CN103705462B - Oral testosterone ester formulation and comprise its treatment testosterone deficiency method - Google Patents
Oral testosterone ester formulation and comprise its treatment testosterone deficiency method Download PDFInfo
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Abstract
The invention provides a kind of combination of oral medication, it comprises the testosterone undecanoate being dissolved in carrier, described carrier comprises at least one lipophilic surfactant and at least one hydrophilic surfactant active with total lipophilic surfactant and total hydrophilic surfactant active ratio (w/w) in the range of about 6:1 to 3.5:1, and the testosterone undecanoate of wherein said dissolving comprises the described compositions of 18 to 22 weight %.Present invention also offers the pharmaceutical preparation of a kind of testosterone undecanoate.Additionally provide the preparation for treating testosterone deficiency by the present invention or the method for its symptom.Including the Therapeutic Method of the Oral testosterone ester formulation of the present invention, owing to described preparation provides optimal level of serum testosterone, within the time period extended, the male of hypogonadism therefore can be effectively treated clinically.
Description
The application is filing date on 04 12nd, 2010, international application no PCT/US2010/030788, national applications number
Be 201080066142.8, invention entitled " Oral testosterone ester formulation and comprise its treatment testosterone deficiency method "
The divisional application of application.
Technical field
The present invention relates generally to the oral formulations of testosterone ester for treating testosterone deficiency.More specifically, the present invention relates to
And comprise the pharmaceutical composition of the testosterone undecanoate (TU) with absorption and the pharmacokinetics strengthening and extending.
Background of invention
Testosterone (T) is a kind of main androgen produced in interstitial cell and is responsible for male genitals and second
The normal growth of sex character (such as, have a low and deep voice, muscle development, facial hair etc.), grow and maintain.In the manhood, testosterone
It is testis and its accessory structure (prostate and seminal vesicle) normal function, happiness and maintains libido, erectile ability institute required
's.
(such as, the T hyposecretion that testosterone deficiency is characterized with low serum T concentration can cause andriatria disease
Hypogonadism).The symptom relevant to hypogonadism in males include sexual impotence and hyposexuality, fatigue and do not have energy,
Depressed, secondary sex characteristics is degenerated, muscle weight reduces and fat weight increases.And, hypogonadism in males is bone
One risk factor of matter osteoporosis, metabolic syndrome, type ii diabetes and cardiovascular disease.
Commercially available multiple testosterone alternative medicine treats hypogonadism in males.Pharmaceutical preparation includes noting with intramuscular
Penetrate liquid, implant, alkylation T(such as, methyltestosterone) oral tablet, topical gel or the testosterone of topical plaster form and testis
Ketone derivatives.But, current all T therapies fail suitably to provide a kind of and deliver the simple of TAndClinical effective method.Example
As, intramuscular injection makes people's pain also relevant to the notable fluctuation of serum T level between dosage；T paster universal with below normal value
T level (invalid i.e., clinically) relevant and generally cause essence skin irritation；And T gel is with T from user insecurely
Transfer to women relevant with child.Equally, unique " approval " oral T therapy, methyltestosterone, then with notable hepatotoxic appearance
Relevant.Therefore, in the course of time, at present the method for the treatment of testosterone deficiency to suffer from compliance the best and therefore cause not making us full
The low T male treatment of meaning.
The bioavailability of testosterone and its ester the best because of headed by cross intestinal and liver metabolism notable or invalid because of
Testosterone can not be discharged from its testosterone prodrug for health.Such as, testosterone and side chain lengths are main less than the testosterone ester of 10 carbon
It is to be absorbed by Portal circulation, causes a large amount of (if not all) first pass metabolism.Long carbon chain (that is, 14 or more carbon) fat
Acid esters can be by intestinal Lymphatic, but fatty acid chain length is the longest, and speed and the degree of esterase hydrolyzed ester release testosterone are the lowest, therefore
Pharmacologically active the best (invalid i.e., clinically).
In addition to the selection of testosterone ester, the preparation of testosterone ester proposes unique challenges.Gastrointestinal tract environment substantially substantially in
Aqueous, this requires that medicine must dissolve for absorption.But, testosterone (especially its ester) extremely difficult water and the aqueous medium of being dissolved in, and
Even and if T or T ester is initially dissolved in preparation, preparation allows for making medicine to maintain solvable or discrete form, and does not precipitates or separately
Separate out from solution in vivo (although this character can be tested in vitro, such as, by dosage contents is mixed in simulated intestinal fluid
Close).And, oral T preparation must discharge T or T ester effectively according to required release profiles.Therefore, effective preparation of T or T ester
Good solubility must be made and most preferably discharge and meet balance between target plasma or serum concentration profile.
Because the reason of these and other, FDA (Food and Drug Adminstration) (FDA) does not ratifies testosterone or testosterone the most yet
The oral formulations of ester.It practice, the Oral testosterone product the most uniquely ratified by FDA is methyltestosterone (wherein, methyl and testosterone
The C-17 position covalent bond of " core " is to suppress hepatic metabolism；Note, the prodrug of methyltestosterone not testosterone simultaneously) and this approval send out
Raw decades ago.Unfortunately, the use of methyltestosterone and hepatotoxic incidence rate significant correlation, seldom open this medicine
Treat low testosterone male.
As it has been described above, health is provided another form of potential testosterone to deliver (that is, with " prodrug " by the fatty acid ester of testosterone
Form).Once absorption, testosterone can be discharged from its ester by the effect of nonspecific tissue and blood plasma esterase.And, as
Determined by its octanol (log P) value, by increasing relative hydrophobicity and the gained molecule of testosterone part
Lipophile, this prodrug can be absorbed at least partially through intestinal lymph, thus be reduced the first pass metabolism of liver.It is said that in general,
The lipophilicity compound that log P value is at least 5 and oil-soluble is at least 50mg/mL is mainly carried by lymphsystem.
Although having prospect, but testosterone prodrug, including testosterone ester, not with reach gonad function normal level effectively and
The mode continuing level of serum testosterone (that is, average serum T concentration is in the range of about 300-1100ng/dL) is prepared.It practice, testis
The Orally administered pharmaceutical preparation of ketone prodrug (including testosterone ester), is ratified by FDA not yet.
Therefore, it is still necessary to the oral formulations of a kind of testosterone ester, it provides optimal level of serum testosterone, its extend time
Between effectively treat the male (that is, those male of serum T concentration≤300ng/dL) of hypogonadism in section clinically.
Brief summary of the invention
In one embodiment of the invention, it is provided that a kind of combination of oral medication, it comprises and is dissolved in carrier
Testosterone undecanoate, described carrier with total lipophilic surfactant and total hydrophilic surfactant active at the model of about 6:1 to 3.5:1
Enclose interior ratio (w/w) and comprise at least one lipophilic surfactant and at least one hydrophilic surfactant active, described group
Compound once a day or every day twice Orally administered after, it is provided that the stable state average serum in the range of about 300 to about 1100ng/dL
Testosterone concentration.When using together with meals, pharmaceutical composition provides less than 2500ng/dL, preferably no more than 1800ng/
DL, and most preferably less than the C of 1500ng/dLmax。
According to a preferred embodiment, at least one hydrophilic surfactant active includes that Cremophor RH40(gathers
Oxygen Ethylene Glycol trihydroxy stearate)；At least one lipophilic surfactant includes oleic acid.The pharmaceutical composition of the present invention
The testosterone undecanoate of the dissolving of 18 to 22 weight % can be comprised, and also monohydric alcohol (such as ethanol) can be substantially free of.
In another embodiment of the present invention, it is provided that the dosage form of a kind of testosterone undecanoate, it comprises and is dissolved in carrier
Testosterone undecanoate, described carrier comprises at least one lipophilic surfactant and at least one hydrophilic surfactant active,
By described dosage form, once a day or administered twice every day is after suffering from the experimenter of hypogonadism or its symptom, it is provided that about
Stable state average serum testosterone concentration in the range of 300 to about 1100ng/dL, avoids the C beyond 2500ng/dL simultaneouslymaxGoing out of value
Existing, more preferably, it is to avoid beyond the C of 1800ng/dLmaxThe appearance of value, most preferably, it is to avoid beyond the C of 1500ng/dLmaxValue
Appearance.
