CN1102095A - Long-acting androgen preparation-undecylic acid testis injection - Google Patents
Long-acting androgen preparation-undecylic acid testis injection Download PDFInfo
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- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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Abstract
The present invention relates to a long-acting androgen type preparation-undecoic acid testosterone injection, and its intramuscular medication can prevent first pass elimination, and its androgen activity is strong, and its effect can be kept for a long period, and once medication can keep the androgen activity to about above 70 days. It is notable in therapeutic effect, low in toxicity, and doesn't damage the function of liver and kidney, and is applicable to diseases having need of androgen to make therapy, in particular having need of long-period therapy or life-long replacement therapy, such as male low sexual function (including klinefetter's syndrome), aplastic anemia and metastatic mammary cancer, etc.. Said invention can be compatible with progestogen or estrogen, and used for male contraception.
Description
The invention belongs to the androgens preparation, especially a kind of Testosterone Phenylacetate esters injection is applicable to the disease that needs Andropatch to do long-term treatment or substituted treatment throughout one's life, and this product is used with a small amount of progestogen or estrogen compatibility and be can be used as long-acting male contraception.
Before the present invention makes, make the disease of treatment of length journey or substituted treatment throughout one's life clinically for the need androgen, as diseases such as the low disease of male sexual function (comprising Crane Fitow syndrome), chronic aplastic anemia, metastatic breast cancers, the domestic testosterone propionate injection that has commonly used is because that this medicine can not be kept is long-acting, so need intramuscular injection 2-3 times weekly, owing to absorb relatively poor, prolonged application causes the large stretch of callosity in injection site, and patient is agonizing, so that can't inject; Oral androgenic preparation also commonly used such as methyl testosterone or stanozolol, because these medicines can damage liver function, then can not life-time service.The external Testosterone Phenylacetate preparation of using has atlatest injection, testosterone cyclopentylpropionate injection, and its long-acting holding time was 2-4 weeks, generally needs per 2 all intramuscular injection 1 time; External oral androgenic preparation has the testosterene undecannoata capsule, and this medicine is harmless to liver function, but oral administration was lost efficacy by metabolism through intestinal and liver major part, (promptly first the mistake eliminated), only fraction absorbs so bioavailability is low through lymph, needs to take every day heavy dose, and the beginning can be obtained effect.Above-mentioned import androgens preparation costs an arm and a leg, and needization are taken a large amount of foreign exchanges, increase the country and people medical fee burden.On the other hand, still do not have both at home and abroad and solve male contraceptive agent safely and effectively, in 20 years, China obtains very great achievement at the research gossypol as male contraceptive agent in the past, can cause because of gossypol that eventually untoward reaction such as hypokalemia can not promote.
The objective of the invention is needs at above-mentioned disease treatment, overcome the shortcoming that existing androgen preparation exists, a kind of long-acting androgen class preparation-testosterene undecannoata injection of androgenic activity for 70 days of keeping is provided, this injection does not damage liver, safe and reliable, and cost is low, if with a small amount of estrogen or progesterone compatibility, can be used as long-acting male contraception.
Testosterene undecannoata injection of the present invention, benzyl benzoate by Testosterone hendecane acid esters, injection vegetable oil and medicinal specification is formed, be mixed solvent with the injection vegetable oil that contains 5-10% benzyl benzoate wherein, the preparation specification is that per 1-2ml injection contains 125-250mg Testosterone hendecane acid esters.The chemistry of used Testosterone hendecane acid esters is called 17 β-hydroxy-androstane-4 alkene-3-ketone-hendecane acid esters, and structural formula is
Molecular formula is C
30H
48O
3, molecular weight is 456.71, this product is a white crystals, or crystalline powder, presses exsiccator and calculates, and contains C
30H
48O
3Should be 97.0-103.0%, specific optical rotation [d]
25 U+ 68 °～+ 72 °, water insoluble and dimethyl sulfoxide can be dissolved in acetoneand ethyl acetate, ultraviolet spectra (PE565 type spectrophotometer)
239-240nm, infrared spectrum (Perkin-Klmer 577 types)
Cm
-12910,1735(ester group V
c=0), 1670(C
3Ketone group V
c=0), 1608(V
C4=C
5), 1170 and 1207(ester V
c=0).Benzyl benzoate is medicinal specification, meets 63 years version regulations of Chinese Pharmacopoeia, and the quality standard of injection vegetable oil meets two appendix P4 regulations of 85 years versions of Chinese Pharmacopoeia.The injection vegetable oil can be Oleum Arachidis hypogaeae semen, Oleum Glycines, Oleum Sesami, Oleum Camelliae, Fructus Canarii albi wet goods.
