CN113967197A - Trifluridine and tipepidine hydrochloride compound tablet and preparation method thereof - Google Patents

Trifluridine and tipepidine hydrochloride compound tablet and preparation method thereof Download PDF

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CN113967197A
CN113967197A CN202010726009.6A CN202010726009A CN113967197A CN 113967197 A CN113967197 A CN 113967197A CN 202010726009 A CN202010726009 A CN 202010726009A CN 113967197 A CN113967197 A CN 113967197A
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trifluridine
tipepidine
hydrochloride
compound tablet
tablet
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CN113967197B (en
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张贵民
郝贵周
杨永
刘忠
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Lunan Pharmaceutical Group Corp
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract

The invention belongs to the technical field of medicinal preparations, and particularly relates to a trifluridine and tipepidine hydrochloride compound tablet which is prepared by the following method: the trifluridine and the tipepidine hydrochloride are mixed with the starlac, then the pharmaceutically common auxiliary materials are added, the mixture is mixed, tableted and coated, and the compound tablet of the trifluridine and the tipepidine hydrochloride prepared by the method has the advantages of small using amount of the auxiliary materials, simple preparation process, good stability of the product and high dissolution speed, and is suitable for industrial production.

Description

Trifluridine and tipepidine hydrochloride compound tablet and preparation method thereof
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a trifluridine and tipepidine hydrochloride compound tablet and a preparation method thereof.
Background
Trifloxuridine (Trifluridine and Tipiracil Hydrochloride, TAS-102, also known as Trifluridine pridine) consists of Trifluridine and a thymine phosphorylase inhibitor, i.e., pirimidine, in a weight ratio of 2:1, and is an oral fluorouracil drug. The mechanism of action of trifluridine tipyrimidine is that after it is taken into cancer cells, trifluridine is incorporated into the DNA of cancer cells, interfering with the synthesis of the DNA of cancer cells and inhibiting the proliferation of cancer cells, while tipyrimidine inhibits the metabolism of trifluridine by thymidine phosphorylase to increase the exposure of trifluridine, and pharmacological experiments prove that trifluridine/tipyrimidine shows antitumor activity against KRAS wild-type and mutant human colorectal cancers in xenografted mice. Trifluridine tipyrimidine, approved by the U.S. FDA at 22/9/2015 for treatment of refractory metastatic colorectal cancer (mCRC) patients who no longer respond to other therapies (chemotherapeutics and biotherapeutics) and approved by european EMA at 2016 at 4, is currently approved in 21 countries and regions of japan, the united states, the uk, canada, the european union, etc. for treatment of metastatic colorectal cancer (mCRC), and is in the registration reporting phase in china, and is also recommended for metastatic colorectal cancer patients (mCRC) who have previously received fluoropyrimidines, oxaliplatin and irinotecan chemotherapy and targeted therapy, based on high-level evidence of evidence and good clinical use experience.
CN101107001A discloses an anticancer agent containing α, α, α -trifluorothymidine and a thymidine phosphorylase inhibitor, and many kinds of excipients are used in the formulation, and the stability of the obtained preparation has not been studied.
CN104105491B discloses a pharmaceutical composition for oral administration containing FTD and TPI, which uses excipient containing saccharide with critical relative humidity above 85% at 25 deg.C to promote tablet stability, but the obtained product has great difference in stability data of one week, two weeks and one month in stability test of 40 deg.C and 75% humidity, the content of total analogues, i.e. total impurities, is increased from 0.00% to 0.40%, which indicates that the self stability of the obtained pharmaceutical composition or tablet is still to be improved.
CN 104105490 a discloses a pharmaceutical composition for oral administration, which is prepared by adding an additive comprising a metal salt to a formulation in such a small amount that the stability of FTD and TPI is not impaired, and an excipient selected from the group consisting of sugar alcohols and disaccharides, and adding 2 to 16% of a disintegrant to improve the disintegratability in oral administration.