In the another embodiment of the present invention, it is provided that a kind of pharmaceutical composition, it comprises 11 be dissolved in carrier
Acid testosterone, described carrier comprises at least one lipophilic surfactant and at least one hydrophilic surfactant active, described group
After compound is Orally administered together with the meals reaching 20 weight % up to 50 weight % low with fat content, it is provided that relatively contain with fat
The most Orally administered rear observed value of meals of amount about 30 weight % is the most inapparent average serum testosterone concentration.
In a further embodiment of the invention, it is provided that a kind of pharmaceutical composition, it comprises 11 be dissolved in carrier
Acid testosterone, described carrier with total lipophilic surfactant and total hydrophilic surfactant active in the range of about 6:1 to 3.5:1
Ratio (w/w) comprise at least one lipophilic surfactant and at least one hydrophilic surfactant active, described compositions
Once a day or every twice-daily Orally administered after, it is provided that the serum testosterone quick phase half-life of about 5 hours and about 29 hours
Serum testosterone t1/2.
In a further embodiment of the invention, it is provided that a kind of pharmaceutical composition, it comprises 11 be dissolved in carrier
Acid testosterone, described carrier with total lipophilic surfactant and total hydrophilic surfactant active in the range of about 6:1 to 3.5:1
Ratio (w/w) comprise at least one lipophilic surfactant and at least one hydrophilic surfactant active, by described combination
Thing once a day or every day twice by oral administration to suffering from the experimenter of testosterone deficiency or its symptom after, it is provided that treat in every day
The average serum testosterone concentration of the 30th day of scheme, it is substantially identical with the 7th day observed value.According to the present invention, every day treats
The average serum testosterone concentration of acquisition in the 30th day of scheme is also the most identical with the observed value of the 60th day.
In another embodiment of the present invention, it is provided that a kind of method treating testosterone deficiency or its symptom, its bag
Include the pharmaceutical composition of effective dose Orally administered to the experimenter suffering from testosterone deficiency or its symptom, described pharmaceutical composition bag
Containing the testosterone undecanoate being dissolved in carrier, described carrier is with the ratio of total lipophilic surfactant with total hydrophilic surfactant active
Example (w/w) comprises at least one lipophilic surfactant and at least one hydrophilic surfactant active at about 6:1 to 3.5:1,
To provide the stable state average serum testosterone concentration in the range of about 300 to about 1100ng/dL.Described compositions can once a day or often
Day administered twice, and can get the C in the range of about 900 with 1100ng/dLmaxValue.
According to this method, described compositions can be used together with the meals comprising at least 20 weight % fat.Described method base
Testosterone pharmacokinetics diurnal variation, average serum T is not caused in basismaxIn the range of being worth the most about 3 to 7 hours, and
After repeat administration, substantially do not observe that the reaction of steady-state serum testosterone is remarkably decreased.
In a preferred embodiment in accordance with this invention, it is provided that a kind of pharmaceutical composition, it comprises:
The testosterone undecanoate of the dissolving of (a) 15-25 weight %；
At least one hydrophilic surfactant active of (b) 12-18 weight %；
At least one lipophilic surfactant of (c) 50-65 weight %；
The borage oil of (d) 10-15 weight % and the mixture of Oleum menthae,
Described compositions generally can be free of monohydric alcohol, particularly ethanol, and after Orally administered to experimenter in need,
Obtain the serum testosterone half-life (T in the range of about 10 hours to about 18 hours1/2).Cremophor RH40 is a kind of preferred
Hydrophilic surfactant active and preferably lipophilic surfactant be oleic acid.Borage oil is regarded as with Oleum menthae
Lipophilic surfactant.
In an especially preferred embodiment, described compositions comprises:
The testosterone undecanoate of the dissolving of (a) 18-22 weight %；
At least one hydrophilic surfactant active of (b) 15-17 weight %；
At least one lipophilic surfactant of (c) 50-55 weight %；And
The borage oil of (d) 10-15 weight % and the mixture of Oleum menthae.
The ratio of borage oil and Oleum menthae can be in the range of 8:1 to 3:1, it is preferable that 6:1 to 5:1, it is highly preferred that 5:1
To 4:1.In addition to Cremophor RH40, Solutol HS-15, Tween80 and TPGS are also preferred hydrophilic surfactant
Agent；And outside oil removing acid, glyceryl monooleate, lauric acid propylene glycol ester and Capmul MCM are also preferred lipophilic surface-active
Agent.It is also contemplated that the combinations of two or more lipophilic surfactants and two or more hydrophilic surfactant actives.
In another embodiment of the present invention, it is provided that a kind of method treating testosterone deficiency, described method includes
The pharmaceutical composition of effective dose Orally administered to hypogonadism experimenter, described pharmaceutical composition comprises:
The testosterone undecanoate of the dissolving of (a) 15-25 weight %；
One or more hydrophilic surfactant actives of (b) 12-18 weight %；
One or more lipophilic surfactants of (c) 50-65 weight %；
The borage oil of (d) 10-15 weight % and the mixture of Oleum menthae,
And without ethanol, described pharmaceutical composition once a day or twice Orally administered pact obtaining experimenter every day
Stable state average serum testosterone concentration in the range of 300 to about 1100ng/dL, Cave.Described compositions optionally with fat content
Use together with about 25 weight % or higher meals in about 15 weight %.According to this method, experimenter can reach and moves with prescribe medicine generation
Any one of mechanics parameter or all:
(a) experimenter serum testosterone CmaxIn the range of 900 to 1100ng/dL；
B () is substantially free of testosterone pharmacokinetics diurnal variation；
C () uses serum T after compositionsmaxIt it is 3 to 7 hours；And
Substantially do not observe after (d) repetitive administration that the reaction of steady-state serum testosterone declines.
In this respect, before at least one embodiment explaining in detail the present invention, it should be understood that the present invention is not answered
With the component configuration of explanation in being limited to structural details and being limited in following description mentioned or accompanying drawing.The present invention can be carried out except institute
Embodiment outside description and can implementing in many ways and carry out.Equally, it should be understood that in literary composition and used in summary
Phrase and term be not construed as to illustrate limit.
Therefore, those skilled in the art's meeting is it will be appreciated that the concept that the disclosure is based on can be easily used as designing other portions
Point, the basis of method and system is for the multiple purpose carrying out the present invention.Such as, some embodiments of the present invention can be by TU
Combine in oral delivery system with other active medicines (including other hormones), described oral delivery system be partially blocked from or
Alleviate the symptom relevant to testosterone deficiency.Therefore, it is important to, it is believed that claim includes without departing from the scope of the invention and essence
The equivalent structure of god.
Accompanying drawing is sketched
Fig. 1 provides once a day or 24 hours interior serum T levels of twice oral administration every day TU of the present invention preparation.
Fig. 2 illustrates after using conventional oral TU preparation (Restandol) that the formulations Comparative of the present invention comprises TU in oleic acid
The male of hypogonadism serum T response in time.
Fig. 3 provides before the TU preparation of the Orally administered present invention, the different fat content (in weight percent) of feed
The T of serum T level of experimenter of mealsmaxValue.
Fig. 4 provides before the TU preparation of the Orally administered present invention, the different fat content (in weight percent) of feed
The C of serum T level of experimenter of mealsmaxValue.
Fig. 5 provides before the TU preparation of the Orally administered present invention, the different fat content (in weight percent) of feed
Area under curve (AUC) value of serum T level of experimenter of meals.
Detailed Description Of The Invention
The invention provides a kind of combination of oral medication comprising TU, said composition is when to be less than administered twice every day
When the male of hypogonadism, it is provided that expect " normally " or gonad function (i.e., about 300-normal range in this male
Testosterone average steady state serum levels (concentration) in 1100ng/dL), avoids being thought right and wrong by FDA (Food and Drug Adminstration) simultaneously
Desired, the most unacceptable high CmaxValue.Such as, the FDA approval guide statement treatment experimenter less than 85% can have
1500ng/dL or higher CmaxIt is worth, and nobody has the C beyond 2500ng/dLmaxValue.Treatment experimenter tool less than 5%
There is the C in the range of 1800-2500ng/dLmaxValue.And, the formulation design of the present invention is become self-emulsifying drug delivery systems
(SEDDS) to form the emulsion (or dispersion) containing TU with gastrointestinal intestinal juice after mixing.
