CN1398590A - Recipe and prepn of progesterone capsule - Google Patents
Recipe and prepn of progesterone capsule Download PDFInfo
- Publication number
- CN1398590A CN1398590A CN02136639.XA CN02136639A CN1398590A CN 1398590 A CN1398590 A CN 1398590A CN 02136639 A CN02136639 A CN 02136639A CN 1398590 A CN1398590 A CN 1398590A
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- Prior art keywords
- progesterone
- prescription
- preparation
- capsule
- carrier
- Prior art date
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- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 216
- 239000000186 progesterone Substances 0.000 title claims abstract description 105
- 229960003387 progesterone Drugs 0.000 title claims abstract description 105
- 239000002775 capsule Substances 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229920002472 Starch Polymers 0.000 claims abstract description 16
- 239000000741 silica gel Substances 0.000 claims abstract description 16
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 16
- 239000008107 starch Substances 0.000 claims abstract description 16
- 235000019698 starch Nutrition 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000004094 surface-active agent Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 238000001291 vacuum drying Methods 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 6
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 229940067606 lecithin Drugs 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 2
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- 239000000843 powder Substances 0.000 abstract description 17
- 239000000583 progesterone congener Substances 0.000 abstract description 12
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- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 4
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
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Images
Abstract
The present invention provides the recipe and preparation process of progesterone capsule. The recipe includes progesterone, carrier, organic solvent, surfactant, silica gel powder, starch, etc. The preparation process includes adding the carrier into the organic solvent, heating to 60 deg.c, dissolving progestin, vacuum drying at 40 deg.c for 4 hr, airflow crushing, mixing with silica gel powder and starch, and capsulizing. The orally taken progesterone capsule preparation may be well absorbed and can raise progestin level obviously and promote secretion of womb endomembrane. It has no adverse reaction discovered and may be used by patient needing natural progestin.
Description
Technical field
The invention belongs to pharmaceutical engineering, relate generally to the progestogens medicine,, be applicable to the oral administration of sex hormone drug treatment especially about prescription of progesterone capsule and preparation method thereof.
Background technology
Progestogen are sex hormone drugs commonly used, are used for the treatment of amenorrhea, dysfunctional uterine hemorrhage (palace blood), postclimacteric hormone replacement etc.Also be used for inadequate luteal function and the miscarriage that causes, infertile treatment.And rise in recent years external fertilization---transplantation of embryo (IVF-ET) must be used progestogen especially as keeping luteal phase.As miscarriage, infertile, IVF-ET, must use natural progestogen in the above-mentioned various diseases treatment.Because natural progestogen is oral can not to be gastrointestinal absorption, has only a kind of injection injection for a long time, administration is very inconvenient, is difficult to adhere to for a long time using.Until the later stage eighties Progesterone is dissolved in Oleum Arachidis hypogaeae semen substrate, micronize has just solved the oral problem of gastrointestinal absorption afterwards.Domestic clinical use also has only the Progesterone fat injection at present, because the oral back of Progesterone very fast inactivation in liver so can only be the fat injection intramuscular injection, not only uses inconvenience, and unusual pain, patient generally is difficult to adhere to for a long time using.Oral formulations report is abroad arranged, and said preparation has certain drug effect, if but make powder preparation or electuary according to this technology, mouthfeel is poor, the inconvenience of swallowing, and preparation has abnormal flavour slightly, and toleration is poor; If make tablet or capsule, because of its content is low excessively, need take in a large number, need twenty or thirty sheet or grain approximately, otherwise do not reach the required blood drug level of treatment, oral very inconvenient, especially long-term pill taker is brought very big difficulty.In technology, when this preparation solidified, its fused solution is thickness very simultaneously, lacked the condition of carrying out suitability for industrialized production.Do not see that at present said preparation appears on the market.Therefore, seek a kind of convenient oral, better tolerance, the effective oral progesterone preparation of being convenient to suitability for industrialized production has again become needs.
