CN103142520B - Kelimycin tablet and preparation method thereof - Google Patents
Kelimycin tablet and preparation method thereof Download PDFInfo
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- CN103142520B CN103142520B CN201310082805.0A CN201310082805A CN103142520B CN 103142520 B CN103142520 B CN 103142520B CN 201310082805 A CN201310082805 A CN 201310082805A CN 103142520 B CN103142520 B CN 103142520B
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Abstract
The invention relates to a kelimycin tablet and a preparation method thereof. The kelimycin tablet comprises kelimycin and a tablet core comprising pharmaceutically acceptable adjuvants; and the pharmaceutically acceptable adjuvants include microcrystalline cellulose, carboxymethyl starch sodium, povidone K30 and magnesium stearate. The preparation method comprises the following step of: preparing the medicated tablet core, wherein an inside and outside addition method is adopted for the carboxymethyl starch sodium in the preparation of the medicated tablet core. The kelimycin tablet disclosed by the invention has the advantages of faster disintegration and better dissolution rate, and is easy to granulate. The preparation method of the kelimycin tablet has the advantages of simple process, large production quantity and low production cost, and easily realize hygienic standard and is suitable for large-scale mechanized production.
Description
Technical field
The invention belongs to the improvement of pharmaceutical dosage form, relate to a kind of Kelimycin tablet and preparation method thereof specifically.
Background technology
Rokitamycin (Kelimycin); cooperated with the applicant by China Medical institute biotechnology research also known as Bitespiramycin (Bitespiramycin), shengjimycin (Shengjimycin); by transgenic technology by 4 ' of Deltamycin A4 producing strains ' and isovaleryl transferase group (4 ' '-o-acyl-transferase) be cloned in spiramycin-producing strain; directed acidylated spiramycin 4 ' '-OH, 4 ' ' position add that isovaleryl side chain formed with 4 ' ' position isovaleryl spiramycin is the new antibiotic of key component.
Rokitamycin is made up of multiple spiramycin derivant, and main active isovaleryl spiramycin (I+II+III) total content is not less than 65%, 4 ' ' total content of acidylated spiramycin is not less than 80%, in being pharmaceutically a kind of acceptable pharmaceutical composition.Division center is 16 yuan of lactonic rings; be formed by connecting with a part good fortune Lip river amine sugar, a part mycaminose and a part 2,6-didesoxy-3-C-methyl-L-ribo-hexose, its main component isovaleryl Spiramycin I, II, III are 2,6-didesoxy-3-C-methyl-L-ribo-hexose 4 ' with spiramycin structure difference ' group that position is connected is isovaleryl instead of hydroxyl.The chemical constitution of rokitamycin, as the formula (1), comprises more than ten altogether and plants component.Current rokitamycin finished product composition standard is isovaleryl spiramycin III >=30%, ratio summation >=65% of isovaleryl Spiramycin I, II, III, ratio >=80% of total acidylated spiramycin, spiramycin≤5% of non-acidylate.
Formula (1)
Rokitamycin belongs to 16 membered macrolide antibiotic, and have the C=C of active group carboxyl, alkoxyl, epoxy radicals, ketone group and aldehyde radical and a pair conjugation, molecular weight is about 884 ~ 982.Owing to having similar chemical constitution, rokitamycin and macrolide antibiotics have a lot of general character: be soluble in most of organic solvents such as esters, acetone, chloroform, alcohols, be slightly soluble in petroleum ether, be insoluble in water; Contain two dimethylamino in molecular structure and in alkalescence, be soluble in acidic aqueous solution; Character that the rising with solubility with temperature reduces " negative dissolubility ".Due to rokitamycin key component isovaleryl spiramycin 4 ', ' position carbochain longer, hydrophilic is poor, and in its water, dissolubility is than spiramycin and 4 ' '-acetyl helicase is little.
Rokitamycin is a kind of white noncrystalline powder, slightly draws moist, specific optical rotation
be about-80.8 °, ultraviolet maximum absorption wavelength is 231 ~ 232nm, and itself is with hypofluorescence chromophoric group, and chance concentrated sulphuric acid or hydrochloric acid are purple color reaction, produces intense violet color fluorescence, has maximum light absorption value at 231 ~ 232nm place.