CN 105963271A discloses a pharmaceutical adjuvant composition and a trifluridine and hydrochloric acid-substituted pyrimidine film-coated tablet, wherein stearic acid is used for replacing magnesium stearate, so as to solve the problems that tablet cores cannot be formed, split, loose, cannot be coated and the like when the magnesium stearate is used as a lubricant for preparing the trifluridine and hydrochloric acid-substituted pyrimidine film-coated tablets, the hardness of the obtained tablet is 5-11N, and the problem that the formability of the obtained tablet is poor is reflected basically under the critical value (10-200N) of the qualified hardness standard of the tablet.
CN 106913580A discloses a pharmaceutical composition containing trifluridine hydrochloride tepa inhaul and application thereof, the pharmaceutical composition specifically comprises FTD, TPI, lactose, pregelatinized starch and glyceryl behenate, the stability of the pharmaceutical composition is improved under high temperature and high humidity conditions, but after raw materials of FTD and TPI are mixed, the raw materials are crushed to the diameter D90 of less than or equal to 100 mu m, after mixed API is obtained, more auxiliary materials are used for preparation, and the preparation is not favorable for improving the safety of medicine taking, in the content of the invention, the total impurity content of the tablet obtained in example 3 in 17 days is increased by nearly 1 time compared with the total impurity content in 7 days, the impurity TPI-B content of the coated tablet obtained in example 3 in 10 days is increased by 1.6 times compared with the content in 7 days, namely, the total impurity content of the pharmaceutical composition obtained in the invention is increased by 1.6 times compared with the impurity content of the tablet sold in markets
Figure BDA0002601697250000021
Decreases, but the stability thereof still remains to be improved.
The trifluridine and tipepidine hydrochloride compound preparation is mainly a common oral compressed tablet, in the preparation of the tablet, in order to ensure that the tablet is easy to take orally, auxiliary materials except main components such as excipient, adhesive, disintegrant, lubricant, flavoring agent and the like are usually added, and the auxiliary materials influence the stability and the weight of the tablet and need to be carefully selected; in addition, when the tablet of the product obtained by the preparation is heavy, the compliance of patients is poor, and when the stability of the obtained product is poor, an independent packaging bag is needed to increase the production cost, which is more unfavorable for environmental protection. In the prior art, the compound preparation of trifluridine and tipepidine hydrochloride has the problems of complex preparation prescription, poor stability, poor formability, poor dissolution performance and the like. Therefore, the development of a novel trifluridine hydrochloride and tipepidine compound tablet is an urgent requirement for the technical personnel in the field.
Disclosure of Invention
In view of the technical problems of the preparation of the compound preparation of trifluridine and tipepidine hydrochloride in the prior art, the invention provides a compound tablet of trifluridine and tipepidine hydrochloride, and the effects of good formability, high dissolution performance and good stability of the obtained tablet are achieved by screening appropriate auxiliary materials, formula proportion and preparation process. The compound preparation of trifluridine and tipepidine hydrochloride and the preparation method thereof provided by the invention have the advantages of fewer types of preparation auxiliary materials, simple preparation process and suitability for industrial production.
A compound tablet of trifluridine and tipepidine hydrochloride comprises trifluridine, tipepidine hydrochloride, starlac and pharmaceutically common adjuvants.
The preparation method of the trifluridine and tipepidine hydrochloride compound tablet comprises the following steps: mixing trifluridine, tipepidine hydrochloride and starlac, adding pharmaceutically-used adjuvants, mixing, tabletting, and coating.
Preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the weight ratio (g/g) of the trifluridine to the tarlac is 1: 2-6.
Further preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the weight ratio (g/g) of the trifluridine to the starlac is 1: 2-4.
More preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the weight ratio (g/g) of the trifluridine to the tarlac is 1: 2-3.
Preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the pharmaceutically commonly used auxiliary material is a lubricant, and the dosage of the auxiliary material is 1-2% of the weight (g/g) of the plain tablet of the compound tablet.
Further preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the lubricant is stearic acid, glycerol diformate, talcum powder and silicon dioxide.
More preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the lubricant is stearic acid.
