CN101797222B

Movatterモバイル変換

Info

Publication number: CN101797222B
Application number: CN2010101584609A
Authority: CN
Inventors: 陈平; 丁明和
Original assignee: Mayinglong Pharmaceutical Group Co Ltd
Current assignee: Mayinglong Pharmaceutical Group Co Ltd
Priority date: 2010-04-28
Filing date: 2010-04-28
Publication date: 2012-06-27
Anticipated expiration: 2030-04-28
Also published as: CN101797222A

Abstract

The invention discloses a morphine sulfate sustained/controlled-release suppository, which comprises the following compositions in percentage by weight: 1 to 10 percent of morphine sulfate, 20 to 35 percent of poloxamer 188, 20 to 35 percent of poloxamer 407, 0.004 to 0.02 percent of antioxidant, and 25 to 48 percent of water absorbent. The morphine sulfate sustained-release/controlled-release suppository can make the effective blood concentration maintain more than 24 hours, show a good blood platform, and fully display the sustained/controlled-release characteristics.

Description

Morphine sulfate sustained/controlled-release suppository and preparation method thereof

Technical field

The present invention relates to a kind of morphine sulfate sustained/controlled-release suppository and preparation method thereof.

Background technology

Morphine is as the analgesia medicine of classics, is the basic medicine of the third level in the cancer three step analgesia principles of World Health Organization's suggestion, is mainly used in severe pain, the low dose of pain relieving that also can be used for the moderate pain patient.

Morphine is an opioid receptor agonist, and powerful analgesic activity is arranged, and simultaneously tangible sedation is arranged also, and antitussive effect is arranged.Morphinization has analgesic effect in the morphine receptor of posterior horn of spinal cord matter and nucleus ventralis posterolateralis thalami to sharp pain; To the morphine receptor effect at positions such as aqueduct of midbrain grey matter, hypothalamus and thalamus, particularly evident to dull pain and Encelialgia effect; Act on limbic system and cancellated morphine receptor, can alleviate, reach calm because of emotional responses such as anxiety that pain causes, anxieties.

The morphine oral administration is to be widely used in the effective therapeutic modality of control cancer pain; Yet clinical experience and bibliographical information show; Long-term oral opium kind analgesics can cause serious patient GI irritation and vomiting reaction, should take other rational route of administration to alleviate above-mentioned symptom.Therefore, Roxanol's rectally clinical remission cancer pain is a kind of preferable alternative method.

Prior art discloses a kind of morphine sulphate suppository (patent 200810197059.9), and its morphine sulfate with percetage by weight 0.5-5% is a principal agent, the mixed fatty glycerides of 36 types of 70-93.49%; The mixed fatty glycerides of 38 types of 2-20%, the tween 80 of 1-6%, the micropowder silica gel of 1-3%; The microcrystalline Cellulose of 2-8%, 2 of the butylated hydroxyarisol of 0.005-0.05% and 0.005-0.05%, 6-d-tert-butyl-p-cresol are that adjuvant is prepared from; Because adjuvant and proportioning thereof, above-mentioned morphine sulphate suppository is an ordinary suppository, can not reach the effect of slow controlled release; After the clinical experiment Chinese medicine was used, its effective alleviating pain time, only about 7 hours, responding time was short; To make that so interior administration number of times of unit interval is many, dosage is big, is prone to cause blood drug level not steady.

Summary of the invention

In order to solve the problems of the technologies described above, the invention provides a kind of morphine sulfate sustained/controlled-release suppository and preparation method thereof.

Morphine sulfate sustained/controlled-release suppository provided by the invention comprises following component in percentage by weight:

Morphine sulfate 1～10%;

Pool Luo Samu 188 (F68) 20～35%;

Pool Luo Samu 407 (F127) 20～35%;

Antioxidant 0.004～0.02%;

Water absorbing agent 25～48%.

