CN106188324B - Hydroxyethyl pachyman preparation and its as sustained release tablets framework material application - Google Patents
Hydroxyethyl pachyman preparation and its as sustained release tablets framework material application Download PDFInfo
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- CN106188324B CN106188324B CN201610548947.5A CN201610548947A CN106188324B CN 106188324 B CN106188324 B CN 106188324B CN 201610548947 A CN201610548947 A CN 201610548947A CN 106188324 B CN106188324 B CN 106188324B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
Abstract
The invention discloses a kind of preparation method of hydroxyethyl pachyman powder and its as the application of sustained release tablets framework material.Dialyzate after the present invention reacts hydroxyethyl pachyman is concentrated by ultrafiltration membrane or directly obtains hydroxyethyl pachyman powder with the concentrate of hydroxyethyl pachyman is spray-dried, it is with good mobility, compressibility and adhesiveness, both it is suitable for direct powder compression, is also suitable for wet granule compression tablet.It can be swollen in artificial gastro-intestinal Fluid by medicinal tablet prepared by hydroxyethyl pachyman and form gel, drug release is less in simulated gastric fluid, and drug has significant slow release effect in simulated intestinal fluid, the release of drug is based on spreading, simultaneously with the corrosion of gel layer, it is adapted as the sustained-release tablet framework material of various drugs especially polysaccharide protein class drug and other water soluble drugs.The speed of its drug release can be adjusted by changing hydroxyethyl pachyman degree of substitution, molecular weight or other auxiliary materials being added.
Description
Technical field
The present invention relates to a kind of preparation method of hydroxyethyl pachyman powder and its as medicament sustained-release tablets framework material
Application.
Background technique
Sustained-release preparation can sustained release drugs have the function that long-acting in long-time after medication, it overcomes common system
The disadvantages of agent times for spraying is more, patient compliance is poor, with administration number of times is few, peak valley blood concentration fluctuation is small, GI irritation
Gently, the features such as curative effect is long, safe, is clinically widely used.The exploitation design of sustained-release preparation has become preparation research
Key issues.
Pharmaceutic adjuvant is excipient or additives used when producing drug and prescription being dispensed, plays drug quality to pass
Important role.In today that pharmaceuticals industry rapidly develops, pharmaceutic adjuvant shows its increasingly consequence in the formulation, by
Extensive attention is arrived.Especially there is new auxiliary material the exploitation of good slow, controlled-release function natural pharmaceutic adjuvant to have more meaning.
The selection of slow-release auxiliary material is the key that prepare sustained release preparation especially water-soluble drug sustained release preparation, carries out the property that can improve drug
The research and development that can, provide specific function, guarantee the new pharmaceutic adjuvant such as drug drug safety and drug effect, can greatly promote correlation
Innovate the research and development of preparation or medicine-releasing system.
As a kind of natural plants, it is not only a kind of extensive Chinese medicine of effect, is more widely used in food Poria cocos,
Have the characteristics that from a wealth of sources, cheap, safe and non-toxic.Pachymaran is the main component of tuckahoe, the polysaccharide
It is dissolved in alkaline solution, dissolubility is poor in acid and neutral polysaccharide, can improve its dissolution in water by structural modification
Property.Hydroxyethyl pachyman is to the hydroxyethylated product of pachymaran, and with good biocompatibility, safe and reliable, source is wide
The advantages that general, easily biodegradable by various enzymes, prospect is very wide.By hydroxyethyl pachyman using epoxychloropropane as crosslinking
Agent makes to be chemically crosslinked between hydroxyethyl pachyman strand in alkaline environment, is preparing the pachymaran of chemical crosslinking
Hydrogel has preferable medicament slow release performance (Hu, Y., Zhou, X.J., Lu, Y., Hu, C.Y., Hu, X.M..Novel
biodegradable hydrogels based on pachyman and its derivatives for drug
delivery.Int.J.Pharm.,2009,371:89–98.).But due to using crosslinking agent, there are residual crosslinkers after crosslinking
Problem；And with the progress that crosslinked polymer reacts, the liquid viscosity constantly increased makes the dispersibility of crosslinking agent in the base
It is poor, there is uneven crosslinking, " incipient scorch " phenomenon locally occurs；It is chemically crosslinked simultaneously and is difficult to control the degree of cross linking, therefore this method
Prepared hydrogel is restricted in application of the field of medicaments especially in oral preparation field.We have found height under study for action
The hydroxyethyl pachyman of concentration easily forms gel in low temperature, therefore attempts it directly as medicament sustained release tablets skeleton
Material has great researching value and development prospect.