This medical instrument has lipotropy good, and tissue penetration capacity is strong, and oral absorption is fast, and length of holding time in body, has lasting post antibiotic effect.According to the relation of drug effect and chemical configuration; macrolide antibiotics 4 ' ' after the acidylate of position; its lipotropy and activity in vivo improve; antibacterial activity in vivo and clinical therapeutic efficacy all obtain remarkable lifting; and antibiotic stability is in vivo along with 4 ' ' carbochain of hydroxy ester increases and strengthens, i.e. isovaleryl spiramycin > propionylspiramycin > acetylspiramycin.
Preliminary inside and outside pharmacodynamics test shows, this medicine is not only to most G
+bacterium has better antibacterial activity, to part G
-bacterium also has certain effect, all technical is obviously better than erythromycin, acetylspiramycin, midecamycin, especially the strongest to the antibacterial activity of mycoplasma pneumoniae, also there is certain antibacterial activity to erythromycin-resistant bacterium, gonococcus, hemophilus influenza, bacteroides fragilis, legionella, multirow bacillus and bacillus perfringens, only have few cross resistance to the staphylococcus aureus of clinical resistance to erythromycin.Rokitamycin will be mainly used in treatment gram positive bacteria infection disease, especially upper respiratory tract infection, and may be used for urinary system infection etc.
Clinical research proves, rokitamycin is an oral antibiotic safely and effectively.But the research carried out for rokitamycin preparation is also less, and especially rokitamycin is as a kind new medicine, less to the report of its preparation research.
The applicant proposes on May 25th, 2011 patent application that application number is 201110136228.X, denomination of invention is " left-handed rokitamycin, its pharmaceutical composition, preparation method and application ", wherein embodiment 12 discloses a kind of left-handed rokitamycin element sheet, and its prescription is calculated as by 10000: the former powder 1000g of left-handed rokitamycin, low-substituted hydroxypropyl cellulose (5%) 92.5g, carboxymethyl starch sodium (3%) 55.5g, magnesium stearate (1%) 18.5g, starch are that gross weight deducts other supplementary material weight, gross weight 1850g; Also disclose the method this plain sheet being made coated tablet, enteric coatel tablets and gastric soluble tablet simultaneously.But further study discovery through the present inventor, because the bonding force of rokitamycin and hygroscopicity are comparatively strong and starch has stronger cohesive, adopt the obtained soft material of this plain tablet recipe not easily to sieve, granulate more difficult, and obtained disintegration of tablet is slow, dissolution rate is bad.
In view of this, special proposition the present invention.
Summary of the invention
Object of the present invention is just to solve the problems of the technologies described above, and provides a kind of and granulates easily, disintegrate is very fast, the good Kelimycin tablet of dissolution rate.
For realizing object of the present invention, the present invention adopts following technical scheme:
A kind of Kelimycin tablet, wherein, described Kelimycin tablet comprises the label be made up of rokitamycin and pharmaceutically acceptable adjuvant; Described pharmaceutically acceptable adjuvant is microcrystalline Cellulose, carboxymethylstach sodium, 30 POVIDONE K 30 BP/USP
30and magnesium stearate.
Kelimycin tablet of the present invention, wherein, described microcrystalline Cellulose and the mass ratio of rokitamycin are 0.35 ~ 1.1:1, preferably 0.55 ~ 1.03:1;
Described carboxymethylstach sodium and the mass ratio of rokitamycin are 0.08 ~ 0.15:1, preferably 0.11 ~ 0.135:1;
Described 30 POVIDONE K 30 BP/USP
30be 0.06 ~ 0.12:1, preferably 0.075 ~ 0.1:1 with the mass ratio of rokitamycin;
Described magnesium stearate and the mass ratio of rokitamycin are 0.01 ~ 0.022:1, preferably 0.015 ~ 0.02:1.
