CN108451916B - Acetaminophen pharmaceutical composition preparation and preparation method thereof - Google Patents
Acetaminophen pharmaceutical composition preparation and preparation method thereof Download PDFInfo
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- CN108451916B CN108451916B CN201810632323.0A CN201810632323A CN108451916B CN 108451916 B CN108451916 B CN 108451916B CN 201810632323 A CN201810632323 A CN 201810632323A CN 108451916 B CN108451916 B CN 108451916B
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 38
- 238000001035 drying Methods 0.000 claims abstract description 30
- 239000011248 coating agent Substances 0.000 claims abstract description 25
- 238000000576 coating method Methods 0.000 claims abstract description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 24
- 235000010443 alginic acid Nutrition 0.000 claims abstract description 19
- 229920000615 alginic acid Polymers 0.000 claims abstract description 19
- 239000000783 alginic acid Substances 0.000 claims abstract description 19
- 229960001126 alginic acid Drugs 0.000 claims abstract description 19
- 150000004781 alginic acids Chemical class 0.000 claims abstract description 19
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 19
- 238000002156 mixing Methods 0.000 claims abstract description 18
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960000913 crospovidone Drugs 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 17
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 17
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229920003081 Povidone K 30 Polymers 0.000 claims abstract description 15
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims abstract description 12
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims abstract description 12
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims abstract description 12
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 12
- 229960003415 propylparaben Drugs 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000853 adhesive Substances 0.000 claims abstract description 10
- 230000001070 adhesive effect Effects 0.000 claims abstract description 10
- 229960003563 calcium carbonate Drugs 0.000 claims abstract description 10
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 230000008859 change Effects 0.000 claims abstract description 7
- 229920000881 Modified starch Polymers 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 11
- 239000002245 particle Substances 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 9
- 230000003179 granulation Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 10
- 238000004090 dissolution Methods 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000007789 sealing Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 230000007794 irritation Effects 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 210000001156 gastric mucosa Anatomy 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 206010067484 Adverse reaction Diseases 0.000 description 5
- 230000006838 adverse reaction Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 5
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 5
- 229960002216 methylparaben Drugs 0.000 description 5
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 5
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000011241 protective layer Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 239000006255 coating slurry Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000011363 dried mixture Substances 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 238000010981 drying operation Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 229940057948 magnesium stearate Drugs 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 230000002572 peristaltic effect Effects 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
Classifications
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a paracetamol pharmaceutical composition preparation and a preparation method thereof, wherein the preparation method comprises the following steps: uniformly mixing acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate, adding an adhesive aqueous solution, and granulating; granulating, drying at 20-40 deg.C by gradient temperature change method, drying, adding alginic acid, calcium carbonate and colloidal silicon dioxide, premixing for 3-5min, adding magnesium stearate, mixing for 3-5min, tabletting, and coating. The preparation method of the acetaminophen pharmaceutical composition preparation provided by the embodiment of the invention has the advantages that the operation steps are simple, the operation conditions are mild, the rapid dissolution of the active ingredients in the preparation can be realized through the preparation method, the dissolution rate is improved, and the preparation method is worthy of wide popularization and application.
Description
Technical Field
The invention relates to the field of pharmacy, and particularly relates to a paracetamol pharmaceutical composition preparation and a preparation method thereof.
Background
Acetaminophen is an aniline antipyretic, analgesic and anti-inflammatory drug, has strong and lasting antipyretic and analgesic effects, is used for treating fever caused by common cold or influenza, and is also used for relieving light to moderate pains such as headache, arthralgia, migraine, toothache, myalgia, neuralgia and dysmenorrheal, and the prepared finished product is orally taken by about 0.3-0.6g once, and children take 10-15mg/kg once according to body weight and 1 time every 4-6 hours; the dosage is not more than 5 times per 24 hours for children under 12 years old, and the treatment course is not more than 5 days. And the product is not suitable for long-term administration.
