CN109419771A - Testosterone undecanoate sustained release pharmaceutical composition, preparation method and the usage - Google Patents
Testosterone undecanoate sustained release pharmaceutical composition, preparation method and the usage Download PDFInfo
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- CN109419771A CN109419771A CN201710751039.0A CN201710751039A CN109419771A CN 109419771 A CN109419771 A CN 109419771A CN 201710751039 A CN201710751039 A CN 201710751039A CN 109419771 A CN109419771 A CN 109419771A
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- testosterone undecanoate
- stabilizer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The invention belongs to pharmaceutical technology field, it is related to a kind of testosterone undecanoate suspension, preparation method and the usage.In particular it relates to a kind of testosterone undecanoate suspension, it includes testosterone undecanoate, stabilizer and water, in which: the content of the testosterone undecanoate is 10%-50%；The partial size of the testosterone undecanoate meets: D10 is 0.2-0.5 μm, and D50 is 0.5-1.5 μm, and D90 is 2.2-6.0 μm；The stabilizer includes the first stabilizer and the second stabilizer, the weight ratio of first stabilizer and the second stabilizer is (1-10): (1-20), and the weight ratio of the testosterone undecanoate and the stabilizer is (1-20): (1-20).Testosterone undecanoate suspension stability of the invention is good, redissolves all right after sedimentation, can maintain hormone in vivo level steadily in the long term, bioavilability is higher, and irritation is smaller.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of testosterone undecanoate suspension, its lyophilized preparation, preparation method
And purposes.
Background technique
Male hypogonadism is to lead to recycle testosterone in abnormal low characterized by endogenous testosterone generates deficiency
Level, i.e. level of serum testosterone are lower than 10nmol/l.Male hypogonadism patients with clinical manifestations is varied.Testosterone lacks
The weary symptom along with different severity such as sex dysfunction, muscle quantity and muscle strength reduce, depressibility mood and
Osteoporosis.Part male, which steps into this old specific period from the middle age, will appear male climacteric syndrome, the reason for this is that
The decline of Serum Testosterone Levels caused by various factors and androgen receptor abnormality.Nowadays, becoming larger with social pressures, part are young
People also will appear hypogonadism shape group.
The main method for the treatment of male hypogonadism is androgen replacement therapy at present.Natural testosterone half-life period
It is very short, only 10-20 minutes.The testosterone of oral administration cannot reach the testosterone levels of clinically relevant degree.Therefore, in order to
Testosterone structure must be improved with chemical method or be administered with other approach by treating male hypogonadism.Work as at these
In, 17 β-hydroxylation esters such as testosterone propionate and testosterone enanthatas (TE) represent most important treatment male available on the market
The compound of hypogonadism.In these testosterone esters, testosterone undecanoate is a kind of domestic unique list marketing
Oral testosterone ester.Testosterone undecanoate is more obvious as the effect of prodrug treatment male climacteric syndrome, supplement male's male
Hormone, the reduction of patient state of an illness, has practical significance.The structural formula of testosterone undecanoate is as shown in following Formulas I:
However, testosterone undecanoate is poorly water soluble drugs, it is clinically main using oral testosterone undecanoate soft capsule at present
(trade name ANDRIOL) and intramuscular injection testosterone undecanoate oil solution (trade name thinks special jade for asking rain).When oral soft capsule, need to it is a large amount of
Fat is with food, and direct enteral Lymphatic, avoids deactivation caused by the first pass effect of liver together with lipoids；The soft capsule is empty
Abdomen, which is taken, not to be absorbed substantially.In addition, since the half-life short of drug is (after testosterone undecanoate enters blood absorption, rapidly by serum ester
Enzyme hydrolysis), patient repeatedly takes (3-4 total) soft capsule daily, and compliance is poor.
And the durative action preparation testosterone undecanoate fat injection clinically used, composition have Ergol and injection
With oil, wherein Ergol may result in allergic reaction, oily then that there may be lung oil embolism and injection pains etc. is bad anti-
It answers.
Therefore, it is necessary to develop new testosterone undecanoate preparation, safe and effective, quality controllable and clinically user
Just.
Summary of the invention
The present inventor has obtained a kind of testosterone undecanoate slow releasing pharmaceutical combination by in-depth study and a large amount of test
Object, such as testosterone undecanoate aqueous suspension.The lyophilized preparation of the suspension has also further been made in the present inventor.Of the invention
Testosterone undecanoate sustained release pharmaceutical composition partial size is suitable for, stability is good.Compared with commercially available oil solution, the local stimulation of intramuscular injection
Property has a degree of reduction.Rat in vivo studies confirms that above-mentioned suspension has certain slow release effect, shows simultaneously
The muscle local organization residual of the new formulation is relatively less than commercially available oil solution preparation out；Bioavilability improves.Thus
Provide following inventions:
One aspect of the present invention is related to a kind of testosterone undecanoate suspension, it includes testosterone undecanoate, stabilizer and water,
Wherein:
The content of the testosterone undecanoate is 10%-50% (w/v, g/ml)；
The partial size of the testosterone undecanoate meets: D10 is 0.2-0.5 μm, and D50 is 0.5-1.5 μm, D90 2.2-
6.0μm；
The stabilizer includes the first stabilizer and the second stabilizer, and the testosterone undecanoate and the stabilizer
Weight ratio is (1-20): (1-20), wherein
First stabilizer selected from soybean lecithin, hydroxypropyl cellulose, poly yamanashi esters such as polyoxyethylene sorbitan monoleate or gathers
Sorb ester 20, PLURONICS F87, poloxamer188, povidone, hydroxypropyl methylcellulose, Arabic gum, western yellow glue, alginic acid
Sodium, methylcellulose, sodium carboxymethylcellulose, alkyl polyglycoside, inulin lauryl carbamate, polyethylene glycol, hydroxypropyl are fine
Dimension element and any one or more in carbohydrate (such as glucose, fructose or sucrose),
Second stabilizer is selected from polyethanediol succinate, lauryl sodium sulfate, phenyl ethylamine, arginine salt or more
Any one or more in sodium ester；And
The weight ratio of first stabilizer and the second stabilizer is (1-10): (1-20).
