CN101327187B - Nonoxynol nonylphenoxy-polyethoxyethanol suppositorium and preparation method thereof - Google Patents

Abstract

The invention discloses a novel nonoxynol-9 suppository and a preparation method thereof, and the nonoxynol-9 suppository is composed of the raw materials with the following weight portions of 1 portion of nonoxynol-9, 2 portions of polyethyleneglycol 1000 and 13 portions of mixed fatty glyceride. The nonoxynol-9 suppository of the invention optimally selects new stroma which replaces the traditional stroma adopted in the nonoxynol-9 suppository, solves the problems of the long response ( easy failure of contraception), easy oxidative rancidity, easy discoloration, difficult forming, great irration, and the like existing in the present nonoxynol-9 suppository, thereby having the advantages of short response, stable quality, difficult oxidative rancidity, avirulence, less irritation, no pollution to clothes in use, etc.

Description

Encare and preparation method thereof

Technical field

The present invention relates to a kind of suppository, relate in particular to a kind of new Encare and preparation method thereof, belong to field of pharmaceutical preparations.

Background technology

The external contraceptive spermicide is to grow up on ancient folk tradition method.The womankind knows to put in intravaginal for a long time orders vinegar, suds or alum steep and just can prevent pregnancy, also has and takes Chinese medicine Calomelas of placing hypertoxicity etc.It is unfavorable to sperm that people summed up sour environment afterwards, so, begin to make and be with tart external use sperm killing preparation, as phenylmercuric acetate etc.But the hydrargyrum compounds is toxic to the people, and the intravaginal normal flora is had killing action, causes the assorted bacterium of disease to grow at last and causes vaginitis.

Adopt the novel sub-medicine of external use sperm killing now, after promptly medicine is placed into vagina, dissolved by vaginal secretions at short notice, dissolved medicinal liquid has the powerful effect of killing sperm.The external applied contraceptive that also has is placed into after the vagina, dissolves rapidly and is diffused into vagina surface and cervical orifice place, forms oil film or foam, makes sperm lose mobility, enters cavity of uterus to stop dead sperm, thereby plays contraceptive efficacy.The external use sperm killing agent generally is as auxiliary contraceptive device, and is the same with condom, is public offering, no Acyclovir.Put into the medicine that intravaginal plays contraceptive efficacy and be called external applied contraceptive, mainly contain external contraceptive membrane, external contraceptive tablet, contraceptive suppository and contraceptive cream etc.

The main component of modal spermicide is nonoxynolum (Nonoxinol), nonoxynolum is the anhydrous mixture that nonyl phenol and oxirane polycondensation form, it is a kind of non-ionic surface active type spermicide that used by International Planned Parenthood Federation's approval in 1964, it also is present modal external use sperm killing agent, have efficient, harmless, not influencing the ecological and no teratogenesis of the normal bacterium vaginae of human body, characteristics such as carcinogenic, is extensive use in the world, safe and reliable contraceptive.The nonoxynolum medicine interacts with the spermatid lipoprotein membrane after entering vagina, reduce its surface tension, change the osmotic pressure of spermatid, make organelle exposure or excessive, kill sperm or sperm can not be moved about, thereby make sperm can not enter the cervix uteri mouth, can't fertilize an egg, reach the contraception purpose with this.

Nonoxynolum is a nonionic surfactant, main effect is to kill sperm or cause sperm not move about by reduction sperm adipose membrane surface tension, change sperm osmotic pressure, thereby make sperm can not enter the cervix uteri mouth, can't fertilize an egg, reach the purpose of contraception.The nonoxynolum contraceptive film is dissolved into gelinite (about 5min) after inserting the vagina depths, and effect keeps about 1-2h.Suppository comes into force through 10min, and 2-10h is kept in effect.In addition, nonoxynolum can also the break virus shell, suppresses to have shell virus effectively, and the performance antiviral activity has prevention of sexually-transmitted diseases effect well,

It mainly is to destroy the biofilm system of sperm that nonoxynolum kills smart mechanism, causes breaking of sperm membrane, makes sperm broken dead.Wang Yixin has carried out scanning electron microscopic observation to killing smart effect, finds that the nonoxynolum spermicide shows as plasma membrane and takes off mistake, and the acrosome film is impaired, or acrosome takes off mistake; Next is mitochondrial swelling or vacuolar degeneration, and the sheath membrane portions disappears, and there is phenomenon of rupture in the flagellum stage casing simultaneously.

