CN113577079B - Preparation method and composition of phosphodiesterase inhibitor - Google Patents
Preparation method and composition of phosphodiesterase inhibitor Download PDFInfo
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- CN113577079B CN113577079B CN202110856264.7A CN202110856264A CN113577079B CN 113577079 B CN113577079 B CN 113577079B CN 202110856264 A CN202110856264 A CN 202110856264A CN 113577079 B CN113577079 B CN 113577079B
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- 239000000203 mixture Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 title claims abstract description 10
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title claims abstract description 10
- 229960000835 tadalafil Drugs 0.000 claims abstract description 60
- 238000002156 mixing Methods 0.000 claims abstract description 52
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 51
- 239000008101 lactose Substances 0.000 claims abstract description 51
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims abstract 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 27
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 27
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 27
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 27
- 239000002994 raw material Substances 0.000 claims description 24
- 238000007873 sieving Methods 0.000 claims description 22
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 21
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 21
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 21
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 21
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 21
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 21
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 21
- 239000011248 coating agent Substances 0.000 claims description 20
- 238000000576 coating method Methods 0.000 claims description 20
- 238000005303 weighing Methods 0.000 claims description 20
- 239000000463 material Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 11
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- 239000008187 granular material Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 4
- 238000005550 wet granulation Methods 0.000 claims description 3
- 239000000080 wetting agent Substances 0.000 claims description 3
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000010902 jet-milling Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 10
- 238000005516 engineering process Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000005063 solubilization Methods 0.000 abstract description 2
- 230000007928 solubilization Effects 0.000 abstract description 2
- 239000004094 surface-active agent Substances 0.000 abstract description 2
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 58
- 239000002245 particle Substances 0.000 description 32
- 230000000052 comparative effect Effects 0.000 description 12
- 238000010298 pulverizing process Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000009826 distribution Methods 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- 229940117229 cialis Drugs 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 2
- 101150098694 PDE5A gene Proteins 0.000 description 2
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000005226 corpus cavernosum Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- 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
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a preparation method of a phosphodiesterase inhibitor and a composition, wherein the preparation method comprises the steps of uniformly mixing tadalafil and lactose, processing by adopting a method of combining mechanical crushing and airflow crushing, and solving the problems of dissolution rate and bioavailability of a product by utilizing a surfactant solubilization technology, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method and a composition of a phosphodiesterase inhibitor.
Background
Tadalafil tablets are selective, reversible inhibitors of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5(PDE5) that, when sexual stimulation results in local nitric oxide release, PDE5 is inhibited by tadalafil, resulting in elevated levels of cGMP within the corpora cavernosa, which leads to smooth muscle relaxation, blood flow into penile tissue, and erection, such as asexual stimulation.
The tadalafil solubility was: it is easily soluble in dimethyl sulfoxide, slightly soluble in acetonitrile, glacial acetic acid or dichloromethane, very slightly soluble in methanol, and hardly soluble in water or isopropanol, and BCS is classified as class II or class IV, and is a poorly soluble drug.
US6841167 discloses that tadalafil has a solubility of 2ug/ml in water at 25 c, so it has a lower dissolution rate and a lower bioavailability.
The tadalafil has the problems of poor water solubility, slow dissolution rate, low bioavailability and the like in the prior art, and the technical problems in the prior art are solved by improving the prescription and the preparation process technology.
Disclosure of Invention
According to the invention, through researching and improving the prescription and the preparation technology, the uniformity of tadalafil in vitro dissolution and in vivo absorption is ensured, and the technical problems of low dissolution speed, low bioavailability and the like of the product are solved.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a process for preparing phosphodiesterase inhibitor includes pulverizing, sieving, weighing, mixing, granulating, tabletting and coating.