Content of the present invention is described further by following examples.
Embodiment 1.
The preparation of injection of the present invention: get the injection vegetable oil and put in the baking oven, sterilized 1 hour for 150 ℃, and put cold, be mixed into by proportional quantity and medicinal benzoate benzyl ester then and contain 5-15% injection vegetable oil and mix molten coal, take out the part solvent and add Testosterone hendecane acid esters, stirring makes molten, add an amount of solvent again to full dose, filter, embedding is in dry ampoule, 100 ℃ of flowing steam sterilizations promptly got injection of the present invention in 30 minutes, and the preparation specification is that per 1-2ml contains 125-250mg Testosterone hendecane acid esters.
Embodiment 2.
2-1 pharmacological action: (1) androgenic activity is relatively given castration male rat and castration cock intramuscular injection testosterene undecannoata (testosterone undecanoate) 13.7mg/kg(3 * 10
-3Mol/kg), produce typical androgenic effect, the persistent period is about 70 days, and the while is with the atlatest intramuscular injection 1.5 * 10 of this dosage
-3Mol/kg, androlin divide intramuscular injection in 7 days in castration Mus great and mighty or powerful and castration cock, and similar action is also arranged, but the persistent period was respectively 50 days and 20 days.See Table 1, table 2, Fig. 1, wherein the TP group for testosterone propionate injection (molecular weight 344.48), TE group for testoviron depot ampoule (molecular weight is 400.60), it is to use the testosterone undecanoate injection that TU organizes.
Table 1 undecanoic acid ketone and other two kinds of testosterone preparations are to castrated rats sexual organ development's influence
The moving heavy X ± SD (mg/100gwb) of the organ of kiling the time that cuts open of testosterone preparation
Thing is (after the administration
And dosage a couple of days number) prostate seminal vesicle levator ani
6 10 22.1±6.4 55.0±19.2 95.2±16.4
Testosterone undecanoate 6 25 17.8 ± 9.8 59.5 ± 28.2 77.2 ± 22.7
3.0×10
3mol/kg 6 40 11.8±6.3 31.1±14.5 70.0±27.2
Single intramuscular injection 6 55 10.4 ± 3.7 26.4 ± 5.3 83.6 ± 6.1
6 70 7.4±3.1 22.2±6.3 79.5±14.4
6 10 43.7±11.2 70.3±19.2 127.0±18.9
Testosterone enanthatas 6 25 27.4 ± 10.7 68.3 ± 19.8 112.4 ± 17.0
3.0×10
5mol/kg 6 40 16.5±8.2 35.2±9.6 78.6±15.7
Single intramuscular injection 6 55 7.5 ± 2.8 15.6 ± 3.7 57.8 ± 7.0
6 70 6.3±1.2 16.3±1.7 53.2±9.5
6 10 33.3±7.0 72.3±25.0 119.0±23.0
Testosterone Propionate 6 25 5.3 ± 2.2 14.3 ± 3.4 39.4 ± 5.2
1.5×10
-5mol/kg 6 40 5.9±2.1 18.4±5.6 38.4±5.8
Divide 7 days intramuscular injection 6 55 3.6 ± 1.8 10.3 ± 2.2 32.2 ± 3.4
6 70 3.0±1.2 8.2±2.4 26.3±4.2
6 10 1.8±0.9 5.0±0.9 21.2±5.5
Matched group 6 25 2.5 ± 1.0 3.9 ± 1.4 27.9 ± 4.1
An amount of refining Oleum Camelliae 6 40 2.4 ± 0.2 6.8 ± 1.1 23.6 ± 4.0
Single intramuscular injection 6 55 1.5 ± 0.7 4.8 ± 1.5 21.9 ± 4.0
6 70 2.2±0.8 6.1±1.8 19.3±4.0
The dosage of TU is 3.0 * 10
-5Mol/kg, the single intramuscular injection.
The dosage of TE is 3.0 * 10
-5Mol/kg, the single intramuscular injection.
The dosage of TP is 1.5 * 10
-5Mol/kg, 7 natural gift intramuscular injection.
Matched group is an amount of with refining Oleum Camelliae, the single intramuscular injection.