Further, above-mentioned morphine sulfate sustained/controlled-release suppository also comprises following component in percentage by weight:

Azone 2～6%;

Carbomer 0.5～2%.

Above-mentioned antioxidant is preferred 2,6-d-tert-butyl-p-cresol, above-mentioned water absorbing agent preferably glycerine.

The present invention provides a kind of method for preparing of above-mentioned morphine sulphate suppository, comprises the steps:

A, morphine sulfate is crossed 180 mesh sieves, pool Luo Samu 188, pool Luo Samu 407 and antioxidant are crossed the 100-200 mesh sieve respectively, and be subsequent use;

B, with the morphine sulfate that sieves, pool Luo Samu 188, pool Luo Samu 407 and antioxidant, be heated to 60～80 ℃ and be melt into homogeneous mixture;

C, the resulting fused homogeneous mixture of step B is added the water absorbing agent of said amount under 40～75 ℃ of stirrings of constant temperature, insulated and stirred is even;

D, the mixture fill while hot that step C is obtained, be to cool off under 18～20 ℃ of conditions in temperature;

E, seal, pack.

The present invention also provides a kind of method for preparing of above-mentioned morphine sulfate sustained/controlled-release suppository, comprises the steps:

A, morphine sulfate is crossed 180 mesh sieves, pool Luo Samu 188, pool Luo Samu 407 and 2, the 6-d-tert-butyl-p-cresol is crossed the 100-200 mesh sieve respectively, and is subsequent use;

B, with the morphine sulfate that sieves, the pool Luo Samu 188, the pool Luo Samu 407 and 2,6-d-tert-butyl-p-cresol mix homogeneously is heated to 60～80 ℃ and is melt into homogeneous mixture;

C, the resulting fused homogeneous mixture of step B is added glycerol, the azone of said amount under 40～75 ℃ of stirrings of constant temperature, insulated and stirred is even;

D, be to cool off under 18～20 ℃ of conditions with the fill while hot of step C mixture, in temperature;

E, seal, pack.

Technical scheme provided by the invention can reach following technique effect:

1, morphine sulfate sustained/controlled-release suppository clinical practice provided by the invention is in middle severe, middle and advanced stage cancer pain, postoperative pain, and curative effect is reliable, and is safe in utilization, and blood drug level is suitable with morphine sulfate slow release sheet.Morphine sulfate ordinary suppository and morphine sulfate sustained/controlled-release suppository dog rectally of the present invention test show: the C of morphine sulfate sustained/controlled-release bolt 35mg/1g specification of the present invention_MaxBe 438.49ng/ml, the peak height of blood drug level is merely 1/3 of common bolt, and blood drug level is steady, presents platform trend; Holdup time (MRT) is 19.237 hours in the body, for the 6-8 of common bolt doubly; Compare with common bolt, morphine sulfate controlled release bolt relative bioavailability is 154.2%, has significantly slow controlled release characteristics.This slow controlled release bolt can obviously reduce administration number of times, reduces dosage in the unit interval, keeps for a long time steadily blood drug level, and (10～1500ng/ml) can keep more than 24 hours effective blood drug concentration.

2, morphine sulfate sustained/controlled-release suppository provided by the invention is the suppository of rectum with hydrogel matrix; By " Chinese pharmacopoeia two appendix ID of version " suppository " in 2000 general rule; The main character of investigating suppository in the development process, melt become the time limit (by " and two appendix XB of Chinese pharmacopoeia version in 2000 melt the overtime check method that becomes) etc. index; Filter out proper supplementary material kind, ratio, make it meet the requirement of Chinese Pharmacopoeia.By carrying out influence factor test (comprising: hot test, high humility test, strong illumination test) under 2000 editions two appendix XIXC medicine stability tests of the Chinese Pharmacopoeia guideline item respectively, investigate its character, content, related substance, melt become the time limit (by " and two appendix XB of Chinese pharmacopoeia version in 2000 melt the overtime check method that becomes) situation of change.Each experimental result shows, suppository of the present invention meets and melts the regulation that becomes the time limit, and under influence factor's experimental condition (high temperature, high humidity, illumination), each item investigation project does not have significant change, shows that suppository of the present invention is to heat, light, the wet steady quality that influences.