Nonoxynolum except having the effect of killing smart, contraception, the effect that still has following several respects:

Prevent spreading of AIDS

When condom usage frequency lower (0%-50%), use the nonoxynolum frequency high more, the AIDS viral infection rate is low more, when being 0%-50% as the nonoxynolum frequency of utilization, the infection rate of acquired immune deficiency syndrome (AIDS) is 36.7%, the frequency of utilization height is to 51%-75% and greater than 75% o'clock, and the incidence rate of AIDS viral infection is reduced to 18.9% and 0.0% respectively.

Prevent the propagation of gonorrhea

Test shows that the women uses nonoxynolum can effectively prevent gonococcus and chlamydia infection when sexual intercourse.

Prevent infection by Treponema pallidum: in vitro tests result proof is 10mg/ml to effective braking drug level Nonoxynol-9 medicine film of treponema pallidum, and gel is 5mg/ml.The Nonoxynol-9 film is at 10min inside brake treponema pallidum, and the Nonoxynol-9 gel can be braked treponema pallidum in 5min.

Reduce the danger of reproductive tract chlamydia infection

Nonoxynolum can make the cervical infection rate reduce by 25%, uses women's infection rate of nonoxynolum to reduce by 40% in the sexual intercourse activity more than 75%.

Nonoxynolum is synthetic in the U.S. in 1969, and domestic in recent years existing Duo Jia pharmaceutical factory produces.The vagina gel that Colombia (Britain) pharmaceutical Co. Ltd produces was registered in China in April, 1997.This colour content of " the Polyoxyethylene p-nonylphenyl ether external lozenge " seen at most on the market is a nonoxynolum, and this brand is to have more than 100 year historical Britain to connect the big pharmaceutical factory of Dare to develop.In addition, also have the medicine film of " tonight ", " Nonoxynol-9 " that produce in Beijing of Tianjin product, " the peaceful and comfortable ether " that produce in Guangzhou or the like Chinese domestic brand, the dosage form of having gone on the market has vaginal tablet, suppository and membrane.

Middle traditional Chinese medicines clinical data that big pharmacy is done shows: 1821 woman months use results, and contraceptive rate reaches 99.2%.Also have clinical data to show: the filial generation preliminary observation behind the nonoxynolum contraceptive failure, pregnant early stage inspection 11 examples, second trimester is checked 16 examples, does not all find chromosome number and textural anomaly.Natus 16 examples are not all found deformity, maximum 5 years old, do not find that intelligence is unusual.

Present domestic contraceptive device is a lot, and wherein groups of people select for use and wear with methods such as intrauterine contraceptive loops, is reluctant with condom more, is willing to use external applied contraceptive.The contraceptive effect of nonoxynolum brilliance, have good vagina cleaning action again, can effectively prevent sexually transmitted disease (STD), alleviate genital disease, because it also has prevention of STD and AIDS disease communication function, has advantage such as efficient, no toxicity, old friends take like a shot again.But the melting of existing Encare becomes the time limit and mostly is greatly about 25 minutes, exists the slower defective of onset, and existing Encare also all in various degree exist defectives such as zest is big, poor stability, have much room for improvement.

Summary of the invention

Technical problem to be solved by this invention is to overcome defectives such as the existing onset of existing Encare is slow, zest big, poor stability, a kind of new Encare is provided, this Encare be placed on behind the site of action general about 10 minutes just can onset, in addition, this Encare also has advantages such as zest is little, good stability.