In the prior art, the common preparation method of the acetaminophen preparation adopts a mode of mixing and granulating raw and auxiliary materials together, the prepared total mixture of the granules mixed by the raw and auxiliary materials can cause the surface of the tablet to hair and influence the appearance due to the water absorption and disintegration of the crospovidone in the process of placing or tabletting, the medicine effect is unstable, the production qualification rate is reduced, unqualified products are reworked, the production efficiency is low, and the GMP management regulation is not met.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a preparation method of a paracetamol pharmaceutical composition preparation, auxiliary materials in the whole preparation process adopt a mode of combining external addition and internal addition, the auxiliary materials such as crospovidone, povidone K30, methylparaben, ethylparaben and propylparaben and a main paracetamol material are added together, calcium carbonate and alginic acid are added in an external mode, the external auxiliary materials can play a role of sealing and retaining water, the addition of magnesium stearate can facilitate tabletting and realize rapid disintegration of tablets, in addition, the calcium carbonate can be rapidly diffused through the external mode to improve the pH value of gastric juice, and the alginic acid can be rapidly diffused to gastric mucosa to form a protective layer, so that double insurance protection stomach is formed, the damage of paracetamol to gastrointestinal tract is avoided, and adverse reactions are reduced, the preparation method is scientific and reasonable, so that the bioavailability of the paracetamol preparation is remarkably improved, is suitable for wide popularization and utilization, has less limitation and simple process step operation.
The second purpose of the invention is to provide a paracetamol pharmaceutical composition preparation prepared by the preparation method of the paracetamol preparation, wherein the paracetamol preparation has uniform texture, stable physical and chemical properties and remarkable drug effect.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the invention provides a preparation method of a paracetamol pharmaceutical composition preparation, which specifically comprises the following steps:
(A) uniformly mixing acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate, adding an adhesive aqueous solution, and granulating;
(B) the stirring speed of the granulation is between 200 and 400rpm, and the granulation time is 90-180 s;
(C) drying by gradient temperature change method, wherein the temperature of each gradient is controlled at 20-40 deg.C, the temperature of the former gradient and the temperature of the latter gradient are alternately changed, the difference between the two adjacent gradients is 4-5 deg.C, drying, adding alginic acid, calcium carbonate and colloidal silicon dioxide, premixing for 3-5min, adding magnesium stearate, mixing for 3-5min, tabletting, and coating.
Generally, the tablet is prepared by adding main and auxiliary materials together in the prior art, but the addition of the auxiliary materials is not favorable for ensuring the quality of the tablet, for example, the added crospovidone easily causes the surface of the tablet to be hairy due to water absorption and disintegration, and the appearance is influenced. And moreover, the preparation prepared by the method has large irritation to intestines and stomach, is easy to cause damage to gastrointestinal tracts and is also easy to cause other adverse reactions of patients.
In order to solve the technical problems, the invention provides a preparation method of a paracetamol pharmaceutical composition preparation, wherein a wrapping and sealing effect is formed by adopting a mode that the inner part and the outer part of auxiliary materials are in accordance with addition, and the first advantage of the sealing effect ensures that the total mixture is not easy to dehydrate and absorb moisture and is stabilized within a range of 2-3 percent, so that the tabletting is ensured to be free from cracking, the long-term storage is ensured, and the stability is high. The second advantage is that the product is not easy to absorb moisture after long-term storage, and the situation that the appearance quality is influenced by disintegration and hair on the surface of the crosslinked polyvidone caused by moisture absorption is prevented. The third benefit is that calcium carbonate and alginic acid are added to solve the irritation of acetaminophen to gastric mucosa and reduce adverse reaction. The principle is as follows: the two substances are added into the mixed particles in a powder form, the two substances are released before the components in the particles, the calcium carbonate neutralizes gastric acid, the pH value in the stomach can be rapidly increased, the alginic acid can be uniformly diffused to form a gastric mucosa protective layer, and the irritation of acetaminophen to gastrointestinal tracts is reduced through double protection. Compared with the common paracetamol preparation in the prior art, the preparation prepared by the method has less irritation to intestines and stomach and is more beneficial to body health.
Preferably, the mesh size of the acetaminophen is controlled to be more than 80 meshes.
Preferably, the mesh size of the crospovidone is controlled to be more than 80 meshes.
Preferably, the mesh size of the povidone K30 is controlled to be more than 80 meshes.
Preferably, the aqueous binder solution is an aqueous pregelatinized starch solution.
