CN104382875B - A kind of pantoprazole sodium enteric tablet and preparation method thereof - Google Patents
A kind of pantoprazole sodium enteric tablet and preparation method thereof Download PDFInfo
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- CN104382875B CN104382875B CN201410603202.5A CN201410603202A CN104382875B CN 104382875 B CN104382875 B CN 104382875B CN 201410603202 A CN201410603202 A CN 201410603202A CN 104382875 B CN104382875 B CN 104382875B
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Abstract
The invention provides a kind of pantoprazole sodium enteric tablet, it is made by Pantoprazole Sodium plain piece outsourcing separation layer, enteric layer, the Pantoprazole Sodium plain piece is made up of the composition of following percentage by weight：Pantoprazole Sodium 35~45%, filler 30~59%, adhesive 0.2~3%, disintegrant 8.1~18%, stabilizer 5~15%, lubricant 0.2~1.5%.The present invention provides pantoprazole sodium enteric tablet and preparation method thereof, and its stripping curve under four kinds of dissolution mediums is consistent with original triturate, meets the requirement of Conformance Assessment, and stability is better than former triturate.
Description
Technical field
The present invention relates to a kind of technical field of medicine, and in particular to a kind of pantoprazole sodium enteric tablet and its preparation side
Method.
Background technology
Pantoprazole Sodium (trade name Pantoloc) is the 3rd proton listed after Omeprazole and Lansoprazole
Pump inhibitor, because substituted radical of the Pantoprazole Sodium on pyridine ring and benzimidazole ring and Omeprazole and Lansoprazole have
Institute is different, so as to determine its difference in properties such as biochemistry, pharmacokinetics, pharmacology, makes it have stronger selectivity
And otherness.That is, Pantoprazole Sodium can specifically suppress secretory micro-pipe and the intracytoplasmic pipe that parietal cell top film is constituted
H on shape bubble+、K+- ATP enzyme, causes the suppression of the enzyme irreversibility, so that the effectively secretion of gastric acid inhibitory, can not only be non-competing
Striving property suppresses gastrins, histamine, gastric acid secretion caused by choline, and can suppress not influenceed by choline or H2 receptor blocking pharmacons
Part basis gastric acid secretion, gastric acid secretion is effectively reduced, for treating duodenal ulcer, gastric ulcer, reflllx oesophagus
Scorching and Zollinger-Eillison syndrome, particularly for ulcer to be with bleeding, vomiting or can not feed and telephium and acute pancreatitis
Deng.Pantoprazole sodium enteric tablet is the common drug for treating the disease of digestive systems such as gastric ulcer, is widely used in clinic.
The chemical entitled 5- difluoro-methoxies -2- of Pantoprazole Sodium (pantoprazole sodium) [(3,4- dimethoxys -
2- pyridine radicals) methyl] sulfinyl-1 H-benzimidazole sodium salt, molecular weight is 423.38, and molecular formula is C16H14F2N3NaO4S·
H2O, structural formula is as follows：
The Chinese invention patent of Application No. 201310025427.2 discloses a kind of pharmaceutical composition of Pantoprazole Sodium
And preparation method thereof.Contain Pantoprazole Sodium, sodium chloride and excipient, wherein Pantoprazole Sodium in the pharmaceutical composition：Chlorination
Sodium：The weight ratio of excipient is 10:1~5:5~20, preferably 10:1~3:8~16.Excipient is selected from mannitol, glucose, the right side
At least one of the sugared acid anhydride of rotation, sorbierite, lactose, preferably mannitol or sorbierite.The patent uses freeze-dried powder, solve because
The problem of species or consumption of addition auxiliary material excessively influence stability.
The Chinese invention patent of Application No. 201210592375.2 discloses a kind of pantoprazole sodium enteric tablet and its system
Preparation Method, the tablet includes Pantoprazole Sodium plain piece, separation layer and enteric layer.Pantoprazole Sodium plain piece is by main ingredient Pantoprazole Sodium
With auxiliary material composition, auxiliary material then includes filler, disintegrant, lubricant, adhesive, pH adjusting agent etc..The patent, which is accelerated, dissolves support
The disintegration time of azoles sodium enteric tablet is drawn to solve the problem of medicine is unstable during storing simultaneously.
Above-mentioned two patented invention purposes are provided to solve the stability problem of medicine, but it is not made in patent
Agent carries out the investigation of stripping curve, is unanimously still not clear so whether the release behavior of product grinds with original.
The Chinese invention patent of Application No. 201310051580.2 discloses a kind of Levpantoprazole Sodium enteric coatel tablets, it
It is made up of the label containing Levpantoprazole Sodium, separation layer, enteric layer, wherein the gain in weight of separation layer is 2~9%, enteric
The gain in weight of layer is 7~15%.Said preparation main ingredient dissolving 85% or more in 30 minutes, and former triturate (i.e. Japanese military field, specification
40mg) experiments verify that find 30 minutes when main ingredient dissolving be less than 85%, therefore can confirm the patent provide enteric coatel tablets with
The release behavior of former triturate is inconsistent, that is to say, that the enteric coatel tablets and the requirement for not meeting imitation medicine Conformance Assessment.
The Chinese invention patent of Application No. 201410207157.1 disclose a kind of S-pantoprazole sodium enteric tablet and its
Preparation method, the enteric coatel tablets are made by S-pantoprazole sodium label outsourcing separation layer, enteric layer；Label includes following weight percent
The composition of ratio：S-pantoprazole sodium 15~20%, filler 60~75%, adhesive 0.2~1%, disintegrant 2~8% is stable
Agent 4~10%, lubricant 0.2~1%；The weightening of separation layer is the 1~10% of label weight, and the weightening of enteric layer is plate core weight
The 8~18% of amount.It can deduce from the patent, the specification of its enteric coatel tablets is 20mg, the preparation that release behavior is ground with the auspicious enlightening original of India
Compare (product specification of the auspicious enlightening of India is 20mg, and compared with the 40mg products in Japanese military field, stripping curve is different), belong to India
The Chinese imitation medicine of auspicious enlightening；In addition, understanding the product not in strict accordance with China from embodiment《Imitation medicine uniformity is commented
Valency》Requirement carry out four kinds of dissolution mediums under stripping curve compare, do not meet the quality control requirement of national regulation.