Technical problem to be solved by this invention is achieved through the following technical solutions:

A kind of Encare comprises that each component of following weight portion is formed:

1 part of nonoxynolum

2 parts of cetomacrogol 1000s

13 parts of mixed fatty glycerides;

Wherein, the mixture formed according to arbitrary proportion by glyceryl monostearate, glycerol distearate and glyceryl tristearate of described mixed fatty glycerides; Preferred, described mixed fatty glycerides is made up of according to 0.5: 1.5: 9 part by weight glyceryl monostearate, glycerol distearate and glyceryl tristearate; Be the further stability of formulation that improves, not perishable becoming sour, further preferred, the acid number of this described mixed fatty glycerides is less than 0.40, and its iodine number is less than or equal to 0.10.

Described mixed fatty glycerides is based on natural Oleum Cocois, to its be hydrolyzed, processing such as hydrogenation, fractional distillation, acidify, make the mixture of saturated fat acid.This mixed fatty glycerides can be bought by commercial sources and obtain, for example, " the rich day medication chemistry company limited in Hunan " produced " mixed fatty glycerides ", its trade name is " mixed fatty glycerides ", the mixture of forming according to arbitrary proportion by glyceryl monostearate, glycerol distearate and glyceryl tristearate, its acid number is less than 0.40, and its iodine number is less than or equal to 0.10.

Above-mentioned Encare can prepare according to the conventional preparation method of conventional suppository.

Preferably, a kind of method for preparing above-mentioned Encare comprises: take by weighing each component by described weight portion; With nonoxynolum, cetomacrogol 1000 and mixed fatty glycerides mix, and with 60 ℃ heating in water bath, mixture are dissolved; Pack into during the medicinal plastics composite hard sheet heat seal that made packs with filling machine behind the abundant mix homogeneously of each component after will dissolving; Cooling after solidifying fully, is sealed, promptly.

Compare with existing Encare, Encare of the present invention has the advantage or the progress of following several respects:

1, can melt the change onset in the shortest time, can quick acting, waited for for a long time when noting be used in sexual life, and contraceptive effect is reliable.Cetomacrogol 1000 is a water-soluble base, the zest that exists when using separately is big, melt when becoming defective such as limit for length, mixed fatty glycerides is fat-soluble substrate, though use existence effect safety as substrate, nontoxic, advantages such as zest is little, but have easy oxidative rancidity simultaneously, defective such as easy to change, that easy-formation, fusing time be not long.If water-soluble base and fat-soluble substrate are simply mixed use, because the polarity difference of the two is difficult to dissolve each other, the two difference plays complementary synergism, and above-mentioned defective still exists.The inventor finds by a large amount of tests, with nonoxynolum, cetomacrogol 1000 and mixed fatty glycerides carry out compatibility according to 1: 2: 13 specified weight ratio, cetomacrogol 1000 and mixed fatty glycerides can play the cooperative synergism effect of mutual hydrotropy, it is big to have solved the existing zest of water-soluble base, melt when becoming defectives such as limit for length, overcome simultaneously the existing easy oxidative rancidity of natural oil type substrate again, easy to change, easy-formation not, defectives such as fusing time is long, kept natural substrates easily to absorb the nonirritant characteristics, can melt fast in 10 minutes in tract and wait for for a long time when onset not be used in sexual life, and contraceptive effect is reliable.

2, suppository of the present invention can keep good character at normal temperatures, far below 25 minutes of the Chinese Pharmacopoeia standard, efficiently solves the problem that onset easily causes contraceptive failure slowly.Encare steady quality of the present invention is difficult for becoming sour and going bad, nonirritant and toxicity, and pollution clothes not in use.

Description of drawings

Fig. 1 matched group is to rabbit vagina mucomembranous pungency test pathological examination;

Fig. 2 a drug matrix group is to rabbit vagina mucomembranous pungency test pathological examination;

Fig. 3 a drug medicine group is to rabbit vagina mucomembranous pungency test pathological examination;

Repeatedly medication matrix group of Fig. 4 is to rabbit vagina mucomembranous pungency test pathological examination;

Fig. 5 repeatedly medication medicine group to rabbit vagina mucomembranous pungency test pathological examination.

The specific embodiment

Further describe the present invention below in conjunction with specific embodiment, advantage of the present invention and characteristics will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not constituted any restriction.It will be understood by those skilled in the art that and down can make amendment or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall within the scope of protection of the present invention the details of technical solution of the present invention and form.