3, the existing good slow-releasing and controlled-releasing action of pool Luo Samu (F68 and F127) composite substrate, not only the slow release time limit extends to 7-8 hour, the coefficient R that zero level discharges behind the adding carbomer (Cb)²Value also increases substantially.Common morphine sulphate suppository 3h stripping 90.87%, 3.5h stripping 98.27% is dissolved near complete; Slow controlled release morphine bolt 3h stripping 35～47%, 7h stripping 76～98%, t_50%=3.5h～4.5h presses zero-order release pattern statistics R²＞0.92, reach the controlled release preparation standard that pharmacopeia is stipulated fully.

Description of drawings

Fig. 1 is morphine sulfate sustained/controlled-release suppository cumulative leaching rate-time graph thatembodiment 1 makes;

Fig. 2 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository rabbit body thatembodiment 1 makes;

Fig. 3 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository dog body thatembodiment 1 makes;

Fig. 4 is morphine sulfate sustained/controlled-release suppository cumulative leaching rate-time graph thatembodiment 2 makes;

Fig. 5 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository rabbit body thatembodiment 2 makes;

Fig. 6 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository dog body thatembodiment 2 makes;

Fig. 7 is that the morphine sulfate sustained/controlled-release suppository thatembodiment 2 makes is placed pharmacokinetic studies curve in the dog body after 3 months;

Fig. 8 is that the morphine sulfate sustained/controlled-release suppository thatembodiment 2 makes is placed pharmacokinetic studies curve in the dog body after 6 months;

Fig. 9 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository rabbit body thatembodiment 4 makes;

Figure 10 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository rabbit body thatembodiment 5 makes;

Figure 11 is the interior pharmacokinetic studies curve of morphine sulfate sustained/controlled-release suppository rabbit body thatembodiment 6 makes.

The specific embodiment

Below in conjunction with accompanying drawing and specific embodiment the present invention is described further so that those skilled in the art can better understand the present invention and implementing, but the embodiment that lifts not conduct to qualification of the present invention.

Embodiment one

The morphine sulfate sustained/controlled-release suppository that present embodiment provides, contain following percentage by weight:

Morphine sulfate 3.48%;

Pool Luo Samu 188 24.00%;

Pool Luo Samu 407 26.40%;

The method for preparing of above-mentioned morphine sulphate suppository comprises the steps:

A. the principal agent morphine sulfate is crossed 180 or 180 above mesh sieves; Adjuvant comprises F68, F127, carbomer, 2, and 6-d-tert-butyl-p-cresol (BHT), adjuvant are crossed 100 orders or 100 above mesh sieves respectively, and be subsequent use;

B.F68, F127, BHT, morphine sulfate, 60-80 ℃ of fusion of carbomer stirring and evenly mixing post-heating, stirring and evenly mixing;

C. with the substrate of step B fusing 60～75 ℃ of stirrings, it is even to add glycerol and azone and insulated and stirred;

D. step C mixture is stirred 60～70 ℃ of constant temperature, the bolt of falling 1.0g mould; In temperature is to cool off under 18～20 ℃ of conditions;

E. seal, pack.

By carrying out influence factor test (comprising: hot test, high humility test, strong illumination test) under 2000 editions two appendix XIXC medicine stability tests of the Chinese Pharmacopoeia guideline item respectively, investigate its character, content, related substance, melt become the time limit (by " and two appendix XB of Chinese pharmacopoeia version in 2000 melt the overtime check method that becomes) situation of change.Each experimental result shows, the suppository of present embodiment meets and melts the regulation that becomes the time limit, and under influence factor's experimental condition (high temperature, high humidity, illumination), each item investigation project does not have significant change, shows that suppository of the present invention is to heat, light, the wet steady quality that influences.

