CN103479583B - Potassium sodium dehydroandroan drographolide succinate enteric dry suspension and preparation method thereof - Google Patents
Potassium sodium dehydroandroan drographolide succinate enteric dry suspension and preparation method thereof Download PDFInfo
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Abstract
The invention relates to potassium sodium dehydroandroan drographolide succinate enteric dry suspension and a preparation method thereof. The prepared potassium sodium dehydroandroan drographolide succinate enteric dry suspension comprises, by weight percentage, 5%-50% of potassium sodium dehydroandroan drographolide succinate pellets or particles, 1%-10% of suspending agents and 50%-95% of taste-masked agents. According to the potassium sodium dehydroandroan drographolide succinate enteric dry suspension, the potassium sodium dehydroandroan drographolide succinate is creatively changed from previous injection administration preparations to oral administration preparations, the blanks of domestic and oversea potassium sodium dehydroandroan drographolide succinate oral administration preparations are filled, the untoward effect incidence rate caused by potassium sodium dehydroandroan drographolide succinate injection administration is greatly reduced, administration routes and dosage forms of the potassium sodium dehydroandroan drographolide succinate are enriched, and great value and superiority are provided for clinical rational drug usage. The prepared potassium sodium dehydroandroan drographolide succinate enteric dry suspension is stable in quality, takes effect rapidly, and is good in suspension effect and convenience for the old, children and patients with odynophagia to use.
Description
Technical field
The present invention relates to a kind of potassium sodium dehydroandroan drographolide succinate enteric dry suspension and preparation method thereof, belong to pharmaceutical field.
Background technology
Andrographolide is the andrographolide that extracts from the Chinese medicine Herba Andrographis PSDS through esterification, dehydration, one-tenth salt refining, its chemical name is 14-deshydroxy-11,12-bis-dehydrogenation andrographolide-3,19-disuccinic acid half ester k-na salt one water thing.Andrographolide can suppress early stage capillary permeability to increase and inflammatory exudation and edema, can excited Pituitary Adrenalcortical function specifically, promotes ACTH release, increases the biosynthesis of ACTH in antepituitary; The external effect with multiple viruses such as inactivated adenovirus, influenza virus, Respiroviruses.Zoopery have anti-morning, in pregnant effect.There are heat-clearing and toxic substances removing and antivirus action, are mainly used in viral pneumonia and viral upper respiratory tract infection clinically at present.Clinical practice effect for many years shows, andrographolide, to viral pneumonia and viral upper respiratory tract infection determined curative effect, has no drug resistance.
The andrographolide preparation of clinical practice only has Andrographolide in Andrographolide for Injection, ' Tanhuning ' injection and injection containing Yanhuning and sodium chloride three kinds at present, all by injecting by way of administration.Andrographolide, as a kind of Chinese medicine, in leaching process, being failed to eliminate tannin wherein or other biological macromole completely, directly being entered blood circulation through injecting, and easily causes allergic reaction or the reaction of pyrogen sample; And pyridine residual in synthesis, subtractive process also easily causes side effect." the total storehouse of CJFD (CNKI online edition) " and the data of " tieing up general Chinese scientific journal full-text database " 1998-2008, collect the ADR data 66 sections of Andrographolide in Andrographolide for Injection, relate to medical journals of Chinese 21 kinds, amounts to 78 examples.In 78 routine ADR, that the fastest is 2min after medication, and the slowest is that continuous use is after 5 days; Occur in medication 30min ~ 5 day that ADR person is maximum, account for 97% of sum.In this statistics, allergies person 10 example is had to account for 12.82% of sum; Without allergies person 68 example, account for 87.18%; Therefore whether the high quick body constitution person of tool easily to cause ADR still unknowable.In May, 2003 ~ in June, 2005, Gaoan City the People's Hospital reports with potassium sodium dehydroandroan drographolide succinate injection treatment infant infectious diseases and causes skin allergy 38 example.Tumour hospital of Xuzhou City Han Feng reports Andrographolide in Andrographolide for Injection pyrogenicity former state reaction 1 on February 4th, 2010 example.Rui Jin specialist out-patient department of Lianyungang of Jiangsu city Tang Shu reports and uses andrographolide on October 3rd, 2010, causes severe allergic reaction 1 example.Along with wide clinical application, its untoward reaction (ARD) Case report increases increasingly.Non-clinical statistical data shows, Andrographolide in Andrographolide for Injection has certain untoward reaction to integumentary system, respiratory system, blood system, wherein reacts the most common with anaphylactic shock and integumentary system.Anaphylaxis can show as erythra, pruritus, maculopapule, and dyspnea, edema, anaphylactic shock etc. even appear in severe patient, how to occur in medication first.Digestive tract reaction often shows as Nausea and vomiting, stomachache, diarrhoea, also has the report of liver function injury.The minimizing of blood system reaction common leukocyte, thrombocytopenia, purpura etc.Other untoward reaction also has shiver with cold, high heat, even dizzy, uncomfortable in chest, cardiopalmus, tachycardia, blood pressure drops etc.