Summary of the invention
Progesterone capsule prescription provided by the invention and preparation method thereof, its prescription mainly comprises Progesterone, carrier, organic solvent, surfactant, micropowder silica gel, starch etc., prescription composition of the present invention is mainly:
Progesterone 15%～65%
Carrier 13%～68%
Organic solvent 10%～30%
Surfactant 0.5%～3.0%
Micropowder silica gel 1.0%～3.0%
Starch 5.0%～20% preparation method mainly may further comprise the steps: the carrier with recipe quantity adds in the organic solvent earlier, be heated to 60 ℃, add Progesterone or add surfactant again and make its dissolving, 40 ℃ of vacuum dryings 4 hours, comminution by gas stream, add micropowder silica gel, starch uniform mixing, capsulation gets final product.
In the capsular prescription of the present invention, Progesterone: carrier is 1: 0.5～1: 3.0.
In the capsular prescription of the present invention, carrier can be glyceryl monostearate, Polyethylene Glycol (PEG) 6000, hexadecanol, octadecanol etc.
In the capsular prescription of the present invention, organic solvent can be ethanol, methanol, acetone etc.
In the capsular prescription of the present invention, surfactant can be sodium lauryl sulphate, Tween 80, lecithin etc.
In the capsular preparation of the present invention, grinding particle size requires at 1～100um.
With the write out a prescription progesterone capsule preparation of preparation of the present invention, oral absorption is good, can significantly improve progesterone level, and acts on endometrium and make it to be converted into secretory reaction by hypertrophy, does not have serious adverse reaction to take place on probation.Therefore the oral microparticles progesterone is safe in utilization, and is effectively convenient, to using natural progesterone patient for selecting preferably.At present, the natural progesterone preparation of seeking to use easily and effectively has important economy and society meaning to replace the intramuscular injection preparation current.Preparation technology of the present invention is easy, and cost is lower, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is normal young rabbit uterus.
Fig. 2 is matched group rabbit uterus (E
2Sc 5 μ g/+excipient po 2ml/ only).
Fig. 3 is progesterone capsule group rabbit uterus (E
2Sc 5 μ g/+progesterone capsule po7.80mg/kg).
Fig. 4 is progesterone capsule group rabbit uterus (E
2Sc 5 μ g/+progesterone capsule po31.3mg/kg).
Fig. 5 is progesterone capsule group rabbit uterus (E
2Sc 5 μ g/+progesterone capsule po12.5mg/kg).
Fig. 6 is progesterone injection group rabbit uterus (E
2Sc 5 μ g/+progesterone injection im0.78mg/kg).
Fig. 7 is progesterone injection group rabbit uterus (E
2Sc 5 μ g/+progesterone injection im31.3mg/kg).
Fig. 8 is progesterone injection group rabbit uterus (E
2Sc 5 μ g/+progesterone injection im12.5mg/kg).
The specific embodiment
The present invention is further described with embodiment in conjunction with the accompanying drawings.
Embodiment one:
1 Progesterone 50g writes out a prescription
Glyceryl monostearate 150g
Ethanol 15ml
Micropowder silica gel 2g
Starch 12.5g
Make 1000
Preparation method
1. the 150g glyceryl monostearate is added in the 15ml ethanol, be heated to 60 ℃, add the 50g Progesterone and make its dissolving, take out, 40 ℃ of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 0～20um.
2. press recipe quantity, add micropowder silica gel, starch uniform mixing.
3. adorn capsule No. 0, packing.
Embodiment two:
2 Progesterone 50g write out a prescription
Glyceryl monostearate 80g
Sodium lauryl sulphate 1.5g
Ethanol 20ml
Micropowder silica gel 1.25g
Starch 12.5g
Make 1000 preparation methoies
1. the 80g glyceryl monostearate is added in the 20ml ethanol, be heated to 60 ℃, add the 50g Progesterone, the 1.5g sodium lauryl sulphate makes its dissolving, take out, 40 ℃ of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 20～40um.
2. press recipe quantity and add micropowder silica gel, starch uniform mixing.
3. adorn capsule No. 0, packing.
Embodiment three prescriptions 3 Progesterone 100g
PEG6000 50g
Acetone 30ml
Micropowder silica gel 1.5g
Starch 14g
Make 1000 preparation methoies
1. 50gPEG6000 is added in the 30ml acetone, be heated to 60 ℃, add 100g
Progesterone makes its dissolving, 40 ℃ of vacuum dryings 4 hours, and comminution by gas stream is pulverized
Granularity requirements is at 60～80um.