Preferably, the mass percent concentration of the pregelatinized starch aqueous solution is more than 15 wt%.
Preferably, in the step (C), the gradient temperature change intervals are three, the temperature of the first gradient is controlled to be 25-30 ℃, the temperature of the second gradient is controlled to be 35-40 ℃, and the temperature of the third gradient is controlled to be 25-30 ℃;
preferably, the drying time is 30-40 min.
Preferably, in the step (C), the hardness during tabletting is controlled to be between 80 and 140N;
preferably, the coating is carried out on the plain tablets with the hardness of 80-140N, and the coating is stopped when the hardness is increased to between 180 and 200N.
Compared with the prior art, the invention has the beneficial effects that:
(1) the auxiliary materials are added in a mode of combining external addition and internal addition, the auxiliary materials such as the crospovidone, the povidone K30, the methylparaben, the ethylparaben and the propylparaben are added in the acetaminophen main material together, the calcium carbonate and the alginic acid are added in an external mode, the external auxiliary materials can play a role in sealing and water retention, and the addition of the magnesium stearate can facilitate tabletting and realize rapid disintegration of tablets;
(2) the invention can lead calcium carbonate to diffuse and neutralize gastric acid rapidly by an additional mode so as to improve the pH value of gastric juice, and alginic acid diffuses to gastric mucosa rapidly to form a protective layer, thereby forming a double insurance protection stomach, avoiding the irritation and damage of acetaminophen to gastrointestinal tracts and reducing adverse reactions;
(3) the preparation method provided by the invention has the advantages that the front step and the back step are closely connected, industrialization is easy to form, and the prepared preparation has a remarkable treatment effect;
(4) the acetaminophen pharmaceutical composition preparation provided by the invention has the advantages of uniform texture, stable physicochemical properties and obvious drug effect.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
According to one aspect of the present invention, a method for preparing a pharmaceutical composition formulation of acetaminophen comprises the steps of:
(A) uniformly mixing acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate, adding an adhesive aqueous solution, and granulating;
(B) the stirring speed of the granulation is between 200 and 400rpm, and the granulation time is 90-180 s;
(C) drying by gradient temperature change method, wherein the temperature of each gradient is controlled at 20-40 deg.C, the temperature of the former gradient and the temperature of the latter gradient are alternately changed, the difference between the two adjacent gradients is 4-5 deg.C, drying, adding alginic acid, calcium carbonate and colloidal silicon dioxide, premixing for 3-5min, adding magnesium stearate, mixing for 3-5min, tabletting, and coating.
The invention provides a preparation method of a paracetamol pharmaceutical composition preparation, wherein a wrapping and sealing effect is formed by adopting a mode that the inner part and the outer part of auxiliary materials are in accordance with addition, and the first benefit of the sealing effect ensures that the total mixture is not easy to dehydrate and absorb moisture and is stabilized within the range of 2-3 percent, so that the tabletting is ensured to be free from cracking, the long-term storage is ensured, and the stability is high. The second advantage is that the product is not easy to absorb moisture after long-term storage, and the situation that the appearance quality is influenced by disintegration and hair on the surface of the crosslinked polyvidone caused by moisture absorption is prevented. The third benefit is that calcium carbonate and alginic acid are added to solve the irritation of acetaminophen to gastric mucosa and reduce adverse reaction. The principle is as follows: the two substances are added into the mixed particles in a powder form and are released before the components in the particles, calcium carbonate can quickly neutralize gastric acid, the pH value in the stomach is increased, alginic acid can uniformly diffuse to form a gastric mucosa protective layer, and the irritation of acetaminophen to gastrointestinal tracts is reduced through double protection. Compared with the common paracetamol preparation in the prior art, the preparation prepared by the method has less irritation to intestines and stomach and is more beneficial to body health.
In a preferred embodiment of the present invention, the mesh size of the acetaminophen is controlled to 80 mesh or more.
In a preferred embodiment of the present invention, the mesh size of the crospovidone is controlled to be 80 mesh or larger.
In a preferred embodiment of the invention, the mesh size of the povidone K30 is controlled to be 80 meshes or more.
By limiting the particle size of each raw material, the mutual fusion degree of the raw materials can be improved, so that the prepared preparation has more uniform texture.