Because andrographolide drug administration by injection adverse reaction rate is higher, particularly concerned to the drug safety day of less than 10 years old child patient to patient.Because drug administration by injection brings misery, easily cause patients ' psychological and physiology resistance, compliance is poor, limits andrographolide to a certain extent and uses.There is no the Patents about andrographolide oral Preparation at present.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of potassium sodium dehydroandroan drographolide succinate enteric dry suspension and preparation method thereof, adjuvant receptible on andrographolide and pharmaceutics is mixed with medicine carrying micropill or medicine carrying granule by the present invention, then by carrying out bag contagion gown to medicine carrying micropill or medicine carrying granule, andrographolide is avoided to be subject to the impact of acidic materials (as enteric coating material), and then it is enteric coated, ensure that andrographolide exempts from stomach acids destroy to reach, dissolve rapidly after smooth arrival intestinal, the object of release, effectively improve andrographolide oral administration bioavailability concerns, the adverse reaction rate of andrographolide drug administration by injection is greatly reduced again while ensure that curative effect.By above-mentioned enteric coated after andrographolide enteric coated micropill or granule, mix homogeneously with the suitable adjuvant such as suspending agent, correctives and make dry suspension.Andrographolide is changed over oral formulations by traditional injection by potassium sodium dehydroandroan drographolide succinate enteric dry suspension prepared by the present invention in a creative way, the incidence rate of its untoward reaction can be reduced while ensureing product curative effect, reduce its side effect, improve the safety of medication, greatly facilitate old people simultaneously, the patient of child and dysphagia uses, andrographolide will be made to be more widely used.
Results of in vitro studies of the present invention shows, andrographolide very easily dissolves in water, but extremely unstable under acid (pH2.0 ~ 5.0) condition, and it is relatively stable in the phosphate buffer, simulated intestinal fluid of pH7.0, prompting andrographolide is very easily degraded in gastric juice, and to make enteric coated preparation be a kind of feasible dosage form.Animal test results shows, take rat as object of study, gavage gives andrographolide enteric coated micropill, adopts the drug level of andrographolide in blood plasma and each intestinal segment content after the administration of high effective liquid chromatography for measuring rat oral gavage, evaluates its absorption in rat body and pharmaco-kinetic properties.Result: do not find that piller exists in 2h small intestinal and large intestine after administration, in 4h small intestinal, the quantity of piller is maximum, in intestinal contents, andrographolide content is the highest, blood concentration-time curve meets one compartment model feature, show that andrographolide has better absorption at rat small intestine, prepare andrographolide enteric coated preparation truly feasible.And make andrographolide into oral formulations by injection, through the Selective absorber of digestive tract cell, when effectively preventing drug administration by injection body because of Passive intake complexity composition kind or cross the harmful material of multipair body, effectively reduce the probability of untoward reaction.From infective use, Chinese medicine generation anaphylaxis is many and heavy, but the reaction of oral formulations is little.So, change andrographolide into oral administration by drug administration by injection significant.Dissolution in vitro experimental study shows, andrographolide enteric coated micropill acts on dissolution≤5% after 2h in simulated gastric fluid, and in simulated intestinal fluid, act on dissolution >=85% after 45min, meets the related request of enteric coated preparation in " Chinese Pharmacopoeia ".Andrographolide enteric coated micropill or granule and suspending agent, correctives are mixed and made into dry suspension, both effectively protect andrographolide from the destruction of gastric acid, facilitate again old people, the patient of child and dysphagia uses.Innovative development potassium sodium dehydroandroan drographolide succinate enteric dry suspension of the present invention, fill up the blank of domestic andrographolide oral formulations, while guarantee therapeutic effect, the incidence rate of untoward reaction can be reduced, improve the safety of patient medication, avoid the misery caused to patient during drug administration by injection, medication is convenient simultaneously, is conducive to the compliance improving patient medication.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of potassium sodium dehydroandroan drographolide succinate enteric dry suspension, comprises in the percentage composition of raw material gross weight: andrographolide micropill or granule 5% ~ 50%, suspending agent 1% ~ 10% and correctives 50% ~ 95%.