The embodiment 12 of CN201110136228.X discloses a kind of left-handed rokitamycin element sheet, and its prescription is calculated as by 10000: the former powder 1000g of left-handed rokitamycin, low-substituted hydroxypropyl cellulose (5%) 92.5g, carboxymethyl starch sodium (3%) 55.5g, magnesium stearate (1%) 18.5g, starch are that gross weight deducts other supplementary material weight, gross weight 1850g; Also disclose the method this plain sheet being made coated tablet, enteric coatel tablets and gastric soluble tablet simultaneously.But because the bonding force of rokitamycin and hygroscopicity are comparatively strong and starch has stronger cohesive, adopt the obtained soft material of this plain tablet recipe not easily to sieve, granulates more difficult, and obtained disintegration of tablet slowly, dissolution rate is bad.
The present invention complexity, the outward appearance of sheet, the hardness of sheet, disintegration time four indexs of sheet that by a large amount of experiment investigation, different prescription is granulated, finally determine Core formulation of the present invention.Through comparing discovery, compared with prior art, dissolution is greatly improved prescription of the present invention.
Specifically, Kelimycin tablet of the present invention, wherein, described label composed as follows:
Or
In the present invention, described 30 POVIDONE K 30 BP/USP
30for 30 POVIDONE K 30 BP/USP
30aqueous solution, preferred 5%(w/w) 30 POVIDONE K 30 BP/USP
30aqueous solution.
More particularly, the preferred Core formulation of the present invention is:
200mg/350mg
Core formulation:
150mg/350mg
Core formulation:
The present invention complexity, the outward appearance of sheet, the hardness of sheet, disintegration time four indexs of sheet that by a large amount of experiment investigation, different prescription is granulated, finally determine above-mentioned preferred Core formulation.Further, Kelimycin tablet of the present invention can also comprise coatings.
In the present invention, described coatings is made up of Opadry II and distilled water.
As a kind of preferred version, coating fluid prescription of the present invention is:
Amplify above-mentioned preferred Core formulation and coating fluid prescription, and carry out dissolution investigation (see Fig. 8 and Fig. 9), upper as can be seen from figure, when 30min, plain sheet and coated tablet accumulation stripping percent are all close to 95%.
In addition, because the assay employing of Kelimycin tablet is microbial method, tiring of every 0.1g rokitamycin should be 100,000 units, but the material content that actual production goes out can not absolutely reach this standard, therefore needs to carry out prescription adjustment by material content.According to the different batches material content measurement result produced, its lower bound is not less than 90%, therefore, rokitamycin input amount is adjusted, to meet tablet content requirement, reduce the amount of diluents microcrystalline cellulose simultaneously according to optimizing prescriptions, to ensure that sheet is heavy constant.Adjustment prescription is as follows:
The Core formulation of adjustment:
After prescription compressed cores, after adopting above-mentioned art for coating coating, carry out dissolution determination, the results are shown in Figure 10:
As can be seen from stripping curve, the prescription after adjustment still well meets stripping requirement.Meanwhile, the present invention also aims to provide the preparation method of described rokitamycin, the method technique is simple, and volume of production is large, and production cost is low, and " sanitary standard " easily reaches, is suitable for mass mechanized production.
The preparation method of Kelimycin tablet provided by the present invention comprises the preparation of pastille label, and in the preparation of described pastille label, carboxymethylstach sodium adopts inside and outside addition.
Specifically, the preparation of pastille label of the present invention comprises the steps:
1) rokitamycin and pharmaceutically acceptable adjuvant are sieved respectively;
2) rokitamycin, microcrystalline Cellulose are mixed homogeneously with carboxymethylstach sodium, then add 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulates with 18 mesh sieves, the wet granular of gained is carried out drying;
3) after drying with 18 mesh sieve granulate, then add after carboxymethylstach sodium mixs homogeneously with magnesium stearate, tabletting, obtained described pastille label.
Wherein, described in step 1) sieve for cross 100 mesh sieves;
Step 2) described in drying be dry 2h under 60 DEG C of ventilation conditions.
Above-mentioned 30 POVIDONE K 30 BP/USP
30aqueous solution is 5% 30 POVIDONE K 30 BP/USP preferably
30aqueous solution.