In a preferred embodiment of the invention, the aqueous binder solution is an aqueous pregelatinized starch solution.
In a preferred embodiment of the present invention, the aqueous pregelatinized starch solution has a concentration of 15% by weight or more. If the concentration of the binder is too high, the effect of the active ingredient is not obtained, and therefore, the concentration is not preferably too high.
In a preferred embodiment of the present invention, in the step (C), the gradient temperature change interval is three, the temperature of the first gradient is controlled to be 25 to 30 ℃, the temperature of the second gradient is controlled to be 35 to 40 ℃, and the temperature of the third gradient is controlled to be 25 to 30 ℃;
in a preferred embodiment of the invention, the drying time is 30-40 min.
It should be noted that the whole drying process of the present invention adopts a low temperature variable temperature drying mode and a mode of alternating back and forth temperature intervals, which is more beneficial to the wall breaking of drug molecules and the exertion of effective components, so the advantage of variable temperature drying is obviously superior to the constant temperature drying mode.
In a preferred embodiment of the present invention, in the step (C), the hardness during tabletting is controlled to be between 80 and 140N;
in a preferred embodiment of the invention, the coating is applied to the plain tablets with a hardness of 80-140N, and the coating is stopped when the hardness rises to between 180 and 200N.
Specifically, during the operation, the tablets with the hardness of 80-140N are coated after being preheated and dried in a coating pot, and after the coating, the coating can be stopped when the hardness naturally rises to between 180 and 200N.
The embodiments of the present invention will be further described with reference to examples and comparative examples.
Example 1
1) Weighing acetaminophen, crospovidone, povidone K30, methylparaben, ethylparaben, propylparaben, alginic acid, calcium carbonate, colloidal silicon dioxide and magnesium stearate according to production requirements, wherein the mesh size of the raw materials and the auxiliary materials is controlled to be more than 80 meshes;
2) preparing an adhesive: weighing pregelatinized starch of the adhesive prepared by a half of prescription amount, adding a proper amount of boiling water for dispersing and dissolving, and cooling to room temperature to obtain a pregelatinized starch water solution;
3) mixing and granulating: adding acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate into a wet granulator, mixing and stirring uniformly, adding pregelatinized starch water solution, stirring at 200rpm, and granulating for 90 s;
4) putting all wet particles into a fluidized bed, and carrying out variable-temperature drying operation, wherein the variable-temperature drying interval is three intervals, the temperature of a first gradient is set at 35 ℃, the temperature of a second gradient is set at 40 ℃, the temperature of a third gradient is set at 35 ℃, and the machine is stopped to discharge after drying until the moisture is 2-3 wt%, and the total drying time is 30 min;
5) calculating tablet weight according to the content of main drug in the granule, adding alginic acid, calcium carbonate and colloidal silicon dioxide into the dried mixture, premixing for 3min, adding magnesium stearate, mixing for 5min, and placing into a tablet press with a rotation speed of 30-40rpm and hardness: 80-140N, manually adjusting the filling amount, then alternately adjusting the pressure, checking indexes such as tablet weight difference, properties and the like, starting tabletting after the indexes are qualified, checking the tablet weight, the average tablet weight and the weight difference once in 20min during tabletting, and recording;
6) coating after tabletting, setting the air inlet temperature to be 45-50 ℃, preheating for 1 hour, adjusting the rotating speed of a coating roller to be 3rpm, adjusting the rotating speed of a peristaltic pump to uniformly spray coating slurry on the plain tablets, naturally increasing the hardness to 180 plus 200N, namely, closing the heating when the coating weight is increased by 2.0-3.0%, continuing air inlet cooling, and stopping coating operation;
7) packaging the prepared paracetamol preparation, labeling, sealing, drying and storing.