External stripping release of above-mentioned morphine sulfate sustained/controlled-release suppository and body giving drugs into nose are tested for dynamics research

One, the external dissolution test data of above-mentioned morphine sulfate sustained/controlled-release suppository, linear statistics

Time (h)	Retention time (min)	Peak area A	The accumulation peak area	2ml solution morphine content	Cumulative leaching rate (%)
						0.5	3.085	172078	172078	7.0845	0.2024
1	3.082	205660	205660	8.4671	0.24191
						1.5	3.080	303324	303324	12.4880	0.3168
2	3.095	266722	266722	10.9811	0.3537
						2.5	3.093	352479	352479	14.5118	0.4146
3	3.092	421455	421455	17.3516	0.4957

4	3.087	196213	617668	25.4298	0.7265
						5	3.090	233023	654478	26.9453	0.7698
6	3.100	282548	704003	28.9843	0.8281
						7	3.097	340704	762159	31.3786	0.8965

External stripping release test result of study shows; The sustained/controlled-release suppository of present embodiment preparation should should be more than 24%, 35%, 49%, 72%, 76%, 82% and 89% of labelled amount respectively mutually 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours burst size; External stripping reaches zero level and discharges, R²Be 0.9571, the linear relationship of release time and cumulative in vitro burst size good (seeing accompanying drawing 1).

Two, above-mentioned morphine sulfate sustained/controlled-release suppository rabbit body giving drugs into nose dynamic test

Screening test in the body: (sulfur acid morphine 18～20mg) dips in a little paraffin, fills in the new zealand rabbit anal of fasting 24h respectively with common bolt with the miniature slow-release suppository (sulfur acid morphine 18-20mg) of scaled preparation.Get blood 1ml respectively at 0.5,1.0,2.0,3.0,4.0,5.0,6.0,8.0,10.0, when 12.0h and 24.0h from the auricular vein of two rabbit, place to contain a small amount of heparin sodium aqua (heparin sodium: centrifuge tube water=1: 4).

Blood sample is handled: the rabbit auricular vein is got blood 1ml, adds 1% anticoagulant heparin, the accurate blood plasma 0.2ml that draws of the centrifugal 10min. of 7000r/min; Add the 0.8ml methanol solution, the centrifugal 10min of 4000r/rain, membrane filtration; Nitrogen dries up in 37 ℃ of water-baths, and 200 μ l methanol solutions dissolve again, filters; The accurate 20 μ l sample introductions of drawing carry out high-performance liquid chromatogram determination blood drug level.Efficient liquid phase chromatographic analysis is with reference to " Chinese pharmacopoeia.

The result sees accompanying drawing 2, explains that (10～1500ng/ml), slow controlled release timeliness reaches 24 hours to the blood drug level that the morphine sulfate sustained/controlled-release bolt suppository of present embodiment remained valid in 24 hours.

Three, blood drug level test and evaluation in the above-mentioned morphine sulfate sustained/controlled-release suppository dog body

Screening test in the body: (sulfur acid morphine 18～20mg) dips in a little paraffin, fills in the domesticated dog anal of fasting 24h respectively with common bolt with the miniature slow-release suppository (sulfur acid morphine 18-20mg) of scaled preparation.Get blood 1ml respectively at 0.5,1.0,2.0,3.0,4.0,6.0,8.0,10.0, when 12.0h, 24.0h, 28.0h, 32h and 38h from the auricular vein of two domesticated dogs, place to contain a small amount of heparin sodium aqua (heparin sodium: centrifuge tube water=1: 4).