As a kind of preferred version, the preparation method of label of the present invention is: principal agent and adjuvant cross 100 mesh sieves respectively, recipe quantity rokitamycin, microcrystalline Cellulose are mixed homogeneously with the carboxymethylstach sodium of 1/2 recipe quantity, then add 5% 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulate with 18 mesh sieves, wet granular is dry 2h under 60 DEG C of ventilation conditions; With 18 mesh sieve granulate after drying, then after the recipe quantity carboxymethylstach sodium adding 1/2 recipe quantity mixs homogeneously with magnesium stearate, with the shallow concave punch tabletting of diameter 11mm, the pastille label of the heavy 350mg of obtained sheet, hardness 6.5kg.Its process chart as shown in Figure 1.
Further, preparation method of the present invention also comprises the further coating of pastille label of gained is prepared into Film coated tablets.
Specifically, described coating comprises the steps:
A) preparation of coating solution: weigh up Opadry II and add water in liquid dispensing container, gradation adds, after all adding, reduces mixing speed, spiral is disappeared, and continues to stir 30min, to obtain final product;
B) preparation of thin membrane coated tablet: described pastille label is put in coating pan, determine coating conditions: main frame speed is 20 ~ 25r/min, inlet temperature 40 ~ 45 DEG C, leaving air temp 30 ~ 35 DEG C, atomisation pressure 0.02 ~ 0.04Mpa, whitewashing flow is that 1 ~ 1.5ml/min carries out coating, constant rear lasting spray bag 1.5 ~ 2h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone, and coating weight gain is 5%.
Compared with prior art, Kelimycin tablet provided by the present invention and preparation method thereof tool has the following advantages:
(1) Kelimycin tablet disintegrate provided by the present invention is rapid, and dissolution rate is better;
(2) Kelimycin tablet provided by the present invention is granulated easily, and obtained sheet is unilateral bright and clean, without pitted skin phenomenon;
(3) preparation method of rokitamycin provided by the present invention is granulated easily, and preparation method is simple, is suitable for mechanization production, and output is large, and cost is low, and " sanitary standard " also easily reaches;
(4) Kelimycin tablet of the present invention facilitates the medication of clinical staff, patient, has stronger Clinical practicability.
Accompanying drawing explanation
Fig. 1 is preparation technology's flow chart of Kelimycin tablet of the present invention;
Fig. 2 is the stripping curve of prescription 11;
Fig. 3 is the stripping curve of prescription 14;
Fig. 4 is the stripping curve of prescription 16;
Fig. 5 is the stripping curve of prescription 18;
Fig. 6 is different coating weight gain stripping curves (200mg/350mg);
Fig. 7 is different coating weight gain stripping curves (150mg/350mg);
Fig. 8 is for amplifying prescription stripping curve (200mg/350mg);
Fig. 9 is for amplifying prescription stripping curve (150mg/350mg);
Figure 10 is the stripping curve according to coated tablet after material content adjustment prescription;
Figure 11 is the stripping curve of the rokitamycin element sheet of rokitamycin of the present invention element sheet and prior art.
Detailed description of the invention
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
[embodiment 1]
Specification: 200mg/350mg
Core formulation:
Coating fluid prescription:
Preparation technology:
The preparation of label: principal agent and adjuvant cross 100 mesh sieves respectively, recipe quantity rokitamycin, microcrystalline Cellulose are mixed homogeneously with the carboxymethylstach sodium of 1/2 recipe quantity, then add 5% 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulate with 18 mesh sieves, wet granular is dry 2h under 60 DEG C of ventilation conditions; With 18 mesh sieve granulate after drying, then after the recipe quantity carboxymethylstach sodium adding 1/2 recipe quantity mixs homogeneously with magnesium stearate, with the shallow concave punch tabletting of diameter 11mm, the pastille label of the heavy 350mg of obtained sheet, hardness 6.5kg.
The preparation of coating solution: weigh up required Opadry II(white) in liquid dispensing container, add the water of aequum, gradation adds, and after all adding, reduces mixing speed, spiral is disappeared, continues stirring 30min, to obtain final product.
The preparation of thin membrane coated tablet: label is put in coating pan, determine coating conditions, main frame speed is 20r/min, inlet temperature 40 DEG C, leaving air temp 30 DEG C, atomisation pressure 0.02Mpa, whitewashing flow is that 1ml/min carries out coating, constant rear lasting spray bag 1.5h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone.Coating weight gain about 5%.