In one embodiment of the invention, use the present invention preparation, individually or with other active ingredient combinations
By oral delivery testosterone and/or the ester of testosterone molecule C17 position.Such as, preferable undecanoic acid testis in some embodiments
The combination of the combination of the oral active inhibitor of ketone and I type or II type 5α-reductase or testosterone undecanoate and synthesis progesterone.
Although described by the undecylate (that is, TU) of testosterone and multiple embodiments of the illustration present invention, but according to saying
The teaching of bright book, can use other esters (including T) of hydrophobic compound for oral delivery.It practice, the common skill in this area
Art personnel should be from teaching herein it is clear that the drug delivery system of the present invention and carry out compositions since then and may be adapted to be administered orally
Deliver other testosterone esters, such as short chain (C2-C6), middle chain (C7-C13) and long-chain (C14-C24) fatty acid ester, preferably testosterone
Medium chain fatty acid ester.
The preparation of the present invention comprises the T-ester being dissolved in mixture, and described mixture comprises one or more lipophilic surfaces
Activating agent and one or more hydrophilic surfactant actives.Lipophilic surfactant as defined herein have less than 10 and
Hydrophilic-lipophilic balance (HLB) (HLB) value of preferably smaller than 5.Hydrophilic surfactant active as defined herein has the HLB more than 10
Value.(HLB is a kind of hydrophilic to surface activity amphiphatic molecule (such as, surfactant) and the warp of hydrophobic group relation
Test expression.It is in order to represent to about 45, surfactant and its value change and include to live in nonionic and ion-type surface about 1
Property agent.HLB value is the highest, and surfactant water-soluble/dispersibility is the strongest).
According to an aspect of the present invention, in delivery system, each component (that is, lipophile and hydrophilic surfactant active) is each
From there is property of solubilizing and partly contributing to active component dissolving.Substantially contribute to those lipophilic surfaces of medicine dissolution
Activating agent is being defined herein as " mainly " solvent.It will be appreciated, however, that dissolubility can be affected by the temperature of solvent/preparation.Such as,
The preparation of the present invention comprising about 20% testosterone undecanoate is protected under 30 DEG C or above temperature (in the range of including 30 to about 40 DEG C)
Hold solvable.
Hydrophilic surfactant active's component be reach the preparation required dispersibility in gastrointestinal tract and drug release needed for.
That is, hydrophilic surfactant active is in addition to as secondary solvent, it is also desirable to its by medicine from lipid carrier substrate or the most molten
Agent discharges.In this regard, high HLB surfactant, such as Cremophor RH40, generally can meet requirement.Can be to height
The level (measuring) of HLB surfactant is adjusted providing optimal drug to discharge, and does not undermine the dissolving of active component.
The lipophilic surfactant of the drug delivery system being suitable to the present invention includes:
Fatty acid (C6-C24, it is preferable that C10-C24, it is highly preferred that C14-C24), such as, octanoic acid, capric acid, undecanoic acid, Laurel
Acid, myristic acid, Palmic acid, stearic acid, oleic acid, linoleic acid plus linolenic acid.Preferably oleic acid.
The list-of fatty acid and/or two-glyceride, such as, Imwitor988(is mono--/bis--glycerol caprylate),
Imwitor742(is mono--/bis--pungent/glycerol decanoate), Imwitor308(mono--glycerol caprylate), Imwitor191(mono--stearic
Acid glyceride), Softigen701(mono--/bis--ricinoleic acid ester), Capmul MCM(mono--/bis--pungent/capric acid glycerol
Ester), Capmul MCM (L) (liquid form of Capmul MCM), Capmul GMO(mono--olein), Capmul GDL
(GLYCERYL DILAURATE), Maisine(be mono--glyceryl linoleate), Peceol(mono--olein), Myverol18-92
(from the distillation monoglyceride of sunflower oil) and Myverol18-06(are from the distillation monoglyceride of oil with hydrogenated soybean),
Precirol ATO5(glyceryl palmitostearate) and the semi-synthetic glyceride of Gelucire39/01(, i.e. C12-18Single-, two and
Three-glycerol ester).The preferred component of this type of lipophilic surfactant be oleic acid, Palmic acid and stearic partial glyceride and
Mixture.
The list-of fatty acid and/or the acetas of two-glyceride, succinate, lactate, citrate and/or tartaric acid
Ester, such as, Myvacet9-45 (distillation acetylated monoglyceride), Miglyol829 (pungent/capric acid two glycerol succinic acid ester),
Myverol SMG (mono bis-succinylated monoglycerides), Imwitor370 (Glyceryl stearate citrate),
Imwitor375 (glyceryl monostearate/citrate/lactate) and Crodatem T22 (the diacetyl base liquor of monoglyceride
Stone acid esters).
The propylene glycol list-of fatty acid and/or two-ester, such as, Lauroglycol (PGML), Mirpyl
(propylene glycol list myristinate), Captex200 (propylene/dicaprate), (propylene glycol two is pungent for Miglyol840
Acid esters/dicaprate) and Neobee M-20 (propylene/dicaprate).
The polyglycerin ester of fatty acid, such as Plurol oleique(polyglycerol acrylate), Caprol ET(polyglycereol mixes
Close fatty acid) and Drewpol10.10.10(polyglycerol acrylate).
There is the castor oil ethoxylate (HLB < 10) of low content ethoxylate, such as Etocas5(5 mole epoxy
Ethane reacts with 1 mole of castor oil) and Sandoxylate5(5 moles of ethylene oxide and 1 mole of castor oil react).
The acid formed by making the glyceride of oxirane and fatty acid or fatty acid react and ester ethoxylate (HLB <
10), the glycerin esters of described fatty acid such as, Crodet04(polyoxyethylene (4) lauric acid), Cithrol2MS(polyoxyethylene (2)
Stearic acid), Marlosol183(polyoxyethylene (3) stearic acid) and Marlowet G12DO(glyceryl 12EO dioleate).
The sorbitan ester of fatty acid, such as, Span20(Span-20), Crill1(sorbose
Alcohol acid anhydride monolaurate) and Crill4(sorbitan monooleate).
The product of transesterification reaction (HLB < 10) of natural or hydrogenated vegetable oil triglycerides and polyalkylene polyol, example
Such as, the polyoxyethylated almond oil of Labrafil M1944CS(), the polyoxyethylated Semen Maydis oil of Labrafil M2125CS() and
The polyoxyethylated hydrogenated Cortex cocois radicis of Gelucire37/06().Preferably Labrafil M1944CS.
Alcohol ethoxylate (HLB < 10), such as, Volpo N3(polyoxyethylated (3) oil ether), Brij93(polyoxyethylene
Change (2) oil ether), Marlowet LA4(polyoxyethylated (4) Laurel ether).
Pluronics, such as, polyoxyethylene-polypropylene oxide copolymers and block copolymer (HLB < 10), such as,
Synperonic PE L42 (HLB=8) and Synperonic PE L61 (HLB=3).
If it is required, the mixture of suitable lipophilic surfactant (such as, those listed above) can be used,
In some instances, find that this mixture is useful.
Any pharmaceutically acceptable hydrophilic surfactant active (that is, HLB value is more than 10) can be used in the present invention.One
A little limiting examples include:
Oleum Ricini or castor oil hydrogenated ethoxylate (HLB > 10), such as, Cremophor EL (polyoxyethylene (35) castor
Oleum Sesami), Cremophor RH40 (polyoxyethylene (40) castor oil hydrogenated), Etocas40 (polyoxyethylene (40) Oleum Ricini),
Nikkol HCO-60 (polyoxyethylene (60) castor oil hydrogenated), Solutol HS-15 (Polyethylene Glycol 660 hydroxy stearic acid ester),
Labrasol (caprylyl caproyl PEG-8 glyceride), alpha-tocopherol-PEG-6000-succinate (TPGS)
With ascorbic acid-6 cetylate.Preferably Cremophor RH40.