2. press recipe quantity, add micropowder silica gel, starch uniform mixing.
2. adorn capsule No. 0, packing.
Embodiment four: 4 Progesterone 100g write out a prescription
Hexadecanol 100g
Lecithin 2.5g
Ethanol 20ml
Micropowder silica gel 1g
Starch 10g
Make 1000
Preparation method
1. the 100g hexadecanol is added in the 20ml ethanol, be heated to 60 ℃, add the 100g Progesterone, 2.5g lecithin makes its dissolving, take out, 40 ℃ of vacuum dryings 4 hours, comminution by gas stream, grinding particle size requires at 60～80um.
2. press recipe quantity, add micropowder silica gel, starch uniform mixing.
3. adorn capsule No. 0, packing.
Embodiment five: the progesterone capsule pharmacodynamics test
One. experiment material
(1), animal
Female New Zealand white rabbits, body weight 0.6-0.8kg; The ICR female mice, body weight 19-20g, 27-35g, available from Zhejiang Province's Experimental Animal Center, the animal quality certification number: accurate word 96001 is tested in Zhejiang.
(2), medicine
1. progesterone capsule: granule content 35.15%, following test dose all by the Progesterone cubage, is mixed with suspension with carboxymethyl cellulose during experiment, gastric infusion, every day 2 times, 6 hours at interval.
2. Progesterone injection: 20mg/ml, Xianju, Zhejiang Pharmacy stock Co., Ltd, lot number 960112, during experiment with the dilution of sterilization refined plant oil, subcutaneous or administered intramuscular, every day 1 time.
3. estradiol (E
2): content 99.5%, Shanghai No.12 Pharmaceutical Factory, lot number 95020 is prepared the subcutaneous injection administration with sterilization refined plant oil during experiment.
Two. experimental technique and result
(1), young rabbit uterus inner membrance conversion test
36 of female New Zealand children rabbits, body weight 0.6-0.8Kg is divided into 7 groups at random, 5 every group.Other stays 1 to be normal young rabbit, raises not administration with condition.Each treated animal is in experiment 1-6 days, E
2Subcutaneous administration (sc) 5 μ g//d, tested 7-11 days, the administration group is Progesterone injection intramuscular injection (im) 0.78,3.13,12.50mg/kg/d or progesterone capsule oral administration (po) 7.80,31.30,125.00mg/kg/d respectively, matched group po equal-volume excipient 2ml//d.After the last administration 24 hours, dissect and take out the uterus, with in Bouin ' s liquid, every Aconitum carmichaeli Debx. palace gets respectively far, in, nearly 3 sections, paraffin section, after the HE dyeing, microscopy, observe the endometrium form, press the endometrial gland hyperplasia degree, make the classification of Mcphail index.
Mcphail index grade scale:
1 grade, lumen of gland develops along tube chamber, and is very short, and darker substrate does not reach deeply;
2 grades, the body of gland number increases, the length lengthening, and darker substrate part is still complete, and dyeing is bright;
3 grades, dark substrate is stretched in the body of gland expansion, and body of gland is narrower;
4 grades, the deeply near Musclar layer of body of gland, body of gland expansion, inner membrance fracture.The young rabbit uterus inner membrance of table 1 conversion test (group dosage (mg/kg/d) number of animals (only) Mcphail average index matched group 5 0.0 ± 0.0 Progesterone injection 0.78 5 3.2 ± 0.2 of X ± SD)
3.13 5 3.6±0.3
12.50 5 3.8 ± 0.2 progesterone capsule (powder) 7.80 5 3.0 ± 0.3
31.30 5 3.1±0.2
125.00 5 3.6±0.4
The results are shown in Table 1, estrogen promotes uterine growth and endo cell division, thereby cause that neointimal hyperplasia thickens, and be converted into the proliferous type inner membrance, Progesterone is converted into endometrium the secreting type inner membrance on this basis: microscopy is the result show, normal young rabbit uterus is tiny, and body of gland (referring to Fig. 1) is seen at the end in the inner membrance; The matched group rabbit uterus under estrogen action, the uterus chap, uterine cavity increases, and is irregular shape, and minority body of gland (＜10) is arranged, little, garden, straight, no branch, have a large amount of between matter (referring to Fig. 2), it is 0 that the Mcphail index is defined the level; Progesterone injection im 0.78,3.13,12.50mg/kg/d or progesterone capsule (powder) po7.80,31.30,125.00mg/kg/d, it is all thicker that each organizes rabbit uterus, slightly be kermesinus, visible inner membrance body of gland increases under the mirror, prolong, crooked, and branch appears, dark substrate is stretched in some inner membrance body of gland expansion, body of gland narrows down, between matter greatly reduce (referring to Fig. 3-8), the Mcphail index is seen ginseng table 1: show that progesterone capsule has stronger progestin after oral, can promote the young rabbit uterus inner membrance glandular hyperplasia through the estrogen stimulation, its effect is suitable with the effect of 1/10 dosage injection.