[embodiment 2]
Specification: 150mg/350mg
Core formulation:
Coating fluid prescription: with embodiment 1.
Preparation technology:
The preparation of label and the preparation of coating solution are with embodiment 1.
The preparation of thin membrane coated tablet: label is put in coating pan, determine coating conditions, main frame speed is 25r/min, inlet temperature 45 DEG C, leaving air temp 35 DEG C, atomisation pressure 0.04Mpa, whitewashing flow is that 1.5ml/min carries out coating, constant rear lasting spray bag 2h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone.Coating weight gain about 5%.
[embodiment 3]
Specification: 225mg/350mg
Core formulation:
Coating fluid prescription: with embodiment 1.
Preparation technology:
The preparation of label and the preparation of coating solution are with embodiment 1.
The preparation of thin membrane coated tablet: label is put in coating pan, determine coating conditions, main frame speed is 22r/min, inlet temperature 43 DEG C, leaving air temp 32 DEG C, atomisation pressure 0.03Mpa, whitewashing flow is that 1.2ml/min carries out coating, constant rear lasting spray bag 1.8h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone.Coating weight gain about 5%.
Be below embodiment 4-10, Core formulation sees the following form shown in 1, and coating fluid prescription and preparation technology are with embodiment 1.
Table 1, embodiment 4-10
Test example 1
Prescription screening is tested
One, 200mg/350mg prescription screening
(1) screening of diluent
Starch, microcrystalline Cellulose, lactose carry out table 2 with rokitamycin, low-substituted hydroxypropyl cellulose, carboxymethylstach sodium and magnesium stearate respectively shown in Formulation.
The screening of table 2, diluent
Note: above prescription is make the consumption of 50
Investigated by the outward appearance of the complexity of more above-mentioned prescription soft material and pelletization bonding pad simultaneously, it is best that discovery microcrystalline Cellulose makes diluent effect; But all there is disintegrate problem slowly in above-mentioned prescription, therefore screens disintegrating agent on the basis of prescription 2.
(2) screening of disintegrating agent
1. the ratio of low-substituted hydroxypropyl cellulose and carboxymethylstach sodium is adjusted, the Formulation shown in carry out table 3 with rokitamycin, microcrystalline Cellulose and magnesium stearate respectively.
The screening of table 3, disintegrating agent
| Prescription 4 | Prescription 5 | |
| Rokitamycin | 10g | 10g |
| Starch | 0.8g | 0.8g |
| Microcrystalline Cellulose | 5.2g | 5.2g |
| Low-substituted hydroxypropyl methylcellulose | 0.7g | 0.9g |
| Carboxymethylstach sodium | 0.7g | 0.5g |
| Magnesium stearate | 0.1g | 0.1g |
| The hardness (kg) of sheet | 6.0 | 6.2 |
| Disintegration time (min) | 15.17 | 35.87 |
Note: above prescription is make the consumption of 50
The disintegrate of above-mentioned two prescriptions does not all reach requirement, and prescription 4 is greatly improved compared to prescription 5 disintegrate.
2. substitute low-substituted hydroxypropyl methylcellulose with carboxymethylstach sodium and make disintegrating agent
Carboxymethylstach sodium carries out Formulation with rokitamycin, microcrystalline Cellulose and magnesium stearate respectively, and the amount of disintegrating agent is respectively 8%, 7%, 6%, 5%, 4%.
The screening of table 4, carboxymethylstach sodium consumption
| Prescription 6 | Prescription 7 | Prescription 8 | Prescription 9 | Prescription 10 | |
| Rokitamycin | 10g | 10g | 10g | 10g | 10g |
| Microcrystalline Cellulose | 5.2g | 5.4g | 5.6g | 5.8g | 6.0g |
| Carboxymethylstach sodium | 0.7g+0.7g | 0.6g+0.6g | 0.5g+0.5g | 0.4g+0.4g | 0.3g+0.3g |
| Starch | 0.8g | 0.8g | 0.8g | 0.8g | 0.8g |
| Magnesium stearate | 0.1g | 0.1g | 0.1g | 0.1g | 0.1g |
| The hardness (kg) of sheet | 5.6 | 5.9 | 7.5 | 7.5 | 6.0 |
| Disintegration time (min) | 8.83 | 9.92 | 6.74 | 10.17 | 12.48 |
Note: above prescription is make the consumption of 50
The disintegration time of the sheet obtained by integrated survey prescription 6 to prescription 10 and hardness find that 6% carboxymethylstach sodium disintegration in prescription 8 is better.Binding agent is screened on the basis of prescription 8.
