CN117338733A - Tenofovir disoproxil fumarate tablet and preparation process thereof - Google Patents
Tenofovir disoproxil fumarate tablet and preparation process thereof Download PDFInfo
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- CN117338733A CN117338733A CN202311319447.0A CN202311319447A CN117338733A CN 117338733 A CN117338733 A CN 117338733A CN 202311319447 A CN202311319447 A CN 202311319447A CN 117338733 A CN117338733 A CN 117338733A
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- tenofovir disoproxil
- disoproxil fumarate
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- fumarate tablet
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 63
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 239000000945 filler Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000000843 powder Substances 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- 239000007884 disintegrant Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 18
- 238000005303 weighing Methods 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 10
- 239000000905 isomalt Substances 0.000 claims description 9
- 235000010439 isomalt Nutrition 0.000 claims description 9
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- SERLAGPUMNYUCK-YJOKQAJESA-N 6-O-alpha-D-glucopyranosyl-D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-YJOKQAJESA-N 0.000 claims description 7
- 238000007907 direct compression Methods 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 238000007580 dry-mixing Methods 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 claims description 2
- PVXPPJIGRGXGCY-TZLCEDOOSA-N 6-O-alpha-D-glucopyranosyl-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)C(O)(CO)O1 PVXPPJIGRGXGCY-TZLCEDOOSA-N 0.000 claims description 2
- 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 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229960004977 anhydrous lactose Drugs 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000004090 dissolution Methods 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000005453 pelletization Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 29
- 230000000052 comparative effect Effects 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000007919 dispersible tablet Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 229960004556 tenofovir Drugs 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- GCMRADJSYIFOBU-UHFFFAOYSA-N methanol;2-methylpropan-2-ol Chemical compound OC.CC(C)(C)O GCMRADJSYIFOBU-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
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- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
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Abstract
The invention belongs to the field of medicines, and particularly discloses a tenofovir disoproxil fumarate tablet and a preparation process thereof. The tenofovir disoproxil fumarate tablet comprises, by weight, 30-65 parts of tenofovir disoproxil fumarate, 40-50 parts of filler, 3-9 parts of disintegrant, 1-5 parts of glidant and 0.5-2.5 parts of lubricant; the mass ratio of the tenofovir disoproxil fumarate to the filler to the glidant is 40:40-45:3-5. The tenofovir disoproxil fumarate tablet can solve the problem of poor uniformity of a powder direct tabletting method on the basis of ensuring better dissolution, and has good stability at high temperature; no pelletization is needed, the preparation method is simple and low in price, and has good market prospect.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to a tenofovir disoproxil fumarate tablet and a preparation process thereof.
Background
Tenofovir disoproxil fumarate (TenoforvirDisoproxilFumarate, TDF) is a nucleotide reverse transcriptase inhibitor, is a water-soluble diester prodrug of tenofovir, and has a main mechanism of action that the tenofovir is hydrolyzed into tenofovir after being orally taken into a human body so as to exert the efficacy. The tenofovir disoproxil fumarate has the characteristics of good tolerance, low drug resistance rate, low withdrawal rate, low renal toxicity and the like, and particularly has good clinical application prospect for HIV and HBV infected patients.
The TDF is mainly taken orally in the form of tablet with accurate dosage, high chemical stability and convenient storage. However, the quality of the oral tablet is controlled by the dissolution rate, the specification of the tenofovir disoproxil fumarate tablet is larger, and the viscosity of the main medicine is larger, so that the dissolution rate of the final product is not high, the biological activity is low, and the bioavailability is low, so that the clinical effect is poor.
