CN106420759A - Preparation method of tegafur gimeracil oteracil potassium composition - Google Patents
Preparation method of tegafur gimeracil oteracil potassium composition Download PDFInfo
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- CN106420759A CN106420759A CN201610959177.3A CN201610959177A CN106420759A CN 106420759 A CN106420759 A CN 106420759A CN 201610959177 A CN201610959177 A CN 201610959177A CN 106420759 A CN106420759 A CN 106420759A
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- China
- Prior art keywords
- preparation
- gimeracil
- oteracil potassium
- tegafur
- filler
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Abstract
The invention provides a preparation method of a tegafur gimeracil oteracil potassium composition. Particularly, the tegafur gimeracil oteracil potassium composition comprises tegafur, gimeracil, oteracil potassium, a filler and a lubricant. The method comprises the steps that tegafur, gimeracil and oteracil potassium are used as raw materials and mixed for wet granulation, and then the filler and the lubricant are additionally added to obtain the tegafur gimeracil oteracil potassium composition. By means of the preparation method, on the premise that rapidly dissolving-out of active ingredients in preparations is ensured, the prepared tegafur gimeracil oteracil potassium composition reduces the increasing rate of impurities in the product during storage and improves the stability of the product.
Description
Technical field
The invention belongs to field of pharmaceutical preparations is and in particular to a kind of contain containing Tegafur, gimeracil and oteracil potassium
Composition preparation method.
Background technology
Tegafur, gimeracil and oteracil potassium is that a kind of Fluorouracil derivative is administered orally anticancer, and it includes Tegafur (FT) and two categories below is adjusted
Agent：Gimeracil (CDHP) and oteracil (Oxo).The effect of its three kinds of components is as follows：FT is the pro-drug of 5-Fu, has
Excellent oral administration biaavailability, can in vivo be converted into 5-Fu.CDHP can suppress under dihydropyrimidine dehydrogenase acts on
The catabolism of the 5-Fu discharging from FT, contribute in long-time blood and tumor tissues in 5-Fu effective depth, thus taking
Obtain the curative effect similar with 5-Fu Intravenous Infusion.Oxo can block the phosphorylation of 5-Fu, and after oral administration, Oxo is in stomach and intestine
There is in tissue very high distributed density, thus affecting 5-Fu in GI distribution, and then reducing the effect of 5-Fu toxicity.Replace
Ji Ao is had the advantage that compared with 5-Fu：Higher blood concentration can be maintained and improve active anticancer；Significantly reduce medicine toxicity；
Convenient drug administration.Tegafur, gimeracil and oteracil potassium is mainly used in the treatment of late gastric cancer at present.
CN 101574326A discloses a kind of preparation method of tegafur, gimeracil and oteracil potassium capsules and adds it is characterised in that containing in capsule to replace
But fluorine micropill, gimeracil micropill and oteracil potassium micropill are although solve preparation stabilization sex chromosome mosaicism preparation process more
Complexity, is not suitable for industrialized production, and these three micropill particle diameters, density are all variant, capsule charge process, and content uniformity is difficult
To ensure.
CN 103816159A discloses a kind of preparation method of tegafur, gimeracil and oteracil potassium capsules, comprises the following steps that：Lip river will be moored first husky
Nurse heating melting, then gimeracil is dissolved in poloxamer fused solution, mixed with Tegafur and oteracil potassium afterwards
Compound is pelletized, and fills capsule.Although the method solves the problems, such as dissolution rate, complicated process of preparation, be not suitable for industrial metaplasia
Produce.
CN 102302499A discloses a kind of preparation method of tegafur, gimeracil and oteracil potassium capsules, using lauryl sodium sulfate aqueous solution
As wetting agent, wet granulation.Although solving the problems, such as dissolution in vitro, lauryl sodium sulfate may promote for plus
Fluorine and the body absorption of gimeracil, consequently, it is possible to strengthen the toxic and side effect of medicine.
CN101843621A discloses a kind of tegafur, gimeracil and oteracil potassium particle, the method that active constituents of medicine is made cyclodextrin inclusion compound
To solve, to improve dissolution rate and the bioavilability of medicine, but cyclodextrin encapsulated technique is complex, workshop industry metaplasia
Product has inconvenience.