Testosterone undecanoate is the effective component or active constituent of pharmaceutical composition of the invention.
If not otherwise specified, " first " and " second " in the first stabilizer and the second stabilizer is only to be convenient for area
Not or different stabilizers is referred to, and does not have the meaning of order.
In one embodiment of the invention, the testosterone undecanoate sustained release pharmaceutical composition, when it is undecanoic acid
When testosterone aqueous prolonged release suspension, wherein the content of testosterone undecanoate is 10%-50% (w/v, g/ml), preferably 10%-
40% (w/v, g/ml), particularly preferably 10%-25% (w/v, g/ml), such as 10%-15% (w/v, g/ml), 10%
(w/v, g/ml), 12% (w/v, g/ml), 12.5% (w/v, g/ml), 15% (w/v, g/ml), 20% (w/v, g/ml) or
25% (w/v, g/ml).
It is not limited to theoretical limitation, if the concentration of main ingredient is higher than the upper limit 50%, early period, quick-release amount increased, and may exceed
Effective treatment concentration.If the concentration of main ingredient be lower than lower limit 10%, burst size is smaller, it may not be possible to reach effectively treat it is dense
Degree, or long-acting effect cannot be maintained.
In one embodiment of the invention, the testosterone undecanoate sustained release pharmaceutical composition, wherein undecanoic acid testis
The weight ratio of ketone and stabilizer is (1-20): (1-20)；Preferably (1-15): (1-10)；More preferably (1-10):
(1-5).For example, the numberical range that 15:1,10:1,5:1 and the specific ratio of any two are constituted.
In one embodiment of the invention, it is characterised in that any one or more in following (1) to (8) item
:
(1) content of the testosterone undecanoate is 10%-30% (g/ml)；
(2) D10 is 0.2-0.3 μm；Preferably 0.2-0.25 μm；
(3) D50 is 0.9 μm -1.4 μm；
(4) first stabilizer is selected from poly yamanashi esters, hydroxypropyl cellulose, hydroxypropylcellulose, soybean lecithin, carboxylic
Any one or more in sodium carboxymethylcellulose pyce and hydroxypropyl cellulose；
(5) second stabilizer be selected from polyethanediol succinate (TPGS) and docusate sodium in any one or it is more
Kind；
(6) weight ratio of testosterone undecanoate and stabilizer is (1-15): (1-15)；Preferably (1-15): (1-10),
More preferably (1-10): (1-5)；
(7) weight ratio of first stabilizer and the second stabilizer is (1-5): (1-20), preferably (1-5):
(1-10)；More preferably (1-2): (1-5) or 1:(1-2)；For example, 1:1,1:1.5,1:1.6,1:1.8,1:2,1:3,1:
4, the numberical range that 1:5 and the specific ratio of any two are constituted；
(8) the testosterone undecanoate suspension also includes bacteriostatic agent and/or pH adjusting agent.
Preferably, D10 is 0.2-0.3 μm；More preferably 0.2-0.25 μm.It is not limited to theoretical limitation, smaller D10
Be conducive to the release of testosterone undecanoate faster, to reach effective treatment concentration in the short time, to play drug effect.
In one embodiment of the invention, it is preferable that the testosterone undecanoate sustained release pharmaceutical composition, wherein
D10 is 0.2-0.4 μm or 0.2-0.3 μm.For example, D10 is that 0.2 μm, 0.3 μm or 0.4 μm and these specific values are any
The numberical range constituted between the two.
In one embodiment of the invention, it is preferable that the testosterone undecanoate sustained release pharmaceutical composition, wherein
D50 is 0.9 μm -1.4 μm；It is highly preferred that D50 is 0.9 μm -1.2 μm.For example, D50 is 0.9 μm, 1.0 μm, 1.1 μm, 1.2 μ
M, the numberical range that 1.3 μm or 1.4 μm and any two specific value are constituted.
In one embodiment of the invention, it is preferable that the testosterone undecanoate sustained release pharmaceutical composition, wherein
D90 is 2.5-5.0 μm, 2.5-4.5 μm, 2.5-4.0 μm, 3.0-5.0 μm, 3.0-4.5 μm, 3.0-4.0 μm or 3.0-
3.5μm.For example, D90 is 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm or 5.0 μm and any two specific value is constituted
Numberical range.
D10 need to be controlled in lesser nanometer size range, realize that comparatively fast release reaches target blood concentration after being administered.D50
With D90 control in micron grain size range, realizes that small particle first dissolves release and is rapidly achieved effective treatment concentration, dissolved after big partial size
Release reaches maintenance releasing effect.
The inventors discovered that D10 is if more than 0.5 μm, then its quick-release effect is deteriorated, and can not achieve after administration that comparatively fast release reaches
To effective treatment concentration.If D10 is less than 0.2 μm, partial size is integrally less than normal in preparation, can generate burst effect, drug release mistake
It is more, in release in 2 minutes more than 20%, after some time it is possible to reach super efficient treatment concentration, while holding time and shortening.
The present inventors have additionally discovered that if D50 is greater than, 1.4 μm of partial sizes are bigger, and irritation is stronger, i.e., internal compatibility is poorer,
The safety of said preparation is poorer.