Summary of the invention
Present invention aim to address residual crosslinker existing in the prior art, crosslinkings unevenly, the degree of cross linking is difficult to control
System and cross-linked hydrogel provide the problems such as the application of oral preparation field is limited and a kind of prepare hydroxyethyl pachyman granular powder
The method at end, and a kind of novel drug sustained-release tablet framework material is provided, i.e., using hydroxyethyl pachyman as medicament slow release
The hydrophilic gel sustained-release matrix of piece.The medicament sustained-release tablets prepared by hydroxyethyl pachyman can form more in dissolution medium
Hole network gel, can significantly delay the rate of release of drug, some drugs discharged in simulated gastric fluid it is less, and in simulated intestinal fluid
In can reach slow release, the slow-released carrier particularly suitable as polypeptide, protide and other labile drugs in gastric juice.
A kind of preparation method of hydroxyethyl pachyman powder, includes the following steps：
(1) under the conditions of 0-10 DEG C, pachymaran after purification is dissolved in sodium hydroxide/urea liquid, is slowly added dropwise and rubs
The ethylene chlorhydrin that your amount is 1-20 times of pachymaran is warming up to 60 DEG C of reactions 0.5-5 hours, then delay after room temperature reaction 0-5 hours
The slow ethylene chlorhydrin that mole is added dropwise and is 0-10 times of pachymaran, the reaction was continued 0-5 hours；
(2) it is adjusted with acid reaction solution after reaction solution is cooled to room temperature to neutrality, filters, filtrate is with molecular cut off
10000 bag filter dialysis, dialyzate are concentrated into the 1/3~1/ of original volume with the ultrafiltration membrane that molecular cut off is 1000-10000
5, make the concentration 5-50wt% of ethoxy Poria cocos in concentrate, the material of the ultrafiltration membrane is cellulose acetate or polyethylene
Alcohol；
(3) (i) ethyl alcohol is added into concentrate is precipitated one of in the following manner, is centrifuged, vacuum drying；
(ii) using spray dryer that concentrate is dry；Or (iii) is dry by concentrate using fluidized bed, obtaining molar substitution is
The hydroxyethyl pachyman powder of 0.1-8.0.
The way of purification of pachymaran is：Pachymaran is worn into 60-200 mesh fine powder, is dissolved in the hydroxide of 0.1-2.0M
In sodium solution, under the conditions of 0-25 DEG C stirring dissolve powder, and in 0-5 DEG C standings 10-20 hours, suction filtration, filtrate tune pH is into
Property, it filters, by 30-50 DEG C of vacuum drying after filter residue freeze-drying or solvent washing.
In the sodium hydroxide/urea liquid, the concentration of sodium hydroxide is 0.5-3.0M, and the concentration of urea is 0.1-
2.0M。
In step (1), pachymaran and sodium hydroxide/urea liquid mass ratio are 1:100.
The inlet air temperature of spray dryer is 160-200 DEG C, and leaving air temp is 60-100 DEG C.
A kind of hydroxyethyl pachyman powder is prepared by the preparation method of above-mentioned hydroxyethyl pachyman powder.
Application of the above-mentioned hydroxyl pachymaran powder as framework material in medicament sustained-release tablets.
A kind of preparation method of hydroxyethyl pachyman sustained release tablets, includes the following steps：
(1) hydroxyethyl pachyman fine powder is taken, 16-60 mesh is crossed, is mixed with fine drug powder and auxiliary material A；
(2) lubricant is added in (i), and direct powder compression prepares sustained release tablets；Or wetting agent, wet granule compression tablet is added in (ii)
Method prepares sustained release tablets；
Wherein, hydroxyethyl pachyman accounts for the 10-90% of gross mass, and the auxiliary material A is adhesive, diluent, sustained release
One of framework material is a variety of.
The wetting agent is the ethanol water that volume fraction is 50%-90%.
A kind of hydroxyethyl pachyman sustained release tablets are prepared by the preparation method of above-mentioned hydroxyethyl pachyman sustained release tablets
It arrives.
The present invention passes through many aspects such as compressibility, mobility, adhesiveness, drug release rate to hydroxyethyl pachyman
Investigate its feasibility as the sustained-release matrix of medicinal tablet：
1. investigating the mobility of hydroxyethyl pachyman powder by solid conical bottom method；
2. investigating the bulk density of hydroxyethyl pachyman powder by fixed frame freely falling body method；
3. wet granule compression tablet or direct powder compression investigate the feasibility for being prepared into tablet；
4. examined using C14H10Cl2NNaO2 as model drug performance of the obtained tablet including sustained release comprehensively
It looks into.