Polyoxyethylene sorbitol acid anhydride derivative of fatty acid, such as, Tween20(polyoxyethylene (20) monolaurate),
Tween80(polyoxyethylene (20) monoleate), Crillet4(polyoxyethylene (20) monoleate) and Montanox40(polyoxy
Ethylene (20) monopalmitate).Preferably Tween80(polysorbate80).
Gelucires, it is preferable that Gelucire50/13(Palmic acid and stearic PEG is mono-and diester).(just
For Gelucires, the fusing point of first digit (that is, 50) tie substance and the corresponding HLB numerical value of second digit (that is, 13)).
Fatty acid ethoxylate (HLB > 10), such as, Myrj45(polyoxyethylene (8) stearate), Tagat L(gathers
Oxygen ethylene (30) monolaurate), Marlosol1820(polyoxyethylene (20) stearate) and Marlosol OL15(polyoxy
Ethylene (15) oleate).Preferably Myrj45.
Alcohol ethoxylate (HLB > 10), such as, Brij96(polyoxyethylene (10) oil ether), Volpo015(polyoxyethylene
(15) oil ether), Marlowet OA30(polyoxyethylene (30) oil ether) and Marlowet LMA20(polyoxyethylene (20) C12–C14
Aliphatic ether).
Polyoxyethylene-polypropylene oxide copolymers and block copolymer (HLB > 10), can with trade name Pluronics or
Poloxamers buys, such as Poloxamers188 and 407, also referred to as Syperonic PE L44(HLB=16) and
Syperonic F127(HLB=22).
Anion surfactant, such as, sodium lauryl sulfate, enuatrol and dioctyl sodium sulphosuccinate.
Alkylphenol surfactant (HLB > 10), such as, Triton N-101(polyoxyethylene (9-10) nonyl phenol)
With Synperonic NP9(polyoxyethylene (9) nonyl phenol).
As discussed, in one aspect of the invention, every kind of component (that is, lipophile and hydrophilic surfactant in delivery system
Agent) each there is solvent properties and partly contribute to active component dissolving.By this way, without being bound by theory or be limited to
This is theoretical, and the present invention is not required to other solvents, such as, cosolvent, but these can be optionally included in present system and preparation.
The optional cosolvent being suitable to the present invention is, such as, and water, short chain monocarbon alcohol, dihydroxylic alcohols and polyhydric alcohol, such as ethanol,
Benzylalcohol, glycerol, propylene glycol, Allyl carbonate, there is the Polyethylene Glycol of the mean molecule quantity of about 200 to about 10,000, diethyl two
Alcohol list ether (such as, Transcutol HP) and combinations thereof.Preferably, this cosolvent, especially ethanol or other lists are not comprised
Ethanol.
May be incorporated into other oil in embodiment of the present invention and include middle chain (C7–C13) or long-chain (C14–C22) fatty acid is with low
Molecular weight (up to C6) unitary, binary or the complete triglyceride of polyhydric alcohol.Therefore, for some examples of oils of the present invention
Including: vegetable oil (such as, soybean oil, safflower oil, Semen Maydis oil, olive oil, Oleum Ricini, cotton seed oil, Oleum Arachidis hypogaeae semen, sunflower seed
Oil, Oleum Cocois, Petiolus Trachycarpi oil, Oleum Brassicae campestris, Radix Oenotherae erythrosepalae oil, Oleum Vitis viniferae, Semen Tritici aestivi germ oil, Oleum sesami, American Avocado Tree oil, Semen Armeniacae Amarum, coloured glaze
Lettuce, Herba Menthae and almond oil) and animal oil (such as, cod-liver oil, shark oil and ermine oil).
In other embodiments of the present invention, method and composition be by be incorporated to can biochemical upper (1) TU of adjustment absorb,
(2) TU is metabolized to T and/or (3) T and is metabolized to the component of dihydrotestosterone (DHT) and adjusts (that is, maintaining) serum testosterone and may utilize
Rate.Such as, in long-chain fatty acid ester, comprise medium can improve TU absorption.By this way, more TU avoid the hydrolysis in intestinal
And enter blood flow.In other words, fatty acid ester can suppress esterase with competing, and otherwise esterase is by metabolism TU.Other esters or a combination thereof
Example include that (such as, propyl p-hydroxybenzoate, acetic acid are pungent as the galenical extract of food additive or optimum ester
Ester and ethyl acetate).
Other components that adjustable TU absorbs include " natural " and the synthetic inhibitor of 5α-reductase, 5α-reductase be
Present in enterocyte and its hetero-organization, a kind of T of catalysis changes into the enzyme of DHT.This suppression wholly or in part converted can be oral
Increase and maintain the increase of T serum levels after being administered TU, simultaneously with reducing serum DHT level.Borage oil, it comprises significantly
5α-reductase inhibitor gamma-Linolenic acid (GLA) of amount, is an example of TU metabolism " natural " regulator.Certainly, except
Beyond in borage oil, GLA directly can be added as the independent component of TU preparation of the present invention.This area is understood multiple
(such as, epigallocatechin gallate (EGCG), it is the youngster mainly obtained from green tea to the natural inhibitor of 5α-reductase
Boheic acid and the Serenoa repens extract of berry from saw leaf palmetto (Serenoa repens) species), all these may be adapted to
The present invention.The limiting examples of the synthesis 5α-reductase inhibitor being applicable to the present invention includes such as finasteride
(finasteride), the compound of dutasteride (dutasteride) etc..
In addition to 5α-reductase inhibitor, the present invention contains the T metabolic poison by other mechanism.This inhibition point a kind of
Can be cytochrome P 450 isozymes CYP3A4, it be present in enterocyte and hepatocyte and therefore, it is possible to metabolism testosterone.Therefore,
The selected embodiment of the present invention includes Oleum menthae, it is known that it contains the component that can suppress CYP3A4 activity.
Other optional members that can be included in the present composition are commonly used for those in oil based drug delivery system
Composition, such as, antioxidant, such as, tocopherol, tocopherol acetas, ascorbic acid, butylated hydroxytoluene (BHT), ascorbic acid palm fibre
Palmitic acid acid esters, fourth hydroxyanisole and propylgallate；PH stabilizer, such as citric acid, tartaric acid, fumaric acid, acetic acid, sweet ammonia
Acid, arginine, lysine and dipotassium hydrogen phosphate；Thickening agent/suspending agent, such as hydrogenated vegetable oil, Apis cerana Fabricius, silica sol,
Mannitol, natural gum, cellulose, silicate, bentonite；Flavoring agent, such as Fructus Pruni pseudocerasi, Fructus Citri Limoniae and Fructus Foeniculi spice；Sweeting agent, such as Ah
This Ba Tian (aspartame), acesulfame potassium, sucralose, saccharin and cyclamate；Deng.
Present inventors have recognized that one or more lipophilic surfactants and one or more hydrophilic surfactant actives
Relative scale most important to the pharmacokinetics needed for reaching the present invention.More specifically, inventor is found that total lipophile
Surfactant and a ratio of total hydrophilic surfactant active, this ratio can not only dissolve relatively great amount of T-ester (example
As, more than 15%, 18%, 20%, 22% or 25%) and the optimal release from preparation of the T-ester can be provided.Preferably, total oil (example
Such as, oleic acid+borage oil+Oleum menthae, all these be considered lipophilic surfactant) with the ratio of hydrophilic surfactant active
Example (w/w) is in the range of about 6:1 to 1:1,6:1 to 3.1,6:1 to 3.5:1 or 6:1 to 4:1, and it is highly preferred that at about 5:1
To 3:1, and most preferably, in the range of about 4:1 to 3:1.
By weight, following relative concentration (percent is based on total formulation weight amount):
Hydrophilic surfactant active: 10-20%, it is highly preferred that 12-18%, and most preferably, 15-17%.
Lipophilic surfactant: 50-70%, it is highly preferred that 50-65%, and most preferably, 50-55%.
Other oils: 5-15%, it is highly preferred that 7-15%, and most preferably, 10-13%.
Medicine: 10-30%, it is highly preferred that 15-25%, and most preferably, 18-22%.
The preparation of the present invention has self emulsifying, forms thin matter emulsifying agent after diluting with aqueous medium or intestinal juice in vivo.