Blood sample is handled: the domesticated dog auricular vein is got blood 1ml, adds 1% anticoagulant heparin, the accurate blood plasma 0.2ml that draws of the centrifugal 10min. of 7000r/min; Add the 0.8ml methanol solution, the centrifugal 10min of 4000r/rain, membrane filtration; Nitrogen dries up in 37 ℃ of water-baths, and 200 μ l methanol solutions dissolve again, filters; The accurate 20 μ l sample introductions of drawing carry out high-performance liquid chromatogram determination blood drug level.Efficient liquid phase chromatographic analysis is with reference to " Chinese pharmacopoeia.

The result sees accompanying drawing 3, explains that the morphine sulfate sustained/controlled-release suppository of present embodiment presented good blood medicine platform in 30 hours, and the blood drug level of remaining valid, and the slow controlled release time limit surpasses 24 hours, reaches the approximate medicine that slowly discharges at regular time and quantity.

Embodiment two

Morphine sulfate 5.94%;

Pool Luo Samu 188 28.05%;

Pool Luo Samu 407 25.25%;

B.F68, F127, BHT, morphine sulfate, 70 ℃ of fusions of carbomer stirring and evenly mixing post-heating, stirring and evenly mixing once more;

C. the substrate that step B is melted adds glycerol and azone and insulated and stirred under 40～45 ℃ of stirrings even;

D. step C mixture is stirred constant temperature to 60～70 ℃, the bolt of falling 1.2g mould; In temperature is to cool off under 18～20 ℃ of conditions;

E. seal, pack.

By carrying out influence factor test (comprising: hot test, high humility test, strong illumination test) under 2000 editions two appendix XIXC medicine stability tests of the Chinese Pharmacopoeia guideline item respectively, investigate its character, content, related substance, melt become the time limit (by " and two appendix XB of Chinese pharmacopoeia version in 2000 melt the overtime check method that becomes) situation of change.Each experimental result shows, suppository of the present invention meets and melts the regulation that becomes the time limit, and under influence factor's experimental condition (high temperature, high humidity, illumination), each item investigation project does not have significant change, shows that suppository of the present invention is to heat, light, the wet steady quality that influences.

Sample time (h)	Retention time (h)	Peak area	The accumulation peak area	External release amount (mg)	Release percentage rate (%)
						0.5h	3.098	347825	347825	14.11945467	0.160768058
1h	3.098	600029	600029	24.35731263	0.27733917
						1.5h	3.092	746247	746247	30.29282164	0.344922535
2h	3.098	831564	831564	33.75614231	0.384356872
						2.5h	3.098	867095	867095	35.19847206	0.400779642
3h	3.092	965072	965072	39.17570719	0.446065553
						4h	3.098	383238	1348310	54.73270156	0.62320184
5h	3.098	525634	1490706	60.51306199	0.689018639
						6h	3.098	537601	1502673	60.99884511	0.694549902
7h	3.098	659114	1624186	65.93149025	0.750714378
						8h	3.097	810743	1775815	72.08665101	0.820798759

Above-mentioned external stripping release test result of study shows; The suppository of present embodiment preparation should should be more than 27.73%, 38.43%, 44.60%, 62.32%, 68.90%, 69.45%, 75.07% and 82.79% of labelled amount respectively mutually 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours burst size; External stripping reaches zero level and discharges, R²Be 0.9491, the linear relationship of release time and cumulative in vitro burst size good (seeing accompanying drawing 4).

Screening test and blood sample treatment step are withembodiment 1 in the body.

The result sees accompanying drawing 5, explains that (10～1500ng/ml), slow controlled release timeliness reaches 24 hours to the blood drug level that the morphine sulfate sustained/controlled-release suppository of present embodiment remained valid in 24 hours.

The result sees accompanying drawing 6, explains that the morphine sulfate sustained/controlled-release suppository of present embodiment presented good blood medicine platform in 30 hours, and the blood drug level of remaining valid, and the slow controlled release time limit surpasses 24 hours, reaches the approximate medicine that slowly discharges at regular time and quantity.