Hydroxyethyl pachyman can prepare tablet by wet granule compression tablet or dry granulation, and auxiliary material composition is removed in preparation
Hydroxyethyl pachyman can also include the ingredients such as lubricant, wetting agent, diluent or other sustained-release matrix materials, drug
Sustained release performance can be adjusted by hydroxyethyl pachyman degree of substitution or diluent.
Compared with prior art, the present invention has the following advantages and beneficial effect：
(1) hydroxyethyl pachyman prepared by the present invention is excellent hydrophilic gels sustained-release matrix material, powder tool
There are good mobility and compressibility, is able to satisfy the basic demand of tablet manufacturing.
(2) for the drug sustained-release tablet as prepared by hydroxyethyl pachyman in gastro-intestinal Fluid, drug can reach slow release
Effect, therefore, the slow-release auxiliary material particularly suitable as hydrophilic medicament slow-release auxiliary material use.
(3) present invention obtains the lesser spheric granules of bulk density by the method for fluidized bed or spray drying, with the present invention
The medicament sustained-release tablets of obtained hydroxyethyl pachyman powder preparation can form gel in dissolution medium, and some drugs are artificial
It discharges less in gastric juice, and slow release can be reached in simulated intestinal fluid, particularly suitable as polypeptide, protide and other in stomach
The slow-released carrier of labile drug uses in liquid.
Detailed description of the invention
Fig. 1 is the scanning electron microscope (SEM) photograph for the hydroxyethyl pachyman powder that spray drying is prepared.
Fig. 2 is the metamorphosis figure of hydroxyethyl pachyman blank different time points in dissolution medium；Wherein, Fig. 2
It (a) is the tablet of dry granulation preparation；Fig. 2 (b) is the tablet of wet granulation preparation；0-2 hours, dissolution medium was the salt of 0.1M
Acid solution；2-8 hours, dissolution medium was the phosphate buffer of pH6.8.
Fig. 3 is the internal structure scanning electron microscope (SEM) photograph of hydroxyethyl pachyman blank tablet after dissolution 8 hours；Wherein,
The hydroxyethyl pachyman blank of Fig. 3 (a) dry granulation preparation, Fig. 3 (b) are that the ethoxy Poria cocos of wet granulation process preparation is more
Sugared blank.
Fig. 4 is that the release in vitro of the diclofenac sustained release tablets with hydroxyethyl pachyman slow-release auxiliary material of dry granulation is bent
Line chart.
Fig. 5 is that the release in vitro of the diclofenac sodium extended action tablet with hydroxyethyl pachyman slow-release auxiliary material of wet granulation is bent
Line chart.
Fig. 6 is the release in vitro of the Propranolol Hydrochloride sustained release tablets with hydroxyethyl pachyman slow-release auxiliary material of wet granulation
Curve graph.
Specific embodiment
In order to make those of ordinary skill in the art be more clearly understood that the present invention, by following embodiment to skill of the invention
Art scheme is described in detail, but do not limit the invention in any way.The raw materials used in the present invention is known compound, can
It is bought by market or is synthesized using synthetic method known in the art.
Embodiment 1：The preparation of hydroxyethyl pachyman powder
The dry Poria cocos block for removing skin wears into fine powder, crosses 60 meshes, 300g Poria cocos fine powder is taken to be dissolved in the sodium hydroxide solution of 1M
In (mass ratio of Poria cocos fine powder and sodium hydroxide solution be 1:100) it after low temperature stirring and dissolving, is placed in refrigerator and stands overnight, from
The heart, filtrate are neutralized with the acetic acid or hydrochloric acid of 10wt%, are filtered, and filter residue is successively washed with ethyl alcohol, acetone and ether, and 40 DEG C of vacuum are dry
It is dry, obtain pachymaran.
