics of release. For example, for a significant release of TP for the two-hour period, the concentration of TP less than about 23% by weight. In one preferred embodiment, the percentage by weight of less than about 20, more preferred percentage by weight of about 18, and most preferred percentage by weight of less than about 15. Not communicating or being limited by theory, it is believed that the TA at a level higher than about 23% by weight may actually slow down your own release. For example, dosage form in accordance with the present invention, including me who her than about 23% by weight TA, can release 50-70% of the medicinal product for 1 hour and from 80 to almost 100% for 2 hours. On the other hand, dosage form in accordance with the present invention comprising more than about 23% TA by weight, frees up less than 5% drug 1 hour and less than 70% for 6 hours.

Table 3 shows details of the composition for various dosage forms of the TA, which in some cases, lower concentrations of TP than those shown in Table 2, in accordance with the doctrine of the present invention. Figure 3 shows the in vitro dissolution of selected dosage forms from Table 3.

Dosage form No. 50, 51 and 54 are the preferred embodiments. As well as, while in the formulations shown in Table 3, can be used a number of solvents, preferred solvents may have the following characteristics: C4-C24 fatty acids and/or glycerol, propylene glycol, polietilenglikolya, sorbitane mono/diesters separately and in mixture. Preferred fatty acids and esters are C8-C18, feast upon the nnye and unsaturated. In addition, the solvents include esters of fatty acids with lower alcohols, such as ethyl oleate, ethyl linoleate, isopropyl-myristate, isopropyl, isopropylacetate and isopropylmalate.

Information confirming the possibility of carrying out the invention

Dosage forms 50 and 54 was used in 6 patients, No. 50 was applied once a day ("QD") in the form of two capsules per dose (100 mg T-equivalent per capsule), and No. 54 used one and twice daily (BID) in the form of three capsules per dose (66 mg T equivalent per capsule). Average inpatient profiles after 7 days of treatment in one of the three relevant modes is shown figure 11. The pharmacokinetic profile of the dosage form 54 BID was relatively homogeneous throughout the entire 24-hour period and had an average profile about 70% of the peak from the average profile. Additional data on the dosage form 54 include:

- average increases in serum T in comparison with the baseline - 275 ng/DL;

the average serum level of T at the lower limit of the normal range, i.e. about 325 ng/DL;

- relatively fast release (T_maxabout 1 hour);

- reached the end of the half-life of T in the steady state is approximately 8-9 hours;

- persistent dose-dependent increase in baseline serum levels of T during a 7-day treatment period;/p>

- average stationary serum level of DHT - 114 ng/DL (Fig).

Performed the stimulation of the pharmacokinetic profile of the dosage form 50, applied twice a day and compared with the observed profile of the dosage form 54, applied twice a day. Stimulation of the predicted increase_cf.24-hour period, approximately 384 ng/DL for the dosage form 50, compared with form 54 (Fig).

In other embodiments of the present invention presents methods and compositions for modulating (i.e. maintain) the level of available serum testosterone by including component(s)that can biochemically modulate (1) the absorbance of the TA (2) the transformation of TA in T, and/or (3) the conversion of T to DHT. For example, the inclusion of esters of fatty acids with medium or long chain may enhance absorption of TP. Not limited to or by binding theory, the authors present invention believe that the use of effective amounts of fatty acid esters, in particular esters palmitate, such as ascorbyl-palmitate, retinyl-palmitate, sorbitol-palmitate and mixtures thereof, thus, may cause competition between these esters and TA in the endogenous esterase activity. Indeed, it is believed that the metabolism of testosterone esters, in General, can be slowed down by applying effective is its number of esters of fatty acids with medium or long chain (e.g., esters of oleic acid, linoleic acid, stearic acid, myristic acid, lauric acid, palmitic acid, capric or decanoas acid, octane or Caprylic acid, pelargoniums acid, undecanoic acid, tridecanoic acid, pentadecanoic acid, and analogues of these acids with branched chain and cyclic). Thus, more TA avoids hydrolysis in the intestine and enters the bloodstream. In other words, the fatty acid esters can competitively inhibit esterase, which in other conditions TA process. Table 4 provides an effective amount of the inhibitors of the metabolism of testosterone. Examples of other esters, or combinations thereof include plant extracts or non-toxic esters, used as food additives (for example, propylparaben, octylated and ethyl acetate).

Other components that can modulate the absorption of the TA include natural and synthetic inhibitors of 5-α-reductase, which is present in enterocytes and catalyzes the conversion of T to DHT. Complete or partial inhibition of this transformation can both promote and maintain a serum level of T after the oral administration of TA with concomitant reduction of serum levels of DHT. The borage oil, which contains a significant amount inhibit the 5-α-reductase gamma-linoleic acid (GLA), is an example of a natural modulator of metabolism TA. In addition to the one that is in the borage oil, GLA can be directly added as a separate component dosage forms TA described above. Many natural inhibitors of 5-α-reductase is known in the art (e.g., epigallocatechin-gallate (EGCG) - catechin, initially isolated from green tea and extract From the saw Palmetto berry species Serenoa repens), any of which may be used in the present invention. Non-limiting examples of synthetic inhibitors of 5-α-reductase inhibitors suitable for the present invention include finasteride and dutasteride.