Preferably, the preparation method of the phosphodiesterase inhibitor comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, binder, and disintegrating agent respectively; premixing sieved lactose and tadalafil raw materials according to a certain proportion, crushing the lactose and tadalafil raw materials by a universal crusher, and crushing the lactose and tadalafil raw materials by a jet mill for later use, wherein the adopted jet milling air pressure is 0.4-1.0MPa, and the feeding air pressure is 0.4-0.6 MPa; the applicant finds that the heat generated by the pulverizer is serious when tadalafil is pulverized independently in the experimental process, and through a large amount of experimental research, lactose which is not less than one time (weight ratio) is added in the pulverizing process for pulverization, so that the pulverizer does not generate heat, the sieving is smooth, and the efficiency is improved; the micro-powder process adopts a method that tadalafil and lactose are premixed and placed in a universal pulverizer to be pulverized for 1 time, and then the tadalafil and lactose are pulverized for 1 time by air flow, so that the particle size distribution D90 of the pulverized tadalafil raw material medicine can be smaller than 10 mu m; the premixing ratio of tadalafil to lactose is 1:1-5 (weight ratio); preferably, the pre-mixing ratio of tadalafil to lactose is 1:5 (weight ratio);
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the disintegrant, the binder and the sieved lactose according to the prescription amount in a wet mixing granulator;
3) and (3) granulating: continuously adding the wetting agent dissolved in the wetting agent into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding a lubricant with a prescribed amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric-soluble film coat.
Another object of the present invention is to provide a novel phosphodiesterase inhibitor composition: the prescription of the composition comprises the following components in percentage by weight: 4 to 6 percent of tadalafil, 71 to 73 percent of lactose, 12 to 14.5 percent of microcrystalline cellulose, 7 to 9 percent of disintegrant, 0.5 to 1 percent of adhesive, 0.29 to 0.35 percent of solubilizer and 0.5 to 1 percent of lubricant.
Further preferably, the composition formula consists of the following weight percentages: 4% tadalafil, 73% lactose, 14.5% microcrystalline cellulose, 7% disintegrant, 0.6% binder, 0.3% solubilizer, 0.6% lubricant.
Preferably, the solubilizer is sodium lauryl sulfate, the disintegrant is croscarmellose sodium, the binder is high-substituted hydroxypropyl cellulose, and the lubricant is magnesium stearate.
Compared with the prior art, the invention has the following advantages:
(1) solves the problem of difficult dissolution of the raw material medicine, and leads the in vitro dissolution to be consistent with the original research.
(2) The invention overcomes the problems of serious heat generation and difficult sieving when the tadalafil raw material medicine is crushed by improving the preparation process.
(3) According to the invention, a method combining mechanical grinding and airflow grinding is adopted in the aspect of micronization technology, so that 90% of particles of the tadalafil raw material medicine are easily made to have a particle size smaller than 10 mu m, and a surfactant solubilization technology is combined, so that the problem that the raw material medicine is difficult to dissolve is effectively solved, and the bioavailability is improved.
Detailed Description
The present invention will be further described by the following examples, but the present invention is not limited to the following examples, which do not limit the scope of the present invention in any way. Certain changes and modifications within the scope of the claims, which may be made by one skilled in the art, are also considered to be within the scope of the invention.
Example 1
Prescription:
tadalafil 10.00mg
Lactose 118.57mg
Microcrystalline cellulose 21.23mg
Croscarmellose sodium 15.03mg
High-substituted hydroxypropyl cellulose 0.84mg
Sodium dodecyl sulfate 0.48mg
Magnesium stearate 0.84mg
The preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose, and croscarmellose sodium respectively; taking the sieved tadalafil and lactose according to the mass ratio of 1:1, pre-mixing in proportion, namely, firstly placing a universal pulverizer to pulverize for 1 time, then pulverizing the pulverized material for 1 time by using an air flow pulverizer (the air pressure of the air flow pulverizer is 0.4-1.0Mpa, and the feeding air pressure is 0.4-0.6 Mpa), measuring the particle size by using a Malvern laser particle size analyzer, wherein the particle size distribution D90 of the tadalafil raw material is smaller than 10 mu m, and sampling to measure the content for later use;
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the croscarmellose sodium, the high-substituted hydroxypropyl cellulose and the sieved lactose according to the remaining prescription amount in a wet mixing granulator;
3) and (3) granulating: continuously adding the lauryl sodium sulfate dissolved in the purified water into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate with the prescription amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric-soluble film coat.