Above-mentioned pachymaran 120g after purification is taken, the hydroxide of sodium hydroxide containing 2M and 1M urea is dissolved under the conditions of 0 DEG C
(wherein, pachymaran and sodium hydroxide/urea liquid mass ratio are 1 in sodium/urea liquid:100) 10 times, are slowly added dropwise to rub
After the ethylene chlorhydrin of your amount reacts at room temperature 3 hours, it is warming up to 60 DEG C and reacts 1 hour, add the ethylene chlorhydrin of 10 times of moles
Reaction 1 hour is dialysed finally with 20% acetum (v/v) adjusting solution to neutrality with the bag filter that molecular weight is 10000,
Small molecule is removed, after dialysate filter, is concentrated into the 1/3 of original volume with the ultrafiltration membrance filter that molecular cut off is 10000, it is spraying
Dry, the inlet air temperature of spray dryer is 160-200 DEG C, and leaving air temp is 60-100 DEG C, obtains white hydroxyethyl pachyman
Powder (ethoxy degree of substitution is 0.51), its configuration of surface of gained powder scanning electron microscopic observation (see Fig. 1).
Embodiment 2
Pachymaran 120g after purification is weighed, the hydroxide of sodium hydroxide containing 1M and 0.5M urea is dissolved under the conditions of 0 DEG C
(pachymaran is 1 with sodium hydroxide/urea liquid mass ratio in sodium/urea liquid:100) 20 times of moles, are slowly added dropwise
Ethylene chlorhydrin, room temperature reaction 5 hours after, be warming up to 60 DEG C react 2 hours, after reaction solution is cooled to room temperature use 0.5M hydrochloric acid
It is adjusted to neutrality, is filtered, the bag filter dialysis that filtrate molecular weight is 10000 removes small molecule, and dialyzate is purified by ultra-filtration and separation
Ethanol precipitation concentrate is added in enriched product, is centrifuged to precipitate and successively be washed with acetone, ether, is dried in vacuo, obtained polysaccharide
Powder is spare (ethoxy degree of substitution is 0.30).
Embodiment 3
Pachymaran 120g after purification is weighed, the hydroxide of sodium hydroxide containing 1M and 0.5M urea is dissolved under the conditions of 0 DEG C
(pachymaran is 1 with sodium hydroxide/urea liquid mass ratio in sodium/urea liquid:100) 20 times of moles, are slowly added dropwise
Ethylene chlorhydrin, after normal-temperature reaction 5 hours, be warming up to 60 DEG C react 2 hours, after reaction solution is cooled to room temperature use 0.5M hydrochloric acid
It is adjusted to neutrality, is filtered, the bag filter dialysis that filtrate molecular weight is 10000 removes small molecule, and dialyzate is purified by ultra-filtration and separation
Ethanol precipitation concentrate is added in enriched product, and centrifugation with deionized water dissolving polysaccharide precipitation, makes polysaccharide concentration about 10%, spraying
Dry, inlet temperature is 180 DEG C, and obtained polysaccharide powder is spare (ethoxy degree of substitution is 0.30).
Embodiment 4
Pachymaran 120g after purification is weighed, the hydroxide of sodium hydroxide containing 1M and 0.5M urea is dissolved under the conditions of 10 DEG C
(pachymaran is 1 with sodium hydroxide/urea liquid mass ratio in sodium/urea liquid:100) 2 times of moles, are slowly added dropwise
Ethylene chlorhydrin after normal-temperature reaction 5 hours, is warming up to 60 DEG C and reacts 2 hours, the ethylene chlorhydrin of 15 times of moles is added dropwise, and 60 DEG C anti-
It answers 2 hours, is adjusted to neutrality with 0.5M hydrochloric acid after reaction solution is cooled to room temperature, filter, the dialysis that filtrate molecular weight is 10000
Bag dialysis remove small molecule, dialyzate by ultra-filtration and separation purify enriched product, be added ethanol precipitation concentrate, be centrifuged, spend from
Sub- water dissolves polysaccharide precipitation, makes polysaccharide concentration about 10%, is spray-dried, and inlet temperature is 180 DEG C, and obtained polysaccharide powder is spare
(ethoxy degree of substitution is 3.0).
Embodiment 5
Pachymaran 120g after purification is weighed, the hydroxide of sodium hydroxide containing 1M and 0.5M urea is dissolved under the conditions of 6 DEG C
(pachymaran is 1 with sodium hydroxide/urea liquid mass ratio in sodium/urea liquid:100) 10 times of moles, are slowly added dropwise
Ethylene chlorhydrin, after normal-temperature reaction 3 hours, be warming up to 60 DEG C and react 0.5 hour, then the ethylene chlorhydrin of 10 times of moles is added dropwise,
60 DEG C are reacted 3 hours, are adjusted to neutrality with 0.5M hydrochloric acid after reaction solution is cooled to room temperature, and are filtered, and filtrate molecular weight is 10000
Bag filter dialysis remove small molecule, dialyzate by ultra-filtration and separation purify enriched product, be added ethanol precipitation concentrate, be centrifuged,
With deionized water dissolving polysaccharide precipitation, make polysaccharide concentration about 10%, be spray-dried, inlet temperature is 180 DEG C, obtained polysaccharide powder
End is spare (ethoxy degree of substitution is 5.0).