Four, slow controlled release stability test of above-mentioned morphine sulfate sustained/controlled-release suppository and pharmacokinetics evaluation

Above-mentioned morphine sulfate sustained/controlled-release suppository is delayed the controlled release properties estimation of stability; Above-mentioned suppository is made determination of plasma concentration in the dog body (process of the test is the same) after placing 3 months; The result sees accompanying drawing 7; Above-mentioned suppository is made determination of plasma concentration in the dog body (process of the test is the same) after placing 6 months, the result sees accompanying drawing 8.The result shows, the morphine sulfate sustained/controlled-release bolt of present embodiment development in accelerated test study condition (30 ℃ ± 2 ℃ of temperature, relative humidity 65% ± 5%) held 3 months, slow controlled release properties was constant in 6 months, slow controlled release timeliness reaches 24 hours.

Five, common morphine sulphate suppository (method for preparing is seen Comparative Examples) compares with present embodiment morphine sulfate sustained/controlled-release bolt dog medicine dynamic test research relevant parameter

Parameter	Unit	Common bolt dosage (2mg/kg)	Sustained/controlled-release suppository dosage (3.5mg/kg)
				A Ke Ka t_1/2Ka t_1/2Ke T(peak) C(max) AUC CL/F(s) V/F(c) MRT	ng·mL-1 h-1 h-1 h h h ng/ml (ng/ml)*h mg/kg/h/(ng/ml) mg/kg/(ng/ml) h	1626.3884 0.54860 11.5801 0.0598 1.2634 0.2764 1331.3123 2824.1201 0.000708 0.001291 2.37	1284.7744 0.1140 0.2988 2.3197 6.0797 5.2139 438.4978 6969.2573 0.000502 0.004405 19.237

Above-mentioned experimental study data show, the C of the morphine sulfate sustained/controlled-release suppository 35mg/1g specification that we develop_MaxBe 438.49ng/ml, the peak height of blood drug level is merely 1/3 of common bolt, and blood drug level is steady, presents platform trend; Holdup time (MRT) is 19.237 hours in the body, for the 6-8 of common bolt doubly; Compare with common bolt, morphine sulfate controlled release bolt relative bioavailability is 154.2%, has significantly slow controlled release characteristics.This slow controlled release bolt can obviously reduce administration number of times, reduces dosage in the unit interval, keeps for a long time steadily blood drug level.

Embodiment three

Morphine sulfate 7.70%;

Pool Luo Samu 188 21.76%;

Pool Luo Samu 407 28.29%;

D. step C mixture is stirred 60～70 ℃ of constant temperature, the bolt of falling 1.5g mould; In temperature is to cool off under 18～20 ℃ of conditions;

E. seal, pack.

Embodiment four

The morphine sulfate sustained/controlled-release suppository that present embodiment provides, contain the component of following parts by weight:

Morphine sulfate 8.11%;

Pool Luo Samu 188 22.93%;

Pool Luo Samu 407 29.80%;

BHT 0.01％；

Glycerol 39.15%

A. the principal agent morphine sulfate is crossed 180 or 180 above mesh sieves; Adjuvant comprises F68, F127,2, and 6-d-tert-butyl-p-cresol (BHT), adjuvant are crossed 100 orders or 100 above mesh sieves respectively, and be subsequent use;

B.F68, F127, BHT, 70 ℃ of fusions of morphine sulfate stirring and evenly mixing post-heating, stirring and evenly mixing once more;

C. the substrate of step B fusing is added glycerol under 40～45 ℃ of stirrings and insulated and stirred even;

E. seal, pack.

One, common morphine sulphate suppository (method for preparing is seen Comparative Examples) compares with the dynamic test research of rabbit medicine and the relevant parameter of morphine sulfate controlled-release suppository of the present invention, and process of the test is withembodiment 1, and the result sees accompanying drawing 9 and following table.