Example 2
Prescription:
tadalafil 20.00mg
Lactose 365.00mg
Microcrystalline cellulose 60.00mg
Croscarmellose sodium 43.25mg
High-substituted hydroxypropyl cellulose 5.00mg
Sodium dodecyl sulfate 1.75mg
Magnesium stearate 5.00mg
The preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose, and croscarmellose sodium respectively; taking the sieved tadalafil and lactose according to the mass ratio of 1: 3, premixing in proportion, firstly placing a universal pulverizer to pulverize for 1 time, then pulverizing the pulverized material for 1 time by using an air flow pulverizer (the air flow pulverizing pressure is 0.4-1.0Mpa, and the feeding pressure is 0.4-0.6 Mpa), measuring the particle size by using a Malvern laser particle size analyzer, sampling and measuring the content, wherein the particle size distribution D90 of the tadalafil raw material is less than 10 mu m;
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the croscarmellose sodium, the high-substituted hydroxypropyl cellulose and the sieved lactose according to the remaining prescription amount in a wet mixing granulator;
3) and (3) granulating: continuously adding the sodium dodecyl sulfate dissolved in the purified water into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate in the formula amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric-soluble film coat.
Example 3
Prescription:
tadalafil 10.00mg
Lactose 182.50mg
Microcrystalline cellulose 36.25mg
Croscarmellose sodium 17.50mg
High-substituted hydroxypropyl cellulose 1.50mg
Sodium dodecyl sulfate 0.75mg
Magnesium stearate 1.50mg
The preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose, and croscarmellose sodium respectively; taking the sieved tadalafil and lactose according to the mass ratio of 1:5, premixing in proportion, firstly placing a universal pulverizer to pulverize for 1 time, then pulverizing the pulverized material for 1 time by using an air flow pulverizer (the air flow pulverizing pressure is 0.4-1.0Mpa, and the feeding pressure is 0.4-0.6 Mpa), determining the particle size by using a Malvern laser particle size analyzer, sampling and determining the content, wherein the particle size distribution D90 of the tadalafil raw material is less than 10 mu m;
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the croscarmellose sodium, the high-substituted hydroxypropyl cellulose and the sieved lactose according to the remaining prescription amount in a wet mixing granulator;
3) granulating: continuously adding the lauryl sodium sulfate dissolved in the purified water into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate with the prescription amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric soluble film coat.
Comparative example 1
Prescription: same as in example 3.
The preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose, and croscarmellose sodium respectively; crushing the sieved tadalafil raw material medicine for 1 time by a universal crusher, measuring the particle size by using a Malvern laser particle size analyzer, wherein the particle size distribution D90 of the tadalafil raw material medicine is smaller than 10 mu m, and sampling to measure the content for later use;
2) weighing and mixing: weighing the tadalafil crushed according to the prescription amount, mixing the tadalafil crushed according to the prescription amount with the microcrystalline cellulose, the croscarmellose sodium, the highly substituted hydroxypropyl cellulose and the screened lactose according to the prescription amount in a wet mixing granulator;
3) and (3) granulating: continuously adding the sodium dodecyl sulfate dissolved in the purified water into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate with the prescription amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric-soluble film coat.
Comparative example 2
Prescription: same as in example 3.
The preparation method comprises the following steps:
1) crushing and sieving: respectively sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose and croscarmellose sodium, crushing the sieved tadalafil raw material for 1 time by using an airflow crusher (airflow crushing pressure is 0.4-1.0Mpa, feeding pressure is 0.4-0.6 Mpa), measuring the particle size by using a Malvern laser particle size analyzer, wherein the particle size distribution D90 of the tadalafil raw material is less than 10 mu m, and sampling to measure the content for later use;
2) weighing and mixing: weighing the tadalafil which is crushed according to the prescription amount, and mixing the tadalafil with the microcrystalline cellulose, the croscarmellose sodium, the high-substituted hydroxypropyl cellulose and the sieved lactose in a wet mixing granulator;
3) and (3) granulating: continuously adding the sodium dodecyl sulfate dissolved in the purified water into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate with the prescription amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric soluble film coat.