Below by way of many aspects such as compressibility, mobility, adhesiveness, drug release rate to hydroxyethyl pachyman into
Row is investigated, to verify it as the feasibility of the sustained-release matrix of medicinal tablet：
Embodiment 6：The research of hydroxyethyl pachyman powder flowbility and bulk density
Fluidity determining uses fixed funnel method：The powder angle of repose for measuring above-described embodiment 1 and embodiment 2 is respectively
35.2 with 31.6.
The bulk density of powder measures：It takes the powder of 30g embodiment 1 and embodiment 2 to be placed in 100mL graduated cylinder, makes in graduated cylinder
Powder surface is paved, with certain amplitude vibration 300 times on rubber mat, record jolt ramming after volume, calculating its bulk density is respectively
0.52 and 0.47g/mL.The above result shows that being that class is spheroidal by the powder that spray drying process and precipitating centrifugal process obtain
Particulate powder, the hydroxyethyl pachyman powder flowbility that spray-dried method obtains are more preferable.
Embodiment 7：The preparation of hydroxyethyl pachyman blank
The hydroxyethyl pachyman of good fluidity prepared by Example 1, with compressing dry granulation and wet granulation pressure
Piece method (ethanol water for being 50% using volume fraction is wetting agent) prepares hydroxyethyl pachyman blank with single-punch tablet press
Piece each 20.The blank for blank and the wet granulation tableting preparation for taking compressing dry granulation to prepare respectively, first exists
2h is placed in the hydrochloric acid solution of 750mL 0.1M, adds the 250mL phosphate buffer (Na containing 0.2M3PO4), make pH 6.8,
Turning basket revolving speed is 100r/min, and medium temperature is 37 DEG C, is taken pictures in 0,2,4,6,8h to the blank of dissolution.Simultaneously to
Two kinds of hydroxyethyl pachyman blanks that 8 hours are impregnated in dissolution medium take out freeze-drying, and longitudal section is taken to split with sweeping
It retouches Electronic Speculum and observes its internal structure.Two kinds of blank hydroxyethyl pachyman piece states of different time in dissolution medium are shown in Fig. 2,
The internal structure of blank is shown in Fig. 3 after 8 hours.
Embodiment 8：Research (compressing dry granulation and the wet granulation of C14H10Cl2NNaO2 hydroxyethyl pachyman sustained release tablets
Pressed disc method)
By 1 prescription of table, by C14H10Cl2NNaO2 and various auxiliary materials, (hydroxypropyl methyl cellulose (HPMC), ethoxy Poria cocos are more
Sugar (HEP), microcrystalline cellulose (MCC), C14H10Cl2NNaO2 (DS), magnesium stearate (MgSA)) after evenly mixing, direct tablet compressing, piece
The diameter of agent is 8mm, and the hardness of tablet is about 90N, and average slice weight 0.2511g, tablet weight variation meets States Pharmacopoeia specifications.
The determination of absorbing wavelength：Certain density solution is made in solubilizer, according to spectrophotometry (Chinese Pharmacopoeia version in 2010
Two annex IV A) it is scanned in 200-400nm wave-length coverage, ultraviolet spectrogram is drawn, determines that maximum absorption wave is a length of
276nm.Take each right amount of auxiliary materials that the analog sample without main ingredient is made in prescription ratio, in 200-400nm wave after solubilization matchmaker dissolution
Scanning, determines that auxiliary material does not interfere and measures the trap of DS everywhere in maximum wavelength in long range.
The foundation of standard curve：The bulk pharmaceutical chemicals that precision weighs after purification are appropriate, are configured to the simulated intestinal fluid of pH 6.8
30mg·L-1Standard Reserving Solution is drawn the stock solution 2,4,6,8,10mL respectively, is set in 10mL volumetric flask.It is artificial with pH 6.8
Intestinal juice is diluted to scale, is configured to the solution of series of concentrations.Trap is surveyed at 276nm wavelength, and trap is carried out with concentration
Linear regression obtains regression equation.DS has good linear relationship, standard curve regression equation within the scope of 6~30 μ g/mL
For：C=23.74A-0.5123 (R2=0.9998, n=6).