Fig. 1: undecanoic acid testosterone and other two kinds of testosterone preparations compare (the cockscomb size variation of 4 typical animals) to castration cock cockscomb development impact
The androgenic activity of testosterene undecannoata intramuscular injection and oral administration compares:
Sexual organ with castration Mus great and mighty or powerful is an index, and oral group at dosage 9.0 * 10
-5During mol/kg the effect faint, dosage is up to 18.0 * 10
-5During mol/kg, the beginning produces and intramuscular injection 3.0 * 10 after 10 days
-5The drug effect that mol/kg is similar, drug effect obviously disappears after 25 days.When the drug effect when the TU intramuscular administration is described is about oral administration 6 times, and the effect also significant prolongation of holding time.The results are shown in Table 3.
Table 3 testosterone undecanoate is to intramuscular injection of castration rat and peroral administration drug effect
The dosage of TU with cut open X ± SD in the organ of kiling the time (mg/100wb)
Number of animals is (after the administration
The route of administration natural law) prostate seminal vesicle levator ani
Testosterone undecanoate 3.0 * 10
-55 10 26.9 ± 6.8 48.8 ± 16.1 101.3 ± 17.1
Mol/kg single intramuscular injection 5 25 17.5 ± 5.3 45.9 ± 21.0 81.9 ± 11.5
Testosterone undecanoate 9.0 * 10
-55 10 3.1 ± 0.4 4.9 ± 1.1 39.4 ± 1.8
Mol/kg divided 7 days oral 5 25 2.2 ± 0.2 9.0 ± 2.5 30.9 ± 2.4
Testosterone undecanoate 18.0 * 10
-55 10 23.4 ± 1.8 40.7 ± 6.5 99.7 ± 13.5
Mol/kg divided 7 days oral 5 25 6.1 ± 1.1 14.9 ± 5.0 43.1 ± 7.8
Contrast an amount of pure Oleum Camelliae 5 10 1.5 ± 0.8 5.6 ± 0.9 22.0 ± 4.2
Divided 7 days oral 5 25 2.5 ± 0.8 4.1 ± 1.5 30.2 ± 4.0
(2) can destroy erythrocytic phenylhydrazine on every side for the castrated rats subcutaneous injection to the therapeutical effect of experimental anemia, every day 25mg/kg, for three days on end, hematochrome (Hb), erythrocyte (RBC) significantly reduce, and reticulocyte (Rtc) ratio increases, and continues subcutaneous injection phenylhydrazine 40mg/kg/ week later on, continuous 11 weeks, causing anemia, from giving the 4th day beginning intramuscular injection testosterene undecannoata 3.0 * 10 behind the phenylhydrazine
-4Divide 4 administrations in mol/kg(12 week), establish the androlin group simultaneously, 4.3 * 10
-4The mol/kg total amount, intramuscular injection is 2 times weekly, treats for 12 weeks altogether, and matched group gives an amount of Oleum Camelliae.During begin treatment, androlin is close with the testosterene undecannoata curative effect, and along with the prolongation of the course of treatment, testosterene undecannoata all obviously is better than androlin at Hb, RBC and three indexs of Rtc.The results are shown in subordinate list 4.Show that testosterene undecannoata has definite curative effect to experimental anemia due to the phenylhydrazine.
(3) testosterene undecannoata merging progestogen or estrogen are got the male rat with fertility to the antifertility action of male mice, 1st month intramuscular injection testosterene undecannoata (TU) 2 times, the 2nd time and each administration in 3rd month 1 time, each 12mg/kg, each compatibility depomedroxy progesterone acetate (MDP) 7mg/kg or estradiol valerate (EDV) 0.7mg/kg respectively, intramuscular injection, successive administration is drug withdrawal after 3 months, during administration with drug withdrawal after in 3 months, mated 10 days with female Mus in every month, the transvaginal plate coating checking is proved conclusively the female Mus of copulation, cutd open in 15 days extremely in post-coitum, by the index of female Mus pregnancy rate as the male Mus fertility of judgement.Beginning in 2nd month of result: TU+EDV group
To 5th month (after the drug withdrawal 2 months), male pindone was lost its fertility entirely.The TU+MDP group was from 3rd month to 5th month, and male Mus also completely loses fertility, all begins to recover fertility in 3rd month in drug withdrawal.See Table 5.