The prior art discloses numerous preparation methods of tenofovir disoproxil fumarate tablets, CN102198110A discloses a tenofovir disoproxil fumarate dispersible tablet and a preparation method thereof, wherein the tenofovir disoproxil fumarate dispersible tablet is prepared by taking tenofovir disoproxil fumarate as an effective medicinal component and together with pharmaceutically acceptable auxiliary components, and the pharmaceutically acceptable auxiliary components comprise a filler, a disintegrating agent, a lubricant, a surfactant and a flavoring agent. The tenofovir disoproxil fumarate dispersible tablet prepared by the invention has the advantages of proper hardness, small weight difference, smooth surface and good taste; completely meets the requirements of disintegration time limit and dispersion uniformity of the dispersible tablet; the dissolution rate is high, the dissolution percentage within 2min is about 80-90%, and the dissolution is basically complete within 5 min; the bioavailability of the medicine is obviously improved. However, the preparation method adopts wet granulation, and tenofovir disoproxil fumarate has poor stability under high-temperature and high-humidity environments, and is poor in stability and easy to degrade in the preparation processing process. For example, CN103830192a discloses a tenofovir disoproxil fumarate tablet capable of being directly tableted in powder and a preparation method thereof, wherein the tablet comprises tenofovir disoproxil fumarate as a main drug and a pre-mixed auxiliary material, wherein the pre-mixed auxiliary material is a mixture of microcrystalline cellulose, talcum powder and component a which are uniformly mixed, and the component a is micro-powder silica gel or poloxamer 188. The preparation method adopts the powder direct compression method to prepare the tablet, which can make up the defect of wet granulation, but the powder direct compression method is easy to have the problems of poor uniformity and poor stability.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a tenofovir disoproxil fumarate tablet and a preparation process thereof, wherein the preparation process adopts a powder direct tabletting method, so that the problems of poor uniformity and poor stability can be solved, granulation is not needed, and the process is shortened.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a tenofovir disoproxil fumarate tablet, which comprises, by weight, 30-65 parts of tenofovir disoproxil fumarate, 40-50 parts of filler, 3-9 parts of disintegrant, 1-5 parts of glidant and 0.5-2.5 parts of lubricant; the mass ratio of the tenofovir disoproxil fumarate to the filler to the glidant is 40:40-45:3-5.
Preferably, the filler includes at least one of anhydrous lactose, microcrystalline cellulose, anhydrous dibasic calcium phosphate, isomalt, and mannitol.
Further preferably, the filler is anhydrous dibasic calcium phosphate and isomalt.
Preferably, the mass ratio of the anhydrous calcium hydrophosphate to the isomalt is 12-20:5-8.
Preferably, the disintegrant comprises at least one of croscarmellose sodium, pregelatinized starch, and sodium carboxymethyl starch.
Further preferably, the disintegrants are croscarmellose sodium and sodium carboxymethyl starch.
Preferably, the glidant comprises silicon dioxide and/or talc.
Preferably, the lubricant includes at least one of magnesium stearate, sodium lauryl sulfate, and polyethylene glycol.
Further preferably, the lubricant is sodium dodecyl sulfate.
The invention also provides a preparation process of the tenofovir disoproxil fumarate tablet, which comprises the following steps:
s1, weighing a formula amount of filler and tenofovir disoproxil fumarate, and dry-mixing to obtain a dry-mixed mixture;
s2, weighing the disintegrating agent in the formula amount, and mixing with the dry mixture;
s3, weighing the flow aid and the lubricant in the formula amount, mixing the mixture with the material obtained in the step S2, and obtaining a mixture;
s4, pressing the mixture into tablets to obtain the medicine.
Preferably, the pressing method in step S4 employs a powder direct compression method.
Compared with the prior art, the invention has the following beneficial effects:
the invention is based on the specific prescription of tenofovir disoproxil fumarate tablet, can improve the problem of poor uniformity of the powder direct compression method on the basis of ensuring better dissolution rate, and has good stability at high temperature; no pelletization is needed, the preparation method is simple and low in price, and has good market prospect.
Detailed Description
The following description of the present invention is provided by way of specific examples to facilitate understanding and grasping of the technical solution of the present invention, but the present invention is not limited thereto, and the described examples are only some, but not all, examples of the present invention.
As used herein, the singular forms "a," "an," and "the" include the singular and plural referents unless the context clearly dictates otherwise. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that corresponding range, and the endpoints recited.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, shall fall within the scope of the invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are commercially available.
Examples 1-4 tenofovir disoproxil fumarate tablet and preparation process thereof
The components and amounts of tenofovir disoproxil fumarate tablets of examples 1-4 are shown in table 1, where "/" indicates absence.
TABLE 1 Components and amounts of tenofovir disoproxil fumarate tablets
The preparation process of the tenofovir disoproxil fumarate tablets of the above examples 1-4 specifically comprises the following steps:
s1, weighing a formula amount of filler and tenofovir disoproxil fumarate for dry mixing;
s2, weighing the disintegrating agent in the formula amount, and mixing the disintegrating agent with the material obtained in the step S1;
s3, weighing the flow aid and the lubricant in the formula amount, mixing the mixture with the material obtained in the step S2, and obtaining a mixture;
s4, pressing the mixture into tablets by adopting a powder direct compression method, and obtaining the tablet.