Example 2
1) Weighing acetaminophen, crospovidone, povidone K30, methylparaben, ethylparaben, propylparaben, alginic acid, calcium carbonate, colloidal silicon dioxide and magnesium stearate according to production requirements, wherein the mesh size of the raw materials and the auxiliary materials is controlled to be more than 90 meshes;
2) preparing an adhesive: weighing pregelatinized starch of the adhesive prepared by a half of prescription amount, adding a proper amount of boiling water for dispersing and dissolving, and cooling to room temperature to obtain a pregelatinized starch aqueous solution with the mass percentage concentration of 15 wt%;
3) mixing and granulating: adding acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate into a wet granulator, mixing and stirring uniformly, adding pregelatinized starch water solution, stirring and shearing, wherein the stirring rate is 400pm, and the granulation time is controlled within 180 s;
4) putting all wet particles into a fluidized bed, and carrying out variable-temperature drying operation, wherein the variable-temperature drying interval is three intervals, the temperature of a first gradient is set at 25 ℃, the temperature of a second gradient is set at 30 ℃, the temperature of a third gradient is set at 25 ℃, and the drying is carried out until the moisture is 2-3 wt%, then stopping the machine for discharging, and the total drying time is 40 min;
5) calculating the tablet weight according to the content of main drugs in the granules, adding alginic acid, calcium carbonate and colloidal silicon dioxide into the dried mixture, premixing for 4min, adding magnesium stearate, mixing for 4min, putting into a tablet press, wherein the tablet press has the rotating speed of 30-40rpm and the hardness: 80-140N, manually adjusting the filling amount, then alternately adjusting the pressure, checking indexes such as tablet weight difference, properties and the like, starting tabletting after the indexes are qualified, checking the tablet weight, the average tablet weight and the weight difference once in 20min during tabletting, and recording;
6) coating after tabletting, setting the air inlet temperature to be 45-50 ℃, preheating for 1 hour, adjusting the rotating speed of a coating roller to be 3rpm, adjusting the rotating speed of a peristaltic pump to uniformly spray coating slurry on the plain tablets, naturally increasing the hardness to 180 plus 200N, namely, closing the heating when the coating weight is increased by 2.0-3.0%, continuing air inlet cooling, and stopping coating operation;
7) packaging the prepared paracetamol preparation, labeling, sealing, drying and storing.
Example 3
1) Weighing acetaminophen, crospovidone, povidone K30, methylparaben, ethylparaben, propylparaben, alginic acid, calcium carbonate, colloidal silicon dioxide and magnesium stearate according to production requirements, wherein the mesh size of the raw materials and the auxiliary materials is controlled to be more than 90 meshes;
2) preparing an adhesive: weighing pregelatinized starch of the adhesive prepared by a half of prescription amount, adding a proper amount of boiling water for dispersing and dissolving, and cooling to room temperature to obtain a pregelatinized starch aqueous solution with the mass percentage concentration of 15 wt%;
3) mixing and granulating: adding acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate into a wet granulator, mixing and stirring uniformly, adding pregelatinized starch water solution, stirring and shearing, wherein the stirring rate is 300pm, and the granulation time is controlled within 100 s;
4) putting all wet particles into a fluidized bed, and carrying out variable-temperature drying operation, wherein the variable-temperature drying interval is three intervals, the temperature of a first gradient is set at 25 ℃, the temperature of a second gradient is set at 30 ℃, the temperature of a third gradient is set at 25 ℃, and the drying is carried out until the moisture is 2-3 wt%, then stopping the machine for discharging, and the total drying time is 35 min;
5) calculating the tablet weight according to the content of main drugs in the granules, adding alginic acid, calcium carbonate and colloidal silicon dioxide into the dried mixture, premixing for 4min, adding magnesium stearate, mixing for 4min, putting into a tablet press, wherein the tablet press has the rotating speed of 30-40rpm and the hardness: 80-140N, manually adjusting the filling amount, then alternately adjusting the pressure, checking indexes such as tablet weight difference, properties and the like, starting tabletting after the indexes are qualified, checking the tablet weight, the average tablet weight and the weight difference once in 20min during tabletting, and recording;
6) coating after tabletting, setting the air inlet temperature to be 45-50 ℃, preheating for 1 hour, adjusting the rotating speed of a coating roller to be 3rpm, adjusting the rotating speed of a peristaltic pump to uniformly spray coating slurry on the plain tablets, naturally increasing the hardness to 180 plus 200N, namely, closing the heating when the coating weight is increased by 2.0-3.0%, continuing air inlet cooling, and stopping coating operation;
7) packaging the prepared paracetamol preparation, labeling, sealing, drying and storing.