Table 5 testosterene undecannoata compatibility medroxyprogesterone or estradiol valerate are to the male rat antifertility action
The male Mus ratio of fertility is arranged
Medicine and dosage
(moon) * between (moon) withdrawal time during the preceding administration of administration
(mg/kg im)
1# 2 3 4 5 6
TU 12.0 6/6 1/6 0/6 0/6 0/6 0/6 1/6
EDV 0.7
TU 12.0 6/6 5/6 3/6 0/6 0/6 0/6 6/6
MDP 7.0
Matched group 6/6 6/6 4/6 5/6 5/6 5/6 5/6
# the 1 month administration 2 times, each administration was 1 time in the 2nd, 3 month, and * calculates by the 1st administration
Absorb in 2-2 bodies, distribute and eliminate: the rat muscle injection [
3H] testosterene undecannoata, blood plasma radioactivity peak appearred after 2 days, and the blood plasma radioactivity after 32 days and 60 days is respectively 13.3% and 9.9% of peak value, and radioactivity t1/2 β is 15.4 days.Distributing with liver, kidney, fat in the body is height, and levator ani, epididymis, prostate etc. take second place.Behind the medicine 60 days, intramuscular injection position residual activity was 19.9% of a dosage; Radioactivity accumulation excretion is respectively 41.9% and 9.3% of dosage in urine and the excrement.In urine, discharge the prototype medicine and account for 7.2%.The results are shown in Figure 2, table 6.
Fig. 2 .4 rat intramuscular injection [
3H] TU12mg(14.76MBq)/kg after blood plasma radioactivity-time graph (X ± SD)
Fig. 2
The intramuscular injection of table 6 rat [
3H] TU12mg(14.76MBq)/kg after the tissue in increased radioactivity (dpm * 10
-3, X ± SD)
Organized 2 days 30 days 60 days
Liver 15.40 ± 2.10 2.20 ± 0.80 0.50 ± 0.20
Kidney 10.00 ± 2.70 3.40 ± 2.30 1.10 ± 0.80
Testis 4.50 ± 1.30 1.50 ± 0.90 0.13 ± 0.07
Epididymis 6.70 ± 1.70 1.30 ± 0.60 0.33 ± 0.07
Prostate 3.30 ± 0.50 0.80 ± 0.50 0.16 ± 0.09
Seminal vesicle 3.90 ± 0.50 0.90 ± 0.50 0.08 ± 0.04
Levator ani 3.50 ± 0.60 2.50 ± 1.00 2.30 ± 0.40
Fat 14.10 ± 7.60 1.60 ± 0.80 0.90 ± 0.50
Annotate: the mean of 4 rats
Embodiment 3.
Acute toxicity, long term toxicity and mutagenicity test
3-1 acute toxicity test mouse subcutaneous injection testosterene undecannoata 3.75g/kg(is 270 times of rat effective dose), observe and do not find death or abnormal response in 14 days.
The NIH mice, body weight 17-20g, male and female half and half, subcutaneous injection testosterene undecannoata injection is observed after the administration toxic reaction and death toll in 14 days, the results are shown in Table 7.
The acute toxicity test of table 7 undecanoic acid testis
The abnormal response of dosage number of animals death toll
(g/kg sc)
2.5 12 0 do not have
3.75 12 0 do not have
3-2 long term toxicity tests (1) rat test: 4 age in week 75 of Wistar rats, be divided into three groups, A organizes 8 ♀, 17 ♂, B organizes 10 ♀, 15 ♂, C organizes 10 ♀, 15 ♂.The intramuscular injection medicine was 1 time in every month.A organizes to injection Oleum Camelliae in contrast, and B organizes to TU42mg/kg, and C organizes to TU14mg/kg, continuous 6 months.Duration of test A, B, C have 3,4,3 Mus death respectively for three groups, like irrelevant with administration.Result of the test shows that TU has no adverse effects to liver, renal function, and ♀ Mus erythrocyte and hemoglobin are increased, and weight increase is accelerated.Except that the TU high dose group makes the convoluted seminiferous tubule spermatogenic cell level minimizing of indivedual Mus, do not see other obvious pathological changes.
(2) Canis familiaris L. result of the test: 10-12 the monthly age 14 of dogs, be divided into 3 groups, A organizes 4 ♀, 2 ♂, B organizes 2 ♀, 2 ♂, C organizes 2 ♀, 2 ♂.The im medicine was 1 time in every month, and A organizes to the injection vegetable oil in contrast, and B organizes to TU100mg/kg, and C organizes to TU20mg/kg continuous 6 months.