Assay：Take test sample 20, it is accurately weighed, it is finely ground, take fine powder appropriate, it is accurately weighed, it is placed in 250mL measuring bottle
In, add ethyl alcohol to dissolve and be diluted to scale, shake up, filter, discard primary filtrate, precision measures subsequent filtrate 1.0mL in 10mL measuring bottle
In, add the hydrochloric acid of 0.1mol/L to scale, shakes up, as test solution；It separately takes DS i.e. reference substance appropriate, adds ethyl alcohol molten
The solution of every l mL 0.03mg containing DS is made, as reference substance solution in solution, the hydrochloric acid of 0.l mol/L.It is taken respectively for examination
Product solution and reference substance solution are surveyed at 276nm wavelength according to ultraviolet spectrophotometry (Chinese Pharmacopoeia I VA of version annex in 2010)
Determine trap, content is calculated using reference substance comparison method.Labelled amount is 75mg, and the content for measuring DS is the 99.27% of labelled amount.
Drug release determination：It is provided by 2010 editions Chinese Pharmacopoeias, C14H10Cl2NNaO2 piece 6 is taken respectively, first in 750mL 0.1M
Hydrochloric acid solution in discharge 2h, add the 250mL phosphate buffer (Na containing 0.2M3PO4), make pH 6.8, turning basket revolving speed is
100r/min, medium temperature are 37 DEG C, are operated according to Chinese Pharmacopoeia (2010 editions) dissolution method Rotating shaker, in 0.5,1,2,
3, dissolution fluid 10mL filtering is measured when 4,5,6,7,8,9h respectively, and above-mentioned solvent 10mL is replenished in time, takes subsequent filtrate 8mL,
Trap is measured at 276nm wavelength, finally calculates the Accumulation dissolution of each sample point C14H10Cl2NNaO2, releasing curve diagram is shown in figure
4。
By 2 prescription of table, by C14H10Cl2NNaO2 and other auxiliary materials and mixings in addition to lubricant, it is 50% that volume fraction, which is added,
The appropriate wet granulation of ethanol water, dry under the conditions of 50 DEG C after crossing 16 meshes, same to mesh sieve, after lubricant mixing is added
Tabletting is carried out, the hardness of tablet is about 90N, measures average slice weight 0.2511g, and tablet weight variation meets States Pharmacopoeia specifications.Ibid method is surveyed
Determine dissolution of sustained-release tablets, releasing curve diagram is shown in Fig. 5.
The prescription of 1 dry granulation of table
Every C14H10Cl2NNaO2 containing 75mg.It was uniformly mixed 16 mesh nylon mesh pelletizing press sheets；40 are pressed altogether.
The prescription of 2 wet granulation of table
Embodiment 9：The research (wet granulation tableting) of Propranolol Hydrochloride hydroxyethyl pachyman sustained release tablets
By the mixing of 8g Propranolol Hydrochloride and 21.5g hydroxyethyl pachyman powder, it is 70% that volume fraction, which is added,
Appropriate ethanol water, wet granulation is dry under the conditions of 50 DEG C after crossing 16 meshes, and lubricant stearic acid is added in same mesh sieve
Magnesium 500mg carries out tabletting, theoretical slice weight 0.30g after mixing.Measure practical 0.3012 ± 0.0361g of slice weight, hardness for 91.7 ±
0.3N, tablet weight variation, face shaping etc. meet States Pharmacopoeia specifications.
The determination of absorbing wavelength：Add dissolution medium that certain density solution is made, according to spectrophotometry (Chinese Pharmacopoeia 2010
Year two annex IV A of version) it is scanned in 200-400nm wave-length coverage, ultraviolet spectrogram is drawn, determines that maximum absorption wave is a length of
290nm takes each right amount of auxiliary materials that the analog sample without main ingredient is made in prescription ratio, scans, determines auxiliary after adding dissolution medium to dissolve
Material does not interfere absorption of the main ingredient at maximum wavelength.
The foundation of standard curve：The bulk pharmaceutical chemicals that precision weighs after purification are appropriate, respectively with the people of 0.1M hydrochloric acid or pH 6.8
Work intestinal juice is configured to 40mgL-1Standard Reserving Solution draws the stock solution 0.8,2,4,6,8,10mL respectively, is placed in 10mL capacity
In bottle.It is diluted to scale with the simulated intestinal fluid of the hydrochloric acid of 0.1M or pH 6.8, is configured to the solution of series of concentrations.In 290nm wave
Strong point surveys trap, carries out linear regression to trap with concentration, obtains regression equation.Propranolol Hydrochloride is in 3.2~40 μ g/mL
There is good linear relationship in range.Wherein the hydrochloric acid solution standard curve of pH1.2 is：C=0.0198A+0.0093 (R2=
0.9996, n=6), the simulated intestinal fluid standard curve regression equation of pH 6.8 is：C=0.0168A+0.253 (R2=
0.9996, n=6).