CN101711765A discloses a kind of tegafur, gimeracil and oteracil potassium dispersible tablet, gimeracil and oteracil potassium can in stomach prior to
Tegafur discharges, and oteracil potassium can be made preferably to play the GI effect of protection, gimeracil preferably plays collaborative
The effect of Tegafur, improves the compliance of patient, but technique adopts coating of pellets technology, and plant manufacturing process is complicated.
CN 102614183A discloses a kind of tegafur, gimeracil and oteracil potassium oral solid formulation, and it adopts wet granulation technology, however it is necessary that
Extra add disintegrant and adhesive, technique is relatively complicated, and this kind of technique may lead to that product is unstable simultaneously, and dissolution is not good.
CN103211820A discloses a kind of preparation method of tegafur, gimeracil and oteracil potassium capsules, in capsule contain Tegafur, gimeracil,
Oteracil potassium, microcrystalline cellulose and lubricant, its preparation process is first each to be dissolved in active component in different solution,
Add microcrystalline cellulose afterwards, be then dried so that active ingredient is attached on microcrystalline cellulose, afterwards and mix lubricant, fill
Encapsulated.But this technique increases raw material exposed amount, is unfavorable for preparation stabilization.
CN103142607A discloses a kind of preparation method of tegafur, gimeracil and oteracil potassium capsules preparation, by active component Tegafur, Ji Mei
Pyrimidine, oteracil potassium are dispersed in the aqueous solution of the water wetted material of mannitol, sucrose and lactose, spray after ball mill grinding
Mist is dried, and then with mix lubricant, spray-dried product is uniformly filled capsule afterwards.But this technique increases supplementary material contact journey
Degree, is unfavorable for preparation stabilization.
CN104147012A discloses a kind of method that employing wet granulation prepares tegafur, gimeracil and oteracil potassium oral disintegrated preparation, but institute
Contain disintegrant in the oral disintegrated preparation stated, contain adhesive further, be unfavorable for preparation stabilization.
For obtaining dissolution and all good tegafur, gimeracil and oteracil potassium preparation of stabilizing effect, still there is the improved space to its preparation method
And it is necessary.
Content of the invention
It is an object of the invention to provide a kind of preparation method of tegafur, gimeracil and oteracil potassium composition, methods described process is simple, more suitable
Close the big production of technology.
The present invention provides a kind of preparation method of the composition containing Tegafur, gimeracil and oteracil potassium, concrete and
Speech, described composition contains following component：Tegafur, gimeracil, oteracil potassium, filler, lubricant is it is characterised in that institute
The method of stating comprises the following steps：
(1) Tegafur, gimeracil and oteracil potassium are mixed, add wetting agent to pelletize, be dried, whole grain；
(2) add filler and lubricant, mix.
The viscosity that heretofore described wetting agent refers to can to make mix wetting to produce sufficient intensity is beneficial to makes particle
Liquid.Wetting agent itself is inviscid or viscosity is not strong, but wettable material induce the viscosity of material itself, make it to be agglomerated into
Softwood simultaneously makes particle.
Described in the preparation method that the present invention provides, composition contains the component of following weight portion：Tegafur 5-50 part, Ji Mei
Pyrimidine 1-20 part, oteracil potassium 5-50 part, filler 10-300 part, lubricant 0.1-10 part.
Further, described in the preparation method that the present invention provides, composition contains the component of following weight portion：Tegafur 5-
30 parts, gimeracil 1-10 part, oteracil potassium 5-30 part, filler 50-150 part, lubricant 0.1-5 part.
Composition containing Tegafur, gimeracil and oteracil potassium of the present invention does not contain disintegrant.Institute of the present invention
Stating disintegrant is that this area is conventional, is selected from PVPP, Ac-Di-Sol, crosslinked carboxylic first
One or more of base sodium starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose.
Composition containing Tegafur, gimeracil and oteracil potassium of the present invention does not contain adhesive.
Adhesive of the present invention refers to stickum, is selected from sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl first
One or more of base cellulose, polyvinylpyrrolidone, methylcellulose, ethyl cellulose, starch slurry.
Composition of the present invention does not contain surfactant, and heretofore described surfactant is selected from dodecane
Base sodium sulphate, sodium alkyl sulfonate, laurate, stearic one or more.
In the present invention, the step with regard to mixing with filler after Tegafur, gimeracil and oteracil potassium whole grain, optional
Operation be first plus filler mix after again plus lubricant mixes, or filler is added together with lubricant mixing, preferably
Operation be first plus filler mix after again plus lubricant mix.