The result shows:
A. general signs etc. changes in administration 3 months, each organize dog food desire all good, 1.4-1.5 times of weight increase.After 6 months, high dose group appetite reduces than all the other groups in medication, and body weight gain is slow relatively, than increasing by 1.7-1.9 times before the medication; And low dose group and matched group body weight gain are approaching, average 2.3-2.4 times before medication.High dose group and matched group compare, and body weight gain significantly slows down.
B. WBC, Hgb and each group of Pt value all do not have obviously change before and after routine blood test and the blood biochemical project observation medication.After 6 months, each is organized the RBC counting and obviously raises in administration, but administration group high and low dose and matched group compare the no marked difference of RBC rising.
Liver, renal function measurement result show: high and low dose medication group and matched group relatively do not have significant difference before SGPT and BUN value and the medication in medication 6 months, all in normal range.
C. each treated animal heart rate of Electrocardioscopy, P-R interval, QRS wave group and Q-T interval is all in normal range, do not have obviously before and after the medication to change, and ectopic rhythm also do not occur., respectively have 1 Canis familiaris L. the ST section to occur in high dose and the matched group and force down 0.5mv after 6 months in administration, this change still belongs to normal range.
D. pathological examination medication 6 months and in drug withdrawal after 7 days, every group is cutd open 2 of Canis familiaris L.s (female, male each 1) extremely, and the important organ heart, liver, kidney, lung, hypophysis cerebri, stomach, intestinal etc. are done perusal, does not find obvious pathological changes.Through microscopy that liver, kidney, testis and epididymis are cut into slices, the result shows: each hepatic parenchymal cells of organizing 2 Canis familiaris L.s does not have obvious change, and the renal cortex organizational structure of administration high and low dose group Canis familiaris L. is normal.High dose group dog convoluted tubule of testis directly dwindles, and spermatid is subjected to press down, and sperm significantly reduces, and spermatogonium does not have change, and low dose group dog convoluted tubule of testis organizational structure is normal substantially.Few essence of high dose group dog epididymis tube chamber or azoospermia, and low dose group Canis familiaris L. epididymis tube chamber sperm quantity has minimizing slightly.
(3) mutagenicity test is mixed with the serial solution of variable concentrations with the pure product of testosterene undecannoata, and test strain is a histidine defect type Salmonella typhimurium, the results are shown in Table 8.
The Salmonella typhimurium mutagenesis testing of table 8 testosterene undecannoata
Every ware returns and becomes clump count (average) * *
Testosterene undecannoata
TA100 TA97 TA98 TA102
(mg/ml)
-S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9
0 168 204 183 145 32 35 309 286
1 181 250 180 157 32 41 329 260
5 167 250 186 170 29 50 335 275
10 170 220 191 166 28 42 340 328
30 187 243 182 159 34 56 331 342
50*** 217 227 192 160 35 60 335 409
* repeats 1～2 time, each 3 wares.
* * concentration is during to 50mg/ml, and the adularescent granule is separated out in the ware.
The every ware of positive control returns and becomes clump count (+S9) TA100 1510(2AF); TA98 3300(2AF).（-S9）TA100 1522（N
2N
3）；TA98 733（2.7AF）；TA97 8222（Dexon）。
Conclusion
5 various dose of testosterene undecannoata, 50mg/ml, 30mg/ml, 10mg/ml, 5mg/ml, 1mg/ml uses TA100 respectively, TA97, TA98 and TA102 carry out flat board and mix test, no matter add or do not add the S9 mixed liquor, and under above-mentioned experiment condition, all not measuring this medicine has mutagenic action.
Embodiment 4.
The clinical verification of testosterene undecannoata injection is summed up
The main purpose of TU clinical verification is for investigating this medicine to the low disease of man's gonad function (being divided into general male sexual disorder and infertility and Crane Fitow syndrome two classes) and the curative effect of aplastic anemia and the untoward reaction of medication process.
Clinical verification is summarized as follows:
(1) male sexual disorder and infertility.Through six hospital clinical checkings, treatment group 80 example and placebo group 35 examples, 1 testosterene undecannoata injection of intramuscular injection in every month 2ml(contains 250mg), the matched group intramuscular injection does not contain the Oleum Camelliae 2ml(placebo of testosterene undecannoata), continuous 4 months, treatment sexual impotence is had significant curative effect, oligospermia is obviously increased sperm count, part patient reaches fertile sperm count level.
Double blind method is adopted in test, studies for two groups for treatment and contrast in 2: 1 ratio random division.End year January April to 1989 time from nineteen eighty-three, has 115 examples and require to have finished treatment in accordance with regulations.