On the basis of technique scheme, the present invention can also do following improvement.
Further, described andrographolide micropill or granule comprise pharmaceutically active layer, sealing coat and enteric layer, wherein, described pharmaceutically active layer accounts for 40% ~ 90% of andrographolide micropill or particle weight, described sealing coat accounts for 5% ~ 30% of andrographolide micropill or particle weight, and described enteric layer accounts for 5% ~ 30% of andrographolide micropill or particle weight; Preferably, described pharmaceutically active layer accounts for 50% ~ 80% of andrographolide micropill or particle weight, and described sealing coat accounts for 5% ~ 15% of andrographolide micropill or particle weight, and described enteric layer accounts for 15% ~ 30% of andrographolide micropill or particle weight;
Further, described pharmaceutically active layer comprises andrographolide, filler, disintegrating agent, binding agent and fluidizer, wherein, described andrographolide accounts for 10% ~ 40% of pharmaceutically active layer weight, described filler accounts for 50% ~ 80% of pharmaceutically active layer weight, described disintegrating agent accounts for 0% ~ 10% of pharmaceutically active layer weight, and described binding agent accounts for 0% ~ 10% of pharmaceutically active layer weight, and described fluidizer accounts for 5% ~ 20% of pharmaceutically active layer weight;
Further, described filler is starch, pregelatinized Starch, dextrin, lactose, sucrose, microcrystalline Cellulose, one or more mixture in mannitol or described filler be starch, pregelatinized Starch, dextrin, lactose, sucrose, microcrystalline Cellulose, the celphere made by one or more mixture in mannitol; Preferably, described filler is one or more the mixture in pregelatinized Starch, lactose, microcrystalline Cellulose; Preferred, described filler is microcrystalline Cellulose;
Further, described disintegrating agent is one or more the mixture in sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose;
Further, described binding agent is one or more the mixture in polyvidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, carboxymethyl cellulose, ethyl cellulose, acid polyethylene, Polyethylene Glycol, ethanol; Preferably, described binding agent is 40% ethanol.
Further, described fluidizer is one or more the mixture in micropowder silica gel, Pulvis Talci, magnesium stearate; Preferably, described fluidizer is micropowder silica gel.
Adopt the beneficial effect of this step to be improve liquidity, reduce material viscosity and be beneficial to pill.
Further, the coating material of described sealing coat is one or more the mixture in starch, lactose, sucrose, microcrystalline Cellulose, mannitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, ethyl cellulose; Preferably, the coating material of described sealing coat is one or more the mixture in hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose; Preferred, the coating material of described sealing coat is hydroxypropyl methylcellulose.
Further, the coating material of described enteric layer is one or more the mixture in acrylic resin, hydroxypropyl methylcellulose acetate succinate (HPMCPCAS), hydroxypropyl methylcellulose dimethyl phthalate (HPMCP), cellulose acetate dimethyl phthalate (CAP), starch, sucrose, Pulvis Talci, Polyethylene Glycol, magnesium stearate, micropowder silica gel, titanium dioxide, SA dibutyl ester, triethyl citrate, stearic acid, glyceryl monostearate, diethyl phthalate; Preferably, the coating material of described enteric layer is one or more the mixture in acrylic resin, cellulose acetate dimethyl phthalate, ethyl cellulose, Polyethylene Glycol, triethyl citrate, micropowder silica gel; Preferred, the coating material of described enteric layer is one or both the mixture in acrylic resin, ethyl cellulose.
