CN1830430A - Dichlofenas sodium slow release suppository and its preparation method - Google Patents
Dichlofenas sodium slow release suppository and its preparation method Download PDFInfo
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- CN1830430A CN1830430A CN 200510120594 CN200510120594A CN1830430A CN 1830430 A CN1830430 A CN 1830430A CN 200510120594 CN200510120594 CN 200510120594 CN 200510120594 A CN200510120594 A CN 200510120594A CN 1830430 A CN1830430 A CN 1830430A
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- dichlofenas
- diclofenac sodium
- release suppository
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Abstract
A slow-release suppository of diclofenac sodium applied via rectum contains proportionally diclofenac sodium, matrix and carbomer.
Description
That technical field the present invention relates to is analgesic, the novel form of analgesia, antibiotic medicine diclofenac sodium, relates in particular to a kind of slow releasing diclofenac sodium slow-release suppository that is used for rectally and preparation method thereof.
Background technology diclofenac sodium (diclofenac sodium) belongs to nonsteroidal antiinflammatory drug, is mainly used in treatment rheumatic arthritis, osteoarthritis clinically, pathological changes and wound cause around the joint tendon, ligament, muscle and joint injury; In recent years, diclofenac sodium also is widely used in postoperative analgesia, cancer pains etc. such as removing cystospasm, operation on prostate, all obtain good relieving spasm to stop pain effect, and untoward reaction is less.
Common diclofenac sodium suppository is made up of diclofenac sodium and common substrate, is the clinical rectum medicine that is used for analgesic, analgesia, antiinflammatory, and it is brought down a fever rapidly, and analgesic effect is obvious, has used the more than ten years clinically.According to clinical and interrelated data, though this drug effect fruit is good, exist the analgesic activity time not long, the patient needs multiple dosing on the one in order to ease pain.In addition, this medicine excessive velocities of bringing down a fever causes patient's dripping sweat easily.
The general method for making of suppository is that medicine and additive are pulverized through pulverizer earlier, crosses the 80-100 mesh sieve then, at last with the fine powder and the substrate mixing of thawing that sieve, and the filling mould.The problem that this method exists is: one, medicine pulverize and when sieving dust bigger, to the pollution of production environment and bigger to the operator ' s health influence; Secondly, pulverize, can cause when sieving about 1% loss; Its three, the equipment and the staff that pulverize, need when sieving are more, the man-hour of expending is also longer, has increased production cost.
Diclofenac sodium rectally absorption rate is very fast, but the half-life is shorter, and it is also fast to eliminate speed, and in order to overcome above shortcoming, the development of rectally slow releasing preparation is imperative.
Summary of the invention main purpose of the present invention is in order to solve the deficiency that the above-mentioned background technology exists, for a kind of drug effect of clinical development can be kept the long period, and the more demulcent Dichlofenas sodium slow release suppository of effect.
For achieving the above object, the present invention adopts following technical scheme: a kind of Dichlofenas sodium slow release suppository that is used for rectally, it is characterized in that containing in this slow-release suppository the medically diclofenac sodium of effective dose, weight is diclofenac sodium 21.885-21.931 substrate doubly, weight is diclofenac sodium 0.069-0.115 blocker doubly, and described blocker is a carbomer.
In such scheme, described substrate is Polyethylene Glycol, polyoxyethylene stearate (40) ester, poloxamer, mixed fatty glycerides, tristearin, cocoa butter or black mortar fat.
Secondary objective of the present invention is the preparation method that proposes a kind of Dichlofenas sodium slow release suppository, to reduce cost, improves working environment, reduces the medicine loss.
For realizing this purpose, the present invention adopts following technical scheme: the above-mentioned Dichlofenas sodium slow release suppository preparation method of a kind of production, the step of this method is as follows: at first with substrate in 60 ℃ of following heating and melting, add diclofenac sodium and carbomer then, by colloid mill or homogenizer grind, mixing, last fill is cooled off in the bolt capsule, seals.