The preparation of embodiment 1 Encare

Take by weighing each component by following weight:

Supplementary material title nonoxynolum cetomacrogol 1000 mixed fatty glycerides	Inventory 100g 200g 5 1300g
		Make	1000 pieces

With nonoxynolum, cetomacrogol 1000 and mixed fatty glycerides mix, and with 60 ℃ heating in water bath, mixture are dissolved; Pack into during the medicinal plastics composite hard sheet heat seal that made packs with filling machine behind the abundant mix homogeneously of each raw material after will dissolving; Cooling after solidifying fully, is sealed, promptly.

The raw material composition of test example 1 Encare of the present invention and the screening test of proportioning

The nonoxynolum raw material is faint yellow thick liquid, add the substrate of appropriate amount and make suppository, the present invention designs following 30 classes prescription, include but not limited to following proportional quantity, grope test through proportional quantity repeatedly, by to the finished product outward appearance of nonoxynolum bolt with melt and become time limit indexs such as (becoming two appendix XB of overtime check method Chinese Pharmacopoeia version in 2000) and investigate according to melting, melt be limited to when becoming 25 minutes up to specification.Determine prescription, the results are shown in Table 1, table 2, table 3, table 4 and table 5.

Table 1 screening test (10 pieces of consumptions, the g of unit)

Supplementary material	Prescription 1	Prescription 2	Prescription 3	Prescription 4	Prescription 5	Prescription 6
							Nonoxynolum	1.0	1.0	1.0	1.0	1.0	1.0
Macrogol 2000	11.0	2.0	-	4.0	-	-
							Cetomacrogol 1000	-	3.0	2.0	9.0	-	-
Glyceryl monostearate	2.0	-	-	-	-	-
							Mixed fatty glycerides	-	10.0	13.0	-	15.0	-
Palm-kernel oil	-	-	-	-	-	15.0
							The finished product outward appearance	The white bolt	The white bolt	The milky bolt	The white bolt	The milky bolt	The milky bolt
Acidity	6.87	6.12	6.32	6.12	6.12	6.02
							Melt and become the time limit	37 minutes	23 minutes	6 minutes	20 minutes	15 minutes	22
Pollution clothes whether	Light contamination	Do not pollute	Do not pollute	Light contamination	Light contamination	Easily pollute

Table 2 screening test (10 pieces of consumptions, the g of unit)

Supplementary material	Prescription 7	Prescription 8	Prescription 9	Prescription 10	Prescription 11	Prescription 12
							Nonoxynolum	0.9	0.8	0.5	1.1	1.2	2.0
Cetomacrogol 1000	3.0	3.0	3.0	3.0	3.0	3.0
							Mixed fatty glycerides	13.0	13.0	13.0	13.0	13.0	13.0
The finished product outward appearance	The milky bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt
							Acidity	6.27	6.22	6.28	6.25	6.24	6.26
Melt and become the time limit	8.4 minute	8.6 minute	8.5 minute	8.4 minute	9.5 minute	8.2 minute
							Pollution clothes whether	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute

Table 3 screening test (10 pieces of consumptions, the g of unit)

Supplementary material	Prescription 13	Prescription 14	Prescription 15	Prescription 16	Prescription 17	Prescription 18
							Nonoxynolum	1.0	1.0	1.0	1.0	1.0	1.0
Cetomacrogol 1000	3.1	3.2	3.8	2.9	2.6	2.25
							Mixed fatty glycerides	13.0	13.0	13.0	13.0	13.0	13.0
The finished product outward appearance	The white bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt
							Acidity	6.23	6.36	6.38	6.29	6.37	6.29
Melt and become the time limit	8.4 minute	8.3 minute	8.8 minute	8.6 minute	8.5 minute	8.4 minute
							Pollution clothes whether	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute

Table 4 screening test (10 pieces of consumptions, the g of unit)

Supplementary material	Prescription 19	Prescription 20	Prescription 21	Prescription 22	Prescription 23	Prescription 24
							Nonoxynolum	1.0	1.0	1.0	1.0	1.0	1.0
Cetomacrogol 1000	3.0	3.0	3.0	3.0	3.0	3.0
							Mixed fatty glycerides	12.5	11	9.0	13.6	15.0	18.5
The finished product outward appearance	The white bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt

Supplementary material	Prescription 19	Prescription 20	Prescription 21	Prescription 22	Prescription 23	Prescription 24
							Acidity	6.37	6.42	6.30	6.31	6.28	6.24
Melt and become the time limit	9.0 minute	8.8 minute	8.5 minute	9.5 minute	9.2 minute	9.1 minute
							Pollution clothes whether	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute

Table 5 screening test (10 pieces of consumptions, the g of unit)

Supplementary material	Prescription 25	Prescription 26	Prescription 27	Prescription 28	Prescription 29	Prescription 30
							Nonoxynolum	1.0	1.0	0.9	0.6	1.1	2.0
Cetomacrogol 1000	2.5	4.0	3.0	3.2	2.8	2.2 5
							Mixed fatty glycerides	14	12.5	13.5	15	11.0	13.6
The finished product outward appearance	The milky bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt	The milky bolt
							Acidity	6.29	6.41	6.42	6.38	6.32	6.27
Melt and become the time limit	8.7 minute	8.4 minute	9.0 minute	8.8 minute	9.5 minute	8.6 minute
							Pollution clothes whether	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute	Do not pollute

Annotate: mixed fatty glycerides

The prescription 1 usefulness Macrogol 2000 as main matrix, the suppository shaping speed is fast, but melt the change time limit against regulation, acidity is higher; Prescription 2 selects for use mixed fatty glycerides as main matrix, and the increase cetomacrogol 1000 is an adjuvant, and the finished product outward appearance is white suppository; Prescription 4 is all to adopt polyethylene glycols; Prescription 5 is all to use mixed fatty glycerides; Prescription 6 all uses palm-kernel oil for market contrast suppository; Prescription 3 increases the amount of mixed fatty glycerides, without Macrogol 2000, it is best that the suppository that obtains melts the change time limit, in 6 minutes, melt to become and have a clear superiority in other gone on the market natural oil and other substrate composition, can effectively guarantee the safety of practising contraception, and pollution clothes not, easy to use, outward appearance and acidity are all in prescribed limit; Prescription 13-30 forms by nonoxynolum, cetomacrogol 1000 and mixed fatty glycerides, the ratio of the composition of each component is all different with prescription 3, from the data of table 3-table 5 as can be seen, prescription 13-20 compares with prescription 3 on three indexs of outward appearance, the acidity pollution clothes with whether at finished product, basically there is not notable difference, but melting on change this important indicator of time limit, the change time limit of melting of prescription 13-30 all will be significantly higher than melting the change time limit of prescription 3, its difference has statistical significance, is the best prescription of nonoxynolum bolt of the present invention so determine prescription 3.

The stability test of test example 2 Encares of the present invention

1. investigation sample

Given the test agent: the embodiment of the invention 1 prepared suppository is divided into 3 batch samples, is numbered given the test agent 1, given the test agent 2 and given the test agent 3 respectively.

The listing control sample: Encare, lot number are 20030320-1, (formula for a product and substrate are prepared according to going on the market).

2. investigation condition

(1) accelerated test (30 ℃, RH75%) 1,2,3,6 month;

(2) long term test (25 ℃, RH60%) 3,6,9,12,18,24 months.

3. investigation project and method

(1) character: range estimation.

(2) acidity: get and investigate 3 in sample, add water 30ml and make dissolving, (two appendix VI of Chinese Pharmacopoeia version in 2000 H) measures in accordance with the law.

(3) acid number: get and investigate 7 in sample, the accurate title, decide, and puts in the 250ml conical flask, measures (two appendix VII of Chinese Pharmacopoeia version in 2000 H) in accordance with the law.

(4) melt the change time limit: get and investigate 3 in sample, measure according to (two appendix XB of Chinese Pharmacopoeia version in 2000).

(5) microbial limit: get the investigation sample, check according to (two appendix XI of Chinese Pharmacopoeia version in 2000 J).

(6) assay: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).

Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-water (90: 10) is mobile phase; The detection wavelength is 276nm.Number of theoretical plate calculates by the nonoxynolum main peak and is not less than 400.

Algoscopy is got 10 of given the test agent, and accurate the title decides, and shreds, precision takes by weighing in right amount (being equivalent to nonoxynolum 50mg approximately), puts in the small beaker, adds methanol 20ml, put and make the nonoxynolum dissolving in 40～50 ℃ of water-baths, move in the 50ml measuring bottle, put coldly, be diluted to scale with methanol, shake up, place, get supernatant 10ul and inject chromatograph of liquid, the record chromatogram; Other gets the nonoxynolum reference substance, measures with method.Press external standard method with calculated by peak area, promptly.

Related substance: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).

Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-water (90: 10) is mobile phase; The detection wavelength is 276nm.Number of theoretical plate calculates by the nonoxynolum main peak and is not less than 400.

It is an amount of to get the investigation sample, adds the solution that methanol is made 5mg/ml, as need testing solution; Precision is measured 3ml, puts in the measuring bottle of 100ml, adds mobile phase and is diluted to scale, shakes up, in contrast solution; Get contrast solution 10 μ l and inject chromatograph of liquid, regulate detection sensitivity, make contrast solution main constituent peak height reach 10% of full scale; Other gets need testing solution 10 μ l and injects chromatograph of liquid, and the record chromatogram is to 2 times of main constituent peak retention time, in the need testing solution chromatogram as show impurity peaks, each impurity peaks peak area and must not be greater than contrast solution main peak area (3.0%).

4. investigation result

The three batches of given the test agent were through accelerated test 6 months, and the result shows: given the test agent character, acid number, pH value, melt every indexs such as becoming time limit, content and there is no significant change; Related substance slightly increases.Concrete outcome sees Table 6.

The three batches of given the test agent were through long term test 24 months, and the result shows: given the test agent character, acid number, pH value, melt leading indicators such as becoming time limit, content and there is no significant change, related substance slightly increases.Concrete outcome sees Table 7.

Three batches of given the test agent accelerated tests of table 6. are investigated the result

Lot number	Time (moon)	Character	Acidity	Acid number	Melt and become the time limit	Microbial limit	Content (%)	Related substance (%)
									The listing control sample	0	The milky bolt	4.67	0.20	23	Up to specification	99.54	1.952
1	The milky bolt	4.64	0.18	25	-	99.54	1.979
								2		The milky bolt	4.68	0.15	22	-	100.31	1.919
3	The milky bolt	4.69	0.19	25	-	98.13	1.959
								6		The milky bolt	4.65	0.16	24	Up to specification	100.67	1.962
Given the test agent 1	0	The milky bolt	6.36	0.17	6	Up to specification	99.36										1.887
								1	The milky bolt	6.34	0.16	6	-	99.20	1.881
	2	The milky bolt	6.27	0.14	6	-	100.61									1.892
								3	The milky bolt	6.23	0.16	6	-	99.22	1.894
	6	The milky bolt	6.16	0.15	6	Up to specification	99.76									1.908
								Given the test agent 2	0	The milky bolt	6.41	0.19	5.5	Up to specification	98.31		1.728
1	The milky bolt	6.35	0.15	5.5	-	99.50	1.745
									2	The milky bolt	6.32	0.17	5.5	-	98.23	1.747
3	The milky bolt	6.29	0.16	5.5	-	98.25	1.759
									6	The milky bolt	6.23	0.18	5.5	Up to specification	98.13	1.762
Given the test agent 3	0	The milky bolt	6.33	0.18	5	Up to specification	100.81										1.542
								1	The milky bolt	6.21	0.16	5	-	100.68	1.579
	2	The milky bolt	6.24	0.17	5	-	99.27									1.565

	3	The milky bolt	6.23	0.15	5	-	99.72	1.559
									6	The milky bolt	6.21	0.15	5	Up to specification	100.21	1.580

Three batches of given the test agent long term tests of table 7. are investigated the result