(2), the mice deciduoma forms test
83 of ICR female mices, body weight 19-20g is divided into 8 groups, at random with pentobarbital sodium 60mg/kg, abdominal cavity (ip) anesthesia, under aseptic technique, from both sides, back spay, matched group is only done sham-operation, spay not, also not administration was tested 7-9 days, other group E every day
2Sc 2 μ g/, from E 10-17 days every days
2Sc 1 μ g/ only, the administration group is Progesterone sc injection 6.25,12.5,25.0mg/kg/d or progesterone capsule (powder) po62.5,125,250mg/kg/d simultaneously, matched group, the isopyknic excipient 0.5ml/ of model group po are only, in the 12nd day, the anesthesia of mice pentobarbital sodium, a silk thread is worn at 1/3 mesentery place at the left side cornua uteri, the 18th day with sacrifice of animal, take out the uterus, both sides, precision takes by weighing weight in wet base, and press Peter Hebborn method poor with both sides cornua uteri weight, and be the index of deciduoma growth, calculate deciduoma and increase percentage rate.
Table 2 mice deciduoma forms test, (the group dosage of X ± SD), (mg/kg/d) number of animals, (only) Mcphail average index matched group 10 7.9 ± 10.0 model group 11 9.9 ± 18.4 Progesterone injections 6.25 10 29.7 ± 20.0*
12.5 10 35.8±22.1**
25.0 10 55.9 ± 14.8*** progesterone capsule (powder) 62.5 10 19.3 ± 18.5
125 12 35.2±25.0*
250 10 53.6±27.1***
Annotate: through the t check, compare with model group,
*P＜0.05,
*P＜0.01, * * * p＜0.001
The results are shown in Table 2, progesterone capsule (powder) can bring out the growth of mice deciduoma significantly, show to have quite strong progestin, and tangible dose-response relationship arranged that the action intensity of progesterone capsule (powder) is equivalent to the action intensity of 1/10 dosage injection approximately.
(3), mouse pregnancy is kept test
The ICR female mice, body weight 27-30g is with 2: 1 and the same cage of male Mus, 8 o'clock of morning next day, observe the cloudy bolt of female Mus, to find that cloudy bolt is gestation the 1st day, in conceived the 8th day, through pentobarbital sodium 60mg/kg, ip anesthesia is from both sides, back spay, observe intrauterine and have or not embryo nidation, not pregnancy is arranged and discard the unpregnancy Mus, operation E on the same day to determine it
2Sc 2 μ g//d, while Progesterone injection sc12.5,25,50mg/kg/d or progesterone capsule (powder) po 125,250,500mg/kg/d, matched group, model group po equal-volume excipient 0.5ml/ are only, continuous 6 days, until pregnant the 14th day, dissect, observe embryo's implant site and write down the live embryo number.Matched group carries out sham-operation, does not give E2 and Progesterone.