Issued according to State Council《National drug safety " 12 " planning》And state food pharmaceuticals administration general bureau
Issue《Notice on 2013 annual imitation medicine quality conformance study on evaluation way tasks》, it is desirable to domestic imitation medicine from now on
Exploitation must strictly carry out the quality conformance evaluation of imitation medicine, that is, need carry out four kinds of dissolution mediums under stripping curve ratio
Compared with to improve the quality level of domestic imitation medicine product.
In summary, how a kind of former product that triturate dissolved corrosion is consistent, stability is high with Japanese military field is provided,
It is the technical barrier that current numerous domestic pharmacist not yet captures.
The content of the invention
It is an object of the invention to provide it is a kind of it is consistent with original triturate dissolved corrosion, meet Conformance Assessment requirement, and
Stability is better than the pantoprazole sodium enteric tablet of former triturate, and solves the defect of prior art presence.
The inventor of present patent application has found through experiment：The former triturate (Japan's force field, specification 40mg) of Pantoprazole Sodium
It is unstable under sour environment and more sensitive to light, heat, the increase of impurity content is easily caused, and containing the crystallization water, therefore inhale
It is moist relatively strong, the dissolved corrosion of preparation is also had a certain impact.
As stated in the Background Art, the pantoprazole sodium enteric tablet technology involved by the document such as presently disclosed patent, periodical,
All it is prescription component by adjusting Pantoprazole Sodium plain piece and consumption this thinking, to improve the stability of medicine, improve medicine
The dissolution rate of thing, does not accomplish that its dissolution is consistent with the dissolved corrosion of former triturate though having and improving, does not meet the one of imitation medicine
The evaluation requirement of cause property.
Therefore, the present invention looks for another way, and changes a kind of Research idea to solve the above problems, thinking is specific as follows：1. pass through
Coating material and the weightening of separation layer and enteric layer are screened, to control the dissolution time of pantoprazole sodium enteric tablet, makes medicine
Release profiles more they tend to former triturate；2. by adjusting the Parameter Conditions of granulation and art for coating, to control Pantoprazole Sodium intestines
The water content of molten, it is to avoid influence the stability and dissolved corrosion of medicine because of the hygroscopicity of main ingredient Pantoprazole Sodium；3. pass through
Optimize the auxiliary material and consumption, preparation technology of Pantoprazole Sodium plain piece, and with 1., 2. collective effect, come control the disintegration of medicine with
Dissolution, complies with Conformance Assessment requirement.
To realize above-mentioned Research idea, the technical solution adopted in the present invention is specific as follows：
A kind of pantoprazole sodium enteric tablet, is made, Pantoprazole Sodium by Pantoprazole Sodium plain piece outsourcing separation layer, enteric layer
Plain piece is made up of the composition of following percentage by weight：Pantoprazole Sodium 35~45%, filler 30~59%, adhesive 0.2~
3%, disintegrant 8.1~18%, stabilizer 5~15%, lubricant 0.2~1.5%；The coating material of separation layer is pharmaceutically may be used
One or more in the film forming auxiliary material hydroxypropyl methyl cellulose of receiving, hydroxypropyl cellulose, PVP, coating solvent is
50% ethanol, coating weight gain is the 6~12% of Pantoprazole Sodium plain piece；The coating material of enteric layer is acrylic copolymer, bag
Clothing solvent is purified water, and coating weight gain (based on enteric materials) is the 6~18% of spacer.
It is preferred that, the coating material of separation layer is hydroxypropyl methyl cellulose or hydroxypropyl cellulose, the coating of enteric layer
Material is 1:1 methacrylic acid and ethyl acrylate copolymer.
It is preferred that, 50% ethanol solution of the adhesive selected from 16% PVP K30, the aqueous solution of 10% hydroxypropyl, 10%
One or more in 50% ethanol solution of PVP；50% ethanol solution of more preferably 16% PVP K30.
It is preferred that, one or more of the filler in lactose, microcrystalline cellulose, mannitol, starch, dextrin；It is more excellent
Elect the mixing of microcrystalline cellulose and mannitol as, the weight ratio of microcrystalline cellulose and mannitol is 1:1~1:4.
It is preferred that, disintegrant is selected from Ac-Di-Sol, PVPP, sodium carboxymethyl starch, low substitution hydroxyl
One or more in propyl cellulose；The more preferably mixing of PVPP and sodium carboxymethyl starch, PVPP and
The weight ratio of sodium carboxymethyl starch is 1:1~2:1.
It is preferred that, one kind in sodium carbonate, natrium carbonicum calcinatum, sodium acid carbonate, saleratus, magnesia of stabilizer or
It is several；More preferably natrium carbonicum calcinatum or magnesia.
It is preferred that, one or more of the lubricant in magnesium stearate, calcium stearate, silica, talcum powder；It is more excellent
Elect magnesium stearate as.
It is preferred that, Pantoprazole Sodium plain piece is made up of the composition of following percentage by weight：Pantoprazole Sodium 35~45%, is filled out
Fill agent 40~51.5%, adhesive 1.5~2.5%, disintegrant 9~15%, stabilizer 6~12%, lubricant 0.5~1.5%；
Wherein filler is that weight compares 1:The mixing of 4 microcrystalline cellulose and mannitol, adhesive is 50% second of 16% PVP K30
Alcoholic solution, disintegrant is that weight compares 2:The mixing of 1 PVPP and sodium carboxymethyl starch, stabilizer is natrium carbonicum calcinatum,
Lubricant is magnesium stearate；The coating material of separation layer is hydroxypropyl methyl cellulose, and coating solvent is 50% ethanol, is coated and increases
Weight is the 6~10% of Pantoprazole Sodium plain piece；The coating material of enteric layer is Utech L30D-55 or Eudragit L100-55, bag
Clothing solvent is purified water, and coating weight gain (based on enteric materials) is the 8~14% of spacer.