Method of the present invention has solved the deficiency that background technology exists, and medicine is after colloid mill grinds, and its fineness is thinner, and through traditional pulverizing, its mean diameter is 240 μ m as diclofenac sodium, and after colloid mill ground, its mean diameter was 60 μ m.Drug particle size in the suppository is thin, is more conducive to rectal mucosal absorption after the administration, thus the performance better therapeutic.
We adopt the blood drug level after 20 healthy volunteer's single dose rectum of HPLC method mensuration give 100mg Dichlofenas sodium slow release suppository and common bolt, calculate its relative bioavailability and relevant pharmacokinetic parameters with the 3P97 program, to carry out evaluation of bioequivalence.In addition, also carried out the multiple dose test, the characteristics of pharmacokinetics of slow-release suppository has been studied, whether had slow release characteristic to estimate it.
1 materials and methods
1.1 medicine and reagent Dichlofenas sodium slow release suppository (Tongyao Medicine Co., Ltd., Wuhan City, lot number 20020226-1, every 50mg); The common bolt of diclofenac sodium (Tongyao Medicine Co., Ltd., Wuhan City, lot number 20030408, every 50mg); Diclofenac sodium reference substance (Tongyao Medicine Co., Ltd., Wuhan City); Methanol (chromatographically pure, Tianjin having ideals, morality, culture, and discipline biomedical technology company limited); Ether (top grade is pure, the Tianjin City Chemical Agent Research Institute); Glacial acetic acid (top grade is pure, the Tianjin City Chemical Agent Research Institute); Hydrochloric acid (top grade is pure, Lanxi City chemical reagent factory); Experimental water is dual aquae destillata.
1.2 the instrument high performance liquid chromatograph is an Agilent1100 series, comprises the G1311A quaternary pump, the online degasser of G1322A, G1315B diode array detector, G1328B manual injector and Agilent chem workstation; Electronic analytical balance (sensitivity 0.1mg); WX-80A vortex instrument.
1.3 the chromatographic condition chromatographic column is Hypersil C
18Post (4.6mm * 250mm, 5 μ, Agilent, USA), guard column is C
18Post.Mobile phase be methanol-1.5% glacial acetic acid (72.5: 27.5, V/V), flow velocity 0.9mLmin
-1Detect wavelength 276nm, column temperature is a room temperature, detection sensitivity 0.1mAU.
Inject 10mL tool plug test tube 1.4 blood plasma 0.5mL is got in the plasma sample pretreatment, add 1molL
-1Add ether 4mL behind HCL100 μ L, the vibration 30s, DL 2min leaves standstill the 10min layering, get organic facies 4mL and inject 10mL scale centrifuge tube, be placed on volatilize in 37 ℃ of water-baths after, add mobile phase 100 μ L and redissolve, sample introduction 20 μ L analyze with the external standard method peak area quantification.
1.5 20 healthy male volunteers of study subject are students, age (22.32 ± 0.75) a, height (173.23 ± 3.61) cm, body weight (62.35 ± 4.45) kg.There are not acute and chronic medical history and Developmental and Metabolic Disorder medical history.Through Health Certificate blood, routine urinalysis, liver, renal function, BP, ECG, item such as Chest X-rays is normal, the signature Informed Consent Form.Do not obey any medicine in the experimenter 2wk, duration of test ban on opium-smoking and the opium trade wine, the unified low fat standard meal of feed.
1.6 dosage regimen
1.6.1 20 experimenters of single dose test are divided into 2 groups at random, behind the fasting 12h, in next day the 7:00 rectum give Dichlofenas sodium slow release suppository or common bolt 100mg, can drink water the laggard unified meal of 4h behind the administration 2h.Get blank blood before the administration, after the administration 0.167,0.333,0.667,1,1.5,2,3,4,6,8,12h gets blood 3mL in ulnar vein, puts into the heparinization test tube, centrifugal (3000rmin
-1* 10min) get blood plasma ,-40 ℃ of preservations are equipped with and survey.