Table 3 castration mouse pregnancy maintenance test group dosage (mg/Kg/d) number of animals (only) pregnancy rate (%) tire on average alive is counted matched group 10 90 9.3 model group 10 00 Progesterone injections 12.5 10 00
25.0 10 60* 4.5
50.0 10 80*, 6.1 progesterone capsules (powder) 125 10 00
250 10 30 5.7
500 10 70** 6.0 annotate: through X
2Check is compared with model group,
*P＜0.05,
*P＜0.01.The results are shown in Table 3, mice because of female in the body, progesterone level descend, can not be kept gestation after spay, cause miscarriage.Progesterone has the formation that suppresses uterine smooth muscle intercellular substance joint, reduces the spontaneous activity of uterus muscle, reduces the irritability of uterus muscle cell, thereby helps pregnancy maintenance.Experiment proves that also progesterone capsule (powder) 500mg/kg can keep removal ovary mouse pregnancy 70%, and its effect is approaching with the effect of 1/10 dosage injection (80%).
The Progesterone clinical dysfunctional uterine bleeding that is mainly used in, threatened abortion and recurrent spontaneous abortion.Because progestogen can stimulate hormone (ICSH) by negative feedback inhibition antepituitary secretion interstitial cell, thereby reduce the Testosterone secretion.In addition, it can also optionally suppress absorption and the 5-alpha-reductase of prostaglandin to testosterone, stops testosterone to be converted into two hydrogen testosterones.Therefore, can be used for treating benign prostate hyperplasia and carcinoma of prostate, the clinical report Progesterone also can be treated urinary system calculus in recent years.
The above results proves, progesterone capsule (powder) is oral effectively, progesterone capsule (powder) po 7.80-125.00mg/kg/d can make the young rabbit uterus inner membrance of E2 under exciting be transformed to the secretory phase by proliferative phase, grows for the implantation of germ cell and blastocyst subsequently and prepares.The mice deciduoma forms evidence, and progesterone capsule (powder) po 125-250 mg/kg/d can cause cell division, promotes the growth of mice deciduoma, and in addition, progesterone capsule (powder) can also be kept the gestation of removal ovary mice.The progestin of progesterone capsule (powder) is equivalent to the effect of 1/10 dosage Progesterone injection approximately.
Embodiment six: progesterone capsule II phase clinical verification
One, case is selected
1. inclusion criteria:
1. menoxenia or amenorrhea;
2. basal body temperature is single-phase;
3. blood progesterone level＜7nmol/L is surveyed in menstruation latter half;
4. the endometrium biopsy person that turns out to be the anovular menstruation.
MethodsThe cases enrolled meets 3 in the above-mentioned standard at least, according to feature separately above-mentioned case is reduced polycystic ovarian syndrome (Pcos), climacteric, anovulatory dysfunctional uterine hemorrhage, secondary amenorrhea and other respectively again.
2, exclusion standard: have following situation person should not be selected into
1. the person that has the digestive tract disease;
2. hepatic and kidney function obstacle person;
3. other endocrinopathy person is arranged;
4. diabetes or other metabolic disease person are arranged;
5. drug allergy history person is arranged;
6. pass by acceptance hormone therapy person in March.
3, rejecting standard:
The person that fails to turn out to be the anovulation; A variety of causes cause this case fail to finish 3 the course of treatment person.
Two, grouping
Plan MethodsThe cases enrolled 120 examples are divided into 2 groups by random fashion, and a winding is treated by MP, are checking group totally 60 examples, and another winding is subjected to the IP treatment to claim matched group totally 60 examples.
Those selected arranges in numerical order in proper order by prescription on individual diagnosis, according to system's arbitrary sampling method grouping.
Three, Therapeutic Method
1, medicine
Progesterone capsule
Progesterone injection Xianju, Zhejiang pharmaceutical Co. Ltd
Premarin Tablet
2, dosage
Premarin Tablet 1.25mg once a day, and is oral, totally 22 days
Progesterone capsule 200mg every day twice, oral in taking Premarin Tablet the 13rd day
Play clothes, totally 10 days (checking group)
Progesterone injection 20mg intramuscular injection once a day is in taking Premarin Tablet the 13rd day
Play injection, totally 10 days (matched group)
3, the every example of usage is observed 3 courses of treatment
1. amenorrhea person is diagnosed as the anovulation through hormone determination the person begins first course of therapy immediately, and second and third course of treatment is in withdrawal bleeding beginning in the 5th day medication.
2. anovulation can not passed through first course of treatment of person naturally in the treatment in the 5th day of passing through, and second and third course of treatment is in withdrawal bleeding beginning in the 5th day medication.