The result
Therapeutic effect
A. few smart infertility
30 examples are organized in treatment, and sperm mean and the 95% credible 2920 ± 6,930,000/ml that is limited to thereof before the treatment are 5691 ± 2,104 ten thousand/ml after the treatment.Significant difference (P＜0.05) before and after the treatment belongs to treatment " effectively " 13 examples, effective percentage be 43.33%(wherein the spouse of 5 examples respectively at begin treatment after pregnancy in 2.5-10 months, in addition 8 routine sperm counts rise reach normally).Treatment engineering noise 17 examples (comprise that 10 routine sperm counts rise, but do not reach normally, 1 routine no change, 6 examples reduce).
B. it is not hard to erect
21 examples are organized in treatment, constitutional not hard 14 examples of erecing wherein, Secondary cases 7 examples.Through treating effective 20 examples (wherein produce effects 14 examples), effective percentage is 95.2%, 1 example of failing to respond to any medical treatment.
Matched group 9 examples, constitutional not hard 5 examples of erecing wherein, Secondary cases 4 examples.Treat effective 6 examples (wherein produce effects 3 examples), effective percentage is 66.67%, 3 examples of failing to respond to any medical treatment.
Two groups of efficient significant differences (P＜0.05) illustrate that TU is to the not hard obvious curative effects that has of erecing.
C. sexual impotence
14 examples are organized in treatment, primary impotence 4 examples wherein, secondary impotence 10 examples.Treat effective 13 examples (wherein produce effects 9 examples), effective percentage is 92.86%, invalid 1 example.
Matched group 12 examples, primary impotence 4 examples wherein, secondary impotence 8 examples.Treat effective 5 examples (wherein produce effects 3 examples), effective percentage 41.67%, invalid 7 examples.
Two groups of efficient difference extremely significantly (P＜0.01) that compare of treatment illustrate that TU has significant curative effect to sexual impotence.
(2) Crane Fitow syndrome.Through BJ Union Hospital's department of endocrinology with testosterene undecannoata injection for treating Crane Fitow syndrome 13 examples, 1 250mg(2ml of intramuscular injection in every month), continuous 4 months, patients serum's testosterone levels obviously raises, sexual function is all obviously strengthened, married patient has near the normality life, and testicular volume enlarges markedly, and the change of property hair is the most obvious with pubes.
This disease is the disease of chromosomal abnormality, and is at present anosis because of Therapeutic Method, and the patient needs the long-term lifelong Testosterone preparation replacement therapy that uses.Injection of the present invention is a durative action preparation, curative effect certainly, the androgen active duration reached about 70 days, absorb well, non-evident effect, longer action time than the atlatest injection and the testosterone cyclopentylpropionate injection of import, can reduce frequency injection, alleviate patient's misery, and price is also cheap than the import injection, easily is accepted as lifelong alternative medicine by the patient.Attached clinical efficacy brief summary (summary).
With the syndromic curative effect of testosterene undecannoata (TU) treatment Crane Fitow.After 13 routine patients injection in every month TU250mg is total to April, patient's muscle power, secondary sex characteristics and sexual function all have improvement, serum testosterone (T) level is the ng/dl of 130.2 ± 107.9(M ± SD) before the medication, treatment during April the serum T level raise respectively in the 10th, 20th and 30 in injection and reach 588.9 ± 350.3,440.5 ± 196.0 and 316.9 ± 183.5ng/dl.Reach blood FSH, LH and E when treating April before the treatment
2Level does not have obvious change, but blood hormone haptoglobin capacity is reduced to 30.2 ± 5.8nmol/L by 39.0 ± 7.4, and patient's testicular volume slightly increases.This result shows that homemade testosterene undecannoata is the low effective durative action preparation that subtracts replacement therapy of male's sexual, should per 3-4 weeks injection 250mg.