A kind of preparation method of pantoprazole sodium enteric tablet, comprises the following steps：
(1) preparation of Pantoprazole Sodium plain piece：Take Pantoprazole Sodium, filler, stabilizer, the interior plus disintegrant of recipe quantity
It is placed in wet mixing pelletizer, stirring mixing；Then the adhesive softwood of recipe quantity is added, shear granulation is stirred, dried,
18 mesh sieve whole grains are crossed, additional lubricant and disintegrant in whole grain；Total mixed, tabletting, obtains Pantoprazole Sodium plain piece again；
(2) coating of separation layer：Spacer layer coating material is taken to be dissolved in 50% ethanol, one added in opacifier, antiplastering aid
Plant or several, be uniformly mixing to obtain isolation coat liquid；Pantoprazole Sodium plain piece obtained by step (1) is placed in coating pan, controlled
Rotating speed spray isolation coat liquid processed is coated so that the coating weight gain of separation layer is the 6~12% of plain piece, and 15 points of heated-air drying
Clock；
(3) coating of enteric layer：Enteric layer coating material is taken to be dissolved in purified water, the one kind added in plasticizer, antiplastering aid
Or it is several, it is uniformly mixing to obtain casing coating solution；Control rotating speed spray casing coating solution, to step (2) be coated after separation layer after
It is continuous to be coated so that the coating weight gain (based on enteric materials) of enteric layer is the 6~18% of spacer；Dry, obtain finished product；
Opacifier is titanium dioxide, and antiplastering aid is the one or more in talcum powder, magnesium stearate；Plasticizer is poly- second two
One or more in alcohol 6000, PEG 8000, triethyl citrate.
It is preferred that, the temperature that step (1), (2) and (3) is dried is 30~50 DEG C, more preferably 40 DEG C；Step (1) wet method
The mixing speed of granulation is 100~120 revs/min, and cutting speed is 1000~1500 revs/min；The tabletting of step (1) is used
7mm scrobicula circular dies.
The prescription and preparation method for the pantoprazole sodium enteric tablet that the present invention is provided, have the following advantages that：
1st, the suitable coating material of present invention screening and consumption prepare separation layer, enteric layer, with reference to prescription component and content
Screening and optimizing (prescription of prescription of the invention and former triturate is otherwise varied), obtained enteric coatel tablets are under four kinds of dissolution mediums
Its stripping curve is all higher than 50 (i.e. explanation is consistent with the dissolution of former triturate) with the similar factors F2 of former triturate, with original development
Agent bioequivalence, meets Conformance Assessment requirement.It has developed under conditions of patent conflict is avoided creative exclusive
Preparation prescription.
2nd, the preparation technology that the present invention is provided, by drying temperature control in 40 DEG C, adhesive using 16% PVP K30
50% ethanol solution, coating solvent are solved main ingredient and dissolved using the amount of many means such as 50% ethanol, all the time strict control moisture
Support drawing azoles sodium preparation stability because caused by hygroscopicity is strong is low, the unmanageable technological deficiency of stripping curve；The system of the present invention
Agent stability is better than former triturate.
3rd, the present invention adds specific auxiliary material (such as plasticizer, antiplastering aid) so that piece when separation layer, enteric layer are coated
Son is more easy to moulding, is easy to follow-up coating.
4th, spacer layer coating of the invention both ensure that coating effect using 50% ethanol as coating solvent, reduce again
The consumption of water so that invention formulation reduces the contact with water, while improving coating efficiency, also improve product matter
Amount.
5th, wet granulation of the invention both ensure that granulation effect using the ethanol of 16% PVP K30 50% as adhesive
Really, the consumption of water is reduced again so that invention formulation reduces the contact with water, while improving drying efficiency.
6th, the laminated structure of former triturate is elliptical piece, because the prescription of its design is not suitable for doing circular piece, present invention warp
Prescription screening, process parameter optimizing are crossed, circular piece can be made, more meets the oral custom of Chinese；And the circle worked it out
The unilateral light of shape piece is clean and tidy, more meets the visual examination standard of pharmacopeia.
Brief description of the drawings
Fig. 1 is the stripping curve comparison diagram under PH=6.0 media
Fig. 2 is the stripping curve comparison diagram under PH=6.8 media
Fig. 3 is the stripping curve comparison diagram under PH=1.2 media
Fig. 4 is the stripping curve comparison diagram under purifying aqueous medium
Embodiment
The preparation of the pantoprazole sodium enteric tablet of embodiment 1
1st, the component and content of Pantoprazole Sodium plain piece
| Supplementary material title | 1000 (g) | Accounting (%) | Effect |
| Pantoprazole Sodium | 44.3 | 35.00 | Main ingredient |
| Mannitol | 44.00 | 34.76 | Filler |
| Microcrystalline cellulose | 11.00 | 8.70 | Filler |
| Sodium carboxymethyl starch (interior to add) | 4.85 | 3.83 | Disintegrant |
| Natrium carbonicum calcinatum | 9.56 | 7.55 | Stabilizer |
| PVPP (additional) | 9.71 | 7.67 | Disintegrant |
| The ethanol solution of 16% PVP K30 50% | 15.75 | 1.99 | Adhesive |
| Magnesium stearate (additional) | 0.63 | 0.50 | Lubricant |
2nd, the component and content of separation layer
| Auxiliary material title | Accounting (%) | Effect |
| Hydroxypropyl methyl cellulose | 31.25 | Every clothing material |
| Titanium dioxide | 18.75 | Opacifier |
| Talcum powder | 50 | Antiplastering aid |
| 50% ethanol | Prepare 8%HPMC50% ethanol solutions | Coating solvent |
The coating weight gain of separation layer is the 8% of plain piece weight.