3. the anovulation anovulatory dysfunctional uterine hemorrhage in operation beginning in the 5th day first course of therapy, begins day second and third course of treatment ditto as the comprehensive dilatation and curettage person of row.
Four, observing time and project
1, observation of curative effect
1. need inquire withdrawal bleeding situation after the medication per course of treatment.
2. hormone determination: before the treatment and finish to measure respectively in preceding 3 days blood FSH, LH, E the 3rd course of treatment
2, P, T, PRL concentration.
3. some cases reached for the 3rd course of treatment end and gets the endometrium specimen and carry out histological examination before treatment.
2, safety is observed
1. measure routine blood test, liver, renal function respectively before the treatment and after the treatment end.
2. untoward reaction is observed.
Five, curative effect determinate standard
1, vaginal hemorrhage after the drug withdrawal
1. alleviate hemorrhage 3-7 days fully
2. the hemorrhage 8-10 of produce effects days
3. invalid hemorrhage＞10 days
2, the blood progesterone level changes
1. alleviation＞32nmol/L fully
2. produce effects 20-32nmol/L
3. progressive 7-19nmol/L
4. invalid＜7nmol/L
3, endometrial tissue is learned and is changed
1. alleviate endometrium fully and be secretory reaction
2. the produce effects endometrium is secretory reaction early or hyposecretion
3. invalid endometrium is proliferation response
Six, case registration and summary
Register item by item by design table (schedule), and by implementing doctor and main researcher signature.
Seven, statistical analysis technique
All add up by the full-time staff, mainly adopt SPSS 10.0 statistical packages.
Eight, result
1, physical data
The checking group is selected in 79 examples, and 5 examples that come off are rejected 6 examples, and several 68 examples of final effectively example are rejected reason, take drug dose mistake 1 example, incomplete 2 examples of final inspection data, diagnostic error (the blood progesterone level is in ovulation back level) 3 examples.5 examples that come off are to lose midway and visit.Matched group is selected in 71 examples, and 6 examples that come off are rejected 4 examples, and several 61 examples of final effectively example are rejected reason, and incomplete 2 examples of final inspection data are diagnosed imprecise 2 examples, and the reason that comes off mostly is to lose midway and visits, and wherein 1 example is found abnormal liver function (referring to table 4).
Table 4 a liang group is selected in, comes off, rejects case relatively
The selected example several 79 71 of the checking group matched group example several 56 that comes off is rejected effectively several 68 61 χ of example of example several 64
2=0.98 P＞0.05 a liang group is selected in, comes off, rejects relatively there was no significant difference of case.
Table 5 liang group age and Body Mass Index are relatively
Liang group Body Mass Index distribution (BMI) of 68 31.3 ± 8.6 21.3 ± 3.1 matched groups 61 38.0 ± 9.3 21.6 ± 2.9t, 0.775 0.627p, 0.439 0.532 table 6 is organized in example Body Mass Index checking in age several years
Checking group (example) matched group (example)＜23 46 4123～27 21 18＞27 12
χ
2＝0.473 P＝0.789
BMI=body weight kg/ height m
2
Press domestic standard＞23 for overweight,＞27 is fat.Referring to table 5,6, two groups of ages, Body Mass Index (BMI) and the BMI difference that distributes that relatively there are no significant,
2, therapeutic outcome
(1) two groups of hormones change before and after the treatment
Referring to table 7, before all controlling, checking group and treatment of control group bleeding from anus progesterone level significantly increase, and rise to 48.9nmol/L and 1.7 by 1.90 respectively and rise to 13.3nmol/L.FSH and LH level have remarkable decline.The blood hormonal readiness changes before and after the table 7 liang group treatment
Checking group matched group
Z PFSH IU/L 11.405 (1.56～100) 7.26 3.18＜0.01 23.32 8.3 (0.7～682) 3.848＜0.01, treatment back before the Z P treatment of treatment back before the treatment
(0.01～60.2) (2.1～127.4)LH?IU/L 25.29(0.05～157.28) 7.9 4.931?＜0.01 20.54 10.35(0.24～53) 4.598 ＜0.01
(0.05～64.6) (1.26～129.2)E2pmo1/L 86(9～1388) 218.3 3.913?＜0.01 99.42 235 4.373 ＜0.01
(29～1153.85) (9.9～2084.56) (5.49～1592.78)Pnmol/L 1.91(0.06～6.33) 48.88 9.726?＜0.01 1.7 13.26 8.795 ＜0.01
(0.73～452.93) (0.32～6.55) (0.64～46.11)T?nmol/L?1.83(0.1～145.6) 2(0.1～180.1)?0.212?0.832 1.5 1.075 1.496 0.135
(0.5～179.10) (0.07～75.2)PRLng/ml?9.18(0.5～86.83) 11(0.46～45.9)1.453?0.146 10.15 11.425 1.949 0.051
The two groups of blood progesterone level groupings in the two groups of blood progesterone level groupings in treatment back, (0.65～48.01) (12～126.3) (2) comparison sheet, 8 treatment backs are progesterone level checking group matched group χ relatively
2Pnmol/L n=68 n=61＞32 45 921-32,5 117-20 16 30＜72 11 36.5＜0.01
Annotate: should reach 6.36nmol/L (2ng/ml) by ovulation bleeding from anus progesterone level
Corpus luteum peak period concentration reaches 31.8nmol/L (10ng/ml) at least, and referring to table 8, through X 2 test, the checking group is better than matched group.