The preparation method that the present invention provides is it is characterised in that described wetting agent is selected from purified water, ethanol or its mixture, excellent
Select purified water.
The present invention provide preparation method it is characterised in that described wetting agent consumption be total weight 5-
50%, preferably 10-40%, most preferably 15-30%.
The preparation method that the present invention provides is it is characterised in that described baking temperature is selected from 30-80 DEG C, preferably 40-70 DEG C.
The preparation method that the present invention provides, further comprises the mixture direct tablet compressing obtaining in step (2) or filling
Encapsulated step.
The preparation method that the present invention provides is it is characterised in that described filler is selected from sugar or glycitols, preferably lactose, sweet dew
One or more of alcohol, xylitol, sorbierite and erythrite.
The preparation method that the present invention provides is it is characterised in that described filler is lactose or mannitol.
Lubricant in the present invention is not particularly limited, it is possible to use the conventional lubricant in this area, such as magnesium stearate,
One or more of talcum powder, silica.
The present invention also provides the composition preparing by said method.The composition that the present invention provides can be tablet
Or capsule.
Compared with prior art, have the following advantages that when the tegafur, gimeracil and oteracil potassium composition that the present invention provides is for capsule preparations：1)
Prescription is simple, does not contain surfactant, do not produce impact to the body absorption of medicine in prescription；2) reduce connecing between supplementary material
Tactile degree, improves preparation stability, drug-eluting is complete rapidly simultaneously；3) using granulation and hybrid technique, preparation process is simple,
Suitable industrialized production.
Specific embodiment
Further describe the present invention by following examples.These embodiment being merely to illustrate property purposes, and not
For limiting the scope of the present invention.
Embodiment 1 to 5
Preparation technology：In the ratio in table 1, supplementary material is crossed 80 mesh sieves, three kinds of raw materials are mixed, add and purify
Water, is pelletized using Glatt wet granulator, 60 DEG C of dryings, and 30 mesh sieves do whole grain, additional filler and magnesium stearate, and mixing is all
Even, fill capsule, prepare tegafur, gimeracil and oteracil potassium capsules.
Table 1
Comparative example 1～4
Preparation technology：In the ratio in table 2, supplementary material is crossed 80 mesh sieves, three kinds of raw materials are mixed, add and purify
Water, is pelletized using Glatt wet granulator, 60 DEG C of dryings, and 30 mesh sieves do whole grain, additional filler and magnesium stearate, and mixing is all
Even, fill capsule, prepare tegafur, gimeracil and oteracil potassium capsules.
Table 2
Comparative example 5～8
Preparation technology：In the ratio in table 3, supplementary material is crossed 80 mesh sieves, mixes, then with purified water for wetting
Agent, is pelletized using Glatt wet granulator, 60 DEG C of dryings, and 30 mesh sieves do whole grain, and additional magnesium stearate mixes, and fills glue
Capsule, prepares tegafur, gimeracil and oteracil potassium capsules.
Table 3
Embodiment 1～5 and comparative example 1～4：Dissolution determination
Using dissolution method (Chinese Pharmacopoeia version general rule 0,931 second method in 2015), Example 1～5 and contrast are real
Apply the capsule in example 1～4, with purification of aqueous solutions as dissolution medium, rotating speed is 50 revs/min, and temperature is 37 ± 0.5 DEG C, in accordance with the law
Operation, in 15min, is taken dissolution fluid 10ml, by dissolution fluid with 0.45 μm of membrane filtration, is replaced using high effective liquid chromatography for measuring
The dissolution rate of Tegafur, gimeracil and oteracil potassium in lucky Austria capsule, limit is the 85% of labelled amount, and dissolution the results are shown in Table
4.
Table 4
Dissolution test result shows：Embodiment 1～5 (filler is lactose or glycitols) active component is 15min's
Dissolution rate is all higher than 85%, and dissolution is rapid.And comparative example 1～4 active component 15min dissolution rate all significantly less than
85%, dissolution rate is unqualified.