3rd, the component and content of enteric layer
| Auxiliary material title | Effect | |
| Utech L30D-55 | Amount of polymer solids is the 12% of separation layer | Enteric materials |
| Macrogol 6000 | For the 10% of amount of polymer solids | Plasticizer |
| Purified water | Prepared polymer solid content is 16% | Coating solvent |
The coating weight gain of enteric layer is calculated as separation layer 12% by enteric materials；Utech L30D-55 be methacrylic acid and
Ethyl acrylate (1:1) copolymer.
4th, preparation method：
(1) preparation of Pantoprazole Sodium plain piece：By the Pantoprazole Sodium of above-mentioned recipe quantity, mannitol, microcrystalline cellulose, nothing
Aqueous sodium carbonate, carboxyrnethyl starch sodium are placed in wet mixing pelletizer, first set mixing speed as 100 revs/min (i.e. r/min, under
Together), cutting speed is 1000r/min, is stirred mixing about 10min；Add 16% PVP K30 of above-mentioned recipe quantity
50% ethanol solution softwood；Mixing speed is reset for 120r/min, cutting speed is 1500r/min, is stirred granulation
About 3min, discharging, with 18 eye mesh screens on oscillating granulator whole wet granular；EAT is set as 40 DEG C, control moisture is extremely
1.0~3.0%, with 18 eye mesh screen whole grains after blanking, PVPP, magnesium stearate are added in whole grain, dry particl is obtained.Then
Obtained dry particl is all placed in Mixers with Multi-direction Movement, always mixed about 10min.7mm scrobicula shapes are finally used on tablet press machine
Drift, tabletting is carried out according to granule content.
(2) coating of separation layer：By plain piece weightening 8%, isolation coat liquid is prepared；Weigh the hydroxypropyl first of above-mentioned recipe quantity
Base cellulose (i.e. HPMC, similarly hereinafter) is dissolved in 50% ethanol, adds titanium dioxide, talcum powder, is uniformly mixing to obtain isolation coat liquid；
Then the Pantoprazole Sodium plain piece after tabletting is put in coating pan, isolation coat liquid bag is sprayed after rotating preheating 5min, adjustment rotating speed
Clothing, controls the spray speed of isolation coat liquid, adhesion is defined between piece, after coating terminates, and heated-air drying 15min is used in continuation.
(3) coating of enteric layer：By spacer 12% (based on enteric materials) of weightening, casing coating solution is prepared；Weigh
The Utech L30D-55 for stating recipe quantity is dissolved in purified water, adds Macrogol 6000, is uniformly mixing to obtain casing coating solution；Turn
Casing coating solution is sprayed after dynamic preheating 5min, adjustment rotating speed, this product after bag barrier gown is continued to be coated, control casing coating solution
Spray speed, adhesion is defined between piece, after coating terminates, and heated-air drying 0.5h is used in continuation, produces pantoprazole sodium enteric tablet finished product.
The preparation of the pantoprazole sodium enteric tablet of embodiment 2
(1) component and content of Pantoprazole Sodium plain piece
| Supplementary material title | 1000 (g) | Accounting (%) | Effect |
| Pantoprazole Sodium | 44.3 | 45 | Main ingredient |
| Mannitol | 14.77 | 15 | Filler |
| Microcrystalline cellulose | 14.77 | 15 | Filler |
| Sodium carboxymethyl starch (interior to add) | 8.86 | 9 | Disintegrant |
| Natrium carbonicum calcinatum | 4.92 | 5 | Stabilizer |
| PVPP (additional) | 8.86 | 9 | Disintegrant |
| The ethanol solution of 16% PVP K30 50% | 9.23 | 1.5 | Adhesive |
| Magnesium stearate (additional) | 0.49 | 0.5 | Lubricant |
(2) component and content of separation layer
The coating weight gain of separation layer is the 6% of plain piece.
(3) component and content of enteric layer
| Auxiliary material title | Effect | |
| Utech L30D-55 | Amount of polymer solids is the 18% of separation layer | Enteric materials |
| Triethyl citrate | For the 10% of amount of polymer solids | Plasticizer |
| Purified water | Prepared polymer solid content is 12% | Coating solvent |
The coating weight gain of enteric layer is calculated as the 18% of separation layer by enteric materials；Utech L30D-55 is methacrylic acid
With ethyl acrylate (1:1) copolymer.
(4) preparation method：
Replaced with the plasticizer in hydroxypropyl cellulose, enteric layer is replaced with every clothing material in above-mentioned prescription separation layer
Triethyl citrate, EAT when prepared by Pantoprazole Sodium plain piece is set as 30 DEG C, remaining preparation method be the same as Example 1.
The preparation of the pantoprazole sodium enteric tablet of embodiment 3
(1) component and content of Pantoprazole Sodium plain piece
| Supplementary material title | 1000 | Accounting (%) | Effect |
| Pantoprazole Sodium | 44.3 | 35 | Main ingredient |
| Mannitol | 52.14 | 41.2 | Filler |
| Microcrystalline cellulose | 13.04 | 10.3 | Filler |
| Sodium carboxymethyl starch (additional) | 3.42 | 2.7 | Disintegrant |
| Magnesia | 6.33 | 5 | Stabilizer |
| PVPP (interior to add) | 6.83 | 5.4 | Disintegrant |
| The ethanol solution of 2% PVP K30 50% | 12.66 | 0.2 | Adhesive |
| Magnesium stearate (additional) | 0.25 | 0.2 | Lubricant |
(2) component and content of separation layer
| Auxiliary material title | Accounting (%) | Effect |
| Hydroxypropyl methyl cellulose | 31.25 | Every clothing material |
| Titanium dioxide | 18.75 | Opacifier |
| Magnesium stearate | 50 | Antiplastering aid |
| 50% ethanol | Prepare 6%HPMC50% ethanol solutions | Coating solvent |
The coating weight gain of separation layer is the 12% of plain piece.