Lot number	Time (moon)	Character	Acidity	Acid number	Melt and become the time limit	Microbial limit	Content (%)	Related substance (%)
									The listing control sample	0	The milky bolt	4.6 7	0.20	23	Up to specification	99.54	1.952
3	The milky bolt	4.65	0.21	23	-	100.82	1.988
								6		The milky bolt	4.68	0.24	25	-	100.12	1.970
9	The milky bolt	4.66	0.23	26	Up to specification	99.21	2.000

Lot number	Time (moon)	Character	Acidity	Acid number	Melt and become the time limit	Microbial limit	Content (%)	Related substance (%)
									Given the test agent 1	0	The milky bolt	6.36	0.17	6	Up to specification	99.36	1.887
3	The milky bolt	6.28	0.18	6	-	100.30	1.899
								6		The milky bolt	6.26	0.16	6	-	99.76	1.922
9	The milky bolt	6.22	0.18	6	Up to specification	98.38	1.988
								12		The milky bolt	6.16	0.19	6	-	98.30	1.999
18	The milky bolt	6.13	0.20	7	-	99.76	2.022
								24		The milky bolt	6.06	0.22	7	Up to specification	98.38	2.088

Lot number	Time (moon)	Character	Acidity	Acid number	Melt and become the time limit	Microbial limit	Content (%)	Related substance (%)
									Given the test agent 2	0	The milky bolt	6.41	0.19	5.5	Up to specification	98.31	1.728
3	The milky bolt	6.33	0.18	5.5	-	98.13	1.775
								6		The milky bolt	6.29	0.17	5.5	-	98.20	1.818
9	The milky bolt	6.22	0.18	6	Up to specification	97.89	1.835
								12		The milky bolt	6.13	0.19	6	-	98.53	1.855
18	The milky bolt	6.09	0.22	6	-	98.20	1.877
								24		The milky bolt	6.02	0.24	7	Up to specification	98.09	1.915

Lot number	Time (moon)	Character	Acidity	Acid number	Melt and become the time limit	Microbial limit	Content (%)	Related substance (%)
									Given the test agent 3	0	The milky bolt	6.33	0.18	5	Up to specification	100.81	1.542
3	The milky bolt	6.30	0.19	5	-	100.50	1.655
								6		The milky bolt	6.21	0.16	5	-	100.80	1.652
9	The milky bolt	6.25	0.18	5	Up to specification	100.05	1.609

	12	The milky bolt	6.20	0.19	6	-	100.40	1.655
									18	The milky bolt	6.11	0.20	6	-	100.30	1.712
	24	The milky bolt	6.05	0.22	6	Up to specification	100.05	1.809

Comprehensive The above results, Encare of the present invention is under the listing terms of packing, and its quality is stable.

The safety testing of test example 3 Encares of the present invention

1 test material

1.1 laboratory animal

White rabbit, body weight 2.0-2.4kg, female.New Zealand's strain provides quality certification numbering: Shandong kinoplaszm word D20021135 by Shandong farming institute warren that herding is planted.

Every rabbit sub-cage rearing in the test, the feeding pellet is freely drunk water, 20 ± 2 ℃ of laboratory conditions, relative humidity 60-80%.

2.2 test sample

(1) Encare: the embodiment of the invention 1 is prepared, specification: 100mg;

(2) blank (adjuvant) sheet is provided by Jilin Aodong Group Dalian Pharmaceutical Co., Ltd.

2 experimental techniques and result

2.1 single administration test

Get 12 of female white rabbit, body weight 2.0-2.4kg is divided into 3 groups at random by body weight, matched group, matrix group, medicine group, every group of 4 animals, matched group does not process, and matrix group gives 1/4 piece of blank (adjuvant) sheet, and the medicine group gives 1/4 piece of the prepared Encare of the embodiment of the invention 1.

Medication: rabbit is got the high low level of buttocks, be fixed in the fixed case, 1/4 piece of substrate or medicine are filled in the rabbit vagina, rabbit is continued to keep original position 4h, to guarantee that medicine fully contacts, 24 hours execution animals after the administration, take out vagina tissue, perusal has or not phenomenons such as hyperemia, redness, and getting specimen with 10% formalin fixed, is carried out histopathologic examination.