In one embodiment of the invention, the testosterone undecanoate suspension includes following component:
Preferably, it includes following components for the testosterone undecanoate suspension:
The testosterone undecanoate aqueous prolonged release suspension can be directly applied to human body, such as pass through intramuscular injection.11
Sour testosterone aqueous prolonged release suspension suspension need to vibrate before to be shaken up, to improve the homogeneity of suspension.It is not limited to theory
Limitation, the suspension of administered intramuscular can reunite after injection in injection site, drug depot be formed, further according to drug granule
Size successively dissolves, and the drug of dissolution enters body circulation and achievees the effect that slow release.In combination with the undecanoic acid of esters structure
Testosterone, there are the processes of esterase hydrolyzed, may will also result in the result of sustained release release.
Another aspect of the present invention relates to a kind of testosterone undecanoate lyophilized preparations, by testosterone undecanoate any in the present invention
Suspension is freeze-dried to be made；
Preferably, freeze drying protectant is selected from one of glucose, mannitol, sucrose, lactose or a variety of；
Preferably, the dosage of freeze drying protectant is 10%-40%, the preferably 10%-30% of solid content, particularly preferably
For 15%-25%, for example, 15%, 20% or 25%.
Testosterone undecanoate lyophilized preparation of the invention can be redissolved by the way that physiological saline or glucose injection is added, and can be used for
Intramuscular injection.
Another aspect of the invention is related to a kind of method for preparing any testosterone undecanoate suspension in the present invention, including under
State step:
(1) the first stabilizer, the second stabilizer and water are uniformly mixed, obtain the first mixture；
(2) testosterone undecanoate is added in the first mixture in step (1), obtains the second mixture；
(3) the second mixture is uniformly dispersed, it is preferable that dispersed the second mixture by dispersion and emulsion homogenizer
It is even；
(4) product of step (3) is carried out by homogeneous by high pressure homogenizer.
In one embodiment of the invention, homogeneous described in step (4) includes the following steps:
At least five recycles under (4-1) 200bar-300bar；Preferably, 5-15 circulation；Such as 8-12 circulation；
Such as 10 circulations；
Under (4-2) 400bar-600bar, 5-15 circulation；Such as 8-12 circulation；Such as 10 circulations；
Under (4-3) 700bar-900bar, 5-15 circulation；Such as 8-12 circulation；Such as 10 circulations；
Under (4-4) 1050bar-1150bar, 5-15 circulation；Such as 8-12 circulation；Such as 10 circulations.
In one embodiment of the invention, it is preferable that in step (4-1), recycled under 200bar-300bar, until
Ceramic bead and valve seat are without apparent strike note.
In one embodiment of the invention, homogeneous described in step (4) includes the following steps:
Under (4-1) 200bar-300bar, 8-12 circulation；Such as 10 circulations；
Under (4-2) 450bar-550bar, 8-12 circulation；Such as 10 circulations；
Under (4-3) 750bar-850bar, 8-12 circulation；Such as 10 circulations；
Under (4-4) 1050bar-1150bar, 8-12 circulation；Such as 10 circulations.
In one embodiment of the invention, homogeneous described in step (4) includes the following steps:
Under (4-1) 200bar-300bar, 10 circulations；
Under (4-2) 500bar, 10 circulations；
Under (4-3) 800bar, 10 circulations；
Under (4-4) 1100bar, 10 circulations.
Another aspect of the invention is related to any testosterone undecanoate suspension or testosterone undecanoate freeze-drying system in the present invention
Agent is in the drug that preparation treats or prevents that endogenous testosterone generates insufficient associated diseases such as male hypogonadism
Purposes；Preferably, the male hypogonadism is selected from male sexual disfunction, male's muscle quantity and muscle strength and subtracts
Less, at least one of male's depressibility mood and Male Osteoporosis.
In the present invention,
D10, D50, D90 respectively refer to the corresponding partial size in 10%, 50%, 90% place in particle-size accumulation distribution map.Partial size is tired
Integral Butut is the map and its provide data that instrument automatically generates by 2000 laser light diffraction principle of Malvern.
In the present invention, if not otherwise specified, testosterone undecanoate aqueous suspension, testosterone undecanoate crystal suspension,
Testosterone undecanoate aqueous prolonged release suspension and testosterone undecanoate suspension have the same meaning.
Advantageous effect of the invention
The present invention at least one of has the following technical effect that:
(1) testosterone undecanoate suspension prepared by the present invention, stability is good, redissolves after sedimentation all right；
(2) experiment of rat vivo pharmacokinetic shows testosterone undecanoate suspension and commercially available testosterone undecanoate oil
Injection has similar slow release effect, can maintain hormone in vivo level steadily in the long term, at the same muscle local organization residual compared with
Commercially available oil solution has to be reduced to a certain degree, and bioavilability is higher than commercially available oil solution；
(3) rabbit muscle irritation is experiments have shown that the muscle irritation of the more commercially available oil solution preparation of the suspension has obviously subtracts
It is few.
Detailed description of the invention
Fig. 1: scanning electron microscopic observation.Figure 1A: bulk pharmaceutical chemicals.Figure 1B: 300nm crystal suspension.Fig. 1 C:1.2 μm crystal is suspended
Liquid.Fig. 1 D:4.8 μm crystal suspension.
The X-ray powder diffraction figure of Fig. 2: 3 different-grain diameters and bulk pharmaceutical chemicals.Sample in Fig. 2 from top to bottom is successively former
Expect medicine, 4.8 μm of crystal suspensions, 1.2 μm of crystal suspensions, 300nm crystal suspension.Counts indicates peak intensity in abscissa
It spends, 2theta indicates 2 θ of the angle of diffraction in ordinate.
Fig. 3: muscle irritation experimental result.Wherein, Fig. 3 A, Fig. 3 C, Fig. 3 E, Fig. 3 G, Fig. 3 I, Fig. 3 K and Fig. 3 M are expressed as
The experimental result of muscle sectional view, Fig. 3 B, Fig. 3 D, Fig. 3 F, Fig. 3 H, Fig. 3 J, Fig. 3 L and Fig. 3 N are expressed as the reality of the longitudinal sectional figure of muscle
Test result.Wherein:
Fig. 3 A, Fig. 3 B, positive controls.