Further, described suspending agent is one or more the mixture in xanthan gum, carrageenan, arabic gum, gelatin, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvidone, pectin, guar gum, sodium alginate, carboxymethyl cellulose; Preferably, described suspending agent is one or more the mixture in xanthan gum, arabic gum, carboxymethyl cellulose; Preferred, described suspending agent is one or both the mixture in xanthan gum, carboxymethyl cellulose;
Further, described correctives is one or more the mixture in sucrose, vine, Mel, aspartame, egg albumen powder, xylitol, mannitol, lactose, sorbitol, maltose alcohol, glycyrrhizin, citric acid, sodium citrate, flavoring banana essence, flavoring pineapple essence, orange taste essence, Mint Essence, Fructus Citri Limoniae essence, Fructus Persicae essence, hawthorn essence, blueberry flavor, rose essence;
Further, described potassium sodium dehydroandroan drographolide succinate enteric dry suspension every bag (1g ~ 3g) is containing andrographolide 10 ~ 200mg, and preferably, every bag contains andrographolide 40 ~ 160mg, preferred, and every bag containing andrographolide 80 ~ 160mg.
Further, the prescription preparing 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension is:
Further, the prescription preparing 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension is:
Further, the prescription preparing 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension is:
The invention has the beneficial effects as follows:
The potassium sodium dehydroandroan drographolide succinate enteric dry suspension steady quality that the present invention obtains, rapid-action, suspendible is effective, pass through Oral administration, greatly can reduce drug administration by injection approach adverse reaction rate, andrographolide can be effectively avoided again to suffer the problem of stomach acids destroy, make medicine rapid emission and absorption in intestinal juice, ensure greatly to facilitate while curative effect old people, the patient of child and dysphagia uses.
Present invention also offers the preparation method of above-mentioned potassium sodium dehydroandroan drographolide succinate enteric dry suspension, comprising:
1) medicine carrying micropill or medicine carrying granule is prepared
Andrographolide is mixed homogeneously with filler, disintegrating agent, binding agent and fluidizer, with centrifugal granulator seed-coating machine or employing extrude-spheronization technique prepares medicine carrying micropill, or adopts granulation machine to prepare medicine carrying granule, the particle diameter of medicine carrying micropill or medicine carrying granule is 30 ~ 100 orders;
2) bag sealing coat
By 1) obtained medicine carrying micropill or medicine carrying granule be placed in coating granulator or fluidized-bed coating machine, carries out coating with the coating material of sealing coat;
3) bag enteric layer
By 2) micropill wrapping sealing coat that obtains or granule be placed in coating granulator or fluidized-bed coating machine, with the coating material coating of enteric layer, obtains andrographolide enteric coated micropill or granule;
4) dry suspension is prepared
By correctives, suspending agent and 3) the andrographolide enteric coated micropill for preparing or granule mix, and obtains potassium sodium dehydroandroan drographolide succinate enteric dry suspension.
Detailed description of the invention
Be described principle of the present invention and feature below, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Embodiment 1 andrographolide enteric coated micropill or granule prescription preferred
1) andrographolide medicine carrying micropill or medicine carrying granule is preferred
Take the supplementary material of following recipe quantity, cross 120 orders respectively, mixing, adopt centrifugal granulator, prepare medicine carrying micropill with different binding agents, observe pill situation, result is as shown in table 1.
Table 1 the selection result
Result of the test shows, prescription 5 pill best results, be namely filler with microcrystalline Cellulose, micropowder silica gel be fluidizer, 40% ethanol for binding agent time, pill effect is best.
2) andrographolide enteric coated micropill or granular sausage soluble layer coating prescription preferred
The supplementary material taking recipe quantity according to above-mentioned best prescription (prescription 5) is prepared into andrographolide medicine carrying micropill, and with 5% hydroxypropyl emthylcellulose aqueous solution for coating solution bag sealing coat, coating weight gain is 8% of andrographolide medicine carrying micropill quality.Then by following proposal bag enteric layer respectively, with the release of coated micropill in simulated gastric fluid and simulated intestinal fluid for index, investigate coating effect, optimize coated formula and coating weight gain (coating weight gain is by contagion gown micropill quality).