Preferably, in the compound tablet of trifluridine and tipepidine hydrochloride, the molar ratio of trifluridine to tipepidine hydrochloride is 2:1, and the total weight (g/g) of trifluridine and tipepidine hydrochloride accounts for 19-42% of the compound tablet, the total weight (g/g) of starlac accounts for 57-79% of the compound tablet, and the weight (g/g) of the lubricant accounts for 1-2% of the compound tablet.
Further preferably, in the compound tablet of trifluridine and tipepidine hydrochloride, the molar ratio of trifluridine to tipepidine hydrochloride is 2:1, and the total amount of trifluridine and tipepidine hydrochloride accounts for 32-42%, the total amount of stallac accounts for 57-66% and the amount of lubricant accounts for 1-2% of the weight (g/g) of the compound tablet.
The type and amount of the coating material and the operation of the compound tablet of trifluridine and tipepidine hydrochloride are not particularly limited, and the coating material may be appropriately selected, and the coating layer may contain a small amount of additives such as a colorant, a flavoring agent, a lubricant, and the like, to such an extent that the stability of trifluridine and tipepidine hydrochloride is not substantially affected.
The trifluridine and tipepidine hydrochloride compound tablet and the preparation method thereof have the following advantages:
(1) the prescription of the trifluridine and tipepidine hydrochloride compound tablet has fewer types of auxiliary materials;
(2) the prescription of the trifluridine and tipepidine hydrochloride compound tablet does not need to be additionally added with a disintegrant;
(3) the preparation process of the trifluridine and tipepidine hydrochloride compound tablet is simple;
(4) the trifluridine and tipepidine hydrochloride compound tablet prepared by the invention has good formability, rapid dissolution and better stability.
Detailed Description
The advantages of the present invention are further described below by way of examples, it being properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
(I) prescription
Figure BDA0002601697250000041
(II) the preparation process comprises the following steps:
respectively crushing trifluridine and tipepidine hydrochloride, sieving by a 100-mesh sieve, weighing according to a prescription amount, mixing with a starlac according to the prescription amount, adding stearic acid, mixing, tabletting, and coating the obtained plain tablets with an opadry solution with the solid content of about 7% (weighing 27g of opadry, adding 360g of purified water, magnetically stirring for 2h, filtering by a 120-mesh sieve, and taking the filtrate, namely the 7% opadry solution).
Example 2
(I) prescription
Figure BDA0002601697250000042
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 120 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with stearic acid, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. a 7% opadry solution.
Example 3
(I) prescription
Figure BDA0002601697250000043
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, mixed with tarlac according to the prescription, added with stearic acid, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Example 4
(I) prescription
Figure BDA0002601697250000051
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with silicon dioxide, mixed and tabletted, and the obtained plain tablets were coated with the same coating solution as the preparation method of example 1, i.e. 7% opadry solution.
Example 5
(I) prescription
Figure BDA0002601697250000052
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with talc powder, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Example 6
(I) prescription
Figure BDA0002601697250000053
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 100 mesh sieve, weighed according to the prescription, mixed with tarlac according to the prescription, added with glycerol dicarboxylate, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation of example 1, i.e. a 7% opadry solution.
Example 7
(I) prescription
Figure BDA0002601697250000061
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with talc powder, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Example 8
(I) prescription
Figure BDA0002601697250000062
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, magnesium stearate was added, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. a 7% opadry solution.
Comparative example 1
(I) prescription
Figure BDA0002601697250000063
(II) the preparation process comprises the following steps:
1) respectively crushing trifluridine and tipepidine hydrochloride, and sieving by a 80-mesh sieve for later use; 2) mixing the trifluridine obtained in the step 1 and the tipepidine hydrochloride, and then uniformly mixing the mixture with the lactose, the pregelatinized starch and the stearic acid in the prescribed amount to obtain an intermediate; 3) calculating the weight of the tabletting sheets according to the FTD content in the intermediate, and tabletting; 4) detecting the quality of the tablet core after tabletting, and coating according with the coating conditions, wherein the coating specifically comprises the following steps: adding water into Opadry gastric-soluble film coating premix to obtain solution, and coating.