In other words, preparation can have high surfactant and lipid content, and it is designed for after mixing being formed reason with water-bearing media
Think dispersion.The qualitative description of the self-emulsifying properties of the preparation of the present invention can be observed during its dissolution in vitro.On the other hand,
May utilize laser light scattering and/or carry out emulsion droplet by UV/VIS spectrophotometric turbidity measurement in dissolving medium
The quantitative measurement of particle diameter.Those of ordinary skill in the art may utilize and understand any one of these methods.
Pharmaceutical composition according to the present invention is preferably liquid or semisolid at ambient temperature.And, by by medicine
Compositions is adsorbed onto on solid carrier particle (such as, silicon dioxide, calcium silicates or Magnesiumaluminumsilicate) to obtain without mobility
Powder, can be filled into this powder in hard capsule or be pressed into tablet, and these pharmaceutical compositions can be changed into solid dosage forms.
See, e.g., US2003/0072798, the disclosure of which is herein incorporated by reference in full.Therefore, term herein " dissolves "
Being interpreted as describing active pharmaceutical ingredient (API), it is dissolved in liquid solution or is homogeneously dispersed in solid carrier.Can be formed
And use the dosage form of encapsulated forms.
Present invention preferably includes in (such as, above-mentioned lipophile and the hydrophilic surface work of lipid surfactant excipient
Property agent combination in any) in the presence of dissolve API.Therefore, the fusing point of surfactant used is to can determine that resulting composition exists
To be liquid or a semisolid factor under ambient temperature.The especially preferred compositions of the present invention is liquid oral unit dose
Type, it is highly preferred that in being filled into hard or soft capsule, such as, gelatin or non-gelatin capsules, such as by cellulose, carrageenin or
Those capsules that Pul (pollulan) is made.Pharmaceutical preparation based on lipid well known within the skill of those ordinarily skilled
Encapsulation techniques.Because the delivery system of invention described herein and preparation are not limited to any encapsulation method, so without entering
One step discusses concrete encapsulation techniques.
Medicament carrier system and pharmaceutical preparation according to the present invention can be by for medicament carrier systems based on lipid
Prepared by conventional art.In typical method prepared by currently preferred carrier system, weigh lipophilic surface-active
Agent component also adds in suitable rustless steel container, then weighs hydrophilic surfactant active's component, and together with other components
Add in container.In a preferred method, first hydrophobic drug can be added lipophilic surfactant component (example
As, oleic acid) in, and add hydrophilic surfactant active's component after complete dissolution.Under any circumstance, the mixing of component can
By using homogenizing mixers or other high-shear devices and high temperature (especially in the case of using high-melting-point surfactant)
Complete to guarantee all components before or after adding medicine in homogeneous liquid.
In the case of in weighing hydrophobic drug and adding the lipid mixture of merging, the most at high temperature continue
Mixing, until preparing homogeneous solution.Preparation can be made to deaerate, be then encapsulated in soft or hard capsule.In some cases, available
Suitably jacketed vessel makes filling preparation keep, under high temperature, being beneficial to processing.Equally, in some cases, homogeneous solution can be
(such as, by 5 micron filters) is filtered before loading capsule.
Delivering referring back to testosterone, the pharmaceutical composition of the present invention may be adapted to testosterone therapy.Testosterone is the main of male
Endogenous androgen.Interstitial cell (Leydig cell) in testis produces about 7mg testosterone every day, causes serum-concentration to exist
In the range of about 300 to about 1100ng/dL.The ovary of women and adrenal gland also synthesize testosterone, but in an amount of from normal in gonad function
In male viewed about 1/10th.Great majority (>=98%) circulation testosterone is attached to sex hormone binding globulin and white egg
When in vain and discharging the most in a free form, just there is biological activity.Therefore, term " dissociates " and is defined as being not bonded to such as, institute herein
The biomolecule of the preparation of the present invention stated, cell and/or lipidic matrix, or be not limited in wherein.Generally, as herein described
The medicine that " dissociates " refers to contact the medicine of the metabolic enzyme of circulation in serum.
Although testosterone or the delivery of its any certain esters should do not limit the invention to, but find TU provide unique chemistry and
Physical characteristic so that it is preferably used in some embodiments.Present inventors have recognized that the undecylate of testosterone especially can produce
The raw bioavailability comparing other equivalence ester (such as, testosterone enanthatas ester (TE)) viewed excellences of use.
And, in the preparation of the present invention TU use with compared with the reported values of T substitute of other forms (include the mouth of TU
Formulation) ratio relevant (table 1) of significantly lower serum DHT:T.Testosterone or testosterone are changed into by the effect of 5α-reductase
Interact with androgen receptor after DHT.DHT is a kind of more more effective androgen than testosterone, and some scientists recognize
The risk adding carcinoma of prostate is raised for DHT level.By this way, the invention provides compare other known testosterones deliver
The unexpected advantage of another of vehicle.
Table 1: by the viewed serum DHT in response to T-substitute of various route of administration and DHT:T ratio
Relatively
1Atkinson, LE, Chang, Y-L and Synder, PJ. (1998) Long-term experience with
testosterone replacement through scrotal skin.In:Testosterone:Action,
Deficiency and Substitution (Nieschlag, E and Behre, HM write) .Springer-Verlag,
Berlin, the 365-388 page
2Swerdloff, RS, wait (2000) .Long-term pharmacokinetics of transdermal
testosterone gel in hypogonadal men.J.Clin.Endocrinol.Metab.85:4500-4510.
3Wang, C etc. (2004) .Long-term testosterone geltreatment
maintains beneficial effects on sexual function and mood,lean and fat mass
and bone mineral density in hypogonadal men.J.Clin.Endocrinol.Metab.89:2085-
2098.
4Houwing, NS etc. (2003) .Pharmacokinetic study in women of three different
doses of a new formulation of oral testosterone undecanoate,Andriol
Testocaps.Pharmcotherapy:23:1257-1265.
5Gooren,LJG(1994).A ten-year safety study of the oral androgen
testosterone undecanoate.J.Androl.15:212-215.
The particular of the present invention will illustrate in non-limiting embodiments.According to the teachings of the present invention, table 2 provides
The composition details of the several formulations of TU.In order to calculate, 1mg T-phase is when in 1.58mg T-undecylate.
The composition details (mg/ capsule and weight %) of table 2 be based on each ' 00' hard gelatin capsule about 800mg filling weight.
But, under the testosterone ester amount of less than about 100mg/ capsule, can be for allowing to use less hard gelatin capsule (such as, ' No. 0'
Or when needing, smaller number) less total filling weight be scaled preparation.
Equally, to those of ordinary skill in the art it should be apparent that kind (such as, lipophile, a hydrophilic
Deng) in many (if not all) surfactants can exchange with from another surfactant same kind of.Therefore, though
So table 1 lists the preparation comprising oleic acid, but those of ordinary skill in the art will be appreciated that other lipophilic surfactant (examples
Such as, enumerated above those) be also likely to be applicable.Similarly, although table 1 lists and comprises Cremophor RH40(HLB
=13) preparation, but those of ordinary skill in the art will be appreciated that other hydrophilic surfactant actives (such as, above listed that
A bit) be probably applicable.Borage oil, Oleum menthae, BHT can replace with the material that chemical property is similar with ascorbyl palmitate
Generation or be removed.
Table 2
1Milligram weight is rounded up to nearest integer；800(±10%)
2±8mg
The preferred formulation of the TU being filled in " 00 " number capsule according to the present invention is:
Preparation A
Preparation B
It is described below the internal and external performance data of the preparation according to the present invention.But, the scope of the invention should not
It is limited in following example or embodiment the particular formulations studied.
The embodiment 1-odd-numbered day is studied
Research preparation B is once a day or administered twice every day odd-numbered day medicine after the male of hypogonadism is for power
Learn curve.Research design is become a kind of open-label, odd-numbered day administration, continuous, the pharmacokinetic of intersection.Give written
After Informed Consent Form, recruit the male of 12 hypogonadisms, and all 12 experimenters complete research.Every is subject to
The preparation B that examination person accepts daily dosage is as follows:
1.200mg T (with TU form) QD, i.e. 2 capsules/dosage
2.200mg T (with TU form) BID (100mg/ dosage), i.e. 1 capsule/dosage
3.400mg T (with TU form) BID (200mg/ dosage)
On the feed after 5 minutes, dosage is applied to experimenter (breakfast QD, and breakfast and dinner BID) with the form of capsule.