(3) component and content of enteric layer
| Auxiliary material title | Effect | |
| Eudragit L100-55 | Amount of polymer solids is the 6% of separation layer | Enteric materials |
| Macrogol 6000 | For the 10% of amount of polymer solids | Plasticizer |
| Purified water | Prepared polymer solid content is 15% | Coating solvent |
The coating weight gain of enteric layer is calculated as the 6% of separation layer by enteric materials；Eudragit L100-55 be methacrylic acid and
Ethyl acrylate (1:1) copolymer.
(4) preparation method：
Enteric materials stabilizer in above-mentioned prescription Pantoprazole Sodium plain piece replaced with magnesia, enteric layer are replaced
For Eudragit L100-55, EAT when prepared by Pantoprazole Sodium plain piece is set as 50 DEG C, remaining preparation method be the same as Example
1。
The preparation of the pantoprazole sodium enteric tablet of embodiment 4
(1) component and content of Pantoprazole Sodium plain piece
| Supplementary material title | 1000 (g) | Accounting (%) | Effect |
| Pantoprazole Sodium | 44.30 | 35.00 | Main ingredient |
| Mannitol | 37.97 | 30.00 | Filler |
| Microcrystalline cellulose | 12.66 | 10.00 | Filler |
| Sodium carboxymethyl starch (additional) | 3.48 | 2.75 | Disintegrant |
| Sodium acid carbonate | 18.99 | 15.00 | Stabilizer |
| PVPP (interior to add) | 3.48 | 2.75 | Disintegrant |
| The ethanol solution of 16% PVP K30 50% | 23.75 | 3.00 | Adhesive |
| Silica (additional) | 1.90 | 1.50 | Lubricant |
(2) component and content of separation layer
| Auxiliary material title | Accounting (%) | Effect |
| Hydroxypropyl methyl cellulose | 30 | Every clothing material |
| Titanium dioxide | 10 | Opacifier |
| Talcum powder | 60 | Antiplastering aid |
| 50% ethanol | Prepare 5%HPMC50% ethanol solutions | Coating solvent |
The coating weight gain of separation layer is the 10% of plain piece.
(3) component and content of enteric layer
| Auxiliary material title | Effect | |
| Eudragit L100-55 | Amount of polymer solids is the 8% of separation layer | Enteric materials |
| PEG 8000 | For the 10% of amount of polymer solids | Plasticizer |
| Talcum powder | For the 20% of amount of polymer solids | Antiplastering aid |
| Purified water | Prepared polymer solid content is 12% | Coating solvent |
The coating weight gain of enteric layer is calculated as the 8% of separation layer by enteric materials；Eudragit L100-55 be methacrylic acid and
Ethyl acrylate (1:1) copolymer.
(4) preparation method：
Stabilizer in above-mentioned prescription Pantoprazole Sodium plain piece is replaced with into sodium acid carbonate, lubricant replacement is titanium dioxide
Enteric materials in silicon, enteric layer replace with Eudragit L100-55, and plasticizer replaces with PEG 8000 enteric layer, and system
Increase antiplastering aid during standby enteric layer, remaining preparation method be the same as Example 1.
The preparation of the pantoprazole sodium enteric tablet of embodiment 5
(1) component and content of Pantoprazole Sodium plain piece
| Supplementary material title | 1000 | Accounting (%) | Effect |
| Pantoprazole Sodium | 44.30 | 40.00 | Main ingredient |
| Mannitol | 22.15 | 20.00 | Filler |
| Microcrystalline cellulose | 11.08 | 10.00 | Filler |
| Sodium carboxymethyl starch (additional) | 5.54 | 5.00 | Disintegrant |
| Saleratus | 13.29 | 12.00 | Stabilizer |
| PVPP (interior to add) | 11.08 | 10.00 | Disintegrant |
| The ethanol solution of 16% PVP K30 50% | 17.31 | 2.50 | Adhesive |
| Calcium stearate (additional) | 0.55 | 0.50 | Lubricant |
(2) component and content of separation layer
| Auxiliary material title | Accounting (%) | Effect |
| Hydroxypropyl methyl cellulose | 22.5 | Every clothing material |
| Titanium dioxide | 22.5 | Opacifier |
| Talcum powder | 55 | Antiplastering aid |
| 50% ethanol | Prepare 5%HPMC50% ethanol solutions | Coating solvent |
The coating weight gain of separation layer is the 10% of plain piece.
(3) component and content of enteric layer
| Auxiliary material title | Effect | |
| Utech L30D-55 | Amount of polymer solids is the 14% of separation layer | Enteric materials |
| PEG 8000 | For the 10% of amount of polymer solids | Plasticizer |
| Purified water | Prepared polymer solid content is 12% | Coating solvent |
The coating weight gain of enteric layer is calculated as the 14% of separation layer by enteric materials；Utech L30D-55 is methacrylic acid
With ethyl acrylate (1:1) copolymer.
(4) preparation method：
Stabilizer in above-mentioned prescription Pantoprazole Sodium plain piece is replaced with into saleratus, lubricant replacement is stearic acid
Plasticizer in calcium, enteric layer replaces with PEG 8000, remaining preparation method be the same as Example 1.
The preparation of the pantoprazole sodium enteric tablet of embodiment 6
(1) component and content of Pantoprazole Sodium plain piece
| Supplementary material title | 1000 | Accounting (%) | Effect |
| Pantoprazole Sodium | 44.30 | 40 | Main ingredient |
| Mannitol | 31.01 | 28 | Filler |
| Microcrystalline cellulose | 15.51 | 14 | Filler |
| Sodium carboxymethyl starch (additional) | 4.43 | 4 | Disintegrant |
| Sodium carbonate | 6.65 | 6 | Stabilizer |
| PVPP (interior to add) | 5.54 | 5 | Disintegrant |
| The ethanol solution of 16% PVP K30 50% | 13.87 | 2 | Adhesive |
| Magnesium stearate (additional) | 1.11 | 1 | Lubricant |
(2) component and content of separation layer
The coating weight gain of separation layer is the 10% of plain piece.