Assay：Take test sample 20, it is accurately weighed, it is finely ground, take fine powder appropriate, it is accurately weighed, it is placed in 500mL measuring bottle
In, add distilled water to dissolve and be diluted to scale, shake up, filter, discard primary filtrate, precision measures subsequent filtrate 1.0mL in 10mL amount
In bottle, adds distilled water to be diluted to scale, shake up, as test solution；It separately takes Propranolol Hydrochloride i.e. reference substance appropriate, adds steaming
Distilled water dissolution, is diluted to scale, the solution of the hydrochloric Propranolol 0.016mg of every 1mL is made, as reference substance solution.Respectively
Test solution and control solution are taken, according to ultraviolet spectrophotometry (Chinese Pharmacopoeia I VA of version annex in 2010), in 290nm wave
Strong point measures trap, calculates content using reference substance comparison method.Labelled amount is 80mg, and the content for measuring Propranolol Hydrochloride is
The 101.3% of labelled amount.
Drug release determination：It is provided by 2010 editions Chinese Pharmacopoeias, propranolol hydrochloride tablets 6 is taken respectively, first in 750mL
2h is discharged in the hydrochloric acid solution of 0.1M, adds the 250mL phosphate buffer (Na containing 0.2M3PO4), make pH 6.8, turns basket and turn
Speed is 100r/min, and medium temperature is 37 DEG C, is operated according to Chinese Pharmacopoeia (2010 editions) dissolution method Rotating shaker, in 0.5,
1, dissolution fluid 5mL filtering is measured when 2,3,4,5,6,7,8,9h respectively, and above-mentioned solvent 5mL is replenished in time, takes subsequent filtrate 3mL,
Trap is measured at 290nm wavelength, finally calculates the Accumulation dissolution of each sample point Propranolol Hydrochloride, releasing curve diagram
See Fig. 6.
Figure 4, it is seen that the In-vitro release curves of dry granulation show that HEP has certain slow-release capability, with HEP
The increase of dosage, slow-release capability enhancing, when slow-release time reaches 9h, release is less than 50%.And the body of wet granulation
Outer releasing result shows that HEP has preferable slow-release capability, with the increase of HEP dosage, slow-release capability enhancing, when the place of HEP
When side's amount is 50mg, slow release effect is better than the HPMC effect of 100mg, and the prescription of the HEP of 125mg and 175mg are in 9h
Its release is less than 10%.
Studies have shown that disintegration and fragmentation do not occur for tablet, but form hydrophilic gel during sustained drug release
Skeleton (see Fig. 3), supplemented by the release of drug is dissolved based on spreading from hydrogel matrix, with gel surface.From Fig. 4 and
It is found that HEP has preferable sustained release performance to C14H10Cl2NNaO2 in Fig. 5, and the slow release effect of its wet process tabletting will be significantly better than
The slow release effect of compressing dry granulation.It can also be seen that either dry method or wet process tabletting from Fig. 4 and Fig. 5, with HEP dosage
Increase, cumulative in vitro release equilibrium concentration gradually decreasing, slow release effect enhancing, this shows the increase with HEP concentration,
HEP gelling ability is gradually increasing, and the burst size of drug gradually decreases, slow releasing function enhancing.
It can be seen that Propranolol Hydrochloride hydroxyethyl pachyman piece has significant slow release effect in Fig. 6.
Above-mentioned experiment shows that hydroxyethyl pachyman is a kind of excellent hydrophilic gels sustained-release matrix material, powder
With good mobility and compressibility, it is able to satisfy the basic demand of tablet manufacturing.In addition, as prepared by hydroxyethyl pachyman
Medicament slow release preparation in gastro-intestinal Fluid, drug can reach slow release, therefore the slow-release auxiliary material is particularly suitable as hydrophily
The slow-release auxiliary material of drug, auxiliary material is constituted in addition to hydroxyethyl pachyman can also include lubricant, wetting agent, diluent in preparation
Or the ingredients such as other sustained-release matrix materials, the sustained release performance of drug can by hydroxyethyl pachyman molecular weight, degree of substitution or
Diluent is adjusted.