Table 3 provides the relevant PK parameters of research:
aInstitute's indicating value of half-life and peak time is intermediate value and scope.
bDosage is to represent with T equivalent.Each TU capsule contains 158.3mg TU, its corresponding 100mg T equivalent.
Average serum T concentration (C in 24 hours sections after administrationavg) represent the serum T of all schemes studied
Level just increases, and wherein scheme 3 obtains optimum response (Cavg385ng/dL).This research in evaluated in response to oral T-ester
Preparation viewed average serum T peak concentration is from without departing from Upper Limit of Normal Value (that is, 1100ng/dL).Although some are indivedual
The C of experimentermaxT value exceeds upper limits of normal, but in these peaks, the overwhelming majority is in the range of 1200 to 1400ng/dL.Any control
The C of the experimenter for the treatment of groupmaxAll without departing from 1500ng/dL.
Serum T half-life (the T of scheme 1 and 21/2) intermediate value is of about 15 hours, and the T of scheme 31/2It it is 8 hours.Each
In scheme, serum DHT concentration increases together with serum T level.By liquid chromatography-mass spectrography (LC/MS/MS) measure in all phases
Between average DHT:T ratio (Ravg) slightly beyond normal range (that is, 0.03-0.1), but the most notable.
The TU being administered together with food by BID with 200mgT equivalent produces the most satisfied result, wherein 75% be subject to
Examination person reaches serum T CavgHigher than 300ng/dL(subnormal gonad function normal limit).Similarly, the experimenter of 75%
The average serum T reached is (that is, 0.03-0.1ng/dL) within normal range.Not up to CavgIt is that those of at least 300ng/dL are subject to
Examination person, at more than 200ng/dL, shows that being slightly increased for these experimenters of TU dosage will be T to be effectively administered orally substitute treatment
Method.
When in the data of baseline correction serum T, it was observed that the serum T of most subjects is consistent with DHT concentration to be increased
And unrelated with T-ester dosage, the dose linear that TU is wherein administered orally is excellent.Although DHT:T ratio is slightly elevated, but any rising exists
The most all it is considered as the most notable.The equivalent agent of other T esters (such as, TE) relatively, it was observed that change between the experimenter of this preparation
Property is little.And, in " BID " dosage regimen, average serum T peak concentration or AM Yu PM be administered during 12 hours AUC without
Difference.
About safety, although reporting headache is a kind of side effect, but in each therapeutic scheme, not tested at one
In person, report has side effect.Serious adverse events or death do not occur during research, and there is no an experimenter because of bad
Event premature interruption research.Therefore, all adverse events are considered as moderate strength event.
The research on the seven of embodiment 2-
Research preparation B acute tolerance after being applied to the male of hypogonadism with two doses twice every day and
Steady-state serum pharmacokinetic curve.Research design is become the pharmacokinetic of a kind of open label, repeat administration, intersection
(checking food effect in a group).
After giving Written informed consent, recruiting the male of 29 hypogonadisms, wherein 24 complete research.
The scheme that every the experimenter completing to study accepts preparation B is as follows:
1.7 daily dose 600mg T(are with TU form), BID(300mg/ dosage), i.e. 3 capsules/dosage
2.8 daily dose 400mgT(are with TU form), BID(200mg/ dosage)
After start to take food (breakfast and dinner) 30 minutes, with capsule form, dosage is applied to experimenter, but the 8th
My god, AM dosage is used on an empty stomach.
T exposes peak value (Cmax) and T always expose (AUC) to endogenous baseline T correct after with dose proportional.T peak value is dense
Degree (Tmax) time there are after each therapeutic administratp about 4 hours.Equally, the serum-concentration of TU and DHTU is at dosing interval
Interior raising and lowering, wherein the concentration that is initial and that terminate of dosing interval is less than the 20% of TU peak concentration and less than DHTU peak
The 25% of value concentration.For treating every kind, because endogenous T produces, baseline T concentration is gradually lowered.Observe and be subject to promoting sexual gland hormone
To exogenous T gradually and lasting suppression is consistent, therefore cause the generation of endogenous T to reduce.At least partly suppression keeps 14 days
The removing phase.
Again, serum T pharmacokinetics does not shows the diurnal variation of serum T concentration.PM is administered (about using at 8PM) and obtains
To using (about using) similar concentration-time curve (Fig. 1) at 8AM with AM.Because the concentration phase between AM and PM administration
Like property (in scheme 1 assess), so being satiated with food from scheme 2() 12-hour PK data for predicated response exactly in
The 200mg T(that BID mode is administered is with the form of TU) the whole day PK curve of 24 hours.Analog result show (a) based on AUC,
The experimenter of 77% is in 24 hours sectionsBloodClear T CavgWithin gonad function normal range, therefore meet current FDA to T
The performance requirements of the 75% of substitute products；And (b) does not has the C of experimentermaxMore than 1500ng/dL, this marks beyond current FDA
Standard, i.e. for T substitute products, the C of the experimenter less than 85%maxMore than 1500ng/dL.Therefore, the effect also specified with current FAD
Energy terminal is consistent, does not has the C of experimentermaxThe C of the studied experimenter of 5% it is less than more than 2500ng/dLmaxAt 1800-
In the range of 2500ng/dL.It should be noted that these results all obtain in the case of not having any dose titration.
Table 4 provides stable state AM of T and the comparison of PM pharmacokinetics under being administered with BID:
Use TU together with high fat diet and produce and use together with standard diet similar serum T-Concentration-time song
Line.On the contrary, using TU under fasting conditions causes serum T to expose (CmaxAnd AUC) decline more than 50% (table 5).At all situations
Under, find the C observedmaxWith the C calculatedavgBetween strong correlation, show with the oral T-specific C of ester formulation targetingavgMay result in
Intended peak value T level after administration.
DHT concentration follows the trail of T concentration, although DHT concentration is only the 11-34% of T concentration.T shows the most non-to the conversion of DHT
Linearly, increase with the concentration ratio speed less than T.When T concentration is the highest, DHT/T ratio is minimum, and is starting TU treatment
Before, DHT/T ratio is about 0.1, and during treating, and in the steady state, average ratio is 0.24 and in about 0.1 to 0.35 scope
In, depend on the sampling time after Orally administered TU.
Mean estradiol concentration is of about 11pg/mL before starting oral TU treatment, and the scope of the 7th of various treatment the day
In the range of 19pg/mL to 33pg/mL (concentration before Gei Yaoing).Stable state estradiol concentration before administration is of about 20-30pg/mL.
The surrounding research of embodiment 3-
Also research preparation B with determine when to hypogonadism every day for men the dosage of twice 200mg T(with TU
Form) (that is, 2 capsules/dosage) when treating 28 days, reaches the time needed for stable state.Research design is become a kind of open label,
The pharmacokinetic of repeat administration.
After giving Written informed consent, recruiting the male of 15 hypogonadisms, all male are completed
Research.Each experimenter accepts the 200mg T(form with TU of two doses every day), continue 28 days.
For each experimenter, the research arrangement of the 32nd day " the 28th day " continuous P K is sampled day.Therefore, each dosage-
It is obedient to experimenter and accepts the 400mg T(of 31 daily doses altogether with TU form) (that is, 200mg T, BID), and for the last time
AM is administered 200mgT(with TU form).With capsule form application dosage, experimenter is wherein instructed to start take food (breakfast and evening
Meal) take medicine after 30 minutes.
The relevant PK data of table 6 offer research:
Within normal range, the experimenter of 86.7% reaches serum T Cavg, there is no the C of an experimentermaxConcentration is more than
1800ng/dL, and the C of only 13.3% experimentermaxConcentration is more than 1500ng/dL.(note: do not carry out during carrying out this research
Dose titration is so that experimenter is in target usefulness and safety margin).In response to the T half-life of TU in the preparation tested
It is considerably longer than only T or the TU institute reported values of the preparation oral with prior art.Such as, consistent with invention described herein
In the clinical research of oral TU preparation, it was observed that eliminate the half-life (α phase) the most about 5 hours, and based on oral administration TU
Serum T curve disclosed after prior art preparations, estimated value the chances are its half (that is, 2 to 3 hours).Use the present invention's
Oral TU preparation, it was similarly observed that long elimination (end i.e., the eventually) half-life of 29 hours.But, the generation of endogenous T is by external source
Property T the suppression used, the most limited suppression occurs 3 days started and it needs to the continued treatment of 5-7 days reaches
Big suppression.
