CN107441049A - A kind of pharmaceutical compositions of clarithromycin suitable for children taking - Google Patents
A kind of pharmaceutical compositions of clarithromycin suitable for children taking Download PDFInfo
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- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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Abstract
The present invention relates to a kind of suitable for pharmaceutical compositions of clarithromycin of children taking and preparation method thereof.Inventor is in the research process to Biaxin, it was found that the mankind feel for the macrolide antibiotics such as CLA bitter taste, come from its residual of undissolved medicine in the oral cavity, confrontation based on residual CLA bitter taste, inventor is attempted after taking with the clarithromycin granule of bitter taste, when still feeling bitter taste, takes some sweeteners, sucrose, find to feel that bitter taste is substantially suppressed.Based on this, inventor attempts sucrose being prepared into slow-releasing granules, when clarithromycin granule is taken, slowly discharges sucrose, to reach the purpose of the CLA flavoring for being remained in oral cavity, the results show, works well.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of pharmaceutical compositions of clarithromycin suitable for children taking
And its production and use.
Background technology
CLA is second generation macrolide antibiotics, and Antibacterial Mechanism is the core egg acted in bacterium 70S systems
Lean type 50S subunits, hinder the synthesis of bacterioprotein.CLA has to gram-positive bacteria, a variety of Gram-negative bacterias
Antibacterial action, still there is stronger antibacterial to make anaerobic bacteria and other pathogens, such as mycoplasma, Chlamydia and Legionella in addition
With.The characteristics of this product is that antibacterial activity in vitro is not significantly better than erythromycin, in vivo to golden yellow staphylococcus, Diplococcus pneumopniae,
Micrococcus scarlatinae, the antibacterial activity of Hemophilus influenzae are but strong compared with erythromycin 2-10 times.CLA to morazella catarrhalis,
Multocida, campylobacter jejuni and campylobacter fetus, Diplococcus gonorrhoeae, salmonella, legionella pneumophilia and detest
The antibacterial action of oxygen coccus is strong compared with erythromycin, and the antibacterial action to helicobacter pylori, chlamydia trachomatis, mycoplasma pulmonis is this
Most strong in class antibiotic, CLA is the choice drug for treating AIDS patient's mycobacteria infections in addition.
The long half time of CLA, it is stable to enzyme, tissue permeability is strong, can be quickly be distributed to except central nervous system
In the various tissues of outer body and body fluid, about 2h plasma concentration peakings, concentration is high especially in schneiderian membrance, tonsillotome and lung.
Concentration of the CLA in immunocyte is higher than extracellular 20-30 times, can also actively stimulate monokaryon macrophage thin
Born of the same parents, strengthen its antibacterial activity, CLA is in be added in the main metabolites 14- hydroxyls CLA of liver with the product in addition
Or synergy, thus its antibacterial activity also improves.
CLA antibacterial activity is strong, bioavilability is high, and being easy to intestines and stomach compared with erythromycin absorbs, and half-life period is longer, group
Knit distribution extensively and concentration is high, there is very extensive clinical practice.Be mainly used in respiratory tract infection, urogenital infections,
Infection of digestive canal, Skin and soft tissue infection etc..CLA is to treatment non gonococcal urethritis and Chlamydia and unknown disease
Former cervicitis has special efficacy.Because itself permeability is strong, infection some drugs concentration is high, to ALRI on acute and chronic
Clinic examine more rate and be higher than 90%, and safe ready.
The researchs such as P.O.Erah find that the stable PH scopes of CLA in aqueous are 5.0-8.0, in PH2.0 water
Degradation half life is 1.3 ± 0.5h in solution, and the degradation half life in PH2.0 gastric juice is 1.0 ± 0.04h (Journal
Of Antimicrobial Chemotherapy 1997,39：5-12) other Nakagawa of etc. result of study is：
The degradation half life of CLA is 17 minutes (ChemPharmBull (Tokyo) .1992Mar during PH1.39；40(3)：725-
8), this shows that CLA is unstable in gastric juice, this also the bioavilability with CLA common oral preparation compared with low phase
Meet；Although the enteric coated preparations of CLA can avoid medicine from being degraded under gastric juice sour environment, solves CLA degraded
Caused by product the problem of stomach adverse reaction, but onset time of medicine that enteric coated preparations undoubtedly postpone.Carat is mould simultaneously
Element has strong bitter taste, and water-soluble extreme difference, the two, which is superimposed, causes its permanent bitter taste, and the compliance of patient is very poor.