1.6.2 20 experimenters of multiple dose test are divided into 2 groups at random, 12h administration 1 time, and successive administration 5 times, each dosage is 100mg, the 3mL that phlebotomizes before the 5th administration gets the blood point and tests with single dose after the 5th administration.To be measured behind the centrifugal separation plasma.
Single dose and multiple dose process of the test, whenever use up a kind of dosage form after, drug withdrawal 1wk carries out cross matching then, method is the same.
1.7 methodology checking
Mix blank plasma 1.7.1 standard curve and lowest detectable limit are got the healthy volunteer, add an amount of diclofenac sodium standard reserving solution, be mixed with mass concentration and be 0.025,0.050,0.100,0.250,0.500,1.000,2.500,5.000mgL
-1The blood plasma standard solution, by 1.4 the operation, with peak area (A) to corresponding concentration (c, mgL
-1) carry out rectilinear regression.Regression equation is A=71.749c-2.5071, r=0.997, and the range of linearity is 0.025～5.000mgL
-1, minimal detectable concentration is 20 μ gL in the blood plasma
-1(r
SN=3).
1.7.2 method response rate compound concentration is 0.1,1.0,4.0mgL
-1The blood plasma standard solution, by 1.4 operations down, record sample peak area, the substitution regression equation is tried to achieve measured concentration, compare to such an extent that the relative recovery of this method is respectively (98.2 ± 6.06) %, (96.9 ± 6.60) %, (94.7 ± 4.40) % with theoretical concentration, average relative recovery is 96.6%.
1.7.3 precision test compound concentration is 1.0,1.0, the blood plasma standard solution of 4.0mgL-1, by 1.4 operations down, record sample peak area, the substitution regression equation is tried to achieve measured concentration, and calculating in a few days, RSD is respectively 3.030%, 5.898%, 7.567%; In the daytime RSD is 3.061%, 5.306%, 2.885%.
1.8 statistical procedures according to survey diclofenac sodium blood drug level-time data, adopts the 3P97 program to handle, with the terminal calculating K e of concentration-time curve, T
1/2=0.639/Ke calculates AUC with trapezoidal method, and cmax and tmas are measured value, cmin be during the stable state administration before last spacing of doses administration with administration after the meansigma methods of actual measurement medicine paddy concentration of 12h.Press the relative bioavailability of column count Dichlofenas sodium slow release suppository: F=AUC
0-12(being subjected to test preparation)/AUC
0-12(reference preparation).
With " 3P97 evaluation of bioequivalence program " main pharmacokinetic parameters is carried out variance analysis, the two single t of survey checks reach (1-2a) confidence interval calculating, estimate the bioequivalence of two preparations.
2. result
Under this experimental condition of chromatogram, the retention time of diclofenac sodium is 8.1min, peak type symmetry, and separating degree is good, the equal interference measurement (Fig. 1) not of endogenous material and metabolite in the blood plasma.
2.1 pharmacokinetic parameters
2.1.1 average blood drug level-time graph was seen Fig. 2 after 20 healthy volunteer's rectum of single dose test gave the 100mg diclofenac sodium, its pharmacokinetic parameters sees Table 1.
20 healthy volunteer's single doses of table 1 give 100mg Dichlofenas sodium slow release suppository and general
Pharmacokinetic parameters behind the logical bolt
| Parameter | Tested suppository | Reference suppository |
| T 1/2(Ke)/h c max/mg·L -1 t max/h AUC 0-12/mg·h·L -1 AUC 0-∞/mg·h·L -1 | 2.346±0.577 1.087±0.298 1.692±0.665 c 3.770±1.223 3.947±1.253 | 2.132±0.699 1.202±0.411 1.108±0.430 3.234±0.737 3.375±0.754 |
Compared with reference suppository，
bP＞0.05，
cP＜0.01
2.2.2 the multiple dose test 20 healthy volunteers give the 100mg diclofenac sodium at every turn, average blood drug level-time graph is seen Fig. 2 after continuous 5 administrations, and its pharmacokinetic parameters sees Table 2.