Release inspection method: measure with reference to drug release determination method (" Chinese Pharmacopoeia " version in 2010 two annex X D) the second method.
In acid, release measures this product (being about equivalent to andrographolide 80mg), adopt dissolution method second subtraction unit, using 750ml0.1mol/L hydrochloric acid solution as release medium, rotating speed is 75 turns/min, operates in accordance with the law, and 2 as a child, get solution appropriate, filter, get subsequent filtrate according to ultraviolet visible spectrophotometry, measure absorbance at 251nm place; Separately get andrographolide reference substance appropriate, accurately weighed, add 0.1mol/L hydrochloric acid solution and make the solution containing 30 μ g in every 1ml, be measured in the same method, calculate burst size (A) in acid.
In buffer, burst size adds the 0.2mol/L sodium radio-phosphate,P-32 solution 250ml (regulating pH value to 6.8 ± 0.05 with 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution if desired) that temperature is 37 ± 0.5 DEG C in above-mentioned acid solution, remain in operation 45 minutes, get solution appropriate, filter, get subsequent filtrate 5ml, put in 10ml, add buffer and be diluted to scale, shake up, according to ultraviolet visible spectrophotometry, measure absorbance at 251nm place; Separately get andrographolide reference substance appropriate, accurately weighed, the phosphate buffer adding pH6.8 makes the solution containing 30 μ g in every 1ml, is measured in the same method, and calculates the burst size (B) in buffer.
By regulation, in the acid of enteric coated preparation, burst size should be no more than 10% of labelled amount, and in buffer, burst size is not less than 80% of labelled amount.
Table 2 enteric layer coating optimization test result
Above-mentioned experimental result is known, is that coating material coating effect is undesirable with Eudragit L 100, and in acid, in burst size and buffer solution, burst size is all against regulation; And best with the use of coating effect with Eudragit L 100 and ethyl cellulose, both mass ratioes are with Eudragit L 100: ethyl cellulose is 75:25 ~ 65:35, and coating weight gain is 20% ~ 25% best results of contagion gown micropill quality.Ethyl cellulose with the use of, the release of the andrographolide that is conducive to slowing down, makes its release profiles in buffer tend towards stability but not affect final Cumulative release amount as blocker.In coating solution, add a small amount of plasticizer (polyethylene glycol 6000), the pliability of coating membrane can be improved, increase coating membrane compactness, thus be more conducive to forming complete thin film, improve the release of andrographolide enteric coated micropill.
Embodiment 2
The present embodiment prepares 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension, adopts following prescription:
Preparation technology:
(1) 120 mesh sieves are crossed in the microcrystalline Cellulose of the andrographolide of recipe quantity and recipe quantity, micropowder silica gel to mix homogeneously, for subsequent use; Prepare 40% alcoholic solution for subsequent use; Adopt centrifugal granulator, prepare medicine carrying micropill (particle diameter is 80 order ~ 100 orders) using above-mentioned 40% alcoholic solution as binding agent, control temperature 37 DEG C ~ 40 DEG C, hydrojet flow velocity is 0.5 ~ 1ml/min.In 40 DEG C of oven dryings after having added medicine to;
(2) above-mentioned dried andrographolide micropill is placed in fluidized-bed coating machine, with 5% hydroxypropyl emthylcellulose aqueous solution for coating solution bag sealing coat.Host parameter rotating speed: 120 ~ 200rpm; Hydrojet: 3 ~ 10rpm; Air quantity: little; Atomizing pressure: 0.05 ~ 0.1mPa.Coating weight gain is about 8%;
(3) by above-mentioned sealing coat micropill, fluidized-bed coating machine is placed in, enteric coated with the alcoholic solution of 6% acrylic resin L100 (adding polyethylene glycol 6000).Host parameter rotating speed: 120 ~ 200rpm; Hydrojet: 3 ~ 10rpm; Air quantity: little; Atomizing pressure: 0.05 ~ 0.1mPa.Coating weight gain is about 25%.
(4) sucrose is pulverized, cross 30 mesh sieves, mix homogeneously with the andrographolide enteric coated micropill prepared, xanthan gum, mannitol, orange taste essence, be distributed into 1000 bags, obtain final product.Every bag is about 80mg containing andrographolide.