CLA (Clarithromycin), chemical entitled (3R, 4S, 5S, 6R, 7R, 9R, 11R, 12R, 13S, 14R)-
4- [(2,6- dideoxy -3-C- methyl -3-0- methyl-α-D- galactopyranosyls glycosyl) epoxide] -14- ethyl -12,13- dihydroxy -
7- methoxyl group -3,5,7,9,11,13- hexamethyls -6- [[the chloro- own pyranoses of 3,4,6- tri- deoxidation -3- (dimethylamino)-β-two
Base] epoxide] oxacyclotetradecane -2,10- diketone, molecular formula：C38H69NO13, molecular weight 748, structural formula is as follows：
The maximum clarithromycin granule product of occupation rate is dry-mixed for the CLA of An Bowei companies on domestic market
Suspension, trade name KLACID, it is enteric coated granule.
Bitter taste is to stimulate caused sensation by the liquid containing chemical substance as other sense of taste.The receptor of the sense of taste
It is taste bud, taste bud is in oval, is mainly made up of gustatory cells and sertoli cell, has microvillus to be stretched to taste pore direction at the top of gustatory cells
Exhibition, with saliva contacts, cell base portion has nerve fibre domination.The formation mechenism of the sense of taste is：It is distributed in taste bud at the top of gustatory cells
Bitterness receptors albumen on microvillus, by intracellular signal transduction, makes with dissolving amaroid combination post activation in the liquid phase
Gustatory membrane depolarization, then triggers nerve cell postsynaptic excitation, and excitatory signal is walked along facial nerve, glossopharyngeal nerve or fan
Nerve enters tractus solitarius medullae oblongatae core, changes neuron to thalamus, finally projects the gustatory center of brain gyrus postcentralis foot, pass through
The final bitter taste that produces of neural integration is crossed to perceive.
It follows that bitter taste caused by the macrolide antibiotic such as CLA, it is essentially to be remained after taking medicine
Caused by insoluble CLA.
Although the technical scheme of many solution clarithromycin granule preparation bitter tastes, its technique are disclosed in the prior art
Complexity, enteric coating particle or micropill are generally prepared into, add sweetener and be made, so both solve CLA
The problem of being degraded in hydrochloric acid in gastric juice, while solve its bitterness problem further through coating, but its complex process, enteric coated preparations with it is common
Gastric solubility preparation is compared, and onset time is delayed.
In summary, this area still suffers from such need：A kind of quick acting is provided, gram for solving the stabilization of bitter taste
Mycin granular preparation is drawn, is easy to the difficult crowd of the oral drugs such as old man and children.
The content of the invention
As described above, CLA poorly water-soluble, its plain particles preparation after oral administration, due to CLA in the oral cavity
Residual, form permanent bitter taste.It is unstable in the sour environment of gastric juice simultaneously, is easy to degrade, so as to produce stomach thorn
Swash property.
Based on this, inventor has obtained a kind of clarithromycin pharmaceutical group suitable for children taking by further investigation design
Compound, said composition are prepared into common stomach dissolution type granule by certain technique.
The pharmaceutical compositions of clarithromycin suitable for children taking, by main ingredient CLA, sweetener, it is sustained material
Material, suspending agent, pH elevators, glidant and filler composition.Common stomach dissolution type particle is further prepared into as follows
Agent：
1) take CLA bulk drug to crush, cross 200 mesh sieves, it is standby；
2) sweetener is taken, filler, suspending agent is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95% ethanol system
Grain, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, pH elevators, is well mixed, purified water granulation, dries, whole grain, medicine must be carried
Grain；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant, be well mixed, obtain clarithromycin granule product；
Characterized in that, the pH elevators are sodium acid carbonate, the slow-release material is HPMC K15M；In administration, by this composition
It is placed in 200ml normal temperature drinking water, stirring is suspended, and is administered in liquid form afterwards, and the pH value of liquid medicine is not less than 8.0.
In the pharmaceutical composition containing CLA, sweetener is sucrose, and glidant is colloidal silica, described
Filler is microcrystalline cellulose, and the suspending agent is octadecyl alcolol.