(3) aplastic anemia.Through the checking of five hospital clinicals, merge a leaf with the testosterene undecannoata injection and obtain alkali and levamisole treatment " aplastic anemia " 60 examples (title test group), merge with the stanozolol sheet simultaneously that a leaf obtains alkali and levamisole is treated 32 examples (title matched group) in contrast.Test group injection testosterene undecannoata 2 times every month, each 500mg(4ml); The oral stanozolol sheet of matched group every day 3 times, each 1 2mg, a leaf that is merged obtains alkali 8mg, intramuscular injection every day 1 time, levamisole 50mg, oral 3 times of every day, serve on weekly 3 days identical on the same group.Continuous use 4-6 months, test group total effective rate are 55.6%, and the matched group total effective rate is 53.3%; Treatment is more than 6 months continuously, and the test group total effective rate is 90%, and the matched group total effective rate is 73.3%.In therapeutic process, matched group has 31.2% patient's Glutamate pyruvate transaminase rises, and the test group liver function does not have obvious influence.Two groups of medicines all do not have remarkable result to heavy " aplastic anemia ", so the testosterene undecannoata injection is applicable to non-heavy chronic aplastic anemia.The results are shown in Table 9, table 10.Definite national aplastic anemia meeting (wide mill) in 1981 and determined standard of national aplastic anemia (Baoji) meeting in 1987 of all meeting of the diagnosis of all cases and typing, criterion of therapeutical effect is by the healing that is divided into of " guideline " defined, the basic healing, obvious progressive and invalid level Four, follow-up period after the treatment of Yin Ben group case was less than 1 year, so the curative effect statistics is cured by basic, obviously progressive and invalid three grades of evaluations.
Table 9: with the testosterene undecannoata is the curative effect of main treatment group
| Type | The treatment persistent period | Total routine number | The basic healing | Obviously progressive | Invalid | Total effective rate % |
| Non-heavy type | 4-6 month | 36 | 5 | 15 | 16 | 55.6 |
| More than 6 months-November | 20 | 5 | 13 | 2 | 90.0 | |
| Heavy | 4-6 month | 4 | 0 | 0 | 4 | 0 |
| Add up to | 60 | 10 | 28 | 22 | 63.3 |
Table 10: with stanozolol is main matched group curative effect
| Type | The treatment persistent period | Total routine number | The basic healing | Obviously progressive | Invalid | Effective percentage % |
| Non-heavy type | 4-6 month | 15 | 2 | 6 | 7 | 53.3 |
| More than June | 15 | 3 | 8 | 4 | 73.3 | |
| Heavy | 4-6 month | 2 | 0 | 0 | 2 | 0 |
| Add up to | 32 | 5 | 14 | 13 | 59.4 |
Annotate: two groups heal the sick substantially in 10 examples, its clinical and bone marrow smear all meets healing, because of following up a case by regular visits to less than 1 year, or loses and visits, pretending is that basic the healing counted.
(4) male contraception.The attached First Academy of Zhejiang Medical university is to 14 routine reproductive male population volunteer tests, and with the testosterene undecannoata injection, 1 250mg of intramuscular injection in every month merges the depomedroxy progesterone acetate injection, 1 200mg of intramuscular injection in every month, continuous 4 months.Drop to below 4,000,000/ml at 1-4 months sperm number averages after the medication, drop to zero subsequently again, most of experimenters just can reach contraceptive efficacy in 2 months, and all experimenters all obtain birth control during medication.2-7 months sperm counts go up after the drug withdrawal, and the tool fertility, 9 examples in addition surpass medication before 1-16.9 times, 3 routine experimenters' spouse was conceived afterwards.Therefore, its antifertility action is mouldable.Attached clinical research brief summary.
Brief summary
The antifertility action of compound recipe TU is sure, and most medication persons' libido and sexual function strengthen to some extent.Every month intramuscular injection compound recipe TU1 agent, great majority just can reach contraceptive efficacy in 2 months.2-7 months sperm counts go up behind the inactive compound recipe TU, and the tool fertility, so its antifertility action is reversible.For safety, after drug withdrawal, just rose in 2 months and should take contraceptives.This research shows that also compound recipe TU is safe to the normal human, and important organ is not had obvious influence.
(5) two kinds of Testosterone injection relatively.The director E.Nieschlag professor of reproduction Institute for Medical Research of Germany Westfalischen Wilhelms university, at its institute testosterene undecannoata injection of the present invention and atlatest injection are compared, utilize the research that experimentizes of the male monkey of castration, the result shows: 1 atlatest of intramuscular injection is after the 13rd week, the male monkey of castration stops ejaculation already, do not detected testosterone in the blood, and 1 testosterene undecannoata of intramuscular injection is after 13 weeks, the male monkey of castration still can ejaculate, and still can measure testosterone in the blood.Therefore think that injection of the present invention has than the longer androgenic activity of external existing atlatest injection.