(3) component and content of enteric layer
| Auxiliary material title | Effect | |
| Eudragit L100-55 | Amount of polymer solids is the 10% of separation layer | Enteric materials |
| Triethyl citrate | For the 10% of amount of polymer solids | Plasticizer |
| Magnesium stearate | For the 10% of amount of polymer solids | Antiplastering aid |
| Purified water | Prepared polymer solid content is 12% | Coating solvent |
The coating weight gain of enteric layer is calculated as the 10% of separation layer by enteric materials；Utech L30D-55 is methacrylic acid
With ethyl acrylate (1:1) copolymer.
(4) preparation method：
Stabilizer in above-mentioned prescription Pantoprazole Sodium plain piece is replaced with into being replaced every clothing material in sodium carbonate, separation layer
For hydroxypropyl cellulose, the enteric materials in enteric layer replace with Eudragit L100-55, and plasticizer replaces with lemon triethylenetetraminehexaacetic acid
Ester, and increase antiplastering aid when preparing enteric layer, remaining preparation method be the same as Example 1.
The selection of the enteric layer coating material of embodiment 7 is investigated
The present invention is in preliminary experiment, and the selection to the coating material of various enteric layers carries out control investigation, investigates result and sees
Following table：
As seen from the table：Stripping curve and former triturate under the different enteric materials of selection, its four kinds of dissolution mediums
Similarity is far from each other, especially in PH=6.0 medium, the phase of both enteric materials of Opadry 93036628 and L100
Like factor F2<50, illustrate inconsistent with the dissolved corrosion of former triturate, do not meet Conformance Assessment requirement；Enteric materials are only selected
When selecting L30D-55, L100-55, four stripping curves can meet Conformance Assessment requirement, especially to select L30D-55 more preferably.
The selection of the disintegrant of embodiment 8 and the investigation of consumption
1st, the selection of disintegrant and its feed postition is investigated
The present invention is in preliminary experiment, and the selection to disintegrant and its feed postition carries out control investigation, with release inspection
Method checks disintegration time, investigates result and see the table below：
As seen from the table：The plain piece of (additional) preparation of Ac-Di-Sol, disintegration time meets the requirements, but through bag
After clothing under release profiles PH6.8, F2 values are less than 50, therefore preferred PVPP is additional, the interior mode added of carboxyrnethyl starch sodium.
2nd, the investigation of disintegrant consumption
Further, consumption selection of the inventor to disintegrant carries out control investigation, is collapsed with release inspection technique to check
The solution time, and investigate under PH=6.0 and PH=6.8 both media the stripping curve after this preparation is coated and former triturate
Similarity, investigates result and see the table below：
As seen from the table：1. when consumption≤8% of disintegrant (PVPP is additional, carboxyrnethyl starch sodium is interior adds, similarly hereinafter)
Or when >=18%, the similar factors F2 of its stripping curve of obtained preparation and former triturate is less than 50, or disintegration time limited is unqualified,
Such as 1, No. 8 groups；Even if 2. when the consumption of disintegrant is 8.1~18%, but PVPP and carboxyrnethyl starch sodium amount ratio not
1:1~2:When 1, the similar factors F2 of its stripping curve of obtained preparation and former triturate is still less than 50, and such as 6, No. 7 groups；③
When disintegrant consumption is 8.1~18%, PVPP：Carboxyrnethyl starch sodium=1:1~2:When 1, release profiles PH6.0 and
Under PH6.8, the similar factors F2 of the stripping curve of invention formulation and former triturate is all higher than 50, illustrates that dissolved corrosion is ground with original
Unanimously, such as 2,3,4, No. 5 groups；4. wherein, when disintegrant consumption is 12%, PVPP：Carboxyrnethyl starch sodium=2:When 1, one
The best results that cause property is evaluated, i.e., No. 4 groups.
The invention formulation of embodiment 9 and the investigation of the stability test of former triturate
1st, method：The invention formulation of embodiment 1~4 is chosen, with former triturate under same experiment condition, according to country
The method of inspection of drug standards YBH01392014 written instructions, the indices for carrying out stability test are investigated, specific as follows.
1. assay：This product 10 is taken, is removed after film-coating, accurately weighed, finely ground, precision is weighed in right amount, puts 100ml
In measuring bottle, plus appropriate amount of ethanol, shaking makes dissolving, plus ethanol be diluted to scale, shakes up, and filters；Precision measures subsequent filtrate 2ml, puts
In 25ml measuring bottles, plus ethanol is diluted to scale, shakes up.According to UV-VIS spectrophotometry, (Chinese Pharmacopoeia version two in 2010 is attached
Record IV A), trap is determined at 292nm wavelength；It is another to take Pantoprazole Sodium reference substance appropriate, it is accurately weighed, plus ethanol dissolving
And the solution in every 1ml containing about 15 μ g is diluted to, it is measured in the same method, calculates, produce.
2. acid-resistant strength is determined：This product is taken, according to the dissolution method (C first of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ
Method), using hydrochloric acid solution (9 → 1000) 900ml as dissolution medium, rotating speed was 100 turns per minute, is operated in accordance with the law, through 120 minutes,
Tablet is taken out, the acid solution of tablet surface is rinsed with water, tablet is put in mortar, plus ethanol is finely ground and is transferred in 100ml measuring bottles,
Plus ethanol is to scale, shake up, filter, precision measures subsequent filtrate 2ml, puts in 50ml measuring bottles, scale is diluted to ethanol, shake up,
It is used as need testing solution.According to content of the method under assay from " shining UV-VIS spectrophotometry ... ", same to method
Determine, calculate the content of every.Every content must not be less than the 90% of labelled amount in 6；If any 1~2 less than labelled amount
90%, but it is not less than the 80% of labelled amount, its average content must not be less than the 90% of labelled amount；It is less than labelled amount if any 1~2
90%, wherein only 1 be less than labelled amount 80%, but be not less than the 70% of labelled amount, its average content is not less than sign
The 90% of amount, should separately take 6 retrials；Just, 1~3 is less than the 90% of labelled amount in 12 of retrial, wherein only 1 low
In the 80% of labelled amount, but the 70% of labelled amount must not be less than, and average content must not be less than the 90% of labelled amount.