(3) treatment back endometrium changes
Do the endometrium biopsy before and after the some cases treatment, endometrium all is proliferative phase or fails to obtain inner membrance before the treatment, and treatment back internal film tissue learns and changes referring to table 9.An endometrial tissue was learned and is changed relatively endometrial tissue checking group control group A (example) 17 22B (example) 8 1C (example) 34 totals 28 27 χ after table 9 a liang group was treated
2=6.21 P＜0.05 annotate A: endometrial secretion phase B: endometrium is secretory phase or hyposecretion C early: the endometrial hyperplasia phase or do not have inner membrance (4) drug withdrawal after vaginal hemorrhage relatively
The vaginal hemorrhage natural law relatively after the table 10 liang group drug withdrawal
Checking group matched group χ
2The hemorrhage natural law 3-7 days 8-10 of P days＞10 days 3-7 days 8-10 days＞10 days
(example) (example) (example) (example) (example) (example) course of treatment 1 63 41 59 20 1.42＞0.05
2 65 3 60 1 0 0.83 ＞0.05
3 67 1 57 22 referring to table 10, and the vaginal hemorrhage natural law compares there was no significant difference after two groups of drug withdrawals.3, treatment finishes relatively (1) the progesterone level evaluation of back curative effect
Table 11 blood progesterone level evaluation curative effect checking group (example) matched group (example) is alleviated 45 9 produce effects, 5 11 progressive 16 30 invalid 2 11 total effective rates, 97% 82%Ridit ｀ s check u=5.23 P＜0.01 fully referring to table 11, finish inspection in preceding 3 days the 3rd course of treatment, checking group blood progesterone level 97% raises, surpass ovulation back level, matched group 87% surpasses ovulation back level, checking group progesterone level reaches luteal phase peak person and accounts for 67%, through Ridit ｀ s check, the checking group is better than matched group.
(2) endometrial tissue is learned to change and is estimated
Table 12 endometrial tissue learn to change is estimated curative effect checking group (example) matched group (example) and is alleviated 17 20 produce effects, 81 invalid 34 total effective rates 89.3% 84% fully
Ridit ｀ s check u=0.95 P＞0.05
Have endometrium biopsy specimen person to analyze referring to table 12 after finishing the course of treatment, checking group and matched group total effective rate reach 89.3% and 84% respectively, and through Ridit ｀ s check, two groups are not had significant difference.(3) vaginal hemorrhage natural law
Vaginal hemorrhage natural law therapeutic evaluation after the table 13 liang group drug withdrawal
Checking group % (example) control group % (example) curative effect is alleviated the invalid total effective rate of produce effects fully and is alleviated the invalid total effective rate 1 92.6 (63) 5.9 (4) 1.5 (1) 98.5 (67) 96.7 (59) 3.3 (2) 0 1,002 95.6 (65) 4.4 (3) 0 100 (68) 98.4 (60) 1.6 (1) 0 1,003 98.5 (67) 1.5 (1) 0 100 (68) 93.4 (57) 3.3 (2) 3.3 (2) 96.7 (59) of produce effects fully
Referring to table 13, the vaginal hemorrhage natural law is limited within 7 days in accordance with regulations after two groups of drug withdrawals, and the results suggest inner membrance peels off fully, relatively checks there was no significant difference through Ridit ｀ s between each course of treatment and between two groups.