To treatment the 7th day, T and DHT concentration reached stable state.The concentration of T and DHT of the 3rd day is more than the 5th day, and this shows right
For the exogenous T used, need a period of time to suppress endogenous T to produce, therefore realize the stable state in response to oral TU.
Really, add exogenous T by endogenous T level from treatment before 276ng/dL be suppressed to 28 days supplementary T treatment after
108ng/dL。
It may be evident, however, that once serum T TU is administered orally twice in response to every day and after reaching stable state, it was observed that serum T responds
Slightly decrease over time to not declining (that is, after continuous T U is administered, without towards lowerBloodThe trend of clear T level).Such as, the 15th
It CavgThe substantially similar C observed for 28th dayavg(Fig. 2).By contrast, it was reported that the oral TU preparation of oral this area
In time towards lower T meansigma methods (Cantrill, J.A.Clinical Endocrinol (1984) 21:97-107).With originally
In the male of the hypogonadism of oral TU preparation for treating known to field, it was reported that the serum T observed after treatment in 4 weeks is rung
Observed value little about 30%-wherein most than the first of the male treatment of hypogonadism day should have constitutional gonad
The baseline values of hypofunction form therefore serum T low (such as, < 100ng/dL), therefore, T reduces can not be only by suppression
Endogenous T is explained.
Serum DHT concentration follows the trail of T concentration closely, DHT and DHT/T value adds 4 to 7 times during treating.12 hours
Average DHT/T ratio during dosing interval is 0.245, although the value during dosing interval can be in average maximum ratio 0.380
To average minimum scale 0.131.In interrupting 36 hours with oral TU treatment, DHT concentration returns to treat front water
Flat.But, T concentration can not return to treat front level soon, hence it is evident that is because endogenous T and produces/discharge by being suppressed
Can not reverse soon.
The concentration of estradiol (E2) shows single and little by little increases to stable state, and this also can reaching in treatment on the 7th day.E2 is dense
Degree follows the trail of the systematic change of T change during displaying that dosing interval.The average C of E2max、CavgAnd CminIt is 30.6pg/ respectively
ML, 22.0pg/mL and 15.5pg/mL.In interrupting 36 hours with oral TU treatment, E2 concentration returns to treat front level.
Average C during T stable state (AM of the 28th day is administered)max、CavgAnd CminConcentration is 995ng/dL, 516ng/dL respectively
And 199ng/dL.Intermediate value T of TmaxOccur 5.0 hours upon administration.CminAverage out to Cmax23.5%, obtaining the index of oscillation is
156%.The only experimenter to about half have evaluated the elimination half-life of T, and the intermediate value of those experimenters is 18.4 hours
(average T1/2It it is 29 hours).
Embodiment 4-food effect is studied
The dietary fat of the male of hypogonadism is a kind of to the research of any effect of the pharmacokinetics of preparation B
Open label, double center, five to crossing research.The removing after date of 4-10 days, by the 300mg T(475mg TU of single dose, 3
Preparation B capsule) it is applied to 16 there is serum baseline T level 205.5 ± 25.3ng/dL(meansigma methods+SE, 23-334.1ng/
The male of hypogonadism dL).Making experimenter accept medicine on an empty stomach at random or feed is followed by by medicine for 30 minutes, meals contain
Have～800 calories and there is the fat (weight %) of specified quantitative: extremely low fat (6-10%)；Low fat (20%)；" normally " meals
Fat (30%)；Or higher fatty acid (50%)." normally " meals are defined as a kind of comparator for statistical (that is, ginseng setly
According to meals).Collect after using medicine the Serial blood of 24 hours to determine serum testis by liquid chromatography-mass spectrography (LC/MS/MS)
Ketone and dihydrotestosterone (DHT) level.
Find pharmacokinetic parameter (table 7, Fig. 3-5) and the low fat of the serum T in response to single oral high dose TU
-actually bioequivalence (that is, 90% confidence interval 85-125% between) similar with normal-fat meals.When normal and higher fatty acid
When meals compare, also been observed similar serum T PK parameter.Although high fat diet generation higher serum T response (though
So difference does not statistically occur), but when comparing with normal-fat meals, the average proportions of least square meansigma methods exists
The m-the most not significant difference of 70-143% is < 30%.
1CAvgIt is with AUC0-∞/ τ calculates (τ=dosing interval=12 hour, BID is administered)
The transmutability of PK reaction seems after being administered for the first time, or the highest after the oral TU starting dosage several times, and with
Treatment to continue and reduce.Therefore, any impact of serum T PK parameter is seemed by the dietary fat in the range of low-normal-height
It is all inapparent during long term administration.This treated (embodiment 2) and within 30 days, treats the PK result one of (embodiment 3) with 7 days
Causing, during wherein the repeat administration at oral TU is studied, the PK in the case of different meals still shows CmaxWith CavgBeing similar to of distribution
Result [the 200mg T(form with TU is used in two kinds of researchs), BID].
Normal-fat meals (that is, with reference to meals) relatively, in extremely low fat of not taking food or taken food, low fat or higher fatty acid
Under meals, after oral TU, the statistics of viewed serum T response compares announcement: at low fat or high fat diet with normal
Between meals, under p < 0.05 level, there is not significant difference statistically.On the contrary, at empty stomach or extremely low fat of having taken food
During breakfast, the using of oral TU with SEDDS dosage form produces and the serum T PK ginseng of normal meals dramatically different (lower)
Number.Therefore, the fat content of the meals used together with the preparation of the present invention can be substantially different from " normally ", and this is clinically
Obtained T level do not had appreciable impact.Therefore, it is allowed to experimenter often eats and the motility of dietary habit of every day, this
Point is that known oral TU preparation before this is not caned.Oral TU preparation known in the art so far under fasted conditions not
It is likely to be breached any significant serum T level.
Embodiment 5-In Vitro Dissolution is tested
The dissolution research of the external preparation carrying out the present invention is to evaluate the dependency with internal viewed PK curve.?
In first research, the dissolution of research preparation B.For comparing, comprise Andriol(each soft capsule wraps
Containing being dissolved in the 40mg TU in Oleum Ricini and lauric acid propylene glycol ester mixture).Grind under TU with substantially dose,equivalent
Study carefully, i.e. 1 preparation B capsule (158.3mg TU) and 4 Testocaps soft capsules (4 × 40mg=160mg TU).At shape of being satiated with food
Studying dissolution (that is, TU discharges from each self-preparing agent) in simulated intestinal fluid (FeSSIF) medium of state, described medium is simulated by meals
The intestinal juice stimulated.FeSSIF contains sodium hydroxide, glacial acetic acid, potassium chloride, lecithin and sodium taurocholate.Final emulsion is adjusted
Joint arrives pH5.0.
In table 8 and 9, the data of presentation show that the preparation of the present invention discharges about 40%TU and at 4 hours in starting 30 minutes
About the 60% of the whole capsule of rear release.But, forWhole 4 hours little or no drug releases are out
(1%).Main Differences from the TU dissolution that both preparations are observed can at least partly be attributed in preparation B exist hydrophilic table
Face activating agent (such as, Cremophor RH40).By contrast, AndriolContain only oil (Oleum Ricini) and parent
Oiliness surfactant (lauric acid propylene glycol ester).
In studying at second, make preparation A carry out similar test, but use 5%Triton X100 kaliumphosphate buffer
(pH6.8) as dissolution medium.Result provides in table 10 below.At this in research, in the beginning 15 minutes of dissolution, from this
Bright preparation discharges 98%TU, and again because the existence of hydrophilic surfactant active Cremophor RH40 is natural
Ground is beneficial to this Fast Stripping and TU release.