Comparative example 1
This comparative example differs from example 1 in that the prescription is different: 15g of anhydrous calcium hydrophosphate and 25g of isomalt. The preparation process was the same as in example 1.
Comparative example 2
This comparative example differs from example 1 in that the prescription is different: 36g of anhydrous calcium hydrophosphate, 12g of isomalt and 2g of silicon dioxide. The preparation process was the same as in example 1.
Comparative example 3
This comparative example differs from example 1 in that the prescription is different: pregelatinized starch replaces isomalt. The preparation process was the same as in example 1.
Comparative example 4
This comparative example differs from example 1 in the preparation process: step S4, wet tabletting is used, and specifically: and (3) after the mixture in the step (S3) is obtained, adding the mixture into a mixing tank of a wet granulator, adding purified water accounting for 4% of the total weight of the mixture, wetting the materials uniformly, stirring to obtain a soft material with proper viscosity, granulating by a 18-mesh sieve, drying at 40 ℃, controlling the moisture of the particles to be within 3.0% based on the dry matter, sieving by a 24-mesh sieve, and tabletting. The recipe is the same as in example 1.
Effect example 1 dissolution test
The tenofovir disoproxil fumarate tablets prepared in examples 1-4 and comparative examples 1-4 were used as test samples for dissolution testing.
According to the second method of the four-part rule 0931 of the year 2020 edition of Chinese pharmacopoeia, 0.01mol/L hydrochloric acid solution is taken as a dissolution medium, the volume is 900mL, and the rotating speed is 50 revolutions per minute. Test solution: taking a proper amount of the dissolved solution, filtering, precisely measuring 3ml of the subsequent filtrate, placing the filtrate into a 50ml measuring flask, diluting to a scale with 0.01mol/L hydrochloric acid solution, and shaking uniformly. Control solution: taking a proper amount of tenofovir disoproxil fumarate reference substance, precisely weighing, adding 0.01mol/L hydrochloric acid solution for dissolution and quantitatively diluting to prepare a solution with about 20 mug in each 1ml, and shaking uniformly. The measurement method comprises taking sample and reference substance, measuring absorbance at 260nm wavelength according to ultraviolet-visible spectrophotometry (Chinese pharmacopoeia 2020 edition four general rule 0401), and sampling and detecting sample dissolution at 2, 5, 10, 15, 25, 35, 45 minutes. The results are shown in the following table.
TABLE 2 dissolution test results (%)
As can be seen from the table, the tenofovir disoproxil fumarate tablets prepared in the examples 1-4 of the invention have a dissolution rate of over 90% within 2min, and the products are basically completely dissolved out after 5min, and meanwhile, the mass ratio of the tenofovir disoproxil fumarate, the filler and the glidant is found to be 40:40-45:3-5, the dissolution effect is better; compared with the wet tabletting of comparative example 4, the direct tabletting has no wet and hot process, improves the stability of the medicine, is more beneficial to the dissolution of the medicine, and can further improve the medicine effect.
Effect example 2 stability detection
The related substances are measured according to high performance liquid chromatography (China pharmacopoeia 2020 edition four general rules 0512). Test solution: taking a tablet, precisely weighing, grinding, precisely weighing a proper amount (about 250mg corresponding to tenofovir disoproxil fumarate), placing in a 100ml measuring flask, adding about 70ml of mobile phase A, carrying out ultrasonic treatment for 10 minutes, cooling, diluting to a scale with the mobile phase A, shaking uniformly, centrifuging, and filtering. 2ml of the subsequent filtrate is measured precisely, placed in a 10ml measuring flask, diluted to the scale with mobile phase A and shaken well. Control solution: taking a proper amount of tenofovir disoproxil fumarate reference substance, precisely weighing, adding the mobile phase A for dissolution, and diluting to prepare a solution containing about 0.5 mug in each 1 ml.
Chromatographic conditions: linear gradient elution was performed using octadecylsilane chemically bonded silica as filler, 0.01mol/L disodium hydrogen phosphate solution (pH adjusted to 5.5 with phosphoric acid) (11:1:28, v/v) as mobile phase A, 0.01mol/L disodium hydrogen phosphate solution (pH adjusted to 5.5 with phosphoric acid) (27:1:12, v/v) as mobile phase B, and methanol-t-butanol as follows; the detection wavelength is 260nm; column temperature is 35 ℃; the sample was introduced in an amount of 10. Mu.l.