Comparative example 3
Prescription:
tadalafil 10.00mg
Lactose 182.50mg
Microcrystalline cellulose 36.25mg
Croscarmellose sodium 18.25mg
High-substituted hydroxypropyl cellulose 1.50mg
Magnesium stearate 1.50mg
The preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose, and croscarmellose sodium respectively; taking the sieved lactose and tadalafil according to the mass ratio of 1:5, premixing in proportion, firstly placing a universal pulverizer to pulverize for 1 time, then pulverizing the pulverized material for 1 time by using an air flow pulverizer (the air flow pulverizing pressure is 0.4-1.0Mpa, and the feeding pressure is 0.4-0.6 Mpa), determining the particle size by using a Malvern laser particle size analyzer, sampling and determining the content, wherein the particle size distribution D90 of the tadalafil raw material is less than 10 mu m;
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the croscarmellose sodium, the high-substituted hydroxypropyl cellulose and the sieved lactose according to the remaining prescription amount in a wet mixing granulator;
3) and (3) granulating: adding purified water into the uniformly mixed material in the step 2), uniformly stirring, performing wet granulation, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate with the prescription amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric-soluble film coat.
Comparative example 4
Prescription:
tadalafil 10.00mg
Lactose 182.50mg
Microcrystalline cellulose 36.25mg
Croscarmellose sodium 17.55mg
High-substituted hydroxypropyl cellulose 1.50mg
Sodium dodecyl sulfate 0.70mg
Magnesium stearate 1.50mg
The preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, high-substituted hydroxypropyl cellulose, and croscarmellose sodium respectively; taking the sieved lactose and tadalafil according to the mass ratio of 1:5, premixing in proportion, firstly placing a universal pulverizer to pulverize for 1 time, then pulverizing the pulverized material for 1 time by using an air flow pulverizer (the air pressure of the air flow pulverizer is 0.4-1.0Mpa, and the feeding air pressure is 0.4-0.6 Mpa), measuring the particle size by using a Malvern laser particle size analyzer, wherein the particle size distribution D90 of the tadalafil raw material drug is smaller than 10 mu m, and sampling to measure the content for later use;
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the croscarmellose sodium, the high-substituted hydroxypropyl cellulose and the sieved lactose according to the remaining prescription amount in a wet mixing granulator;
3) and (3) granulating: continuously adding the sodium dodecyl sulfate dissolved in the purified water into the uniformly mixed material in the step 2), uniformly stirring, granulating by a wet method, drying and finishing;
4) total mixing and tabletting: adding magnesium stearate with the prescription amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating with gastric soluble film coat.
Experimental example 1
The change in particle size data before and after the treatments of examples 1 to 3 and comparative examples 1 to 2 was measured, and the results are shown in Table 1.
Table 1: particle size detection data comparison
| Name of experimental project | Particle size (μm) before raw Material treatment | Particle size (μm) before raw Material treatment | Particle size (μm) before raw Material treatment | Particle size (mum) after raw material treatment | Particle size (mum) after raw material treatment | Particle size (mum) after raw material treatment |
| D10 | D50 | D90 | D10 | D50 | D90 | |
| Example 1 | 7.0 | 18.9 | 40.0 | 2.13 | 5.68 | 7.02 |
| Example 2 | 7.0 | 18.9 | 40.0 | 1.66 | 4.32 | 6.45 |
| Example 3 | 7.0 | 18.9 | 40.0 | 1.02 | 3.76 | 5.38 |
| Comparative example 1 | 7.0 | 18.9 | 40.0 | 5.99 | 12.89 | 26.77 |
| Comparative example 2 | 7.0 | 18.9 | 40.0 | 4.68 | 11.12 | 20.82 |
Experimental example 2
The dissolution rate of the tadalafil tablets prepared in examples 1-3 of the invention, the tablets prepared in comparative examples 1-4 and the original Cialis tablets (purchased commercially) was determined by high performance liquid chromatography in 0.25% sodium dodecyl sulfate solution as dissolution medium according to the standard of Chinese pharmacopoeia 2015 edition, and the experimental results are shown in Table 2.
TABLE 2 dissolution data comparison
| Name of experimental project | 5min | 10min | 15min | 30min | 45min | 60min | 90min | 120min |
| Original research Cialis ® Sheet | 47.3% | 61.4% | 82.1% | 92.9% | 96.1% | 97.6% | 98.3% | 98.1% |
| Example 1 | 48.8% | 75.1% | 88.7% | 93.8% | 96.8% | 97.9% | 98.4% | 100.3% |
| Example 2 | 50.9% | 83.6% | 92.4% | 94.3% | 97.2% | 98.5% | 98.9% | 100.5% |
| Example 3 | 52.7% | 86.0% | 94.9% | 97.7% | 97.8% | 98.9% | 99.8% | 100.9% |
| Comparative example 1 | 28.2% | 60.9% | 77.4% | 89.9% | 94.2% | 94.9% | 95.2% | 95.7% |
| Comparative example 2 | 33.4% | 71.8% | 81.0% | 89.4% | 92.1% | 92.1% | 91.5% | 92.8% |
| Comparative example 3 | 20.1% | 45.2% | 65.7% | 84.4% | 87.3% | 88.1% | 89.4% | 90.0% |
| Comparative example 4 | 24.7% | 55.6% | 75.0% | 90.2% | 91.6% | 91.8% | 92.4% | 94.1% |
As shown in Table 2, the dissolution rate of the Tadalafil tablet prepared by the invention is different from that of Cialis in the original research ® The tablets dissolve out substantially consistently.