Comparative example 1
The specific operation steps are consistent with those of the embodiment 3, and the temperature in the boiling drying granulator in the step 4) is controlled between 20 ℃ and 30 ℃, and a variable temperature drying mode is not adopted.
Comparative example 2
The specific operation steps are the same as those of the example 3, except that in the step 4), the temperature-variable drying interval is three intervals, the temperature of the first gradient is set at 40 ℃, the temperature of the second gradient is set at 50 ℃, and the temperature of the third gradient is set at 40 ℃.
Comparative example 3
The specific procedure was the same as in example 3 except that alginic acid, calcium carbonate and colloidal silica were added during the granulation process.
Experimental example 1
Mice of Kunming species were randomly divided into: the blank control group, examples 1 to 3 were a group of samples, and a group of three samples, and comparative examples 1 to 3 were a group of four samples, a group of five samples, and a group of six samples, respectively, and after the samples were continuously administered with the same dose of the acetaminophen pharmaceutical composition preparation for 7 days, stomach tissues were taken for visual observation and histopathological examination, and the results showed that: the gastric tissue of one group of samples to three groups of samples has no obvious abnormality in the visual and pathological examination of the mucous membrane, and the gastric tissues of four groups of samples to six groups of samples have different mucous membrane atrophy and edema, wherein the gastric tissue edema of six groups of samples is more serious.
Experimental example 2
The acetaminophen pharmaceutical composition preparations in the above examples and comparative examples were tested by the dissolution method using the quality standard of acetaminophen tablets in the second part of the "chinese pharmacopoeia" 2015, wherein the specific results are shown in table 1 below.
Table 1 dissolution data results
As can be seen from the data in the table, the acetaminophen pharmaceutical composition preparation of the present invention is excellent in dissolution effect, and the drug effect is more remarkable than that of the comparative preparation method.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (7)
1. A preparation method of a paracetamol pharmaceutical composition preparation is characterized by comprising the following steps:
(A) uniformly mixing acetaminophen, crospovidone, povidone K30, methyl hydroxybenzoate, ethylparaben and propylhydroxybenzoate, adding an adhesive aqueous solution, and granulating;
(B) the stirring speed of the granulation is between 200 and 400rpm, and the granulation time is 90-180 s;
(C) drying by gradient temperature change method, wherein the temperature of each gradient is controlled at 20-40 deg.C, the temperature of the former gradient and the temperature of the latter gradient are alternately changed, the difference between the two adjacent gradients is 4-5 deg.C, drying, adding alginic acid, calcium carbonate and colloidal silicon dioxide, premixing for 3-5min, adding magnesium stearate, mixing for 3-5min, tabletting, and coating;
the mesh particle size of the acetaminophen is controlled to be more than 80 meshes;
the mesh particle size of the crospovidone is controlled to be more than 80 meshes;
the mesh size of the povidone K30 is controlled to be more than 80 meshes;
in the step (C), three gradient temperature change intervals are adopted, the temperature of the first gradient is controlled to be 25-30 ℃, the temperature of the second gradient is controlled to be 35-40 ℃, and the temperature of the third gradient is controlled to be 25-30 ℃.
2. The method according to claim 1, wherein the aqueous binder solution in step (a) is an aqueous pregelatinized starch solution.
3. The method according to claim 2, wherein the aqueous pregelatinized starch solution is present at a concentration of 15 wt% or more.
4. The production method according to claim 1, wherein in the step (C),
the drying time is 30-40 min.
5. The method according to claim 4, wherein in the step (C), the hardness during tabletting is controlled to be 80 to 140N.
6. The method as claimed in claim 5, wherein in the step (C), the coating is performed on the plain tablet with the hardness of 80-140N, and the coating is stopped when the hardness is increased to between 180 and 200N.
7. A paracetamol pharmaceutical composition formulation prepared by the process of any one of claims 1 to 6.
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| CN110501441B (en) * | 2019-09-27 | 2021-11-26 | 地奥集团成都药业股份有限公司 | Method for detecting related substances in acetaminophen tablet |
| CN111012750A (en) * | 2019-12-27 | 2020-04-17 | 北京济美堂医药研究有限公司 | Paracetamol tablet and preparation method thereof |
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