The pharmaceutical composition containing CLA, unit formulation composition are as follows：
The pharmaceutical composition containing CLA suitable for children taking, it is further prepared into as follows
Granule：
1) CLA bulk drug, sucrose are taken, sodium acid carbonate crushes, and crosses 200 mesh sieves, standby；
2) recipe quantity sucrose is taken, microcrystalline cellulose, octadecyl alcolol is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95%
Alcohol granulation, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, sodium acid carbonate, is well mixed, purified water granulation, dries, 40 mesh sieve whole grains, obtains
Carry medicine particle；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant colloidal silica, be well mixed, obtain carat
Mycin grain products.
By testing further explanation present patent application as follows：
Inventor is in the research process to Biaxin, and the mankind are for macrolide antibiotics such as CLAs for discovery
Bitter taste is felt, comes from its residual of undissolved medicine in the oral cavity, and based on the confrontation of residual CLA bitter taste, inventor tastes
Examination is after taking with the clarithromycin granule of bitter taste, when still feeling bitter taste, takes some sweeteners, sucrose, finds
Feel that bitter taste is substantially suppressed.Based on this, inventor attempts sucrose being prepared into slow-releasing granules, is taken in clarithromycin granule
When, sucrose is slowly discharged, to reach the purpose of the CLA flavoring for being remained in oral cavity, the results show, effect
Well.
In addition, CLA is easily degraded under gastric acid environment produces impurity, while stomach adverse reaction is produced, it is main former
Because CLA is unstable to hydrochloric acid in gastric juice.Inventor attempts to add pH elevators on the basis of above-mentioned particle, sodium acid carbonate, clothes
The pH value of stomach liquid is improved during medicine, reduces the degraded of medicine, experiment results proved, effect is equally good.
On the basis of as above contemplating, inventor passes through a series of experiment, is finally obtained flavoring and works well, in stomach
The stable clarithromycin granule preparation in portion, this granule technique is simple, quality controllable, suitable for children taking, is applied to simultaneously
Industrialized production.
Experiment one：Auxiliary material compatibility test
By CLA bulk drug；CLA bulk drug respectively with sucrose, sodium acid carbonate, sodium carbonate, microcrystalline cellulose according to
Weight is than 1:5, it is well mixed, CLA bulk drug is with glidant colloidal silica by weight 20:1, it is well mixed, point
Do not put in culture dish stand into<Thin layer thick 5mm.Sample number into spectrum is respectively A, B, C, D, E, F.
Above-mentioned sample is put 60 DEG C respectively, RH20% ± 5%；Illumination 4500Lx ± 500Lx, RH20% ± 5%；Strong striation
Place 10 days under part, sampled in the 5th day and the 10th day, detect CLA content and relevant material.Detect the following table institute of data
Show.
The CLA bulk drug of table 1 and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
The CLA bulk drug of table 2 and auxiliary material compatibility experiments result to be selected (strong light 4500Lx ± 500Lx, RH20% ±
5%)
Selected auxiliary material is can be seen that from above experimental result to pass through under the conditions of RH20% ± 5% with bulk drug CLA
60 DEG C of high temperature are crossed, are stored under intense light conditions, compared with CLA bulk drug, no significant change.That is CLA and crystallite is fine
Element, sucrose, sodium acid carbonate are tieed up, sodium carbonate and colloidal silica compatibility are good, can be with above-mentioned auxiliary material in solid states
Under be grouped compound, and be further prepared into solid pharmaceutical preparation.
Experiment two：Prescription screening is tested
In order to lift the pH value that granular preparation is dispersed in water, various dose sodium acid carbonate is added respectively in four prescriptions, together
When sustained release sweetener, i.e. sucrose have adjusted according to the addition of sodium acid carbonate, microcrystalline cellulose, octadecyl alcolol, HPMC K15M's is total
Amount, adjusted finally for the ratio of each component in sustained release sweetener：
Preparation technology：
1) CLA bulk drug, sucrose are taken, sodium acid carbonate crushes, and crosses 200 mesh sieves, standby；
2) recipe quantity sucrose, microcrystalline cellulose are taken, suspending agent octadecyl alcolol is well mixed with slow-release material hydroxypropyl methylcellulose K15M,
It is round as a ball with 95% alcohol granulation, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, sodium acid carbonate, is well mixed, purified water granulation, dries, 40 mesh sieve whole grains, obtains
Carry medicine particle；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant colloidal silica, be well mixed, obtain carat
Mycin grain products.