Content of the present invention, pass through the foregoing description, more existing injection Testosterone esters preparation is described, keep the more lasting (intramuscular injection 1 time of androgenic activity time, the sustainable drug effect of castration Mus great and mighty or powerful and cock is more than 70 days, the sustainable drug effect of the male monkey of castration is more than 13 weeks), untoward reaction is few, and important organs such as liver, kidney are not had obvious influence.Compare with oral testosterene undecannoata capsule (Organon pharmaceutical factory product), intramuscular administration of the present invention can avoid first the mistake to eliminate, the bioavailability height, and it imitates Jie's 6 times for oral capsule.Based on advantage of the present invention, be applicable to the disease that needs androgen to make long-term treatment or lifelong replacement therapy, because consumption is little, price only needed injection 1 time in every month far below like product, alleviated patient's misery and expenses for medicine burden, was easily accepted by the patient.Injection compatibility medroxyprogesterone of the present invention, by to adenohypophyseal negative feedback, reversibility suppresses spermatogenesis, can be used for male's long-acting contraception.
Claims (1)
1, a kind of long-acting androgen class preparation-testosterene undecannoata injection, it is characterized in that injection is made up of the benzyl benzoate of Testosterone hendecane acid esters (17 beta-hydroxy androstane-4 alkene-3-ketone-hendecane acid esters), injection vegetable oil and medicinal specification, be mixed solvent with the injection vegetable oil that contains the 5-10% benzyl benzoate wherein, the preparation specification is that every 1-2ml injection contains 125-250mg Testosterone hendecane acid esters.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93114002 CN1102095A (en) | 1993-10-30 | 1993-10-30 | Long-acting androgen preparation-undecylic acid testis injection |
| AU79889/94A AU7988994A (en) | 1993-10-30 | 1994-10-31 | An injectable solution of testosterone undecanoate |
| PCT/CN1994/000084 WO1995012383A1 (en) | 1993-10-30 | 1994-10-31 | An injectable solution of testosterone undecanoate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93114002 CN1102095A (en) | 1993-10-30 | 1993-10-30 | Long-acting androgen preparation-undecylic acid testis injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1102095A true CN1102095A (en) | 1995-05-03 |
Family
ID=4990325
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93114002 Pending CN1102095A (en) | 1993-10-30 | 1993-10-30 | Long-acting androgen preparation-undecylic acid testis injection |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1102095A (en) |
| AU (1) | AU7988994A (en) |
| WO (1) | WO1995012383A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112638365A (en) * | 2018-07-23 | 2021-04-09 | 株式会社钟根堂 | Stable pharmaceutical composition comprising testosterone undecanoate |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA01009919A (en) * | 1999-04-01 | 2002-04-24 | Akzo Nobel Nv | Formulation comprising testosteron undecanoate and castor oil. |
| GB0000313D0 (en) | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
| US7025979B2 (en) | 2000-02-15 | 2006-04-11 | Schering Ag | Male contraceptive formulation comprising norethisterone |
| CA2398063A1 (en) * | 2000-02-15 | 2001-08-23 | Schering Aktiengesellschaft | Male contraceptive formulation comprising norethisterone |
| TW200404552A (en) * | 2002-05-30 | 2004-04-01 | Akzo Nobel Nv | Self administered contraception |
| JO2505B1 (en) * | 2003-03-14 | 2009-10-05 | باير شيرنغ فارما اكتنجيسيلشافت | method and pharmaceutical compositions for reliable achievements of acceptable serum testosterone levels |
| US9925200B2 (en) | 2014-06-17 | 2018-03-27 | Merck Sharp & Dohme B.V. | Stable formulations of testosterone undecanoate |
| CN111529482A (en) * | 2020-05-20 | 2020-08-14 | 祝培 | Testosterone undecanoate sustained-release implant and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7711916A (en) * | 1977-10-29 | 1979-05-02 | Akzo Nv | PROCESS FOR PREPARING HIGHLY CONCENTRATED PHARMACEUTICAL PREPARATIONS OF STEROIDS. |
-
1993
- 1993-10-30 CN CN 93114002 patent/CN1102095A/en active Pending
-
1994
- 1994-10-31 AU AU79889/94A patent/AU7988994A/en not_active Withdrawn
- 1994-10-31 WO PCT/CN1994/000084 patent/WO1995012383A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112638365A (en) * | 2018-07-23 | 2021-04-09 | 株式会社钟根堂 | Stable pharmaceutical composition comprising testosterone undecanoate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995012383A1 (en) | 1995-05-11 |
| AU7988994A (en) | 1995-05-23 |
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