Fig. 3 C, Fig. 3 D, negative control group.
Fig. 3 E, Fig. 3 F, blank auxiliary group.
Fig. 3 G, Fig. 3 H, 300nm suspension (sample 3).
Fig. 3 I, Fig. 3 J, 1.2 μm of suspensions (sample 2).
Fig. 3 K, Fig. 3 L, 4.8 μm of suspensions (sample 1).
Fig. 3 M, Fig. 3 N, oil solution preparation.
Fig. 4: testosterone undecanoate receive micro-crystal suspension and the drug concentration of testosterone undecanoate fat injection in vivo with
The curve graph of time change.
Fig. 5: testosterone undecanoate receive micro-crystal suspension and the drug concentration of testosterone undecanoate fat injection in vivo with
The curve graph of time change.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
Preparation example 1-3: the preparation (sample 1-3) of testosterone undecanoate suspension
Preparation method:
By said ratio, at room temperature, soybean lecithin and docusate sodium is added to the water stirring, are uniformly dispersed
Afterwards, the testosterone undecanoate bulk pharmaceutical chemicals of sieving are added, at dispersion and emulsion homogenizer (Shanghai Heng Chuan mechanical equipment Co., Ltd, C25)
Under again it is fully dispersed uniformly (A grades, 2min), be subsequently poured into the specimen cup of the high pressure homogenizer with condensing unit, low pressure
It is recycled under 200bar-300bar several times, after ceramic bead and valve seat are without apparent strike note, can be forced into 500bar*10 can
4.8 μm of crystal suspensions (corresponding to sample 1) is obtained, continues the available 1.2 μm of crystal of 800bar*10,1100bar*10 and is suspended
Liquid (corresponds to sample 2), continues 1300bar*10, then 800bar*10, and 300nm crystal suspension can be obtained and (correspond to sample
3)。
Then be added suitable bacteriostatic agent benzalkonium chloride and suitable sodium carbonate into each product respectively, adjust PH to
Between 7.35-7.45.
Sample 1-3 is made.
According to the measurement method in the following examples 1, the D50 of actually measured sample 2 is 1.150 μm, the D50 of sample 3
For 293.3nm.
Preparation example 4-8: the preparation (sample 4-8) of testosterone undecanoate suspension
4 composition of sample: testosterone undecanoate 12.5g, polysorbas20 1g, docusate sodium 0.5g.
5 composition of sample: testosterone undecanoate 12.5g, Macrogol 4000 2g, docusate sodium 1g.
6 composition of sample: testosterone undecanoate 12.5g, hydroxypropyl cellulose 1g, docusate sodium 1g.
7 composition of sample: testosterone undecanoate 12.5g, hydroxypropyl methylcellulose 1g, TPGS0.5g.
8 composition of sample: testosterone undecanoate 12.5g, polyoxyethylene sorbitan monoleate 1g, TPGS 1g.
The preparation method is as follows:
By said ratio, at room temperature, two kinds of stabilizers of recipe quantity is successively added to the water stirring, are uniformly dispersed
Afterwards, the testosterone undecanoate bulk pharmaceutical chemicals of sieving are added, at dispersion and emulsion homogenizer (Shanghai Heng Chuan mechanical equipment Co., Ltd, C25)
Under again it is fully dispersed uniformly (A grades, 2min).Above-mentioned finely dispersed suspension is poured into the high-pressure homogeneous of condensing unit
In the specimen cup of machine, recycled under low pressure 200bar-300bar several times, it, can after ceramic bead and valve seat are without apparent strike note
It is forced into 500bar*10, continues 800bar*10,1100bar*10.
Then be added respectively into each product suitable bacteriostatic agent benzalkonium chloride and suitable sodium carbonate adjust PH to
Between 7.35-7.45.
Sample 4-8 is made.
Preparation example 9-11: the preparation (freeze-drying sample 1-3) of testosterone undecanoate freeze-dried powder
Each 2ml of sample 1-3 for taking preparation example 1-3 to prepare respectively is placed in cillin bottle, and the sweet dew of solid content 20% is added
Alcohol, after mixing, until pre-freeze at -60 DEG C, and be slowly heated under vacuumized conditions and distil at -40 DEG C, and finally maintain+
25 DEG C of heating under vacuum distillations, obtain testosterone undecanoate freeze-dried powder, i.e. freeze-drying sample 1-3.Specification is 0.25g/ bottles.
Compare preparation example A-B: the preparation (control sample A-B) of testosterone undecanoate suspension
Control sample A composition: testosterone undecanoate 12.5g, polysorbas20 1g, docusate sodium 0.5g.
Control sample B composition: testosterone undecanoate 12.5g, Macrogol 4000 2g, docusate sodium 1g.
Above-mentioned two prescription is identical as the preparation example 4 of front and 5 prescription of preparation example respectively.
The preparation method is as follows:
At room temperature, two kinds of stabilizers in corresponding composition are taken successively to be added to the water stirring respectively, dispersion is equal
After even, the testosterone undecanoate bulk pharmaceutical chemicals of sieving are added, dispersion and emulsion homogenizer (Shanghai Heng Chuan mechanical equipment Co., Ltd,
C25 under) again fully dispersed uniform (A grades, 2min).Above-mentioned finely dispersed suspension is poured into the high pressure with condensing unit
In the specimen cup of homogenizer, recycled under low pressure 200bar-300bar several times, to ceramic bead and valve seat without apparent strike note
Afterwards, it gradually pressurizes.
Control preparation example A pressure process: 500bar*10,800bar*10,1000bar*10 are gradually forced into.