Parameter	Common bolt	Slow controlled release bolt
			α/h^-1 β/h^-1 Ka/h^-1 V/F(c)/mgml/(ugkg) T_1/2α/h T_1/2β/h T_1/2Ka/h K₂₁/h^-1 K₁₀/h^-1 K₁₂/h^-1 AUC/(ug/ml)h CL(s)/mgkgh(ug/ml) T_peak/h C_max/ug/ml MRT/h	0.641 0.0005 0.744 0.129 1.081 1287.778 0.931 0.0007 0.511 0.130 121.538 0.0658 1.438 24.586 3.320	0.220 0.120 0.596 0.365 3.150 5.783 1.164 0.153 0.172 0.015 127.275 0.0629 2.857 12.944 8.221

Above-mentioned experimental study data show, the C of the morphine sulfate sustained/controlled-release suppository 35mg/1g specification of present embodiment_MaxBe 12.944ug/ml, the peak height of blood drug level is merely 1/2 of common bolt, and blood drug level is steady, presents platform trend; The holdup time (MRT) is 8.221 hours in the body, is 3 times of common bolt, has significantly slow controlled release characteristics.This slow controlled release bolt can obviously reduce administration number of times, reduces dosage in the unit interval, keeps for a long time steadily blood drug level.The blood drug level that the morphine sulfate sustained/controlled-release suppository of present embodiment was remained valid in 16 hours, slow controlled release timeliness reaches 16 hours.

Embodiment five

Morphine sulfate 2.692%;

Pool Luo Samu 188 20.50%;

Pool Luo Samu 407 34.50%;

The dynamic test of present embodiment morphine sulfate controlled release bolt rabbit medicine; Process of the test is withembodiment 1; The result sees accompanying drawing 10, explains that (10～1500ng/ml), slow controlled release timeliness reaches 24 hours to the blood drug level that the morphine sulfate sustained/controlled-release suppository of present embodiment remained valid in 24 hours.

Embodiment six

Morphine sulfate 9.20%;

Pool Luo Samu 188 34.10%;

Pool Luo Samu 407 20.80%;

The dynamic test of present embodiment morphine sulfate controlled release bolt rabbit medicine; Process of the test is withembodiment 1; The result sees accompanying drawing 11, explains that (10～1500ng/ml), slow controlled release timeliness reaches 24 hours to the blood drug level that the morphine sulfate sustained/controlled-release suppository of present embodiment remained valid in 24 hours.

Comparative Examples

Morphine sulfate 3.9%

The mixed fatty glycerides 75% of 36 types

Themixed fatty glycerides 8% of 38 types

Tween 80 5%

Micropowder silica gel 2%

Microcrystalline Cellulose 6%

Butylated hydroxyarisol 0.05%

2,6-d-tert-butyl-p-cresol 0.05%,

Be prepared from through following method, comprise the following steps:

A, morphine sulfate is crossed the 190-210 mesh sieve, adjuvant comprises micropowder silica gel, microcrystalline Cellulose, butylated hydroxyarisol, 2, and 6-d-tert-butyl-p-cresol, adjuvant are crossed the 90-100 mesh sieve respectively, and be subsequent use;

B, with 45～50 ℃ of fusions of mixed fatty glycerides heating, the mixing of the mixed fatty glycerides of 36 types and 38 types;

C, the substrate of step B fusing is added adjuvant that steps A sieved and tween 80 and insulated and stirred in the substrate of above-mentioned fusing under 40～45 ℃ of stirrings even, under agitation adds morphine sulfate then and insulated and stirred is even;

D, step C mixture is stirred reverse mould when being cooled to 37～40 ℃, is to cool off under 18～20 ℃ of conditions in temperature;

E, the overflow of pruning, the demoulding.

The above embodiment is the preferred embodiment that proves absolutely that the present invention lifts, and protection scope of the present invention is not limited thereto.Being equal to that the technical staff in present technique field is done on basis of the present invention substitutes or conversion, all within protection scope of the present invention.Protection scope of the present invention is as the criterion with claims.