In another embodiment of the present invention, pharmaceutical composition disclosed herein can be equally applicable for alleviating for male
The side effect of some strategies of contraception.Such as, male contraception based on progesterone substantially suppress lutropin (LH) and
Follicle stimulating hormone (FSH), and therefore Inhibit sperm occurs, and causes clinical azoospermia (to be defined as continuous 2 months less than about 100
Ten thousand sperms/mL seminal fluid).But, use progesterone and there is non-required side effect equally that significantly decrease steady-state serum testosterone levels.
Such as, in such a situation it is preferred that offer contain testosterone or the progesterone system of testosterone derivative (such as, TU) simultaneously
Agent.More preferably, it is provided that according to the pharmaceutical preparation of the present invention, it comprises progesterone-present in an amount at least sufficient to substantially suppress LH and FSH to produce
Raw-and testosterone.In some embodiments, pharmaceutical preparation described in oral delivery once a day.
The preparation of the present invention can provide the preparation that release extends, being delivered in serum in several hours by testosterone.Real
On border, according to half-life of the serum testosterone of the present invention between 3 and 7 hours, it is preferable that more than 4,5 or 6 hours.Compare it
Under, the serum half-life of male's testosterone was considered in the range of 10 to 100 minutes.
The most bound by theory or limit, it is believed that on the one hand, the preparation of the present invention can by strengthen literary composition Chinese medicine be drenched by intestinal
The absorption of bar system rather than absorbed by Portal circulation and reach these effects.On the other hand, the most bound by theory or
Limit, it is believed that by using the ester of testosterone, de-ester required time causes the longer T half-life.
The oral dose of the present invention can be administered orally once by the experimenter needing testosterone therapy for the most every 12 hours, to maintain needs
Level of serum testosterone.In a more preferred, oral dose is by the most every 24 hours mouths of the experimenter needing testosterone therapy
Take once.Usually will, " required " testosterone levels is to be characterized as not having in the people experimenter of testosterone deficiency that find
A little levels.
Although the present invention has combined its specific embodiments and has been been described by, it will be appreciated that can revise further and this explanation
Book is intended to all changes of the invention below, purposes or change.Generally, the principle of the invention with comprise that to belong to the present invention relevant
Known or conventional convention in technology also can be used for above-described basic feature and right in appended claims
Those variations of the present invention.
Claims (10)
1. a combination of oral medication, it comprises the testosterone undecanoate being dissolved in carrier, and described carrier is with total lipophilic surface
Activating agent and total hydrophilic surfactant active ratio (w/w) in the range of 6: 1 to 3.5: 1 comprise at least one lipophilic surface
Activating agent and at least one hydrophilic surfactant active, wherein said lipophilic surfactant has the Hydrophile-Lipophile less than 5
Equilibrium valve and described hydrophilic surfactant active have the hydrophile-lipophile balance value more than 10, and wherein, described compositions comprises
At least one lipophilic surfactant described of 50-70 weight % and described compositions comprise 10-20 weight % described extremely
Few a kind of hydrophilic surfactant active, the testosterone undecanoate of wherein said dissolving constitutes the described compositions of 18 to 22 weight %,
Described compositions once a day or every day twice Orally administered after the average blood of stable state in the range of 300 to 1100ng/dL is provided
Clear testosterone concentration.
2. combination of oral medication as claimed in claim 1, at least one hydrophilic surfactant active wherein said is polyoxy
Ethylene Glycol-trihydroxy-stearate.
3. combination of oral medication as claimed in claim 1, at least one hydrophilic surfactant active wherein said is
Cremophor RH 40。
4. combination of oral medication as claimed in claim 1, at least one lipophilic surfactant wherein said is oleic acid.
5. combination of oral medication as claimed in claim 1, wherein said testosterone undecanoate is dissolved in and is substantially free of ethanol
In carrier.
6. combination of oral medication as claimed in claim 1, it comprises at least one hydrophilic described in 15 to 17 weight %
Surfactant.
7. combination of oral medication as claimed in claim 1, it comprises at least one lipophile described in 50 to 55 weight %
Surfactant.
8. a pharmaceutical composition, described pharmaceutical composition comprises the testosterone undecanoate being dissolved in carrier, and described carrier is with total parent
Oiliness surfactant and total hydrophilic surfactant active ratio (w/w) in the range of 6: 1 to 3.5: 1 comprise at least one parent
Oiliness surfactant and at least one hydrophilic surfactant active, wherein said lipophilic surfactant has less than 5
Hydrophile-lipophile balance value and described hydrophilic surfactant active have the hydrophile-lipophile balance value more than 10, wherein, described group
At least one lipophilic surfactant described and described compositions that compound comprises 50-70 weight % comprise 10-20 weight %
At least one hydrophilic surfactant active described, to provide the stable state average serum testosterone in the range of 300 to 1100ng/dL dense
Degree, the testosterone undecanoate of wherein said dissolving constitutes the described compositions of 18 to 22 weight %, and described compositions is used for treating testis
In the method for ketone deficiency disease or its symptom, described method includes that the experimenter to suffering from testosterone deficiency or its symptom is Orally administered
The described pharmaceutical composition of effective dose.
9. the pharmaceutical composition in described method as claimed in claim 8, wherein said compositions is used once a day.
10. the pharmaceutical composition in described method as claimed in claim 8, wherein said compositions administered twice every day.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410005764.XA CN103705462B (en) | 2010-04-12 | 2010-04-12 | Oral testosterone ester formulation and comprise its treatment testosterone deficiency method |
| HK14109461.5A HK1196765A1 (en) | 2010-04-12 | 2013-07-05 | Oral testosterone ester formulations and methods of treating testoterone deficiency comprising same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410005764.XA CN103705462B (en) | 2010-04-12 | 2010-04-12 | Oral testosterone ester formulation and comprise its treatment testosterone deficiency method |
| CN201080066142.8A CN102883710B (en) | 2010-04-12 | 2010-04-12 | Oral testosterone ester formulations and methods of treating testoterone deficiency comprising same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080066142.8A Division CN102883710B (en) | 2010-04-12 | 2010-04-12 | Oral testosterone ester formulations and methods of treating testoterone deficiency comprising same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103705462A CN103705462A (en) | 2014-04-09 |
| CN103705462B true CN103705462B (en) | 2016-08-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410005764.XA Active CN103705462B (en) | 2010-04-12 | 2010-04-12 | Oral testosterone ester formulation and comprise its treatment testosterone deficiency method |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103705462B (en) |
| HK (1) | HK1196765A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109419771B (en) * | 2017-08-28 | 2022-02-01 | 中国人民解放军军事医学科学院毒物药物研究所 | Testosterone undecanoate sustained-release pharmaceutical composition, and preparation method and application thereof |
| BR112021011525A2 (en) * | 2018-12-14 | 2021-08-31 | Acerus Biopharma Inc. | TESTOSTERONE ACTIVE ESTER DERIVATIVES, COMPOSITIONS AND USES THEREOF |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035511A (en) * | 2004-08-04 | 2007-09-12 | 卡穆鲁斯公司 | Compositions forming non-lamellar dispersions |
| CN101217963A (en) * | 2005-04-15 | 2008-07-09 | 克劳拉斯医疗有限公司 | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
| CN102271665A (en) * | 2009-01-08 | 2011-12-07 | 利珀辛公司 | Steroidal Compositions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
| GB9608719D0 (en) * | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
-
2010
- 2010-04-12 CN CN201410005764.XA patent/CN103705462B/en active Active
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2013
- 2013-07-05 HK HK14109461.5A patent/HK1196765A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035511A (en) * | 2004-08-04 | 2007-09-12 | 卡穆鲁斯公司 | Compositions forming non-lamellar dispersions |
| CN101217963A (en) * | 2005-04-15 | 2008-07-09 | 克劳拉斯医疗有限公司 | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
| CN102271665A (en) * | 2009-01-08 | 2011-12-07 | 利珀辛公司 | Steroidal Compositions |
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| Publication number | Publication date |
|---|---|
| CN103705462A (en) | 2014-04-09 |
| HK1196765A1 (en) | 2014-12-24 |
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Effective date of registration: 20230810 Address after: Colorado, USA Patentee after: Tolmar, Inc. Address before: Illinois, America Patentee before: CLARUS THERAPEUTICS, Inc. |