Control preparation example B pressure process: 500bar*10,800bar*10,1000bar*10,1200bar* are gradually forced into
10。
Then be added respectively into each sample suitable bacteriostatic agent benzalkonium chloride and suitable sodium carbonate adjust PH to
Between 7.35-7.45.
Obtain control sample A-B.
Embodiment 1: particle diameter distribution measurement experiment
1. laboratory sample and instrument
Testosterone undecanoate suspension (sample 2) made from preparation example 2.
Testosterone undecanoate freeze-dried powder (freeze-drying sample 2) prepared by preparation example 10.
Compare testosterone undecanoate suspension (control sample A-B) made from preparation example A-B
2000 laser particle analyzer of Malvern.
2. experimental method
After cleaning instrument is clean, testosterone undecanoate suspension is added into decentralized medium pure water, reaches its shading rate
Then 5%-20% measures its partial size using 2000 laser particle analyzer of Malvern.
Take one bottle of testosterone undecanoate freeze-dried powder product, specification is 0.25g/ bottle, is added the redissolution of 2ml pure water, and ultrasound makes point
After dissipating uniformly, partial size is measured with 2000 laser particle analyzer of Malvern.
3. experimental result
As shown in Table 1 below.
Table 1: particle diameter distribution result
| Sample ID | D10(μm) | D50(μm) | D90(μm) |
| Sample 2 | 0.260 | 1.150 | 3.051 |
| Sample 2 is lyophilized | 0.456 | 1.268 | 3.343 |
| Control sample A | 0.563 | 1.895 | 4.674 |
| Control sample B | 0.132 | 0.981 | 2.241 |
Seen from table 1:
In 2 suspension of sample partial size cumulative distribution reach 10% corresponding to partial size be 0.260 μm.Partial size is tired in suspension
Score cloth reach 50% corresponding to partial size be 1.150 μm.In suspension partial size cumulative distribution reach 90% corresponding to partial size
It is 3.051 μm.
After the freeze-dried redissolution of 2 suspension of sample, only D10, which has, a little increases, and D50, D90 value do not have apparent increase.It says
The stability of bright above-mentioned suspension is preferable.
The D10 of control sample A is greater than 0.5 μm, and the D10 of control sample B is less than 0.2 μm.
Embodiment 2: scanning electron microscopic observation
1. laboratory sample and instrument
Sample 1-3 made from preparation example 1-3.
Testosterone undecanoate bulk pharmaceutical chemicals (Zhejiang Province XianJu Pharmacy stock Co., Ltd, lot number: 20160301).
Cold field emission scanning electron microscope (Hitachi S4800).
2. experimental method
Each sample is diluted to suitable concentration respectively, is dripped on masking foil, then sample is placed on sample by naturally dry
On product frame, sputtered with 20 × 80 gold plating, voltage is set in 20 kilovolts.
3. experimental result
As shown in figures 1A-d.
It is seen that the particle diameter distribution of sample produced by the present invention is more uniform, particle size and instrument measurements
It is consistent.
Embodiment 3:X ray diffraction experiments
1. laboratory sample and instrument
Sample 1-3 made from preparation example 1-3.
Testosterone undecanoate bulk pharmaceutical chemicals (Zhejiang Province XianJu Pharmacy stock Co., Ltd, lot number: 20160301).
D/MAX2000 turns target anode X-ray diffractometer, Japanese Rigaku company.
2. experimental method
Each sample is diluted to suitable concentration, is dripped on masking foil, then sample is placed on instrument sample by naturally dry
On product frame, automatically determine.
3. experimental result
As shown in Figure 2.
The result shows that the diffraction Angle Position and characteristic absorption peak of the characteristic absorption peak of the suspension and bulk pharmaceutical chemicals of each partial size
Number does not change, it may thus be appreciated that there is no variations for its crystal form.
Embodiment 4: stability experiment (1)
1. experimental material
Sample: testosterone undecanoate suspension (sample 2), the pure water of the preparation of preparation example 2.
Instrument: 2000 laser particle analyzer of Malvern.
2. experimental method
Preparation example 2 prepare testosterone undecanoate suspension, under room temperature respectively place 0,30,60,90,120,150,
After 180 days, partial size is measured with 2000 laser particle analyzer of Malvern.
3. experimental result
As shown in Table 2 below.
Table 2: the experimental data of testosterone undecanoate suspension stability
The result shows that partial size keeps stablizing, the prescription is preferable, and the stabilizer used is relatively applicable in.
Embodiment 5: stability experiment (2)
1. experimental material
Sample: the testosterone undecanoate suspension sample 4-8 of preparation example 4-8 preparation.
Instrument: 2000 laser particle analyzer of Malvern.
2. experimental method
The testosterone undecanoate suspension of preparation example 4-8 preparation after placing 0,1,3,5,10 day respectively under room temperature, is used
2000 laser particle analyzer of Malvern measures partial size.
3. experimental result
As shown in Table 3 below.
Table 3: the stability test data of sample 4-8
Data in table 3 show, sample 4 place 5 and 10 days, sample 5 place 5 days, sample 6 place 5 days, sample 7 place 5
Place 5 days data (being marked with italic) with 10 days and sample 8, the partial size measured have occurred that rise appreciably, partial size group
Phenomena such as poly-, i.e. suspension, are unstable, and the selection of stabilizer is less suitable.
Since the stability of nanocrystal suspension is the major obstacle that it is promoted and applied, during prescription screening
The stability of suspension is mainly investigated using change of size as index.
In addition, partial size and the control sample of identical composition in preceding embodiment 1 by sample 4 and sample 5 at the 0th day
A and control sample B are compared, and discovery preparation process is affected to partial size especially D10.When last repeating query of homogeneous
Ring such as 1000bar*10 under lesser pressure, the numerical value of D10 is larger, could possibly be higher than 0.5 μm；When last repeating query of homogeneous
Ring such as 1200bar*10 under lesser pressure, the numerical value of D10 is smaller, is likely lower than 0.2 μm.