Embodiment 3
The present embodiment prepares 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension, adopts following prescription:
Preparation technology:
(1) 120 mesh sieves are crossed in the andrographolide of recipe quantity and the micropowder silica gel of recipe quantity to mix homogeneously, for subsequent use; Prepare 60% alcoholic solution for subsequent use; Microcrystalline Cellulose ball core is placed in centrifugal granulator, adds medicine to using above-mentioned 60% alcoholic solution as binding agent, control temperature 37 DEG C ~ 40 DEG C, hydrojet flow velocity is 0.5 ~ 1ml/min.In 40 DEG C of oven dryings after having added medicine to;
(2) above-mentioned dried andrographolide micropill is placed in fluidized-bed coating machine, with 5% hydroxypropyl emthylcellulose aqueous solution for coating solution bag sealing coat.Host parameter rotating speed: 120 ~ 200rpm; Hydrojet: 3 ~ 10rpm; Air quantity: little; Atomizing pressure: 0.05 ~ 0.1mPa.Coating weight gain is about 8%.Coating completes and is placed on 40 DEG C of oven dryings;
(3) by above-mentioned dried sealing coat micropill, fluidized-bed coating machine is placed in, enteric coated with the alcoholic solution of 6% acrylic resin L100 (adding triethyl citrate).Host parameter rotating speed: 120 ~ 200rpm; Hydrojet: 3 ~ 10rpm; Air quantity: little; Atomizing pressure: 0.05 ~ 0.1mPa.Coating weight gain is about 25%.After coating completes, taking-up is placed in 40 DEG C of oven dryings and obtains Lansoprazole enteric pellet;
(4) sucrose is pulverized, cross 30 mesh sieves, mix homogeneously with the andrographolide enteric coated micropill prepared, carboxymethyl cellulose, mannitol, orange taste essence, be distributed into 1000 bags, obtain final product.Every bag is about 80mg containing andrographolide.
Embodiment 4
The present embodiment prepares 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension, adopts following prescription:
Preparation technology:
(1) 120 mesh sieves are crossed in the microcrystalline Cellulose of the andrographolide of recipe quantity and recipe quantity, micropowder silica gel to mix homogeneously, the soft material of the matters being wetting agent with 40% alcoholic solution; Adopt extrusion spheronization legal system for micropill (particle diameter is 0.35mm ~ 2.0mm), extruded velocity 1080r/min, round as a ball speed 960r/min, round as a ball time 5min, can obtain roundness better, the pastille micropill that yield is higher, fluid bed screens 40 order ~ 60 object micropills after drying;
(2) above-mentioned andrographolide medicine carrying micropill is placed in fluidized-bed coating machine, with 5% hydroxypropyl emthylcellulose aqueous solution for coating solution bag sealing coat.Host parameter rotating speed: 120 ~ 200rpm; Hydrojet: 3 ~ 10rpm; Air quantity: little; Atomizing pressure: 0.05 ~ 0.1mPa.Coating weight gain is about 8%;
(3) by above-mentioned sealing coat micropill, fluidized-bed coating machine is placed in, enteric coated with the alcoholic solution of 6% acrylic resin L100 (add ethyl cellulose and enter polyethylene glycol 6000).Host parameter rotating speed: 120 ~ 200rpm; Hydrojet: 3 ~ 10rpm; Air quantity: little; Atomizing pressure: 0.05 ~ 0.1mPa.Coating weight gain is about 20%.
(4) sucrose is pulverized, cross 30 mesh sieves, mix homogeneously with the andrographolide enteric coated micropill prepared, xanthan gum, orange taste essence, be distributed into 1000 bags, obtain final product.Every bag is about 80mg containing andrographolide.