Above experimental result shows that progesterone capsule 400mg/ day, oral post-absorption was good, can significantly improve progesterone level, and acts on endometrium and make it to be converted into secretory reaction by hypertrophy, does not find serious adverse reaction on probation.Oral progesterone capsule is safe in utilization, and is effectively convenient, and the patient that must use natural progesterone is selection preferably.
Need not further to elaborate, believe and adopt the disclosed content in front, those skilled in the art can use the present invention to greatest extent.Therefore, the preferred specific embodiments of front is interpreted as only illustrating, but not limits the scope of the invention by any way.
Claims (6)
1. progesterone capsule is write out a prescription and preparation method thereof, and prescription mainly comprises Progesterone, carrier etc., it is characterized in that also comprising organic solvent, surfactant, micropowder silica gel, starch etc. in the prescription, and the prescription composition is mainly:
Progesterone 15%～65%
Carrier 13%～68%
Organic solvent 10%～30%
Surfactant 0.5%～3.0%
Micropowder silica gel 1.0%～3.0%
Starch 5.0%～20% preparation method may further comprise the steps: the carrier with recipe quantity adds in the organic solvent earlier, be heated to 60 ℃, add Progesterone or add surfactant again and make its dissolving, 40 ℃ of vacuum dryings 4 hours, comminution by gas stream, add micropowder silica gel, starch uniform mixing, capsulation gets final product.
2. progesterone capsule prescription as claimed in claim 1 and preparation method thereof, it is characterized in that: Progesterone in the prescription: carrier is 1: 0.5～1: 3.0.
3. progesterone capsule prescription as claimed in claim 1 and preparation method thereof, it is characterized in that: carrier can be glyceryl monostearate, polyethylene glycol 6000, hexadecanol, octadecanol etc. in the prescription.
4. progesterone capsule prescription as claimed in claim 1 and preparation method thereof, it is characterized in that: organic solvent can be ethanol, methanol, acetone etc. in the prescription.
5. progesterone capsule prescription as claimed in claim 1 and preparation method thereof, it is characterized in that: surfactant can be sodium lauryl sulphate, Tween 80, lecithin etc. in the prescription.
6. progesterone capsule prescription as claimed in claim 1 and preparation method thereof is characterized in that: grinding particle size requires at 1～100um in preparation.
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| CN103893144A (en) * | 2014-03-26 | 2014-07-02 | 邵娜 | Oral progestin composition for improving dissolution and preparation method of oral progestin composition |
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| CN112999187A (en) * | 2021-03-08 | 2021-06-22 | 河北今水生物科技有限公司 | Progesterone capsule and preparation method thereof |
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Assignee: Zhejiang Xianju Pharmaceutical Co.,Ltd. Assignor: Hangzhou Rongli Pharmaceutical Technology Co.,Ltd. Contract fulfillment period: 2007.8.18 to 2012.12.31 Contract record no.: 2008330001108 Denomination of invention: Recipe and prepn of progesterone capsule Granted publication date: 20051214 License type: Exclusive license Record date: 20081016 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2007.8.18 TO 2012.12.31; CHANGE OF CONTRACT Name of requester: ZHEJIANG PROVINCE XIANJU PHARMACY STOCK CO., LTD. Effective date: 20081016 |
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Owner name: ZHEJIANG XIANJU PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HANGZHOU RONGLI MEDICINE SCIENCE +. TECHNOLOGY CO., LTD. Effective date: 20120105 |
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Effective date of registration: 20120105 Address after: A county of Taizhou City, Zhejiang province 317300 Xianju Road No. 1 Patentee after: Zhejiang Xianju Pharmaceutical Co.,Ltd. Address before: 310012 hi tech building, No. 212, Wen two road, Zhejiang, Hangzhou Patentee before: Hangzhou Rongli Pharmaceutical Technology Co.,Ltd. |
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