Result of the test: matched group rabbit vagina mucosa is not seen changes such as hyperemia, redness, and behind the administration 24h, matrix group, medicine group no abnormality seen change.The result of histopathologic examination shows: matched group vaginal mucosa organizational structure is normal, and vagina epithelium is a stratified squamous epithelium, does not see obviously to thicken and hypertrophy, does not also see morphological changes such as obvious degeneration, scorching card, necrosis, and lamina propria, flesh layer there is no unusually.Matrix group vagina tissue structure is normal, and vagina epithelium is a stratified squamous epithelium, does not see obviously to thicken and hypertrophy, does not also see morphological changes such as obvious degeneration, scorching card, necrosis, and lamina propria, flesh layer there is no unusually.Medicine group organizational structure is normal, and vagina epithelium is a stratified squamous epithelium, does not see obviously to thicken and hypertrophy, does not also see morphological changes such as obvious degeneration, scorching card, necrosis, and lamina propria, flesh layer there is no unusually.1 in every group of accompanying drawing, Fig. 1 is a matched group, and Fig. 2 is its matter group of a drug, and Fig. 3 is an a drug medicine group.

2.2 multiple dosing test

Get 12 of female white rabbit, body weight 2.0-2.4kg, grouping, medication is with a medicine-feeding test, and once a day, successive administration 7 days is observed rabbit vaginal mucosa irritation reaction performance.Put to death animal in 24 hours after the last administration, take out vagina tissue, perusal has or not phenomenons such as hyperemia, redness, will get specimen with 10% formalin fixed, carries out histopathologic examination.

Result of the test: the matched group vaginal mucosa is not seen changes such as hyperemia, redness.24h matrix group after the last administration, medicine treated animal are no abnormal, the result of histopathologic examination shows: matched group vaginal mucosa organizational structure is normal, vagina epithelium is a stratified squamous epithelium, do not see and obviously thicken and hypertrophy, do not see that also ON states such as obvious degeneration, inflammation, necrosis change, lamina propria, flesh layer there is no unusually.Matrix group vagina tissue structure is normal, and vagina epithelium is a stratified squamous epithelium, and the vaginal mucosa organizational structure is normal, vagina epithelium is a stratified squamous epithelium, do not see obviously to thicken and hypertrophy that do not see that also ON states such as obvious degeneration, inflammation, necrosis change, lamina propria, flesh layer there is no unusually.Fig. 4 is repeatedly medication matrix group, and Fig. 5 is medication medicine group repeatedly.

3 conclusion (of pressure testing)s

The nonoxynolum bolt that the present invention is prepared in single or divided doses result shows that nonoxynolum bolt of the present invention has no stimulation to the rabbit vagina mucosa, to the not significantly effect of flesh layer.Illustrate that nonoxynolum bolt vagina medicinal of the present invention to rabbit vagina mucosa nonirritant, can guarantee clinical application safety.

Claims (5)

1. Encare, form by each component of following weight portion:

1 part of nonoxynolum

2 parts of cetomacrogol 1000s

13 parts of mixed fatty glycerides.

2. according to the Encare of claim 1, it is characterized in that: described mixed fatty glycerides is meant the mixture that glyceryl monostearate, glycerol distearate and glyceryl tristearate are formed according to arbitrary proportion.

3. according to the Encare of claim 2, it is characterized in that: described mixed fatty glycerides is made up of according to 0.5: 1.5: 9 part by weight glyceryl monostearate, glycerol distearate and glyceryl tristearate.

4. according to the Encare of claim 2, it is characterized in that: the acid number of described mixed fatty glycerides is less than 0.40, and its iodine number is less than or equal to 0.10.

5. a method for preparing any one Encare of claim 1-4 comprises: take by weighing each component by described weight portion; With nonoxynolum, cetomacrogol 1000 and mixed fatty glycerides mix, and with 60 ℃ heating in water bath, mixture are dissolved; Pack into during the medicinal plastics composite hard sheet heat seal that made packs with filling machine behind the abundant mix homogeneously of each component after will dissolving; Cooling after solidifying fully, is sealed, promptly.

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