Comparative example 2:
50g of trifluridine, 23.55g of tipepidine hydrochloride, 196.45g of lactose hydrate, 30g of corn starch as a disintegrant and 3g of stearic acid were mixed in a polyethylene bag, and the mixture was formed into a general tablet having a mass of 121.2mg by a rotary tablet machine, and the obtained plain tablet was coated with a 7% opadry solution which was the same coating solution as the preparation method of example 1.
Comparative example 3:
50g of trifluridine, 23.55g of tipepidine hydrochloride, 196.45g of lactose hydrate, 30g of partially gelatinized starch as a disintegrant, and 3g of stearic acid were mixed in a polyethylene bag, and the mixture was formed into a general tablet having a mass of 121.2mg by a rotary tablet machine, and the obtained plain tablet was coated with a 7% opadry solution which was the same coating solution as the preparation method of example 1.
Comparative example 4:
50g of trifluridine, 23.55g of tipepidine hydrochloride, 196.45g of lactose hydrate, 30g of low-substituted hydroxypropylcellulose as a disintegrant, and 3g of stearic acid were mixed in a polyethylene bag, and the mixture was formed into a general tablet having a mass of 121.2mg by a rotary tablet machine, and the obtained plain tablet was coated with a 7% opadry solution which was the same coating solution as that of the preparation method of example 1. Comparative example 5:
(I) prescription
Figure BDA0002601697250000071
(II) the preparation process comprises the following steps:
weighing trifluridine and tipepidine hydrochloride according to the prescription amount, mixing with lactose, corn starch and hydroxypropyl cellulose according to the prescription amount, and preparing granules.
Comparative example 6:
(I) prescription
Figure BDA0002601697250000072
Figure BDA0002601697250000081
(II) the preparation process comprises the following steps:
weighing trifluridine and tipepidine hydrochloride according to the prescription amount, mixing with lactose and crystalline cellulose according to the prescription amount, adding magnesium stearate, and preparing capsules.
Comparative example 7:
(I) prescription
Figure BDA0002601697250000082
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 100 mesh sieve, weighed according to the prescription, then mixed with lactose and corn starch according to the prescription, and then stearic acid was added, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Verification examples
Measurement of hardness: measured using a tablet hardness tester.
Determination of dissolution: according to the determination method of dissolution rate and release rate of the four parts (0931) of the Chinese pharmacopoeia 2015 edition, the dissolution conditions are that potassium dihydrogen phosphate-sodium hydroxide solution with pH6.8 is used as dissolution medium, the volume is 900mL, the rotating speed is 50 r/min, 5mL is sampled in 5 minutes, and then filtered, and the subsequent filtrate is taken and determined according to the following method: the mobile phase is disodium hydrogen phosphate solution (8.92 g of disodium hydrogen phosphate is taken, water is added to 1000mL, the pH value is adjusted to 7.3 by phosphoric acid) -methanol (76:24), an ultraviolet detector is used for detecting the wavelength of 275nm, octadecylsilane chemically bonded silica is used as a filler for a chromatographic column, Waters Xbridge is used, the particle size of the filler is 5 mu m, and the length is 150 cm; flow rate: 1.0mL/min, sample size: 10 mu; preparation of a reference solution: taking a trifluridine reference substance and a tipepidine hydrochloride reference substance, precisely weighing, dissolving with water, and quantitatively diluting to prepare a mixed solution containing about 22 mu g of trifluridine and 10 mu g of tipepidine hydrochloride in 1mL, wherein the mixed solution is used as a reference substance solution; the determination method comprises the following steps: the elution amount of trifluridine and tipepidine hydrochloride in each tablet is calculated by an external standard method.
And (3) determination of the total impurity content in related substances: the tablets obtained in examples 1 to 8 and comparative examples 1 to 7 were stored open at 40 ℃/75% r.h. for 3 months, and the total analog content (i.e., total impurities) was measured, and the total analog mass was calculated by taking peaks other than the peaks of trifluridine, tipirimidine hydrochloride and additives as analog mass peaks and calculating the total of the similar substance amounts based on the effective component area from the areas.
Measurement results of examples and comparative examples
Figure BDA0002601697250000091
Figure BDA0002601697250000101