Embodiment 6: muscle irritation test
1. laboratory sample and experimental animal
Laboratory sample is as shown in Table 3 below.Wherein, commercially available testosterone undecanoate fat injection is purchased from Zhejiang celestial being jade pendant pharmacy stock
Part Co., Ltd, specification: 2ml:250mg.
Male rabbit, new zealand rabbit, weight 2.5-3.0kg, cultivate limited duty purchased from Beijing Jin Muyang experimental animal by 7
Ren company.
2. experimental group and dosage regimen
As shown in Table 4 below.
Table 4: experimental group and administrations
Note: in table 3, right side refers to right side quadriceps muscle of thigh, and left side refers to left side quadriceps muscle of thigh.
3. experimental method
After every rabbit right hindlimb is sterilized with Iodophors, the intramuscular injection testosterone undecanoate suspension at quadriceps muscle of thigh
2ml, injection site select the vertical inserting needle of central portion of rabbit quadriceps muscle of thigh, are pierced into 1cm, and slowly inject, and 2mL solution needs 10s,
Needle is pulled out after having injected rapidly.Left side corresponding position is with method injection isometric(al) sterile saline as control.48 hours after administration,
Every group of animal anaesthetized with yellow Jackets after through femoral artery sacrificed by exsanguination, visually observe and record injection site whether there is or not it is red and swollen, fill
Phenomena such as blood, exudation, denaturation or necrosis.Further histopathologic examination is done to injection site simultaneously.It is dehydrated, wrapped after materials
Bury, be sliced and HE dyeing, carried out under the microscope after film-making histopathological examination observation situation.Referring to shown in following table 5
Muscular irritation reacts grade scale and carries out muscular irritation reaction classification.
Table 5: grade scale is reacted in muscular irritation
4. experimental result
As shown in Fig. 3 A- Fig. 3 N.
After rabbit gives each partial size crystal suspension injection of testosterone undecanoate, the phase of the weight of animals and weight gain aspect is had no
It closes and changes；Discovery is checked in anatomic course from the appearance, testosterone undecanoate oil solution preparation causes injection site appearance to be filled on a small quantity
Blood, and without significant change at each partial size crystal suspension intramuscular injection of testosterone undecanoate.It checks under mirror as it can be seen that testosterone undecanoate is each
Mainly based on a small amount of inflammatory cell exudation, muscular irritation order of reaction is for partial size crystal suspension and its blank auxiliary solution control
0 grade；Street drug testosterone undecanoate oil solution is mainly with fibrous connective tissue hyperplasia, vacuolar degeneration and a small amount of inflammatory infiltration
Main, muscular irritation order of reaction is 1 grade.
It is above-mentioned the experimental results showed that, compare testosterone undecanoate oil solution, the crystal of testosterone undecanoate different-grain diameter specification is mixed
The muscle irritation of suspension is smaller.There was no significant difference in terms of irritation between the suspension of different D50.
Embodiment 7: the vivo pharmacokinetic research of testosterone undecanoate different-grain diameter crystal suspension
1. experimental material
Test sample:
The sample 1-3 of preparation example 1-3 preparation.
Commercially available testosterone undecanoate fat injection (being purchased from Zhejiang Province XianJu Pharmacy stock Co., Ltd, specification: 2ml:250mg).
Experimental animal: being provided by Military Medical Science Institute's Experimental Animal Center, zoopery quality certification number: SCXK (army)
2007-004.Female sd inbred rats, weight 180-220g, are randomly divided into four groups by totally 20.
2. dosage regimen
Rat muscle injection, dosage 26mg/kg adjust sample infiltration and are depressed into 280mmol/L- before being administered
320mmol/L.Sampling time point be 0min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, for 24 hours, 36h, 48h,
60h, 72h, 96h, 120h, 144h, 168h, every 48h eye socket takes blood 0.3ml or so after 169h, and taking the blood period in total is about 20 days.
It takes blood 0.2-0.3ml to be placed in test tube of hepari EP pipe every time, is centrifuged 14000rpm*10min, takes supernatant blood plasma, freeze in -80 DEG C
Refrigerator, it is to be measured.
3. the processing method of plasma sample
Precision draw 100 μ L blood plasma be added 1.5mlEP pipe in, be added in EP pipe 100 μ L methanol and 100 μ L it is left-handed
Benzene ring nonyl ester inner mark solution (2ng/ml) is eventually adding the methanol of 100 μ L, and vortex 1min is centrifuged 14000rpm*10min,
Take supernatant into sample introduction casing, sample introduction LC-MS/MS analysis.
4. the measuring method of plasma sample
Using Liquid Chromatography/Mass Spectrometry, it is inside designated as left-handed benzene ring nonyl ester, mobile phase: A (formic acid and 5mM first containing 0.05%
Sour ammonium)-B (methanol), flow velocity 0.45ml/min, column temperature is 40 DEG C, and sample volume is 20 μ L.
Elution requirement is as shown in Table 6 below.
Table 6: elution requirement
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 1.8 | 10 | 90 |
| 2.5 | 5 | 95 |
| 2.8 | 90 | 10 |
| 5 | 90 | 10 |
5. experimental result
After the suspension of intramuscular injection testosterone undecanoate, testosterone ester is gradually released into blood circulation simultaneously from injection site
Testosterone and free fatty acid are resolved by serum esterase.After rat muscle drug administration by injection, the blood concentration at each time point is measured, ten
The curve that one sour each crystal suspension of testosterone and the testosterone concentration of testosterone undecanoate fat injection in vivo change over time is shown in Fig. 4
And Fig. 5.