Embodiment 5
Pharmacokinetics after potassium sodium dehydroandroan drographolide succinate enteric dry suspension gastric infusion in dog body and absolute bioavailability research:
Choose rat 20, (200 ± 20) g, male and female half and half, (Sida Pharmaceutical Co Ltd, Hainan produces to be divided into andrographolide intravenous injection group at random, 20120801) and oral group of potassium sodium dehydroandroan drographolide succinate enteric dry suspension (embodiment 2) lot number:, fasting 12 hours before experiment, water is freely drunk and is got.Vein group: under etherization, inserts its right femoral artery by polyethylene tube, with 4mg/kg intravenously administrable under waking state.After administration respectively at 0,5,10,15,30,45,60,90,120,180,240min tremulous pulse extracts 0.25ml blood sample, in order to the blood volume of supplementary minimizing after every sub-sampling, injected heparin sodium (100IU/ml) normal saline of same volume by intubate.Oral group: andrographolide (20mg/kg) the enteric dry suspension taking respective amount according to dog body weight, gavages with 3ml warm water.Respectively at after administration 0,15,30,60,120,180,240,300,360,420,480min tremulous pulse extracts 0.25ml blood sample, in order to the blood volume of supplementary minimizing after every sub-sampling, injected heparin sodium (100IU/ml) normal saline of same volume by intubate.
Being proceeded to immediately by the blood sample at every turn gathered scribbles in the centrifuge tube of heparin, and the centrifugal 5min of 10000r/min, obtains different time blood plasma.Get this blood plasma 0.1ml, after adding the methanol 0.4ml containing internal standard substance (stabilizing) 1.2 μ g/ml, vortex concussion mixes 30s, leaves standstill 10min, by centrifugal for this mixed liquor 5in, remove protein, upper strata organic solvent crosses the plasma sample that 0.45 μm of microporous filter membrane obtains different time.Wherein, the blood plasma of 0min adopts not containing the methanol process of internal standard substance, as blank plasma as stated above.
All plasma samples adopt HPLC method to carry out measuring the concentration of andrographolide in blood plasma respectively.Chromatographic condition is as follows:
Chromatographic column: VP-ODS C
18column (4.6mm × 150mm, 5 μm); Mobile phase: methanol-1% acetic acid-triethylamine (65:35:0.02); Flow velocity: 1.0ml/min; Determined wavelength: 251nm; Temperature: 40 DEG C; Sample size: 20 μ l.
Draw the average blood medicine-time graph of andrographolide according to measurement result, all market demand pharmaceutical statistics software DAS1.0 process, matching compartment model also calculates pharmacokinetic parameters.In the AUC of oral group than vein group AUC(namely with the absolute bioavailability of intravenously administrable for 100%), calculate absolute bioavailability, because qf oral administration dosage is 5 times of vein group dosage, therefore last result of calculation need divided by coefficient 5.Result shows, potassium sodium dehydroandroan drographolide succinate enteric dry suspension oral administration group medicine-time data fit two Room pharmacokinetic model, its mean absolute bioavailability is 31.16%.
Table 3 andrographolide vein and oral administration are at Pharmacokinetics in Rat parameter (n=10)
| Intravenously administrable | Oral administration | |
| T 1/2α（min） | 0.95±4.4 | 2.17±3.0 |
| T 1/2β（min） | 20.24±1.1 | 18.43±2.3 |
| T max（min） | 5.03±1.2 | 76.35±8.6 |
| C max（mg·L -1） | 3.86±1.4 | 3.09±2.1 |
| AUC (0～∞)（mg·min·L -1） | 18.14±1.1 | 28.26±3.8 |
| F(%) | 100 | 31.16 |
Result shows, potassium sodium dehydroandroan drographolide succinate enteric dry suspension can pass through intestinal absorption, and absolute bioavailability is 31.16%, and prompting andrographolide is effectively avoided the destruction of gastric acid by intestinal canal administration mode and plays and effectively treat concentration.Although the maximum plasma concentration of single oral administration is lower than the peak concentration of intravenously administrable, by the mode of low dose of multiple dosing to ensure therapeutic effect, the generation of the various untoward reaction that higher blood drug level may cause can be reduced again.
Embodiment 6
Potassium sodium dehydroandroan drographolide succinate enteric dry suspension is to the therapeutic effect of H1N1 type influenza infection pneumonia of rats:
Experiment is used rat random packet, often organize 10 (male and female half and half), test is divided into four groups: Normal group, virus control group, (Sida Pharmaceutical Co Ltd, Hainan produces the peaceful injection matched group of scorching tiger, lot number: 20120801), potassium sodium dehydroandroan drographolide succinate enteric dry suspension group (taking from embodiment 2).