Claims (10)

1. The compound tablet of trifluridine and tipepidine hydrochloride is characterized by comprising trifluridine, tipepidine hydrochloride, starlac and pharmaceutically commonly used auxiliary materials.
2. The compound tablet of claim 1, wherein the weight ratio of trifluridine to starlac is 1: 2-6.
3. The compound tablet according to claim 1 or 2, wherein the weight ratio of trifluridine to starlac is 1: 2-4.
4. The compound tablet according to claim 1 or 2, wherein the weight ratio of trifluridine to starlac is 1: 2-3.
5. The compound tablet according to claim 1, wherein the pharmaceutically common auxiliary material is a lubricant, and the dosage of the lubricant is 1-2% of the weight of the tablet of the compound tablet.
6. The compound tablet of claim 5, wherein the lubricant is stearic acid, a glycol ester, talc, and silicon dioxide.
7. The compound tablet of claim 5 or 6, wherein the lubricant is stearic acid.
8. The compound tablet according to claim 1, wherein the molar ratio of trifluridine to tipepidine hydrochloride is 2:1, and the total amount of trifluridine and tipepidine hydrochloride is 19-42%, the amount of stallac is 57-79% and the amount of lubricant is 1-2% of the weight of the compound tablet.
9. The compound tablet according to claim 1, wherein the molar ratio of trifluridine to tipepidine hydrochloride in the compound tablet of trifluridine and tipepidine hydrochloride is 2:1, and the total amount of trifluridine and tipepidine hydrochloride is 32-42%, the total amount of stalllac is 57-66% and the amount of lubricant is 1-2% of the weight of the compound tablet.
10. The preparation method of the compound tablet as claimed in claim 1, wherein the preparation method comprises the steps of fully mixing trifluridine, tipepidine hydrochloride and starlac, adding pharmaceutically common auxiliary materials, mixing, tabletting and coating.
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Citations (5)

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CN106551946A (en) * 2015-09-24 2017-04-05 江苏奥赛康药业股份有限公司 It is a kind of containing trifluorothymidine and hydrochloric acid for the pharmaceutical composition and preparation method than pyrimidine
CN109999053A (en) * 2019-04-26 2019-07-12 周德旺 Trifluridine or Trifluridine replace the medical usage of a pyrimidine compositions
WO2019171394A1 (en) * 2018-03-03 2019-09-12 Natco Pharma Limited Stable pharmaceutical compositions comprising trifluridine and tipiracil hydrochloride

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102885787A (en) * 2011-07-22 2013-01-23 重庆华邦制药股份有限公司 Moxifloxacin hydrochloride tablets for preventing color change and cracking and preparation method thereof
CN106551946A (en) * 2015-09-24 2017-04-05 江苏奥赛康药业股份有限公司 It is a kind of containing trifluorothymidine and hydrochloric acid for the pharmaceutical composition and preparation method than pyrimidine
CN105963271A (en) * 2016-06-01 2016-09-28 国药心制药有限公司 Pharmaceutical adjuvant composition and floxuridine and hydrochloric acid substituted pyrimidine film-coated tablets
WO2019171394A1 (en) * 2018-03-03 2019-09-12 Natco Pharma Limited Stable pharmaceutical compositions comprising trifluridine and tipiracil hydrochloride
CN109999053A (en) * 2019-04-26 2019-07-12 周德旺 Trifluridine or Trifluridine replace the medical usage of a pyrimidine compositions

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