Experiment in vivo the result shows that, testosterone undecanoate crystal suspension of the invention have long-acting slow-release effect.
By drug metabolism software for calculation DAS2.0 (Drug And Statistics, drug and statistics) calculate Tmax,
Cmax, AUC and MRT.Tmax means the time needed for drug reaches maximum concentration, determines drug effect or adverse reaction that drug generates
Speed.Cmax means concentration when drug reaches peak value in vivo, determines whether drug generates drug effect or bring adverse reaction.
AUC (0- ∞) indicates area under time graph, indicates that drug enters the relative quantity of body circulation, reflects the size of drug absorption.
MRT is average residence time, indicates that drug eliminates the parameter of process as clearance rate, MRT value is independent of dosage.
As shown in Table 7 below.
Table 7:DAS2.0 statistical result
The result shows that:
(1) the internal release of 300nm suspension is very fast, and cmax value is higher, and the internal residence time is shorter.
(2) comparison oil solution group and other three groups of discoveries, oil solution group AUC value is lower than other three groups, in conjunction with the blood of the group
Concentration illustrates that oil has residual at muscle, can not release completely, bioavilability is caused to be omited already close to 0ng/ml
Lower than suspension group.
(3) 4.8 μm of suspensions prepare appropriate particle size distribution since partial size is larger, by improving technique, but find its blood
Concentration is there are multi-peaks phenomenon, and possible cause is the wider fluctuation for causing blood concentration of the particle diameter distribution in the suspension, together
When, the blood concentration of said preparation is lower, may be therapeutically effective concentration.
Embodiment 8: extracorporeal releasing experiment (one)
This experiment purpose is to be controlled by the cumulative release amount of extracorporeal releasing test to the particle size range of suspension
System.
1. laboratory sample and instrument
Testosterone undecanoate suspension (sample 2) made from preparation example 2.
ZRS-8G type intelligence dissolving-out tester (Tianjin Xin Zhou technology company).
2. experimental method
Release takes this product 125mg/ml testosterone undecanoate nanosuspension, according to 2015 editions Chinese Pharmacopoeia dissolution measurement slurries
Method, using PH=7.4 phosphate-buffered salt and 0.5% lauryl sodium sulfate as dissolution medium 900ml, medium temperature is 37 ± 0.5
DEG C, revolving speed is 25 turns per minute, and the homogenous suspension sample of 2ml is added into each stripping rotor.
The preparation method of PH=7.4 phosphate-buffered salt: taking potassium dihydrogen phosphate 1.36g, takes 0.1mol/l sodium hydroxide solution
79ml, be diluted with water to 200ml to get.
Sample loading alternative: or it will be pre-mixed injection about 2ml, it sets in the band needle applicator of 2ml specification, it is accurately weighed,
When paddle rotation, above-mentioned suspension is added in each stripping rotor, the accurately weighed empty syringe with syringe needle, contains syringe
With the empty syringe of residual liquor after administration, practical dosage is obtained.
Sample time: at 2 minutes, 30 minutes and 120 minutes, taking dissolution medium 5ml respectively, immediately with 0.22 μm of aperture
Filter membrane filtration, discards primary filtrate at least 3ml, takes subsequent filtrate 1.5ml as test solution；
If every glass should be respectively 10-20% in 2 minutes, 30 minutes and 120 minutes burst sizes, 45%-60% and
65%-90% is considered as and meets the requirements.It does not need to supplement dissolution medium in process container during test, in calculation formula not
It needs to be corrected the volume of dissolution medium.
Using the content of high effective liquid chromatography for measuring testosterone undecanoate:
Mobile phase: acetonitrile: isopropanol: water=20:70:10
Sample volume: 20 μ L
Detection wavelength: 240nm
Column temperature: 40 DEG C
Flow velocity: 1.0ml/min
3. experimental result
As shown in Table 8 below.
Table 8: Cumulative release amount (%)
| Time (minute) | Cumulative release amount (%) |
| 0 | 0 |
| 2 | 15.2 |
| 5 | 25.9 |
| 15 | 35.2 |
| 30 | 49.1 |
| 60 | 65.3 |
| 120 | 81.4 |
The results show that every glass of this product should be respectively 15.2% in 2 minutes, 30 minutes and 120 minutes cumulative release amounts,
49.1% and 81.4%.
The result shows that the particle diameter distribution of suspension made from preparation example 2 and release are ideal, meet wanting for setting
It asks.
Embodiment 9: extracorporeal releasing experiment (two)
1. laboratory sample and instrument
Front compares the control sample A and control sample B of preparation example A-B preparation.
ZRS-8G type intelligence dissolving-out tester (Tianjin Xin Zhou technology company).
2. experimental method
With the embodiment 8 of front.
3. experimental result
As shown in following table 9-10.
Table 9: the Cumulative release amount (%) of control sample A
Table 10: the Cumulative release amount (%) of control sample B
| Time (minute) | Cumulative release amount (%) |
| 0 | 0 |
| 2 | 26.8 |
| 5 | 35.3 |
| 15 | 43.1 |
| 30 | 53.4 |
| 60 | 67.3 |
| 120 | 85.6 |
The experimental result of comprehensive front is it is found that the D10 of control sample A is greater than 0.5 μm, then its each sampling time point is tired
Meter burst size can reduce, and 2 minutes burst sizes are lower than 10%, and burst size is less, fails to reach release in vitro quality standard
10-20%.The D10 of control sample B is less than 0.2 μm, then partial size is integrally less than normal in preparation, can generate burst effect, drug release
Excessively, it is 26.8% more than 20% in release in 2 minutes, has exceeded release in vitro quality standard 10-20%.