(3) screening of binding agent
The screening of table 5, binding agent
Note: above prescription is make the consumption of 50
The disintegration time of Integrated comparative granulation complexity and sheet, finds that prescription 11 is better; But prescription 11 is carried out finding when stripping percent is investigated that stripping percent is less than 85%(see Fig. 2 when 15min), do not reach pharmacopeia dissolution time regulation.
(4) ratio of each adjuvant of prescription 11 is finely tuned
Prescription 14:
Find that prescription 14 is optimum by investigating dissolution (see figure 3), when water temperature 37 DEG C, dissolution time conforms with the regulations, and unilateral smooth, without pitted skin phenomenon.
Two, 150mg/350mg prescription screening
Table 6,150mg/350mg prescription screening
| Prescription 15 | Prescription 16 | Prescription 17 | |
| Rokitamycin | 7.5g | 7.5g | 7.5g |
| Microcrystalline Cellulose | 8.1g | 7.9g | 7.7g |
| Carboxymethylstach sodium | 0.5g+0.5g | 0.6g+0.6g | 0.7g+0.7g |
| 30 POVIDONE K 30 BP/USP 30(water) | 0.8g | 0.8g | 0.8g |
| Magnesium stearate | 0.1g | 0.1g | 0.1g |
| Granulation difficulty or ease | Soft material processed is easy, granulation of easily sieving | Soft material processed is easy, granulation of easily sieving | Soft material processed is easy, granulation of easily sieving |
| The form of sheet | Obtained sheet any surface finish | Obtained sheet any surface finish | Obtained sheet any surface finish |
| The hardness (kg) of sheet | 6.4 | 6.5 | 6.5 |
| Disintegration time (min) | 6.10 | 2.28 | 3.35 |
Note: above prescription is make the consumption of 50
Find that prescription 16 is better by the tablet disintegration times investigating prescription 15 to 17, but its stripping percent is less than 85%(see Fig. 4 when 15min), there is faint gap with standards of pharmacopoeia.
Improve: the ratio of each adjuvant of prescription 16 is finely tuned.
Prescription 18:
Find that prescription 18 is optimum by investigating dissolution (see figure 5), when water temperature 37 DEG C, dissolution time conforms with the regulations, and unilateral smooth, without pitted skin phenomenon.
Three, the screening of coating solution
Prescription 14:
Preparation technology:
Principal agent and adjuvant cross 100 mesh sieves respectively, recipe quantity rokitamycin, microcrystalline Cellulose are mixed homogeneously with carboxymethylstach sodium, then add 5% 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulate with 18 mesh sieves, wet granular is dry 2h under 60 DEG C of ventilation conditions.With 18 mesh sieve granulate after drying, then add after recipe quantity carboxymethylstach sodium mixs homogeneously with magnesium stearate, with the shallow concave punch tabletting of diameter 11mm, the pastille label of the heavy 350mg of obtained sheet, hardness 6.5kg.
The selection of coating material:
Due to rokitamycin bitter in the mouth, therefore film coating need be carried out to label, the color selecting white of coating materials.Tradition coating solution often uses organic solvent dissolution (as acetone, dichloromethane), this brings unsafe factor to enrobing processes, such as organic solvent is poisonous, contaminated environment, Determination of Residual Organic Solvents is large, and operating process is complicated, therefore in recent years, aqueous polymer dispersion coating is more and more subject to the favor of people.It take water as disperse medium, and polymer is dispersed in water formed aqueous coatings system, also referred to as latex or pseudo-latex with the solid-state or semisolid spheroidal particle form of <1 μm.Aqueous dispersion, except avoiding with an organic solvent, also has the advantages such as solids content is high and viscosity is low, and preparation is convenient, is conducive to coating operations and shortens Coating times, significant to industrialization.This experimental selection Opadry II(white) be coating material, investigate the dissolution of self-control rokitamycin Film coated tablets.