Bitter taste detects：
Above-mentioned prescription 1-4 particles are taken, every bag of particle is suspended, with (8-10 year) mouth containing of 6 children volunteers with 200ml normal-temperature waters
15s, take, the oral process of aids drug, as a result record as follows afterwards：
The prescription 1-4 clarithromycin granule bitter taste test results of table 3
It can be seen from the results above that prescription 1, the particle of prescription 2 shows slightly sweet taste without rear bitter taste, and 6 volunteers represent
It is satisfied.
Simulate the gastric juice pH value detects：
By Chinese Pharmacopoeia 2015 editions, described in rules of preparations, each three bags of prescription 1-4 clarithromycin granule samples are taken, puts fill respectively
In the beaker of 200ml purified waters, water temperature is about 20 DEG C, stands 5min observations whether there is sedimentation, while determines pH value 1.Backward Sheng
Have and put into 100ml pH1.2 hydrochloric acid (low ph value and capacity of simulate the gastric juice) in the beaker of decoction respectively, be well mixed, measure is mixed
Suspension pH value 2, result of the test is as follows：
As above sucrose is with the addition of shown in result of the test, in prescription and is prepared into sustained release pellet as sweetener, while by sucrose,
And suspending agent is added, allow in the water that it suspends, and sucrose is slowly released, to alleviate CLA bulk drug lower tape
Bitter taste, the sucrose that experiment proves to add 394mg and the above in prescription can play a part of overcoming bitter taste.
In addition it is used as pH value elevator by adding sodium acid carbonate in prescription, after the tablet has been ingested, can be used for lifting gastric juice
PH value, so as to alleviating destruction of the sour environment to CLA, reduce impurity, mitigate side effect.Experiment proves, adds in prescription
Adding 2000mg sodium acid carbonates both to effectively improve final solution pH value, and be further added by sodium acid carbonate dosage, pH value raising is limited,
The reason for possible is sodium acid carbonate as weak base, certain dissociation limitation be present.
By above-mentioned screening, it is determined that the prescription and preparation technology of the clarithromycin granule of a specification (125mg), by this
Specification prescription amplifies 2 times and obtains following 250mg specifications particle prescription：
The pharmaceutical composition containing CLA, is further prepared into granule as follows：
1) CLA bulk drug, sucrose are taken, sodium acid carbonate crushes, and crosses 200 mesh sieves, standby；
2) recipe quantity sucrose is taken, microcrystalline cellulose, octadecyl alcolol is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95%
Alcohol granulation, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, sodium acid carbonate, is well mixed, purified water granulation, dries, 40 mesh sieve whole grains, obtains
Carry medicine particle；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant colloidal silica, be well mixed, obtain carat
Mycin grain products.
Experiment five：Accelerated stability experiment in 6 months.
Above-mentioned 2 specification granules (embodiment 1-2) and An Bowei companies is taken to produce 125mg specification commercial particulate agent and (contain
Packaging) numbering A-C puts 40 DEG C ± 2 DEG C to three groups of samples respectively respectively, stored 12 months under the conditions of 75% ± 5%RH, respectively at 0
Month, in January, in March, in June, in December, relevant nature is measured by sampling, obtains corresponding data, it is as shown in the table：
The embodiment of table 4 is compared with commercial particulate agent sample stability
It can be seen from upper table data according to embodiment prescription of the present invention and technique prepared by clarithromycin granule
Agent, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 12 months, its content, relevant material is varied from,
But content, more than 98.5%, maximum single impurity is less than 0.18%, and total impurities is below 1.7%；Correspond, commercially available gram
Mycin granule is drawn after accelerating storage in 12 months, its content falls to approximately 95%, and maximum single impurity rises to about 0.3%,
Total impurities is then more than 2.5%.
Based on as above analyzing, accelerating according to the clarithromycin granule agent prepared by embodiment prescription of the present invention and technique
Under the conditions of, the data after storage 12 months shows that its stability be significantly better than commercial particulate agent, i.e., by prescription of the invention with
Technique is remarkably reinforced the stability of clarithromycin granule agent, while is obtained from above-mentioned experiment, the bitter taste of its preparation
Improve to obvious, be adapted to children taking, and be common gastric solubility preparation, compared with commercially available enteric clarithromycin granule, fast
Speed work while, reduce the degraded of bulk drug, avoid by impurity band Lai stomach adverse reaction.It is so that of the invention
With prominent substantive distinguishing features and marked improvement, and there is practicality.