Normal group does not do viral infection process, yet not administration, diet.
All the other each group, anaesthetized by rat ether, then collunarium infects H1N1 virus, and every rat infection amount is 80 μ g, the not administration of virus control group.Potassium sodium dehydroandroan drographolide succinate enteric dry suspension group infects administration after 4 hours, and gastric infusion dosage is every 40mg/kg, administration every day secondary; Injection matched group administered intramuscular, dosage is each 40mg/kg, and every day is administered once.
The 5th day after administration, put to death by each group of rat, precision balance claimed its body weight, dissected rat, got Mus lung, and normal saline immersion, rinses, filter paper suck dry moisture, claims lung weight, observed pneumonopathy and became, and calculated average Lung Exponent and pneumonopathy change suppression ratio.
The therapeutic effect of table 4 andrographolide oral formulations infected by influenza H1N1 type infected rats pneumonia
* lung lesion degree is in "+": 75<++++<100,50<+++<75,25<++<50,0<+<25 ,-there is not pathological changes.
The average Lung Exponent of *=average lung weight/average weight
* * lung index=(the average Lung Exponent of the average Lung Exponent-experimental group of virus control group)/average Lung Exponent of virus control group
Statistical result shows, potassium sodium dehydroandroan drographolide succinate enteric dry suspension group lung index is 51.58%, a little more than 47.74% of injection group; Average Lung Exponent compares there was no significant difference with injection matched group, and compare with virus control group, average Lung Exponent has statistical significant difference, illustrate that potassium sodium dehydroandroan drographolide succinate enteric dry suspension infected by influenza H1N1 type infecting mouse pneumonia has good therapeutic effect, and therapeutic effect and injection basically identical.
In a word, potassium sodium dehydroandroan drographolide succinate enteric dry suspension prepared by the present invention protects andrographolide and makes not to be subject to stomach acids destroy, achieves the Oral administration of andrographolide no pain, improves the compliance of patient.Meanwhile, intestinal release ensure that the drug level of higher level in intestinal, substantially increases the bioavailability of andrographolide, ensure that product curative effect.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (1)
1. a potassium sodium dehydroandroan drographolide succinate enteric dry suspension, is characterized in that, the prescription of preparation 1000 bags of potassium sodium dehydroandroan drographolide succinate enteric dry suspension is:
Andrographolide 80g
Microcrystalline Cellulose 350g
Hydroxypropyl emthylcellulose 30g
Eudragit L 100 100g
Polyethylene glycol 6000 20g
Micropowder silica gel 80g
Xanthan gum 30g
Sucrose 1000g
Mannitol 200g
Orange taste essence 15g.
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| CN107982240B (en) * | 2017-12-15 | 2020-11-17 | 黄山中皇制药有限公司 | Potassium sodium dehydroandroan drographolide succinate enteric coated granules capable of being accurately dissolved out and preparation method thereof |
| CN107982241B (en) * | 2017-12-15 | 2020-11-13 | 黄山中皇制药有限公司 | Potassium sodium dehydroandroan drographolide succinate enteric preparation and preparation method thereof |
| CN110420179A (en) * | 2019-08-12 | 2019-11-08 | 韩育娟 | A kind of andrographolide dry suspensoid agent and preparation method thereof |
| CN111317726A (en) * | 2020-03-30 | 2020-06-23 | 黄山中皇制药有限公司 | Andrographolide enteric dry suspension |
| CN114224850B (en) * | 2022-02-21 | 2022-04-29 | 北京罗诺强施医药技术研发中心有限公司 | Solid pharmaceutical composition, preparation method thereof and pharmaceutical preparation |
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| CN101991542A (en) * | 2009-08-10 | 2011-03-30 | 杭州赛利药物研究所有限公司 | Lansoprazole enteric dry suspension and preparation method thereof |
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| CN101991542A (en) * | 2009-08-10 | 2011-03-30 | 杭州赛利药物研究所有限公司 | Lansoprazole enteric dry suspension and preparation method thereof |
Non-Patent Citations (3)
| Title |
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| . * |
| 炎琥宁肠溶微丸的制备工艺研究;徐淼等;《中国生化药物杂志》;20101231;第31卷(第1期);第6-9，13页 * |
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