In short, hydroxyethyl pachyman powder prepared by the present invention has extensively as a kind of hydrophilic gel sustained-release matrix material
Wealthy application prospect, sustained release performance can pass through the composition of the degree of substitution of high molecular material, the size of molecular weight and auxiliary material
It is adjusted, using hydroxyethyl pachyman as sustained-release matrix material, most of drug can be made hardly to discharge under one's belt, mainly
Carrier in enteron aisle slow release, particularly suitable for unstable drug in gastric acid.
Above in conjunction with embodiment, the embodiments of the present invention are described in detail, but the present invention is not limited to above-mentioned realities
Mode is applied, it within the knowledge of one of ordinary skill in the art, can also be before not departing from present inventive concept
It puts and makes a variety of changes.
Claims (3)
1. a kind of preparation method of hydroxyethyl pachyman sustained release tablets, which is characterized in that include the following steps：
(1) hydroxyethyl pachyman powder is taken, 16-60 mesh is crossed, is mixed with fine drug powder and auxiliary material A；
(2) lubricant is added in (i), and direct powder compression prepares sustained release tablets；Or wetting agent, wet granulation tableting system is added in (ii)
Standby sustained release tablets；
Wherein, hydroxyethyl pachyman accounts for the 10-90% of gross mass, the auxiliary material A be one of adhesive, diluent or
It is a variety of；
The hydroxyethyl pachyman powder is prepared by the preparation method of following hydroxyethyl pachyman powder：
1. under the conditions of 0-10 DEG C, pachymaran after purification is dissolved in sodium hydroxide/urea liquid, mole, which is slowly added dropwise, is
1-20 times of pachymaran of ethylene chlorhydrin is warming up to 60 DEG C of reaction 0.5-5 after room temperature reaction was greater than 0 hour less than or equal to 5 hours
Hour, then the ethylene chlorhydrin that mole is 0-10 times of pachymaran is slowly added dropwise, the reaction was continued 0-5 hours；
2. being adjusted with acid reaction solution after reaction solution is cooled to room temperature to neutrality, filter, filtrate molecular cut off is 10000
Bag filter dialysis, dialyzate are concentrated into the 1/3~1/5 of original volume with the ultrafiltration membrane that molecular cut off is 1000-10000, make dense
The concentration of ethoxy Poria cocos is 5-50wt% in contracting liquid, and the material of the ultrafiltration membrane is cellulose acetate or polyvinyl alcohol；
One of 3. in the following manner：(i) ethyl alcohol is added into concentrate to be precipitated, is centrifuged, vacuum drying；(ii) sharp
It is with spray dryer that concentrate is dry；Or (iii) is dry by concentrate using fluidized bed, obtaining molar substitution is 0.1-
8.0 hydroxyethyl pachyman powder.
2. the preparation method of hydroxyethyl pachyman sustained release tablets according to claim 1, it is characterised in that：The wetting
Agent is the ethanol water that volume fraction is 50%-90%.
3. a kind of hydroxyethyl pachyman sustained release tablets, which is characterized in that by hydroxyethyl pachyman of any of claims 1 or 2
The preparation method of sustained release tablets is prepared.
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| CN115521386A (en) * | 2022-08-18 | 2022-12-27 | 安徽中医药大学 | Novel pharmaceutic adjuvant pachyman alkaline solution polysaccharide and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1840197A (en) * | 2006-01-12 | 2006-10-04 | 武汉大学 | Application of pachyman as disintegrating agent in preparation of medicinal tablet |
| CN103027930A (en) * | 2012-12-22 | 2013-04-10 | 普洱淞茂制药股份有限公司 | Biomass composition capable of forming and slowly releasing short-molecular polysaccharide, preparation method and preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1840197A (en) * | 2006-01-12 | 2006-10-04 | 武汉大学 | Application of pachyman as disintegrating agent in preparation of medicinal tablet |
| CN103027930A (en) * | 2012-12-22 | 2013-04-10 | 普洱淞茂制药股份有限公司 | Biomass composition capable of forming and slowly releasing short-molecular polysaccharide, preparation method and preparation thereof |
Non-Patent Citations (2)
| Title |
|---|
| Novel biodegradable hydrogels based on pachyman and its derivatives for drug delivery;Yan Hu et al.;《International Journal of Pharmaceutics》;20081227;第371卷;摘要，第2.1-2.2、2.7、3.1、3.5节 * |
| 海藻酸钠与羟乙基茯苓多糖复合凝胶球的制备及性能;胡燕 等;《材料科学与工程学报》;20120630;第30卷(第3期);第2.2.1、4节 * |
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