Embodiment 1～5 and comparative example 5～8：Preparation stability is investigated
(1) influence factor test：Tegafur, gimeracil and oteracil potassium capsules in Example 1～5 and comparative example 5～8 are appropriate, put respectively
Place under the conditions of strong illumination (4500lx ± 500lx), high temperature (60 DEG C, high humidity 90%), took respectively at the 5th day and the 10th day
Sample checks relevant material, the results are shown in Table 5：
Table 5
(2) accelerated test：Tegafur, gimeracil and oteracil potassium capsules in Example 1～5 and comparative example 5～8, underlying in commercially available back
Place 6 months in 40 DEG C of temperature, the climatic chamber of relative humidity 75%, and in the 1st, 2,3,6 the end of month take a sample to check relevant
Material, the results are shown in Table 6：
Table 6
Influence factor test and accelerated test result show, the relevant material of capsule of the present invention does not have significant change substantially,
Illustrate that the tegafur, gimeracil and oteracil potassium capsules preparation stability prepared by the present invention is good, and comparative example then has more degradation impurity to produce.
Claims (14)
1. a kind of preparation method of the composition containing Tegafur, gimeracil and oteracil potassium, described composition contains such as the following group
Point：Tegafur, gimeracil, oteracil potassium, filler, lubricant is it is characterised in that the method comprising the steps of：1)
Tegafur, gimeracil and oteracil potassium are mixed, adds wetting agent to pelletize, be dried, whole grain；2) add filler and
Lubricant, mixes.
2. preparation method according to claim 1 is it is characterised in that described composition contains the component of following weight portion：Replace and add
Fluorine 5-50 part, gimeracil 1-20 part, oteracil potassium 5-50 part, filler 10-300 part, lubricant 0.1-10 part.
3. preparation method according to claim 2 is it is characterised in that described composition contains the component of following weight portion：Replace and add
Fluorine 5-30 part, gimeracil 1-10 part, oteracil potassium 5-30 part, filler 50-150 part, lubricant 0.1-5 part.
4. preparation method according to claim 3 is not it is characterised in that described composition contains disintegrant.
5. preparation method according to claim 4 it is characterised in that described disintegrant be selected from PVPP,
One of Ac-Di-Sol, crosslinked carboxymethyl fecula sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or
Multiple.
6. preparation method according to claim 3 is not it is characterised in that described composition contains adhesive.
7. preparation method according to claim 6 is it is characterised in that described adhesive is selected from sodium carboxymethylcellulose, hydroxyl
One of propyl cellulose, HPMC, polyvinylpyrrolidone, methylcellulose, ethyl cellulose, starch slurry
Or it is multiple.
8. preparation method according to claim 3 is not it is characterised in that described composition contains surfactant.
9. preparation method according to claim 8 it is characterised in that described surfactant be selected from lauryl sodium sulfate,
Sodium alkyl sulfonate, laurate, stearic one or more.
10. preparation method according to claim 3 is it is characterised in that described wetting agent is selected from purified water, ethanol or it is mixed
Compound, preferably purified water.
11. preparation methods according to claim 10 are it is characterised in that the consumption of described wetting agent is composition total weight
5-50%, preferably 10-40%, most preferably 15-30%.
12. preparation methods according to claim 3, further comprise step 2) in the mixture compressing tablet that obtains or filling
Encapsulated step.
13. preparation methods according to claim 3 are it is characterised in that described filler is selected from sugar or glycitols, preferably newborn
One or more of sugar, mannitol, xylitol, sorbierite and erythrite, more preferably lactose or mannitol.
The composition that preparation method described in a kind of 14. any one according to claim 1-13 obtains.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610959177.3A CN106420759B (en) | 2016-11-03 | 2016-11-03 | A kind of preparation method of tegafur, gimeracil and oteracil potassium composition |
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|---|---|---|---|
| CN201610959177.3A CN106420759B (en) | 2016-11-03 | 2016-11-03 | A kind of preparation method of tegafur, gimeracil and oteracil potassium composition |
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| CN106420759A true CN106420759A (en) | 2017-02-22 |
| CN106420759B CN106420759B (en) | 2019-03-12 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103816159A (en) * | 2014-03-20 | 2014-05-28 | 山东新时代药业有限公司 | Tegafur gimeracil oteracil potassium capsule and preparation method thereof |
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2016
- 2016-11-03 CN CN201610959177.3A patent/CN106420759B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103816159A (en) * | 2014-03-20 | 2014-05-28 | 山东新时代药业有限公司 | Tegafur gimeracil oteracil potassium capsule and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| R.C.罗等编: "《药用辅料手册》", 31 January 2005, 化学工业出版社 * |
| 崔福德: "《药剂学》", 31 August 2007, 人民卫生出版社 * |
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