TABLE 3 elution procedure
Taking the tenofovir disoproxil fumarate tablets prepared in examples 1-4 and comparative examples 1-4 as test samples for stability test, taking the requirements of stability test guidelines of pharmaceutical preparations in Chinese pharmacopoeia as standards, specifically putting the tenofovir disoproxil fumarate tablets of each group into a condition of 60 ℃ for examining the stability for 15 days, and the results are shown in the following table.
TABLE 4 stability test results
According to the results, the tenofovir disoproxil fumarate tablets of the embodiments 1-4 have low impurity content and good stability under the high-temperature condition; while the comparative examples have poor stability.
Effect example 3 content uniformity
The content uniformity of tenofovir disoproxil fumarate tablets of examples 1-4 and comparative examples 1-4 were examined according to the content uniformity check method of the fourth general rule 0941 of the chinese pharmacopoeia 2020 edition, and the results are shown in the following table.
TABLE 5 content uniformity results
| Group of | Content uniformity (A+2.2S) |
| Example 1 | 1.5 |
| Example 2 | 1.8 |
| Example 3 | 2.0 |
| Example 4 | 2.7 |
| Comparative example 1 | 4.9 |
| Comparative example 2 | 7.2 |
| Comparative example 3 | 5.8 |
| Comparative example 4 | 7.8 |
The results show that the content uniformity of examples 1-4 of the present invention is significantly better than that of the comparative examples, indicating that the formulation of tenofovir disoproxil fumarate affects the content uniformity of the tablet, and that the anhydrous dibasic calcium phosphate and isomalt can exert a synergistic effect during dry blending of the filler and tenofovir disoproxil fumarate, and can improve the problem of poor uniformity. Because the anhydrous calcium hydrophosphate is rough in surface and anhydrous, water is not introduced in the preparation of the tenofovir disoproxil fumarate tablet, and the isomaltulose alcohol has low moisture absorption performance, and the tenofovir disoproxil fumarate can be attached to the surface of the anhydrous calcium hydrophosphate, so that the contact area with other auxiliary materials is increased, the tenofovir disoproxil fumarate is easier to mix with other materials, and the content in the tablet is more uniform. The special prescription of the invention can solve the problem of poor uniformity of the powder direct compression method.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A tenofovir disoproxil fumarate tablet, which is characterized in that: comprises, by weight, 30-65 parts of tenofovir disoproxil fumarate, 40-50 parts of filler, 3-9 parts of disintegrant, 1-5 parts of glidant and 0.5-2.5 parts of lubricant; the mass ratio of the tenofovir disoproxil fumarate to the filler to the glidant is 40:40-45:3-5.
2. Tenofovir disoproxil fumarate tablet according to claim 1, characterized in that: the filler comprises at least one of anhydrous lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, isomalt and mannitol.
3. The tenofovir disoproxil fumarate tablet of claim 2, wherein: the filler is anhydrous calcium hydrogen phosphate and isomalt.
4. A tenofovir disoproxil fumarate tablet according to claim 3, wherein: the mass ratio of the anhydrous calcium hydrophosphate to the isomaltulose alcohol is 12-20:5-8.
5. Tenofovir disoproxil fumarate tablet according to claim 1, characterized in that: the disintegrant comprises at least one of croscarmellose sodium, pregelatinized starch, and sodium carboxymethyl starch.
6. The tenofovir disoproxil fumarate tablet of claim 5, wherein: the disintegrating agent is croscarmellose sodium and sodium carboxymethyl starch.
7. Tenofovir disoproxil fumarate tablet according to claim 1, characterized in that: the glidant comprises silicon dioxide and/or talcum powder.
8. Tenofovir disoproxil fumarate tablet according to claim 1, characterized in that: the lubricant includes at least one of magnesium stearate, sodium lauryl sulfate, and polyethylene glycol.
9. The process for preparing tenofovir disoproxil fumarate tablet as claimed in any one of claims 1-8, characterized in that: the method comprises the following steps:
s1, weighing a formula amount of filler and tenofovir disoproxil fumarate, and dry-mixing to obtain a dry-mixed mixture;
s2, weighing the disintegrating agent in the formula amount, and mixing with the dry mixture;
s3, weighing the flow aid and the lubricant in the formula amount, mixing the mixture with the material obtained in the step S2, and obtaining a mixture;
s4, pressing the mixture into tablets to obtain the medicine.
10. The manufacturing process according to claim 9, characterized in that: the pressing method in the step S4 adopts a powder direct compression method.
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