In addition to inhibitors of 5-α-reductase present invention considers the use of inhibitors of the metabolism of T through other mechanisms. One such point of inhibition can be isoenzyme of cytochrome P450 CYP3A4, which is present in enterocytes and liver cells and is able to convert testosterone. According to the dosage forms of the present invention, in some embodiments, include peppermint oil, which, as you know, contains factors that can inhibit CYP3A4.

Table 4 provides details of the composition of various dosage forms of the TA, including the ingredients for the modulation of the absorption TP (i.e. ascorbyl-palmitate, borage oil and peppermint oil re the Noi). Fig and 15 show exemplary profiles of dissolution in vitro of selected dosage forms TA or in phosphate buffer solution (FBI), or stimulated food intake putting fluid (SPIJ), respectively.

In yet another embodiment of the present invention for the delivery of drugs disclosed herein may is also be appropriate to reduce some of the side effects of certain strategies of male contraception. For example, male contraception based on progestine, significantly suppresses luteinizing hormone (LH) and folliculo-stimulating hormone (FSH), and thus suppresses spermatogenesis, leading to clinical azoospermia (defined as having less than 1 million sperm/ml of the seed within the next 2 months). However, the use of progestins also has an unwanted side effect, greatly reducing stationary serum testosterone level.

In such situations, for example, it may be preferable to take progestin drugs with testosterone or a derivative of testosterone (e.g., TA). More preferably, is provided a pharmaceutical preparation in accordance with the present invention, including a progestin in an amount sufficient to substantially inhibit the production of LH and FSH in combination with testosterone. In some embodiments the pharmaceutical preparation intended for oral administration once a day.

System drug delivery in one aspect of the present invention provide flexibility in achieving the desired pharmacokinetic profile. In particular, the dosage form can be designed to deliver the drug with a relatively early peak serum concentration (T_max), or to pojavljatsja. Cm. 1, 3, 5 and 7 compared to 2, 4, 6 and 8, respectively. Similarly, the dosage form can be designed so as to obtain a relatively steep or prolonged decline in serum concentrations of drugs after reaching T_max. Cm. 1, 3, 5 and 7 compared to 2, 4, 6 and 8, respectively. Therefore, the pharmaceutical preparations of the present invention can be applied once a day, twice a day or in multiple doses throughout the day, depending on, for example, from the preferences and convenience of the patient.

One way that these dosage forms can be modified to affect these changes is the ratio of lipophilic surfactants. The magnitude and duration of T_maxfor example, can influence not only the type of the used lipids, but their ratio. For example, to get a relatively early T_maxor rapid release of the drug from the delivery system, the concentration of the lipophilic surfactant "controlled release" (for example, Precirol) can be reduced relative to the concentrations of other lipophilic solvents (for example, Labrafil M1944CS). On the other hand, in order to achieve slow-T_maxthe percentage of lipophilic surfactant "controlled release" in the composition can be increased. Figures 9 and 10 show curves of dissolution in vitro TA of the three dosage forms, respectively, in the medium dilution with phosphate buffer containing Triton X-100 as surfactant, in accordance with the present invention.

Not communicating and not being limited by theory, it is believed that the inventive dosage forms described herein, in one aspect, increase absorption of the medicine through putting in the lymphatic system. Thus, the system of drug delivery of the present invention can provide a prolonged release dosage forms, which can deliver testosterone in the serum within a few hours. The half-life of serum testosterone in men, as I believe, is in the range from 10 to 100 minutes, with an upper limit for testosterone, used in forms (for example, TA), improves lymphatic absorption. However, oral dosing of the present invention must be patient if necessary testosterone therapy approximately every 12 hours to maintain the desired level of serum testosterone. In the preferred embodiment oral dosing by the patient if necessary testosterone therapy approximately every 24 hours. In General, the "desired" levels of testosterone is the testosterone levels, which are seen in people who do not have testosterone deficiency.

Since the invention described in SV is, due to its specific embodiments, it is clear that the possibility of further modification, and this application is intended to protect any variations, uses, or changes to the following inventions. In General, the principles of the present invention that includes a retreat from the present disclosure within known and customary practice, to which the invention relates, and that can be applied to the essential features set forth above, is set to continue, and as follows in the scope of the attached claims.

1. Pharmaceutical composition for the prevention or relief of symptoms of testosterone deficiency in mammals, suitable for oral administration, including:
a) ether of testosterone and fatty acids with an average size of chain, and
b) two or more lipid component, at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant, the two or more lipid component together provide the solubilization of such quantity of air testosterone and fatty acids with an average size of the chain, which is in the range of 10-20% by weight of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, in which the ester of testosterone and fatty acids with medium chain is selected from testosterone decanoate, testosterone is undecanoate and testosterone of dodecanoate.