20 healthy volunteer's multiple doses of table 2 give the 100mg Dichlofenas sodium slow release suppository and
Pharmacokinetic parameters behind the common bolt
| Parameter | Tested suppository | Reference suppository |
| c max/mg·L -1 c min/mg·L -1 t max/h AUC 0-12/mg·h·L -1 AUC 0-∞/mg·h·L -1 MRTO-12 DF/％ | 1.370±0.315 c 0.103±0.032 c 2.175±0.654 o 5.459±1.278 6.019±1.250 3.774±0.340 b 279.453±47.041 c | 1.641±0.518 0.076±0.035 1.458±0.458 5.299±0.964 5.779±0.989 3.302±0.305 347.195±71.655 |
Compared with reference suppository，
bP＞0.05，
cP＜0.01
2.3 relative bioavailability and evaluation of bioequivalence relative bioavailability: as calculated, the average relative bioavailability of test preparation is (115.5 ± 19.8) %, between 80%～125%.
2.3 evaluation of bioequivalence: in single dose and multiple dose test, the AUC of test preparation and reference preparation
0-12, AUC
0-∞After to number conversion, do the multifactor analysis of variance and two one-side t check and calculate 90% credibility interval, the result all shows there was no significant difference (P＞0.05).Single dose test: AUC
0-1290% credibility interval is 105.4%～122.5%, AUC
0-∞90% credibility interval is 106.0%～123.0%; Multiple dose test: AUC
0-1290% credibility interval is 97.9%～107.1%, AUC
0-∞90% credibility interval is that 97.9%～110.0%, two preparations have bioequivalence.
From the pharmacokinetic parameters of gained as seen, the more common bolt of the peak time of this Dichlofenas sodium slow release suppository is obviously delayed, peak concentration is low, the common bolt of paddy concentration ratio is big, and the average retention time is long, and blood concentration fluctuation is little, be stationary curve, illustrate that this slow-release suppository has tangible sustained releasing character, therefore, the clinical side reaction of Dichlofenas sodium slow release suppository is littler than common diclofenac sodium bolt, still less.
Dichlofenas sodium slow release suppository of the present invention in vivo various kinetic parameters after the rabbit rectum administration are: AUC:71.8 (ug/ml*h); t
1/2 (Ka): 0.19h; t
1/2 (Ke): 1.4h; T
Max: 0.54h; C
Max: 27.6 (ug/ml) * h; CL:0.76g/h/ (ug/ml); Ka:8.9 (1/h); Ke:0.56 (1/h).The common bolt of rabbit administration various kinetic parameters in vivo are: AUC:61.58 (ug/ml*h); t
1/2 (Ka): 0.15h; t
1/2 (Ke): 1.09h; T
Max: 0.49h; C
Max: 29.38 (ug/ml) * h; CL:0.82mg/h/ (ug/ml); Ka:5.12 (1/h); Ke:0.67 (1/h).Use area under curve AUC
0-∞Asking the relative bioavailability of calculating Dichlofenas sodium slow release suppository is 116.5%.AUC, C to two kinds of preparations
Max, T
Max, t
1/2 (ka), CL, t
1/2 (Ke), ka, ke parameter carry out result two, the one-side t check and show the AUC of two preparations, C
Max, T
Max, t
1/2 (ka), CL, t
1/2 (Ke), ka, ke there was no significant difference (P＞0.05), the C of slow-release suppository
MaxBe lower than common bolt, T
MaxLonger than common bolt, t1/2 (ka) is longer than common bolt.And the visible common bolt of curve chart (Fig. 3) can't detect drug level when 12h during by medicine, and slow-release suppository still had at 24 hours and can measure drug level.
The result shows: the AUC of Dichlofenas sodium slow release suppository is than the AUC height of common bolt, and it is long to have a peak time, the characteristics that blood concentration fluctuation is little, and long action time have long-acting, slow releasing function, and toxic and side effects is littler in vivo.
Description of drawings
Fig. 1 is a diclofenac sodium HPLC chromatogram.
Fig. 2 is the average blood drug level-time plot of diclofenac sodium.