The preparation of coating solution:
Weigh up required Opadry II(white) in liquid dispensing container, add the water of aequum, gradation adds, and after all adding, reduces mixing speed, makes dissipation of vorticity, continues to stir 30min, to obtain final product.
The preparation of thin membrane coated tablet:
Label is put in coating pan, determine coating conditions, main frame speed is 20 ~ 25r/min, inlet temperature 40 ~ 45 DEG C, leaving air temp 30 ~ 35 DEG C, atomisation pressure 0.02 ~ 0.04Mpa, whitewashing flow is that 1 ~ 1.5ml/min carries out coating, constant rear lasting spray bag 1.5 ~ 2h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone.Coating weight gain 3%, 5%, 7%.Dissolution determination result is as shown in Figure 6:
The same stripping curve recording different coating weight gain when rokitamycin content is 150mg/350mg, the results are shown in Figure shown in 7:
Result: by dissolution determination, three kinds of coating weight gain dissolutions all conform to quality requirements.Coating 3% just encases label completely, be easy to control, coating weight gain is decided to be 5% in order to produce.
By investigating complexity, the outward appearance of sheet, the hardness of sheet, disintegration time four indexs of sheet that different prescription is granulated, finally determine that optimum formulation and technology is as follows:
200mg/350mg
Core formulation:
150mg/350mg
Core formulation:
Coating fluid prescription:
Preparation technology:
The preparation of label: principal agent and adjuvant cross 100 mesh sieves respectively, recipe quantity rokitamycin, microcrystalline Cellulose are mixed homogeneously with carboxymethylstach sodium, then add 5% 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulate with 18 mesh sieves, wet granular is dry 2h under 60 DEG C of ventilation conditions.With 18 mesh sieve granulate after drying, then add after recipe quantity carboxymethylstach sodium mixs homogeneously with magnesium stearate, with the shallow concave punch tabletting of diameter 11mm, the pastille label of the heavy 350mg of obtained sheet, hardness 6.5kg.
The preparation of coating solution: weigh up required Opadry II(white) in liquid dispensing container, add the water of aequum, gradation adds, and after all adding, reduces mixing speed, spiral is disappeared, continues stirring 30min, to obtain final product.
The preparation of thin membrane coated tablet: label is put in coating pan, determine coating conditions, main frame speed is 20 ~ 25r/min, inlet temperature 40 ~ 45 DEG C, leaving air temp 30 ~ 35 DEG C, atomisation pressure 0.02 ~ 0.04Mpa, whitewashing flow is that 1 ~ 1.5ml/min carries out coating, constant rear lasting spray bag 1.5 ~ 2h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone.Coating weight gain about 5%.
Carry out dissolution investigation (see Fig. 8 and Fig. 9) to amplification prescription, upper as can be seen from figure, when 30min, plain sheet and coated tablet accumulation stripping percent are all close to 95%.
In addition, because the assay employing of Kelimycin tablet is microbial method, tiring of every 0.1g rokitamycin should be 100,000 units, but the material content that actual production goes out can not absolutely reach this standard, therefore needs to carry out prescription adjustment by material content.According to the different batches material content measurement result produced, its lower bound is not less than 90%, therefore, rokitamycin input amount is adjusted, to meet tablet content requirement, reduce the amount of diluents microcrystalline cellulose simultaneously according to optimum prescription, to ensure that sheet is heavy constant.Adjustment prescription is as follows:
The Core formulation of adjustment:
After prescription compressed cores, after adopting above-mentioned art for coating coating, carry out dissolution determination, the results are shown in Figure 10: as can be seen from stripping curve, the prescription after adjustment still well meets stripping requirement.
Comparative example 1
The dissolution of this comparative example to the rokitamycin element sheet of rokitamycin of the present invention element sheet and prior art is investigated.
Test drug: the rokitamycin element sheet that the Core formulation of the embodiment of the present invention 1 and the preparation technology of label obtain;
Contrast medicine: according to the left-handed rokitamycin element sheet that the embodiment 12 of CN102247396A is obtained.
The dissolution of experimental drug and contrast medicine is investigated, the results are shown in Figure 11.