3. drug release determination：This product is taken, according to the drug release determination method (D second of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ
Method), using dissolution method (the first methods of C of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ) device, with hydrochloric acid solution (9 →
1000) 900ml is dissolution medium, and rotating speed is 100 turns per minute, is operated in accordance with the law.Through 120 minutes, basket emersion liquid level will be turned immediately,
Hydrochloric acid solution is discarded, the phosphate buffer that addition immediately is preheated to 37 DEG C (takes 0.1mol/L hydrochloric acid solutions and 0.2mol/L
Sodium radio-phosphate,P-32 solution is well mixed by 3: 1, and regulation pH value to 6.8) 900ml, continuation is operated in accordance with the law, during through 45 minutes, takes solution
10ml, filtration, precision measures subsequent filtrate 4ml, puts in 10ml measuring bottles, adds and states phosphate buffer and be diluted to scale, shakes up, make
For need testing solution.It is appropriate that another precision weighs Pantoprazole Sodium reference substance, adds and states phosphate buffer and make dissolving, and quantitative dilute
The solution for being made and containing 16 μ g in every 1ml is released, reference substance solution is used as.Above two solution is taken, using phosphate buffer as blank,
According to UV-VIS spectrophotometry (two A of annex IV of Chinese Pharmacopoeia version in 2010), trap is determined at 288nm wavelength,
The burst size of calculating every.Limit is the 80% of labelled amount, should meet regulation.
4. about substance-measuring：Determined according to high performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia version in 2010).Its
In, chromatographic condition：Using octadecylsilane chemically bonded silica as filler (chromatogram column type number Kromasil100-5；Specification is
250mm × 4.6mm, or performance are suitable)；With buffer solution [ammonium acetate 3.85g, 4-butyl ammonium hydrogen sulfate 1.1g are weighed, is made into
1000ml solution, pH to 7.9 is adjusted with the solution of ammoniacal liquor-water (1: 1)]-acetonitrile (65: 35) is mobile phase；Flow velocity 1.0ml/
min；Detection wavelength is 290nm；The μ l of sample size 20.
It is 0.36 μ g/ml that impure A, B, C, D+F, E, which is made, with acetonitrile -0.001mol/L sodium hydroxides (1: 1) solution
Solution, the pin of continuous sample introduction 6, each impurity peak area RSD cannot be greater than 10%.
Assay method：Face with newly matching somebody with somebody.Take this product appropriate, it is finely ground, plus acetonitrile -0.001mol/L sodium hydroxides (1:1) solution
The solution of the 0.92mg containing Pantoprazole Sodium in every 1ml is made, filters, takes subsequent filtrate as need testing solution.Precision, which is weighed, dissolves support
Draw azoles sodium reference substance appropriate, be made of acetonitrile -0.001mol/L sodium hydroxides (1: 1) solution in every 1ml and contain Pantoprazole Sodium
0.03mg solution, is used as reference substance solution.Above-mentioned solution is injected into liquid chromatograph, at least recorded to main peak retention time
3 times.The percentage composition of each impurity is calculated with below equation：
100×f×(Cs/Cu)×(ri/rs)×(Mr1/Mr2)
Wherein Cs is the concentration (mg/ml) of Pantoprazole Sodium in reference substance solution；Cu is Pantoprazole in need testing solution
The concentration (mg/ml) of sodium；F is response factor of each impurities phase to Pantoprazole；Ri is need testing solution impurity peak area；Rs is
Pantoprazole peak area in reference substance solution；Mr1 is Pantoprazole molecular weight 383.37；Mr2 is Pantoprazole Sodium molecular weight
405.35.Reporting limit is 0.05%.
2nd, result：The result data of long-term stable experiment see the table below.
As seen from the table：The stability of invention formulation is better than former triturate, and the prescription that embodiment 1 is provided is steady for a long time
Qualitative effect is optimal.
The Conformance Assessment of the invention formulation of embodiment 10 and former triturate
1st, method：The invention formulation of embodiment 1 is chosen, with former triturate under same experiment condition, according to national medicine
The method of inspection of product standard YBH01392014 written instructions, carries out Conformance Assessment investigation, investigates result and sees below：
1. stripping curve of the invention formulation with former triturate under PH=6.0 media is contrasted
The result of stripping curve contrast is as shown in figure 1, through measuring and calculating, under PH6.0 medium, invention formulation is developed with former
The stripping curve similar factors F2=58.14 of agent.
2. stripping curve of the invention formulation with former triturate under PH=6.8 media is contrasted
The result of stripping curve contrast is as shown in Fig. 2 through measuring and calculating, under PH6.8 medium, invention formulation is developed with former
The stripping curve similar factors F2=68.18 of agent.
3. stripping curve of the invention formulation with former triturate under PH=1.2 media is contrasted
The result of stripping curve contrast is as shown in figure 3, through measuring and calculating, under PH1.2 medium, invention formulation is developed with former
The stripping curve similar factors F2=96.43 of agent.
4. stripping curve of the invention formulation with former triturate under purifying aqueous medium is contrasted
The result of stripping curve contrast is as shown in figure 4, through measuring and calculating, under the medium of purified water, invention formulation is ground with original
The stripping curve similar factors F2=97.55 of preparation.