3. The pharmaceutical composition according to claim 1, characterized by the percent (%) dissolution profile in vitro in phosphate buffer solution, which indicates the release of the song actually only ester testosterone and fatty acids with medium chain from solubilising environment for about 2 hours

4. The pharmaceutical composition according to claim 1, which includes at least three lipid component, at least the first of which include hydrophilic surfactant, at least the second and third of which comprises a lipophilic surfactant, each of which provides the solubilization ester of testosterone.

5. The pharmaceutical composition according to claim 4, which further includes a second fat-soluble therapeutic agent.

6. The pharmaceutical composition according to claim 5, in which the second fat-soluble therapeutic agent includes a synthetic progestin, an inhibitor of 5α-reductase I and/or type II, finasteride, dutasteride, or a combination of both.

7. The pharmaceutical composition according to claim 1, in which at least the first lipiny component has products HLB of 10 to 45.

8. The pharmaceutical composition according to claim 7, in which at least a first lipid component is Cremophor EL, Cremophor RH 40, Etocas 35, Etocas 40 and their combination.

9. The pharmaceutical composition according to claim 1, in which at least a first lipid component of the om is glycerin and PEG-esters.

10. The pharmaceutical composition according to claim 9, in which at least a first lipid component is Cremophor RH 40.

11. The pharmaceutical composition according to claim 1, in which at least the second lipid component has products HLB less than 10.

12. The pharmaceutical composition according to claim 11, in which at least the second lipid component has products HLB of less than 5.

13. The pharmaceutical composition according to item 12, in which at least the second lipid component has products HLB less than or equal to 2.

14. The pharmaceutical composition according to item 13, in which at least the second lipid component is glycerol-palmitostearate, palmitostearate, borage oil, peppermint oil, oleic acid and mixtures thereof.

15. The pharmaceutical composition according to 14, in which at least the second lipid component is borage oil, peppermint oil, oleic acid and mixtures thereof.

16. The pharmaceutical composition according to item 15, in which at least a third of the lipid component is borage oil, peppermint oil, oleic acid and mixtures thereof.

17. The pharmaceutical composition according to claim 5, comprising Cremophor RH 40, borage oil, oleic acid and oil of peppermint.

18. The pharmaceutical composition according to claim 4, further comprising an antioxidant.

19. The pharmaceutical composition according p in which antioxid Tom is tocopherol, tocopherol acetate, ascorbic acid, butyl-hydroxytoluene, butyl-hydroxyanisole, propylgallate, or combinations thereof.

20. The pharmaceutical composition according to claim 4, further comprising a fatty acid ester with a medium or long chain.

21. The pharmaceutical composition according to claim 20, where the fatty acid ester with a medium or long chain is ascorbyl-palmitate, retinyl-palmitate, sorbitan palmitate and mixtures thereof.

22. The pharmaceutical composition according to claim 1, which comprises from about 10 to about 50% of the ester of testosterone by weight.

23. The pharmaceutical composition according to item 22, which includes from about 10 to about 35% ether of testosterone by weight.

24. The pharmaceutical composition according to claim 1, filled into hard or soft gelatine capsules.

25. The way to prevent or relieve symptoms of testosterone deficiency in a mammal, comprising oral administration to a mammal an effective amount of the composition containing the ester of testosterone with a fatty acid with an average size of chain, solubilizing in two or more lipid components, where at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant, and the two or more lipid component together provide the solubilization of such quantity of ether is of testosterone and fatty acids with medium chain which is in the range of 10-20% by weight of the pharmaceutical composition, so that the maintenance of specified composition increases the average equilibrium serum levels of total testosterone in mammals to a level that is detected in mammals that do not have testosterone deficiency, and provides at least some relief of such symptoms.

26. The method according A.25, in which the ester of testosterone and fatty acids with medium chain solubilization at least three lipid components.

27. The method according A.25 in which mammals subjects are people, male and female.

28. The method according to item 27, in which the average stationary serum levels of total testosterone in men rises until it reaches the range from about 300 to about 1100 ng/DL.

29. The method according A.25 which further includes the introduction of a second fat-soluble therapeutic agent containing the inhibitor I and/or type II 5α-reductase, finasteride, dutasteride, or combinations thereof.

30. The way to ensure long-term oral release pharmaceutical compositions of testosterone, including solubilization ester testosterone and fatty acids with an average size of chains in the lipid mixture composed of two or more lipid component, at least the first of which includes hydrophilic with fractint and at least the second of which comprises a lipophilic surfactant having a melting point above 30°C, where the two or more lipid components are to solubilize the number of ester testosterone and fatty acids with an average size of the chain, which is in the range of 10-20% by weight of the pharmaceutical composition.