As can be seen from Figure 11, the dissolution of rokitamycin element sheet of the present invention is obviously better than according to the obtained left-handed rokitamycin element sheet of the embodiment 12 of CN102247396A.
Also carried out above-mentioned test to the rokitamycin element sheet prepared by other embodiment of the present invention, its result obtained is similar.
Claims (7)
1. a Kelimycin tablet, is characterized in that, described Kelimycin tablet comprises the label be made up of rokitamycin and pharmaceutically acceptable adjuvant; Described label composed as follows:
Rokitamycin 1 weight portion
Microcrystalline Cellulose 0.55 weight portion
Carboxymethylstach sodium 0.11 weight portion
30 POVIDONE K 30 BP/USP
300.075 weight portion
Magnesium stearate 0.015 weight portion;
The preparation method of described Kelimycin tablet comprises the preparation of pastille label, and the preparation of described pastille label comprises the steps:
1) rokitamycin and pharmaceutically acceptable adjuvant are sieved respectively;
2) rokitamycin, microcrystalline Cellulose are mixed homogeneously with carboxymethylstach sodium, then add 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulates with 18 mesh sieves, the wet granular of gained is carried out drying;
3) after drying with 18 mesh sieve granulate, then add after carboxymethylstach sodium mixs homogeneously with magnesium stearate, tabletting, obtained described pastille label;
Wherein carboxymethylstach sodium adopts inside and outside equivalent additive process.
2. Kelimycin tablet according to claim 1, is characterized in that, described Kelimycin tablet also comprises coatings.
3. Kelimycin tablet according to claim 2, is characterized in that, described coatings is made up of Opadry II and distilled water.
4. a preparation method for the Kelimycin tablet described in claim 1-3 any one, is characterized in that, described preparation method comprises the preparation of pastille label; The preparation of described pastille label comprises the steps:
1) rokitamycin and pharmaceutically acceptable adjuvant are sieved respectively;
2) rokitamycin, microcrystalline Cellulose are mixed homogeneously with carboxymethylstach sodium, then add 30 POVIDONE K 30 BP/USP
30aqueous solution soft material, granulates with 18 mesh sieves, the wet granular of gained is carried out drying;
3) after drying with 18 mesh sieve granulate, then add after carboxymethylstach sodium mixs homogeneously with magnesium stearate, tabletting, obtained described pastille label;
Wherein carboxymethylstach sodium adopts inside and outside equivalent additive process.
5. preparation method according to claim 4, is characterized in that, described in step 1) sieve for cross 100 mesh sieves; Step 2) described in drying be dry 2 h under 60 DEG C of ventilation conditions.
6. the preparation method according to claim 4-5 any one, is characterized in that, described preparation method also comprises the further coating of pastille label of gained is prepared into Film coated tablets.
7. preparation method according to claim 6, is characterized in that, described coating comprises the steps:
A) preparation of coating solution: weigh up Opadry II and add water in liquid dispensing container, gradation adds, after all adding, reduces mixing speed, spiral is disappeared, and continues to stir 30min, to obtain final product;
B) preparation of thin membrane coated tablet: described pastille label is put in coating pan, determine coating conditions: main frame speed is 20 ~ 25 r/min, inlet temperature 40 ~ 45 DEG C, leaving air temp 30 ~ 35 DEG C, atomisation pressure 0.02 ~ 0.04Mpa, whitewashing flow is that 1 ~ 1.5ml/min carries out coating, constant rear lasting spray bag 1.5 ~ 2h, to sheet grain smooth surface, uniform color, it is qualified for meeting film-coat touchstone, and coating weight gain is 5%.
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| AU2018247555B2 (en) | 2017-04-06 | 2024-04-18 | Shenyang Fuyang Pharmaceutical Technology Co., Ltd. | Use of carrimycin and pharmaceutically acceptable salt thereof for manufacture of medicament for treatment and/or prevention of tumors |
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Denomination of invention: Kelimycin tablet and preparation method thereof Effective date of registration: 20150901 Granted publication date: 20150401 Pledgee: Shengjing bank Yingkou branch of Limited by Share Ltd Pledgor: Tonglian Group Co., Ltd., Shenyang Registration number: 2015210000009 |
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