To sum up, conclusion is obtained：Invention formulation is consistent with the dissolved corrosion of former triturate, meets Conformance Assessment requirement.
Claims (4)
1. a kind of pantoprazole sodium enteric tablet, is made, the Pantoprazole by Pantoprazole Sodium plain piece outsourcing separation layer, enteric layer
Sodium plain piece is made up of the composition of following percentage by weight：Pantoprazole Sodium 35 ~ 45%, filler 40 ~ 51.5%, adhesive 1.5 ~
2.5%, disintegrant 9 ~ 15%, stabilizer 6 ~ 12%, lubricant 0.5 ~ 1.5%；Each composition sum is in the Pantoprazole Sodium plain piece
100%；Wherein filler is that weight compares 1:The mixing of 4 microcrystalline cellulose and mannitol, adhesive is 16% PVP K30
50% ethanol solution, disintegrant is that weight compares 2:The mixing of 1 PVPP and sodium carboxymethyl starch, stabilizer is anhydrous carbon
Sour sodium, lubricant is magnesium stearate；
Coating material in the separation layer is hydroxypropyl methyl cellulose, and coating solvent is 50% ethanol；In the enteric layer
Coating material is Utech L30D-55 or Eudragit L100-55, and coating solvent is purified water；
The enteric coatel tablets are prepared as follows and obtained：
（1）The preparation of Pantoprazole Sodium plain piece：Take Pantoprazole Sodium, filler, stabilizer, the interior plus disintegrating agent carboxymethyl of recipe quantity
Base sodium starch, is placed in wet mixing pelletizer, stirring mixing；Then the adhesive softwood of recipe quantity, stirring shearing are added
Granulation, is dried, and crosses 18 mesh sieve whole grains, additional disintegrant PVPP and lubricant in whole grain；Total mixed, tabletting, is obtained again
Pantoprazole Sodium plain piece；
（2）The coating of separation layer：Take spacer layer coating material to be dissolved in 50% ethanol, add opacifier and antiplastering aid, stir
To isolation coat liquid；By step（1）The Pantoprazole Sodium plain piece of gained is placed in coating pan, and control rotating speed spray isolation coat liquid enters
Row is coated so that the coating weight gain of separation layer is the 6% ~ 10% of plain piece, and heated-air drying 15 minutes, obtains being surrounded by dissolving for separation layer
Support draws azoles sodium spacer；
（3）The coating of enteric layer：Take enteric layer coating material to be dissolved in purified water, add plasticizer, be uniformly mixing to obtain casing bag
Clothing liquid；Rotating speed spray casing coating solution is controlled, to step（2）Piece after bag separation layer continues to be coated so that the coating of enteric layer increases
Again the 8% ~ 14% of spacer is calculated as by enteric layer coating material Utech L30D-55 or Eudragit L100-55；Dry, obtain finished product；
The opacifier is titanium dioxide, and the antiplastering aid is the one or more in talcum powder, magnesium stearate；The plasticizer
For the one or more in Macrogol 6000, PEG 8000；
The preparation process of the enteric coatel tablets（1）、（2）、（3）In, dry temperature is 40 DEG C ~ 50 DEG C.
2. pantoprazole sodium enteric tablet according to claim 1, it is characterised in that the preparation process of the enteric coatel tablets（1）、
（2）With（3）In, dry temperature is 40 DEG C.
3. pantoprazole sodium enteric tablet according to claim 1, it is characterised in that the preparation process of the enteric coatel tablets（1）
In, the mixing speed of wet mixing pelletizer is 100 ~ 120 revs/min, and cutting speed is 1000 ~ 1500 revs/min；Step
（1）In tabletting 7mm scrobicula circular dies.
4. pantoprazole sodium enteric tablet according to claim 1, it is characterised in that the preparation process of the enteric coatel tablets（2）
In, the coating weight gain of separation layer is the 8% of plain piece；The preparation process of enteric coatel tablets（3）In, the coating weight gain of enteric layer presses enteric layer
Coating material Utech L30D-55 is calculated as the 12% of spacer.
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| CN104856994A (en) * | 2015-05-26 | 2015-08-26 | 苗怡文 | Medical pantoprazole sodium composition tablet for treating gastric ulcer |
| CN105816436B (en) * | 2016-03-22 | 2019-10-22 | 广州共禾医药科技有限公司 | A kind of Pantoprazole enteric-coated micro-pill, Pantoprazole enteric slow-release tablet agent and preparation method thereof |
| CN106667948B (en) * | 2016-11-24 | 2019-10-25 | 乐普制药科技有限公司 | A kind of preparation and preparation method containing rosuvastain calcium |
| CN107153769A (en) * | 2017-05-15 | 2017-09-12 | 杭州安德科技有限公司 | Reach the method for imitation medicine bioequivalence with IVIVC mathematical modelings |
| CN110487918B (en) * | 2018-05-14 | 2022-02-08 | 中国医学科学院药物研究所 | Method for analyzing genotoxic impurities in pantoprazole sodium and initial raw material thereof |
| CN111053750A (en) * | 2018-09-29 | 2020-04-24 | 湖南九典制药股份有限公司 | Preparation method of pantoprazole sodium enteric-coated tablets |
| CN110585166A (en) * | 2019-10-16 | 2019-12-20 | 武汉润欣科技股份有限公司 | Pantoprazole sodium enteric-coated micro-tablet capsule and preparation method thereof |
| CN112137980B (en) * | 2020-10-29 | 2022-12-06 | 广州美迪高生物医药科技有限公司 | Lansoprazole enteric-coated tablet and preparation method thereof |
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| CN103961330A (en) * | 2014-05-16 | 2014-08-06 | 广东华南药业集团有限公司 | S-pantoprazole sodium enteric-coated tablet and preparation method thereof |
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| CN103961330A (en) * | 2014-05-16 | 2014-08-06 | 广东华南药业集团有限公司 | S-pantoprazole sodium enteric-coated tablet and preparation method thereof |
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