The result shows that D10 if more than 0.5 μm, then its quick-release effect is deteriorated, can not achieve comparatively fast to discharge to reach after being administered has
Imitate treatment concentration.If D10 is less than 0.2 μm, partial size is integrally less than normal in preparation, can generate burst effect, and drug release is excessive,
Release is more than 20% within 2 minutes, after some time it is possible to reach super efficient treatment concentration, while holding time and shortening.
Although a specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change in guarantor of the invention
Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (10)
1. a kind of testosterone undecanoate suspension, it includes testosterone undecanoate, stabilizer and water, in which:
The content of the testosterone undecanoate is 10%-50% (g/ml)；
The partial size of the testosterone undecanoate meets: D10 is 0.2-0.5 μm, and D50 is 0.5-1.5 μm, and D90 is 2.2-6.0 μm；
The stabilizer includes the first stabilizer and the second stabilizer, and the weight of the testosterone undecanoate and the stabilizer
Than for (1-20): (1-20), wherein
First stabilizer is selected from soybean lecithin, hydroxypropyl cellulose, poly yamanashi esters such as polyoxyethylene sorbitan monoleate or poly- mountain
Pear ester 20, PLURONICS F87, poloxamer188, povidone, hydroxypropyl methylcellulose, Arabic gum, western yellow glue, sodium alginate,
Methylcellulose, sodium carboxymethylcellulose, alkyl polyglycoside, inulin lauryl carbamate, polyethylene glycol, hydroxypropyl cellulose
With any one or more in carbohydrate,
Second stabilizer is selected from polyethanediol succinate, lauryl sodium sulfate, phenyl ethylamine, arginine salt or more library esters
Any one or more in sodium；And
The weight ratio of first stabilizer and the second stabilizer is (1-10): (1-20).
2. testosterone undecanoate suspension according to claim 1, it is characterised in that any in following (1) to (8) item
One or more:
(1) content of the testosterone undecanoate is 10%-30% (g/ml)；
(2) D10 is 0.2-0.3 μm；Preferably 0.2-0.25 μm；
(3) D50 is 0.9 μm -1.4 μm；
(4) first stabilizer is selected from poly yamanashi esters, hydroxypropyl cellulose, hydroxypropylcellulose, soybean lecithin, carboxymethyl
Any one or more in sodium cellulosate and hydroxypropyl cellulose；
(5) second stabilizer is selected from any one or more in polyethanediol succinate (TPGS) and docusate sodium；
(6) weight ratio of testosterone undecanoate and stabilizer is (1-15): (1-15)；Preferably (1-15): (1-10), it is more excellent
It is selected as (1-10): (1-3)；
(7) weight ratio of first stabilizer and the second stabilizer is (1-5): (1-20), preferably (1-5): (1-
10)；More preferably (1-2): (1-5)；
(8) the testosterone undecanoate suspension also includes bacteriostatic agent and/or pH adjusting agent.
3. testosterone undecanoate suspension according to claim 1 or 2, it includes the components matched as follows:
Preferably, it includes the components matched as follows for the testosterone undecanoate suspension:
4. a kind of testosterone undecanoate lyophilized preparation, the testosterone undecanoate as described in any claim in claims 1 to 3 mix
Suspension is freeze-dried to be made；
Preferably, freeze drying protectant is selected from one of glucose, mannitol, sucrose, lactose or a variety of；
Preferably, the dosage of freeze drying protectant is 10%-40%, the preferably 10%-30% of solid content, particularly preferably
15%-25%.
5. a kind of method for preparing testosterone undecanoate suspension described in any claim in claims 1 to 3, including it is following
Step:
(1) the first stabilizer, the second stabilizer and water are uniformly mixed, obtain the first mixture；
(2) testosterone undecanoate is added in the first mixture in step (1), obtains the second mixture；
(3) the second mixture is uniformly dispersed, it is preferable that the second mixture is uniformly dispersed by dispersion and emulsion homogenizer；
(4) product of step (3) is carried out by homogeneous by high pressure homogenizer.
6. preparation method according to claim 5, wherein homogeneous described in step (4) includes the following steps:
At least five recycles under (4-1) 200bar-300bar；Preferably, 5-15 circulation；
Under (4-2) 400bar-600bar, 5-15 circulation；
Under (4-3) 700bar-900bar, 5-15 circulation；
Under (4-4) 1050bar-1150bar, 5-15 circulation.
7. preparation method according to claim 6, wherein in step (4-1), recycled under 200bar-300bar, until
Ceramic bead and valve seat are without apparent strike note.
8. the preparation method according to any claim in claim 5 to 7, wherein homogeneous described in step (4) includes
Following steps:
Under (4-1) 200bar-300bar, 8-12 circulation；
Under (4-2) 450bar-550bar, 8-12 circulation；
Under (4-3) 750bar-850bar, 8-12 circulation；
Under (4-4) 1050bar-1150bar, 8-12 circulation.
9. the preparation method according to any claim in claim 5 to 7, wherein homogeneous described in step (4) includes
Following steps:
Under (4-1) 200bar-300bar, 10 circulations；
Under (4-2) 500bar, 10 circulations；
Under (4-3) 800bar, 10 circulations；
Under (4-4) 1100bar, 10 circulations.
10. testosterone undecanoate suspension described in any claim or as claimed in claim 4 ten in claims 1 to 3
One sour testosterone lyophilized preparation treats or prevents the insufficient associated diseases such as male gonad function of endogenous testosterone generation in preparation and subtracts
Move back the purposes in the drug of disease；Preferably, the male hypogonadism is selected from male sexual disfunction, male's muscle number
At least one of amount and muscle strength reduction, male's depressibility mood and Male Osteoporosis.
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| CN114668719A (en) * | 2022-02-21 | 2022-06-28 | 广东食品药品职业学院 | Dihydrotestosterone suspension, dihydrotestosterone freeze-dried powder and preparation method thereof |
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