Curve chart when Fig. 3 is the medicine of two kinds of preparations in the rabbit body.
The specific embodiment
Embodiment 1: composition of raw materials: get diclofenac sodium 100g, Polyethylene Glycol 2188.5g, low viscosity carbomer 11.5g.
Preparation method: at first with Polyethylene Glycol in 60 ℃ of following heating and melting, add diclofenac sodium and low viscosity carbomer then, by colloid mill or homogenizer grind, mixing, last fill is cooled off in the bolt capsule, seals.
Present embodiment is prepared 2000 Dichlofenas sodium slow release suppositories altogether.
Embodiment 2: composition of raw materials: get diclofenac sodium 100g, polyoxyethylene stearate (40) ester 2193.1g, high viscosity carbomer 6.9g.Preparation method and other are identical with embodiment 1.
Embodiment 3: composition of raw materials: get diclofenac sodium 100g, poloxamer 2190g, medium viscosity carbomer 10g.Preparation method and other are identical with embodiment 1.
Embodiment 4: composition of raw materials: get diclofenac sodium 100g, mixed fatty glycerides 2192g, high viscosity carbomer 8g.Preparation method and other are identical with embodiment 1.
Embodiment 5: composition of raw materials: get diclofenac sodium 100g, stearic 2189g, low viscosity carbomer 11g.Preparation method and other are identical with embodiment 1.
Embodiment 6: get diclofenac sodium 100g, cocoa butter 2191.5g, medium viscosity carbomer 8.5g.Preparation method and other are identical with embodiment 1.
Embodiment 7: get diclofenac sodium 100g, black mortar fat 2192.8g, high viscosity carbomer 7.2g.Preparation method and other are identical with embodiment 1.
Claims (4)
1, a kind of Dichlofenas sodium slow release suppository that is used for rectally, it is characterized in that containing in this slow-release suppository the pharmaceutically diclofenac sodium of effective dose, weight is diclofenac sodium 21.885-21.931 substrate doubly, weight is diclofenac sodium 0.069-0.115 blocker doubly, and described blocker is a carbomer.
2,, it is characterized in that described substrate is Polyethylene Glycol, polyoxyethylene stearate (40) ester, poloxamer, mixed fatty glycerides, tristearin, cocoa butter or black mortar fat according to the described Dichlofenas sodium slow release suppository of claim 1.
3,, it is characterized in that containing in every slow-release suppository 50 milligrams diclofenac sodium according to the described Dichlofenas sodium slow release suppository of claim 1.
4, a kind of production claim 1 or 2 or 3 described Dichlofenas sodium slow release suppository preparation methoies, the step of this method is as follows: at first with substrate in 60 ℃ of following heating and melting, add diclofenac sodium and carbomer then, by colloid mill or homogenizer grind, mixing, last fill is cooled off in the bolt capsule, seals.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756789B (en) * | 2009-05-22 | 2012-07-25 | 刘加升 | Preferential three-step method of production process for diclofenac sodium mucilage |
| US10327876B2 (en) | 2011-07-25 | 2019-06-25 | Braun Gmbh | Oral cleaning tool for an oral hygiene device |
-
2005
- 2005-12-31 CN CNB2005101205940A patent/CN100350906C/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756789B (en) * | 2009-05-22 | 2012-07-25 | 刘加升 | Preferential three-step method of production process for diclofenac sodium mucilage |
| US10327876B2 (en) | 2011-07-25 | 2019-06-25 | Braun Gmbh | Oral cleaning tool for an oral hygiene device |
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|---|---|
| CN100350906C (en) | 2007-11-28 |
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Effective date of registration: 20180705 Address after: 430040 776 Huian Avenue, Dongxihu District, Wuhan, Hubei Patentee after: WUHAN ZHENGTONG PHARMACEUTICAL CO., LTD. Address before: 430021 Hankou air road, Wuhan, Wuhan, Hubei Province, No. 13 Patentee before: Tongyao Medicine Co., Ltd., Wuhan City |
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