Experimental example 3
The Tadalafil tablets and the original Cialis tablets prepared by the method are respectively subjected to a Bigged dog pharmacokinetic experiment, and the experimental results are shown in Table 3.
Table 3: comparison of pharmacokinetic experiments
| Name of experimental project | AUC（0-∞）(ng*h/mL) | Cmax(ng/mL) | Tmax（h） |
| Example 1 | 763.44±767.56 | 85.6±22.14 | 1.48±0.13 |
| Example 2 | 813.45±795.21 | 91.3±19.86 | 1.50±0.12 |
| Example 3 | 956.39±701.21 | 88.56±29.01 | 1.46±0.11 |
| Original research Cialis ® Sheet | 732.39±711.89 | 75.86±29.99 | 1.76±0.39 |
And (4) conclusion: AUC and Cmax data show that the bioavailability and the peak concentration of the tadalafil tablet prepared by the invention are improved and are superior to those of the tadalafil tablet prepared by the prior art (original product).
Claims (4)
1. The preparation method of the phosphodiesterase inhibitor is characterized by comprising the steps of crushing, sieving, weighing, mixing, granulating, total mixing, tabletting and coating, wherein the crushing process adopts mechanical crushing, and then airflow crushing treatment is carried out on the crushed material, and the preparation method comprises the following steps:
1) crushing and sieving: sieving lactose, microcrystalline cellulose, binder, and disintegrating agent respectively; premixing sieved lactose and tadalafil raw materials according to a certain proportion, crushing the mixture by a universal crusher, and crushing the crushed mixture by an airflow crusher for later use; the air pressure of the jet milling is 0.4-1.0MPa, and the feeding air pressure is 0.4-0.6 MPa; the premixing ratio of the tadalafil to the lactose is 1:1-5 by weight;
2) weighing and mixing: weighing a mixture of the crushed tadalafil and lactose according to the prescription amount, and mixing the mixture with the microcrystalline cellulose, the disintegrant, the binder and the sieved lactose according to the prescription amount in a wet mixing granulator;
3) and (3) granulating: adding a solubilizer into the uniformly mixed material obtained in the step 2), uniformly stirring, performing wet granulation, drying and finishing; in the granulating process, the solubilizer is dissolved in the wetting agent and is continuously added into the materials for wet granulation;
4) total mixing and tabletting: adding a lubricant with a prescribed amount into the granules in the step 3), mixing, performing tabletting operation, and tabletting;
5) coating: coating gastric soluble film coat;
wherein the prescription consists of the following components in percentage by weight: 4 to 6 percent of tadalafil, 71 to 73 percent of lactose, 12 to 14.5 percent of microcrystalline cellulose, 7 to 9 percent of disintegrant, 0.5 to 1 percent of adhesive, 0.29 to 0.35 percent of solubilizer and 0.5 to 1 percent of lubricant; the solubilizer is sodium dodecyl sulfate, the disintegrant is croscarmellose sodium, the binder is high-substituted hydroxypropyl cellulose, and the lubricant is magnesium stearate.
2. The method of preparing a phosphodiesterase inhibitor according to claim 1, wherein the pre-mixing ratio of tadalafil to lactose in step 1) is 1:5 by weight.
3. The method of preparing a phosphodiesterase inhibitor according to any one of claims 1-2, wherein the formula consists of the following weight percentages: 4% tadalafil, 73% lactose, 14.5% microcrystalline cellulose, 7% disintegrant, 0.6% binder, 0.3% solubilizer, 0.6% lubricant.
4. A pharmaceutical composition obtained by the process according to any one of claims 1 to 3.
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