Embodiment
Beneficial effects of the present invention are further illustrated by following experiment.But it is not limited to following embodiments, this area
Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this
Within the protection domain of invention.
The 125mg specification clarithromycin granule agent of embodiment 1 prepares (unit：g)
Prescription：
The pharmaceutical composition containing CLA, is further prepared into granule as follows：
1) CLA bulk drug, sucrose are taken, sodium acid carbonate crushes, and crosses 200 mesh sieves, standby；
2) recipe quantity sucrose is taken, microcrystalline cellulose, octadecyl alcolol is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95%
Alcohol granulation, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, sodium acid carbonate, is well mixed, purified water granulation, dries, 40 mesh sieve whole grains, obtains
Carry medicine particle；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant colloidal silica, be well mixed, obtain carat
Mycin grain products.
Embodiment 2250mg specification clarithromycin granule agent prepares (unit：g)
Prescription：
The pharmaceutical composition containing CLA, is further prepared into granule as follows：
1) CLA bulk drug, sucrose are taken, sodium acid carbonate crushes, and crosses 200 mesh sieves, standby；
2) recipe quantity sucrose is taken, microcrystalline cellulose, octadecyl alcolol is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95%
Alcohol granulation, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, sodium acid carbonate, is well mixed, purified water granulation, dries, 40 mesh sieve whole grains, obtains
Carry medicine particle；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant colloidal silica, be well mixed, obtain carat
Mycin grain products.
Claims (5)
1. a kind of pharmaceutical compositions of clarithromycin suitable for children taking, by main ingredient CLA, sweetener, slow-release material, help
Suspension, pH elevators, glidant and filler composition, are further prepared into common stomach dissolution type granule as follows：
1) take CLA bulk drug to crush, cross 200 mesh sieves, it is standby；
2) sweetener is taken, filler, suspending agent is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95% ethanol system
Grain, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, pH elevators, is well mixed, purified water granulation, dries, whole grain, medicine must be carried
Grain；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant, be well mixed, obtain clarithromycin granule product；
Characterized in that, the pH elevators are sodium acid carbonate, the slow-release material is HPMC K15M；In administration, by this composition
It is placed in 200ml normal temperature drinking water, stirring is suspended, and is administered in liquid form afterwards, and the pH value of liquid medicine is not less than 8.0.
2. it is suitable to the pharmaceutical composition containing CLA of children taking as claimed in claim 1, it is characterised in that sweetener
For sucrose, glidant is colloidal silica, and the filler is microcrystalline cellulose, and the suspending agent is octadecyl alcolol.
3. it is suitable to the pharmaceutical composition containing CLA of children taking as claimed in claim 2, it is characterised in that described to contain
There is a pharmaceutical composition of CLA, unit formulation composition is as follows：
4. it is suitable to the pharmaceutical composition containing CLA of children taking as claimed in claim 2, it is characterised in that described to contain
There is a pharmaceutical composition of CLA, unit formulation composition is as follows：
5. any pharmaceutical composition containing CLA suitable for children taking as described in claim 1-4, it is characterised in that
The pharmaceutical composition containing CLA suitable for children taking, granule is further prepared into as follows：
1) CLA bulk drug, sucrose are taken, sodium acid carbonate crushes, and crosses 200 mesh sieves, standby；
2) recipe quantity sucrose is taken, microcrystalline cellulose, octadecyl alcolol is well mixed with slow-release material hydroxypropyl methylcellulose K15M, with 95%
Alcohol granulation, it is round as a ball, dry, obtain sustained release granular sweetener；
3) recipe quantity CLA bulk drug is taken, sodium acid carbonate, is well mixed, purified water granulation, dries, 40 mesh sieve whole grains, obtains
Carry medicine particle；
4) take recipe quantity CLA to carry medicine particle, be sustained sweetener, glidant colloidal silica, be well mixed, obtain carat
Mycin grain products.
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|---|---|---|---|---|
| CN115518043A (en) * | 2022-10-12 | 2022-12-27 | 江苏集萃新型药物制剂技术研究所有限公司 | Controlled release composition, granules, tablets and preparation method thereof |
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